Breast Cancer

Methods 52 patients (50 women, 2 men) enrolled within a year of diagnosis of MBC completed a cross-sectional, self-administered paper survey that included patient demographics, the Toronto Informational Needs Questionnaire-Breast Cancer (TINQ), the Hospital Anxiety and Depression Scale (HADS), and Medical Outcomes Study Short Form-36 (SF-36). High informational need was defined as a TINQ score of ≥ 200.

Results Of the total 52 patients, 69% (35/52) had high informational needs, 20% met the criteria for anxiety (HADS-Anxiety score, ≥ 11), and 8% met the criteria for depression. SF-36 scores were lower in all 8 subscales compared with the general population. Multivariate analyses showed that patients who were married or living as married (OR, 6.1; 95% CI, 1.4-28.9) and patients with de novo MBC (OR, 2.8; 95% CI, 0.5-14.3) or a shorter disease-free interval (DFI; < 5 years; OR, 24.2; 95% CI, 3.1-187.4) were more likely to have more informational needs (C statistic, 0.824) than were patients with a longer DFI (≥ 5 years).

Limitations This is a small cross-sectional study of a single academic institution.

Conclusion Patients with recently diagnosed MBC have high informational needs and decreased overall QOL. Additional research and supportive services meeting the informational and psychosocial needs of patients living with MBC are warranted.

Funding Metastatic Research Fund (anonymous donor), the Megan Lally Memorial Fund, the Nancy and Randy Berry Junior Faculty Award, the Karen Webster & David Evans Metastatic Research Fund, and the Susan G Komen for the Cure. 

Methods 52 patients (50 women, 2 men) enrolled within a year of diagnosis of MBC completed a cross-sectional, self-administered paper survey that included patient demographics, the Toronto Informational Needs Questionnaire-Breast Cancer (TINQ), the Hospital Anxiety and Depression Scale (HADS), and Medical Outcomes Study Short Form-36 (SF-36). High informational need was defined as a TINQ score of ≥ 200.

Results Of the total 52 patients, 69% (35/52) had high informational needs, 20% met the criteria for anxiety (HADS-Anxiety score, ≥ 11), and 8% met the criteria for depression. SF-36 scores were lower in all 8 subscales compared with the general population. Multivariate analyses showed that patients who were married or living as married (OR, 6.1; 95% CI, 1.4-28.9) and patients with de novo MBC (OR, 2.8; 95% CI, 0.5-14.3) or a shorter disease-free interval (DFI; < 5 years; OR, 24.2; 95% CI, 3.1-187.4) were more likely to have more informational needs (C statistic, 0.824) than were patients with a longer DFI (≥ 5 years).

Limitations This is a small cross-sectional study of a single academic institution.

Conclusion Patients with recently diagnosed MBC have high informational needs and decreased overall QOL. Additional research and supportive services meeting the informational and psychosocial needs of patients living with MBC are warranted.

Funding Metastatic Research Fund (anonymous donor), the Megan Lally Memorial Fund, the Nancy and Randy Berry Junior Faculty Award, the Karen Webster & David Evans Metastatic Research Fund, and the Susan G Komen for the Cure. 

Methods 52 patients (50 women, 2 men) enrolled within a year of diagnosis of MBC completed a cross-sectional, self-administered paper survey that included patient demographics, the Toronto Informational Needs Questionnaire-Breast Cancer (TINQ), the Hospital Anxiety and Depression Scale (HADS), and Medical Outcomes Study Short Form-36 (SF-36). High informational need was defined as a TINQ score of ≥ 200.

Results Of the total 52 patients, 69% (35/52) had high informational needs, 20% met the criteria for anxiety (HADS-Anxiety score, ≥ 11), and 8% met the criteria for depression. SF-36 scores were lower in all 8 subscales compared with the general population. Multivariate analyses showed that patients who were married or living as married (OR, 6.1; 95% CI, 1.4-28.9) and patients with de novo MBC (OR, 2.8; 95% CI, 0.5-14.3) or a shorter disease-free interval (DFI; < 5 years; OR, 24.2; 95% CI, 3.1-187.4) were more likely to have more informational needs (C statistic, 0.824) than were patients with a longer DFI (≥ 5 years).

Limitations This is a small cross-sectional study of a single academic institution.

Conclusion Patients with recently diagnosed MBC have high informational needs and decreased overall QOL. Additional research and supportive services meeting the informational and psychosocial needs of patients living with MBC are warranted.

Funding Metastatic Research Fund (anonymous donor), the Megan Lally Memorial Fund, the Nancy and Randy Berry Junior Faculty Award, the Karen Webster & David Evans Metastatic Research Fund, and the Susan G Komen for the Cure. 

MADRID – Liquid biopsies to track genetic changes in a patient’s tumor by serial blood specimens rather than multiple tissue biopsies seem poised to enter routine clinical use. But several experts speaking at a session on the topic agreed that liquid biopsy technologies largely remain too unproven to enter everyday practice right now.

“I have no doubt [liquid biopsy] will become routine, but right now the evidence is lacking,” said Alberto Bardelli, Ph.D., summarizing a session he cochaired at the European Society for Medical Oncology Congress.

Mitchel L. Zoler/Frontine Medical News

“I think the potential is very high to use liquid biopsy to monitor residual disease in patients with breast cancer or other tumor types. There is also the possibility of using CTCs [circulating tumor cells] to interrogate the genome of single tumor cells or to grow the cells and use them functionally” to, for example, help identify effective treatments against the tumor, said Dr. Bardelli, a molecular biologist at the University of Torino, Italy.

Liquid biopsies are generally divided into two categories. One approach involves the isolation and analysis of individual, living tumor cells that slough off a primary tumor or metastasis and can be isolated from a patient’s peripheral blood, although tumor cell concentrations are very low, on the order of one tumor cell in a million normal blood cells or even 10- to 100-fold more dilute than that.

In 2004, the Food and Drug Administration approved CellSearch, a commercial test that quantifies CTCs in patients with metastatic breast cancer to predict the likelihood of survival. CellSearch remains the only FDA-approved liquid biopsy assay for cancer, though its use has expanded to patients with prostate or colorectal cancer as well as breast cancer.

Circulating tumor DNA

The second option is to isolate and analyze the DNA that slips out of dead tumor cells and enters a patient’s circulation. One advantage of focusing on circulating tumor DNA (ctDNA) is that it is more than 100 times as common in a patent’s blood as tumor cells; however, tumor DNA is limited to providing a broad-brush average of what is going on genetically in a primary tumor and its metastases at any time, rather than giving the specificity of a genome isolated from a single, circulating tumor cell.

Both approaches seem to have value, and both seem on course to continue in development and be used in complementary ways.

An example of the potential benefit of analyzing ctDNA came in a study published last year, in which investigators identified genetic alterations that they could use to follow patients with metastatic breast cancer. They found ctDNA in the blood of 29 out of 52 women, and saw a strong, inverse relationship between increased levels of ctDNA and survival. Patients with a below-average level of ctDNA had significantly better survival, while patients with relatively higher ctDNA levels had significantly worse survival, the British researchers reported last year (New Engl. J. Med. 2013;368:1199-209). The study results also showed that quantifying ctDNA provided better correlation with changes in tumor burden than did quantifying CTCs or measuring an immune marker for breast cancer, CA 15-3.

Mitchel L. Zoler/Frontine Medical News

More recently, these investigators expanded the mutation panel they use to identify ctDNA, and now can find a single-nucleotide or structural variant in the DNAs of 48 of these 52 patients, Dr. Carlos Caldas, one of the investigators, said in a talk at the meeting. Dr. Caldas added that he and his associates have now seen a patient from this series with triple-negative breast cancer and an elevated level of ctDNA who then showed a dramatic reduction in ctDNA level following several treatment cycles. This drop in ctDNA level tracked with the patient’s complete pathological response to treatment.

“This is preliminary evidence that you can use ctDNA as a very early marker of treatment response,” said Dr. Caldas, professor of cancer medicine at the University of Cambridge, England.

Other advantages of measuring ctDNA, especially compared with tracking a tumor using CTCs, is that it is simple and relatively inexpensive, with no need for special isolation technology, and it reflects the patient’s total tumor burden, noted Dr. Gerald Prager, an oncologist at the Medical University of Vienna. He cited a recent example of the power of ctDNA analysis in a report on 106 patients with colorectal cancer, who underwent ctDNA analysis for KRAS and BRAF mutations. Comparison of results from the ctDNA analysis and conventional mutation determinations showed 100% sensitivity and specificity for detecting tumors with the BRAF V600E mutation, and 98% specificity and 92% sensitivity for detecting any of seven KRAS point mutations (Nature Med. 2014;20:430-5).

Mitchel L. Zoler/Frontine Medical News

“We think that liquid biopsies can help deliver the right treatment to a patient at the right time, and less invasively” than tissue biopsies, Dr. Prager said in a talk at the meeting. “They are useful for monitoring tumor growth and therapeutic activity.” He and his associates now have a study in progress evaluating the ability of serial ctDNA analysis to improve treatment with regorafenib in patients with metastatic colorectal cancer.

Analyses using ctDNA “are accurate, but we need to perform clinical trials to know what we should do with the information,” Dr. Prager said in an interview. “When we see a clone has been selected, should we change treatment before we see actual disease progression? This question has not yet been answered,” he said.

Circulating tumor cells

Liquid biopsy for CTCs has the advantage over ctDNA of having an FDA-approved test, which uses epithelial-marker antigens on the surface of CTCs to isolate the cells from a 7.5-mL specimen of blood. Study results showed a clear link between increased numbers of CTCs in patients and their rate of metastatic progression. For example, a meta-analysis published this year summarized data on CTC analysis in 1,944 patients with metastatic breast cancer evaluated in 20 separate studies done at 17 European centers. This meta-analysis showed that 47% of patients had a CTC count at baseline of 5 cells or more in a 7.5-mL specimen, and that this was significantly linked to diminished overall survival (hazard ratio, 1.92; 95% confidence interval, 1.73-2.14; P < .0001) (Lancet Oncol. 2014;15:406-14). The data also showed significantly reduced survival when CTC count increased either 3-5 weeks after treatment started or 6-8 weeks after treatment started. All these findings “confirm the independent, prognostic effect of CTC count on progression-free survival and overall survival,” the authors concluded.

Mitchel L. Zoler/Frontine Medical News

This report confirmed the added value of CTC number, which was first reported using the same CellSearch technology a decade before (New Engl. J. Med. 2004;351:781-91).

The 2014 meta-analysis “provides level I evidence that CTC detection with CellSearch is an adverse prognostic factor in metastatic breast cancer,” said Dr. Michail Ignatiadis, an oncologist at the Jules Bordet Institute in Brussels.

But while CTC number “gives us very good prognostication, what we want is to know whether a treatment is working, and [whether we] can we get enough information from these cells to decide on what treatment to use. That is more challenging,” said Dr. Klaus Pantel, a professor of oncology and director of tumor biology at the University of Hamburg, Germany.

Mitchel L. Zoler/Frontine Medical News

“We can now say, by monitoring CTCs in blood, whether or not treatment is going in the right direction; and it is important to have an early indicator of treatment response, but the challenge is to get a good picture” of the tumor to guide drug selection, Dr. Pantel said in an interview. He has recently used a new approach to collect CTCs developed by Gilupi that employs a receptor-coated needle placed in a patient’s blood vessel and left there for 30 minutes, during which roughly a liter of blood passes by the needle, allowing for collection of many more CTCs than is possible from a 7.5-mL specimen.

Another question about CTCs is that collection works well in metastatic-stage disease, when CTCs are relatively plentiful, but can it also play a role in assessing mortality risk in patients with early-stage cancer? Dr. Pantel and his associates recently addressed this question by using the CellSearch assay in 2,026 patients with early-stage breast cancer prior to treatment with adjuvant chemotherapy, and 1,492 patients after chemotherapy. The results showed that the presence of CTCs was linked to worse prognosis, with the worst outcomes occurring in women with 5 or more CTCs in 30 mL of blood (J. Natl. Cancer Inst. 2014;106:dju066 [doi: 10.1093/jnci/dju066]). The findings are the first “to provide strong evidence for the prognostic relevance of CTCs in early breast cancer before and after adjuvant chemotherapy in a large patient cohort,” Dr. Pantel and his coauthors concluded. “Our data offer support for the clinical potential of CTCs to assess the individual risk of patients at the time of primary diagnosis.”

Coupling liquid biopsies with better treatments

One of the challenges of using liquid biopsies to improve cancer treatment is the inherent limitation researchers often encounter of having to rely on inadequate treatment regimens with limited efficacy, Dr. Ignatiadis noted. That limitation came into play in a recent report of a study that used CTCs to stratify risk in patients with metastatic breast cancer and randomize them to either of two different treatment regimens. The results confirmed the prognostic significance of CTC number but failed to show that changing treatment based on CTC number improved outcomes, likely because the alternative regimen applied offered no real advantages over the comparator, the researchers concluded (J. Clin. Oncol. 2014 June 2 [doi: 10.1200/JCO.2014.56.2561]).

Studies now in progress have been designed to specifically test the efficacy of new treatment approaches in cancer populations selected for their CTC or ctDNA profile, such as the TREAT CTC trial, which is evaluating the efficacy of trastuzumab for treating women with detectable CTCs and HER2-negative primary breast cancer. Another example is the DETECT III trial, which is investigating the efficacy of lapatinib in patients with metastatic breast cancer who have HER2-positive CTCs.

“Until now we have mostly had proof-of-principle studies. Now we need to see how CTCs and ctDNA work in real practice” and in coordination with new approaches to treatment, Dr. Pantel said.

Dr. Bardelli is a shareholder in Horizon Discovery and has been an adviser to Biocartis, Trovagene, and HD. Dr. Caldas had no disclosures. Dr. Prager has been an adviser and consultant to Bayer, Roche, Amgen, Merck Serono, and Sanofi-Aventis. Dr. Ignatiadis has received educational grants from Janssen Diagnostics and Roche. Dr. Pantel has been an adviser to Veridex/Janssen, Alere, and Gilupi.

mzoler@frontlinemedcom.com 


On Twitter @mitchelzoler

MADRID – Liquid biopsies to track genetic changes in a patient’s tumor by serial blood specimens rather than multiple tissue biopsies seem poised to enter routine clinical use. But several experts speaking at a session on the topic agreed that liquid biopsy technologies largely remain too unproven to enter everyday practice right now.

“I have no doubt [liquid biopsy] will become routine, but right now the evidence is lacking,” said Alberto Bardelli, Ph.D., summarizing a session he cochaired at the European Society for Medical Oncology Congress.

Mitchel L. Zoler/Frontine Medical News

“I think the potential is very high to use liquid biopsy to monitor residual disease in patients with breast cancer or other tumor types. There is also the possibility of using CTCs [circulating tumor cells] to interrogate the genome of single tumor cells or to grow the cells and use them functionally” to, for example, help identify effective treatments against the tumor, said Dr. Bardelli, a molecular biologist at the University of Torino, Italy.

Liquid biopsies are generally divided into two categories. One approach involves the isolation and analysis of individual, living tumor cells that slough off a primary tumor or metastasis and can be isolated from a patient’s peripheral blood, although tumor cell concentrations are very low, on the order of one tumor cell in a million normal blood cells or even 10- to 100-fold more dilute than that.

In 2004, the Food and Drug Administration approved CellSearch, a commercial test that quantifies CTCs in patients with metastatic breast cancer to predict the likelihood of survival. CellSearch remains the only FDA-approved liquid biopsy assay for cancer, though its use has expanded to patients with prostate or colorectal cancer as well as breast cancer.

Circulating tumor DNA

The second option is to isolate and analyze the DNA that slips out of dead tumor cells and enters a patient’s circulation. One advantage of focusing on circulating tumor DNA (ctDNA) is that it is more than 100 times as common in a patent’s blood as tumor cells; however, tumor DNA is limited to providing a broad-brush average of what is going on genetically in a primary tumor and its metastases at any time, rather than giving the specificity of a genome isolated from a single, circulating tumor cell.

Both approaches seem to have value, and both seem on course to continue in development and be used in complementary ways.

An example of the potential benefit of analyzing ctDNA came in a study published last year, in which investigators identified genetic alterations that they could use to follow patients with metastatic breast cancer. They found ctDNA in the blood of 29 out of 52 women, and saw a strong, inverse relationship between increased levels of ctDNA and survival. Patients with a below-average level of ctDNA had significantly better survival, while patients with relatively higher ctDNA levels had significantly worse survival, the British researchers reported last year (New Engl. J. Med. 2013;368:1199-209). The study results also showed that quantifying ctDNA provided better correlation with changes in tumor burden than did quantifying CTCs or measuring an immune marker for breast cancer, CA 15-3.

Mitchel L. Zoler/Frontine Medical News

More recently, these investigators expanded the mutation panel they use to identify ctDNA, and now can find a single-nucleotide or structural variant in the DNAs of 48 of these 52 patients, Dr. Carlos Caldas, one of the investigators, said in a talk at the meeting. Dr. Caldas added that he and his associates have now seen a patient from this series with triple-negative breast cancer and an elevated level of ctDNA who then showed a dramatic reduction in ctDNA level following several treatment cycles. This drop in ctDNA level tracked with the patient’s complete pathological response to treatment.

“This is preliminary evidence that you can use ctDNA as a very early marker of treatment response,” said Dr. Caldas, professor of cancer medicine at the University of Cambridge, England.

Other advantages of measuring ctDNA, especially compared with tracking a tumor using CTCs, is that it is simple and relatively inexpensive, with no need for special isolation technology, and it reflects the patient’s total tumor burden, noted Dr. Gerald Prager, an oncologist at the Medical University of Vienna. He cited a recent example of the power of ctDNA analysis in a report on 106 patients with colorectal cancer, who underwent ctDNA analysis for KRAS and BRAF mutations. Comparison of results from the ctDNA analysis and conventional mutation determinations showed 100% sensitivity and specificity for detecting tumors with the BRAF V600E mutation, and 98% specificity and 92% sensitivity for detecting any of seven KRAS point mutations (Nature Med. 2014;20:430-5).

Mitchel L. Zoler/Frontine Medical News

“We think that liquid biopsies can help deliver the right treatment to a patient at the right time, and less invasively” than tissue biopsies, Dr. Prager said in a talk at the meeting. “They are useful for monitoring tumor growth and therapeutic activity.” He and his associates now have a study in progress evaluating the ability of serial ctDNA analysis to improve treatment with regorafenib in patients with metastatic colorectal cancer.

Analyses using ctDNA “are accurate, but we need to perform clinical trials to know what we should do with the information,” Dr. Prager said in an interview. “When we see a clone has been selected, should we change treatment before we see actual disease progression? This question has not yet been answered,” he said.

Circulating tumor cells

Liquid biopsy for CTCs has the advantage over ctDNA of having an FDA-approved test, which uses epithelial-marker antigens on the surface of CTCs to isolate the cells from a 7.5-mL specimen of blood. Study results showed a clear link between increased numbers of CTCs in patients and their rate of metastatic progression. For example, a meta-analysis published this year summarized data on CTC analysis in 1,944 patients with metastatic breast cancer evaluated in 20 separate studies done at 17 European centers. This meta-analysis showed that 47% of patients had a CTC count at baseline of 5 cells or more in a 7.5-mL specimen, and that this was significantly linked to diminished overall survival (hazard ratio, 1.92; 95% confidence interval, 1.73-2.14; P < .0001) (Lancet Oncol. 2014;15:406-14). The data also showed significantly reduced survival when CTC count increased either 3-5 weeks after treatment started or 6-8 weeks after treatment started. All these findings “confirm the independent, prognostic effect of CTC count on progression-free survival and overall survival,” the authors concluded.

Mitchel L. Zoler/Frontine Medical News

This report confirmed the added value of CTC number, which was first reported using the same CellSearch technology a decade before (New Engl. J. Med. 2004;351:781-91).

The 2014 meta-analysis “provides level I evidence that CTC detection with CellSearch is an adverse prognostic factor in metastatic breast cancer,” said Dr. Michail Ignatiadis, an oncologist at the Jules Bordet Institute in Brussels.

But while CTC number “gives us very good prognostication, what we want is to know whether a treatment is working, and [whether we] can we get enough information from these cells to decide on what treatment to use. That is more challenging,” said Dr. Klaus Pantel, a professor of oncology and director of tumor biology at the University of Hamburg, Germany.

Mitchel L. Zoler/Frontine Medical News

“We can now say, by monitoring CTCs in blood, whether or not treatment is going in the right direction; and it is important to have an early indicator of treatment response, but the challenge is to get a good picture” of the tumor to guide drug selection, Dr. Pantel said in an interview. He has recently used a new approach to collect CTCs developed by Gilupi that employs a receptor-coated needle placed in a patient’s blood vessel and left there for 30 minutes, during which roughly a liter of blood passes by the needle, allowing for collection of many more CTCs than is possible from a 7.5-mL specimen.

Another question about CTCs is that collection works well in metastatic-stage disease, when CTCs are relatively plentiful, but can it also play a role in assessing mortality risk in patients with early-stage cancer? Dr. Pantel and his associates recently addressed this question by using the CellSearch assay in 2,026 patients with early-stage breast cancer prior to treatment with adjuvant chemotherapy, and 1,492 patients after chemotherapy. The results showed that the presence of CTCs was linked to worse prognosis, with the worst outcomes occurring in women with 5 or more CTCs in 30 mL of blood (J. Natl. Cancer Inst. 2014;106:dju066 [doi: 10.1093/jnci/dju066]). The findings are the first “to provide strong evidence for the prognostic relevance of CTCs in early breast cancer before and after adjuvant chemotherapy in a large patient cohort,” Dr. Pantel and his coauthors concluded. “Our data offer support for the clinical potential of CTCs to assess the individual risk of patients at the time of primary diagnosis.”

Coupling liquid biopsies with better treatments

One of the challenges of using liquid biopsies to improve cancer treatment is the inherent limitation researchers often encounter of having to rely on inadequate treatment regimens with limited efficacy, Dr. Ignatiadis noted. That limitation came into play in a recent report of a study that used CTCs to stratify risk in patients with metastatic breast cancer and randomize them to either of two different treatment regimens. The results confirmed the prognostic significance of CTC number but failed to show that changing treatment based on CTC number improved outcomes, likely because the alternative regimen applied offered no real advantages over the comparator, the researchers concluded (J. Clin. Oncol. 2014 June 2 [doi: 10.1200/JCO.2014.56.2561]).

Studies now in progress have been designed to specifically test the efficacy of new treatment approaches in cancer populations selected for their CTC or ctDNA profile, such as the TREAT CTC trial, which is evaluating the efficacy of trastuzumab for treating women with detectable CTCs and HER2-negative primary breast cancer. Another example is the DETECT III trial, which is investigating the efficacy of lapatinib in patients with metastatic breast cancer who have HER2-positive CTCs.

“Until now we have mostly had proof-of-principle studies. Now we need to see how CTCs and ctDNA work in real practice” and in coordination with new approaches to treatment, Dr. Pantel said.

Dr. Bardelli is a shareholder in Horizon Discovery and has been an adviser to Biocartis, Trovagene, and HD. Dr. Caldas had no disclosures. Dr. Prager has been an adviser and consultant to Bayer, Roche, Amgen, Merck Serono, and Sanofi-Aventis. Dr. Ignatiadis has received educational grants from Janssen Diagnostics and Roche. Dr. Pantel has been an adviser to Veridex/Janssen, Alere, and Gilupi.

mzoler@frontlinemedcom.com 


On Twitter @mitchelzoler

MADRID – Liquid biopsies to track genetic changes in a patient’s tumor by serial blood specimens rather than multiple tissue biopsies seem poised to enter routine clinical use. But several experts speaking at a session on the topic agreed that liquid biopsy technologies largely remain too unproven to enter everyday practice right now.

“I have no doubt [liquid biopsy] will become routine, but right now the evidence is lacking,” said Alberto Bardelli, Ph.D., summarizing a session he cochaired at the European Society for Medical Oncology Congress.

Mitchel L. Zoler/Frontine Medical News

“I think the potential is very high to use liquid biopsy to monitor residual disease in patients with breast cancer or other tumor types. There is also the possibility of using CTCs [circulating tumor cells] to interrogate the genome of single tumor cells or to grow the cells and use them functionally” to, for example, help identify effective treatments against the tumor, said Dr. Bardelli, a molecular biologist at the University of Torino, Italy.

Liquid biopsies are generally divided into two categories. One approach involves the isolation and analysis of individual, living tumor cells that slough off a primary tumor or metastasis and can be isolated from a patient’s peripheral blood, although tumor cell concentrations are very low, on the order of one tumor cell in a million normal blood cells or even 10- to 100-fold more dilute than that.

In 2004, the Food and Drug Administration approved CellSearch, a commercial test that quantifies CTCs in patients with metastatic breast cancer to predict the likelihood of survival. CellSearch remains the only FDA-approved liquid biopsy assay for cancer, though its use has expanded to patients with prostate or colorectal cancer as well as breast cancer.

Circulating tumor DNA

The second option is to isolate and analyze the DNA that slips out of dead tumor cells and enters a patient’s circulation. One advantage of focusing on circulating tumor DNA (ctDNA) is that it is more than 100 times as common in a patent’s blood as tumor cells; however, tumor DNA is limited to providing a broad-brush average of what is going on genetically in a primary tumor and its metastases at any time, rather than giving the specificity of a genome isolated from a single, circulating tumor cell.

Both approaches seem to have value, and both seem on course to continue in development and be used in complementary ways.

An example of the potential benefit of analyzing ctDNA came in a study published last year, in which investigators identified genetic alterations that they could use to follow patients with metastatic breast cancer. They found ctDNA in the blood of 29 out of 52 women, and saw a strong, inverse relationship between increased levels of ctDNA and survival. Patients with a below-average level of ctDNA had significantly better survival, while patients with relatively higher ctDNA levels had significantly worse survival, the British researchers reported last year (New Engl. J. Med. 2013;368:1199-209). The study results also showed that quantifying ctDNA provided better correlation with changes in tumor burden than did quantifying CTCs or measuring an immune marker for breast cancer, CA 15-3.

Mitchel L. Zoler/Frontine Medical News

More recently, these investigators expanded the mutation panel they use to identify ctDNA, and now can find a single-nucleotide or structural variant in the DNAs of 48 of these 52 patients, Dr. Carlos Caldas, one of the investigators, said in a talk at the meeting. Dr. Caldas added that he and his associates have now seen a patient from this series with triple-negative breast cancer and an elevated level of ctDNA who then showed a dramatic reduction in ctDNA level following several treatment cycles. This drop in ctDNA level tracked with the patient’s complete pathological response to treatment.

“This is preliminary evidence that you can use ctDNA as a very early marker of treatment response,” said Dr. Caldas, professor of cancer medicine at the University of Cambridge, England.

Other advantages of measuring ctDNA, especially compared with tracking a tumor using CTCs, is that it is simple and relatively inexpensive, with no need for special isolation technology, and it reflects the patient’s total tumor burden, noted Dr. Gerald Prager, an oncologist at the Medical University of Vienna. He cited a recent example of the power of ctDNA analysis in a report on 106 patients with colorectal cancer, who underwent ctDNA analysis for KRAS and BRAF mutations. Comparison of results from the ctDNA analysis and conventional mutation determinations showed 100% sensitivity and specificity for detecting tumors with the BRAF V600E mutation, and 98% specificity and 92% sensitivity for detecting any of seven KRAS point mutations (Nature Med. 2014;20:430-5).

Mitchel L. Zoler/Frontine Medical News

“We think that liquid biopsies can help deliver the right treatment to a patient at the right time, and less invasively” than tissue biopsies, Dr. Prager said in a talk at the meeting. “They are useful for monitoring tumor growth and therapeutic activity.” He and his associates now have a study in progress evaluating the ability of serial ctDNA analysis to improve treatment with regorafenib in patients with metastatic colorectal cancer.

Analyses using ctDNA “are accurate, but we need to perform clinical trials to know what we should do with the information,” Dr. Prager said in an interview. “When we see a clone has been selected, should we change treatment before we see actual disease progression? This question has not yet been answered,” he said.

Circulating tumor cells

Liquid biopsy for CTCs has the advantage over ctDNA of having an FDA-approved test, which uses epithelial-marker antigens on the surface of CTCs to isolate the cells from a 7.5-mL specimen of blood. Study results showed a clear link between increased numbers of CTCs in patients and their rate of metastatic progression. For example, a meta-analysis published this year summarized data on CTC analysis in 1,944 patients with metastatic breast cancer evaluated in 20 separate studies done at 17 European centers. This meta-analysis showed that 47% of patients had a CTC count at baseline of 5 cells or more in a 7.5-mL specimen, and that this was significantly linked to diminished overall survival (hazard ratio, 1.92; 95% confidence interval, 1.73-2.14; P < .0001) (Lancet Oncol. 2014;15:406-14). The data also showed significantly reduced survival when CTC count increased either 3-5 weeks after treatment started or 6-8 weeks after treatment started. All these findings “confirm the independent, prognostic effect of CTC count on progression-free survival and overall survival,” the authors concluded.

Mitchel L. Zoler/Frontine Medical News

This report confirmed the added value of CTC number, which was first reported using the same CellSearch technology a decade before (New Engl. J. Med. 2004;351:781-91).

The 2014 meta-analysis “provides level I evidence that CTC detection with CellSearch is an adverse prognostic factor in metastatic breast cancer,” said Dr. Michail Ignatiadis, an oncologist at the Jules Bordet Institute in Brussels.

But while CTC number “gives us very good prognostication, what we want is to know whether a treatment is working, and [whether we] can we get enough information from these cells to decide on what treatment to use. That is more challenging,” said Dr. Klaus Pantel, a professor of oncology and director of tumor biology at the University of Hamburg, Germany.

Mitchel L. Zoler/Frontine Medical News

“We can now say, by monitoring CTCs in blood, whether or not treatment is going in the right direction; and it is important to have an early indicator of treatment response, but the challenge is to get a good picture” of the tumor to guide drug selection, Dr. Pantel said in an interview. He has recently used a new approach to collect CTCs developed by Gilupi that employs a receptor-coated needle placed in a patient’s blood vessel and left there for 30 minutes, during which roughly a liter of blood passes by the needle, allowing for collection of many more CTCs than is possible from a 7.5-mL specimen.

Another question about CTCs is that collection works well in metastatic-stage disease, when CTCs are relatively plentiful, but can it also play a role in assessing mortality risk in patients with early-stage cancer? Dr. Pantel and his associates recently addressed this question by using the CellSearch assay in 2,026 patients with early-stage breast cancer prior to treatment with adjuvant chemotherapy, and 1,492 patients after chemotherapy. The results showed that the presence of CTCs was linked to worse prognosis, with the worst outcomes occurring in women with 5 or more CTCs in 30 mL of blood (J. Natl. Cancer Inst. 2014;106:dju066 [doi: 10.1093/jnci/dju066]). The findings are the first “to provide strong evidence for the prognostic relevance of CTCs in early breast cancer before and after adjuvant chemotherapy in a large patient cohort,” Dr. Pantel and his coauthors concluded. “Our data offer support for the clinical potential of CTCs to assess the individual risk of patients at the time of primary diagnosis.”

Coupling liquid biopsies with better treatments

One of the challenges of using liquid biopsies to improve cancer treatment is the inherent limitation researchers often encounter of having to rely on inadequate treatment regimens with limited efficacy, Dr. Ignatiadis noted. That limitation came into play in a recent report of a study that used CTCs to stratify risk in patients with metastatic breast cancer and randomize them to either of two different treatment regimens. The results confirmed the prognostic significance of CTC number but failed to show that changing treatment based on CTC number improved outcomes, likely because the alternative regimen applied offered no real advantages over the comparator, the researchers concluded (J. Clin. Oncol. 2014 June 2 [doi: 10.1200/JCO.2014.56.2561]).

Studies now in progress have been designed to specifically test the efficacy of new treatment approaches in cancer populations selected for their CTC or ctDNA profile, such as the TREAT CTC trial, which is evaluating the efficacy of trastuzumab for treating women with detectable CTCs and HER2-negative primary breast cancer. Another example is the DETECT III trial, which is investigating the efficacy of lapatinib in patients with metastatic breast cancer who have HER2-positive CTCs.

“Until now we have mostly had proof-of-principle studies. Now we need to see how CTCs and ctDNA work in real practice” and in coordination with new approaches to treatment, Dr. Pantel said.

Dr. Bardelli is a shareholder in Horizon Discovery and has been an adviser to Biocartis, Trovagene, and HD. Dr. Caldas had no disclosures. Dr. Prager has been an adviser and consultant to Bayer, Roche, Amgen, Merck Serono, and Sanofi-Aventis. Dr. Ignatiadis has received educational grants from Janssen Diagnostics and Roche. Dr. Pantel has been an adviser to Veridex/Janssen, Alere, and Gilupi.

mzoler@frontlinemedcom.com 


On Twitter @mitchelzoler

MADRID – Assessing the genetic profile of tumor DNA circulating in a cancer patient’s blood is a potentially attractive way to track a tumor without the need for multiple tissue biopsies. The limitation of these liquid biopsies is that the clinical relevance of periodically assessing circulating tumor DNA has not yet been proven, Dr. Gerald Prager said during a video interview at the European Society for Medical Oncology Congress.

“We need to perform clinical trials to know what to do” with the information that comes from evaluating circulating tumor DNA, said Dr. Prager, an oncologist at the Medical University of Vienna.

“Should we change” a patient’s treatment based on genetic results “before we see disease progression? We have not answered that yet.”

Dr. Prager has been an adviser and consultant to Bayer, Roche, Amgen, Merck Serono, and Sanofi-Aventis.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

MADRID – Assessing the genetic profile of tumor DNA circulating in a cancer patient’s blood is a potentially attractive way to track a tumor without the need for multiple tissue biopsies. The limitation of these liquid biopsies is that the clinical relevance of periodically assessing circulating tumor DNA has not yet been proven, Dr. Gerald Prager said during a video interview at the European Society for Medical Oncology Congress.

“We need to perform clinical trials to know what to do” with the information that comes from evaluating circulating tumor DNA, said Dr. Prager, an oncologist at the Medical University of Vienna.

“Should we change” a patient’s treatment based on genetic results “before we see disease progression? We have not answered that yet.”

Dr. Prager has been an adviser and consultant to Bayer, Roche, Amgen, Merck Serono, and Sanofi-Aventis.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

MADRID – Assessing the genetic profile of tumor DNA circulating in a cancer patient’s blood is a potentially attractive way to track a tumor without the need for multiple tissue biopsies. The limitation of these liquid biopsies is that the clinical relevance of periodically assessing circulating tumor DNA has not yet been proven, Dr. Gerald Prager said during a video interview at the European Society for Medical Oncology Congress.

“We need to perform clinical trials to know what to do” with the information that comes from evaluating circulating tumor DNA, said Dr. Prager, an oncologist at the Medical University of Vienna.

“Should we change” a patient’s treatment based on genetic results “before we see disease progression? We have not answered that yet.”

Dr. Prager has been an adviser and consultant to Bayer, Roche, Amgen, Merck Serono, and Sanofi-Aventis.

mzoler@frontlinemedcom.com

On Twitter @mitchelzoler

Remarks given during a session of the ASCO Breast Cancer Symposium titled Ductal Carcinoma in Situ Debate: Treatment vs. Observation

Dr. Kuerer comments: There has been a marked increase ductal carcinoma in situ (DCIS) in what is being called overdiagnosis, and this is leading to concerns of overtreatment, which has been in the news now for several years. We have more than 60,000 cases of DCIS diagnosed per year in the United States. We’re trying to prevent invasive breast cancer and distant metastases. The problem is identifying which patients will go on to develop invasive disease. That’s really unknown.

At M.D. Anderson, looking at 10-year follow-up of 2,449 patients, the rate of developing distant metastases was 0.1%. The problem with this is that no prominent variables were associated with the development of invasive metastatic disease. Overall, we are doing a good job at preventing death from breast cancer when we treat DCIS, with less than 1% of patients dying of breast cancer (Ann. Surg. Onc. 2011;18:2873-8).

Dr. Shelley E. Hwang and her group very elegantly started exploring preoperative systemic therapy as a way to get a clue about which patients might be safely observed alone (that is, a core biopsy diagnosis of DCIS and then just follow-up without surgery or other treatments). At M.D. Anderson, we studied whether or not we could eradicate DCIS in patients with human epidermal growth factor receptor 2 (HER2) overexpression by treatment with trastuzumab prior to surgery, under the hypothesis that if we could eradicate the DCIS, we might eventually use this drug potentially to prevent HER2-positive invasive breast cancers. We saw very dramatic responses in their immune response with antibody-dependent cellular cytotoxicity mediated by natural killer cells, which is exciting, but there were no histopathologic changes. The most important finding was that 42% of our patients who we thought only had DCIS actually had occult invasive breast cancer (Cancer 2011;117:39-47). This is concerning because without surgery, we may be missing or leaving untreated invasive breast cancers in some patients.

So, we have an underestimation of invasive breast cancer at DCIS diagnosis. A very elegant meta-analysis of 7,350 patients reported that even if we take patients with non–high-grade, very-small DCIS, we’re still looking at an upgrade to invasive cancer of about 20% (Radiology 2011;260:119-28). The best and most recent studies of MRI and DCIS again found a diagnostic upgrade of about 27%. There were no MRI features correlating with invasive breast cancer, and this resulted in a 31% increase in procedures and more biopsies with the use of MRI.

So where are we? In active surveillance of 14 patients with DCIS at the University of California, San Francisco, 8 went on to surgery at a median follow-up of 28 months, and 5 of the 8 (62%) had invasive breast cancer (The Breast 2011;20:529-33).

What’s the cost to the health care system of surveillance if we biopsy only the DCIS and follow it without surgery or other adjuvant therapies? The psychological cost to our patients? What is the natural history of DCIS if left in place? What will be the result of microcalcifications? How are we going to follow this? What are the criteria that we will use for repeat biopsy? This really is not known.

Which are the patients that we’re going to select for observation alone? There are trials in Europe that have begun or will begin to address the safety of just observing DCIS without surgery and other therapies.

The United Kingdom Low-Risk DCIS Trial is randomizing patients with low and intermediate grade DCIS of any size to biopsy alone without surgical intervention (active monitoring) or standard therapy. Another trial, a joint Dutch Breast Cancer Research Group and European Organization for the Research and Treatment of Cancer trial is randomizing women with low-risk, low-grade DCIS to active surveillance or standard treatment. If we look at M.D. Anderson’s data and our National Cancer Database, only about 10%-15% of patients would be eligible for the latter study. I don’t think with these numbers we’d have a great impact, but it is a start.

I submit that the best U.S. patients to study will be patients with a diagnosis of atypical ductal hyperplasia (generally the smallest lesions and perhaps the earliest form of DCIS) because we have about 100,000 cases each year.

What’s the patient’s perspective? What about the need for continued repeat biopsies, and how this will affect their overall quality of life? Do patients in the United States really want to observe the DCIS in an era when our patients are requesting more and more mastectomy with reconstruction and contralateral mastectomy at diagnosis of DCIS? I seriously doubt that our patients in the United States would agree to be randomized in DCIS trials to no treatment at all. I really don’t know.

Dr. Kuerer is a professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston. He reported financial associations with Gerson Lehrman Group and McGraw-Hill Publishing.

Dr. Hwang comments: Today, about 1/1,300 screening mammograms result in a diagnosis of DCIS. There are two important considerations when we talk about active surveillance or doing less aggressive treatment. First, what is the rate at which progression to invasive cancer can occur, either with or without treatment? Second, what is the fate of these DCIS lesions? These are issues for which we currently don’t have good answers.

We’re treating all disease detected at an early stage, and for the sake of argument, I’ll include DCIS, as if it likely will cause harm if we did absolutely nothing when, in fact, there could be many cancers that progress so slowly and have such a low propensity for developing metastatic disease that they would not likely cause any symptoms or harm during a patient’s lifetime.

In autopsy series, the disease reservoir of unrecognized DCIS is about 9% and the disease reservoir of invasive cancer is about 1%. It’s not that different from prostate cancer, although at a much lower rate. These data show that there certainly are women who die with DCIS rather than of it.

We really don’t have a very solid understanding of the natural history of DCIS. If we do nothing, but maybe surgically biopsy it, what happens to these patients in the long term? In a meta-analysis, the world’s literature included only 151 cases of women who had surgical biopsy of DCIS that initially was misdiagnosed as a benign lesion and therefore didn’t undergo any further therapy, some with up to 31 years of follow-up. The long-term risk of invasive cancer in this cohort is only 22% (Breast Cancer Res. Treat. 2006;97:135-44). The annual risk of breast cancer in women with atypia is 1% per year, so this ends up looking very similar to the risk of progression that you see for atypical ductal hyperplasia or lobular carcinoma in situ.

The most common treatment for DCIS in the United States is lumpectomy with radiation. A meta-analysis by the European Breast Cancer Trialists’ Group found a 50% proportional reduction in local recurrence risk in women treated with lumpectomy and radiation vs. lumpectomy alone. The absolute magnitude of reduction was dependent on baseline recurrence risk. That’s a really important concept, because if your baseline risk is only 5%, then the 50% proportional reduction only translates into a 2.5% reduction in risk in 10 years.

The prospective, randomized Radiation Therapy Oncologists Group 9804 study randomized low-risk women with DCIS, unlike prior randomized trials that included broad eligibility criteria for DCIS. In 5 years of follow-up, the ipsilateral recurrence risk (which includes both invasive cancer and DCIS) was 3.2% in the lumpectomy-only group vs. 0.4% in the lumpectomy and radiation therapy group. The difference is highly statistically significant, however, given the small absolute difference between groups, the clinical significance certainly can be argued. There was no significant difference between groups in contralateral new primary lesions (Radiat. Oncol. 2012;84:S5).

We just presented a study this year looking at DCIS and competing causes of mortality in different age groups with different types of treatment. Among women with DCIS over 70 years of age, there was a significant difference in overall survival but none of the treatments conferred any benefit in disease-specific survival.

Active surveillance alone may be reasonable to consider in some patients. We can learn a lot from our colleagues who treat prostate cancer. They’re at least 10 years ahead of us in thinking about reducing the harms that have been introduced by screening for prostate cancer. When you look at breast cancer–specific and other-cause mortality in the setting of DCIS, the mortality curves look very similar to those with early-stage prostate cancer. Women with DCIS, regardless of what they are treated with, die of other causes and very rarely die of breast cancer.

When we compare such different options as mastectomy to active surveillance only, it’s really hard for a patient to feel that both of those approaches can offer them the same outcomes. But when you look at the actual data and evidence, the differences in recurrence or progression to invasive cancer don’t translate easily into a large difference in breast cancer mortality provided that patients are diagnosed at stage I or II, with more than a 90% survival from breast cancer.

We have an opportunity to take a big step back and redefine our goals of DCIS “treatment” from “curing” DCIS to trying to reduce breast cancer-specific mortality. This will help us reduce the harms that can result from screening and will reserve our aggressive treatments for those most likely to benefit from them.

Dr. Hwang is a professor of surgery at Duke University, Durham, N.C. She serves as a consultant for Genomic Health.

Remarks given during a session of the ASCO Breast Cancer Symposium titled Ductal Carcinoma in Situ Debate: Treatment vs. Observation

Dr. Kuerer comments: There has been a marked increase ductal carcinoma in situ (DCIS) in what is being called overdiagnosis, and this is leading to concerns of overtreatment, which has been in the news now for several years. We have more than 60,000 cases of DCIS diagnosed per year in the United States. We’re trying to prevent invasive breast cancer and distant metastases. The problem is identifying which patients will go on to develop invasive disease. That’s really unknown.

At M.D. Anderson, looking at 10-year follow-up of 2,449 patients, the rate of developing distant metastases was 0.1%. The problem with this is that no prominent variables were associated with the development of invasive metastatic disease. Overall, we are doing a good job at preventing death from breast cancer when we treat DCIS, with less than 1% of patients dying of breast cancer (Ann. Surg. Onc. 2011;18:2873-8).

Dr. Shelley E. Hwang and her group very elegantly started exploring preoperative systemic therapy as a way to get a clue about which patients might be safely observed alone (that is, a core biopsy diagnosis of DCIS and then just follow-up without surgery or other treatments). At M.D. Anderson, we studied whether or not we could eradicate DCIS in patients with human epidermal growth factor receptor 2 (HER2) overexpression by treatment with trastuzumab prior to surgery, under the hypothesis that if we could eradicate the DCIS, we might eventually use this drug potentially to prevent HER2-positive invasive breast cancers. We saw very dramatic responses in their immune response with antibody-dependent cellular cytotoxicity mediated by natural killer cells, which is exciting, but there were no histopathologic changes. The most important finding was that 42% of our patients who we thought only had DCIS actually had occult invasive breast cancer (Cancer 2011;117:39-47). This is concerning because without surgery, we may be missing or leaving untreated invasive breast cancers in some patients.

So, we have an underestimation of invasive breast cancer at DCIS diagnosis. A very elegant meta-analysis of 7,350 patients reported that even if we take patients with non–high-grade, very-small DCIS, we’re still looking at an upgrade to invasive cancer of about 20% (Radiology 2011;260:119-28). The best and most recent studies of MRI and DCIS again found a diagnostic upgrade of about 27%. There were no MRI features correlating with invasive breast cancer, and this resulted in a 31% increase in procedures and more biopsies with the use of MRI.

So where are we? In active surveillance of 14 patients with DCIS at the University of California, San Francisco, 8 went on to surgery at a median follow-up of 28 months, and 5 of the 8 (62%) had invasive breast cancer (The Breast 2011;20:529-33).

What’s the cost to the health care system of surveillance if we biopsy only the DCIS and follow it without surgery or other adjuvant therapies? The psychological cost to our patients? What is the natural history of DCIS if left in place? What will be the result of microcalcifications? How are we going to follow this? What are the criteria that we will use for repeat biopsy? This really is not known.

Which are the patients that we’re going to select for observation alone? There are trials in Europe that have begun or will begin to address the safety of just observing DCIS without surgery and other therapies.

The United Kingdom Low-Risk DCIS Trial is randomizing patients with low and intermediate grade DCIS of any size to biopsy alone without surgical intervention (active monitoring) or standard therapy. Another trial, a joint Dutch Breast Cancer Research Group and European Organization for the Research and Treatment of Cancer trial is randomizing women with low-risk, low-grade DCIS to active surveillance or standard treatment. If we look at M.D. Anderson’s data and our National Cancer Database, only about 10%-15% of patients would be eligible for the latter study. I don’t think with these numbers we’d have a great impact, but it is a start.

I submit that the best U.S. patients to study will be patients with a diagnosis of atypical ductal hyperplasia (generally the smallest lesions and perhaps the earliest form of DCIS) because we have about 100,000 cases each year.

What’s the patient’s perspective? What about the need for continued repeat biopsies, and how this will affect their overall quality of life? Do patients in the United States really want to observe the DCIS in an era when our patients are requesting more and more mastectomy with reconstruction and contralateral mastectomy at diagnosis of DCIS? I seriously doubt that our patients in the United States would agree to be randomized in DCIS trials to no treatment at all. I really don’t know.

Dr. Kuerer is a professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston. He reported financial associations with Gerson Lehrman Group and McGraw-Hill Publishing.

Dr. Hwang comments: Today, about 1/1,300 screening mammograms result in a diagnosis of DCIS. There are two important considerations when we talk about active surveillance or doing less aggressive treatment. First, what is the rate at which progression to invasive cancer can occur, either with or without treatment? Second, what is the fate of these DCIS lesions? These are issues for which we currently don’t have good answers.

We’re treating all disease detected at an early stage, and for the sake of argument, I’ll include DCIS, as if it likely will cause harm if we did absolutely nothing when, in fact, there could be many cancers that progress so slowly and have such a low propensity for developing metastatic disease that they would not likely cause any symptoms or harm during a patient’s lifetime.

In autopsy series, the disease reservoir of unrecognized DCIS is about 9% and the disease reservoir of invasive cancer is about 1%. It’s not that different from prostate cancer, although at a much lower rate. These data show that there certainly are women who die with DCIS rather than of it.

We really don’t have a very solid understanding of the natural history of DCIS. If we do nothing, but maybe surgically biopsy it, what happens to these patients in the long term? In a meta-analysis, the world’s literature included only 151 cases of women who had surgical biopsy of DCIS that initially was misdiagnosed as a benign lesion and therefore didn’t undergo any further therapy, some with up to 31 years of follow-up. The long-term risk of invasive cancer in this cohort is only 22% (Breast Cancer Res. Treat. 2006;97:135-44). The annual risk of breast cancer in women with atypia is 1% per year, so this ends up looking very similar to the risk of progression that you see for atypical ductal hyperplasia or lobular carcinoma in situ.

The most common treatment for DCIS in the United States is lumpectomy with radiation. A meta-analysis by the European Breast Cancer Trialists’ Group found a 50% proportional reduction in local recurrence risk in women treated with lumpectomy and radiation vs. lumpectomy alone. The absolute magnitude of reduction was dependent on baseline recurrence risk. That’s a really important concept, because if your baseline risk is only 5%, then the 50% proportional reduction only translates into a 2.5% reduction in risk in 10 years.

The prospective, randomized Radiation Therapy Oncologists Group 9804 study randomized low-risk women with DCIS, unlike prior randomized trials that included broad eligibility criteria for DCIS. In 5 years of follow-up, the ipsilateral recurrence risk (which includes both invasive cancer and DCIS) was 3.2% in the lumpectomy-only group vs. 0.4% in the lumpectomy and radiation therapy group. The difference is highly statistically significant, however, given the small absolute difference between groups, the clinical significance certainly can be argued. There was no significant difference between groups in contralateral new primary lesions (Radiat. Oncol. 2012;84:S5).

We just presented a study this year looking at DCIS and competing causes of mortality in different age groups with different types of treatment. Among women with DCIS over 70 years of age, there was a significant difference in overall survival but none of the treatments conferred any benefit in disease-specific survival.

Active surveillance alone may be reasonable to consider in some patients. We can learn a lot from our colleagues who treat prostate cancer. They’re at least 10 years ahead of us in thinking about reducing the harms that have been introduced by screening for prostate cancer. When you look at breast cancer–specific and other-cause mortality in the setting of DCIS, the mortality curves look very similar to those with early-stage prostate cancer. Women with DCIS, regardless of what they are treated with, die of other causes and very rarely die of breast cancer.

When we compare such different options as mastectomy to active surveillance only, it’s really hard for a patient to feel that both of those approaches can offer them the same outcomes. But when you look at the actual data and evidence, the differences in recurrence or progression to invasive cancer don’t translate easily into a large difference in breast cancer mortality provided that patients are diagnosed at stage I or II, with more than a 90% survival from breast cancer.

We have an opportunity to take a big step back and redefine our goals of DCIS “treatment” from “curing” DCIS to trying to reduce breast cancer-specific mortality. This will help us reduce the harms that can result from screening and will reserve our aggressive treatments for those most likely to benefit from them.

Dr. Hwang is a professor of surgery at Duke University, Durham, N.C. She serves as a consultant for Genomic Health.

Remarks given during a session of the ASCO Breast Cancer Symposium titled Ductal Carcinoma in Situ Debate: Treatment vs. Observation

Dr. Kuerer comments: There has been a marked increase ductal carcinoma in situ (DCIS) in what is being called overdiagnosis, and this is leading to concerns of overtreatment, which has been in the news now for several years. We have more than 60,000 cases of DCIS diagnosed per year in the United States. We’re trying to prevent invasive breast cancer and distant metastases. The problem is identifying which patients will go on to develop invasive disease. That’s really unknown.

At M.D. Anderson, looking at 10-year follow-up of 2,449 patients, the rate of developing distant metastases was 0.1%. The problem with this is that no prominent variables were associated with the development of invasive metastatic disease. Overall, we are doing a good job at preventing death from breast cancer when we treat DCIS, with less than 1% of patients dying of breast cancer (Ann. Surg. Onc. 2011;18:2873-8).

Dr. Shelley E. Hwang and her group very elegantly started exploring preoperative systemic therapy as a way to get a clue about which patients might be safely observed alone (that is, a core biopsy diagnosis of DCIS and then just follow-up without surgery or other treatments). At M.D. Anderson, we studied whether or not we could eradicate DCIS in patients with human epidermal growth factor receptor 2 (HER2) overexpression by treatment with trastuzumab prior to surgery, under the hypothesis that if we could eradicate the DCIS, we might eventually use this drug potentially to prevent HER2-positive invasive breast cancers. We saw very dramatic responses in their immune response with antibody-dependent cellular cytotoxicity mediated by natural killer cells, which is exciting, but there were no histopathologic changes. The most important finding was that 42% of our patients who we thought only had DCIS actually had occult invasive breast cancer (Cancer 2011;117:39-47). This is concerning because without surgery, we may be missing or leaving untreated invasive breast cancers in some patients.

So, we have an underestimation of invasive breast cancer at DCIS diagnosis. A very elegant meta-analysis of 7,350 patients reported that even if we take patients with non–high-grade, very-small DCIS, we’re still looking at an upgrade to invasive cancer of about 20% (Radiology 2011;260:119-28). The best and most recent studies of MRI and DCIS again found a diagnostic upgrade of about 27%. There were no MRI features correlating with invasive breast cancer, and this resulted in a 31% increase in procedures and more biopsies with the use of MRI.

So where are we? In active surveillance of 14 patients with DCIS at the University of California, San Francisco, 8 went on to surgery at a median follow-up of 28 months, and 5 of the 8 (62%) had invasive breast cancer (The Breast 2011;20:529-33).

What’s the cost to the health care system of surveillance if we biopsy only the DCIS and follow it without surgery or other adjuvant therapies? The psychological cost to our patients? What is the natural history of DCIS if left in place? What will be the result of microcalcifications? How are we going to follow this? What are the criteria that we will use for repeat biopsy? This really is not known.

Which are the patients that we’re going to select for observation alone? There are trials in Europe that have begun or will begin to address the safety of just observing DCIS without surgery and other therapies.

The United Kingdom Low-Risk DCIS Trial is randomizing patients with low and intermediate grade DCIS of any size to biopsy alone without surgical intervention (active monitoring) or standard therapy. Another trial, a joint Dutch Breast Cancer Research Group and European Organization for the Research and Treatment of Cancer trial is randomizing women with low-risk, low-grade DCIS to active surveillance or standard treatment. If we look at M.D. Anderson’s data and our National Cancer Database, only about 10%-15% of patients would be eligible for the latter study. I don’t think with these numbers we’d have a great impact, but it is a start.

I submit that the best U.S. patients to study will be patients with a diagnosis of atypical ductal hyperplasia (generally the smallest lesions and perhaps the earliest form of DCIS) because we have about 100,000 cases each year.

What’s the patient’s perspective? What about the need for continued repeat biopsies, and how this will affect their overall quality of life? Do patients in the United States really want to observe the DCIS in an era when our patients are requesting more and more mastectomy with reconstruction and contralateral mastectomy at diagnosis of DCIS? I seriously doubt that our patients in the United States would agree to be randomized in DCIS trials to no treatment at all. I really don’t know.

Dr. Kuerer is a professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston. He reported financial associations with Gerson Lehrman Group and McGraw-Hill Publishing.

Dr. Hwang comments: Today, about 1/1,300 screening mammograms result in a diagnosis of DCIS. There are two important considerations when we talk about active surveillance or doing less aggressive treatment. First, what is the rate at which progression to invasive cancer can occur, either with or without treatment? Second, what is the fate of these DCIS lesions? These are issues for which we currently don’t have good answers.

We’re treating all disease detected at an early stage, and for the sake of argument, I’ll include DCIS, as if it likely will cause harm if we did absolutely nothing when, in fact, there could be many cancers that progress so slowly and have such a low propensity for developing metastatic disease that they would not likely cause any symptoms or harm during a patient’s lifetime.

In autopsy series, the disease reservoir of unrecognized DCIS is about 9% and the disease reservoir of invasive cancer is about 1%. It’s not that different from prostate cancer, although at a much lower rate. These data show that there certainly are women who die with DCIS rather than of it.

We really don’t have a very solid understanding of the natural history of DCIS. If we do nothing, but maybe surgically biopsy it, what happens to these patients in the long term? In a meta-analysis, the world’s literature included only 151 cases of women who had surgical biopsy of DCIS that initially was misdiagnosed as a benign lesion and therefore didn’t undergo any further therapy, some with up to 31 years of follow-up. The long-term risk of invasive cancer in this cohort is only 22% (Breast Cancer Res. Treat. 2006;97:135-44). The annual risk of breast cancer in women with atypia is 1% per year, so this ends up looking very similar to the risk of progression that you see for atypical ductal hyperplasia or lobular carcinoma in situ.

The most common treatment for DCIS in the United States is lumpectomy with radiation. A meta-analysis by the European Breast Cancer Trialists’ Group found a 50% proportional reduction in local recurrence risk in women treated with lumpectomy and radiation vs. lumpectomy alone. The absolute magnitude of reduction was dependent on baseline recurrence risk. That’s a really important concept, because if your baseline risk is only 5%, then the 50% proportional reduction only translates into a 2.5% reduction in risk in 10 years.

The prospective, randomized Radiation Therapy Oncologists Group 9804 study randomized low-risk women with DCIS, unlike prior randomized trials that included broad eligibility criteria for DCIS. In 5 years of follow-up, the ipsilateral recurrence risk (which includes both invasive cancer and DCIS) was 3.2% in the lumpectomy-only group vs. 0.4% in the lumpectomy and radiation therapy group. The difference is highly statistically significant, however, given the small absolute difference between groups, the clinical significance certainly can be argued. There was no significant difference between groups in contralateral new primary lesions (Radiat. Oncol. 2012;84:S5).

We just presented a study this year looking at DCIS and competing causes of mortality in different age groups with different types of treatment. Among women with DCIS over 70 years of age, there was a significant difference in overall survival but none of the treatments conferred any benefit in disease-specific survival.

Active surveillance alone may be reasonable to consider in some patients. We can learn a lot from our colleagues who treat prostate cancer. They’re at least 10 years ahead of us in thinking about reducing the harms that have been introduced by screening for prostate cancer. When you look at breast cancer–specific and other-cause mortality in the setting of DCIS, the mortality curves look very similar to those with early-stage prostate cancer. Women with DCIS, regardless of what they are treated with, die of other causes and very rarely die of breast cancer.

When we compare such different options as mastectomy to active surveillance only, it’s really hard for a patient to feel that both of those approaches can offer them the same outcomes. But when you look at the actual data and evidence, the differences in recurrence or progression to invasive cancer don’t translate easily into a large difference in breast cancer mortality provided that patients are diagnosed at stage I or II, with more than a 90% survival from breast cancer.

We have an opportunity to take a big step back and redefine our goals of DCIS “treatment” from “curing” DCIS to trying to reduce breast cancer-specific mortality. This will help us reduce the harms that can result from screening and will reserve our aggressive treatments for those most likely to benefit from them.

Dr. Hwang is a professor of surgery at Duke University, Durham, N.C. She serves as a consultant for Genomic Health.

ORLANDO – As dermatologists do their routine skin checks, they also should pay attention to the breast and the nipple, Dr. David T. Harvey advised in a presentation at the annual meeting of the Florida Society of Dermatologic Surgeons.

Although nipple and areolar tumors are relatively rare, “we have an important role in their evaluation and a wonderful opportunity to impact breast cancer awareness and detection,” said Dr. Harvey, a dermatologist and cosmetic surgeon in Newnan, Ga.

Literature on nipple tumors is limited, but in general, benign breast lesions are much more frequent than the malignant ones. The differential diagnosis can be confusing, “so you don’t want to over or underreact,” while still giving patients the best advice, Dr. Harvey said.

Begin with history

The first step in assessing a lesion on the nipple or areola is to take a thorough history and physical.

The questions to ask include: Is there a discharge? Is there atrophy? Is there a cutaneous erosion? Has the lesion been changing in size? Is the patient pregnant? Is the lesion painful? Perform a visual inspection of the breast and areolar skin, looking for unusual lumps and masses. If the patient will allow, cursory palpation of the breast tissue is helpful.

Ask patients if they have a record of their latest mammograms or MRI. “Get on the phone if you’re not sure. Call a trusted breast specialist, general plastic surgeon, or a surgical oncologist,” he said.

If there’s a lesion that’s erosive and has been there for 6 or 7 months, get a full-thickness incisional biopsy. It also is important to document the presence or absence of axillary lymphadenopathy.

The nipple discharge can be cultured, although most times cultures don’t yield specific data.

And finally, educate patients about the benefits and risks of undergoing regular breast cancer screenings.

Benign tumors

Common benign tumors of the nipple and areola include leiomyoma, erosive adenomatosis, angiolipoma, glomus tumor, neurofibromas, cherry angioma, tags, and epidermal nevus.

Hyperkeratosis around the nipple is another benign condition and can be caused by lack of hygiene. “In these cases, education about how to clean and care for this area is helpful,” Dr. Harvey said.

Erosive adenoma of the nipple is another rare condition. It is usually 0.5-1.5 cm in diameter and arises from apocrine sweat ducts of the nipple’s epithelium. Its clinical symptoms include serosanguinous discharge, bleeding, crusting, erythema, swelling, ulceration, and, in some cases, recurrence because of incomplete removal. This tumor usually occurs in middle-aged women and sometimes is associated with fibrocystic breast disease, breast cancer, and supernumerary nipple. It also can be bilateral. The best treatment is Mohs micrographic surgery.

Malignant tumors

Malignant tumors of the breast and nipple usually present as a lump, hard knot, or thickening inside the breast or underarm area. There’s usually swelling, warmth, redness, or skin hyperpigmentation, in addition to change in the size or shape of the breast.

Other clinical features include dimpling and puckering of the skin and an itchy, scaling sore or rash on the nipple, said Dr. Harvey.

Look for the “pulling in” of the nipple or other parts of the breast, nipple discharge, and discomfort in the breast that doesn’t resolve, he said.

Examples of malignant tumors of the nipple include intraductal breast carcinoma, well-differentiated adenocarcinoma, melanoma, leiomyosarcoma, and squamous cell carcinoma.

Paget’s disease (PD), another breast malignancy, is rare and can mimic eczema or dermatitis. In PD, the nipple may be flattened or eroded. This condition often presents with a discharge and affects older women.

Between 50% and 70% of patients with biopsy-proven mammary PD show positive findings on mammography. The majority of patients who have biopsy-proven Paget’s disease of the nipple as the only physical finding have an underlying deeper breast carcinoma, said Dr. Harvey.

Negative preoperative mammography findings do not reliably exclude an underlying carcinoma. “MRI of the involved breast is a more sensitive way to detect occult PD and is an important tool to help with treatment planning for patients with PD,” he said.

The treatment is radical or modified mastectomy, and lymph node clearance for mammary PD with a palpable mass and underlying invasive breast carcinoma. Estrogen receptor antagonists also can be used in selected cases.

In summary, Dr. Harvey said that it is vital to biopsy a nipple or areolar lesion that is not responding to traditional therapies.

And don’t limit your examination to women

Dr. Christopher Moeller of Wichita, Kan., said that he had diagnosed three men with breast cancer, none of whom where aware of it. One patient had a retracted nipple, another had one breast larger than the other, and he found another lump through palpation.

“Always ask patients,” about their breast health and examine the area, he advised.

Dr. Harvey and Dr. Moeller had no relevant financial disclosures.

ORLANDO – As dermatologists do their routine skin checks, they also should pay attention to the breast and the nipple, Dr. David T. Harvey advised in a presentation at the annual meeting of the Florida Society of Dermatologic Surgeons.

Although nipple and areolar tumors are relatively rare, “we have an important role in their evaluation and a wonderful opportunity to impact breast cancer awareness and detection,” said Dr. Harvey, a dermatologist and cosmetic surgeon in Newnan, Ga.

Literature on nipple tumors is limited, but in general, benign breast lesions are much more frequent than the malignant ones. The differential diagnosis can be confusing, “so you don’t want to over or underreact,” while still giving patients the best advice, Dr. Harvey said.

Begin with history

The first step in assessing a lesion on the nipple or areola is to take a thorough history and physical.

The questions to ask include: Is there a discharge? Is there atrophy? Is there a cutaneous erosion? Has the lesion been changing in size? Is the patient pregnant? Is the lesion painful? Perform a visual inspection of the breast and areolar skin, looking for unusual lumps and masses. If the patient will allow, cursory palpation of the breast tissue is helpful.

Ask patients if they have a record of their latest mammograms or MRI. “Get on the phone if you’re not sure. Call a trusted breast specialist, general plastic surgeon, or a surgical oncologist,” he said.

If there’s a lesion that’s erosive and has been there for 6 or 7 months, get a full-thickness incisional biopsy. It also is important to document the presence or absence of axillary lymphadenopathy.

The nipple discharge can be cultured, although most times cultures don’t yield specific data.

And finally, educate patients about the benefits and risks of undergoing regular breast cancer screenings.

Benign tumors

Common benign tumors of the nipple and areola include leiomyoma, erosive adenomatosis, angiolipoma, glomus tumor, neurofibromas, cherry angioma, tags, and epidermal nevus.

Hyperkeratosis around the nipple is another benign condition and can be caused by lack of hygiene. “In these cases, education about how to clean and care for this area is helpful,” Dr. Harvey said.

Erosive adenoma of the nipple is another rare condition. It is usually 0.5-1.5 cm in diameter and arises from apocrine sweat ducts of the nipple’s epithelium. Its clinical symptoms include serosanguinous discharge, bleeding, crusting, erythema, swelling, ulceration, and, in some cases, recurrence because of incomplete removal. This tumor usually occurs in middle-aged women and sometimes is associated with fibrocystic breast disease, breast cancer, and supernumerary nipple. It also can be bilateral. The best treatment is Mohs micrographic surgery.

Malignant tumors

Malignant tumors of the breast and nipple usually present as a lump, hard knot, or thickening inside the breast or underarm area. There’s usually swelling, warmth, redness, or skin hyperpigmentation, in addition to change in the size or shape of the breast.

Other clinical features include dimpling and puckering of the skin and an itchy, scaling sore or rash on the nipple, said Dr. Harvey.

Look for the “pulling in” of the nipple or other parts of the breast, nipple discharge, and discomfort in the breast that doesn’t resolve, he said.

Examples of malignant tumors of the nipple include intraductal breast carcinoma, well-differentiated adenocarcinoma, melanoma, leiomyosarcoma, and squamous cell carcinoma.

Paget’s disease (PD), another breast malignancy, is rare and can mimic eczema or dermatitis. In PD, the nipple may be flattened or eroded. This condition often presents with a discharge and affects older women.

Between 50% and 70% of patients with biopsy-proven mammary PD show positive findings on mammography. The majority of patients who have biopsy-proven Paget’s disease of the nipple as the only physical finding have an underlying deeper breast carcinoma, said Dr. Harvey.

Negative preoperative mammography findings do not reliably exclude an underlying carcinoma. “MRI of the involved breast is a more sensitive way to detect occult PD and is an important tool to help with treatment planning for patients with PD,” he said.

The treatment is radical or modified mastectomy, and lymph node clearance for mammary PD with a palpable mass and underlying invasive breast carcinoma. Estrogen receptor antagonists also can be used in selected cases.

In summary, Dr. Harvey said that it is vital to biopsy a nipple or areolar lesion that is not responding to traditional therapies.

And don’t limit your examination to women

Dr. Christopher Moeller of Wichita, Kan., said that he had diagnosed three men with breast cancer, none of whom where aware of it. One patient had a retracted nipple, another had one breast larger than the other, and he found another lump through palpation.

“Always ask patients,” about their breast health and examine the area, he advised.

Dr. Harvey and Dr. Moeller had no relevant financial disclosures.

ORLANDO – As dermatologists do their routine skin checks, they also should pay attention to the breast and the nipple, Dr. David T. Harvey advised in a presentation at the annual meeting of the Florida Society of Dermatologic Surgeons.

Although nipple and areolar tumors are relatively rare, “we have an important role in their evaluation and a wonderful opportunity to impact breast cancer awareness and detection,” said Dr. Harvey, a dermatologist and cosmetic surgeon in Newnan, Ga.

Literature on nipple tumors is limited, but in general, benign breast lesions are much more frequent than the malignant ones. The differential diagnosis can be confusing, “so you don’t want to over or underreact,” while still giving patients the best advice, Dr. Harvey said.

Begin with history

The first step in assessing a lesion on the nipple or areola is to take a thorough history and physical.

The questions to ask include: Is there a discharge? Is there atrophy? Is there a cutaneous erosion? Has the lesion been changing in size? Is the patient pregnant? Is the lesion painful? Perform a visual inspection of the breast and areolar skin, looking for unusual lumps and masses. If the patient will allow, cursory palpation of the breast tissue is helpful.

Ask patients if they have a record of their latest mammograms or MRI. “Get on the phone if you’re not sure. Call a trusted breast specialist, general plastic surgeon, or a surgical oncologist,” he said.

If there’s a lesion that’s erosive and has been there for 6 or 7 months, get a full-thickness incisional biopsy. It also is important to document the presence or absence of axillary lymphadenopathy.

The nipple discharge can be cultured, although most times cultures don’t yield specific data.

And finally, educate patients about the benefits and risks of undergoing regular breast cancer screenings.

Benign tumors

Common benign tumors of the nipple and areola include leiomyoma, erosive adenomatosis, angiolipoma, glomus tumor, neurofibromas, cherry angioma, tags, and epidermal nevus.

Hyperkeratosis around the nipple is another benign condition and can be caused by lack of hygiene. “In these cases, education about how to clean and care for this area is helpful,” Dr. Harvey said.

Erosive adenoma of the nipple is another rare condition. It is usually 0.5-1.5 cm in diameter and arises from apocrine sweat ducts of the nipple’s epithelium. Its clinical symptoms include serosanguinous discharge, bleeding, crusting, erythema, swelling, ulceration, and, in some cases, recurrence because of incomplete removal. This tumor usually occurs in middle-aged women and sometimes is associated with fibrocystic breast disease, breast cancer, and supernumerary nipple. It also can be bilateral. The best treatment is Mohs micrographic surgery.

Malignant tumors

Malignant tumors of the breast and nipple usually present as a lump, hard knot, or thickening inside the breast or underarm area. There’s usually swelling, warmth, redness, or skin hyperpigmentation, in addition to change in the size or shape of the breast.

Other clinical features include dimpling and puckering of the skin and an itchy, scaling sore or rash on the nipple, said Dr. Harvey.

Look for the “pulling in” of the nipple or other parts of the breast, nipple discharge, and discomfort in the breast that doesn’t resolve, he said.

Examples of malignant tumors of the nipple include intraductal breast carcinoma, well-differentiated adenocarcinoma, melanoma, leiomyosarcoma, and squamous cell carcinoma.

Paget’s disease (PD), another breast malignancy, is rare and can mimic eczema or dermatitis. In PD, the nipple may be flattened or eroded. This condition often presents with a discharge and affects older women.

Between 50% and 70% of patients with biopsy-proven mammary PD show positive findings on mammography. The majority of patients who have biopsy-proven Paget’s disease of the nipple as the only physical finding have an underlying deeper breast carcinoma, said Dr. Harvey.

Negative preoperative mammography findings do not reliably exclude an underlying carcinoma. “MRI of the involved breast is a more sensitive way to detect occult PD and is an important tool to help with treatment planning for patients with PD,” he said.

The treatment is radical or modified mastectomy, and lymph node clearance for mammary PD with a palpable mass and underlying invasive breast carcinoma. Estrogen receptor antagonists also can be used in selected cases.

In summary, Dr. Harvey said that it is vital to biopsy a nipple or areolar lesion that is not responding to traditional therapies.

And don’t limit your examination to women

Dr. Christopher Moeller of Wichita, Kan., said that he had diagnosed three men with breast cancer, none of whom where aware of it. One patient had a retracted nipple, another had one breast larger than the other, and he found another lump through palpation.

“Always ask patients,” about their breast health and examine the area, he advised.

Dr. Harvey and Dr. Moeller had no relevant financial disclosures.

This much is clear: Women with loss-of-function mutations in the tumor suppressor genes BRCA1 and BRCA2 are at very high risk for developing breast and ovarian cancers.

What is far less certain, however, is whether all women – not just a relatively small number of those known to be at high risk for inherited mutations – should be offered genetic screening for BRCA1 and BRCA2 mutations.

In a provocative study published online Sept. 5 in the Proceedings of the National Academy of Sciences (doi:10.1073/pnas.1415979111) and expanded on in the Journal of the American Medical Association, Dr. Mary-Claire King and colleagues in Israel propose offering genetic screening for BRCA1 and BRCA2 mutations to young adult women in the general population.

Dr. King, professor of genome sciences and medical genetics at the University of Washington, Seattle, is credited with the discovery of BRCA1 and BRCA2 mutations in familial breast and ovarian cancers. She received the 2014 Lasker~Koshland Special Achievement Award in Medical Science from the Lasker Foundation for the discovery, and for her other work in human genetics.

“Based on our 20 years’ experience working with families with cancer-predisposing mutations in BRCA1 and BRCA2, it is time to offer genetic screening of these genes to every woman, at about age 30, in the course of routine medical care. Women with cancer-predisposing mutations in BRCA1 and BRCA2 are a high-risk group in whom special screening and counseling can be focused,” Dr. King and colleague Dr. Ephrat Levy-Lahad of the Medical Genetics Institute at Shaare Zedek Medical Center, Jerusalem, write in an opinion piece adapted from her award speech (JAMA. 2014;312(11):1091-2).

Israeli study

The investigators base their recommendation on a study they conducted in the Ashkenazi Jewish population of Israel. Ashkenazi Jews, of central or Eastern European origin, have a higher prevalence of deleterious mutations in BRCA1 and BRCA2 than the general population. Three inherited mutations in the genes account for 11% of breast cancers and 40% of ovarian cancers among Ashkenazi Jews.

To see whether they could determine the risks of breast and ovarian cancers among Ashkenazi Jewish women without considering either their personal or family histories of those cancers, the investigators looked for healthy Ashkenazi Jewish men and screened them for the mutations of interest. They then enrolled adult female relatives of the men identified as carriers of at least one of the mutations and performed genotyping to ascertain the women’s mutational status.

National Breast Cancer Coalition

They found that for women related to men who carried a BRCA1 mutation, the risk of developing either breast or ovarian cancer by age 60 was 60%, and by age 80 was 83%. For women related to BRCA2 mutation carriers, the respective risks were 33% and 76%. They also found that women in more recent birth cohorts had a significantly higher risk than women in older cohorts (P = .006)

The investigators contend that the finding of high cancer risks among women identified through their healthy male relatives “provide an evidence base for initiating a general screening program in the Ashkenazi Jewish population.”

So far, so good. Where it gets controversial, however, is in the following sentences, from the study published in the Proceedings of the National Academy of Sciences:

“BRCA1 and BRCA2 were identified in the mid-1990s, and patent issues that in the United States previously limited complete genomic analysis of BRCA1 and BRCA2 have been largely resolved. We suggest that the time has come to apply our knowledge of these genes to consideration of a general screening program, with the aim of reducing the burden of breast and ovarian cancer.”

But critics say that it is far too early to make such sweeping recommendations, given the potentially harmful consequences.

“I think it is a very bad message for women. It is not based on evidence,” said Frances M. Visco, president of the National Breast Cancer Coalition.

“To extrapolate to all women over 30 from a very small population makes no sense. It can be very harmful, and it is once again trying to give women this ‘one-size-fits-all’ message. To put in place another screening program – we have no idea if it will save lives, we have no idea what the harms can be because we haven’t looked at it in this population. I think it’s the absolute wrong message to get,” she said in an interview.

‘A fresh look’

Dr. Harold J. Burstein, an oncologist at the Breast Oncology Center, Dana-Farber Cancer Institute in Boston, applauds the investigators for raising the issue of widespread screening for the mutations.

“It has really, I think, done a service, because it has made people take a fresh look at some of the ideas that have been kicking around for quite a while,” he said in an interview.

He noted that testing for the mutations has usually been reserved for breast cancer patients or other women who had an estimated 10% or greater chance of having a hereditary mutation, based on factors such as age of onset, family history of breast cancer, and Ashkenazi ancestry.

But since the advent of genetic testing for BRCA mutations, technological advances have made screening easier, faster, and less expensive. More importantly, clinicians and patients have become better informed about the significance of positive results, and the discussion of clinical options such as surveillance or prophylactic salpingo-oophorectomy or mastectomy has become more nuanced, Dr. Burstein said.

“A lot of the earlier concerns about how people would deal with positive results have not materialized,” he said. “The benefit of 1-2 decades of experience with this is that when the results are clear, it’s clear that people can process the information, they can make well-informed choices, and they can be carefully followed or make informed decisions about prophylactic surgery that reflect their own preferences.”

Dr. Kelly Metcalfe, a breast cancer geneticist at the University of Toronto, Canada, has studied the frequency of BRCA1 and BRCA2 mutations in Jewish women and in a referral-based population in Ontario (Br. J. Cancer 2013;109:777-9).

“I think that Mary-Claire does raise an interesting point,” she said in an interview. “In order for cancer prevention to be successful when we’re thinking about genetic testing, we need to identify those carriers before they develop it, and do something about it, because we do have very effective strategies to reduce and almost eliminate the chance that these people will ever get cancer.”

Dr. Metcalfe, who is also a professor at the University of Toronto, said that although current guidelines call for genetic testing only of those individuals with a personal or family history of cancer, her experience testing populations of Ashkenazi Jewish women and referral-based patients has demonstrated that the rules are too narrow.

“The majority of people that we found mutations in wouldn’t have even qualified for genetic testing, because they have no family history,” she said.

Ms. Visco points out, however, that the recommendations are based on data from a very small, well-defined population, 2.5% of whom carry one of the three high-risk mutations. Of this subset of the Ashkenazi population, some but not all women will develop breast or ovarian cancers and some but not all will die from the disease.

“It’s much too little data on which to base a recommendation to all women around the globe over 30,” she said.

Courtesy Wikimedia Commons/Michael Ströck/Creative Commons

‘A public health nightmare’

Dr. Burstein acknowledges that the recommendation for widespread screening may be premature.

“The dilemma in testing everybody is that the chance of any given woman having a mutation is very low. In the U.S., it’s not 10%, it’s more like less than 1%,” he said. “With BRCA testing, it invites the possibility that when you start testing lots and lots of people, you end up getting false-positive results. That’s probably less of a worry with the well-known half-dozen mutations that specifically affect Ashkenazi families.”

He notes that genetic testing companies have cataloged myriad variations in the genes, the vast majority of which are of unknown significance.

In a random, large population sample, “because of the cruel math of probabilities, the number of people who had mutations of unknown significance would dwarf the number of people identified with hereditary mutations. That would create a public health nightmare, because we would not be able to tell millions of people what their true risk of breast cancer or ovarian cancer developing was, and therefore it would be very hard to advise them on exactly what surveillance or what kind of prophylactic surgery they should get,” he said.

For their part, Dr. King and Dr. Levy-Lahad acknowledge that “population-wide-screening will require significant efforts to educate the public and to develop new counseling strategies, but this investment will both save women’s lives and provide a model for other public health programs in genomic medicine. Women do not benefit by practices that ‘protect’ them from information regarding their own health. They should have the choice to learn if they carry an actionable mutation in BRCA1 or BRCA2.”

Dr. King declared no conflicts of interest relevant to the research.

This much is clear: Women with loss-of-function mutations in the tumor suppressor genes BRCA1 and BRCA2 are at very high risk for developing breast and ovarian cancers.

What is far less certain, however, is whether all women – not just a relatively small number of those known to be at high risk for inherited mutations – should be offered genetic screening for BRCA1 and BRCA2 mutations.

In a provocative study published online Sept. 5 in the Proceedings of the National Academy of Sciences (doi:10.1073/pnas.1415979111) and expanded on in the Journal of the American Medical Association, Dr. Mary-Claire King and colleagues in Israel propose offering genetic screening for BRCA1 and BRCA2 mutations to young adult women in the general population.

Dr. King, professor of genome sciences and medical genetics at the University of Washington, Seattle, is credited with the discovery of BRCA1 and BRCA2 mutations in familial breast and ovarian cancers. She received the 2014 Lasker~Koshland Special Achievement Award in Medical Science from the Lasker Foundation for the discovery, and for her other work in human genetics.

“Based on our 20 years’ experience working with families with cancer-predisposing mutations in BRCA1 and BRCA2, it is time to offer genetic screening of these genes to every woman, at about age 30, in the course of routine medical care. Women with cancer-predisposing mutations in BRCA1 and BRCA2 are a high-risk group in whom special screening and counseling can be focused,” Dr. King and colleague Dr. Ephrat Levy-Lahad of the Medical Genetics Institute at Shaare Zedek Medical Center, Jerusalem, write in an opinion piece adapted from her award speech (JAMA. 2014;312(11):1091-2).

Israeli study

The investigators base their recommendation on a study they conducted in the Ashkenazi Jewish population of Israel. Ashkenazi Jews, of central or Eastern European origin, have a higher prevalence of deleterious mutations in BRCA1 and BRCA2 than the general population. Three inherited mutations in the genes account for 11% of breast cancers and 40% of ovarian cancers among Ashkenazi Jews.

To see whether they could determine the risks of breast and ovarian cancers among Ashkenazi Jewish women without considering either their personal or family histories of those cancers, the investigators looked for healthy Ashkenazi Jewish men and screened them for the mutations of interest. They then enrolled adult female relatives of the men identified as carriers of at least one of the mutations and performed genotyping to ascertain the women’s mutational status.

National Breast Cancer Coalition

They found that for women related to men who carried a BRCA1 mutation, the risk of developing either breast or ovarian cancer by age 60 was 60%, and by age 80 was 83%. For women related to BRCA2 mutation carriers, the respective risks were 33% and 76%. They also found that women in more recent birth cohorts had a significantly higher risk than women in older cohorts (P = .006)

The investigators contend that the finding of high cancer risks among women identified through their healthy male relatives “provide an evidence base for initiating a general screening program in the Ashkenazi Jewish population.”

So far, so good. Where it gets controversial, however, is in the following sentences, from the study published in the Proceedings of the National Academy of Sciences:

“BRCA1 and BRCA2 were identified in the mid-1990s, and patent issues that in the United States previously limited complete genomic analysis of BRCA1 and BRCA2 have been largely resolved. We suggest that the time has come to apply our knowledge of these genes to consideration of a general screening program, with the aim of reducing the burden of breast and ovarian cancer.”

But critics say that it is far too early to make such sweeping recommendations, given the potentially harmful consequences.

“I think it is a very bad message for women. It is not based on evidence,” said Frances M. Visco, president of the National Breast Cancer Coalition.

“To extrapolate to all women over 30 from a very small population makes no sense. It can be very harmful, and it is once again trying to give women this ‘one-size-fits-all’ message. To put in place another screening program – we have no idea if it will save lives, we have no idea what the harms can be because we haven’t looked at it in this population. I think it’s the absolute wrong message to get,” she said in an interview.

‘A fresh look’

Dr. Harold J. Burstein, an oncologist at the Breast Oncology Center, Dana-Farber Cancer Institute in Boston, applauds the investigators for raising the issue of widespread screening for the mutations.

“It has really, I think, done a service, because it has made people take a fresh look at some of the ideas that have been kicking around for quite a while,” he said in an interview.

He noted that testing for the mutations has usually been reserved for breast cancer patients or other women who had an estimated 10% or greater chance of having a hereditary mutation, based on factors such as age of onset, family history of breast cancer, and Ashkenazi ancestry.

But since the advent of genetic testing for BRCA mutations, technological advances have made screening easier, faster, and less expensive. More importantly, clinicians and patients have become better informed about the significance of positive results, and the discussion of clinical options such as surveillance or prophylactic salpingo-oophorectomy or mastectomy has become more nuanced, Dr. Burstein said.

“A lot of the earlier concerns about how people would deal with positive results have not materialized,” he said. “The benefit of 1-2 decades of experience with this is that when the results are clear, it’s clear that people can process the information, they can make well-informed choices, and they can be carefully followed or make informed decisions about prophylactic surgery that reflect their own preferences.”

Dr. Kelly Metcalfe, a breast cancer geneticist at the University of Toronto, Canada, has studied the frequency of BRCA1 and BRCA2 mutations in Jewish women and in a referral-based population in Ontario (Br. J. Cancer 2013;109:777-9).

“I think that Mary-Claire does raise an interesting point,” she said in an interview. “In order for cancer prevention to be successful when we’re thinking about genetic testing, we need to identify those carriers before they develop it, and do something about it, because we do have very effective strategies to reduce and almost eliminate the chance that these people will ever get cancer.”

Dr. Metcalfe, who is also a professor at the University of Toronto, said that although current guidelines call for genetic testing only of those individuals with a personal or family history of cancer, her experience testing populations of Ashkenazi Jewish women and referral-based patients has demonstrated that the rules are too narrow.

“The majority of people that we found mutations in wouldn’t have even qualified for genetic testing, because they have no family history,” she said.

Ms. Visco points out, however, that the recommendations are based on data from a very small, well-defined population, 2.5% of whom carry one of the three high-risk mutations. Of this subset of the Ashkenazi population, some but not all women will develop breast or ovarian cancers and some but not all will die from the disease.

“It’s much too little data on which to base a recommendation to all women around the globe over 30,” she said.

Courtesy Wikimedia Commons/Michael Ströck/Creative Commons

‘A public health nightmare’

Dr. Burstein acknowledges that the recommendation for widespread screening may be premature.

“The dilemma in testing everybody is that the chance of any given woman having a mutation is very low. In the U.S., it’s not 10%, it’s more like less than 1%,” he said. “With BRCA testing, it invites the possibility that when you start testing lots and lots of people, you end up getting false-positive results. That’s probably less of a worry with the well-known half-dozen mutations that specifically affect Ashkenazi families.”

He notes that genetic testing companies have cataloged myriad variations in the genes, the vast majority of which are of unknown significance.

In a random, large population sample, “because of the cruel math of probabilities, the number of people who had mutations of unknown significance would dwarf the number of people identified with hereditary mutations. That would create a public health nightmare, because we would not be able to tell millions of people what their true risk of breast cancer or ovarian cancer developing was, and therefore it would be very hard to advise them on exactly what surveillance or what kind of prophylactic surgery they should get,” he said.

For their part, Dr. King and Dr. Levy-Lahad acknowledge that “population-wide-screening will require significant efforts to educate the public and to develop new counseling strategies, but this investment will both save women’s lives and provide a model for other public health programs in genomic medicine. Women do not benefit by practices that ‘protect’ them from information regarding their own health. They should have the choice to learn if they carry an actionable mutation in BRCA1 or BRCA2.”

Dr. King declared no conflicts of interest relevant to the research.

This much is clear: Women with loss-of-function mutations in the tumor suppressor genes BRCA1 and BRCA2 are at very high risk for developing breast and ovarian cancers.

What is far less certain, however, is whether all women – not just a relatively small number of those known to be at high risk for inherited mutations – should be offered genetic screening for BRCA1 and BRCA2 mutations.

In a provocative study published online Sept. 5 in the Proceedings of the National Academy of Sciences (doi:10.1073/pnas.1415979111) and expanded on in the Journal of the American Medical Association, Dr. Mary-Claire King and colleagues in Israel propose offering genetic screening for BRCA1 and BRCA2 mutations to young adult women in the general population.

Dr. King, professor of genome sciences and medical genetics at the University of Washington, Seattle, is credited with the discovery of BRCA1 and BRCA2 mutations in familial breast and ovarian cancers. She received the 2014 Lasker~Koshland Special Achievement Award in Medical Science from the Lasker Foundation for the discovery, and for her other work in human genetics.

“Based on our 20 years’ experience working with families with cancer-predisposing mutations in BRCA1 and BRCA2, it is time to offer genetic screening of these genes to every woman, at about age 30, in the course of routine medical care. Women with cancer-predisposing mutations in BRCA1 and BRCA2 are a high-risk group in whom special screening and counseling can be focused,” Dr. King and colleague Dr. Ephrat Levy-Lahad of the Medical Genetics Institute at Shaare Zedek Medical Center, Jerusalem, write in an opinion piece adapted from her award speech (JAMA. 2014;312(11):1091-2).

Israeli study

The investigators base their recommendation on a study they conducted in the Ashkenazi Jewish population of Israel. Ashkenazi Jews, of central or Eastern European origin, have a higher prevalence of deleterious mutations in BRCA1 and BRCA2 than the general population. Three inherited mutations in the genes account for 11% of breast cancers and 40% of ovarian cancers among Ashkenazi Jews.

To see whether they could determine the risks of breast and ovarian cancers among Ashkenazi Jewish women without considering either their personal or family histories of those cancers, the investigators looked for healthy Ashkenazi Jewish men and screened them for the mutations of interest. They then enrolled adult female relatives of the men identified as carriers of at least one of the mutations and performed genotyping to ascertain the women’s mutational status.

National Breast Cancer Coalition

They found that for women related to men who carried a BRCA1 mutation, the risk of developing either breast or ovarian cancer by age 60 was 60%, and by age 80 was 83%. For women related to BRCA2 mutation carriers, the respective risks were 33% and 76%. They also found that women in more recent birth cohorts had a significantly higher risk than women in older cohorts (P = .006)

The investigators contend that the finding of high cancer risks among women identified through their healthy male relatives “provide an evidence base for initiating a general screening program in the Ashkenazi Jewish population.”

So far, so good. Where it gets controversial, however, is in the following sentences, from the study published in the Proceedings of the National Academy of Sciences:

“BRCA1 and BRCA2 were identified in the mid-1990s, and patent issues that in the United States previously limited complete genomic analysis of BRCA1 and BRCA2 have been largely resolved. We suggest that the time has come to apply our knowledge of these genes to consideration of a general screening program, with the aim of reducing the burden of breast and ovarian cancer.”

But critics say that it is far too early to make such sweeping recommendations, given the potentially harmful consequences.

“I think it is a very bad message for women. It is not based on evidence,” said Frances M. Visco, president of the National Breast Cancer Coalition.

“To extrapolate to all women over 30 from a very small population makes no sense. It can be very harmful, and it is once again trying to give women this ‘one-size-fits-all’ message. To put in place another screening program – we have no idea if it will save lives, we have no idea what the harms can be because we haven’t looked at it in this population. I think it’s the absolute wrong message to get,” she said in an interview.

‘A fresh look’

Dr. Harold J. Burstein, an oncologist at the Breast Oncology Center, Dana-Farber Cancer Institute in Boston, applauds the investigators for raising the issue of widespread screening for the mutations.

“It has really, I think, done a service, because it has made people take a fresh look at some of the ideas that have been kicking around for quite a while,” he said in an interview.

He noted that testing for the mutations has usually been reserved for breast cancer patients or other women who had an estimated 10% or greater chance of having a hereditary mutation, based on factors such as age of onset, family history of breast cancer, and Ashkenazi ancestry.

But since the advent of genetic testing for BRCA mutations, technological advances have made screening easier, faster, and less expensive. More importantly, clinicians and patients have become better informed about the significance of positive results, and the discussion of clinical options such as surveillance or prophylactic salpingo-oophorectomy or mastectomy has become more nuanced, Dr. Burstein said.

“A lot of the earlier concerns about how people would deal with positive results have not materialized,” he said. “The benefit of 1-2 decades of experience with this is that when the results are clear, it’s clear that people can process the information, they can make well-informed choices, and they can be carefully followed or make informed decisions about prophylactic surgery that reflect their own preferences.”

Dr. Kelly Metcalfe, a breast cancer geneticist at the University of Toronto, Canada, has studied the frequency of BRCA1 and BRCA2 mutations in Jewish women and in a referral-based population in Ontario (Br. J. Cancer 2013;109:777-9).

“I think that Mary-Claire does raise an interesting point,” she said in an interview. “In order for cancer prevention to be successful when we’re thinking about genetic testing, we need to identify those carriers before they develop it, and do something about it, because we do have very effective strategies to reduce and almost eliminate the chance that these people will ever get cancer.”

Dr. Metcalfe, who is also a professor at the University of Toronto, said that although current guidelines call for genetic testing only of those individuals with a personal or family history of cancer, her experience testing populations of Ashkenazi Jewish women and referral-based patients has demonstrated that the rules are too narrow.

“The majority of people that we found mutations in wouldn’t have even qualified for genetic testing, because they have no family history,” she said.

Ms. Visco points out, however, that the recommendations are based on data from a very small, well-defined population, 2.5% of whom carry one of the three high-risk mutations. Of this subset of the Ashkenazi population, some but not all women will develop breast or ovarian cancers and some but not all will die from the disease.

“It’s much too little data on which to base a recommendation to all women around the globe over 30,” she said.

Courtesy Wikimedia Commons/Michael Ströck/Creative Commons

‘A public health nightmare’

Dr. Burstein acknowledges that the recommendation for widespread screening may be premature.

“The dilemma in testing everybody is that the chance of any given woman having a mutation is very low. In the U.S., it’s not 10%, it’s more like less than 1%,” he said. “With BRCA testing, it invites the possibility that when you start testing lots and lots of people, you end up getting false-positive results. That’s probably less of a worry with the well-known half-dozen mutations that specifically affect Ashkenazi families.”

He notes that genetic testing companies have cataloged myriad variations in the genes, the vast majority of which are of unknown significance.

In a random, large population sample, “because of the cruel math of probabilities, the number of people who had mutations of unknown significance would dwarf the number of people identified with hereditary mutations. That would create a public health nightmare, because we would not be able to tell millions of people what their true risk of breast cancer or ovarian cancer developing was, and therefore it would be very hard to advise them on exactly what surveillance or what kind of prophylactic surgery they should get,” he said.

For their part, Dr. King and Dr. Levy-Lahad acknowledge that “population-wide-screening will require significant efforts to educate the public and to develop new counseling strategies, but this investment will both save women’s lives and provide a model for other public health programs in genomic medicine. Women do not benefit by practices that ‘protect’ them from information regarding their own health. They should have the choice to learn if they carry an actionable mutation in BRCA1 or BRCA2.”

Dr. King declared no conflicts of interest relevant to the research.

My mother was 36 when she was diagnosed with a very aggressive breast cancer. It metastasized a year later at age 37. My mother chose to stay alive as long as humanly possible, opting for every possible surgery and treatment. We watched her suffer and her quality of life deteriorate for 13 years, before she died at age 50.

My father was diagnosed with cancer at age 66. He refused most treatment understanding it would only prolong his suffering and passed away a year later at age 67.

When I was 16, I saw a genetic counselor with my mother and since then have stayed up to date on the latest recommendations for people at high risk. The recommendation until I was tested for a BRCA mutation was to treat myself like I was positive. So at age 25 it was recommended I start annual MRIs and mammograms.

When I turned 30, with my second parent dying of cancer, I decided I wanted to be tested for BRCA1/BRCA2. I tested positive.

I am sure I will have to reevaluate things if and when I have children, but currently I believe the annual tests do nothing but increase my risks.

At 25, after my first MRI, the doctor said they couldn’t make something out because my breasts were so dense and they needed me to come back in. I didn’t. I was living in Iowa, didn’t trust my doctor, was working 7 days a week, and honestly couldn’t be bothered. I stayed away from breast doctors for 5 years after that.

The second abnormal result came at 30, after I tested positive for BRCA2. I allowed a needle biopsy as follow-up. It came back normal.

After the third abnormal result 1 year later at age 31, I said to myself, “this is going to happen every single time I have an MRI because my breasts are dense and big.”

I touch my breasts more than once a day and am very in tune with how they are feeling.

If I have a slow tumor growing, I am confident I will find/feel it before it has taken over my body. It will be removed and I will be fine.

If I have an aggressive tumor, I will also find it before it has taken over my body, but because of its aggressiveness, it will ultimately kill me. I know a test may find it sooner and may increase my chances of living with cancer longer. However, if I don’t have kids, I would rather die than go through anything close to what my mother went through.

My breasts are high risk so before I have children I am willing to do whatever it takes to keep them as healthy as possible. To me, this includes walking away from doctors telling me I need annual MRIs and mammograms. I have had three MRIs and all three have come back abnormal.

I told the doctors as nicely as humanly possible, to find someone else’s high risk breasts to prick because my future children deserved to be born with a mother that has done everything possible to keep her breasts healthy.

From what I know, breasts are incredibly sensitive, and we need to keep our breast environment as safe and quiet as possible. Annual needles going into them doesn’t do that. I am fully aware that I may wake up tomorrow and feel a tumor that is “big and dangerous.” But, I am hopeful that won’t happen and confident with my own thought process and decisions.

My mother was 36 when she was diagnosed with a very aggressive breast cancer. It metastasized a year later at age 37. My mother chose to stay alive as long as humanly possible, opting for every possible surgery and treatment. We watched her suffer and her quality of life deteriorate for 13 years, before she died at age 50.

My father was diagnosed with cancer at age 66. He refused most treatment understanding it would only prolong his suffering and passed away a year later at age 67.

When I was 16, I saw a genetic counselor with my mother and since then have stayed up to date on the latest recommendations for people at high risk. The recommendation until I was tested for a BRCA mutation was to treat myself like I was positive. So at age 25 it was recommended I start annual MRIs and mammograms.

When I turned 30, with my second parent dying of cancer, I decided I wanted to be tested for BRCA1/BRCA2. I tested positive.

I am sure I will have to reevaluate things if and when I have children, but currently I believe the annual tests do nothing but increase my risks.

At 25, after my first MRI, the doctor said they couldn’t make something out because my breasts were so dense and they needed me to come back in. I didn’t. I was living in Iowa, didn’t trust my doctor, was working 7 days a week, and honestly couldn’t be bothered. I stayed away from breast doctors for 5 years after that.

The second abnormal result came at 30, after I tested positive for BRCA2. I allowed a needle biopsy as follow-up. It came back normal.

After the third abnormal result 1 year later at age 31, I said to myself, “this is going to happen every single time I have an MRI because my breasts are dense and big.”

I touch my breasts more than once a day and am very in tune with how they are feeling.

If I have a slow tumor growing, I am confident I will find/feel it before it has taken over my body. It will be removed and I will be fine.

If I have an aggressive tumor, I will also find it before it has taken over my body, but because of its aggressiveness, it will ultimately kill me. I know a test may find it sooner and may increase my chances of living with cancer longer. However, if I don’t have kids, I would rather die than go through anything close to what my mother went through.

My breasts are high risk so before I have children I am willing to do whatever it takes to keep them as healthy as possible. To me, this includes walking away from doctors telling me I need annual MRIs and mammograms. I have had three MRIs and all three have come back abnormal.

I told the doctors as nicely as humanly possible, to find someone else’s high risk breasts to prick because my future children deserved to be born with a mother that has done everything possible to keep her breasts healthy.

From what I know, breasts are incredibly sensitive, and we need to keep our breast environment as safe and quiet as possible. Annual needles going into them doesn’t do that. I am fully aware that I may wake up tomorrow and feel a tumor that is “big and dangerous.” But, I am hopeful that won’t happen and confident with my own thought process and decisions.

My mother was 36 when she was diagnosed with a very aggressive breast cancer. It metastasized a year later at age 37. My mother chose to stay alive as long as humanly possible, opting for every possible surgery and treatment. We watched her suffer and her quality of life deteriorate for 13 years, before she died at age 50.

My father was diagnosed with cancer at age 66. He refused most treatment understanding it would only prolong his suffering and passed away a year later at age 67.

When I was 16, I saw a genetic counselor with my mother and since then have stayed up to date on the latest recommendations for people at high risk. The recommendation until I was tested for a BRCA mutation was to treat myself like I was positive. So at age 25 it was recommended I start annual MRIs and mammograms.

When I turned 30, with my second parent dying of cancer, I decided I wanted to be tested for BRCA1/BRCA2. I tested positive.

I am sure I will have to reevaluate things if and when I have children, but currently I believe the annual tests do nothing but increase my risks.

At 25, after my first MRI, the doctor said they couldn’t make something out because my breasts were so dense and they needed me to come back in. I didn’t. I was living in Iowa, didn’t trust my doctor, was working 7 days a week, and honestly couldn’t be bothered. I stayed away from breast doctors for 5 years after that.

The second abnormal result came at 30, after I tested positive for BRCA2. I allowed a needle biopsy as follow-up. It came back normal.

After the third abnormal result 1 year later at age 31, I said to myself, “this is going to happen every single time I have an MRI because my breasts are dense and big.”

I touch my breasts more than once a day and am very in tune with how they are feeling.

If I have a slow tumor growing, I am confident I will find/feel it before it has taken over my body. It will be removed and I will be fine.

If I have an aggressive tumor, I will also find it before it has taken over my body, but because of its aggressiveness, it will ultimately kill me. I know a test may find it sooner and may increase my chances of living with cancer longer. However, if I don’t have kids, I would rather die than go through anything close to what my mother went through.

My breasts are high risk so before I have children I am willing to do whatever it takes to keep them as healthy as possible. To me, this includes walking away from doctors telling me I need annual MRIs and mammograms. I have had three MRIs and all three have come back abnormal.

I told the doctors as nicely as humanly possible, to find someone else’s high risk breasts to prick because my future children deserved to be born with a mother that has done everything possible to keep her breasts healthy.

From what I know, breasts are incredibly sensitive, and we need to keep our breast environment as safe and quiet as possible. Annual needles going into them doesn’t do that. I am fully aware that I may wake up tomorrow and feel a tumor that is “big and dangerous.” But, I am hopeful that won’t happen and confident with my own thought process and decisions.

Adjuvant radiotherapy continues to protect against recurrences – ­albeit “modestly” – for a full 20 years after women undergo breast-conserving surgery for DCIS, according to a report published online Oct. 13 in the Journal of Clinical Oncology.

In an extended follow-up study involving 1,046 of the 1,067 original participants in the Swedish Ductal Carcinoma in Situ (SweDCIS) clinical trial in 1987-1999, there were 258 recurrences: 129 cases of DCIS and 129 cases of invasive cancer in the ipsilateral breast. Another 115 women developed contralateral DCIS or invasive cancer. A total of 232 women died, including 41 who died from breast cancer, said Dr. Fredrik Warnberg of the department of surgical sciences, Uppsala (Sweden) Academic Hospital, and his associates.

There were 93 recurrences among women who had been randomized to adjuvant radiotherapy, compared with 165 recurrences in the control group treated with breast-conserving surgery only. This corresponds to an absolute risk reduction of 12% and a relative risk reduction of 37.5% for adjuvant radiotherapy. The absolute risk reduction was more pronounced for recurrent DCIS (10%) than for invasive cancer (2%), and it occurred mainly among women in the older age groups – those aged 52 years and older at diagnosis, the investigators said (J. Clin. Oncol. 2014 October 13 [doi:10.1200/JCO.2014.56.2595]).

Contralateral breast cancer developed more often in the radiotherapy group (67 cases) than in the control group (48 cases), but this difference was not statistically significant, said Dr. Warnberg and his associates.

“The balance between protection against local recurrences and the downsides of radiotherapy currently speaks in favor of adjuvant breast irradiation. However, the more modest protective effect specifically for invasive recurrences and the possible increase in risk of contralateral cancer still call for the need to find groups of patients for whom radiotherapy could be avoided,” they noted.

Adjuvant radiotherapy continues to protect against recurrences – ­albeit “modestly” – for a full 20 years after women undergo breast-conserving surgery for DCIS, according to a report published online Oct. 13 in the Journal of Clinical Oncology.

In an extended follow-up study involving 1,046 of the 1,067 original participants in the Swedish Ductal Carcinoma in Situ (SweDCIS) clinical trial in 1987-1999, there were 258 recurrences: 129 cases of DCIS and 129 cases of invasive cancer in the ipsilateral breast. Another 115 women developed contralateral DCIS or invasive cancer. A total of 232 women died, including 41 who died from breast cancer, said Dr. Fredrik Warnberg of the department of surgical sciences, Uppsala (Sweden) Academic Hospital, and his associates.

There were 93 recurrences among women who had been randomized to adjuvant radiotherapy, compared with 165 recurrences in the control group treated with breast-conserving surgery only. This corresponds to an absolute risk reduction of 12% and a relative risk reduction of 37.5% for adjuvant radiotherapy. The absolute risk reduction was more pronounced for recurrent DCIS (10%) than for invasive cancer (2%), and it occurred mainly among women in the older age groups – those aged 52 years and older at diagnosis, the investigators said (J. Clin. Oncol. 2014 October 13 [doi:10.1200/JCO.2014.56.2595]).

Contralateral breast cancer developed more often in the radiotherapy group (67 cases) than in the control group (48 cases), but this difference was not statistically significant, said Dr. Warnberg and his associates.

“The balance between protection against local recurrences and the downsides of radiotherapy currently speaks in favor of adjuvant breast irradiation. However, the more modest protective effect specifically for invasive recurrences and the possible increase in risk of contralateral cancer still call for the need to find groups of patients for whom radiotherapy could be avoided,” they noted.

Adjuvant radiotherapy continues to protect against recurrences – ­albeit “modestly” – for a full 20 years after women undergo breast-conserving surgery for DCIS, according to a report published online Oct. 13 in the Journal of Clinical Oncology.

In an extended follow-up study involving 1,046 of the 1,067 original participants in the Swedish Ductal Carcinoma in Situ (SweDCIS) clinical trial in 1987-1999, there were 258 recurrences: 129 cases of DCIS and 129 cases of invasive cancer in the ipsilateral breast. Another 115 women developed contralateral DCIS or invasive cancer. A total of 232 women died, including 41 who died from breast cancer, said Dr. Fredrik Warnberg of the department of surgical sciences, Uppsala (Sweden) Academic Hospital, and his associates.

There were 93 recurrences among women who had been randomized to adjuvant radiotherapy, compared with 165 recurrences in the control group treated with breast-conserving surgery only. This corresponds to an absolute risk reduction of 12% and a relative risk reduction of 37.5% for adjuvant radiotherapy. The absolute risk reduction was more pronounced for recurrent DCIS (10%) than for invasive cancer (2%), and it occurred mainly among women in the older age groups – those aged 52 years and older at diagnosis, the investigators said (J. Clin. Oncol. 2014 October 13 [doi:10.1200/JCO.2014.56.2595]).

Contralateral breast cancer developed more often in the radiotherapy group (67 cases) than in the control group (48 cases), but this difference was not statistically significant, said Dr. Warnberg and his associates.

“The balance between protection against local recurrences and the downsides of radiotherapy currently speaks in favor of adjuvant breast irradiation. However, the more modest protective effect specifically for invasive recurrences and the possible increase in risk of contralateral cancer still call for the need to find groups of patients for whom radiotherapy could be avoided,” they noted.

Using a 70-gene signature screening tool for adjuvant chemotherapy decisions cost significantly more than did other methods, including giving chemotherapy to all patients, but did not confer any additional advantages in survival or quality of life, for women with node-negative breast cancer.

The estimated cost per woman with a node-negative tumor was 12,780 euros for using the MammaPrint test – significantly higher than either an online decision tool, or a strategy of systematic chemotherapy for all, according to Julia Bonastre, Ph.D., and her colleagues (J. Clin. Oncol. 2014 October [doi:10.1200/JCO.2013.54.9931]).

©Kativ/iStockphoto

The study compared cost and clinical outcomes among 307 women treated for node-negative breast cancers as part of a MammaPrint validation trial. Chemotherapy choice was guided either by MammaPrint, the Adjuvant! Online program, or a scheme of systematic chemotherapy for every patient.

The mean cost of the 70-gene MammaPrint profile was 12,780 euros; the mean cost of Adjuvant! Online, 10,743 euros; and the mean cost of systematic chemotherapy, 12,123 euros. Over the 10-year follow-up period, there were no differences in life-years or quality-adjusted life-years.

Treatment de-escalation is critical for ensuring high-quality survivorship over the long term, wrote Dr. Bonastre of Gustave Roussy Institute of Oncology, Paris, and her associates. “However, our study shows that the health benefits associated with the use of molecular tests are modest. In addition, the high price of these tests results in poor value for the money, limiting their usefulness in routine practice,” they said.

The study was funded by the French National Cancer Institute, and the authors reported no conflicts of interest.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

Using a 70-gene signature screening tool for adjuvant chemotherapy decisions cost significantly more than did other methods, including giving chemotherapy to all patients, but did not confer any additional advantages in survival or quality of life, for women with node-negative breast cancer.

The estimated cost per woman with a node-negative tumor was 12,780 euros for using the MammaPrint test – significantly higher than either an online decision tool, or a strategy of systematic chemotherapy for all, according to Julia Bonastre, Ph.D., and her colleagues (J. Clin. Oncol. 2014 October [doi:10.1200/JCO.2013.54.9931]).

©Kativ/iStockphoto

The study compared cost and clinical outcomes among 307 women treated for node-negative breast cancers as part of a MammaPrint validation trial. Chemotherapy choice was guided either by MammaPrint, the Adjuvant! Online program, or a scheme of systematic chemotherapy for every patient.

The mean cost of the 70-gene MammaPrint profile was 12,780 euros; the mean cost of Adjuvant! Online, 10,743 euros; and the mean cost of systematic chemotherapy, 12,123 euros. Over the 10-year follow-up period, there were no differences in life-years or quality-adjusted life-years.

Treatment de-escalation is critical for ensuring high-quality survivorship over the long term, wrote Dr. Bonastre of Gustave Roussy Institute of Oncology, Paris, and her associates. “However, our study shows that the health benefits associated with the use of molecular tests are modest. In addition, the high price of these tests results in poor value for the money, limiting their usefulness in routine practice,” they said.

The study was funded by the French National Cancer Institute, and the authors reported no conflicts of interest.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

Using a 70-gene signature screening tool for adjuvant chemotherapy decisions cost significantly more than did other methods, including giving chemotherapy to all patients, but did not confer any additional advantages in survival or quality of life, for women with node-negative breast cancer.

The estimated cost per woman with a node-negative tumor was 12,780 euros for using the MammaPrint test – significantly higher than either an online decision tool, or a strategy of systematic chemotherapy for all, according to Julia Bonastre, Ph.D., and her colleagues (J. Clin. Oncol. 2014 October [doi:10.1200/JCO.2013.54.9931]).

©Kativ/iStockphoto

The study compared cost and clinical outcomes among 307 women treated for node-negative breast cancers as part of a MammaPrint validation trial. Chemotherapy choice was guided either by MammaPrint, the Adjuvant! Online program, or a scheme of systematic chemotherapy for every patient.

The mean cost of the 70-gene MammaPrint profile was 12,780 euros; the mean cost of Adjuvant! Online, 10,743 euros; and the mean cost of systematic chemotherapy, 12,123 euros. Over the 10-year follow-up period, there were no differences in life-years or quality-adjusted life-years.

Treatment de-escalation is critical for ensuring high-quality survivorship over the long term, wrote Dr. Bonastre of Gustave Roussy Institute of Oncology, Paris, and her associates. “However, our study shows that the health benefits associated with the use of molecular tests are modest. In addition, the high price of these tests results in poor value for the money, limiting their usefulness in routine practice,” they said.

The study was funded by the French National Cancer Institute, and the authors reported no conflicts of interest.

msullivan@frontlinemedcom.com

On Twitter @alz_gal