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Gene Expression Signatures in Breast Cancer: A Surgical Oncologist’s Perspective
The use of systemic chemotherapy and estrogen ablation (EA) for the treatment of breast cancer historically have been based on both the histologic prognostic parameters of the invasive breast cancer and on traditional estimates of recurrence risk. These estimates take into account the patient’s age, tumor size, grade, lymphovascular invasion, hormonal receptor status (estrogen receptor/progesterone receptor [ER/PR]), and human epidermal growth factor receptor 2 (HER2) overexpression.1
The recent description of 4 primary breast cancer subtypes on the basis of gene expression profiles has led to the identification of more specific gene prognostic signatures.2 These may serve to supplement, and possibly supersede, the assessment of recurrence risk currently employed as the basis for chemotherapy or EA recommendations for patients with breast cancer. As a result, many
patients who would have been treated with chemotherapy previously may now safely avoid it. The information provided by these prognostic signatures may also alter surgical decision making for many patients and, consequently, should be within the purview of dedicated cancer surgeons.
BREAST CANCER SUBTYPES
The 4 breast cancer subtypes are (1) the HER2 type, these can be ER/PR positive or negative; (2) basal-like tumors, typically ER, PR, and HER2 negative (ER-, PR-, and HER2-); and ER-positive (ER+) or luminal tumors, usually divided into (3) luminal A and (4) luminal B.2
HER2 Type
The advent of the first targeted breast cancer therapy, trastuzumab, and its immense salutary effect on survival of patients with previously poor prognoses has made the use of chemotherapy in combination with trastuzumab nearly mandatory in all HER2+ patients with breast cancer. Remarkably, the huge improvement in survival of these formerly doomed patients has led to the recommendation that trastuzumab-containing chemotherapy regimens should be used in the management of even subcentimeter, node-negative patients.3 This recommendation represents a clear change from the traditional recommendations for chemotherapy, which held that the benefits of systemic chemotherapy were more likely to be seen in patients with tumors in excess of 1 cm and/or who were node positive.
Basal-like Tumors
The discovery of trastuzumab made the basal-like tumor, which is usually ER-, PR-, and HER2- (triple negative), the subtype with the worst prognosis. Further, the natural course of this illness is markedly different from that of ER+/PR+ breast cancer. Nearly all basal-like or triple-negative patients with breast cancer who experience a recurrence do so within the first 5 years after diagnosis.4 In contrast, nearly 40% of ER+/PR+ HER2- breast cancer survivors experience their first recurrence beyond the 5-year milestone, with many even later in their course.5 Thus, the patient with triple-negative breast cancer is more likely to benefit from chemotherapy predominantly during the first 5 post-diagnosis years, as suggested by the Early Breast Cancer Trialists’ Collaborative Group meta-analyses.1
HER2+ and triple-negative breast cancers account for 20% and 15% of all breast cancers, respectively.6,7 In both subtypes, the benefit of chemotherapy is immense and chemotherapy will rarely be omitted from the treatment plan. Many of these patients are considered ideal candidates for preoperative chemotherapy (PCT), which results in increased rates of breast-conserving surgery (BCS), decreased positive margin rates at BCS, and decreased need for axillary node dissection. In the setting of PCT, a pathologic complete response (pCR) in the breast and axilla is increasingly recognized as a marker for improved disease-free survival (DFS) and overall survival (OS).8 For these reasons, preoperative consultation with medical oncologists is now even more important. Many of these patients will benefit from the use of PCT before any surgical treatment is undertaken.
Luminal Type (A and B)
The remaining two-thirds of all patients with breast cancer are ER+, primarily postmenopausal, and fall within the 2 remaining molecular subtypes: luminal A and luminal B. It is for these patients that the relative benefits of chemotherapy vs EA, or both, are currently being debated. For these patients the use of gene prognostic signatures, in concert with traditional histopathologic and clinical risk factors, may alter estimates of recurrence risk and the impact of chemotherapy on survival and recurrence estimates.
It is now evident that even the strongest predictors for breast cancer recurrence—histologic grade, patient age, and nodal status—are inconsistent predictors of the behavior of any individual tumor. While the use of chemotherapy can reduce the risk of metastases in these luminal-type patients with breast cancer, the majority of patients so stratified would survive without chemotherapy.9
GENE EXPRESSION SIGNATURE ASSAYS
One of the best demonstrations of the shortcomings of the standard risk predictors for ER+, HER2- breast cancers is provided by the Oncotype DX breast cancer assay’s recurrence score (RS) or gene expression signature (GES).10,11
Oncotype DX
The Oncotype DX assay is the first commercially available GES assay to illustrate the variability in survival of patients with node-negative, ER+ breast tumors. Sixteen selected cancer proliferative genes are paired with 5 control nonproliferative genes whose relative activity can be measured in paraffin-embedded breast cancer tissue. The ability to retrieve reliable ribonucleic acid (RNA) expression from cancer cells embedded in paraffin was a stroke of genius; it enabled the investigators to correlate the gene expression profile of patient subgroups treated decades earlier with their long-term clinical outcomes and survival.
The normalized summation of the proliferative activity of the 16 cancerproliferation genes in the Oncotype DX assay is expressed as the RS. The RS increases linearly and so does the average rate of distant recurrence in 10 years as a function of the RS. Three risk recurrence groups are defined by the RS: low risk (RS < 18); intermediate risk (RS > 18 to 30); and high risk (RS > 31).10,11
Clinical Trials
In the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial B-14, ER+ node-negative patients were randomized to observation or tamoxifen. In the untreated control patients, a low RS (< 18) was accompanied by a 6.8% risk of metastasis at 10 years, and a high RS (> 31) was accompanied by a 30.5% rate of distant recurrence.11 In another study, the low RS tamoxifen-treated arm showed a 2.8% risk of breast cancer death at 10 years vs a 15.5% risk in the high RS cohort.12
The remarkable significance of the RS is demonstrated when the RS is plotted against patient age, grade, or tumor size.10 This illustrates the huge variability in these traditional histopathologic and clinical features within a given RS group. For any patient with a low RS, there is marked variability in patient age, tumor grade, or tumor size. A very small or low-grade tumor can have a very high 10-year recurrence rate, as measured by the gene prognostic signature or RS. Similarly, a very large tumor in a young patient can have a very low 10-year recurrence rate or RS. This is due to the heterogeneity of the biology of these cancers, regardless of their favorable or unfavorable histologic features.
In most cases, decisions about chemotherapy in patient who are postmenopausal, node-negative, and ER+ are made by risk estimates based on patient age, tumor grade, and tumor size, without knowledge of their RS. However, the large variability in 10-year rates of metastases and death among patients clearly demonstrates that, for some, chemotherapy affords no benefit. Their RS suggest that their risk of metastases at 10 years is only 2.8% when treated with EA (ie, tamoxifen) and no chemotherapy. In fact, 51% of the patients who are postmenopausal, node-negative, and ER+ in NSABP B-14 fell within the low risk RS category for 10-year distant recurrence, whereas about 27% fell within the high risk (RS > 31) category.13
Confidence in the Oncotype DX assay RS stems from the ability of investigators to plot the recurrence rates of distant metastases in patientstreated with tamoxifen vs placebo in the NSABP B-14 trial. Their clinicaloutcomes could be correlated with their GES samples retrieved from paraffin-embedded archival tissue many years after treatment. Corresponding plotting was done for similar patient cohorts treated with chemotherapy with or without tamoxifen in NSABP Trial B-20.
Among patients with low RS, the distant recurrence rate at 10 years was 2.2%, whether treated with systemic chemotherapy plus tamoxifenor with tamoxifen alone. Thus, in study participants with low RS, regardless of tumor size, grade, or patient age, 10-year recurrence rates were not affected by the addition of chemotherapy.13
Note that, in the absence of the new information provided by the Oncotype gene prognostic signature, nearly all these patients would be treated with systemic chemotherapy. Studies have shown that the additional risk assessment estimate provided by the Oncotype assay causes a change in systemic therapy recommendations from chemotherapy to no chemotherapy in 30% of patients.14,15 Among patients with high RS, 10-year distant recurrence rates decreased by an absolute 27% with the addition of chemotherapy to tamoxifen. These patients clearly benefited from chemotherapy.13
The relative benefits of chemotherapy vs tamoxifen in a third RS group with an intermediate RS of 18-21 awaits publication of the now-closed Trial Assigning Individualized Options for Treatment (TAILORx) trial. This group accounts for 22% of patients who are postmenopausal, node-negative, and ER+ identified by the Oncotype DX assay. Initial reports show no significant benefit from the addition of chemotherapy to tamoxifen in this group.10
MammaPrint
Other gene prognostic signatures have recently been validated. Of these, the MammaPrint assay is the best established and validated.16 The MammaPrint uses a panel of 70 proliferation genes that were selected without bias by scanning the entire human genome. Unlike the Oncotype DX, the MammaPrint panel was randomly selected without any prior knowledge of the role of the proliferation genes in breast carcinogenesis. Furthermore, the reliability of the MammaPrint gene signature is independent of nodal status.17 This suggests that the intrinsic genetic makeup of the cancer establishes its biologic behavior and supersedes the impact of the traditional assessment of nodal involvement as a significant risk factor for distant metastases.
The MammaPrint GES was developed to identify patients at high risk of recurrence within 5 years of diagnosis; those for whom, as noted earlier, the salutary effect of chemotherapy is most evident.18 The assay is reliable for both pre- and postmenopausal women and stratifies patients into 2 risk groups only: high vs low.19-21 The probability of remaining free of recurrent disease at 10 years is 85% in the low risk GES patients vs 50.6% in those with high risk MammaPrint prognosis signatures.17
Subsequent validation trials examined the accuracy of the MammaPrint as a prognostic indicator as well as a predictor of response to chemotherapy. These studies included node-negative, node-positive, pre- and postmenopausal women.18-23 The risk of metastatic disease within the first 5 years after diagnosis was more significant in the high-risk than in the low-risk group. However, because the MammaPrint signature is independent of ER status, not all MammaPrint low-risk signatures are ER+. This reflects the contribution of unselected proliferation genes to the MammaPrint signature that results in the luminal A and luminal B breast cancer subtypes. In postmenopausal, node-negative patients, 61% may have good prognosis signatures, regardless of ER status.18,22
A poor prognosis signature, then, would suggest the use of chemotherapy to prevent early (< 5 years from diagnosis) breast cancer deaths, but would still allow for EA to prevent late (> 5 years after diagnosis) recurrence for patients whose tumors were ER+. It should be noted that these findings also apply to patients treated with contemporary anthracycline chemotherapy regimens.22 The MammaPrint poor prognostic signature identifies patients at risk for early recurrence who may therefore benefit from chemotherapy, whereas the good prognostic signature identifies patients with a very low risk of distant metastases < 5 years.22 In the latter group, this low risk may not warrant use of systemic chemotherapy, but treatment with EA would confer a decrease in systemic metastases.
THE SURGEON’S PERSPECTIVE
To the surgeon, as suggested earlier, perhaps more pertinent is the available information on the use of chemotherapy before planned surgery for basal-type triple negative and HER-2+ breast cancers in the setting of luminal ER+ tumors. Mounting evidence suggests that the GES, such as those determined via the Oncotype and MammaPrint assays, can provide a very reliable indication of an individual patient’s response to PCT or chemotherapy in the neoadjuvant setting.24,25 These clinical responses are easily quantitated on physical examination or by imaging in the few months during which a patient can receive PCT.
Furthermore, the absence of residual microscopic tumor in the breast and axilla (ie, pCR) after PCT can be predicted by the Oncotype DX RS and the MammaPrint GES. More than 11 reports (5,210 patients) have demonstrated a higher DFS and OS in patients who achieve a pCR after PCT.8 A pCR in a locally advanced patient with breast cancer can provide the surgeon with a margin-negative surgical procedure (BCS or mastectomy) and inform the patient of the potential for a much better DFS or OS than anticipated from the stage of breast cancer at presentation.
In some patients amenable to BCS at presentation but whose tumor is too close to the chest wall or is proximate to a silicone augmentation prosthesis, the predicted response to systemic chemotherapy or hormonal ablation provided by GES can lead to a decrease in margin-positive rates and salvage of the previous cosmetic augmentation.
In patients at risk for carrying a BRCA mutation, the interval of PCT can be used for appropriate genetic testing and counseling and plastic surgery and gynecologic oncology consultations. Identified BRCA gene carriers may benefit from risk reduction surgery because of their increased breast and ovarian cancerrisk. Non-BRCA patients can consider BCS as an option, with decreased margin-positive rates and improved cosmesis. Information provided by GES can be essential to a good surgical outcome and underlines the need for preoperative consultation with medical oncology.26
CONCLUSION
Gene expression signatures provide information about the biologic behavior of each individual patient’s breast cancer. As new GES are introduced into clinical practice, surgeons must become fully informed about these advances in order to provide truly personalized cancer care plans to our patients.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect an endorsement by or opinion of Federal Practitioner, Frontline Medical Communications, the U.S. Air Force, the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drug combinations–including indications, contraindications, warnings, and adverse effects–before administering pharmacologic therapy to patients.
1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.
2. Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinoma distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98(19):10869-10874.
3. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013;24(9):2206-2223.
4. Pagoda K, Niwinska A, Murawska M, Pienkowski T. Analysis of pattern, time, and risk factors influencing recurrence in triple-negative breast cancer patients. Med Oncol. 2013;30(1):388.
5. Brewster AM, Hortobagyi GN, Broglio KR. Residual risk of breast cancer recurrence 5 years after adjuvant therapy. J Natl Cancer Inst. 2008;100(16):1179-1183.
6. Reynolds S. Triple-negative breast cancer disproportionately affects african american and Hispanic women. NCI Cancer Bulletin. 2007;4(22). www.cancer.gov/ncicancerbulletin/archive/2007/072407/page7. Accessed July 17, 2014.
7. Phillips C. Treatment Options for HER2-positive breast cancer expand and evolve. NCI Cancer Bulletin. 2012;9(20). www.cancer.gov/ncicancerbulletin/101612/page2. Accessed July 17, 2014.
8. Kaufmann M, von Minckwitz G, Mamounas EP, et al. Recommendations from an international conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol. 2012;19(5):1508-1516.
9. Coates AS, Colleoni M, Goldhirsch A. Is adjuvant chemotherapy useful for women with luminal A breast cancer? J Clin Oncol. 2012;30(12):1260-1263.
10. Paik S, Tang G, Kim C, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24(23):3726-3734.
11. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351(27):2817-2826.
12. Habel LA, Shak S, Jacobs MK, et al. A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res. 2006;8(3):1-15.
13. Sparano JA, Paik S. Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol. 2008;26(5):721-728.
14. Lo SS, Mumby PB, Norton J, et al. Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologists and patient adjuvant breast cancer treatment selection. J Clin Oncol. 2010;28(10):1671-1676.
15. Hassett MJ, Silver SM, Hughes ME, et al. Adoption of gene expression profile testing and association with the use of chemotherapy among women with breast cancer. J Clin Oncol. 2012;30(18):2218-2226.
16. van’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415(6871):530-536.
17. van de Vijver MJ, He YD, van’t Veer LJ, et al. A gene expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347(25):1999-2009.
18. Mook S, Schmidt MK, Weigelt B, et al. The 70-gene prognostic signature predicts early metastasis in breast cancer patients between 55 and 70 years of age. Ann Oncol. 2010;21(4):717-722.
19. Drukker CA, Bueno-de-Mesquita JM, Retél VP, et al. A prospective evaluation of a breast cancer prognostic signature in the observational RASTER study. Intl J Cancer. 2013;133(4):929-936.
20. Buyse M, Loi S, van’t Veer L, et al. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. 2006;98(17): 1183-1192.
21. Bueno-de-Mesquita JM, Linn SC, Keijzer R, et al. Validation of 70-gene prognostic signature in node-negative breast cancer. Breast Cancer Res Treat. 2009;117(3):483-495.
22. Knauer M, Mook S, Rutgers EJ, et al. The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat. 2010;120(3):655-661.
23. Mook S, Schmidt MK, Viale G, et al; TRANSBIG Consortium. The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1-3 positive lymph nodes in an independent validation study. Breast Cancer Res Treat. 2009;116(2):295-302.
24. Gianni L, Zambetti M, Clark K, et al. Gene expression profiles in paraffin-embedded core biopsy tissue predicts response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol. 2005;23(29):7265-7277.
25. Straver ME, Glas AM, Hannemann J, et al. The 70-gene signature as a response predictor for neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat. 2010;119(3):551-558.
26. Silva E. Targeted tailored management of the breast cancer patient at risk for harboring a germline mutation: current trends affecting the selection of patients considering surgical prophylaxis. Breast J. 2009;15(suppl 1):S76-S80.
The use of systemic chemotherapy and estrogen ablation (EA) for the treatment of breast cancer historically have been based on both the histologic prognostic parameters of the invasive breast cancer and on traditional estimates of recurrence risk. These estimates take into account the patient’s age, tumor size, grade, lymphovascular invasion, hormonal receptor status (estrogen receptor/progesterone receptor [ER/PR]), and human epidermal growth factor receptor 2 (HER2) overexpression.1
The recent description of 4 primary breast cancer subtypes on the basis of gene expression profiles has led to the identification of more specific gene prognostic signatures.2 These may serve to supplement, and possibly supersede, the assessment of recurrence risk currently employed as the basis for chemotherapy or EA recommendations for patients with breast cancer. As a result, many
patients who would have been treated with chemotherapy previously may now safely avoid it. The information provided by these prognostic signatures may also alter surgical decision making for many patients and, consequently, should be within the purview of dedicated cancer surgeons.
BREAST CANCER SUBTYPES
The 4 breast cancer subtypes are (1) the HER2 type, these can be ER/PR positive or negative; (2) basal-like tumors, typically ER, PR, and HER2 negative (ER-, PR-, and HER2-); and ER-positive (ER+) or luminal tumors, usually divided into (3) luminal A and (4) luminal B.2
HER2 Type
The advent of the first targeted breast cancer therapy, trastuzumab, and its immense salutary effect on survival of patients with previously poor prognoses has made the use of chemotherapy in combination with trastuzumab nearly mandatory in all HER2+ patients with breast cancer. Remarkably, the huge improvement in survival of these formerly doomed patients has led to the recommendation that trastuzumab-containing chemotherapy regimens should be used in the management of even subcentimeter, node-negative patients.3 This recommendation represents a clear change from the traditional recommendations for chemotherapy, which held that the benefits of systemic chemotherapy were more likely to be seen in patients with tumors in excess of 1 cm and/or who were node positive.
Basal-like Tumors
The discovery of trastuzumab made the basal-like tumor, which is usually ER-, PR-, and HER2- (triple negative), the subtype with the worst prognosis. Further, the natural course of this illness is markedly different from that of ER+/PR+ breast cancer. Nearly all basal-like or triple-negative patients with breast cancer who experience a recurrence do so within the first 5 years after diagnosis.4 In contrast, nearly 40% of ER+/PR+ HER2- breast cancer survivors experience their first recurrence beyond the 5-year milestone, with many even later in their course.5 Thus, the patient with triple-negative breast cancer is more likely to benefit from chemotherapy predominantly during the first 5 post-diagnosis years, as suggested by the Early Breast Cancer Trialists’ Collaborative Group meta-analyses.1
HER2+ and triple-negative breast cancers account for 20% and 15% of all breast cancers, respectively.6,7 In both subtypes, the benefit of chemotherapy is immense and chemotherapy will rarely be omitted from the treatment plan. Many of these patients are considered ideal candidates for preoperative chemotherapy (PCT), which results in increased rates of breast-conserving surgery (BCS), decreased positive margin rates at BCS, and decreased need for axillary node dissection. In the setting of PCT, a pathologic complete response (pCR) in the breast and axilla is increasingly recognized as a marker for improved disease-free survival (DFS) and overall survival (OS).8 For these reasons, preoperative consultation with medical oncologists is now even more important. Many of these patients will benefit from the use of PCT before any surgical treatment is undertaken.
Luminal Type (A and B)
The remaining two-thirds of all patients with breast cancer are ER+, primarily postmenopausal, and fall within the 2 remaining molecular subtypes: luminal A and luminal B. It is for these patients that the relative benefits of chemotherapy vs EA, or both, are currently being debated. For these patients the use of gene prognostic signatures, in concert with traditional histopathologic and clinical risk factors, may alter estimates of recurrence risk and the impact of chemotherapy on survival and recurrence estimates.
It is now evident that even the strongest predictors for breast cancer recurrence—histologic grade, patient age, and nodal status—are inconsistent predictors of the behavior of any individual tumor. While the use of chemotherapy can reduce the risk of metastases in these luminal-type patients with breast cancer, the majority of patients so stratified would survive without chemotherapy.9
GENE EXPRESSION SIGNATURE ASSAYS
One of the best demonstrations of the shortcomings of the standard risk predictors for ER+, HER2- breast cancers is provided by the Oncotype DX breast cancer assay’s recurrence score (RS) or gene expression signature (GES).10,11
Oncotype DX
The Oncotype DX assay is the first commercially available GES assay to illustrate the variability in survival of patients with node-negative, ER+ breast tumors. Sixteen selected cancer proliferative genes are paired with 5 control nonproliferative genes whose relative activity can be measured in paraffin-embedded breast cancer tissue. The ability to retrieve reliable ribonucleic acid (RNA) expression from cancer cells embedded in paraffin was a stroke of genius; it enabled the investigators to correlate the gene expression profile of patient subgroups treated decades earlier with their long-term clinical outcomes and survival.
The normalized summation of the proliferative activity of the 16 cancerproliferation genes in the Oncotype DX assay is expressed as the RS. The RS increases linearly and so does the average rate of distant recurrence in 10 years as a function of the RS. Three risk recurrence groups are defined by the RS: low risk (RS < 18); intermediate risk (RS > 18 to 30); and high risk (RS > 31).10,11
Clinical Trials
In the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial B-14, ER+ node-negative patients were randomized to observation or tamoxifen. In the untreated control patients, a low RS (< 18) was accompanied by a 6.8% risk of metastasis at 10 years, and a high RS (> 31) was accompanied by a 30.5% rate of distant recurrence.11 In another study, the low RS tamoxifen-treated arm showed a 2.8% risk of breast cancer death at 10 years vs a 15.5% risk in the high RS cohort.12
The remarkable significance of the RS is demonstrated when the RS is plotted against patient age, grade, or tumor size.10 This illustrates the huge variability in these traditional histopathologic and clinical features within a given RS group. For any patient with a low RS, there is marked variability in patient age, tumor grade, or tumor size. A very small or low-grade tumor can have a very high 10-year recurrence rate, as measured by the gene prognostic signature or RS. Similarly, a very large tumor in a young patient can have a very low 10-year recurrence rate or RS. This is due to the heterogeneity of the biology of these cancers, regardless of their favorable or unfavorable histologic features.
In most cases, decisions about chemotherapy in patient who are postmenopausal, node-negative, and ER+ are made by risk estimates based on patient age, tumor grade, and tumor size, without knowledge of their RS. However, the large variability in 10-year rates of metastases and death among patients clearly demonstrates that, for some, chemotherapy affords no benefit. Their RS suggest that their risk of metastases at 10 years is only 2.8% when treated with EA (ie, tamoxifen) and no chemotherapy. In fact, 51% of the patients who are postmenopausal, node-negative, and ER+ in NSABP B-14 fell within the low risk RS category for 10-year distant recurrence, whereas about 27% fell within the high risk (RS > 31) category.13
Confidence in the Oncotype DX assay RS stems from the ability of investigators to plot the recurrence rates of distant metastases in patientstreated with tamoxifen vs placebo in the NSABP B-14 trial. Their clinicaloutcomes could be correlated with their GES samples retrieved from paraffin-embedded archival tissue many years after treatment. Corresponding plotting was done for similar patient cohorts treated with chemotherapy with or without tamoxifen in NSABP Trial B-20.
Among patients with low RS, the distant recurrence rate at 10 years was 2.2%, whether treated with systemic chemotherapy plus tamoxifenor with tamoxifen alone. Thus, in study participants with low RS, regardless of tumor size, grade, or patient age, 10-year recurrence rates were not affected by the addition of chemotherapy.13
Note that, in the absence of the new information provided by the Oncotype gene prognostic signature, nearly all these patients would be treated with systemic chemotherapy. Studies have shown that the additional risk assessment estimate provided by the Oncotype assay causes a change in systemic therapy recommendations from chemotherapy to no chemotherapy in 30% of patients.14,15 Among patients with high RS, 10-year distant recurrence rates decreased by an absolute 27% with the addition of chemotherapy to tamoxifen. These patients clearly benefited from chemotherapy.13
The relative benefits of chemotherapy vs tamoxifen in a third RS group with an intermediate RS of 18-21 awaits publication of the now-closed Trial Assigning Individualized Options for Treatment (TAILORx) trial. This group accounts for 22% of patients who are postmenopausal, node-negative, and ER+ identified by the Oncotype DX assay. Initial reports show no significant benefit from the addition of chemotherapy to tamoxifen in this group.10
MammaPrint
Other gene prognostic signatures have recently been validated. Of these, the MammaPrint assay is the best established and validated.16 The MammaPrint uses a panel of 70 proliferation genes that were selected without bias by scanning the entire human genome. Unlike the Oncotype DX, the MammaPrint panel was randomly selected without any prior knowledge of the role of the proliferation genes in breast carcinogenesis. Furthermore, the reliability of the MammaPrint gene signature is independent of nodal status.17 This suggests that the intrinsic genetic makeup of the cancer establishes its biologic behavior and supersedes the impact of the traditional assessment of nodal involvement as a significant risk factor for distant metastases.
The MammaPrint GES was developed to identify patients at high risk of recurrence within 5 years of diagnosis; those for whom, as noted earlier, the salutary effect of chemotherapy is most evident.18 The assay is reliable for both pre- and postmenopausal women and stratifies patients into 2 risk groups only: high vs low.19-21 The probability of remaining free of recurrent disease at 10 years is 85% in the low risk GES patients vs 50.6% in those with high risk MammaPrint prognosis signatures.17
Subsequent validation trials examined the accuracy of the MammaPrint as a prognostic indicator as well as a predictor of response to chemotherapy. These studies included node-negative, node-positive, pre- and postmenopausal women.18-23 The risk of metastatic disease within the first 5 years after diagnosis was more significant in the high-risk than in the low-risk group. However, because the MammaPrint signature is independent of ER status, not all MammaPrint low-risk signatures are ER+. This reflects the contribution of unselected proliferation genes to the MammaPrint signature that results in the luminal A and luminal B breast cancer subtypes. In postmenopausal, node-negative patients, 61% may have good prognosis signatures, regardless of ER status.18,22
A poor prognosis signature, then, would suggest the use of chemotherapy to prevent early (< 5 years from diagnosis) breast cancer deaths, but would still allow for EA to prevent late (> 5 years after diagnosis) recurrence for patients whose tumors were ER+. It should be noted that these findings also apply to patients treated with contemporary anthracycline chemotherapy regimens.22 The MammaPrint poor prognostic signature identifies patients at risk for early recurrence who may therefore benefit from chemotherapy, whereas the good prognostic signature identifies patients with a very low risk of distant metastases < 5 years.22 In the latter group, this low risk may not warrant use of systemic chemotherapy, but treatment with EA would confer a decrease in systemic metastases.
THE SURGEON’S PERSPECTIVE
To the surgeon, as suggested earlier, perhaps more pertinent is the available information on the use of chemotherapy before planned surgery for basal-type triple negative and HER-2+ breast cancers in the setting of luminal ER+ tumors. Mounting evidence suggests that the GES, such as those determined via the Oncotype and MammaPrint assays, can provide a very reliable indication of an individual patient’s response to PCT or chemotherapy in the neoadjuvant setting.24,25 These clinical responses are easily quantitated on physical examination or by imaging in the few months during which a patient can receive PCT.
Furthermore, the absence of residual microscopic tumor in the breast and axilla (ie, pCR) after PCT can be predicted by the Oncotype DX RS and the MammaPrint GES. More than 11 reports (5,210 patients) have demonstrated a higher DFS and OS in patients who achieve a pCR after PCT.8 A pCR in a locally advanced patient with breast cancer can provide the surgeon with a margin-negative surgical procedure (BCS or mastectomy) and inform the patient of the potential for a much better DFS or OS than anticipated from the stage of breast cancer at presentation.
In some patients amenable to BCS at presentation but whose tumor is too close to the chest wall or is proximate to a silicone augmentation prosthesis, the predicted response to systemic chemotherapy or hormonal ablation provided by GES can lead to a decrease in margin-positive rates and salvage of the previous cosmetic augmentation.
In patients at risk for carrying a BRCA mutation, the interval of PCT can be used for appropriate genetic testing and counseling and plastic surgery and gynecologic oncology consultations. Identified BRCA gene carriers may benefit from risk reduction surgery because of their increased breast and ovarian cancerrisk. Non-BRCA patients can consider BCS as an option, with decreased margin-positive rates and improved cosmesis. Information provided by GES can be essential to a good surgical outcome and underlines the need for preoperative consultation with medical oncology.26
CONCLUSION
Gene expression signatures provide information about the biologic behavior of each individual patient’s breast cancer. As new GES are introduced into clinical practice, surgeons must become fully informed about these advances in order to provide truly personalized cancer care plans to our patients.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect an endorsement by or opinion of Federal Practitioner, Frontline Medical Communications, the U.S. Air Force, the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drug combinations–including indications, contraindications, warnings, and adverse effects–before administering pharmacologic therapy to patients.
The use of systemic chemotherapy and estrogen ablation (EA) for the treatment of breast cancer historically have been based on both the histologic prognostic parameters of the invasive breast cancer and on traditional estimates of recurrence risk. These estimates take into account the patient’s age, tumor size, grade, lymphovascular invasion, hormonal receptor status (estrogen receptor/progesterone receptor [ER/PR]), and human epidermal growth factor receptor 2 (HER2) overexpression.1
The recent description of 4 primary breast cancer subtypes on the basis of gene expression profiles has led to the identification of more specific gene prognostic signatures.2 These may serve to supplement, and possibly supersede, the assessment of recurrence risk currently employed as the basis for chemotherapy or EA recommendations for patients with breast cancer. As a result, many
patients who would have been treated with chemotherapy previously may now safely avoid it. The information provided by these prognostic signatures may also alter surgical decision making for many patients and, consequently, should be within the purview of dedicated cancer surgeons.
BREAST CANCER SUBTYPES
The 4 breast cancer subtypes are (1) the HER2 type, these can be ER/PR positive or negative; (2) basal-like tumors, typically ER, PR, and HER2 negative (ER-, PR-, and HER2-); and ER-positive (ER+) or luminal tumors, usually divided into (3) luminal A and (4) luminal B.2
HER2 Type
The advent of the first targeted breast cancer therapy, trastuzumab, and its immense salutary effect on survival of patients with previously poor prognoses has made the use of chemotherapy in combination with trastuzumab nearly mandatory in all HER2+ patients with breast cancer. Remarkably, the huge improvement in survival of these formerly doomed patients has led to the recommendation that trastuzumab-containing chemotherapy regimens should be used in the management of even subcentimeter, node-negative patients.3 This recommendation represents a clear change from the traditional recommendations for chemotherapy, which held that the benefits of systemic chemotherapy were more likely to be seen in patients with tumors in excess of 1 cm and/or who were node positive.
Basal-like Tumors
The discovery of trastuzumab made the basal-like tumor, which is usually ER-, PR-, and HER2- (triple negative), the subtype with the worst prognosis. Further, the natural course of this illness is markedly different from that of ER+/PR+ breast cancer. Nearly all basal-like or triple-negative patients with breast cancer who experience a recurrence do so within the first 5 years after diagnosis.4 In contrast, nearly 40% of ER+/PR+ HER2- breast cancer survivors experience their first recurrence beyond the 5-year milestone, with many even later in their course.5 Thus, the patient with triple-negative breast cancer is more likely to benefit from chemotherapy predominantly during the first 5 post-diagnosis years, as suggested by the Early Breast Cancer Trialists’ Collaborative Group meta-analyses.1
HER2+ and triple-negative breast cancers account for 20% and 15% of all breast cancers, respectively.6,7 In both subtypes, the benefit of chemotherapy is immense and chemotherapy will rarely be omitted from the treatment plan. Many of these patients are considered ideal candidates for preoperative chemotherapy (PCT), which results in increased rates of breast-conserving surgery (BCS), decreased positive margin rates at BCS, and decreased need for axillary node dissection. In the setting of PCT, a pathologic complete response (pCR) in the breast and axilla is increasingly recognized as a marker for improved disease-free survival (DFS) and overall survival (OS).8 For these reasons, preoperative consultation with medical oncologists is now even more important. Many of these patients will benefit from the use of PCT before any surgical treatment is undertaken.
Luminal Type (A and B)
The remaining two-thirds of all patients with breast cancer are ER+, primarily postmenopausal, and fall within the 2 remaining molecular subtypes: luminal A and luminal B. It is for these patients that the relative benefits of chemotherapy vs EA, or both, are currently being debated. For these patients the use of gene prognostic signatures, in concert with traditional histopathologic and clinical risk factors, may alter estimates of recurrence risk and the impact of chemotherapy on survival and recurrence estimates.
It is now evident that even the strongest predictors for breast cancer recurrence—histologic grade, patient age, and nodal status—are inconsistent predictors of the behavior of any individual tumor. While the use of chemotherapy can reduce the risk of metastases in these luminal-type patients with breast cancer, the majority of patients so stratified would survive without chemotherapy.9
GENE EXPRESSION SIGNATURE ASSAYS
One of the best demonstrations of the shortcomings of the standard risk predictors for ER+, HER2- breast cancers is provided by the Oncotype DX breast cancer assay’s recurrence score (RS) or gene expression signature (GES).10,11
Oncotype DX
The Oncotype DX assay is the first commercially available GES assay to illustrate the variability in survival of patients with node-negative, ER+ breast tumors. Sixteen selected cancer proliferative genes are paired with 5 control nonproliferative genes whose relative activity can be measured in paraffin-embedded breast cancer tissue. The ability to retrieve reliable ribonucleic acid (RNA) expression from cancer cells embedded in paraffin was a stroke of genius; it enabled the investigators to correlate the gene expression profile of patient subgroups treated decades earlier with their long-term clinical outcomes and survival.
The normalized summation of the proliferative activity of the 16 cancerproliferation genes in the Oncotype DX assay is expressed as the RS. The RS increases linearly and so does the average rate of distant recurrence in 10 years as a function of the RS. Three risk recurrence groups are defined by the RS: low risk (RS < 18); intermediate risk (RS > 18 to 30); and high risk (RS > 31).10,11
Clinical Trials
In the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial B-14, ER+ node-negative patients were randomized to observation or tamoxifen. In the untreated control patients, a low RS (< 18) was accompanied by a 6.8% risk of metastasis at 10 years, and a high RS (> 31) was accompanied by a 30.5% rate of distant recurrence.11 In another study, the low RS tamoxifen-treated arm showed a 2.8% risk of breast cancer death at 10 years vs a 15.5% risk in the high RS cohort.12
The remarkable significance of the RS is demonstrated when the RS is plotted against patient age, grade, or tumor size.10 This illustrates the huge variability in these traditional histopathologic and clinical features within a given RS group. For any patient with a low RS, there is marked variability in patient age, tumor grade, or tumor size. A very small or low-grade tumor can have a very high 10-year recurrence rate, as measured by the gene prognostic signature or RS. Similarly, a very large tumor in a young patient can have a very low 10-year recurrence rate or RS. This is due to the heterogeneity of the biology of these cancers, regardless of their favorable or unfavorable histologic features.
In most cases, decisions about chemotherapy in patient who are postmenopausal, node-negative, and ER+ are made by risk estimates based on patient age, tumor grade, and tumor size, without knowledge of their RS. However, the large variability in 10-year rates of metastases and death among patients clearly demonstrates that, for some, chemotherapy affords no benefit. Their RS suggest that their risk of metastases at 10 years is only 2.8% when treated with EA (ie, tamoxifen) and no chemotherapy. In fact, 51% of the patients who are postmenopausal, node-negative, and ER+ in NSABP B-14 fell within the low risk RS category for 10-year distant recurrence, whereas about 27% fell within the high risk (RS > 31) category.13
Confidence in the Oncotype DX assay RS stems from the ability of investigators to plot the recurrence rates of distant metastases in patientstreated with tamoxifen vs placebo in the NSABP B-14 trial. Their clinicaloutcomes could be correlated with their GES samples retrieved from paraffin-embedded archival tissue many years after treatment. Corresponding plotting was done for similar patient cohorts treated with chemotherapy with or without tamoxifen in NSABP Trial B-20.
Among patients with low RS, the distant recurrence rate at 10 years was 2.2%, whether treated with systemic chemotherapy plus tamoxifenor with tamoxifen alone. Thus, in study participants with low RS, regardless of tumor size, grade, or patient age, 10-year recurrence rates were not affected by the addition of chemotherapy.13
Note that, in the absence of the new information provided by the Oncotype gene prognostic signature, nearly all these patients would be treated with systemic chemotherapy. Studies have shown that the additional risk assessment estimate provided by the Oncotype assay causes a change in systemic therapy recommendations from chemotherapy to no chemotherapy in 30% of patients.14,15 Among patients with high RS, 10-year distant recurrence rates decreased by an absolute 27% with the addition of chemotherapy to tamoxifen. These patients clearly benefited from chemotherapy.13
The relative benefits of chemotherapy vs tamoxifen in a third RS group with an intermediate RS of 18-21 awaits publication of the now-closed Trial Assigning Individualized Options for Treatment (TAILORx) trial. This group accounts for 22% of patients who are postmenopausal, node-negative, and ER+ identified by the Oncotype DX assay. Initial reports show no significant benefit from the addition of chemotherapy to tamoxifen in this group.10
MammaPrint
Other gene prognostic signatures have recently been validated. Of these, the MammaPrint assay is the best established and validated.16 The MammaPrint uses a panel of 70 proliferation genes that were selected without bias by scanning the entire human genome. Unlike the Oncotype DX, the MammaPrint panel was randomly selected without any prior knowledge of the role of the proliferation genes in breast carcinogenesis. Furthermore, the reliability of the MammaPrint gene signature is independent of nodal status.17 This suggests that the intrinsic genetic makeup of the cancer establishes its biologic behavior and supersedes the impact of the traditional assessment of nodal involvement as a significant risk factor for distant metastases.
The MammaPrint GES was developed to identify patients at high risk of recurrence within 5 years of diagnosis; those for whom, as noted earlier, the salutary effect of chemotherapy is most evident.18 The assay is reliable for both pre- and postmenopausal women and stratifies patients into 2 risk groups only: high vs low.19-21 The probability of remaining free of recurrent disease at 10 years is 85% in the low risk GES patients vs 50.6% in those with high risk MammaPrint prognosis signatures.17
Subsequent validation trials examined the accuracy of the MammaPrint as a prognostic indicator as well as a predictor of response to chemotherapy. These studies included node-negative, node-positive, pre- and postmenopausal women.18-23 The risk of metastatic disease within the first 5 years after diagnosis was more significant in the high-risk than in the low-risk group. However, because the MammaPrint signature is independent of ER status, not all MammaPrint low-risk signatures are ER+. This reflects the contribution of unselected proliferation genes to the MammaPrint signature that results in the luminal A and luminal B breast cancer subtypes. In postmenopausal, node-negative patients, 61% may have good prognosis signatures, regardless of ER status.18,22
A poor prognosis signature, then, would suggest the use of chemotherapy to prevent early (< 5 years from diagnosis) breast cancer deaths, but would still allow for EA to prevent late (> 5 years after diagnosis) recurrence for patients whose tumors were ER+. It should be noted that these findings also apply to patients treated with contemporary anthracycline chemotherapy regimens.22 The MammaPrint poor prognostic signature identifies patients at risk for early recurrence who may therefore benefit from chemotherapy, whereas the good prognostic signature identifies patients with a very low risk of distant metastases < 5 years.22 In the latter group, this low risk may not warrant use of systemic chemotherapy, but treatment with EA would confer a decrease in systemic metastases.
THE SURGEON’S PERSPECTIVE
To the surgeon, as suggested earlier, perhaps more pertinent is the available information on the use of chemotherapy before planned surgery for basal-type triple negative and HER-2+ breast cancers in the setting of luminal ER+ tumors. Mounting evidence suggests that the GES, such as those determined via the Oncotype and MammaPrint assays, can provide a very reliable indication of an individual patient’s response to PCT or chemotherapy in the neoadjuvant setting.24,25 These clinical responses are easily quantitated on physical examination or by imaging in the few months during which a patient can receive PCT.
Furthermore, the absence of residual microscopic tumor in the breast and axilla (ie, pCR) after PCT can be predicted by the Oncotype DX RS and the MammaPrint GES. More than 11 reports (5,210 patients) have demonstrated a higher DFS and OS in patients who achieve a pCR after PCT.8 A pCR in a locally advanced patient with breast cancer can provide the surgeon with a margin-negative surgical procedure (BCS or mastectomy) and inform the patient of the potential for a much better DFS or OS than anticipated from the stage of breast cancer at presentation.
In some patients amenable to BCS at presentation but whose tumor is too close to the chest wall or is proximate to a silicone augmentation prosthesis, the predicted response to systemic chemotherapy or hormonal ablation provided by GES can lead to a decrease in margin-positive rates and salvage of the previous cosmetic augmentation.
In patients at risk for carrying a BRCA mutation, the interval of PCT can be used for appropriate genetic testing and counseling and plastic surgery and gynecologic oncology consultations. Identified BRCA gene carriers may benefit from risk reduction surgery because of their increased breast and ovarian cancerrisk. Non-BRCA patients can consider BCS as an option, with decreased margin-positive rates and improved cosmesis. Information provided by GES can be essential to a good surgical outcome and underlines the need for preoperative consultation with medical oncology.26
CONCLUSION
Gene expression signatures provide information about the biologic behavior of each individual patient’s breast cancer. As new GES are introduced into clinical practice, surgeons must become fully informed about these advances in order to provide truly personalized cancer care plans to our patients.
Author disclosures
The author reports no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the author and do not necessarily reflect an endorsement by or opinion of Federal Practitioner, Frontline Medical Communications, the U.S. Air Force, the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review complete prescribing information for specific drug combinations–including indications, contraindications, warnings, and adverse effects–before administering pharmacologic therapy to patients.
1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.
2. Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinoma distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98(19):10869-10874.
3. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013;24(9):2206-2223.
4. Pagoda K, Niwinska A, Murawska M, Pienkowski T. Analysis of pattern, time, and risk factors influencing recurrence in triple-negative breast cancer patients. Med Oncol. 2013;30(1):388.
5. Brewster AM, Hortobagyi GN, Broglio KR. Residual risk of breast cancer recurrence 5 years after adjuvant therapy. J Natl Cancer Inst. 2008;100(16):1179-1183.
6. Reynolds S. Triple-negative breast cancer disproportionately affects african american and Hispanic women. NCI Cancer Bulletin. 2007;4(22). www.cancer.gov/ncicancerbulletin/archive/2007/072407/page7. Accessed July 17, 2014.
7. Phillips C. Treatment Options for HER2-positive breast cancer expand and evolve. NCI Cancer Bulletin. 2012;9(20). www.cancer.gov/ncicancerbulletin/101612/page2. Accessed July 17, 2014.
8. Kaufmann M, von Minckwitz G, Mamounas EP, et al. Recommendations from an international conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol. 2012;19(5):1508-1516.
9. Coates AS, Colleoni M, Goldhirsch A. Is adjuvant chemotherapy useful for women with luminal A breast cancer? J Clin Oncol. 2012;30(12):1260-1263.
10. Paik S, Tang G, Kim C, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24(23):3726-3734.
11. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351(27):2817-2826.
12. Habel LA, Shak S, Jacobs MK, et al. A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res. 2006;8(3):1-15.
13. Sparano JA, Paik S. Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol. 2008;26(5):721-728.
14. Lo SS, Mumby PB, Norton J, et al. Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologists and patient adjuvant breast cancer treatment selection. J Clin Oncol. 2010;28(10):1671-1676.
15. Hassett MJ, Silver SM, Hughes ME, et al. Adoption of gene expression profile testing and association with the use of chemotherapy among women with breast cancer. J Clin Oncol. 2012;30(18):2218-2226.
16. van’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415(6871):530-536.
17. van de Vijver MJ, He YD, van’t Veer LJ, et al. A gene expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347(25):1999-2009.
18. Mook S, Schmidt MK, Weigelt B, et al. The 70-gene prognostic signature predicts early metastasis in breast cancer patients between 55 and 70 years of age. Ann Oncol. 2010;21(4):717-722.
19. Drukker CA, Bueno-de-Mesquita JM, Retél VP, et al. A prospective evaluation of a breast cancer prognostic signature in the observational RASTER study. Intl J Cancer. 2013;133(4):929-936.
20. Buyse M, Loi S, van’t Veer L, et al. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. 2006;98(17): 1183-1192.
21. Bueno-de-Mesquita JM, Linn SC, Keijzer R, et al. Validation of 70-gene prognostic signature in node-negative breast cancer. Breast Cancer Res Treat. 2009;117(3):483-495.
22. Knauer M, Mook S, Rutgers EJ, et al. The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat. 2010;120(3):655-661.
23. Mook S, Schmidt MK, Viale G, et al; TRANSBIG Consortium. The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1-3 positive lymph nodes in an independent validation study. Breast Cancer Res Treat. 2009;116(2):295-302.
24. Gianni L, Zambetti M, Clark K, et al. Gene expression profiles in paraffin-embedded core biopsy tissue predicts response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol. 2005;23(29):7265-7277.
25. Straver ME, Glas AM, Hannemann J, et al. The 70-gene signature as a response predictor for neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat. 2010;119(3):551-558.
26. Silva E. Targeted tailored management of the breast cancer patient at risk for harboring a germline mutation: current trends affecting the selection of patients considering surgical prophylaxis. Breast J. 2009;15(suppl 1):S76-S80.
1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.
2. Sørlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinoma distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98(19):10869-10874.
3. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013;24(9):2206-2223.
4. Pagoda K, Niwinska A, Murawska M, Pienkowski T. Analysis of pattern, time, and risk factors influencing recurrence in triple-negative breast cancer patients. Med Oncol. 2013;30(1):388.
5. Brewster AM, Hortobagyi GN, Broglio KR. Residual risk of breast cancer recurrence 5 years after adjuvant therapy. J Natl Cancer Inst. 2008;100(16):1179-1183.
6. Reynolds S. Triple-negative breast cancer disproportionately affects african american and Hispanic women. NCI Cancer Bulletin. 2007;4(22). www.cancer.gov/ncicancerbulletin/archive/2007/072407/page7. Accessed July 17, 2014.
7. Phillips C. Treatment Options for HER2-positive breast cancer expand and evolve. NCI Cancer Bulletin. 2012;9(20). www.cancer.gov/ncicancerbulletin/101612/page2. Accessed July 17, 2014.
8. Kaufmann M, von Minckwitz G, Mamounas EP, et al. Recommendations from an international conference on the current status and future of neoadjuvant systemic therapy in primary breast cancer. Ann Surg Oncol. 2012;19(5):1508-1516.
9. Coates AS, Colleoni M, Goldhirsch A. Is adjuvant chemotherapy useful for women with luminal A breast cancer? J Clin Oncol. 2012;30(12):1260-1263.
10. Paik S, Tang G, Kim C, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24(23):3726-3734.
11. Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351(27):2817-2826.
12. Habel LA, Shak S, Jacobs MK, et al. A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res. 2006;8(3):1-15.
13. Sparano JA, Paik S. Development of the 21-gene assay and its application in clinical practice and clinical trials. J Clin Oncol. 2008;26(5):721-728.
14. Lo SS, Mumby PB, Norton J, et al. Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologists and patient adjuvant breast cancer treatment selection. J Clin Oncol. 2010;28(10):1671-1676.
15. Hassett MJ, Silver SM, Hughes ME, et al. Adoption of gene expression profile testing and association with the use of chemotherapy among women with breast cancer. J Clin Oncol. 2012;30(18):2218-2226.
16. van’t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415(6871):530-536.
17. van de Vijver MJ, He YD, van’t Veer LJ, et al. A gene expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347(25):1999-2009.
18. Mook S, Schmidt MK, Weigelt B, et al. The 70-gene prognostic signature predicts early metastasis in breast cancer patients between 55 and 70 years of age. Ann Oncol. 2010;21(4):717-722.
19. Drukker CA, Bueno-de-Mesquita JM, Retél VP, et al. A prospective evaluation of a breast cancer prognostic signature in the observational RASTER study. Intl J Cancer. 2013;133(4):929-936.
20. Buyse M, Loi S, van’t Veer L, et al. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. 2006;98(17): 1183-1192.
21. Bueno-de-Mesquita JM, Linn SC, Keijzer R, et al. Validation of 70-gene prognostic signature in node-negative breast cancer. Breast Cancer Res Treat. 2009;117(3):483-495.
22. Knauer M, Mook S, Rutgers EJ, et al. The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat. 2010;120(3):655-661.
23. Mook S, Schmidt MK, Viale G, et al; TRANSBIG Consortium. The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1-3 positive lymph nodes in an independent validation study. Breast Cancer Res Treat. 2009;116(2):295-302.
24. Gianni L, Zambetti M, Clark K, et al. Gene expression profiles in paraffin-embedded core biopsy tissue predicts response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol. 2005;23(29):7265-7277.
25. Straver ME, Glas AM, Hannemann J, et al. The 70-gene signature as a response predictor for neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat. 2010;119(3):551-558.
26. Silva E. Targeted tailored management of the breast cancer patient at risk for harboring a germline mutation: current trends affecting the selection of patients considering surgical prophylaxis. Breast J. 2009;15(suppl 1):S76-S80.
PALB2 mutation increased lifetime risk of breast cancer
Women with inherited loss-of-function mutations in the PALB2 gene were more than nine times as likely to develop breast cancer, compared with the general population, according to a large multicenter study reported Aug. 6 in the New England Journal of Medicine.
The study showed that women with germline loss-of-function PALB2 mutations had a 14% cumulative risk of breast cancer by age 50 years and a 35% risk by age 70, said Antonis C. Antoniou, Ph.D., of the University of Cambridge, England, and his associates.
"On the basis of our estimates, the breast-cancer risk for a PALB2 mutation carrier, even in the absence of a family history of breast cancer, would be classified as high according to various guidelines. This level of risk may justify adding PALB2 to genetic testing for BRCA1 and BRCA2," the researchers said.
Germline PALB2 mutations affect about 0.08% of the population and are a known risk factor for breast cancer. To better characterize lifetime risk in PALB2 mutation carriers, the researchers studied 154 families in the United Kingdom whose 362 members had inherited harmful truncating, splice, or deletion mutations in PALB2 (N. Engl. J. Med. 2014;371:497-506). The cohort included 311 women, of whom 229 had breast cancer, the researchers said.
After controlling for other familial factors, the risk of breast cancer in PALB2 mutation carriers was 9.47 times (95% confidence interval, 7.16-12.57) greater than in the United Kingdom overall between 1993 and 1997, the investigators reported.
Risk correlated inversely with age and also was affected by family history of breast cancer, they found. Women with the mutation whose first-degree relatives were cancer free had a 33% risk of breast cancer at age 70 years (95% CI, 25%-44%), but this risk was 58% if the women had at least two first-degree relatives who developed breast cancer by age 50 years (95% CI, 50%-66%), Dr. Antoniou and his associates said.
"Our study includes most of the reported families with PALB2 mutation carriers, as well as many not previously reported, but it is still based on small numbers," Dr. Antoniou and associates said. As screening for these mutations enters clinical practice, more families with the PALB2 mutation will be identified and risk estimates can be refined, they said, adding that future studies should evaluate whether the heightened breast cancer surveillance that women with BRCA2 mutations receive can affect outcomes in women who carry the PALB2 loss-of-function mutation.
The study was funded by the European Research Council and 25 other nonprofit and governmental entities in Europe, the United States, Canada, and Australia. Two authors reported being listed on patents related to breast cancer susceptibility genes. The authors disclosed no other conflicts of interest.
The results point to new opportunities to pursue the "synthetic lethality of cancer therapy," said Dr. Michele Evans and Dr. Dan Longo.
In synthetic lethality, two related genes simultaneously lose function, which has a cumulative effect and spurs cell death instead of sublethal changes. "Loss of heterozygosity at the PALB2 locus is likely to result in increased sensitivity to cell death with PARP inhibition as well, given that synthetic lethality is seen with other proteins that are involved in homologous recombination," they said.
"The promise of synthetic lethality in breast-cancer treatment through genetic and pharmacologic targeting of the Fanconi’s anemia-breast cancer pathway will lead the way to the examination and exploitation of defective DNA-repair mechanisms in other cancers," they wrote.
Based on the findings, women with germline PALB2 mutations face about the same risk of breast cancer as women who carry the BRCA2 mutation, Dr. Evans and Dr. Longo said. They noted that PALB2 encodes a protein that binds and colocalizes with BRCA2 in cell nuclei, which enables tumor suppression by preventing DNA damage and promoting repair.
The analyses also indicate that risks linked to PALB2 mutations "synergize with unknown environmental, lifestyle, or additional genetic factors," which "highlights the need to use genetic information within the context of family history and lifestyle factors when assessing risk," they added.
Because the study cohort was racially homogeneous, future studies need to characterize PALB2 in other populations, they noted.
Dr. Evans and Dr. Longo are with the National Institute on Aging, Baltimore. These remarks were excerpted from their editorial accompanying Dr. Antoniou’s report (N. Engl. J. Med. 2014;371:566-8 [doi: 10.1056/NEJMe1405784]).
The results point to new opportunities to pursue the "synthetic lethality of cancer therapy," said Dr. Michele Evans and Dr. Dan Longo.
In synthetic lethality, two related genes simultaneously lose function, which has a cumulative effect and spurs cell death instead of sublethal changes. "Loss of heterozygosity at the PALB2 locus is likely to result in increased sensitivity to cell death with PARP inhibition as well, given that synthetic lethality is seen with other proteins that are involved in homologous recombination," they said.
"The promise of synthetic lethality in breast-cancer treatment through genetic and pharmacologic targeting of the Fanconi’s anemia-breast cancer pathway will lead the way to the examination and exploitation of defective DNA-repair mechanisms in other cancers," they wrote.
Based on the findings, women with germline PALB2 mutations face about the same risk of breast cancer as women who carry the BRCA2 mutation, Dr. Evans and Dr. Longo said. They noted that PALB2 encodes a protein that binds and colocalizes with BRCA2 in cell nuclei, which enables tumor suppression by preventing DNA damage and promoting repair.
The analyses also indicate that risks linked to PALB2 mutations "synergize with unknown environmental, lifestyle, or additional genetic factors," which "highlights the need to use genetic information within the context of family history and lifestyle factors when assessing risk," they added.
Because the study cohort was racially homogeneous, future studies need to characterize PALB2 in other populations, they noted.
Dr. Evans and Dr. Longo are with the National Institute on Aging, Baltimore. These remarks were excerpted from their editorial accompanying Dr. Antoniou’s report (N. Engl. J. Med. 2014;371:566-8 [doi: 10.1056/NEJMe1405784]).
The results point to new opportunities to pursue the "synthetic lethality of cancer therapy," said Dr. Michele Evans and Dr. Dan Longo.
In synthetic lethality, two related genes simultaneously lose function, which has a cumulative effect and spurs cell death instead of sublethal changes. "Loss of heterozygosity at the PALB2 locus is likely to result in increased sensitivity to cell death with PARP inhibition as well, given that synthetic lethality is seen with other proteins that are involved in homologous recombination," they said.
"The promise of synthetic lethality in breast-cancer treatment through genetic and pharmacologic targeting of the Fanconi’s anemia-breast cancer pathway will lead the way to the examination and exploitation of defective DNA-repair mechanisms in other cancers," they wrote.
Based on the findings, women with germline PALB2 mutations face about the same risk of breast cancer as women who carry the BRCA2 mutation, Dr. Evans and Dr. Longo said. They noted that PALB2 encodes a protein that binds and colocalizes with BRCA2 in cell nuclei, which enables tumor suppression by preventing DNA damage and promoting repair.
The analyses also indicate that risks linked to PALB2 mutations "synergize with unknown environmental, lifestyle, or additional genetic factors," which "highlights the need to use genetic information within the context of family history and lifestyle factors when assessing risk," they added.
Because the study cohort was racially homogeneous, future studies need to characterize PALB2 in other populations, they noted.
Dr. Evans and Dr. Longo are with the National Institute on Aging, Baltimore. These remarks were excerpted from their editorial accompanying Dr. Antoniou’s report (N. Engl. J. Med. 2014;371:566-8 [doi: 10.1056/NEJMe1405784]).
Women with inherited loss-of-function mutations in the PALB2 gene were more than nine times as likely to develop breast cancer, compared with the general population, according to a large multicenter study reported Aug. 6 in the New England Journal of Medicine.
The study showed that women with germline loss-of-function PALB2 mutations had a 14% cumulative risk of breast cancer by age 50 years and a 35% risk by age 70, said Antonis C. Antoniou, Ph.D., of the University of Cambridge, England, and his associates.
"On the basis of our estimates, the breast-cancer risk for a PALB2 mutation carrier, even in the absence of a family history of breast cancer, would be classified as high according to various guidelines. This level of risk may justify adding PALB2 to genetic testing for BRCA1 and BRCA2," the researchers said.
Germline PALB2 mutations affect about 0.08% of the population and are a known risk factor for breast cancer. To better characterize lifetime risk in PALB2 mutation carriers, the researchers studied 154 families in the United Kingdom whose 362 members had inherited harmful truncating, splice, or deletion mutations in PALB2 (N. Engl. J. Med. 2014;371:497-506). The cohort included 311 women, of whom 229 had breast cancer, the researchers said.
After controlling for other familial factors, the risk of breast cancer in PALB2 mutation carriers was 9.47 times (95% confidence interval, 7.16-12.57) greater than in the United Kingdom overall between 1993 and 1997, the investigators reported.
Risk correlated inversely with age and also was affected by family history of breast cancer, they found. Women with the mutation whose first-degree relatives were cancer free had a 33% risk of breast cancer at age 70 years (95% CI, 25%-44%), but this risk was 58% if the women had at least two first-degree relatives who developed breast cancer by age 50 years (95% CI, 50%-66%), Dr. Antoniou and his associates said.
"Our study includes most of the reported families with PALB2 mutation carriers, as well as many not previously reported, but it is still based on small numbers," Dr. Antoniou and associates said. As screening for these mutations enters clinical practice, more families with the PALB2 mutation will be identified and risk estimates can be refined, they said, adding that future studies should evaluate whether the heightened breast cancer surveillance that women with BRCA2 mutations receive can affect outcomes in women who carry the PALB2 loss-of-function mutation.
The study was funded by the European Research Council and 25 other nonprofit and governmental entities in Europe, the United States, Canada, and Australia. Two authors reported being listed on patents related to breast cancer susceptibility genes. The authors disclosed no other conflicts of interest.
Women with inherited loss-of-function mutations in the PALB2 gene were more than nine times as likely to develop breast cancer, compared with the general population, according to a large multicenter study reported Aug. 6 in the New England Journal of Medicine.
The study showed that women with germline loss-of-function PALB2 mutations had a 14% cumulative risk of breast cancer by age 50 years and a 35% risk by age 70, said Antonis C. Antoniou, Ph.D., of the University of Cambridge, England, and his associates.
"On the basis of our estimates, the breast-cancer risk for a PALB2 mutation carrier, even in the absence of a family history of breast cancer, would be classified as high according to various guidelines. This level of risk may justify adding PALB2 to genetic testing for BRCA1 and BRCA2," the researchers said.
Germline PALB2 mutations affect about 0.08% of the population and are a known risk factor for breast cancer. To better characterize lifetime risk in PALB2 mutation carriers, the researchers studied 154 families in the United Kingdom whose 362 members had inherited harmful truncating, splice, or deletion mutations in PALB2 (N. Engl. J. Med. 2014;371:497-506). The cohort included 311 women, of whom 229 had breast cancer, the researchers said.
After controlling for other familial factors, the risk of breast cancer in PALB2 mutation carriers was 9.47 times (95% confidence interval, 7.16-12.57) greater than in the United Kingdom overall between 1993 and 1997, the investigators reported.
Risk correlated inversely with age and also was affected by family history of breast cancer, they found. Women with the mutation whose first-degree relatives were cancer free had a 33% risk of breast cancer at age 70 years (95% CI, 25%-44%), but this risk was 58% if the women had at least two first-degree relatives who developed breast cancer by age 50 years (95% CI, 50%-66%), Dr. Antoniou and his associates said.
"Our study includes most of the reported families with PALB2 mutation carriers, as well as many not previously reported, but it is still based on small numbers," Dr. Antoniou and associates said. As screening for these mutations enters clinical practice, more families with the PALB2 mutation will be identified and risk estimates can be refined, they said, adding that future studies should evaluate whether the heightened breast cancer surveillance that women with BRCA2 mutations receive can affect outcomes in women who carry the PALB2 loss-of-function mutation.
The study was funded by the European Research Council and 25 other nonprofit and governmental entities in Europe, the United States, Canada, and Australia. Two authors reported being listed on patents related to breast cancer susceptibility genes. The authors disclosed no other conflicts of interest.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Inherited loss-of-function mutations in PALB2 significantly increase women’s lifetime risk of breast cancer.
Major finding: Women with inherited loss-of-function mutations in the PALB2 gene were 9.47 times more likely to develop breast cancer than the general population.
Data source: Modified segregation analysis of breast cancer risk among 154 families in the United Kingdom whose 362 members had truncating, splice, or deletion mutations in the PALB2 gene.
Disclosures: The study was funded by the European Research Council and 25 other nonprofit and governmental entities in Europe, the United States, Canada, and Australia. Two authors reported having been listed on patents related to breast cancer susceptibility genes. The authors reported no other conflicts of interest.
Recent use of oral contraceptives linked to breast cancer
Women who recently used oral contraceptives had a 50% greater chance of developing breast cancer than that of women who formerly used or never used oral contraceptives, according to a case-control study published Aug. 1 in Cancer Research.
For the nested case-control study, the researchers compared 1,102 women aged 20-49 years who had been diagnosed with invasive breast cancer from 1990 to 2009 with 21, 755 controls sampled from the same health care delivery system, matched for age, year, enrollment length, and medical chart availability.
Oral contraceptive use within the prior year was associated with an increased breast cancer risk (odds ratio, 1.5; 95% confidence interval, 1.3-1.9) relative to never or former use of oral contraceptives, reported Dr. Elisabeth Beaber at the University of Washington, Seattle, and her associates.
Their findings suggest that risk may vary by oral contraceptive formulation. The investigators found significant associations between breast cancer and recent use of oral contraceptives involving high-dose estrogen (OR, 2.7; 95% CI, 1.1-6.2), ethynodiol diacetate (OR, 2.6; 95% CI, 1.4-4.7), or triphasic dosing with an average of 0.75 mg of norethindrone (OR, 3.1; 95% CI, 1.9-5.1). But other types of oral birth control, including low-dose estrogen oral contraceptives, were not associated with breast cancer (OR, 1.0; 95% CI, 0.6-1.7), Dr. Beaber and her associates noted (Cancer Res. 2014;74:4078-89).
"If confirmed, consideration of the breast cancer risk associated with different oral contraceptive types could impact discussions weighing recognized health benefits and potential risks," they concluded.
The study was funded by the National Cancer Institute. The authors reported no financial conflicts of interest.
Women who recently used oral contraceptives had a 50% greater chance of developing breast cancer than that of women who formerly used or never used oral contraceptives, according to a case-control study published Aug. 1 in Cancer Research.
For the nested case-control study, the researchers compared 1,102 women aged 20-49 years who had been diagnosed with invasive breast cancer from 1990 to 2009 with 21, 755 controls sampled from the same health care delivery system, matched for age, year, enrollment length, and medical chart availability.
Oral contraceptive use within the prior year was associated with an increased breast cancer risk (odds ratio, 1.5; 95% confidence interval, 1.3-1.9) relative to never or former use of oral contraceptives, reported Dr. Elisabeth Beaber at the University of Washington, Seattle, and her associates.
Their findings suggest that risk may vary by oral contraceptive formulation. The investigators found significant associations between breast cancer and recent use of oral contraceptives involving high-dose estrogen (OR, 2.7; 95% CI, 1.1-6.2), ethynodiol diacetate (OR, 2.6; 95% CI, 1.4-4.7), or triphasic dosing with an average of 0.75 mg of norethindrone (OR, 3.1; 95% CI, 1.9-5.1). But other types of oral birth control, including low-dose estrogen oral contraceptives, were not associated with breast cancer (OR, 1.0; 95% CI, 0.6-1.7), Dr. Beaber and her associates noted (Cancer Res. 2014;74:4078-89).
"If confirmed, consideration of the breast cancer risk associated with different oral contraceptive types could impact discussions weighing recognized health benefits and potential risks," they concluded.
The study was funded by the National Cancer Institute. The authors reported no financial conflicts of interest.
Women who recently used oral contraceptives had a 50% greater chance of developing breast cancer than that of women who formerly used or never used oral contraceptives, according to a case-control study published Aug. 1 in Cancer Research.
For the nested case-control study, the researchers compared 1,102 women aged 20-49 years who had been diagnosed with invasive breast cancer from 1990 to 2009 with 21, 755 controls sampled from the same health care delivery system, matched for age, year, enrollment length, and medical chart availability.
Oral contraceptive use within the prior year was associated with an increased breast cancer risk (odds ratio, 1.5; 95% confidence interval, 1.3-1.9) relative to never or former use of oral contraceptives, reported Dr. Elisabeth Beaber at the University of Washington, Seattle, and her associates.
Their findings suggest that risk may vary by oral contraceptive formulation. The investigators found significant associations between breast cancer and recent use of oral contraceptives involving high-dose estrogen (OR, 2.7; 95% CI, 1.1-6.2), ethynodiol diacetate (OR, 2.6; 95% CI, 1.4-4.7), or triphasic dosing with an average of 0.75 mg of norethindrone (OR, 3.1; 95% CI, 1.9-5.1). But other types of oral birth control, including low-dose estrogen oral contraceptives, were not associated with breast cancer (OR, 1.0; 95% CI, 0.6-1.7), Dr. Beaber and her associates noted (Cancer Res. 2014;74:4078-89).
"If confirmed, consideration of the breast cancer risk associated with different oral contraceptive types could impact discussions weighing recognized health benefits and potential risks," they concluded.
The study was funded by the National Cancer Institute. The authors reported no financial conflicts of interest.
FROM CANCER RESEARCH
Key clinical point: Recent use of oral contraceptives may increase breast cancer risk.
Major finding: Oral contraceptive use within the prior year was associated with an increased breast cancer risk (OR, 1.5; 95% CI, 1.3–1.9) relative to never or former use of oral contraceptives.
Data source: Nested case-control study of 1,102 women aged 20-49 years diagnosed with invasive breast cancer, compared with 21,755 controls.
Disclosures: The study was funded by The National Cancer Institute. The authors reported no financial conflicts of interest.
Encouraging data at ASCO 2014 for survival and fertility in some cancers
The American Society of Clinical Oncology marked its 50th anniversary at this year’s annual conference in Chicago, where it showcased the latest scientific advances in oncology and explored the translation of research findings into practice under its umbrella theme, Science and Society.
Drug combo extends survival by more than 1 year in metastatic prostate cancer patients
Key clinical finding Adding docetaxel to hormonal therapy at the time of diagnosis of metastatic prostate cancer extends survival. Major finding Patients receiving docetaxel and androgen deprivation therapy at the time of diagnoses had median overall survival that was 13.6 months longer than men who received androgen deprivation therapy alone. Data source Randomized trial in 790 men with newly diagnosed metastatic hormone-sensitive prostate cancer...
Click on the PDF icon at the top of this introduction to read the full article.
The American Society of Clinical Oncology marked its 50th anniversary at this year’s annual conference in Chicago, where it showcased the latest scientific advances in oncology and explored the translation of research findings into practice under its umbrella theme, Science and Society.
Drug combo extends survival by more than 1 year in metastatic prostate cancer patients
Key clinical finding Adding docetaxel to hormonal therapy at the time of diagnosis of metastatic prostate cancer extends survival. Major finding Patients receiving docetaxel and androgen deprivation therapy at the time of diagnoses had median overall survival that was 13.6 months longer than men who received androgen deprivation therapy alone. Data source Randomized trial in 790 men with newly diagnosed metastatic hormone-sensitive prostate cancer...
Click on the PDF icon at the top of this introduction to read the full article.
The American Society of Clinical Oncology marked its 50th anniversary at this year’s annual conference in Chicago, where it showcased the latest scientific advances in oncology and explored the translation of research findings into practice under its umbrella theme, Science and Society.
Drug combo extends survival by more than 1 year in metastatic prostate cancer patients
Key clinical finding Adding docetaxel to hormonal therapy at the time of diagnosis of metastatic prostate cancer extends survival. Major finding Patients receiving docetaxel and androgen deprivation therapy at the time of diagnoses had median overall survival that was 13.6 months longer than men who received androgen deprivation therapy alone. Data source Randomized trial in 790 men with newly diagnosed metastatic hormone-sensitive prostate cancer...
Click on the PDF icon at the top of this introduction to read the full article.
Early results show promise of topical tamoxifen for women with DCIS
The encouraging results of a small study of women with ductal carcinoma in situ comparing oral tamoxifen to a gel formulation of a tamoxifen metabolite support further testing of local transdermal therapy, investigators report.
The data "support the notion that local transdermal drug delivery to the breast will achieve sufficient drug concentrations to be effective, with low systemic exposure," wrote the authors, led by Dr. Oukseub Lee of the Robert H. Lurie Cancer Center of Northwestern University, Chicago. The study was published on July 15 in Clinical Cancer Research (Clin. Cancer Res. 2014;20:3672-82).
The randomized, double-blind, phase II study compared transdermal application of a gel containing 4-hydroxytamoxifen (4-OHT), an antiestrogenic metabolite of tamoxifen (4 mg/day), to oral tamoxifen (20 mg/day) in pre- and postmenopausal women with estrogen receptor–positive ductal carcinoma in situ (DCIS). Women were treated for a median of 6 weeks, between the time of the diagnostic core needle biopsy and surgical excision.
Among the 26 women who completed the study (14 on oral treatment and 12 on topical treatment), the drop in a marker for cancer cell growth (Ki-67) in the breast tissue was similar in both groups – based on comparisons of tissue from the core biopsy and the surgical excision. The mean concentration of 4-OHT in the breasts was also similar in the two groups, but mean plasma 4-OHT levels were about fivefold higher among those on oral tamoxifen (1.1 ng/mL vs. 0.2 ng/mL). Increases in coagulation-related proteins were detected among those on oral tamoxifen, but not in the women on topical treatment. The rate of hot flashes was not different in the two groups.
"Delivering the drug through a gel, if proven effective in larger trials, could potentially replace oral tamoxifen for breast cancer prevention and DCIS and encourage many more women to take it," another author, surgical oncologist Dr. Seema Khan, said in a press release on the results issued by Northwestern on July 15. "The gel minimized exposure to the rest of the body and concentrated the drug in the breast where it is needed, ... which should avoid potential blood clots as well as an elevated risk for uterine cancer," added Dr. Khan, professor of surgery and coleader of the breast cancer program at the Lurie cancer center.
The authors, which included others from Northwestern University; Washington University, St. Louis; and the National Cancer Institute, Bethesda, Md.; had no disclosures. The study was funded by the National Institutes of Health and BHR Pharma.
The encouraging results of a small study of women with ductal carcinoma in situ comparing oral tamoxifen to a gel formulation of a tamoxifen metabolite support further testing of local transdermal therapy, investigators report.
The data "support the notion that local transdermal drug delivery to the breast will achieve sufficient drug concentrations to be effective, with low systemic exposure," wrote the authors, led by Dr. Oukseub Lee of the Robert H. Lurie Cancer Center of Northwestern University, Chicago. The study was published on July 15 in Clinical Cancer Research (Clin. Cancer Res. 2014;20:3672-82).
The randomized, double-blind, phase II study compared transdermal application of a gel containing 4-hydroxytamoxifen (4-OHT), an antiestrogenic metabolite of tamoxifen (4 mg/day), to oral tamoxifen (20 mg/day) in pre- and postmenopausal women with estrogen receptor–positive ductal carcinoma in situ (DCIS). Women were treated for a median of 6 weeks, between the time of the diagnostic core needle biopsy and surgical excision.
Among the 26 women who completed the study (14 on oral treatment and 12 on topical treatment), the drop in a marker for cancer cell growth (Ki-67) in the breast tissue was similar in both groups – based on comparisons of tissue from the core biopsy and the surgical excision. The mean concentration of 4-OHT in the breasts was also similar in the two groups, but mean plasma 4-OHT levels were about fivefold higher among those on oral tamoxifen (1.1 ng/mL vs. 0.2 ng/mL). Increases in coagulation-related proteins were detected among those on oral tamoxifen, but not in the women on topical treatment. The rate of hot flashes was not different in the two groups.
"Delivering the drug through a gel, if proven effective in larger trials, could potentially replace oral tamoxifen for breast cancer prevention and DCIS and encourage many more women to take it," another author, surgical oncologist Dr. Seema Khan, said in a press release on the results issued by Northwestern on July 15. "The gel minimized exposure to the rest of the body and concentrated the drug in the breast where it is needed, ... which should avoid potential blood clots as well as an elevated risk for uterine cancer," added Dr. Khan, professor of surgery and coleader of the breast cancer program at the Lurie cancer center.
The authors, which included others from Northwestern University; Washington University, St. Louis; and the National Cancer Institute, Bethesda, Md.; had no disclosures. The study was funded by the National Institutes of Health and BHR Pharma.
The encouraging results of a small study of women with ductal carcinoma in situ comparing oral tamoxifen to a gel formulation of a tamoxifen metabolite support further testing of local transdermal therapy, investigators report.
The data "support the notion that local transdermal drug delivery to the breast will achieve sufficient drug concentrations to be effective, with low systemic exposure," wrote the authors, led by Dr. Oukseub Lee of the Robert H. Lurie Cancer Center of Northwestern University, Chicago. The study was published on July 15 in Clinical Cancer Research (Clin. Cancer Res. 2014;20:3672-82).
The randomized, double-blind, phase II study compared transdermal application of a gel containing 4-hydroxytamoxifen (4-OHT), an antiestrogenic metabolite of tamoxifen (4 mg/day), to oral tamoxifen (20 mg/day) in pre- and postmenopausal women with estrogen receptor–positive ductal carcinoma in situ (DCIS). Women were treated for a median of 6 weeks, between the time of the diagnostic core needle biopsy and surgical excision.
Among the 26 women who completed the study (14 on oral treatment and 12 on topical treatment), the drop in a marker for cancer cell growth (Ki-67) in the breast tissue was similar in both groups – based on comparisons of tissue from the core biopsy and the surgical excision. The mean concentration of 4-OHT in the breasts was also similar in the two groups, but mean plasma 4-OHT levels were about fivefold higher among those on oral tamoxifen (1.1 ng/mL vs. 0.2 ng/mL). Increases in coagulation-related proteins were detected among those on oral tamoxifen, but not in the women on topical treatment. The rate of hot flashes was not different in the two groups.
"Delivering the drug through a gel, if proven effective in larger trials, could potentially replace oral tamoxifen for breast cancer prevention and DCIS and encourage many more women to take it," another author, surgical oncologist Dr. Seema Khan, said in a press release on the results issued by Northwestern on July 15. "The gel minimized exposure to the rest of the body and concentrated the drug in the breast where it is needed, ... which should avoid potential blood clots as well as an elevated risk for uterine cancer," added Dr. Khan, professor of surgery and coleader of the breast cancer program at the Lurie cancer center.
The authors, which included others from Northwestern University; Washington University, St. Louis; and the National Cancer Institute, Bethesda, Md.; had no disclosures. The study was funded by the National Institutes of Health and BHR Pharma.
FROM CLINICAL CANCER RESEARCH
Key clinical point: The use of a topical formulation of tamoxifen applied directly to the breast could achieve the same benefits as oral tamoxifen, but with fewer systemic effects, in the treatment of ductal carcinoma in situ (DCIS) or prevention of breast cancer.
Major finding: Concentrations of the tamoxifen metabolite 4-OHT and evidence of anticancer effects in breast tissue were comparable after 6-10 weeks of treatment in women treated with a gel formulation of 4-OHT and those treated with oral tamoxifen, but coagulation markers and 4-OHT levels in the plasma were higher among those on oral medication.
Data source: A phase II, double-blind, placebo-controlled study compared antiproliferative effects, breast tissue and plasma levels of 4-OHT, and coagulation parameters in 26 women with DCIS, randomized to daily treatment with 4-OHT gel applied to both breasts or oral tamoxifen, after 6-10 weeks of treatment, ending the day before surgical excision.
Disclosures: The authors had no disclosures. The study was funded by the National Institutes of Health and BHR Pharma.
Early results show promise of topical tamoxifen for women with DCIS
The encouraging results of a small study of women with ductal carcinoma in situ comparing oral tamoxifen to a gel formulation of a tamoxifen metabolite support further testing of local transdermal therapy, investigators report.
The data "support the notion that local transdermal drug delivery to the breast will achieve sufficient drug concentrations to be effective, with low systemic exposure," wrote the authors, led by Dr. Oukseub Lee of the Robert H. Lurie Cancer Center of Northwestern University, Chicago. The study was published on July 15 in Clinical Cancer Research (Clin. Cancer Res. 2014;20:3672-82).
The randomized, double-blind, phase II study compared transdermal application of a gel containing 4-hydroxytamoxifen (4-OHT), an antiestrogenic metabolite of tamoxifen (4 mg/day), to oral tamoxifen (20 mg/day) in pre- and postmenopausal women with estrogen receptor–positive ductal carcinoma in situ (DCIS). Women were treated for a median of 6 weeks, between the time of the diagnostic core needle biopsy and surgical excision.
Among the 26 women who completed the study (14 on oral treatment and 12 on topical treatment), the drop in a marker for cancer cell growth (Ki-67) in the breast tissue was similar in both groups – based on comparisons of tissue from the core biopsy and the surgical excision. The mean concentration of 4-OHT in the breasts was also similar in the two groups, but mean plasma 4-OHT levels were about fivefold higher among those on oral tamoxifen (1.1 ng/mL vs. 0.2 ng/mL). Increases in coagulation-related proteins were detected among those on oral tamoxifen, but not in the women on topical treatment. The rate of hot flashes was not different in the two groups.
"Delivering the drug through a gel, if proven effective in larger trials, could potentially replace oral tamoxifen for breast cancer prevention and DCIS and encourage many more women to take it," another author, surgical oncologist Dr. Seema Khan, said in a press release on the results issued by Northwestern on July 15. "The gel minimized exposure to the rest of the body and concentrated the drug in the breast where it is needed, ... which should avoid potential blood clots as well as an elevated risk for uterine cancer," added Dr. Khan, professor of surgery and coleader of the breast cancer program at the Lurie cancer center.
The authors, which included others from Northwestern University; Washington University, St. Louis; and the National Cancer Institute, Bethesda, Md.; had no disclosures. The study was funded by the National Institutes of Health and BHR Pharma.
The encouraging results of a small study of women with ductal carcinoma in situ comparing oral tamoxifen to a gel formulation of a tamoxifen metabolite support further testing of local transdermal therapy, investigators report.
The data "support the notion that local transdermal drug delivery to the breast will achieve sufficient drug concentrations to be effective, with low systemic exposure," wrote the authors, led by Dr. Oukseub Lee of the Robert H. Lurie Cancer Center of Northwestern University, Chicago. The study was published on July 15 in Clinical Cancer Research (Clin. Cancer Res. 2014;20:3672-82).
The randomized, double-blind, phase II study compared transdermal application of a gel containing 4-hydroxytamoxifen (4-OHT), an antiestrogenic metabolite of tamoxifen (4 mg/day), to oral tamoxifen (20 mg/day) in pre- and postmenopausal women with estrogen receptor–positive ductal carcinoma in situ (DCIS). Women were treated for a median of 6 weeks, between the time of the diagnostic core needle biopsy and surgical excision.
Among the 26 women who completed the study (14 on oral treatment and 12 on topical treatment), the drop in a marker for cancer cell growth (Ki-67) in the breast tissue was similar in both groups – based on comparisons of tissue from the core biopsy and the surgical excision. The mean concentration of 4-OHT in the breasts was also similar in the two groups, but mean plasma 4-OHT levels were about fivefold higher among those on oral tamoxifen (1.1 ng/mL vs. 0.2 ng/mL). Increases in coagulation-related proteins were detected among those on oral tamoxifen, but not in the women on topical treatment. The rate of hot flashes was not different in the two groups.
"Delivering the drug through a gel, if proven effective in larger trials, could potentially replace oral tamoxifen for breast cancer prevention and DCIS and encourage many more women to take it," another author, surgical oncologist Dr. Seema Khan, said in a press release on the results issued by Northwestern on July 15. "The gel minimized exposure to the rest of the body and concentrated the drug in the breast where it is needed, ... which should avoid potential blood clots as well as an elevated risk for uterine cancer," added Dr. Khan, professor of surgery and coleader of the breast cancer program at the Lurie cancer center.
The authors, which included others from Northwestern University; Washington University, St. Louis; and the National Cancer Institute, Bethesda, Md.; had no disclosures. The study was funded by the National Institutes of Health and BHR Pharma.
The encouraging results of a small study of women with ductal carcinoma in situ comparing oral tamoxifen to a gel formulation of a tamoxifen metabolite support further testing of local transdermal therapy, investigators report.
The data "support the notion that local transdermal drug delivery to the breast will achieve sufficient drug concentrations to be effective, with low systemic exposure," wrote the authors, led by Dr. Oukseub Lee of the Robert H. Lurie Cancer Center of Northwestern University, Chicago. The study was published on July 15 in Clinical Cancer Research (Clin. Cancer Res. 2014;20:3672-82).
The randomized, double-blind, phase II study compared transdermal application of a gel containing 4-hydroxytamoxifen (4-OHT), an antiestrogenic metabolite of tamoxifen (4 mg/day), to oral tamoxifen (20 mg/day) in pre- and postmenopausal women with estrogen receptor–positive ductal carcinoma in situ (DCIS). Women were treated for a median of 6 weeks, between the time of the diagnostic core needle biopsy and surgical excision.
Among the 26 women who completed the study (14 on oral treatment and 12 on topical treatment), the drop in a marker for cancer cell growth (Ki-67) in the breast tissue was similar in both groups – based on comparisons of tissue from the core biopsy and the surgical excision. The mean concentration of 4-OHT in the breasts was also similar in the two groups, but mean plasma 4-OHT levels were about fivefold higher among those on oral tamoxifen (1.1 ng/mL vs. 0.2 ng/mL). Increases in coagulation-related proteins were detected among those on oral tamoxifen, but not in the women on topical treatment. The rate of hot flashes was not different in the two groups.
"Delivering the drug through a gel, if proven effective in larger trials, could potentially replace oral tamoxifen for breast cancer prevention and DCIS and encourage many more women to take it," another author, surgical oncologist Dr. Seema Khan, said in a press release on the results issued by Northwestern on July 15. "The gel minimized exposure to the rest of the body and concentrated the drug in the breast where it is needed, ... which should avoid potential blood clots as well as an elevated risk for uterine cancer," added Dr. Khan, professor of surgery and coleader of the breast cancer program at the Lurie cancer center.
The authors, which included others from Northwestern University; Washington University, St. Louis; and the National Cancer Institute, Bethesda, Md.; had no disclosures. The study was funded by the National Institutes of Health and BHR Pharma.
FROM CLINICAL CANCER RESEARCH
Key clinical point: The use of a topical formulation of tamoxifen applied directly to the breast could achieve the same benefits as oral tamoxifen, but with fewer systemic effects, in the treatment of ductal carcinoma in situ (DCIS) or prevention of breast cancer.
Major finding: Concentrations of the tamoxifen metabolite 4-OHT and evidence of anticancer effects in breast tissue were comparable after 6-10 weeks of treatment in women treated with a gel formulation of 4-OHT and those treated with oral tamoxifen, but coagulation markers and 4-OHT levels in the plasma were higher among those on oral medication.
Data source: A phase II, double-blind, placebo-controlled study compared antiproliferative effects, breast tissue and plasma levels of 4-OHT, and coagulation parameters in 26 women with DCIS, randomized to daily treatment with 4-OHT gel applied to both breasts or oral tamoxifen, after 6-10 weeks of treatment, ending the day before surgical excision.
Disclosures: The authors had no disclosures. The study was funded by the National Institutes of Health and BHR Pharma.
Survival benefit from contralateral prophylactic mastectomy small
The absolute 20-year survival benefit from contralateral prophylactic mastectomy stands at less than 1%, regardless of age, estrogen receptor status, and cancer stage, a decision analysis demonstrated.
"Long-term survival in women with unilateral breast cancer treated with or without CPM depends upon several factors, including mortality of the primary breast cancer, risk of CBC [contralateral breast cancer], stage and mortality of the CBC, and the individual patient’s overall life expectancy," wrote Dr. Pamela R. Portschy of the University of Minnesota, Minneapolis.
The report was published July 16 in the Journal of the National Cancer Institute.
"Prospective randomized trials comparing CPM with no CPM are not feasible. Retrospective studies evaluating a potential survival benefit with CPM are limited by short follow-up, potential selection bias, and lack of important clinical information," noted Dr. Portschy and her associates.
They limited their analysis to women with stage I and II breast cancer without BRCA mutations. They developed a Markov model to simulate survival outcomes among those who did and did not have contralateral prophylactic mastectomy (CPM), and they used published studies to estimate probabilities for developing CBC, dying from CBC, dying from primary breast cancer, and age-specific mortality rates. Data were extracted from numerous sources including Surveillance, Epidemiology, and End Results (SEER), the Early Breast Cancer Trialists’ Collaborative Group, and the Oregon State Cancer Registry.
The researchers estimated the 20-year overall survival and life expectancy, but not quality of life or cost, and their analysis considered variation in age, estrogen receptor status, and cancer stage (J. Natl. Cancer Inst. 2014 July 16 [doi:10.1093/jnci/dju160]).
The predicted life expectancy gain from CPM ranged from .13 to .59 years for women with stage I breast cancer, and .08 to .29 years for those with stage II breast cancer. CPM conferred a life expectancy benefit among younger women and among those who had stage I and estrogen receptor–positive disease. "The potential benefit of CPM was consistently lower for patients with stage II breast cancer because of the worse prognosis associated with the primary breast cancer," the researchers wrote. "Similarly, the potential benefits of CPM are more modest for older women because they have relatively fewer years remaining of [life expectancy]."
Dr. Portschy and her associates could not identify any cohort of women that had a greater than 1% absolute survival difference at 20 years. In fact, the predicted 20-year survival differences ranged from .56 to .94% for women with stage I breast cancer and .36 to .61% for those with stage II breast cancer.
The researchers acknowledged limitations of the study, including the fact that the results "do not apply to BRCA gene mutation carriers with unilateral breast cancer who have a cumulative 10-year risk of CBC of approximately 30% to 40%," they wrote. "The outcomes of this analysis were limited to overall and disease-specific survival; we did not evaluate other important outcomes such as surgical complications and quality of life. Also, we assumed the mortality of CBC was the same as the mortality of the index cancer reported by SEER."
They also noted that survival is not the only potential benefit of a cancer risk reduction strategy. "Effects on cancer-related anxiety, cosmesis, and self-image are also important in the decision-making process," they wrote. "For some women, the negative impact of CPM on quality of life may outweigh a potential survival benefit. For others who are very anxious about CBC, CPM may result in a psychological benefit even if survival benefits are minimal."
They concluded that the survival estimates from their Markov model "may be useful for physicians and breast cancer patients to arrive at evidence-based informed decisions regarding CPM. Moreover, the use of accurate and easily understood decision aids may reverse some of the mastectomy trends recently observed in the United States."
The researchers stated that they had no relevant financial conflicts to disclose.
The decision of whether or not to undergo a contralateral prophylactic mastectomy after being treated for breast cancer is a difficult one for many women. The goal of such aggressive therapy is to lower the likelihood of a second primary carcinoma. The downsides are operative risk, impairment of the woman’s self-image, and short-term and long-term morbidities.
This is a well done analysis from an experienced group of investigators and is based on the currently available data. Given the JNCI audience, we shall refrain from niggling points about modeling. Rather, we will stick to the big picture and clinical implications. Although the survival benefit from CPM is small as demonstrated in this model, it is greater than zero, which suggests that for some patients even that small gain may be enough to make it a not unreasonable choice.
From a societal perspective, which was not addressed by Portschy et al., the associated costs of CPM, including the procedure, its complications, reconstruction, and perhaps psychotherapy, may outweigh the modest benefit CPM provides. The small denominator of the cost-effectiveness ratio, were one to be calculated, would imply that the ratio would be very high, making CPM a suboptimal use of health care dollars. Further, we suspect that adding quality of life to the analysis would diminish the benefit and well might turn it into a net harm, in particular for patients with high concern for negative impact of CPM on cosmesis, self image, and morbidity. However, in a fraction of patients who are very troubled by a 0.7% risk of a second, contralateral cancer, CPM might provide an acceptable benefit. The balance between harm and benefit depends on the patient’s preferences and highlights the importance of capturing the patient’s values and expectations before considering CPM.
Of course, these conclusions are based on analysis of women who are at average risk for a contralateral second primary. In women at substantially higher risk (based either on family history or genetics), the benefit of CPM might be far greater, and CPM might be a good choice for the patient or for society.
Dr. Stephen G. Pauker and Dr. Mohamed Alseiari are with the division of clinical decision making in the department of medicine at Tufts Medical Center, Boston. They reported no relevant financial conflicts. This was excerpted from an editorial (J. Natl. Cancer Inst. 2014 July 16 [doi:10.1093/jnci/dju175]).
The decision of whether or not to undergo a contralateral prophylactic mastectomy after being treated for breast cancer is a difficult one for many women. The goal of such aggressive therapy is to lower the likelihood of a second primary carcinoma. The downsides are operative risk, impairment of the woman’s self-image, and short-term and long-term morbidities.
This is a well done analysis from an experienced group of investigators and is based on the currently available data. Given the JNCI audience, we shall refrain from niggling points about modeling. Rather, we will stick to the big picture and clinical implications. Although the survival benefit from CPM is small as demonstrated in this model, it is greater than zero, which suggests that for some patients even that small gain may be enough to make it a not unreasonable choice.
From a societal perspective, which was not addressed by Portschy et al., the associated costs of CPM, including the procedure, its complications, reconstruction, and perhaps psychotherapy, may outweigh the modest benefit CPM provides. The small denominator of the cost-effectiveness ratio, were one to be calculated, would imply that the ratio would be very high, making CPM a suboptimal use of health care dollars. Further, we suspect that adding quality of life to the analysis would diminish the benefit and well might turn it into a net harm, in particular for patients with high concern for negative impact of CPM on cosmesis, self image, and morbidity. However, in a fraction of patients who are very troubled by a 0.7% risk of a second, contralateral cancer, CPM might provide an acceptable benefit. The balance between harm and benefit depends on the patient’s preferences and highlights the importance of capturing the patient’s values and expectations before considering CPM.
Of course, these conclusions are based on analysis of women who are at average risk for a contralateral second primary. In women at substantially higher risk (based either on family history or genetics), the benefit of CPM might be far greater, and CPM might be a good choice for the patient or for society.
Dr. Stephen G. Pauker and Dr. Mohamed Alseiari are with the division of clinical decision making in the department of medicine at Tufts Medical Center, Boston. They reported no relevant financial conflicts. This was excerpted from an editorial (J. Natl. Cancer Inst. 2014 July 16 [doi:10.1093/jnci/dju175]).
The decision of whether or not to undergo a contralateral prophylactic mastectomy after being treated for breast cancer is a difficult one for many women. The goal of such aggressive therapy is to lower the likelihood of a second primary carcinoma. The downsides are operative risk, impairment of the woman’s self-image, and short-term and long-term morbidities.
This is a well done analysis from an experienced group of investigators and is based on the currently available data. Given the JNCI audience, we shall refrain from niggling points about modeling. Rather, we will stick to the big picture and clinical implications. Although the survival benefit from CPM is small as demonstrated in this model, it is greater than zero, which suggests that for some patients even that small gain may be enough to make it a not unreasonable choice.
From a societal perspective, which was not addressed by Portschy et al., the associated costs of CPM, including the procedure, its complications, reconstruction, and perhaps psychotherapy, may outweigh the modest benefit CPM provides. The small denominator of the cost-effectiveness ratio, were one to be calculated, would imply that the ratio would be very high, making CPM a suboptimal use of health care dollars. Further, we suspect that adding quality of life to the analysis would diminish the benefit and well might turn it into a net harm, in particular for patients with high concern for negative impact of CPM on cosmesis, self image, and morbidity. However, in a fraction of patients who are very troubled by a 0.7% risk of a second, contralateral cancer, CPM might provide an acceptable benefit. The balance between harm and benefit depends on the patient’s preferences and highlights the importance of capturing the patient’s values and expectations before considering CPM.
Of course, these conclusions are based on analysis of women who are at average risk for a contralateral second primary. In women at substantially higher risk (based either on family history or genetics), the benefit of CPM might be far greater, and CPM might be a good choice for the patient or for society.
Dr. Stephen G. Pauker and Dr. Mohamed Alseiari are with the division of clinical decision making in the department of medicine at Tufts Medical Center, Boston. They reported no relevant financial conflicts. This was excerpted from an editorial (J. Natl. Cancer Inst. 2014 July 16 [doi:10.1093/jnci/dju175]).
The absolute 20-year survival benefit from contralateral prophylactic mastectomy stands at less than 1%, regardless of age, estrogen receptor status, and cancer stage, a decision analysis demonstrated.
"Long-term survival in women with unilateral breast cancer treated with or without CPM depends upon several factors, including mortality of the primary breast cancer, risk of CBC [contralateral breast cancer], stage and mortality of the CBC, and the individual patient’s overall life expectancy," wrote Dr. Pamela R. Portschy of the University of Minnesota, Minneapolis.
The report was published July 16 in the Journal of the National Cancer Institute.
"Prospective randomized trials comparing CPM with no CPM are not feasible. Retrospective studies evaluating a potential survival benefit with CPM are limited by short follow-up, potential selection bias, and lack of important clinical information," noted Dr. Portschy and her associates.
They limited their analysis to women with stage I and II breast cancer without BRCA mutations. They developed a Markov model to simulate survival outcomes among those who did and did not have contralateral prophylactic mastectomy (CPM), and they used published studies to estimate probabilities for developing CBC, dying from CBC, dying from primary breast cancer, and age-specific mortality rates. Data were extracted from numerous sources including Surveillance, Epidemiology, and End Results (SEER), the Early Breast Cancer Trialists’ Collaborative Group, and the Oregon State Cancer Registry.
The researchers estimated the 20-year overall survival and life expectancy, but not quality of life or cost, and their analysis considered variation in age, estrogen receptor status, and cancer stage (J. Natl. Cancer Inst. 2014 July 16 [doi:10.1093/jnci/dju160]).
The predicted life expectancy gain from CPM ranged from .13 to .59 years for women with stage I breast cancer, and .08 to .29 years for those with stage II breast cancer. CPM conferred a life expectancy benefit among younger women and among those who had stage I and estrogen receptor–positive disease. "The potential benefit of CPM was consistently lower for patients with stage II breast cancer because of the worse prognosis associated with the primary breast cancer," the researchers wrote. "Similarly, the potential benefits of CPM are more modest for older women because they have relatively fewer years remaining of [life expectancy]."
Dr. Portschy and her associates could not identify any cohort of women that had a greater than 1% absolute survival difference at 20 years. In fact, the predicted 20-year survival differences ranged from .56 to .94% for women with stage I breast cancer and .36 to .61% for those with stage II breast cancer.
The researchers acknowledged limitations of the study, including the fact that the results "do not apply to BRCA gene mutation carriers with unilateral breast cancer who have a cumulative 10-year risk of CBC of approximately 30% to 40%," they wrote. "The outcomes of this analysis were limited to overall and disease-specific survival; we did not evaluate other important outcomes such as surgical complications and quality of life. Also, we assumed the mortality of CBC was the same as the mortality of the index cancer reported by SEER."
They also noted that survival is not the only potential benefit of a cancer risk reduction strategy. "Effects on cancer-related anxiety, cosmesis, and self-image are also important in the decision-making process," they wrote. "For some women, the negative impact of CPM on quality of life may outweigh a potential survival benefit. For others who are very anxious about CBC, CPM may result in a psychological benefit even if survival benefits are minimal."
They concluded that the survival estimates from their Markov model "may be useful for physicians and breast cancer patients to arrive at evidence-based informed decisions regarding CPM. Moreover, the use of accurate and easily understood decision aids may reverse some of the mastectomy trends recently observed in the United States."
The researchers stated that they had no relevant financial conflicts to disclose.
The absolute 20-year survival benefit from contralateral prophylactic mastectomy stands at less than 1%, regardless of age, estrogen receptor status, and cancer stage, a decision analysis demonstrated.
"Long-term survival in women with unilateral breast cancer treated with or without CPM depends upon several factors, including mortality of the primary breast cancer, risk of CBC [contralateral breast cancer], stage and mortality of the CBC, and the individual patient’s overall life expectancy," wrote Dr. Pamela R. Portschy of the University of Minnesota, Minneapolis.
The report was published July 16 in the Journal of the National Cancer Institute.
"Prospective randomized trials comparing CPM with no CPM are not feasible. Retrospective studies evaluating a potential survival benefit with CPM are limited by short follow-up, potential selection bias, and lack of important clinical information," noted Dr. Portschy and her associates.
They limited their analysis to women with stage I and II breast cancer without BRCA mutations. They developed a Markov model to simulate survival outcomes among those who did and did not have contralateral prophylactic mastectomy (CPM), and they used published studies to estimate probabilities for developing CBC, dying from CBC, dying from primary breast cancer, and age-specific mortality rates. Data were extracted from numerous sources including Surveillance, Epidemiology, and End Results (SEER), the Early Breast Cancer Trialists’ Collaborative Group, and the Oregon State Cancer Registry.
The researchers estimated the 20-year overall survival and life expectancy, but not quality of life or cost, and their analysis considered variation in age, estrogen receptor status, and cancer stage (J. Natl. Cancer Inst. 2014 July 16 [doi:10.1093/jnci/dju160]).
The predicted life expectancy gain from CPM ranged from .13 to .59 years for women with stage I breast cancer, and .08 to .29 years for those with stage II breast cancer. CPM conferred a life expectancy benefit among younger women and among those who had stage I and estrogen receptor–positive disease. "The potential benefit of CPM was consistently lower for patients with stage II breast cancer because of the worse prognosis associated with the primary breast cancer," the researchers wrote. "Similarly, the potential benefits of CPM are more modest for older women because they have relatively fewer years remaining of [life expectancy]."
Dr. Portschy and her associates could not identify any cohort of women that had a greater than 1% absolute survival difference at 20 years. In fact, the predicted 20-year survival differences ranged from .56 to .94% for women with stage I breast cancer and .36 to .61% for those with stage II breast cancer.
The researchers acknowledged limitations of the study, including the fact that the results "do not apply to BRCA gene mutation carriers with unilateral breast cancer who have a cumulative 10-year risk of CBC of approximately 30% to 40%," they wrote. "The outcomes of this analysis were limited to overall and disease-specific survival; we did not evaluate other important outcomes such as surgical complications and quality of life. Also, we assumed the mortality of CBC was the same as the mortality of the index cancer reported by SEER."
They also noted that survival is not the only potential benefit of a cancer risk reduction strategy. "Effects on cancer-related anxiety, cosmesis, and self-image are also important in the decision-making process," they wrote. "For some women, the negative impact of CPM on quality of life may outweigh a potential survival benefit. For others who are very anxious about CBC, CPM may result in a psychological benefit even if survival benefits are minimal."
They concluded that the survival estimates from their Markov model "may be useful for physicians and breast cancer patients to arrive at evidence-based informed decisions regarding CPM. Moreover, the use of accurate and easily understood decision aids may reverse some of the mastectomy trends recently observed in the United States."
The researchers stated that they had no relevant financial conflicts to disclose.
FROM THE JOURNAL OF THE NATIONAL CANCER INSTITUTE
Key clinical point: The long-term survival benefit of contralateral prophylactic mastectomy is small.
Major Finding: The absolute 20-year survival benefit from contralateral prophylactic mastectomy was less than 1% among all age groups, regardless of estrogen receptor status and cancer stage.
Data Source: Results from a Markov model designed to simulate 20-year survival outcomes among those who did and did not have CPM, with considerations for variation in age, estrogen receptor status, and cancer stage.
Disclosures: The researchers disclosed no relevant financial conflicts.
Extending Therapy for Breast Cancer
For more presentations from the 9th Annual Meeting of the Association of VA Hematology/Oncology (AVAHO), click here: AVAHO Meeting Presentations
For more presentations from the 9th Annual Meeting of the Association of VA Hematology/Oncology (AVAHO), click here: AVAHO Meeting Presentations
For more presentations from the 9th Annual Meeting of the Association of VA Hematology/Oncology (AVAHO), click here: AVAHO Meeting Presentations
New Breast Cancer Research Group Aims To Improve Veteran Survival Rates
Over 200,000 new cases of breast cancer are diagnosed in the U.S. annually, according to the National Cancer Institute. Dr. Anita Aggarwal, an oncologist at the Washington, DC VAMC, recently completed an extensive study to compare male and female breast cancer in VA patients. The study found that males with breast cancer had higher stage and grade at presentation and higher mortality compared with females. But, when adjusted for age, stage, and grade, males had better survival rates.
Federal Practitioner talked with Dr. Aggarwal about the new breast cancer research group she is currently developing at the Washington, DC VAMC. Dr. Aggarwal’s hope is to help doctors in the federal health system to identify etiology, biology, and improve treatment of both male and female patients with breast cancer.
Federal Practitioner: What is a breast cancer research group, and why do you think one needs to be created at the VA?
Anita Aggarwal, MD: I would like to build a breast cancer research group with the help of all oncologists and health professionals who take care of patients with breast cancer at all VAMCs nationwide. From my retrospective comparison study, breast cancer in our veterans seems to be different than in the general population. The goal of this research group will be to build a data bank with all the pertinent information as well as tissue gene profiling. This will help us to diagnose them early and treat accordingly in a timely fashion.
FP: As more women join the military, do you think breast cancer treatment at the VA will change?
AA: As the number of female veterans increases, I suspect we will see an increase in the number of female patients with breast cancer. As reported by the 2012 Women’s Task Force, women are now the fastest growing cohort within the veteran community. In 2011, there were about 1.8 million women veterans, which is about 8% of the 22.2 million vets in the VA system. That is expected to increase to 2 million in 2020, at which time women will make up to 10.7% of the total vet population. To accommodate these changing needs, the VHA made women’s health programs a priority in 2007, including a recommendation to improve access to screening, mammograms, and related breast care services. The treatment of breast cancer is becoming more personalized with the advent of new, targeted therapies. The treatment will change if we can identify different biological targets in veterans with breast cancer.
FP: Do you think all veterans, male and female, are more susceptible to breast cancer than is the general population?
AA: In general, incidence of breast cancer is decreasing but, as per the Walter Reed General Hospital and USA Today, breast cancer is one of the most common cancers in our veterans. Not only is the number of women with breast cancer increasing, but so too is the number of male veterans with breast cancer. In general, breast cancer in males is rare, < 1% of all breast cancer cases. Our retrospective data from 1995 to 2012 had more than 6,000 patients with breast cancer; out of that, 1,100 were males with breast cancer.
FP: What do you think needs to be changed about how breast cancer is approached in veterans?
AA: I don’t have an answer to that, but if we can build a breast cancer research group, we may be able to answer some of these questions. Collection of the data prospectively on all of breast cancer at all VA facilities will help us to understand etiology, risk factors, and biology by molecular profiling. In turn, this will help health professionals to give personalized treatment to veterans.
Email: anita.aggarwal@va.gov
Read more about Dr. Aggarwal’s breast cancer initiative: http://www.research.va.gov/currents/spring2014/spring2014-45.cfm
Over 200,000 new cases of breast cancer are diagnosed in the U.S. annually, according to the National Cancer Institute. Dr. Anita Aggarwal, an oncologist at the Washington, DC VAMC, recently completed an extensive study to compare male and female breast cancer in VA patients. The study found that males with breast cancer had higher stage and grade at presentation and higher mortality compared with females. But, when adjusted for age, stage, and grade, males had better survival rates.
Federal Practitioner talked with Dr. Aggarwal about the new breast cancer research group she is currently developing at the Washington, DC VAMC. Dr. Aggarwal’s hope is to help doctors in the federal health system to identify etiology, biology, and improve treatment of both male and female patients with breast cancer.
Federal Practitioner: What is a breast cancer research group, and why do you think one needs to be created at the VA?
Anita Aggarwal, MD: I would like to build a breast cancer research group with the help of all oncologists and health professionals who take care of patients with breast cancer at all VAMCs nationwide. From my retrospective comparison study, breast cancer in our veterans seems to be different than in the general population. The goal of this research group will be to build a data bank with all the pertinent information as well as tissue gene profiling. This will help us to diagnose them early and treat accordingly in a timely fashion.
FP: As more women join the military, do you think breast cancer treatment at the VA will change?
AA: As the number of female veterans increases, I suspect we will see an increase in the number of female patients with breast cancer. As reported by the 2012 Women’s Task Force, women are now the fastest growing cohort within the veteran community. In 2011, there were about 1.8 million women veterans, which is about 8% of the 22.2 million vets in the VA system. That is expected to increase to 2 million in 2020, at which time women will make up to 10.7% of the total vet population. To accommodate these changing needs, the VHA made women’s health programs a priority in 2007, including a recommendation to improve access to screening, mammograms, and related breast care services. The treatment of breast cancer is becoming more personalized with the advent of new, targeted therapies. The treatment will change if we can identify different biological targets in veterans with breast cancer.
FP: Do you think all veterans, male and female, are more susceptible to breast cancer than is the general population?
AA: In general, incidence of breast cancer is decreasing but, as per the Walter Reed General Hospital and USA Today, breast cancer is one of the most common cancers in our veterans. Not only is the number of women with breast cancer increasing, but so too is the number of male veterans with breast cancer. In general, breast cancer in males is rare, < 1% of all breast cancer cases. Our retrospective data from 1995 to 2012 had more than 6,000 patients with breast cancer; out of that, 1,100 were males with breast cancer.
FP: What do you think needs to be changed about how breast cancer is approached in veterans?
AA: I don’t have an answer to that, but if we can build a breast cancer research group, we may be able to answer some of these questions. Collection of the data prospectively on all of breast cancer at all VA facilities will help us to understand etiology, risk factors, and biology by molecular profiling. In turn, this will help health professionals to give personalized treatment to veterans.
Email: anita.aggarwal@va.gov
Read more about Dr. Aggarwal’s breast cancer initiative: http://www.research.va.gov/currents/spring2014/spring2014-45.cfm
Over 200,000 new cases of breast cancer are diagnosed in the U.S. annually, according to the National Cancer Institute. Dr. Anita Aggarwal, an oncologist at the Washington, DC VAMC, recently completed an extensive study to compare male and female breast cancer in VA patients. The study found that males with breast cancer had higher stage and grade at presentation and higher mortality compared with females. But, when adjusted for age, stage, and grade, males had better survival rates.
Federal Practitioner talked with Dr. Aggarwal about the new breast cancer research group she is currently developing at the Washington, DC VAMC. Dr. Aggarwal’s hope is to help doctors in the federal health system to identify etiology, biology, and improve treatment of both male and female patients with breast cancer.
Federal Practitioner: What is a breast cancer research group, and why do you think one needs to be created at the VA?
Anita Aggarwal, MD: I would like to build a breast cancer research group with the help of all oncologists and health professionals who take care of patients with breast cancer at all VAMCs nationwide. From my retrospective comparison study, breast cancer in our veterans seems to be different than in the general population. The goal of this research group will be to build a data bank with all the pertinent information as well as tissue gene profiling. This will help us to diagnose them early and treat accordingly in a timely fashion.
FP: As more women join the military, do you think breast cancer treatment at the VA will change?
AA: As the number of female veterans increases, I suspect we will see an increase in the number of female patients with breast cancer. As reported by the 2012 Women’s Task Force, women are now the fastest growing cohort within the veteran community. In 2011, there were about 1.8 million women veterans, which is about 8% of the 22.2 million vets in the VA system. That is expected to increase to 2 million in 2020, at which time women will make up to 10.7% of the total vet population. To accommodate these changing needs, the VHA made women’s health programs a priority in 2007, including a recommendation to improve access to screening, mammograms, and related breast care services. The treatment of breast cancer is becoming more personalized with the advent of new, targeted therapies. The treatment will change if we can identify different biological targets in veterans with breast cancer.
FP: Do you think all veterans, male and female, are more susceptible to breast cancer than is the general population?
AA: In general, incidence of breast cancer is decreasing but, as per the Walter Reed General Hospital and USA Today, breast cancer is one of the most common cancers in our veterans. Not only is the number of women with breast cancer increasing, but so too is the number of male veterans with breast cancer. In general, breast cancer in males is rare, < 1% of all breast cancer cases. Our retrospective data from 1995 to 2012 had more than 6,000 patients with breast cancer; out of that, 1,100 were males with breast cancer.
FP: What do you think needs to be changed about how breast cancer is approached in veterans?
AA: I don’t have an answer to that, but if we can build a breast cancer research group, we may be able to answer some of these questions. Collection of the data prospectively on all of breast cancer at all VA facilities will help us to understand etiology, risk factors, and biology by molecular profiling. In turn, this will help health professionals to give personalized treatment to veterans.
Email: anita.aggarwal@va.gov
Read more about Dr. Aggarwal’s breast cancer initiative: http://www.research.va.gov/currents/spring2014/spring2014-45.cfm
Hormone therapy for menopausal vasomotor symptoms
Estrogen therapy is highly effective in the treatment of hot flashes among postmenopausal women. For postmenopausal women with a uterus, estrogen treatment for hot flashes is almost always combined with a progestin to reduce the risk of endometrial polyps, hyperplasia, and cancer. For instance, in the Postmenopausal Estrogen/Progestin Interventions Trial, 62% of the women with a uterus treated with conjugated equine estrogen (CEE) 0.625 mg daily without a progestin developed endometrial hyperplasia.1
In the United States, the most commonly prescribed progestin for hormone therapy has been medroxyprogesterone acetate (MPA; Provera). However, data from the Women’s Health Initiative (WHI) trials indicate that MPA, when combined with CEE, may have adverse health effects among postmenopausal women.
Let’s examine the WHI data
Among women 50 to 59 years of age with a uterus, the combination of CEE plus MPA was associated with a trend toward an increased risk of breast cancer, coronary heart disease, and myocardial infarction.2 In contrast, among women 50 to 59 years of age without a uterus, CEE monotherapy was associated with a trend toward a decreased risk of invasive breast cancer, coronary heart disease, and myocardial infarction (TABLE 1). 
Among women 50 to 79 years of age with a uterus, the combination of CEE plus MPA was associated with a significantly increased risk of breast cancer (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.01–1.53; P = .04).2 In contrast, among women 50 to 79 years of age without a uterus, CEE monotherapy was associated with a trend toward a decreased risk of breast cancer (HR, 0.79; 95% CI, 0.61–1.02, P = .07).2
Related article: In the latest report from the WHI, the data contradict the conclusions. Holly Thacker, MD (Commentary; March 2014)
When the analysis was limited to women consistently adherent to their CEE monotherapy, the estrogen treatment significantly decreased the risk of invasive breast cancer (HR, 0.67; 95% CI, 0.47–0.97; P = .03).3
The addition of MPA to CEE appears to reverse some of the health benefits of CEE monotherapy, although the biological mechanisms are unclear. This observation should prompt us to explore alternative and novel treatments of vasomotor symptoms that do not utilize MPA. Some options for MPA-free hormone therapy include:
- transdermal estradiol plus micronized progesterone
- CEE plus a levonorgestrel-releasing intrauterine system
- bazedoxifene plus CEE.
In addition, nonhormonal treatment of hot flashes is an option, with selective serotonin reuptake inhibitors (SSRIs).
Related article: Is one oral estrogen formulation safer than another for menopausal women? Andrew M. Kaunitz, MD (Examining the Evidence; January 2014)
MPA-free hormone therapy for hot flashes
Estrogen plus micronized progesterone
When using an estrogen plus progestin regimen to treat hot flashes, many experts favor a combination of low-dose transdermal estradiol and oral micronized progesterone (Prometrium). This combination is believed by some experts to result in a lower risk of venous thromboembolism, stroke, cardiovascular disease, and breast cancer than an estrogen-MPA combination.4–7
When prescribing transdermal estradiol plus oral micronized progesterone for a woman within 1 to 2 years of her last menses, a cyclic regimen can help reduce episodes of irregular, unscheduled uterine bleeding. I often use this cyclic regimen: transdermal estradiol 0.0375 mg plus cyclic oral micronized progesterone 200 mg prior to bedtime for calendar days 1 to 12.
When using transdermal estradiol plus oral micronized progesterone in a woman more than 2 years from her last menses, a continuous regimen is often prescribed. I often use this continuous regimen: transdermal estradiol 0.0375 mg plus continuous oral micronized progesterone 100 mg daily prior to bedtime.
Related article: When should a menopausal woman discontinue hormone therapy? Andrew M. Kaunitz, MD (Cases in Menopause; February 2014)
Estrogen plus a levonorgestrel-releasing intrauterine systemThe levonorgestrel intrauterine system (LNG-IUS; 20 µg daily; Mirena) is frequently used in Europe to protect the endometrium against the adverse effects of estrogen therapy in postmenopausal women. In a meta-analysis of five clinical trials involving postmenopausal women, the LNG-IUS provided excellent protection against endometrial hyperplasia, compared with MPA.8
One caution about using the LNG-IUS system with estrogen in postmenopausal women is that an observational study of all women with breast cancer in Finland from 1995 through 2007 reported a significantly increased risk of breast cancer among postmenopausal women using an LNG-IUS compared with women who did not use hormones or used only estrogen because they had a hysterectomy (TABLE 2).9 This study was not a randomized clinical trial and patients at higher baseline risk for breast cancer, including women with a high body mass index, may have been preferentially treated with an LNG-IUS. More information is needed to better understand the relationship between the LNG-IUS and breast cancer in postmenopausal women. 
Related article: What we’ve learned from 2 decades’ experience with the LNG-IUS. Q&A with Oskari Heikinheimo, MD, PhD (February 2011)
Progestin-free hormone treatment, bazedoxifene plus CEE
The main reason for adding a progestin to estrogen therapy for vasomotor symptoms in postmenopausal women with a uterus is to prevent estrogen-induced development of endometrial polyps, hyperplasia, and cancer. A major innovation in hormone therapy is the discovery that third-generation selective estrogen receptor modulators (SERMs), such as bazedoxifene (BZA), can prevent estrogen-induced development of endometrial polyps, hyperplasia, and cancer but do not interfere with the efficacy of estrogen in the treatment of vasomotor symptoms.
BZA is an estrogen agonist in bone and an estrogen antagonist in the endometrium.10–12 The combination of BZA (20 mg daily) plus CEE (0.45 mg daily) (Duavee) is approved for the treatment of moderate to severe vasomotor symptoms and prevention of osteoporosis.13–15 Over 24 months of therapy, various doses of BZA plus CEE reduced reported daily hot flashes by 52% to 86%.16 In the same study, placebo treatment was associated with a 17% reduction in hot flashes.16
The main adverse effect of BZA/CEE is an increased risk of deep venous thrombosis. Therefore, BZA/CEE is contraindicated in women with a known thrombophilia or a personal history of hormone-induced deep venous thrombosis. The effect of BZA/CEE on the risk of developing invasive breast cancer is not known; over 52 weeks of therapy it did not increase breast density on mammogram.17,18
BZA/CEE is a remarkable advance in hormone therapy. It is progestin-free, uses estrogen to treat vasomotor symptoms, and uses BZA to protect the endometrium against estrogen-induced hyperplasia.
Related article: New option for treating menopausal vasomotor symptoms receives FDA approval. (News for your Practice; October 2013)
Nonhormone treatment of vasomotor symptoms Paroxetine mesylateFor postmenopausal women with vasomotor symptoms who cannot take estrogen, SSRIs are modestly effective in reducing moderate to severe hot flashes. The US Food and Drug Administration recently approved paroxetine mesylate (Brisdelle) for the treatment of postmenopausal vasomotor symptoms. The approved dose is 7.5 mg daily taken at bedtime.
Data supporting the efficacy of paroxetine mesylate are available from two studies involving 1,184 menopausal women with vasomotor symptoms randomly assigned to receive paroxetine 7.5 mg daily or placebo for 12 weeks of treatment.19-22 In one of the two clinical trials, women treated with paroxetine mesylate 7.5 mg daily had 5.6 fewer moderate to severe hot flashes daily after 12 weeks of treatment compared with 3.9 fewer hot flashes with placebo (median treatment difference, 1.7; P<.001).21
Paroxetine can block the metabolism of tamoxifen to its highly potent metabolite, endoxifen. Consequently, paroxetine may reduce the effectiveness of tamoxifen treatment for breast cancer and should be used with caution in postmenopausal women with breast cancer being treated with tamoxifen.
Related article: Paroxetine mesylate 7.5 mg found to be a safe alternative to hormone therapy for menopausal women with hot flashes. (News for your Practice; June 2014)
Escitalopram
Gynecologists are familiar with the use of venlafaxine, desvenlafaxine, clonidine, citalopram, sertraline, and fluoxetine for the treatment of postmenopausal hot flashes. Recently, escitalopram (Lexapro) at doses of 10 to 20 mg daily has been shown to be more effective than placebo in the treatment of hot flashes and sleep disturbances in postmenopausal women.23,24 In one trial of escitalopram 10 to 20 mg daily versus placebo in 205 postmenopausal women averaging 9.8 hot flashes daily at baseline, escitalopram and placebo reduced mean daily hot flashes by 4.6 and 3.2, respectively (P<.001), after 8 weeks of treatment.
In a meta-analysis of SSRIs for the treatment of hot flashes, data from a mixed-treatment comparison analysis indicated that the rank order from most to least effective therapy for hot flashes was: escitalopram > paroxetine > sertraline > citalopram > fluoxetine.25 Venlafaxine and desvenlafaxine, two serotonin and norepinephrine reuptake inhibitors that are effective in the treatment of hot flashes, were not included in the mixed-treatment comparison.
Use of alternatives to MPA could mean fewer health risks for women on a wide scale
Substantial data indicate that MPA is not an optimal progestin to combine with estrogen for hormone therapy. Currently, many health insurance plans and Medicare use pharmacy management formularies that prioritize dispensing MPA for postmenopausal hormone therapy. Dispensing an alternative to MPA, such as micronized progesterone, often requires the patient to make a significant copayment.
Hopefully, health insurance companies, Medicare, and their affiliated pharmacy management administrators will soon stop their current policy of using financial incentives to favor dispensing MPA when hormone therapy is prescribed because alternatives to MPA appear to be associated with fewer health risks for postmenopausal women.
WE WANT TO HEAR FROM YOU! Share your thoughts on this article. Send your Letter to the Editor to: rbarbieri@frontlinemedcom.com
1. The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1996;275(5):370–375.
2. Manson JE, Chlebowski RT, Stefnick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353–1368.
3. Stefanick ML, Anderson GL, Margolis KL, et al; WHI Investigators. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006;295(14):1647–1657.
4. Simon JA. What if the Women’s Health Initiative had used transdermal estradiol and oral progesterone instead? [published online head of print January 6, 2014]. Menopause. PMID: 24398406.
5. Manson JE. Current recommendations: What is the clinician to do? Fertil Steril. 2014;101(4):916–921.
6. Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: Results from the E3N cohort study [published correction appears in Breast Cancer Res Treat. 2008;107(2):307–308]. Breast Cancer Res Treat. 2008;107(1):103–111.
7. Renoux C, Dell’aniello S, Garbe E, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: A nested case-control study. BMJ. 2010;340:c2519.
8. Somboonpom W, Panna S, Temtanakitpaisan T, Kaewrudee S, Soontrapa S. Effects of the levonorgestrel-releasing intrauterine system plus estrogen therapy in perimenopausal and postmenopausal women: Systematic review and meta-analysis. Menopause. 2011;18(10):1060–1066.
9. Lyytinen HK, Dyba T, Ylikorkala O, Pukkala EI. A case-control study on hormone therapy as a risk factor for breast cancer in Finland: Intrauterine system carries a risk as well. Int J Cancer. 2010;126(2):483–489.
10. Komm BS, Mirkin S. An overview of current and emerging SERMs. J Steroid Biochem Mol Biol. 2014;143C:207–222.
11. Ethun KF, Wood CE, Cline JM, Register TC, Appt SE, Clarkson TB. Endometrial profile of bazedoxifene acetate alone and in combination with conjugated equine estrogens in a primate model. Menopause. 2013;20(7):777–784.
12. Pinkerton JV, Harvey JA, Lindsay R, et al; SMART-5 Investigators. Effects of bazedoxifene/conjugated estrogens on the endometrium and bone: A randomized trial. J Clin Endocrinol Metab. 2014;99(2):E189–E198.
13. Pinkerton JV, Pickar JH, Racketa J, Mirkin S. Bazedoxifene/conjugated estrogens for menopausal symptom treatment and osteoporosis prevention. Climacteric. 2012;15(5):411–418.
14. Pinkerton JV, Abraham L, Bushmakin AG, et al. Evaluation of the efficacy and safety of bazedoxifene/conjugated estrogens for secondary outcomes including vasomotor symptoms in postmenopausal women by years since menopause in the Selective estrogens, Menopause and Response to Therapy (SMART) trials. J Womens Health (Larchmt). 2014;23(1):18–28.
15. Pinkerton JV, Harvey JA, Pan K, et al. Breast effects of bazedoxifene-conjugated estrogens: A randomized controlled trial. Obstet Gynecol. 2013;121(5):959–968.
16. Lobo RA, Pinkerton JV, Gass ML, et al. Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile. Fertil Steril. 2009;92(3):1025–1038.
17. Harvey JA, Holm MK, Ranganath R, Guse PA, Trott EA, Helzner E. The effects of bazedoxifene on mammographic breast density in postmenopausal women with osteoporosis. Menopause. 2009;16(6):1193–1196.
18. Harvey JA, Pinkerton JV, Baracat EC, Shi H, Chines AA, Mirkin S. Breast density changes in a randomized controlled trial evaluating bazedoxifene/conjugated estrogens. Menopause. 2013;20(2):138–145.
19. Simon JA, Portman DJ, Kaunitz AM, et al. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: Two randomized controlled trials. Menopause. 2013;20(10):1027–1035.
20. Simon JA, Portman DJ, Kazempour K, Mekonnen H, Bhaskar S, Lippman J. Safety profile of paroxetine 7.5 mg in women with moderate-to-severe vasomotor symptoms. Obstet Gynecol. 2014;123(suppl 1):132S–133S.
21. Orleans RJ, Li L, Kim MJ, et al. FDA approval of paroxetine for menopausal hot flashes. N Engl J Med. 2014;370(19):1777–1779.
22. Paroxetine (Brisdelle) for hot flashes. Med Lett Drugs Ther. 2013;55(1428):85–86.
23. Freeman EW, Guthrie KA, Caan B, et al. Efficacy of escitalopram for hot flashes in health menopausal women. A randomized controlled trial. JAMA. 2011;305(3):267–274.
24. Ensrud KE, Joffe H, Guthrie KA, et al. Effect of escitalopram on insomnia symptoms and subjective sleep quality in healthy perimenopausal and postmenopausal women with hot flashes: A randomized controlled trial. Menopause. 2012;19(8):848–855.
25. Shams T, Firwana B, Habib F, et al. SSRIs for hot flashes: A systematic review and meta-analysis of randomized trials. J Gen Intern Med. 2014;29(1):204–213.
Robert L. Barbieri, MD
Editor in Chief, OBG Management Chair, Obstetrics and Gynecology Brigham and Women’s Hospital, Boston, Massachusetts Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology Harvard Medical School, Boston.
Dr. Barbieri reports no financial relationships relevant to this article.
Robert L. Barbieri, MD
Editor in Chief, OBG Management Chair, Obstetrics and Gynecology Brigham and Women’s Hospital, Boston, Massachusetts Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology Harvard Medical School, Boston.
Dr. Barbieri reports no financial relationships relevant to this article.
Robert L. Barbieri, MD
Editor in Chief, OBG Management Chair, Obstetrics and Gynecology Brigham and Women’s Hospital, Boston, Massachusetts Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology Harvard Medical School, Boston.
Dr. Barbieri reports no financial relationships relevant to this article.
Estrogen therapy is highly effective in the treatment of hot flashes among postmenopausal women. For postmenopausal women with a uterus, estrogen treatment for hot flashes is almost always combined with a progestin to reduce the risk of endometrial polyps, hyperplasia, and cancer. For instance, in the Postmenopausal Estrogen/Progestin Interventions Trial, 62% of the women with a uterus treated with conjugated equine estrogen (CEE) 0.625 mg daily without a progestin developed endometrial hyperplasia.1
In the United States, the most commonly prescribed progestin for hormone therapy has been medroxyprogesterone acetate (MPA; Provera). However, data from the Women’s Health Initiative (WHI) trials indicate that MPA, when combined with CEE, may have adverse health effects among postmenopausal women.
Let’s examine the WHI data
Among women 50 to 59 years of age with a uterus, the combination of CEE plus MPA was associated with a trend toward an increased risk of breast cancer, coronary heart disease, and myocardial infarction.2 In contrast, among women 50 to 59 years of age without a uterus, CEE monotherapy was associated with a trend toward a decreased risk of invasive breast cancer, coronary heart disease, and myocardial infarction (TABLE 1).
Among women 50 to 79 years of age with a uterus, the combination of CEE plus MPA was associated with a significantly increased risk of breast cancer (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.01–1.53; P = .04).2 In contrast, among women 50 to 79 years of age without a uterus, CEE monotherapy was associated with a trend toward a decreased risk of breast cancer (HR, 0.79; 95% CI, 0.61–1.02, P = .07).2
Related article: In the latest report from the WHI, the data contradict the conclusions. Holly Thacker, MD (Commentary; March 2014)
When the analysis was limited to women consistently adherent to their CEE monotherapy, the estrogen treatment significantly decreased the risk of invasive breast cancer (HR, 0.67; 95% CI, 0.47–0.97; P = .03).3
The addition of MPA to CEE appears to reverse some of the health benefits of CEE monotherapy, although the biological mechanisms are unclear. This observation should prompt us to explore alternative and novel treatments of vasomotor symptoms that do not utilize MPA. Some options for MPA-free hormone therapy include:
- transdermal estradiol plus micronized progesterone
- CEE plus a levonorgestrel-releasing intrauterine system
- bazedoxifene plus CEE.
In addition, nonhormonal treatment of hot flashes is an option, with selective serotonin reuptake inhibitors (SSRIs).
Related article: Is one oral estrogen formulation safer than another for menopausal women? Andrew M. Kaunitz, MD (Examining the Evidence; January 2014)
MPA-free hormone therapy for hot flashes
Estrogen plus micronized progesterone
When using an estrogen plus progestin regimen to treat hot flashes, many experts favor a combination of low-dose transdermal estradiol and oral micronized progesterone (Prometrium). This combination is believed by some experts to result in a lower risk of venous thromboembolism, stroke, cardiovascular disease, and breast cancer than an estrogen-MPA combination.4–7
When prescribing transdermal estradiol plus oral micronized progesterone for a woman within 1 to 2 years of her last menses, a cyclic regimen can help reduce episodes of irregular, unscheduled uterine bleeding. I often use this cyclic regimen: transdermal estradiol 0.0375 mg plus cyclic oral micronized progesterone 200 mg prior to bedtime for calendar days 1 to 12.
When using transdermal estradiol plus oral micronized progesterone in a woman more than 2 years from her last menses, a continuous regimen is often prescribed. I often use this continuous regimen: transdermal estradiol 0.0375 mg plus continuous oral micronized progesterone 100 mg daily prior to bedtime.
Related article: When should a menopausal woman discontinue hormone therapy? Andrew M. Kaunitz, MD (Cases in Menopause; February 2014)
Estrogen plus a levonorgestrel-releasing intrauterine systemThe levonorgestrel intrauterine system (LNG-IUS; 20 µg daily; Mirena) is frequently used in Europe to protect the endometrium against the adverse effects of estrogen therapy in postmenopausal women. In a meta-analysis of five clinical trials involving postmenopausal women, the LNG-IUS provided excellent protection against endometrial hyperplasia, compared with MPA.8
One caution about using the LNG-IUS system with estrogen in postmenopausal women is that an observational study of all women with breast cancer in Finland from 1995 through 2007 reported a significantly increased risk of breast cancer among postmenopausal women using an LNG-IUS compared with women who did not use hormones or used only estrogen because they had a hysterectomy (TABLE 2).9 This study was not a randomized clinical trial and patients at higher baseline risk for breast cancer, including women with a high body mass index, may have been preferentially treated with an LNG-IUS. More information is needed to better understand the relationship between the LNG-IUS and breast cancer in postmenopausal women.
Related article: What we’ve learned from 2 decades’ experience with the LNG-IUS. Q&A with Oskari Heikinheimo, MD, PhD (February 2011)
Progestin-free hormone treatment, bazedoxifene plus CEE
The main reason for adding a progestin to estrogen therapy for vasomotor symptoms in postmenopausal women with a uterus is to prevent estrogen-induced development of endometrial polyps, hyperplasia, and cancer. A major innovation in hormone therapy is the discovery that third-generation selective estrogen receptor modulators (SERMs), such as bazedoxifene (BZA), can prevent estrogen-induced development of endometrial polyps, hyperplasia, and cancer but do not interfere with the efficacy of estrogen in the treatment of vasomotor symptoms.
BZA is an estrogen agonist in bone and an estrogen antagonist in the endometrium.10–12 The combination of BZA (20 mg daily) plus CEE (0.45 mg daily) (Duavee) is approved for the treatment of moderate to severe vasomotor symptoms and prevention of osteoporosis.13–15 Over 24 months of therapy, various doses of BZA plus CEE reduced reported daily hot flashes by 52% to 86%.16 In the same study, placebo treatment was associated with a 17% reduction in hot flashes.16
The main adverse effect of BZA/CEE is an increased risk of deep venous thrombosis. Therefore, BZA/CEE is contraindicated in women with a known thrombophilia or a personal history of hormone-induced deep venous thrombosis. The effect of BZA/CEE on the risk of developing invasive breast cancer is not known; over 52 weeks of therapy it did not increase breast density on mammogram.17,18
BZA/CEE is a remarkable advance in hormone therapy. It is progestin-free, uses estrogen to treat vasomotor symptoms, and uses BZA to protect the endometrium against estrogen-induced hyperplasia.
Related article: New option for treating menopausal vasomotor symptoms receives FDA approval. (News for your Practice; October 2013)
Nonhormone treatment of vasomotor symptoms Paroxetine mesylateFor postmenopausal women with vasomotor symptoms who cannot take estrogen, SSRIs are modestly effective in reducing moderate to severe hot flashes. The US Food and Drug Administration recently approved paroxetine mesylate (Brisdelle) for the treatment of postmenopausal vasomotor symptoms. The approved dose is 7.5 mg daily taken at bedtime.
Data supporting the efficacy of paroxetine mesylate are available from two studies involving 1,184 menopausal women with vasomotor symptoms randomly assigned to receive paroxetine 7.5 mg daily or placebo for 12 weeks of treatment.19-22 In one of the two clinical trials, women treated with paroxetine mesylate 7.5 mg daily had 5.6 fewer moderate to severe hot flashes daily after 12 weeks of treatment compared with 3.9 fewer hot flashes with placebo (median treatment difference, 1.7; P<.001).21
Paroxetine can block the metabolism of tamoxifen to its highly potent metabolite, endoxifen. Consequently, paroxetine may reduce the effectiveness of tamoxifen treatment for breast cancer and should be used with caution in postmenopausal women with breast cancer being treated with tamoxifen.
Related article: Paroxetine mesylate 7.5 mg found to be a safe alternative to hormone therapy for menopausal women with hot flashes. (News for your Practice; June 2014)
Escitalopram
Gynecologists are familiar with the use of venlafaxine, desvenlafaxine, clonidine, citalopram, sertraline, and fluoxetine for the treatment of postmenopausal hot flashes. Recently, escitalopram (Lexapro) at doses of 10 to 20 mg daily has been shown to be more effective than placebo in the treatment of hot flashes and sleep disturbances in postmenopausal women.23,24 In one trial of escitalopram 10 to 20 mg daily versus placebo in 205 postmenopausal women averaging 9.8 hot flashes daily at baseline, escitalopram and placebo reduced mean daily hot flashes by 4.6 and 3.2, respectively (P<.001), after 8 weeks of treatment.
In a meta-analysis of SSRIs for the treatment of hot flashes, data from a mixed-treatment comparison analysis indicated that the rank order from most to least effective therapy for hot flashes was: escitalopram > paroxetine > sertraline > citalopram > fluoxetine.25 Venlafaxine and desvenlafaxine, two serotonin and norepinephrine reuptake inhibitors that are effective in the treatment of hot flashes, were not included in the mixed-treatment comparison.
Use of alternatives to MPA could mean fewer health risks for women on a wide scale
Substantial data indicate that MPA is not an optimal progestin to combine with estrogen for hormone therapy. Currently, many health insurance plans and Medicare use pharmacy management formularies that prioritize dispensing MPA for postmenopausal hormone therapy. Dispensing an alternative to MPA, such as micronized progesterone, often requires the patient to make a significant copayment.
Hopefully, health insurance companies, Medicare, and their affiliated pharmacy management administrators will soon stop their current policy of using financial incentives to favor dispensing MPA when hormone therapy is prescribed because alternatives to MPA appear to be associated with fewer health risks for postmenopausal women.
WE WANT TO HEAR FROM YOU! Share your thoughts on this article. Send your Letter to the Editor to: rbarbieri@frontlinemedcom.com
Estrogen therapy is highly effective in the treatment of hot flashes among postmenopausal women. For postmenopausal women with a uterus, estrogen treatment for hot flashes is almost always combined with a progestin to reduce the risk of endometrial polyps, hyperplasia, and cancer. For instance, in the Postmenopausal Estrogen/Progestin Interventions Trial, 62% of the women with a uterus treated with conjugated equine estrogen (CEE) 0.625 mg daily without a progestin developed endometrial hyperplasia.1
In the United States, the most commonly prescribed progestin for hormone therapy has been medroxyprogesterone acetate (MPA; Provera). However, data from the Women’s Health Initiative (WHI) trials indicate that MPA, when combined with CEE, may have adverse health effects among postmenopausal women.
Let’s examine the WHI data
Among women 50 to 59 years of age with a uterus, the combination of CEE plus MPA was associated with a trend toward an increased risk of breast cancer, coronary heart disease, and myocardial infarction.2 In contrast, among women 50 to 59 years of age without a uterus, CEE monotherapy was associated with a trend toward a decreased risk of invasive breast cancer, coronary heart disease, and myocardial infarction (TABLE 1).
Among women 50 to 79 years of age with a uterus, the combination of CEE plus MPA was associated with a significantly increased risk of breast cancer (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.01–1.53; P = .04).2 In contrast, among women 50 to 79 years of age without a uterus, CEE monotherapy was associated with a trend toward a decreased risk of breast cancer (HR, 0.79; 95% CI, 0.61–1.02, P = .07).2
Related article: In the latest report from the WHI, the data contradict the conclusions. Holly Thacker, MD (Commentary; March 2014)
When the analysis was limited to women consistently adherent to their CEE monotherapy, the estrogen treatment significantly decreased the risk of invasive breast cancer (HR, 0.67; 95% CI, 0.47–0.97; P = .03).3
The addition of MPA to CEE appears to reverse some of the health benefits of CEE monotherapy, although the biological mechanisms are unclear. This observation should prompt us to explore alternative and novel treatments of vasomotor symptoms that do not utilize MPA. Some options for MPA-free hormone therapy include:
- transdermal estradiol plus micronized progesterone
- CEE plus a levonorgestrel-releasing intrauterine system
- bazedoxifene plus CEE.
In addition, nonhormonal treatment of hot flashes is an option, with selective serotonin reuptake inhibitors (SSRIs).
Related article: Is one oral estrogen formulation safer than another for menopausal women? Andrew M. Kaunitz, MD (Examining the Evidence; January 2014)
MPA-free hormone therapy for hot flashes
Estrogen plus micronized progesterone
When using an estrogen plus progestin regimen to treat hot flashes, many experts favor a combination of low-dose transdermal estradiol and oral micronized progesterone (Prometrium). This combination is believed by some experts to result in a lower risk of venous thromboembolism, stroke, cardiovascular disease, and breast cancer than an estrogen-MPA combination.4–7
When prescribing transdermal estradiol plus oral micronized progesterone for a woman within 1 to 2 years of her last menses, a cyclic regimen can help reduce episodes of irregular, unscheduled uterine bleeding. I often use this cyclic regimen: transdermal estradiol 0.0375 mg plus cyclic oral micronized progesterone 200 mg prior to bedtime for calendar days 1 to 12.
When using transdermal estradiol plus oral micronized progesterone in a woman more than 2 years from her last menses, a continuous regimen is often prescribed. I often use this continuous regimen: transdermal estradiol 0.0375 mg plus continuous oral micronized progesterone 100 mg daily prior to bedtime.
Related article: When should a menopausal woman discontinue hormone therapy? Andrew M. Kaunitz, MD (Cases in Menopause; February 2014)
Estrogen plus a levonorgestrel-releasing intrauterine systemThe levonorgestrel intrauterine system (LNG-IUS; 20 µg daily; Mirena) is frequently used in Europe to protect the endometrium against the adverse effects of estrogen therapy in postmenopausal women. In a meta-analysis of five clinical trials involving postmenopausal women, the LNG-IUS provided excellent protection against endometrial hyperplasia, compared with MPA.8
One caution about using the LNG-IUS system with estrogen in postmenopausal women is that an observational study of all women with breast cancer in Finland from 1995 through 2007 reported a significantly increased risk of breast cancer among postmenopausal women using an LNG-IUS compared with women who did not use hormones or used only estrogen because they had a hysterectomy (TABLE 2).9 This study was not a randomized clinical trial and patients at higher baseline risk for breast cancer, including women with a high body mass index, may have been preferentially treated with an LNG-IUS. More information is needed to better understand the relationship between the LNG-IUS and breast cancer in postmenopausal women.
Related article: What we’ve learned from 2 decades’ experience with the LNG-IUS. Q&A with Oskari Heikinheimo, MD, PhD (February 2011)
Progestin-free hormone treatment, bazedoxifene plus CEE
The main reason for adding a progestin to estrogen therapy for vasomotor symptoms in postmenopausal women with a uterus is to prevent estrogen-induced development of endometrial polyps, hyperplasia, and cancer. A major innovation in hormone therapy is the discovery that third-generation selective estrogen receptor modulators (SERMs), such as bazedoxifene (BZA), can prevent estrogen-induced development of endometrial polyps, hyperplasia, and cancer but do not interfere with the efficacy of estrogen in the treatment of vasomotor symptoms.
BZA is an estrogen agonist in bone and an estrogen antagonist in the endometrium.10–12 The combination of BZA (20 mg daily) plus CEE (0.45 mg daily) (Duavee) is approved for the treatment of moderate to severe vasomotor symptoms and prevention of osteoporosis.13–15 Over 24 months of therapy, various doses of BZA plus CEE reduced reported daily hot flashes by 52% to 86%.16 In the same study, placebo treatment was associated with a 17% reduction in hot flashes.16
The main adverse effect of BZA/CEE is an increased risk of deep venous thrombosis. Therefore, BZA/CEE is contraindicated in women with a known thrombophilia or a personal history of hormone-induced deep venous thrombosis. The effect of BZA/CEE on the risk of developing invasive breast cancer is not known; over 52 weeks of therapy it did not increase breast density on mammogram.17,18
BZA/CEE is a remarkable advance in hormone therapy. It is progestin-free, uses estrogen to treat vasomotor symptoms, and uses BZA to protect the endometrium against estrogen-induced hyperplasia.
Related article: New option for treating menopausal vasomotor symptoms receives FDA approval. (News for your Practice; October 2013)
Nonhormone treatment of vasomotor symptoms Paroxetine mesylateFor postmenopausal women with vasomotor symptoms who cannot take estrogen, SSRIs are modestly effective in reducing moderate to severe hot flashes. The US Food and Drug Administration recently approved paroxetine mesylate (Brisdelle) for the treatment of postmenopausal vasomotor symptoms. The approved dose is 7.5 mg daily taken at bedtime.
Data supporting the efficacy of paroxetine mesylate are available from two studies involving 1,184 menopausal women with vasomotor symptoms randomly assigned to receive paroxetine 7.5 mg daily or placebo for 12 weeks of treatment.19-22 In one of the two clinical trials, women treated with paroxetine mesylate 7.5 mg daily had 5.6 fewer moderate to severe hot flashes daily after 12 weeks of treatment compared with 3.9 fewer hot flashes with placebo (median treatment difference, 1.7; P<.001).21
Paroxetine can block the metabolism of tamoxifen to its highly potent metabolite, endoxifen. Consequently, paroxetine may reduce the effectiveness of tamoxifen treatment for breast cancer and should be used with caution in postmenopausal women with breast cancer being treated with tamoxifen.
Related article: Paroxetine mesylate 7.5 mg found to be a safe alternative to hormone therapy for menopausal women with hot flashes. (News for your Practice; June 2014)
Escitalopram
Gynecologists are familiar with the use of venlafaxine, desvenlafaxine, clonidine, citalopram, sertraline, and fluoxetine for the treatment of postmenopausal hot flashes. Recently, escitalopram (Lexapro) at doses of 10 to 20 mg daily has been shown to be more effective than placebo in the treatment of hot flashes and sleep disturbances in postmenopausal women.23,24 In one trial of escitalopram 10 to 20 mg daily versus placebo in 205 postmenopausal women averaging 9.8 hot flashes daily at baseline, escitalopram and placebo reduced mean daily hot flashes by 4.6 and 3.2, respectively (P<.001), after 8 weeks of treatment.
In a meta-analysis of SSRIs for the treatment of hot flashes, data from a mixed-treatment comparison analysis indicated that the rank order from most to least effective therapy for hot flashes was: escitalopram > paroxetine > sertraline > citalopram > fluoxetine.25 Venlafaxine and desvenlafaxine, two serotonin and norepinephrine reuptake inhibitors that are effective in the treatment of hot flashes, were not included in the mixed-treatment comparison.
Use of alternatives to MPA could mean fewer health risks for women on a wide scale
Substantial data indicate that MPA is not an optimal progestin to combine with estrogen for hormone therapy. Currently, many health insurance plans and Medicare use pharmacy management formularies that prioritize dispensing MPA for postmenopausal hormone therapy. Dispensing an alternative to MPA, such as micronized progesterone, often requires the patient to make a significant copayment.
Hopefully, health insurance companies, Medicare, and their affiliated pharmacy management administrators will soon stop their current policy of using financial incentives to favor dispensing MPA when hormone therapy is prescribed because alternatives to MPA appear to be associated with fewer health risks for postmenopausal women.
WE WANT TO HEAR FROM YOU! Share your thoughts on this article. Send your Letter to the Editor to: rbarbieri@frontlinemedcom.com
1. The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1996;275(5):370–375.
2. Manson JE, Chlebowski RT, Stefnick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310(13):1353–1368.
3. Stefanick ML, Anderson GL, Margolis KL, et al; WHI Investigators. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006;295(14):1647–1657.
4. Simon JA. What if the Women’s Health Initiative had used transdermal estradiol and oral progesterone instead? [published online head of print January 6, 2014]. Menopause. PMID: 24398406.
5. Manson JE. Current recommendations: What is the clinician to do? Fertil Steril. 2014;101(4):916–921.
6. Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: Results from the E3N cohort study [published correction appears in Breast Cancer Res Treat. 2008;107(2):307–308]. Breast Cancer Res Treat. 2008;107(1):103–111.
7. Renoux C, Dell’aniello S, Garbe E, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: A nested case-control study. BMJ. 2010;340:c2519.
8. Somboonpom W, Panna S, Temtanakitpaisan T, Kaewrudee S, Soontrapa S. Effects of the levonorgestrel-releasing intrauterine system plus estrogen therapy in perimenopausal and postmenopausal women: Systematic review and meta-analysis. Menopause. 2011;18(10):1060–1066.
9. Lyytinen HK, Dyba T, Ylikorkala O, Pukkala EI. A case-control study on hormone therapy as a risk factor for breast cancer in Finland: Intrauterine system carries a risk as well. Int J Cancer. 2010;126(2):483–489.
10. Komm BS, Mirkin S. An overview of current and emerging SERMs. J Steroid Biochem Mol Biol. 2014;143C:207–222.
11. Ethun KF, Wood CE, Cline JM, Register TC, Appt SE, Clarkson TB. Endometrial profile of bazedoxifene acetate alone and in combination with conjugated equine estrogens in a primate model. Menopause. 2013;20(7):777–784.
12. Pinkerton JV, Harvey JA, Lindsay R, et al; SMART-5 Investigators. Effects of bazedoxifene/conjugated estrogens on the endometrium and bone: A randomized trial. J Clin Endocrinol Metab. 2014;99(2):E189–E198.
13. Pinkerton JV, Pickar JH, Racketa J, Mirkin S. Bazedoxifene/conjugated estrogens for menopausal symptom treatment and osteoporosis prevention. Climacteric. 2012;15(5):411–418.
14. Pinkerton JV, Abraham L, Bushmakin AG, et al. Evaluation of the efficacy and safety of bazedoxifene/conjugated estrogens for secondary outcomes including vasomotor symptoms in postmenopausal women by years since menopause in the Selective estrogens, Menopause and Response to Therapy (SMART) trials. J Womens Health (Larchmt). 2014;23(1):18–28.
15. Pinkerton JV, Harvey JA, Pan K, et al. Breast effects of bazedoxifene-conjugated estrogens: A randomized controlled trial. Obstet Gynecol. 2013;121(5):959–968.
16. Lobo RA, Pinkerton JV, Gass ML, et al. Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile. Fertil Steril. 2009;92(3):1025–1038.
17. Harvey JA, Holm MK, Ranganath R, Guse PA, Trott EA, Helzner E. The effects of bazedoxifene on mammographic breast density in postmenopausal women with osteoporosis. Menopause. 2009;16(6):1193–1196.
18. Harvey JA, Pinkerton JV, Baracat EC, Shi H, Chines AA, Mirkin S. Breast density changes in a randomized controlled trial evaluating bazedoxifene/conjugated estrogens. Menopause. 2013;20(2):138–145.
19. Simon JA, Portman DJ, Kaunitz AM, et al. Low-dose paroxetine 7.5 mg for menopausal vasomotor symptoms: Two randomized controlled trials. Menopause. 2013;20(10):1027–1035.
20. Simon JA, Portman DJ, Kazempour K, Mekonnen H, Bhaskar S, Lippman J. Safety profile of paroxetine 7.5 mg in women with moderate-to-severe vasomotor symptoms. Obstet Gynecol. 2014;123(suppl 1):132S–133S.
21. Orleans RJ, Li L, Kim MJ, et al. FDA approval of paroxetine for menopausal hot flashes. N Engl J Med. 2014;370(19):1777–1779.
22. Paroxetine (Brisdelle) for hot flashes. Med Lett Drugs Ther. 2013;55(1428):85–86.
23. Freeman EW, Guthrie KA, Caan B, et al. Efficacy of escitalopram for hot flashes in health menopausal women. A randomized controlled trial. JAMA. 2011;305(3):267–274.
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