Breast Cancer

Five breast cancer researchers have won 3 years of funding from the National Comprehensive Cancer Network’s Oncology Research Program and Pfizer Global Medical Grants. The researchers will receive up to $1.4 million.

Allison Lipitz-Snyderman, PhD, and Erin Gillespie, MD, of Memorial Sloan Kettering Cancer Center in New York, have won funding for a project entitled, “Leveraging an academic-community partnership model to improve the quality of radiation treatment for metastatic breast cancer patients.”

jensmith@mdedge.com

Five breast cancer researchers have won 3 years of funding from the National Comprehensive Cancer Network’s Oncology Research Program and Pfizer Global Medical Grants. The researchers will receive up to $1.4 million.

Allison Lipitz-Snyderman, PhD, and Erin Gillespie, MD, of Memorial Sloan Kettering Cancer Center in New York, have won funding for a project entitled, “Leveraging an academic-community partnership model to improve the quality of radiation treatment for metastatic breast cancer patients.”

jensmith@mdedge.com

Five breast cancer researchers have won 3 years of funding from the National Comprehensive Cancer Network’s Oncology Research Program and Pfizer Global Medical Grants. The researchers will receive up to $1.4 million.

Allison Lipitz-Snyderman, PhD, and Erin Gillespie, MD, of Memorial Sloan Kettering Cancer Center in New York, have won funding for a project entitled, “Leveraging an academic-community partnership model to improve the quality of radiation treatment for metastatic breast cancer patients.”

jensmith@mdedge.com

The 21-gene assay recurrence score can aid decisions about radiotherapy for postmenopausal patients with node-positive breast cancer, according to researchers.

The researchers analyzed patients who underwent mastectomy or breast-conserving surgery (excision and radiation) and received chemotherapy plus tamoxifen or tamoxifen alone. Results showed that patients with an intermediate or high recurrence score, according to the 21-gene assay OncotypeDX, were more likely to have locoregional recurrence (LRR).

“We believe that the recurrence score adds independent prognostic information that could be used with standard clinical factors for identifying LRR risk and making radiotherapy decisions,” Wendy A. Woodward, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, and coauthors wrote in JAMA Oncology.

Dr. Woodward and colleagues analyzed data from a phase 3 trial (NCT00929591) of postmenopausal women with estrogen or progesterone receptor–positive, node-positive breast cancer. There were 367 patients who received tamoxifen alone (n = 148) or cyclophosphamide, doxorubicin, and fluorouracil followed by tamoxifen (n = 219).

Of the 367 patients, 316 were included in the primary analysis. This includes 252 patients who underwent mastectomy without radiotherapy and 64 patients who underwent breast-conserving surgery with radiotherapy.

The researchers defined LRR as a recurrence in the breast; chest wall; or axillary, infraclavicular, supraclavicular, or internal mammary lymph nodes.

The LRR incidence was 5.8% (7/121) among patients with a low recurrence score and 13.8% (27/195) among patients with an intermediate or high recurrence score. The estimated 10-year cumulative LRR incidence rates were 9.7% and 16.5%, respectively (P = .02).

The researchers conducted a multivariable analysis for LRR, which included the recurrence score, randomized treatment (combination regimen vs. tamoxifen alone), number of positive nodes (three or fewer vs. four or more), and type of surgery (mastectomy vs. excision and radiation).

Having intermediate or high recurrence scores was a significant predictor of LRR, with a hazard ratio of 2.36 (P = .04). Having four or more involved nodes was a significant predictor of LRR as well (hazard ratio, 3.37; P = .001). Randomized treatment and surgery were not significantly associated with LRR.

The researchers also conducted an exploratory analysis and found that a recurrence score of 18 was the optimal cutoff for the association of recurrence score and LRR.

“This study found that higher recurrence scores were associated with increased LRR after adjustment for treatment, type of surgical procedure, and number of positive nodes,” Dr. Woodward and colleagues wrote. “This finding suggests that the recurrence score may be used, along with accepted clinical variables, to assess the risk of LRR during radiotherapy decision making. We recommend considering the recurrence score, when available, as one of the factors in selecting patients for postmastectomy radiotherapy.”

This research was funded by the National Cancer Institute of Canada, Canadian Cancer Society, and Genomic Health, which markets the 21-gene assay OncotypeDX. Dr. Woodward disclosed receiving personal fees from Genomic Health outside this research as well as an advisory fee from Merck.

SOURCE: Woodward WA et al. JAMA Oncol. 2020 Jan 9. doi: 10.1001/jamaoncol.2019.5559.

The 21-gene assay recurrence score can aid decisions about radiotherapy for postmenopausal patients with node-positive breast cancer, according to researchers.

The researchers analyzed patients who underwent mastectomy or breast-conserving surgery (excision and radiation) and received chemotherapy plus tamoxifen or tamoxifen alone. Results showed that patients with an intermediate or high recurrence score, according to the 21-gene assay OncotypeDX, were more likely to have locoregional recurrence (LRR).

“We believe that the recurrence score adds independent prognostic information that could be used with standard clinical factors for identifying LRR risk and making radiotherapy decisions,” Wendy A. Woodward, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, and coauthors wrote in JAMA Oncology.

Dr. Woodward and colleagues analyzed data from a phase 3 trial (NCT00929591) of postmenopausal women with estrogen or progesterone receptor–positive, node-positive breast cancer. There were 367 patients who received tamoxifen alone (n = 148) or cyclophosphamide, doxorubicin, and fluorouracil followed by tamoxifen (n = 219).

Of the 367 patients, 316 were included in the primary analysis. This includes 252 patients who underwent mastectomy without radiotherapy and 64 patients who underwent breast-conserving surgery with radiotherapy.

The researchers defined LRR as a recurrence in the breast; chest wall; or axillary, infraclavicular, supraclavicular, or internal mammary lymph nodes.

The LRR incidence was 5.8% (7/121) among patients with a low recurrence score and 13.8% (27/195) among patients with an intermediate or high recurrence score. The estimated 10-year cumulative LRR incidence rates were 9.7% and 16.5%, respectively (P = .02).

The researchers conducted a multivariable analysis for LRR, which included the recurrence score, randomized treatment (combination regimen vs. tamoxifen alone), number of positive nodes (three or fewer vs. four or more), and type of surgery (mastectomy vs. excision and radiation).

Having intermediate or high recurrence scores was a significant predictor of LRR, with a hazard ratio of 2.36 (P = .04). Having four or more involved nodes was a significant predictor of LRR as well (hazard ratio, 3.37; P = .001). Randomized treatment and surgery were not significantly associated with LRR.

The researchers also conducted an exploratory analysis and found that a recurrence score of 18 was the optimal cutoff for the association of recurrence score and LRR.

“This study found that higher recurrence scores were associated with increased LRR after adjustment for treatment, type of surgical procedure, and number of positive nodes,” Dr. Woodward and colleagues wrote. “This finding suggests that the recurrence score may be used, along with accepted clinical variables, to assess the risk of LRR during radiotherapy decision making. We recommend considering the recurrence score, when available, as one of the factors in selecting patients for postmastectomy radiotherapy.”

This research was funded by the National Cancer Institute of Canada, Canadian Cancer Society, and Genomic Health, which markets the 21-gene assay OncotypeDX. Dr. Woodward disclosed receiving personal fees from Genomic Health outside this research as well as an advisory fee from Merck.

SOURCE: Woodward WA et al. JAMA Oncol. 2020 Jan 9. doi: 10.1001/jamaoncol.2019.5559.

The 21-gene assay recurrence score can aid decisions about radiotherapy for postmenopausal patients with node-positive breast cancer, according to researchers.

The researchers analyzed patients who underwent mastectomy or breast-conserving surgery (excision and radiation) and received chemotherapy plus tamoxifen or tamoxifen alone. Results showed that patients with an intermediate or high recurrence score, according to the 21-gene assay OncotypeDX, were more likely to have locoregional recurrence (LRR).

“We believe that the recurrence score adds independent prognostic information that could be used with standard clinical factors for identifying LRR risk and making radiotherapy decisions,” Wendy A. Woodward, MD, PhD, of the University of Texas MD Anderson Cancer Center, Houston, and coauthors wrote in JAMA Oncology.

Dr. Woodward and colleagues analyzed data from a phase 3 trial (NCT00929591) of postmenopausal women with estrogen or progesterone receptor–positive, node-positive breast cancer. There were 367 patients who received tamoxifen alone (n = 148) or cyclophosphamide, doxorubicin, and fluorouracil followed by tamoxifen (n = 219).

Of the 367 patients, 316 were included in the primary analysis. This includes 252 patients who underwent mastectomy without radiotherapy and 64 patients who underwent breast-conserving surgery with radiotherapy.

The researchers defined LRR as a recurrence in the breast; chest wall; or axillary, infraclavicular, supraclavicular, or internal mammary lymph nodes.

The LRR incidence was 5.8% (7/121) among patients with a low recurrence score and 13.8% (27/195) among patients with an intermediate or high recurrence score. The estimated 10-year cumulative LRR incidence rates were 9.7% and 16.5%, respectively (P = .02).

The researchers conducted a multivariable analysis for LRR, which included the recurrence score, randomized treatment (combination regimen vs. tamoxifen alone), number of positive nodes (three or fewer vs. four or more), and type of surgery (mastectomy vs. excision and radiation).

Having intermediate or high recurrence scores was a significant predictor of LRR, with a hazard ratio of 2.36 (P = .04). Having four or more involved nodes was a significant predictor of LRR as well (hazard ratio, 3.37; P = .001). Randomized treatment and surgery were not significantly associated with LRR.

The researchers also conducted an exploratory analysis and found that a recurrence score of 18 was the optimal cutoff for the association of recurrence score and LRR.

“This study found that higher recurrence scores were associated with increased LRR after adjustment for treatment, type of surgical procedure, and number of positive nodes,” Dr. Woodward and colleagues wrote. “This finding suggests that the recurrence score may be used, along with accepted clinical variables, to assess the risk of LRR during radiotherapy decision making. We recommend considering the recurrence score, when available, as one of the factors in selecting patients for postmastectomy radiotherapy.”

This research was funded by the National Cancer Institute of Canada, Canadian Cancer Society, and Genomic Health, which markets the 21-gene assay OncotypeDX. Dr. Woodward disclosed receiving personal fees from Genomic Health outside this research as well as an advisory fee from Merck.

SOURCE: Woodward WA et al. JAMA Oncol. 2020 Jan 9. doi: 10.1001/jamaoncol.2019.5559.

Better insurance coverage within minority populations can help close racial disparities in the detection of early-stage breast cancer, according to new study.

Insurance coverage “mediates nearly half of the increased risk for later-stage breast cancer diagnosis seen among racial/ethnic minorities,” Naomi Ko, MD, of Boston University and colleagues wrote in a research report published in JAMA Oncology.

With Surveillance, Epidemiology, and End Results Program data, the researchers looked at patient records on 177,075 women (148,124 insured and 28,951 uninsured or on Medicaid) aged 40-64 years who received a breast cancer diagnosis between Jan. 1, 2010, and Dec. 31, 2016. They found that a higher proportion of women (20%) uninsured or on Medicaid received a diagnosis of a higher-stage breast cancer (stage III), compared with women who had health insurance (11%).

More non-Hispanic black women (17%), American Indian or Alaskan native (15%), and Hispanic women (16%) received a stage III breast cancer diagnosis, compared with non-Hispanic white women (12%). Non-Hispanic white women were more likely to have insurance coverage at the time of diagnosis (89%), compared with non-Hispanic black women (75%), American Indian or Alaskan native (58%), and Hispanic women (67%).

“Without insurance coverage, the lack of prevention, screening, and access to care, as well as delays in diagnosis, lead to later stage of disease at diagnosis and thus worse survival,” Dr. Ko and colleagues wrote, adding that patients with a diagnosis of later-stage cancer require more intensive treatment and are at higher risk for treatment-associated morbidity and poorer overall quality of life.

Another consequence of the later-stage diagnosis is increased financial costs related to treatment for these patients, according to the investigator. They cite research that shows stage III cancer was 58% more costly to treat than was stage I or II breast cancer.

“Overall, earlier stage at diagnosis of breast cancer is not only beneficial for individual patients and families but also on society as a whole to decrease costs and equity among all populations,” Dr. Ko and colleagues added.

The researchers noted some of the limitations of the study, which include the source of data (the Surveillance, Epidemiology, and End Results Program, which covers 18 regions and might not be generalizable to all populations), as well as the age range of the studied population.

That being said, the authors also acknowledged that the findings “do not suggest that insurance alone will eliminate racial/ethnic disparities in breast cancer,” but “the ability to quantify the association that insurance has with breast cancer stage is relevant to potential policy changes regarding insurance and a prioritization of solutions for the increased burden of cancer mortality and morbidity disproportionately placed on racial/ethnic minority populations.”

Funding sources include the National Institutes of Health, National Center for Advancing Translational Sciences, National Cancer Institute, and National Institute on Minority Health and Health Disparities. The authors reported no conflicts of interest related to this study.

gtwachtman@mdedge.com

SOURCE: Ko N et al. JAMA Onc. 2020 Jan 9. doi: 10.1001/jamaoncol.2019.5672.

Better insurance coverage within minority populations can help close racial disparities in the detection of early-stage breast cancer, according to new study.

Insurance coverage “mediates nearly half of the increased risk for later-stage breast cancer diagnosis seen among racial/ethnic minorities,” Naomi Ko, MD, of Boston University and colleagues wrote in a research report published in JAMA Oncology.

With Surveillance, Epidemiology, and End Results Program data, the researchers looked at patient records on 177,075 women (148,124 insured and 28,951 uninsured or on Medicaid) aged 40-64 years who received a breast cancer diagnosis between Jan. 1, 2010, and Dec. 31, 2016. They found that a higher proportion of women (20%) uninsured or on Medicaid received a diagnosis of a higher-stage breast cancer (stage III), compared with women who had health insurance (11%).

More non-Hispanic black women (17%), American Indian or Alaskan native (15%), and Hispanic women (16%) received a stage III breast cancer diagnosis, compared with non-Hispanic white women (12%). Non-Hispanic white women were more likely to have insurance coverage at the time of diagnosis (89%), compared with non-Hispanic black women (75%), American Indian or Alaskan native (58%), and Hispanic women (67%).

“Without insurance coverage, the lack of prevention, screening, and access to care, as well as delays in diagnosis, lead to later stage of disease at diagnosis and thus worse survival,” Dr. Ko and colleagues wrote, adding that patients with a diagnosis of later-stage cancer require more intensive treatment and are at higher risk for treatment-associated morbidity and poorer overall quality of life.

Another consequence of the later-stage diagnosis is increased financial costs related to treatment for these patients, according to the investigator. They cite research that shows stage III cancer was 58% more costly to treat than was stage I or II breast cancer.

“Overall, earlier stage at diagnosis of breast cancer is not only beneficial for individual patients and families but also on society as a whole to decrease costs and equity among all populations,” Dr. Ko and colleagues added.

The researchers noted some of the limitations of the study, which include the source of data (the Surveillance, Epidemiology, and End Results Program, which covers 18 regions and might not be generalizable to all populations), as well as the age range of the studied population.

That being said, the authors also acknowledged that the findings “do not suggest that insurance alone will eliminate racial/ethnic disparities in breast cancer,” but “the ability to quantify the association that insurance has with breast cancer stage is relevant to potential policy changes regarding insurance and a prioritization of solutions for the increased burden of cancer mortality and morbidity disproportionately placed on racial/ethnic minority populations.”

Funding sources include the National Institutes of Health, National Center for Advancing Translational Sciences, National Cancer Institute, and National Institute on Minority Health and Health Disparities. The authors reported no conflicts of interest related to this study.

gtwachtman@mdedge.com

SOURCE: Ko N et al. JAMA Onc. 2020 Jan 9. doi: 10.1001/jamaoncol.2019.5672.

Better insurance coverage within minority populations can help close racial disparities in the detection of early-stage breast cancer, according to new study.

Insurance coverage “mediates nearly half of the increased risk for later-stage breast cancer diagnosis seen among racial/ethnic minorities,” Naomi Ko, MD, of Boston University and colleagues wrote in a research report published in JAMA Oncology.

With Surveillance, Epidemiology, and End Results Program data, the researchers looked at patient records on 177,075 women (148,124 insured and 28,951 uninsured or on Medicaid) aged 40-64 years who received a breast cancer diagnosis between Jan. 1, 2010, and Dec. 31, 2016. They found that a higher proportion of women (20%) uninsured or on Medicaid received a diagnosis of a higher-stage breast cancer (stage III), compared with women who had health insurance (11%).

More non-Hispanic black women (17%), American Indian or Alaskan native (15%), and Hispanic women (16%) received a stage III breast cancer diagnosis, compared with non-Hispanic white women (12%). Non-Hispanic white women were more likely to have insurance coverage at the time of diagnosis (89%), compared with non-Hispanic black women (75%), American Indian or Alaskan native (58%), and Hispanic women (67%).

“Without insurance coverage, the lack of prevention, screening, and access to care, as well as delays in diagnosis, lead to later stage of disease at diagnosis and thus worse survival,” Dr. Ko and colleagues wrote, adding that patients with a diagnosis of later-stage cancer require more intensive treatment and are at higher risk for treatment-associated morbidity and poorer overall quality of life.

Another consequence of the later-stage diagnosis is increased financial costs related to treatment for these patients, according to the investigator. They cite research that shows stage III cancer was 58% more costly to treat than was stage I or II breast cancer.

“Overall, earlier stage at diagnosis of breast cancer is not only beneficial for individual patients and families but also on society as a whole to decrease costs and equity among all populations,” Dr. Ko and colleagues added.

The researchers noted some of the limitations of the study, which include the source of data (the Surveillance, Epidemiology, and End Results Program, which covers 18 regions and might not be generalizable to all populations), as well as the age range of the studied population.

That being said, the authors also acknowledged that the findings “do not suggest that insurance alone will eliminate racial/ethnic disparities in breast cancer,” but “the ability to quantify the association that insurance has with breast cancer stage is relevant to potential policy changes regarding insurance and a prioritization of solutions for the increased burden of cancer mortality and morbidity disproportionately placed on racial/ethnic minority populations.”

Funding sources include the National Institutes of Health, National Center for Advancing Translational Sciences, National Cancer Institute, and National Institute on Minority Health and Health Disparities. The authors reported no conflicts of interest related to this study.

gtwachtman@mdedge.com

SOURCE: Ko N et al. JAMA Onc. 2020 Jan 9. doi: 10.1001/jamaoncol.2019.5672.

In this edition of “How I Will Treat My Next Patient,” I highlight two presentations from the recent San Antonio Breast Cancer Symposium (SABCS) that will likely change practice for some breast cancer patients – even before the ball drops in Times Square on New Year’s Eve.

Residual cancer burden

Researchers reported a multi-institutional analysis of individual patient-level data on 5,160 patients who had received neoadjuvant chemotherapy (NAC) for localized breast cancer at 11 different centers. They found that residual cancer burden (RCB) was significantly associated with event-free (EFS) and distant recurrence-free survival. The value of calculating RCB was seen across all breast cancer tumor phenotypes (SABCS 2019, Abstract GS5-01).

RCB is calculated by analyzing the residual disease after NAC for the primary tumor bed, the number of positive axillary nodes, and the size of largest node metastasis. It is graded from RCB-0 (pCR) to RCB-III (extensive residual disease).

Both EFS and distant recurrence-free survival were strongly associated with RCB for the overall population and for each breast cancer subtype. For hormone receptor–positive/HER2-negative disease there was a slight hiccup in that RCB-0 was associated with a 10-year EFS of 81%, but EFS was 86% for RCB-I. Fortunately, the prognostic reliability of RCB was clear for RCB-II (69%) and RCB-III (52%). The presenter, W. Fraser Symmans, MD, commented that RCB is most prognostic when higher levels of residual disease are present. RCB remained prognostic in multivariate models adjusting for age, grade, and clinical T and N stage at diagnosis.

How these results influence practice

After neoadjuvant chemotherapy in patients with localized breast cancer, we struggle when patients ask: “So, doctor, how am I likely to do?” We piece together a complicated – and inconsistent – answer, based on breast cancer subtype, original stage of disease, whether pCR was attained, and other factors.

For patients with triple-negative breast cancer, we have the option of adding capecitabine and/or participation in ongoing clinical trials, for patients with residual disease after NAC. Among the HER2-positive patients, we have data from the KATHERINE, ExtaNET, and APHINITY trials that provide options for additional treatment in those patients, as well. For patients with potentially hormonally responsive, HER2-negative disease, we can emphasize the importance of postoperative adjuvant endocrine therapy, the mandate for continued adherence to oral therapy, and the lower likelihood of (and prognostic value of) pCR in that breast cancer subtype.

Where we previously had a complicated, nuanced discussion, we now have data from a multi-institutional, meticulous analysis to guide further treatment, candidacy for clinical trials, and our expectations of what would be meaningful results from additional therapy. This meets my definition of “practice-changing” research.
 

APHINITY follow-up

APHINITY was a randomized, multicenter, double-blind, placebo-controlled trial that previously demonstrated that pertuzumab added to standard chemotherapy plus 1 year of trastuzumab in operable HER2-positive breast cancer was associated with modest, but statistically significant, improvement in invasive disease–free survival (IDFS), compared with placebo and chemotherapy plus trastuzumab (hazard ratio, 0.81; P = .04). When the initial results – with a median follow-up of 45.4 months – were published, the authors promised an update at 6 years. Martine Piccart, MD, PhD, provided that update at the 2019 SABCS (Abstract GS1-04).

In the updated analysis, overall survival was 94.8% among patients on the pertuzumab arm and 93.9% among patients taking placebo (HR, 0.85). IDFS rates were 90.6% versus 87.8% in the intent-to-treat population. The investigator commented that this difference was caused mainly by a reduction in distant and loco-regional recurrences.

Central nervous system metastases, contralateral invasive breast cancers, and death without a prior event were no different between the two treatment groups.

Improvement in IDFS (the primary endpoint) from pertuzumab was most impressive in the node-positive cohort, 87.9% versus 83.4% for placebo (HR, 0.72). There was no benefit in the node-negative population (95.0% vs. 94.9%; HR, 1.02).

In contrast to the 3-year analysis, the benefits in IDFS were seen regardless of hormone receptor status. Additionally, no new safety concerns emerged. The rate of severe cardiac events was below 1% in both groups.

How these results influence practice

“Patience is a virtue” appeared for the first time in the English language around 1360, in William Langland’s poem “Piers Plowman.” They are true words, indeed.

When the initial results of APHINITY were published in 2017, they led to the approval of pertuzumab as an addition to chemotherapy plus trastuzumab for high-risk, early, HER2-positive breast cancer patients. Still, the difference in IDFS curves was visually unimpressive (absolute difference 1.7% in the intent-to-treat and 3.2% in the node-positive patients) and pertuzumab was associated with more grade 3 toxicities (primarily diarrhea) and treatment discontinuations.

An optimist would have observed that the IDFS curves in 2017 did not start to diverge until 24 months and would have noted that the divergence increased with time. That virtuously patient person would have expected that the second interim analysis would show larger absolute benefits, and that the hormone receptor–positive patients (64% of the total) would not yet have relapsed by the first interim analysis and that pertuzumab’s benefit in that group would emerge late.

That appears to be what is happening. It provides hope that an overall survival benefit will become more evident with time. If the target P value for an overall survival difference (.0012) is met by the time of the third interim analysis, our patience (and the FDA’s decision to grant approval for pertuzumab for this indication) will have been amply rewarded. For selected HER2-posiitve patients with high RCB, especially those who tolerated neoadjuvant trastuzumab plus pertuzumab regimens, postoperative adjuvant pertuzumab may be an appealing option.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I Will Treat My Next Patient,” I highlight two presentations from the recent San Antonio Breast Cancer Symposium (SABCS) that will likely change practice for some breast cancer patients – even before the ball drops in Times Square on New Year’s Eve.

Residual cancer burden

Researchers reported a multi-institutional analysis of individual patient-level data on 5,160 patients who had received neoadjuvant chemotherapy (NAC) for localized breast cancer at 11 different centers. They found that residual cancer burden (RCB) was significantly associated with event-free (EFS) and distant recurrence-free survival. The value of calculating RCB was seen across all breast cancer tumor phenotypes (SABCS 2019, Abstract GS5-01).

RCB is calculated by analyzing the residual disease after NAC for the primary tumor bed, the number of positive axillary nodes, and the size of largest node metastasis. It is graded from RCB-0 (pCR) to RCB-III (extensive residual disease).

Both EFS and distant recurrence-free survival were strongly associated with RCB for the overall population and for each breast cancer subtype. For hormone receptor–positive/HER2-negative disease there was a slight hiccup in that RCB-0 was associated with a 10-year EFS of 81%, but EFS was 86% for RCB-I. Fortunately, the prognostic reliability of RCB was clear for RCB-II (69%) and RCB-III (52%). The presenter, W. Fraser Symmans, MD, commented that RCB is most prognostic when higher levels of residual disease are present. RCB remained prognostic in multivariate models adjusting for age, grade, and clinical T and N stage at diagnosis.

How these results influence practice

After neoadjuvant chemotherapy in patients with localized breast cancer, we struggle when patients ask: “So, doctor, how am I likely to do?” We piece together a complicated – and inconsistent – answer, based on breast cancer subtype, original stage of disease, whether pCR was attained, and other factors.

For patients with triple-negative breast cancer, we have the option of adding capecitabine and/or participation in ongoing clinical trials, for patients with residual disease after NAC. Among the HER2-positive patients, we have data from the KATHERINE, ExtaNET, and APHINITY trials that provide options for additional treatment in those patients, as well. For patients with potentially hormonally responsive, HER2-negative disease, we can emphasize the importance of postoperative adjuvant endocrine therapy, the mandate for continued adherence to oral therapy, and the lower likelihood of (and prognostic value of) pCR in that breast cancer subtype.

Where we previously had a complicated, nuanced discussion, we now have data from a multi-institutional, meticulous analysis to guide further treatment, candidacy for clinical trials, and our expectations of what would be meaningful results from additional therapy. This meets my definition of “practice-changing” research.
 

APHINITY follow-up

APHINITY was a randomized, multicenter, double-blind, placebo-controlled trial that previously demonstrated that pertuzumab added to standard chemotherapy plus 1 year of trastuzumab in operable HER2-positive breast cancer was associated with modest, but statistically significant, improvement in invasive disease–free survival (IDFS), compared with placebo and chemotherapy plus trastuzumab (hazard ratio, 0.81; P = .04). When the initial results – with a median follow-up of 45.4 months – were published, the authors promised an update at 6 years. Martine Piccart, MD, PhD, provided that update at the 2019 SABCS (Abstract GS1-04).

In the updated analysis, overall survival was 94.8% among patients on the pertuzumab arm and 93.9% among patients taking placebo (HR, 0.85). IDFS rates were 90.6% versus 87.8% in the intent-to-treat population. The investigator commented that this difference was caused mainly by a reduction in distant and loco-regional recurrences.

Central nervous system metastases, contralateral invasive breast cancers, and death without a prior event were no different between the two treatment groups.

Improvement in IDFS (the primary endpoint) from pertuzumab was most impressive in the node-positive cohort, 87.9% versus 83.4% for placebo (HR, 0.72). There was no benefit in the node-negative population (95.0% vs. 94.9%; HR, 1.02).

In contrast to the 3-year analysis, the benefits in IDFS were seen regardless of hormone receptor status. Additionally, no new safety concerns emerged. The rate of severe cardiac events was below 1% in both groups.

How these results influence practice

“Patience is a virtue” appeared for the first time in the English language around 1360, in William Langland’s poem “Piers Plowman.” They are true words, indeed.

When the initial results of APHINITY were published in 2017, they led to the approval of pertuzumab as an addition to chemotherapy plus trastuzumab for high-risk, early, HER2-positive breast cancer patients. Still, the difference in IDFS curves was visually unimpressive (absolute difference 1.7% in the intent-to-treat and 3.2% in the node-positive patients) and pertuzumab was associated with more grade 3 toxicities (primarily diarrhea) and treatment discontinuations.

An optimist would have observed that the IDFS curves in 2017 did not start to diverge until 24 months and would have noted that the divergence increased with time. That virtuously patient person would have expected that the second interim analysis would show larger absolute benefits, and that the hormone receptor–positive patients (64% of the total) would not yet have relapsed by the first interim analysis and that pertuzumab’s benefit in that group would emerge late.

That appears to be what is happening. It provides hope that an overall survival benefit will become more evident with time. If the target P value for an overall survival difference (.0012) is met by the time of the third interim analysis, our patience (and the FDA’s decision to grant approval for pertuzumab for this indication) will have been amply rewarded. For selected HER2-posiitve patients with high RCB, especially those who tolerated neoadjuvant trastuzumab plus pertuzumab regimens, postoperative adjuvant pertuzumab may be an appealing option.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I Will Treat My Next Patient,” I highlight two presentations from the recent San Antonio Breast Cancer Symposium (SABCS) that will likely change practice for some breast cancer patients – even before the ball drops in Times Square on New Year’s Eve.

Residual cancer burden

Researchers reported a multi-institutional analysis of individual patient-level data on 5,160 patients who had received neoadjuvant chemotherapy (NAC) for localized breast cancer at 11 different centers. They found that residual cancer burden (RCB) was significantly associated with event-free (EFS) and distant recurrence-free survival. The value of calculating RCB was seen across all breast cancer tumor phenotypes (SABCS 2019, Abstract GS5-01).

RCB is calculated by analyzing the residual disease after NAC for the primary tumor bed, the number of positive axillary nodes, and the size of largest node metastasis. It is graded from RCB-0 (pCR) to RCB-III (extensive residual disease).

Both EFS and distant recurrence-free survival were strongly associated with RCB for the overall population and for each breast cancer subtype. For hormone receptor–positive/HER2-negative disease there was a slight hiccup in that RCB-0 was associated with a 10-year EFS of 81%, but EFS was 86% for RCB-I. Fortunately, the prognostic reliability of RCB was clear for RCB-II (69%) and RCB-III (52%). The presenter, W. Fraser Symmans, MD, commented that RCB is most prognostic when higher levels of residual disease are present. RCB remained prognostic in multivariate models adjusting for age, grade, and clinical T and N stage at diagnosis.

How these results influence practice

After neoadjuvant chemotherapy in patients with localized breast cancer, we struggle when patients ask: “So, doctor, how am I likely to do?” We piece together a complicated – and inconsistent – answer, based on breast cancer subtype, original stage of disease, whether pCR was attained, and other factors.

For patients with triple-negative breast cancer, we have the option of adding capecitabine and/or participation in ongoing clinical trials, for patients with residual disease after NAC. Among the HER2-positive patients, we have data from the KATHERINE, ExtaNET, and APHINITY trials that provide options for additional treatment in those patients, as well. For patients with potentially hormonally responsive, HER2-negative disease, we can emphasize the importance of postoperative adjuvant endocrine therapy, the mandate for continued adherence to oral therapy, and the lower likelihood of (and prognostic value of) pCR in that breast cancer subtype.

Where we previously had a complicated, nuanced discussion, we now have data from a multi-institutional, meticulous analysis to guide further treatment, candidacy for clinical trials, and our expectations of what would be meaningful results from additional therapy. This meets my definition of “practice-changing” research.
 

APHINITY follow-up

APHINITY was a randomized, multicenter, double-blind, placebo-controlled trial that previously demonstrated that pertuzumab added to standard chemotherapy plus 1 year of trastuzumab in operable HER2-positive breast cancer was associated with modest, but statistically significant, improvement in invasive disease–free survival (IDFS), compared with placebo and chemotherapy plus trastuzumab (hazard ratio, 0.81; P = .04). When the initial results – with a median follow-up of 45.4 months – were published, the authors promised an update at 6 years. Martine Piccart, MD, PhD, provided that update at the 2019 SABCS (Abstract GS1-04).

In the updated analysis, overall survival was 94.8% among patients on the pertuzumab arm and 93.9% among patients taking placebo (HR, 0.85). IDFS rates were 90.6% versus 87.8% in the intent-to-treat population. The investigator commented that this difference was caused mainly by a reduction in distant and loco-regional recurrences.

Central nervous system metastases, contralateral invasive breast cancers, and death without a prior event were no different between the two treatment groups.

Improvement in IDFS (the primary endpoint) from pertuzumab was most impressive in the node-positive cohort, 87.9% versus 83.4% for placebo (HR, 0.72). There was no benefit in the node-negative population (95.0% vs. 94.9%; HR, 1.02).

In contrast to the 3-year analysis, the benefits in IDFS were seen regardless of hormone receptor status. Additionally, no new safety concerns emerged. The rate of severe cardiac events was below 1% in both groups.

How these results influence practice

“Patience is a virtue” appeared for the first time in the English language around 1360, in William Langland’s poem “Piers Plowman.” They are true words, indeed.

When the initial results of APHINITY were published in 2017, they led to the approval of pertuzumab as an addition to chemotherapy plus trastuzumab for high-risk, early, HER2-positive breast cancer patients. Still, the difference in IDFS curves was visually unimpressive (absolute difference 1.7% in the intent-to-treat and 3.2% in the node-positive patients) and pertuzumab was associated with more grade 3 toxicities (primarily diarrhea) and treatment discontinuations.

An optimist would have observed that the IDFS curves in 2017 did not start to diverge until 24 months and would have noted that the divergence increased with time. That virtuously patient person would have expected that the second interim analysis would show larger absolute benefits, and that the hormone receptor–positive patients (64% of the total) would not yet have relapsed by the first interim analysis and that pertuzumab’s benefit in that group would emerge late.

That appears to be what is happening. It provides hope that an overall survival benefit will become more evident with time. If the target P value for an overall survival difference (.0012) is met by the time of the third interim analysis, our patience (and the FDA’s decision to grant approval for pertuzumab for this indication) will have been amply rewarded. For selected HER2-posiitve patients with high RCB, especially those who tolerated neoadjuvant trastuzumab plus pertuzumab regimens, postoperative adjuvant pertuzumab may be an appealing option.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

SAN ANTONIO – The high accuracy and efficiency of circulating tumor DNA (ctDNA) testing allows for routine clinical use in advanced breast cancer, according to investigators.

Will Pass/MDedge News

The plasmaMATCH trial showed that gene level agreement between ctDNA results measured by digital PCR versus sequencing was as high as 99.4%, reported lead author Nicholas Turner, MA, MRCP, PhD, of The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London.

Dr. Turner, who presented findings at the San Antonio Breast Cancer Symposium, said that ctDNA testing can detect rare mutations and link patients with targeted therapies that have clinically relevant response rates.

“Multiple somatic mutations are potentially targetable in the treatment of advanced breast cancer,” Dr. Turner said. “In addition, mutations may be acquired [during treatment].”

The diverse and dynamic landscape of mutations in breast cancer creates a need to genotype tumors without repeating biopsies, Dr. Turner said. He noted that ctDNA is one possible means of fulfilling this need, although more prospective research is required to determine clinical utility.

To this end, the investigators conducted the phase II plasmaMATCH trial, a multiple parallel cohort, multicenter study involving 1,044 patients with advanced breast cancer. All patients had ctDNA testing performed prospectively with digital droplet PCR (ddPCR); in addition, ctDNA testing was performed with error-corrected sequencing using Guardant360, either prospectively or retrospectively. If actionable mutations were identified, and consent was provided, then patients entered the treatment cohort, which was composed of 142 participants.

Patients were divided into four parallel treatment cohorts based on ctDNA mutation results and accompanying treatments, as follows:

• (A) ESR1 mutation; extended-dose fulvestrant.
• (B) HER2 mutation; neratinib with or without fulvestrant.
• (C) AKT1 in estrogen receptor–positive disease; capivasertib plus fulvestrant.
• (D) “AKT basket” – AKT1 in estrogen receptor–negative disease or PTEN inactivating mutation; capivasertib.

The primary objective was response rate. For cohort A, at least 13 out of 78 evaluable patients (17%) needed to have a response to infer sufficient efficacy of the matched therapy. For the remaining cohorts, sufficient efficacy was defined by responses in at least 3 out of 16 evaluable patients (19%).

SOURCE: Turner et al. SABCS. 2019 Dec 12. Abstract GS3-06.

SAN ANTONIO – The high accuracy and efficiency of circulating tumor DNA (ctDNA) testing allows for routine clinical use in advanced breast cancer, according to investigators.

Will Pass/MDedge News

The plasmaMATCH trial showed that gene level agreement between ctDNA results measured by digital PCR versus sequencing was as high as 99.4%, reported lead author Nicholas Turner, MA, MRCP, PhD, of The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London.

Dr. Turner, who presented findings at the San Antonio Breast Cancer Symposium, said that ctDNA testing can detect rare mutations and link patients with targeted therapies that have clinically relevant response rates.

“Multiple somatic mutations are potentially targetable in the treatment of advanced breast cancer,” Dr. Turner said. “In addition, mutations may be acquired [during treatment].”

The diverse and dynamic landscape of mutations in breast cancer creates a need to genotype tumors without repeating biopsies, Dr. Turner said. He noted that ctDNA is one possible means of fulfilling this need, although more prospective research is required to determine clinical utility.

To this end, the investigators conducted the phase II plasmaMATCH trial, a multiple parallel cohort, multicenter study involving 1,044 patients with advanced breast cancer. All patients had ctDNA testing performed prospectively with digital droplet PCR (ddPCR); in addition, ctDNA testing was performed with error-corrected sequencing using Guardant360, either prospectively or retrospectively. If actionable mutations were identified, and consent was provided, then patients entered the treatment cohort, which was composed of 142 participants.

Patients were divided into four parallel treatment cohorts based on ctDNA mutation results and accompanying treatments, as follows:

• (A) ESR1 mutation; extended-dose fulvestrant.
• (B) HER2 mutation; neratinib with or without fulvestrant.
• (C) AKT1 in estrogen receptor–positive disease; capivasertib plus fulvestrant.
• (D) “AKT basket” – AKT1 in estrogen receptor–negative disease or PTEN inactivating mutation; capivasertib.

The primary objective was response rate. For cohort A, at least 13 out of 78 evaluable patients (17%) needed to have a response to infer sufficient efficacy of the matched therapy. For the remaining cohorts, sufficient efficacy was defined by responses in at least 3 out of 16 evaluable patients (19%).

SOURCE: Turner et al. SABCS. 2019 Dec 12. Abstract GS3-06.

SAN ANTONIO – The high accuracy and efficiency of circulating tumor DNA (ctDNA) testing allows for routine clinical use in advanced breast cancer, according to investigators.

Will Pass/MDedge News

The plasmaMATCH trial showed that gene level agreement between ctDNA results measured by digital PCR versus sequencing was as high as 99.4%, reported lead author Nicholas Turner, MA, MRCP, PhD, of The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London.

Dr. Turner, who presented findings at the San Antonio Breast Cancer Symposium, said that ctDNA testing can detect rare mutations and link patients with targeted therapies that have clinically relevant response rates.

“Multiple somatic mutations are potentially targetable in the treatment of advanced breast cancer,” Dr. Turner said. “In addition, mutations may be acquired [during treatment].”

The diverse and dynamic landscape of mutations in breast cancer creates a need to genotype tumors without repeating biopsies, Dr. Turner said. He noted that ctDNA is one possible means of fulfilling this need, although more prospective research is required to determine clinical utility.

To this end, the investigators conducted the phase II plasmaMATCH trial, a multiple parallel cohort, multicenter study involving 1,044 patients with advanced breast cancer. All patients had ctDNA testing performed prospectively with digital droplet PCR (ddPCR); in addition, ctDNA testing was performed with error-corrected sequencing using Guardant360, either prospectively or retrospectively. If actionable mutations were identified, and consent was provided, then patients entered the treatment cohort, which was composed of 142 participants.

Patients were divided into four parallel treatment cohorts based on ctDNA mutation results and accompanying treatments, as follows:

• (A) ESR1 mutation; extended-dose fulvestrant.
• (B) HER2 mutation; neratinib with or without fulvestrant.
• (C) AKT1 in estrogen receptor–positive disease; capivasertib plus fulvestrant.
• (D) “AKT basket” – AKT1 in estrogen receptor–negative disease or PTEN inactivating mutation; capivasertib.

The primary objective was response rate. For cohort A, at least 13 out of 78 evaluable patients (17%) needed to have a response to infer sufficient efficacy of the matched therapy. For the remaining cohorts, sufficient efficacy was defined by responses in at least 3 out of 16 evaluable patients (19%).

SOURCE: Turner et al. SABCS. 2019 Dec 12. Abstract GS3-06.

SAN ANTONIO – For detection of genomic aberrations in patients with advanced breast cancer, sensitivity of circulating tumor DNA (ctDNA) testing is effectively equivalent to that of tumor tissue sequencing, based on results of the plasmaMATCH trial.

Will Pass/MDedge News

When plasma and tumor tissue samples were collected within 60 days of one another, sensitivity of ctDNA testing was 98% for digital droplet PCR (ddPCR) and 100% for targeted sequencing with Guardant360, reported lead author Belinda Kingston, MB, ChB, of The Institute of Cancer Research, London.

In addition to analyzing ctDNA accuracy, Dr. Kingston and colleagues explored characteristics of genomic alterations in relation to one another and to disease subtypes.

“We have defined the genomic landscape of advanced breast cancer using ctDNA analysis,” Dr. Kingston said during a presentation at the San Antonio Breast Cancer Symposium.

The open-label plasmaMATCH trial, conducted at multiple centers in the United Kingdom, involved more than 1,000 patients with advanced breast cancer. The present analysis included 1,025 patients who underwent ctDNA testing via ddPCR, which screened for alterations in PIK3CA, ESR1, AKT1, and ERBB2. Eight hundred patients also underwent ctDNA testing with Guardant360 targeted sequencing (a 73-gene panel), while 77 patients additionally had tumor tissue sequencing performed on a fresh or frozen sample of metastatic tissue (a 16-gene panel).

Results showed that individual gene level agreement between the two ctDNA techniques ranged from 96% to 99% with kappa scores of at least 0.89. As described above, sensitivity of these tests, compared with tumor tissue sequencing, approached 100%.

Following this overview of diagnostic accuracy, Dr. Kingston described a series of genomic trends, focusing first on targetable alterations.

Both ctDNA techniques revealed that ESR1 mutations were common in cases of hormone receptor (HR)-positive disease, including approximately 40% of patients with HER2-negative breast cancer and approximately 20% of patients with HER2-positive breast cancer. In contrast, ESR1 mutations were found in less than 1% of patients with HR-negative disease. Although ERBB2 amplification was predominantly found in patients with HER2-positive breast cancer, this alteration was found in 1%-2% of patients with HER2-negative disease.

For the remainder of the presentation, Dr. Kingston focused on ctDNA targeted sequencing data.

Within this cohort of 800 participants, 92.9% of patients had a ctDNA alteration. The mean number of pathogenic alterations was 2.7; Dr. Kingston noted that, on average, patients with HR-positive, HER2-negative disease had significantly more alterations than did those with triple-negative breast cancer (3.0 vs 1.8; P less than .0001).

“We found that specific genes are enriched in certain breast cancer subtypes,” Dr. Kingston said, pointing out the “notable” rate of ERBB2 mutations (14%) in HER2-amplified disease.

Among patients with HR-positive disease, those who were HER2-negative often had ESR1 and KRAS mutations, whereas those with HER2-positive disease often had ESR1 mutations but not KRAS mutations.

Heterogeneity analysis showed that alterations in certain genes were clonally dominant, including AKT1, PIK3CA, GATA3, and TP53, while others were more often subclonal, including ESR1, RB1, SMAD4, and KRAS.

A closer look at frequency of alterations showed that AKT1, CDH1, and GATA3 were typically found as the only gene alteration present; in contrast, ESR1 alterations were often accompanied by multiple other gene hits.

Returning to targetable genes, the investigators found that there was significant variation in clonal dominance of pathogenic mutations in ESR1 and PIK3CA. A deeper analysis revealed that PIK3CA mutations were often double mutations in HR-positive disease, and that subclonal second mutations were found at APOBEC mutagenesis sites.

Carlos Arteaga, MD, of the University of Texas Southwestern Medical Center, Dallas, commented on the findings after the presentation and asked Dr. Kingston about a potential blind spot in the data.

Will Pass/MDedge News

SOURCE: Kingston et al. SABCS. 2019 Abstract GS3-07.

SAN ANTONIO – For detection of genomic aberrations in patients with advanced breast cancer, sensitivity of circulating tumor DNA (ctDNA) testing is effectively equivalent to that of tumor tissue sequencing, based on results of the plasmaMATCH trial.

Will Pass/MDedge News

When plasma and tumor tissue samples were collected within 60 days of one another, sensitivity of ctDNA testing was 98% for digital droplet PCR (ddPCR) and 100% for targeted sequencing with Guardant360, reported lead author Belinda Kingston, MB, ChB, of The Institute of Cancer Research, London.

In addition to analyzing ctDNA accuracy, Dr. Kingston and colleagues explored characteristics of genomic alterations in relation to one another and to disease subtypes.

“We have defined the genomic landscape of advanced breast cancer using ctDNA analysis,” Dr. Kingston said during a presentation at the San Antonio Breast Cancer Symposium.

The open-label plasmaMATCH trial, conducted at multiple centers in the United Kingdom, involved more than 1,000 patients with advanced breast cancer. The present analysis included 1,025 patients who underwent ctDNA testing via ddPCR, which screened for alterations in PIK3CA, ESR1, AKT1, and ERBB2. Eight hundred patients also underwent ctDNA testing with Guardant360 targeted sequencing (a 73-gene panel), while 77 patients additionally had tumor tissue sequencing performed on a fresh or frozen sample of metastatic tissue (a 16-gene panel).

Results showed that individual gene level agreement between the two ctDNA techniques ranged from 96% to 99% with kappa scores of at least 0.89. As described above, sensitivity of these tests, compared with tumor tissue sequencing, approached 100%.

Following this overview of diagnostic accuracy, Dr. Kingston described a series of genomic trends, focusing first on targetable alterations.

Both ctDNA techniques revealed that ESR1 mutations were common in cases of hormone receptor (HR)-positive disease, including approximately 40% of patients with HER2-negative breast cancer and approximately 20% of patients with HER2-positive breast cancer. In contrast, ESR1 mutations were found in less than 1% of patients with HR-negative disease. Although ERBB2 amplification was predominantly found in patients with HER2-positive breast cancer, this alteration was found in 1%-2% of patients with HER2-negative disease.

For the remainder of the presentation, Dr. Kingston focused on ctDNA targeted sequencing data.

Within this cohort of 800 participants, 92.9% of patients had a ctDNA alteration. The mean number of pathogenic alterations was 2.7; Dr. Kingston noted that, on average, patients with HR-positive, HER2-negative disease had significantly more alterations than did those with triple-negative breast cancer (3.0 vs 1.8; P less than .0001).

“We found that specific genes are enriched in certain breast cancer subtypes,” Dr. Kingston said, pointing out the “notable” rate of ERBB2 mutations (14%) in HER2-amplified disease.

Among patients with HR-positive disease, those who were HER2-negative often had ESR1 and KRAS mutations, whereas those with HER2-positive disease often had ESR1 mutations but not KRAS mutations.

Heterogeneity analysis showed that alterations in certain genes were clonally dominant, including AKT1, PIK3CA, GATA3, and TP53, while others were more often subclonal, including ESR1, RB1, SMAD4, and KRAS.

A closer look at frequency of alterations showed that AKT1, CDH1, and GATA3 were typically found as the only gene alteration present; in contrast, ESR1 alterations were often accompanied by multiple other gene hits.

Returning to targetable genes, the investigators found that there was significant variation in clonal dominance of pathogenic mutations in ESR1 and PIK3CA. A deeper analysis revealed that PIK3CA mutations were often double mutations in HR-positive disease, and that subclonal second mutations were found at APOBEC mutagenesis sites.

Carlos Arteaga, MD, of the University of Texas Southwestern Medical Center, Dallas, commented on the findings after the presentation and asked Dr. Kingston about a potential blind spot in the data.

Will Pass/MDedge News

SOURCE: Kingston et al. SABCS. 2019 Abstract GS3-07.

SAN ANTONIO – For detection of genomic aberrations in patients with advanced breast cancer, sensitivity of circulating tumor DNA (ctDNA) testing is effectively equivalent to that of tumor tissue sequencing, based on results of the plasmaMATCH trial.

Will Pass/MDedge News

When plasma and tumor tissue samples were collected within 60 days of one another, sensitivity of ctDNA testing was 98% for digital droplet PCR (ddPCR) and 100% for targeted sequencing with Guardant360, reported lead author Belinda Kingston, MB, ChB, of The Institute of Cancer Research, London.

In addition to analyzing ctDNA accuracy, Dr. Kingston and colleagues explored characteristics of genomic alterations in relation to one another and to disease subtypes.

“We have defined the genomic landscape of advanced breast cancer using ctDNA analysis,” Dr. Kingston said during a presentation at the San Antonio Breast Cancer Symposium.

The open-label plasmaMATCH trial, conducted at multiple centers in the United Kingdom, involved more than 1,000 patients with advanced breast cancer. The present analysis included 1,025 patients who underwent ctDNA testing via ddPCR, which screened for alterations in PIK3CA, ESR1, AKT1, and ERBB2. Eight hundred patients also underwent ctDNA testing with Guardant360 targeted sequencing (a 73-gene panel), while 77 patients additionally had tumor tissue sequencing performed on a fresh or frozen sample of metastatic tissue (a 16-gene panel).

Results showed that individual gene level agreement between the two ctDNA techniques ranged from 96% to 99% with kappa scores of at least 0.89. As described above, sensitivity of these tests, compared with tumor tissue sequencing, approached 100%.

Following this overview of diagnostic accuracy, Dr. Kingston described a series of genomic trends, focusing first on targetable alterations.

Both ctDNA techniques revealed that ESR1 mutations were common in cases of hormone receptor (HR)-positive disease, including approximately 40% of patients with HER2-negative breast cancer and approximately 20% of patients with HER2-positive breast cancer. In contrast, ESR1 mutations were found in less than 1% of patients with HR-negative disease. Although ERBB2 amplification was predominantly found in patients with HER2-positive breast cancer, this alteration was found in 1%-2% of patients with HER2-negative disease.

For the remainder of the presentation, Dr. Kingston focused on ctDNA targeted sequencing data.

Within this cohort of 800 participants, 92.9% of patients had a ctDNA alteration. The mean number of pathogenic alterations was 2.7; Dr. Kingston noted that, on average, patients with HR-positive, HER2-negative disease had significantly more alterations than did those with triple-negative breast cancer (3.0 vs 1.8; P less than .0001).

“We found that specific genes are enriched in certain breast cancer subtypes,” Dr. Kingston said, pointing out the “notable” rate of ERBB2 mutations (14%) in HER2-amplified disease.

Among patients with HR-positive disease, those who were HER2-negative often had ESR1 and KRAS mutations, whereas those with HER2-positive disease often had ESR1 mutations but not KRAS mutations.

Heterogeneity analysis showed that alterations in certain genes were clonally dominant, including AKT1, PIK3CA, GATA3, and TP53, while others were more often subclonal, including ESR1, RB1, SMAD4, and KRAS.

A closer look at frequency of alterations showed that AKT1, CDH1, and GATA3 were typically found as the only gene alteration present; in contrast, ESR1 alterations were often accompanied by multiple other gene hits.

Returning to targetable genes, the investigators found that there was significant variation in clonal dominance of pathogenic mutations in ESR1 and PIK3CA. A deeper analysis revealed that PIK3CA mutations were often double mutations in HR-positive disease, and that subclonal second mutations were found at APOBEC mutagenesis sites.

Carlos Arteaga, MD, of the University of Texas Southwestern Medical Center, Dallas, commented on the findings after the presentation and asked Dr. Kingston about a potential blind spot in the data.

Will Pass/MDedge News

SOURCE: Kingston et al. SABCS. 2019 Abstract GS3-07.

SAN ANTONIO – For patients with newly diagnosed HER2-negative breast cancer who are BRCA carriers, neoadjuvant cisplatin does not offer a higher pathologic complete response (pCR) rate than standard doxorubicin/cyclophosphamide (AC), based on results from the phase 2 INFORM trial.

Will Pass/MDedge News

Findings from this trial and others suggest that BRCA deficiency may be a marker of sensitivity to DNA-damaging chemotherapy generally, instead of platinum agents specifically, reported lead author Nadine Tung, MD, of Beth Israel Deaconess Medical Center in Boston.

While single-agent platinum chemotherapy has shown significant clinical activity in the neoadjuvant and metastatic settings for BRCA-mutated triple-negative breast cancer (TNBC), prospective trials comparing platinum-based therapy with non–platinum-based therapy have been lacking, Dr. Tung said during a presentation at the San Antonio Breast Cancer Symposium.

“Almost no data exist for the response to platinum agents among BRCA carriers with hormone receptor–positive breast cancer,” Dr. Tung said.

The investigators aimed to address both of these knowledge gaps with a head-to-head trial. Although the investigators aimed for an accrual of 170 participants, all newly diagnosed patients, only 118 were enrolled, of whom 117 were included in the final analysis. All patients had HER2-negative breast cancer with at least one germline BRCA mutation. About two-thirds of patients (69%) were BRCA1 positive, about one-third (30%) were BRCA2 positive, and the small remainder (2%) had both mutations. Clinical stage proportions were as follows: I (19%), II (63%), and III (18%). Almost three-fourths of patients (70%) had TNBC, and 45% had nodal involvement upon enrollment.

Patients were randomized at a 1:1 ratio to receive either cisplatin (75 mg/m² every 3 weeks for four cycles) or standard AC (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2-3 weeks for four cycles). These treatments were followed by surgery. The primary endpoint was pCR . Secondary endpoints included residual cancer burden of 0-1 (RCB 0/1), 3-year disease-free survival, and toxicities.

Most patients completed the regimens as planned; however, seven patients received more than four cycles of chemotherapy while four patients completed fewer than four cycles. These 11 patients were categorized as not having a pathologic complete response.

Among the remaining patients, platinum-based chemotherapy was associated with an 18% pCR rate, compared with 26% for standard AC, which translated to a risk ratio of 0.70 that was not significant. Among patients with TNBC (n = 82), pCR rates followed a similar trend (22% vs. 28%), again without statistical significance. For patients with estrogen receptor–positive disease, the numerical disparity in pCR rate was greater (cisplatin at 6% vs. AC at 21%); however, once more, this difference was not statistically significant. Because of the small number of patients in this subgroup (n = 35), Dr. Tung advised that results be interpreted with caution.

Results for RCB 0/1 were similar to pCR. AC was associated with a higher rate of RCB 0-1 for all patients (46% vs. 33%), patients with TNBC (47% vs. 36%), and patients with hormone receptor–positive disease (42% vs. 25%). Across all patients and subtypes, these differences were not statistically significant.

Safety profiles were similar to previously published data for both regimens.

“In conclusion, contrary to our initial expectations, the pCR rate and RCB 0/1 rate is not significantly higher after cisplatin than after AC in BRCA carriers with early-stage breast cancer, whether triple-negative or estrogen receptor–positive HER2-negative disease,” Dr. Tung said. “Our statistician has concluded that there is no realistic scenario by which the pCR with cisplatin would have been significantly higher than with AC had this study met its accrual.”

“We believe the results of the INFORM trial are consistent with those of the GeparSixto and BrightTNess neoadjuvant trials,” Dr. Tung said. “One interpretation of the INFORM trial results, as well as these two trials, is that breast cancer in BRCA carriers is more sensitive than in noncarriers to DNA-damaging agents. … BRCA deficiency or homologous combination deficiency may simply be a marker of sensitivity to DNA-damaging chemotherapy rather than platinum agents specifically.”

The investigators disclosed relationships with Merck, AstraZeneca, Genentech, and others.

SOURCE: Tung N et al. SABCS 2019, Abstract GS6-03.

SAN ANTONIO – For patients with newly diagnosed HER2-negative breast cancer who are BRCA carriers, neoadjuvant cisplatin does not offer a higher pathologic complete response (pCR) rate than standard doxorubicin/cyclophosphamide (AC), based on results from the phase 2 INFORM trial.

Will Pass/MDedge News

Findings from this trial and others suggest that BRCA deficiency may be a marker of sensitivity to DNA-damaging chemotherapy generally, instead of platinum agents specifically, reported lead author Nadine Tung, MD, of Beth Israel Deaconess Medical Center in Boston.

While single-agent platinum chemotherapy has shown significant clinical activity in the neoadjuvant and metastatic settings for BRCA-mutated triple-negative breast cancer (TNBC), prospective trials comparing platinum-based therapy with non–platinum-based therapy have been lacking, Dr. Tung said during a presentation at the San Antonio Breast Cancer Symposium.

“Almost no data exist for the response to platinum agents among BRCA carriers with hormone receptor–positive breast cancer,” Dr. Tung said.

The investigators aimed to address both of these knowledge gaps with a head-to-head trial. Although the investigators aimed for an accrual of 170 participants, all newly diagnosed patients, only 118 were enrolled, of whom 117 were included in the final analysis. All patients had HER2-negative breast cancer with at least one germline BRCA mutation. About two-thirds of patients (69%) were BRCA1 positive, about one-third (30%) were BRCA2 positive, and the small remainder (2%) had both mutations. Clinical stage proportions were as follows: I (19%), II (63%), and III (18%). Almost three-fourths of patients (70%) had TNBC, and 45% had nodal involvement upon enrollment.

Patients were randomized at a 1:1 ratio to receive either cisplatin (75 mg/m² every 3 weeks for four cycles) or standard AC (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2-3 weeks for four cycles). These treatments were followed by surgery. The primary endpoint was pCR . Secondary endpoints included residual cancer burden of 0-1 (RCB 0/1), 3-year disease-free survival, and toxicities.

Most patients completed the regimens as planned; however, seven patients received more than four cycles of chemotherapy while four patients completed fewer than four cycles. These 11 patients were categorized as not having a pathologic complete response.

Among the remaining patients, platinum-based chemotherapy was associated with an 18% pCR rate, compared with 26% for standard AC, which translated to a risk ratio of 0.70 that was not significant. Among patients with TNBC (n = 82), pCR rates followed a similar trend (22% vs. 28%), again without statistical significance. For patients with estrogen receptor–positive disease, the numerical disparity in pCR rate was greater (cisplatin at 6% vs. AC at 21%); however, once more, this difference was not statistically significant. Because of the small number of patients in this subgroup (n = 35), Dr. Tung advised that results be interpreted with caution.

Results for RCB 0/1 were similar to pCR. AC was associated with a higher rate of RCB 0-1 for all patients (46% vs. 33%), patients with TNBC (47% vs. 36%), and patients with hormone receptor–positive disease (42% vs. 25%). Across all patients and subtypes, these differences were not statistically significant.

Safety profiles were similar to previously published data for both regimens.

“In conclusion, contrary to our initial expectations, the pCR rate and RCB 0/1 rate is not significantly higher after cisplatin than after AC in BRCA carriers with early-stage breast cancer, whether triple-negative or estrogen receptor–positive HER2-negative disease,” Dr. Tung said. “Our statistician has concluded that there is no realistic scenario by which the pCR with cisplatin would have been significantly higher than with AC had this study met its accrual.”

“We believe the results of the INFORM trial are consistent with those of the GeparSixto and BrightTNess neoadjuvant trials,” Dr. Tung said. “One interpretation of the INFORM trial results, as well as these two trials, is that breast cancer in BRCA carriers is more sensitive than in noncarriers to DNA-damaging agents. … BRCA deficiency or homologous combination deficiency may simply be a marker of sensitivity to DNA-damaging chemotherapy rather than platinum agents specifically.”

The investigators disclosed relationships with Merck, AstraZeneca, Genentech, and others.

SOURCE: Tung N et al. SABCS 2019, Abstract GS6-03.

SAN ANTONIO – For patients with newly diagnosed HER2-negative breast cancer who are BRCA carriers, neoadjuvant cisplatin does not offer a higher pathologic complete response (pCR) rate than standard doxorubicin/cyclophosphamide (AC), based on results from the phase 2 INFORM trial.

Will Pass/MDedge News

Findings from this trial and others suggest that BRCA deficiency may be a marker of sensitivity to DNA-damaging chemotherapy generally, instead of platinum agents specifically, reported lead author Nadine Tung, MD, of Beth Israel Deaconess Medical Center in Boston.

While single-agent platinum chemotherapy has shown significant clinical activity in the neoadjuvant and metastatic settings for BRCA-mutated triple-negative breast cancer (TNBC), prospective trials comparing platinum-based therapy with non–platinum-based therapy have been lacking, Dr. Tung said during a presentation at the San Antonio Breast Cancer Symposium.

“Almost no data exist for the response to platinum agents among BRCA carriers with hormone receptor–positive breast cancer,” Dr. Tung said.

The investigators aimed to address both of these knowledge gaps with a head-to-head trial. Although the investigators aimed for an accrual of 170 participants, all newly diagnosed patients, only 118 were enrolled, of whom 117 were included in the final analysis. All patients had HER2-negative breast cancer with at least one germline BRCA mutation. About two-thirds of patients (69%) were BRCA1 positive, about one-third (30%) were BRCA2 positive, and the small remainder (2%) had both mutations. Clinical stage proportions were as follows: I (19%), II (63%), and III (18%). Almost three-fourths of patients (70%) had TNBC, and 45% had nodal involvement upon enrollment.

Patients were randomized at a 1:1 ratio to receive either cisplatin (75 mg/m² every 3 weeks for four cycles) or standard AC (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2-3 weeks for four cycles). These treatments were followed by surgery. The primary endpoint was pCR . Secondary endpoints included residual cancer burden of 0-1 (RCB 0/1), 3-year disease-free survival, and toxicities.

Most patients completed the regimens as planned; however, seven patients received more than four cycles of chemotherapy while four patients completed fewer than four cycles. These 11 patients were categorized as not having a pathologic complete response.

Among the remaining patients, platinum-based chemotherapy was associated with an 18% pCR rate, compared with 26% for standard AC, which translated to a risk ratio of 0.70 that was not significant. Among patients with TNBC (n = 82), pCR rates followed a similar trend (22% vs. 28%), again without statistical significance. For patients with estrogen receptor–positive disease, the numerical disparity in pCR rate was greater (cisplatin at 6% vs. AC at 21%); however, once more, this difference was not statistically significant. Because of the small number of patients in this subgroup (n = 35), Dr. Tung advised that results be interpreted with caution.

Results for RCB 0/1 were similar to pCR. AC was associated with a higher rate of RCB 0-1 for all patients (46% vs. 33%), patients with TNBC (47% vs. 36%), and patients with hormone receptor–positive disease (42% vs. 25%). Across all patients and subtypes, these differences were not statistically significant.

Safety profiles were similar to previously published data for both regimens.

“In conclusion, contrary to our initial expectations, the pCR rate and RCB 0/1 rate is not significantly higher after cisplatin than after AC in BRCA carriers with early-stage breast cancer, whether triple-negative or estrogen receptor–positive HER2-negative disease,” Dr. Tung said. “Our statistician has concluded that there is no realistic scenario by which the pCR with cisplatin would have been significantly higher than with AC had this study met its accrual.”

“We believe the results of the INFORM trial are consistent with those of the GeparSixto and BrightTNess neoadjuvant trials,” Dr. Tung said. “One interpretation of the INFORM trial results, as well as these two trials, is that breast cancer in BRCA carriers is more sensitive than in noncarriers to DNA-damaging agents. … BRCA deficiency or homologous combination deficiency may simply be a marker of sensitivity to DNA-damaging chemotherapy rather than platinum agents specifically.”

The investigators disclosed relationships with Merck, AstraZeneca, Genentech, and others.

SOURCE: Tung N et al. SABCS 2019, Abstract GS6-03.

SAN ANTONIO – Maintenance therapy with the immune checkpoint inhibitor durvalumab (Imfinzi) did not improve outcomes compared with chemotherapy for patients with metastatic breast cancer, although there was a trend toward benefit for patients with triple-negative breast cancer and those whose tumors were positive for programmed death ligand 1 (PD-L1), a substudy of SAFIR-02 Breast.

Neil Osterweil/MDedge News

Median progression-free survival for 131 patients with metastatic or locally advanced, HER2-negative, hormone receptor–negative or endocrine-resistant breast cancer who received durvalumab maintenance following chemotherapy in the study was 2.7 months, compared with 4.4 months for 68 patients who received maintenance chemotherapy, reported Florence Dalenc, MD, of Institut Claudius Regaud, Toulouse, France.

“For hormone receptor–positive metastatic breast cancer, exploratory analyses suggest that anti-PD-L1 as a single agent is less effective than chemotherapy as maintenance,” she said at the San Antonio Breast Cancer Symposium.

The rationale for investigating an anti-PD-L1 agent for maintenance in patients with metastatic breast cancer is that the tumor is (presumably) not growing when immunotherapy is introduced and disease burden, a mechanism of immune suppression, has been reduced by chemotherapy. In addition, chemotherapy attracts tumor infiltrating lymphocytes (TILs) to the tumor bed, and response to chemotherapy may be a marker for immunogenic tumors, she said.

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of the programmed death protein 1 with PD-L1. In the GeparNuevo trial, the addition of durvalumab to anthracycline-/taxane-based neoadjuvant chemotherapy increased the pathologic complete response (pCR) rate particularly in patients treated with durvalumab alone before the start of chemotherapy.

To see whether durvalumab could offer a benefit over chemotherapy in the maintenance setting, Dr. Dalenc and colleagues studied patients who were enrolled in SAFIR-02 Breast, which was designed to assess the efficacy of genomic analysis as a therapeutic decision tool in patients with metastatic breast cancer.

In the trial, patients with HER2-negative metastatic breast cancer who have a complete or partial response or stable disease following six to eight chemotherapy cycles (or 4 cycles if chemotherapy was stopped for toxicities) are randomized based on the presence or absence of targetable molecular alterations. Patients with identified alteration are then randomized to either targeted therapy matched to genomics, or to maintenance chemotherapy.

Patients without molecular alterations – the population included in the SAFIR02-IMMUNO substudy reported by Dr. Dalenc and colleagues – are stratified by one or two prior lines of chemotherapy and by response type, and then stratified on a 2:1 basis to maintenance with either durvalumab 10 mg/kg every 14 days or standard maintenance chemotherapy for up to 2 years.

In each arm, the median patient age was 56, and approximately 58% of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0. Approximately 43% of patients in each arm had three or more metastatic sites, and roughly half had liver metastases, while slightly more than one-fourth had metastases to lung.

As noted before, median PFS in the overall substudy population, the primary endpoint, was 4.6 months for patients on maintenance chemotherapy, compared with 2.7 months with durvalumab. This difference translated into an adjusted hazard ratio for progression with durvalumab of 1.40 (P = .047).

Also as noted, there were nonsignificant trends toward benefit with durvalumab among patients with triple-negative breast cancer or PD-L1-positive tumors. For all other subgroups, however, maintenance chemotherapy was favored, with significant benefit seen among patients with disease that progressed after second-line chemotherapy, patients with a clinical response at the time of re-randomization, those 50 years and older, patients with non-triple-negative disease, patients with liver metastases, and those whose tumors were negative for PD-L1.

Median overall survival (OS) was numerically longer with durvalumab (21.7 vs. 17.9 months), but this difference was not statistically significant.

In exploratory analyses, median OS for patients with triple-negative disease was 21 vs. 14 months, respectively, with an unadjusted hazard ratio favoring durvalumab of 0.54 (P = .0377). Among patients with PD-L1 positive tumors, the median OS was 26 months with durvalumab vs. 12 months with chemotherapy, with an unadjusted hazard ratio of 0.42, which just missed statistical significance (P = .0552).

Dr. Dalenc said that the study generates the hypothesis that single-agent durvalumab could improve outcomes in metastatic triple-negative breast cancer, but also raises questions about which disease parameters limit the response to anti-PD-L1 therapy.

The study was sponsored by UNICANCER with support from Fondation ARC and AstraZeneca. Dr. Dalenc reported research grants, travel, and/or advisory board activity for AstraZeneca and others.

SOURCE: Dalenc F et al. SABCS 2019. Abstract GS3-02.

SAN ANTONIO – Maintenance therapy with the immune checkpoint inhibitor durvalumab (Imfinzi) did not improve outcomes compared with chemotherapy for patients with metastatic breast cancer, although there was a trend toward benefit for patients with triple-negative breast cancer and those whose tumors were positive for programmed death ligand 1 (PD-L1), a substudy of SAFIR-02 Breast.

Neil Osterweil/MDedge News

Median progression-free survival for 131 patients with metastatic or locally advanced, HER2-negative, hormone receptor–negative or endocrine-resistant breast cancer who received durvalumab maintenance following chemotherapy in the study was 2.7 months, compared with 4.4 months for 68 patients who received maintenance chemotherapy, reported Florence Dalenc, MD, of Institut Claudius Regaud, Toulouse, France.

“For hormone receptor–positive metastatic breast cancer, exploratory analyses suggest that anti-PD-L1 as a single agent is less effective than chemotherapy as maintenance,” she said at the San Antonio Breast Cancer Symposium.

The rationale for investigating an anti-PD-L1 agent for maintenance in patients with metastatic breast cancer is that the tumor is (presumably) not growing when immunotherapy is introduced and disease burden, a mechanism of immune suppression, has been reduced by chemotherapy. In addition, chemotherapy attracts tumor infiltrating lymphocytes (TILs) to the tumor bed, and response to chemotherapy may be a marker for immunogenic tumors, she said.

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of the programmed death protein 1 with PD-L1. In the GeparNuevo trial, the addition of durvalumab to anthracycline-/taxane-based neoadjuvant chemotherapy increased the pathologic complete response (pCR) rate particularly in patients treated with durvalumab alone before the start of chemotherapy.

To see whether durvalumab could offer a benefit over chemotherapy in the maintenance setting, Dr. Dalenc and colleagues studied patients who were enrolled in SAFIR-02 Breast, which was designed to assess the efficacy of genomic analysis as a therapeutic decision tool in patients with metastatic breast cancer.

In the trial, patients with HER2-negative metastatic breast cancer who have a complete or partial response or stable disease following six to eight chemotherapy cycles (or 4 cycles if chemotherapy was stopped for toxicities) are randomized based on the presence or absence of targetable molecular alterations. Patients with identified alteration are then randomized to either targeted therapy matched to genomics, or to maintenance chemotherapy.

Patients without molecular alterations – the population included in the SAFIR02-IMMUNO substudy reported by Dr. Dalenc and colleagues – are stratified by one or two prior lines of chemotherapy and by response type, and then stratified on a 2:1 basis to maintenance with either durvalumab 10 mg/kg every 14 days or standard maintenance chemotherapy for up to 2 years.

In each arm, the median patient age was 56, and approximately 58% of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0. Approximately 43% of patients in each arm had three or more metastatic sites, and roughly half had liver metastases, while slightly more than one-fourth had metastases to lung.

As noted before, median PFS in the overall substudy population, the primary endpoint, was 4.6 months for patients on maintenance chemotherapy, compared with 2.7 months with durvalumab. This difference translated into an adjusted hazard ratio for progression with durvalumab of 1.40 (P = .047).

Also as noted, there were nonsignificant trends toward benefit with durvalumab among patients with triple-negative breast cancer or PD-L1-positive tumors. For all other subgroups, however, maintenance chemotherapy was favored, with significant benefit seen among patients with disease that progressed after second-line chemotherapy, patients with a clinical response at the time of re-randomization, those 50 years and older, patients with non-triple-negative disease, patients with liver metastases, and those whose tumors were negative for PD-L1.

Median overall survival (OS) was numerically longer with durvalumab (21.7 vs. 17.9 months), but this difference was not statistically significant.

In exploratory analyses, median OS for patients with triple-negative disease was 21 vs. 14 months, respectively, with an unadjusted hazard ratio favoring durvalumab of 0.54 (P = .0377). Among patients with PD-L1 positive tumors, the median OS was 26 months with durvalumab vs. 12 months with chemotherapy, with an unadjusted hazard ratio of 0.42, which just missed statistical significance (P = .0552).

Dr. Dalenc said that the study generates the hypothesis that single-agent durvalumab could improve outcomes in metastatic triple-negative breast cancer, but also raises questions about which disease parameters limit the response to anti-PD-L1 therapy.

The study was sponsored by UNICANCER with support from Fondation ARC and AstraZeneca. Dr. Dalenc reported research grants, travel, and/or advisory board activity for AstraZeneca and others.

SOURCE: Dalenc F et al. SABCS 2019. Abstract GS3-02.

SAN ANTONIO – Maintenance therapy with the immune checkpoint inhibitor durvalumab (Imfinzi) did not improve outcomes compared with chemotherapy for patients with metastatic breast cancer, although there was a trend toward benefit for patients with triple-negative breast cancer and those whose tumors were positive for programmed death ligand 1 (PD-L1), a substudy of SAFIR-02 Breast.

Neil Osterweil/MDedge News

Median progression-free survival for 131 patients with metastatic or locally advanced, HER2-negative, hormone receptor–negative or endocrine-resistant breast cancer who received durvalumab maintenance following chemotherapy in the study was 2.7 months, compared with 4.4 months for 68 patients who received maintenance chemotherapy, reported Florence Dalenc, MD, of Institut Claudius Regaud, Toulouse, France.

“For hormone receptor–positive metastatic breast cancer, exploratory analyses suggest that anti-PD-L1 as a single agent is less effective than chemotherapy as maintenance,” she said at the San Antonio Breast Cancer Symposium.

The rationale for investigating an anti-PD-L1 agent for maintenance in patients with metastatic breast cancer is that the tumor is (presumably) not growing when immunotherapy is introduced and disease burden, a mechanism of immune suppression, has been reduced by chemotherapy. In addition, chemotherapy attracts tumor infiltrating lymphocytes (TILs) to the tumor bed, and response to chemotherapy may be a marker for immunogenic tumors, she said.

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of the programmed death protein 1 with PD-L1. In the GeparNuevo trial, the addition of durvalumab to anthracycline-/taxane-based neoadjuvant chemotherapy increased the pathologic complete response (pCR) rate particularly in patients treated with durvalumab alone before the start of chemotherapy.

To see whether durvalumab could offer a benefit over chemotherapy in the maintenance setting, Dr. Dalenc and colleagues studied patients who were enrolled in SAFIR-02 Breast, which was designed to assess the efficacy of genomic analysis as a therapeutic decision tool in patients with metastatic breast cancer.

In the trial, patients with HER2-negative metastatic breast cancer who have a complete or partial response or stable disease following six to eight chemotherapy cycles (or 4 cycles if chemotherapy was stopped for toxicities) are randomized based on the presence or absence of targetable molecular alterations. Patients with identified alteration are then randomized to either targeted therapy matched to genomics, or to maintenance chemotherapy.

Patients without molecular alterations – the population included in the SAFIR02-IMMUNO substudy reported by Dr. Dalenc and colleagues – are stratified by one or two prior lines of chemotherapy and by response type, and then stratified on a 2:1 basis to maintenance with either durvalumab 10 mg/kg every 14 days or standard maintenance chemotherapy for up to 2 years.

In each arm, the median patient age was 56, and approximately 58% of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0. Approximately 43% of patients in each arm had three or more metastatic sites, and roughly half had liver metastases, while slightly more than one-fourth had metastases to lung.

As noted before, median PFS in the overall substudy population, the primary endpoint, was 4.6 months for patients on maintenance chemotherapy, compared with 2.7 months with durvalumab. This difference translated into an adjusted hazard ratio for progression with durvalumab of 1.40 (P = .047).

Also as noted, there were nonsignificant trends toward benefit with durvalumab among patients with triple-negative breast cancer or PD-L1-positive tumors. For all other subgroups, however, maintenance chemotherapy was favored, with significant benefit seen among patients with disease that progressed after second-line chemotherapy, patients with a clinical response at the time of re-randomization, those 50 years and older, patients with non-triple-negative disease, patients with liver metastases, and those whose tumors were negative for PD-L1.

Median overall survival (OS) was numerically longer with durvalumab (21.7 vs. 17.9 months), but this difference was not statistically significant.

In exploratory analyses, median OS for patients with triple-negative disease was 21 vs. 14 months, respectively, with an unadjusted hazard ratio favoring durvalumab of 0.54 (P = .0377). Among patients with PD-L1 positive tumors, the median OS was 26 months with durvalumab vs. 12 months with chemotherapy, with an unadjusted hazard ratio of 0.42, which just missed statistical significance (P = .0552).

Dr. Dalenc said that the study generates the hypothesis that single-agent durvalumab could improve outcomes in metastatic triple-negative breast cancer, but also raises questions about which disease parameters limit the response to anti-PD-L1 therapy.

The study was sponsored by UNICANCER with support from Fondation ARC and AstraZeneca. Dr. Dalenc reported research grants, travel, and/or advisory board activity for AstraZeneca and others.

SOURCE: Dalenc F et al. SABCS 2019. Abstract GS3-02.

In this edition of “How I Will Treat My Next Patient,” I highlight two recent studies that reinforce prior diagnostic and treatment preferences among many oncologists and will certainly influence the discussions we all will have with our patients in the coming weeks and months.

Rituximab maintenance in follicular lymphoma

The largest trial addressing the role of maintenance CD20-targeted antibody therapy was the Primary Rituximab and Maintenance (PRIMA) phase 3, intergroup study in 1,018 advanced follicular lymphoma patients with an initial response to induction chemoimmunotherapy. The induction regimen could be either of three commonly used regimens plus rituximab. Importantly, none of the induction regimens included bendamustine.

Patients were randomized to 2 years of rituximab maintenance or observation. Prior interim analyses at 3 and 6 years showed improvements for the rituximab maintenance patients in progression-free survival and other secondary endpoints, but no improvement in overall survival. Emmanuel Bachy, MD, PhD, and colleagues published the final survival data after 9 years of follow-up, including a final safety analysis (J Clin Oncol. 2019 Nov 1;37[31]:2815-24).

Among the 607 patients consenting to extended follow-up, median progression-free survival was 10.5 years with rituximab maintenance, compared with 4.1 years for observation (hazard ratio, 0.61; P less than .001). There were more patients with progression-free survival at 3 years, complete response or unconfirmed complete response at 2 years, longer time to next antilymphoma treatment, and later time to next chemotherapy. But the 10-year overall survival was similar in the two groups, as were the quality of life ratings.

In all, 503 patients experienced disease progression. Overall survival after progression was shorter in the rituximab maintenance arm versus the observation arm. Among the approximately 4% of patients experiencing transformation from follicular lymphoma to a more aggressive histology, there was no difference observed in time to transformation. Results were independent of the induction regimen received, response to induction, Follicular Lymphoma International Prognostic Index score, and other clinical factors.

In the safety analysis, there were more grade 3-4 adverse events among the rituximab maintenance patients – primarily cytopenia and infections – more serious adverse events, and more adverse events overall. Fatal adverse events were low in both groups (1.6 vs. 0.6%).
 

How these results influence practice

Many years ago, a senior mentor of mine taught that “progression-free survival is an important endpoint since the quality of life for patients is generally superior before relapse than afterwards.”

With that mantra playing in my mind and with the reality that discussions about relapse and subsequent treatment are never easy, the results of PRIMA seem straightforward: Rituximab maintenance is beneficial, despite the absence of an overall survival benefit, in a disease with multiple options for subsequent therapy and a long natural history. In this 9-year, final analysis of PRIMA, rituximab maintenance seems to have achieved its goals of deepening responses with low (but not inconsequential) toxicity and delaying substantially those difficult conversations with patients about how to proceed after relapse.

The influence of the final analysis of PRIMA, however, may be more complicated that it would initially seem. Bendamustine-containing regimens were not employed, are commonly used now, and some studies with bendamustine have suggested higher nonrelapse mortality with rituximab maintenance.

Low-grade adverse events take on greater importance for patients on long-term therapy than they do for patients receiving abbreviated treatment, and with noncurative treatment, the higher adverse event profile with 2 years of rituximab maintenance needs to be taken seriously. Induction and maintenance regimens involving rituximab alone, lenalidomide, or obinutuzumab may be preferred for some patients. For all of those reasons, the discussion about rituximab with advanced follicular lymphoma patients remains a long one, demanding detailed descriptions of risks, benefits, limitations of the data, and multiple modern day alternatives to the treatments employed in PRIMA.
 

Supplemental MRI for dense breast tissue

In the DENSE trial, investigators assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to be offered either supplemental MRI or mammography screening every other year only. The women were 50-75 years old and were enrolled in the Dutch population-based digital mammography screening program. The primary outcome was the difference in the number of cancers that developed in the 2-year interval between mammograms (N Engl J Med 2019;381:2091-102).

The interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the “MRI-invitation” group (41% of whom did not actually agree to have an MRI), and 5 per 1,000 in the 32,312 women in the “mammography-only” group, a difference of 2.5 per 1,000 screenings (P less than .001).

Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the 59% of women who had undergone MRI (0.8 per 1,000 screenings). The remaining 16 were diagnosed in those who had declined an MRI (4.9 per 1,000 screenings) – virtually identical to the rate of interval cancers in the group that was not invited to have an MRI. This speaks against nonrandom allocation of patients between the mammography-only and the supplemental MRI groups.

Although supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings, there was a false positive rate of 8.0% (79.8 per 1,000 screenings). Of the women who underwent a breast biopsy after MRI, 73.7% did not have cancer. Among the women who had MRI-detected cancers, in general, the malignancies diagnosed were smaller, more likely node negative, better differentiated, and more often hormone receptor–positive, compared with those in the mammography-only group.

At the next screening mammogram, the cancer detection rate was lower in the MRI-screened group (2 per 1,000 screenings) than in the MRI–“offered but declined” (7.1 per 1,000 screenings) or mammogram-only groups (6 per 1,000 screenings).
 

How these results influence practice

American physicians are obligated to inform women with dense breast tissue about the limitations (for them) of conventional mammography, an unquantified, but elevated, risk of breast cancer in women with dense breast tissue, and the fact that there are no universally accepted recommended subsequent steps those women should take.

One side benefit of the requirement to disclose information about breast density, however, is that disclosure can prompt discussions about breast cancer risk reduction – an important discussion with multiple possible health-maintaining interventions.

The DENSE trial is very important news, with potential for even more value in future years. It is finite (2 years of study, with only one MRI scan mandated), narrow (Vopara or BI-RADs breast density grade 4 only), and oligo-institutional (eight participating centers in the Netherlands). Still, it provides randomized, rigorously gathered and analyzed data where there were previously none. Importantly, it answers the question, “So what can I do now, doctor?”

I have some concerns about whether we, as a medical community, have the discipline to restrict application of supplemental MRI screening beyond the population that was studied in the Netherlands. Will we be able to restrain ourselves from ordering MRI scans in women with heterogeneously dense – but not extremely dense – breasts? Will we truly manage patients whose MRI scans had BI-RADs readings of less than 4 in the rigorous, but conservative, fashion employed in the trial? Would we miss fewer significant cancers and subject fewer patients to potential expense and harm with annual mammography, instead of the biennial screening performed in the Netherlands? Does tomo-synthesis improve the interpretation of screening mammograms so much that the interval cancer rate is a lot closer to the rate obtained with supplemental MRI scans? Is the expense of MRI scanning, with the resultant subsequent tests and procedures, justified by the reduction in detecting relatively favorable breast cancers that may not materially impact overall survival?

The DENSE study promises to be a “gift that keeps on giving” as the investigators continue to assess a number of factors including: the value of ongoing supplemental MRI scans (compared with the one-time-only screening reported here); whether there will be a reduction in the advanced cancers and subsequent mortality benefit; the extent of over diagnosis, costs, and impact on quality-of-life; and the applicability of artificial intelligence techniques to reduce false positive MRI results.

While the study may not be practice changing in the United States at the present time, it may be just that as subsequent analyses emerge.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I Will Treat My Next Patient,” I highlight two recent studies that reinforce prior diagnostic and treatment preferences among many oncologists and will certainly influence the discussions we all will have with our patients in the coming weeks and months.

Rituximab maintenance in follicular lymphoma

The largest trial addressing the role of maintenance CD20-targeted antibody therapy was the Primary Rituximab and Maintenance (PRIMA) phase 3, intergroup study in 1,018 advanced follicular lymphoma patients with an initial response to induction chemoimmunotherapy. The induction regimen could be either of three commonly used regimens plus rituximab. Importantly, none of the induction regimens included bendamustine.

Patients were randomized to 2 years of rituximab maintenance or observation. Prior interim analyses at 3 and 6 years showed improvements for the rituximab maintenance patients in progression-free survival and other secondary endpoints, but no improvement in overall survival. Emmanuel Bachy, MD, PhD, and colleagues published the final survival data after 9 years of follow-up, including a final safety analysis (J Clin Oncol. 2019 Nov 1;37[31]:2815-24).

Among the 607 patients consenting to extended follow-up, median progression-free survival was 10.5 years with rituximab maintenance, compared with 4.1 years for observation (hazard ratio, 0.61; P less than .001). There were more patients with progression-free survival at 3 years, complete response or unconfirmed complete response at 2 years, longer time to next antilymphoma treatment, and later time to next chemotherapy. But the 10-year overall survival was similar in the two groups, as were the quality of life ratings.

In all, 503 patients experienced disease progression. Overall survival after progression was shorter in the rituximab maintenance arm versus the observation arm. Among the approximately 4% of patients experiencing transformation from follicular lymphoma to a more aggressive histology, there was no difference observed in time to transformation. Results were independent of the induction regimen received, response to induction, Follicular Lymphoma International Prognostic Index score, and other clinical factors.

In the safety analysis, there were more grade 3-4 adverse events among the rituximab maintenance patients – primarily cytopenia and infections – more serious adverse events, and more adverse events overall. Fatal adverse events were low in both groups (1.6 vs. 0.6%).
 

How these results influence practice

Many years ago, a senior mentor of mine taught that “progression-free survival is an important endpoint since the quality of life for patients is generally superior before relapse than afterwards.”

With that mantra playing in my mind and with the reality that discussions about relapse and subsequent treatment are never easy, the results of PRIMA seem straightforward: Rituximab maintenance is beneficial, despite the absence of an overall survival benefit, in a disease with multiple options for subsequent therapy and a long natural history. In this 9-year, final analysis of PRIMA, rituximab maintenance seems to have achieved its goals of deepening responses with low (but not inconsequential) toxicity and delaying substantially those difficult conversations with patients about how to proceed after relapse.

The influence of the final analysis of PRIMA, however, may be more complicated that it would initially seem. Bendamustine-containing regimens were not employed, are commonly used now, and some studies with bendamustine have suggested higher nonrelapse mortality with rituximab maintenance.

Low-grade adverse events take on greater importance for patients on long-term therapy than they do for patients receiving abbreviated treatment, and with noncurative treatment, the higher adverse event profile with 2 years of rituximab maintenance needs to be taken seriously. Induction and maintenance regimens involving rituximab alone, lenalidomide, or obinutuzumab may be preferred for some patients. For all of those reasons, the discussion about rituximab with advanced follicular lymphoma patients remains a long one, demanding detailed descriptions of risks, benefits, limitations of the data, and multiple modern day alternatives to the treatments employed in PRIMA.
 

Supplemental MRI for dense breast tissue

In the DENSE trial, investigators assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to be offered either supplemental MRI or mammography screening every other year only. The women were 50-75 years old and were enrolled in the Dutch population-based digital mammography screening program. The primary outcome was the difference in the number of cancers that developed in the 2-year interval between mammograms (N Engl J Med 2019;381:2091-102).

The interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the “MRI-invitation” group (41% of whom did not actually agree to have an MRI), and 5 per 1,000 in the 32,312 women in the “mammography-only” group, a difference of 2.5 per 1,000 screenings (P less than .001).

Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the 59% of women who had undergone MRI (0.8 per 1,000 screenings). The remaining 16 were diagnosed in those who had declined an MRI (4.9 per 1,000 screenings) – virtually identical to the rate of interval cancers in the group that was not invited to have an MRI. This speaks against nonrandom allocation of patients between the mammography-only and the supplemental MRI groups.

Although supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings, there was a false positive rate of 8.0% (79.8 per 1,000 screenings). Of the women who underwent a breast biopsy after MRI, 73.7% did not have cancer. Among the women who had MRI-detected cancers, in general, the malignancies diagnosed were smaller, more likely node negative, better differentiated, and more often hormone receptor–positive, compared with those in the mammography-only group.

At the next screening mammogram, the cancer detection rate was lower in the MRI-screened group (2 per 1,000 screenings) than in the MRI–“offered but declined” (7.1 per 1,000 screenings) or mammogram-only groups (6 per 1,000 screenings).
 

How these results influence practice

American physicians are obligated to inform women with dense breast tissue about the limitations (for them) of conventional mammography, an unquantified, but elevated, risk of breast cancer in women with dense breast tissue, and the fact that there are no universally accepted recommended subsequent steps those women should take.

One side benefit of the requirement to disclose information about breast density, however, is that disclosure can prompt discussions about breast cancer risk reduction – an important discussion with multiple possible health-maintaining interventions.

The DENSE trial is very important news, with potential for even more value in future years. It is finite (2 years of study, with only one MRI scan mandated), narrow (Vopara or BI-RADs breast density grade 4 only), and oligo-institutional (eight participating centers in the Netherlands). Still, it provides randomized, rigorously gathered and analyzed data where there were previously none. Importantly, it answers the question, “So what can I do now, doctor?”

I have some concerns about whether we, as a medical community, have the discipline to restrict application of supplemental MRI screening beyond the population that was studied in the Netherlands. Will we be able to restrain ourselves from ordering MRI scans in women with heterogeneously dense – but not extremely dense – breasts? Will we truly manage patients whose MRI scans had BI-RADs readings of less than 4 in the rigorous, but conservative, fashion employed in the trial? Would we miss fewer significant cancers and subject fewer patients to potential expense and harm with annual mammography, instead of the biennial screening performed in the Netherlands? Does tomo-synthesis improve the interpretation of screening mammograms so much that the interval cancer rate is a lot closer to the rate obtained with supplemental MRI scans? Is the expense of MRI scanning, with the resultant subsequent tests and procedures, justified by the reduction in detecting relatively favorable breast cancers that may not materially impact overall survival?

The DENSE study promises to be a “gift that keeps on giving” as the investigators continue to assess a number of factors including: the value of ongoing supplemental MRI scans (compared with the one-time-only screening reported here); whether there will be a reduction in the advanced cancers and subsequent mortality benefit; the extent of over diagnosis, costs, and impact on quality-of-life; and the applicability of artificial intelligence techniques to reduce false positive MRI results.

While the study may not be practice changing in the United States at the present time, it may be just that as subsequent analyses emerge.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I Will Treat My Next Patient,” I highlight two recent studies that reinforce prior diagnostic and treatment preferences among many oncologists and will certainly influence the discussions we all will have with our patients in the coming weeks and months.

Rituximab maintenance in follicular lymphoma

The largest trial addressing the role of maintenance CD20-targeted antibody therapy was the Primary Rituximab and Maintenance (PRIMA) phase 3, intergroup study in 1,018 advanced follicular lymphoma patients with an initial response to induction chemoimmunotherapy. The induction regimen could be either of three commonly used regimens plus rituximab. Importantly, none of the induction regimens included bendamustine.

Patients were randomized to 2 years of rituximab maintenance or observation. Prior interim analyses at 3 and 6 years showed improvements for the rituximab maintenance patients in progression-free survival and other secondary endpoints, but no improvement in overall survival. Emmanuel Bachy, MD, PhD, and colleagues published the final survival data after 9 years of follow-up, including a final safety analysis (J Clin Oncol. 2019 Nov 1;37[31]:2815-24).

Among the 607 patients consenting to extended follow-up, median progression-free survival was 10.5 years with rituximab maintenance, compared with 4.1 years for observation (hazard ratio, 0.61; P less than .001). There were more patients with progression-free survival at 3 years, complete response or unconfirmed complete response at 2 years, longer time to next antilymphoma treatment, and later time to next chemotherapy. But the 10-year overall survival was similar in the two groups, as were the quality of life ratings.

In all, 503 patients experienced disease progression. Overall survival after progression was shorter in the rituximab maintenance arm versus the observation arm. Among the approximately 4% of patients experiencing transformation from follicular lymphoma to a more aggressive histology, there was no difference observed in time to transformation. Results were independent of the induction regimen received, response to induction, Follicular Lymphoma International Prognostic Index score, and other clinical factors.

In the safety analysis, there were more grade 3-4 adverse events among the rituximab maintenance patients – primarily cytopenia and infections – more serious adverse events, and more adverse events overall. Fatal adverse events were low in both groups (1.6 vs. 0.6%).
 

How these results influence practice

Many years ago, a senior mentor of mine taught that “progression-free survival is an important endpoint since the quality of life for patients is generally superior before relapse than afterwards.”

With that mantra playing in my mind and with the reality that discussions about relapse and subsequent treatment are never easy, the results of PRIMA seem straightforward: Rituximab maintenance is beneficial, despite the absence of an overall survival benefit, in a disease with multiple options for subsequent therapy and a long natural history. In this 9-year, final analysis of PRIMA, rituximab maintenance seems to have achieved its goals of deepening responses with low (but not inconsequential) toxicity and delaying substantially those difficult conversations with patients about how to proceed after relapse.

The influence of the final analysis of PRIMA, however, may be more complicated that it would initially seem. Bendamustine-containing regimens were not employed, are commonly used now, and some studies with bendamustine have suggested higher nonrelapse mortality with rituximab maintenance.

Low-grade adverse events take on greater importance for patients on long-term therapy than they do for patients receiving abbreviated treatment, and with noncurative treatment, the higher adverse event profile with 2 years of rituximab maintenance needs to be taken seriously. Induction and maintenance regimens involving rituximab alone, lenalidomide, or obinutuzumab may be preferred for some patients. For all of those reasons, the discussion about rituximab with advanced follicular lymphoma patients remains a long one, demanding detailed descriptions of risks, benefits, limitations of the data, and multiple modern day alternatives to the treatments employed in PRIMA.
 

Supplemental MRI for dense breast tissue

In the DENSE trial, investigators assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to be offered either supplemental MRI or mammography screening every other year only. The women were 50-75 years old and were enrolled in the Dutch population-based digital mammography screening program. The primary outcome was the difference in the number of cancers that developed in the 2-year interval between mammograms (N Engl J Med 2019;381:2091-102).

The interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the “MRI-invitation” group (41% of whom did not actually agree to have an MRI), and 5 per 1,000 in the 32,312 women in the “mammography-only” group, a difference of 2.5 per 1,000 screenings (P less than .001).

Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the 59% of women who had undergone MRI (0.8 per 1,000 screenings). The remaining 16 were diagnosed in those who had declined an MRI (4.9 per 1,000 screenings) – virtually identical to the rate of interval cancers in the group that was not invited to have an MRI. This speaks against nonrandom allocation of patients between the mammography-only and the supplemental MRI groups.

Although supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings, there was a false positive rate of 8.0% (79.8 per 1,000 screenings). Of the women who underwent a breast biopsy after MRI, 73.7% did not have cancer. Among the women who had MRI-detected cancers, in general, the malignancies diagnosed were smaller, more likely node negative, better differentiated, and more often hormone receptor–positive, compared with those in the mammography-only group.

At the next screening mammogram, the cancer detection rate was lower in the MRI-screened group (2 per 1,000 screenings) than in the MRI–“offered but declined” (7.1 per 1,000 screenings) or mammogram-only groups (6 per 1,000 screenings).
 

How these results influence practice

American physicians are obligated to inform women with dense breast tissue about the limitations (for them) of conventional mammography, an unquantified, but elevated, risk of breast cancer in women with dense breast tissue, and the fact that there are no universally accepted recommended subsequent steps those women should take.

One side benefit of the requirement to disclose information about breast density, however, is that disclosure can prompt discussions about breast cancer risk reduction – an important discussion with multiple possible health-maintaining interventions.

The DENSE trial is very important news, with potential for even more value in future years. It is finite (2 years of study, with only one MRI scan mandated), narrow (Vopara or BI-RADs breast density grade 4 only), and oligo-institutional (eight participating centers in the Netherlands). Still, it provides randomized, rigorously gathered and analyzed data where there were previously none. Importantly, it answers the question, “So what can I do now, doctor?”

I have some concerns about whether we, as a medical community, have the discipline to restrict application of supplemental MRI screening beyond the population that was studied in the Netherlands. Will we be able to restrain ourselves from ordering MRI scans in women with heterogeneously dense – but not extremely dense – breasts? Will we truly manage patients whose MRI scans had BI-RADs readings of less than 4 in the rigorous, but conservative, fashion employed in the trial? Would we miss fewer significant cancers and subject fewer patients to potential expense and harm with annual mammography, instead of the biennial screening performed in the Netherlands? Does tomo-synthesis improve the interpretation of screening mammograms so much that the interval cancer rate is a lot closer to the rate obtained with supplemental MRI scans? Is the expense of MRI scanning, with the resultant subsequent tests and procedures, justified by the reduction in detecting relatively favorable breast cancers that may not materially impact overall survival?

The DENSE study promises to be a “gift that keeps on giving” as the investigators continue to assess a number of factors including: the value of ongoing supplemental MRI scans (compared with the one-time-only screening reported here); whether there will be a reduction in the advanced cancers and subsequent mortality benefit; the extent of over diagnosis, costs, and impact on quality-of-life; and the applicability of artificial intelligence techniques to reduce false positive MRI results.

While the study may not be practice changing in the United States at the present time, it may be just that as subsequent analyses emerge.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

SAN ANTONIO – An oral formulation of paclitaxel given with the P-glycoprotein pump inhibitor encequidar improved outcomes and reduced neuropathy risk, compared with intravenous paclitaxel, in women with metastatic breast cancer in a randomized, open-label, phase 3 study.

Sharon Worcester/MDedge News

The primary study endpoint of radiologically confirmed tumor response rate was 35.8% among 265 patients randomized to receive oral paclitaxel plus encequidar, compared with 23.4% among 137 who received intravenous paclitaxel – a statistically significant 12.4% difference, Gerardo Umanzor, MD, reported at the San Antonio Breast Cancer Symposium.

In the prespecified modified intent-to-treat (mITT) population of patients who had evaluable scans at baseline and who received at least seven doses of oral therapy or one dose of intravenous therapy, the corresponding confirmed tumor response rates were 40.4% and 25.5% (absolute improvement, 14.8%), said Dr. Umanzor, a medical oncologist with Liga Contra el Cancer in San Pedro Sulas, Honduras.

Tumor responses in all clinically important subgroups were consistent with the overall confirmed response profiles, he said, noting that the responses were durable, with ongoing analyses showing median response durations of 39.0 weeks versus 30.1 weeks with oral versus intravenous therapy.

Further, a higher percentage of oral versus intravenous paclitaxel recipients were receiving ongoing treatment at the time of the study endpoint (19% vs. 13%, respectively), he said.

Progression-free survival also showed a trend toward improved outcome with oral therapy in ongoing analyses in the mITT population (9.3 vs. 8.3 months, respectively), and an early analysis of overall survival also showed significant improvement (27.9 vs. 16.9 months; P = .035), he said.

Oral paclitaxel also was associated with a lower incidence of chemotherapy-induced peripheral neuropathy – a “highly debilitating side effect of IV paclitaxel,” he said, adding that “the difference between the arms is quite dramatic.”

The overall rates of neuropathy to week 23 were 17% versus 15% with oral versus intravenous therapy, and the rates of grade 3 neuropathy were 1% versus 8%, he said.

Alopecia incidence was reduced by about 50% with oral versus intravenous therapy, he added.

Toxicity was generally similar in the two groups, although the oral paclitaxel patients experienced higher rates of neutropenia and gastrointestinal effects. “These were low grade and manageable,” Dr. Umanzor said.

Study participants were patients with any type of metastatic breast cancer randomized 2:1 to receive a 15-mg tablet of encequidar followed by 205 mg/m² of oral paclitaxel (about 11 capsules, each containing 30 mg of solubilized paclitaxel) for 3 consecutive days each week for 3 weeks or intravenous paclitaxel at the labeled dose of 175 mg/m² over a 3-hour infusion every 3 weeks.

Confirmed tumor response rates were based on blinded assessment at two consecutive time points, 3-6 weeks apart, by study day 160.

The treatment groups were similar with respect to demographic characteristics and prior taxane therapy, he noted.

The findings have important implications, because while intravenous paclitaxel is an efficacious chemotherapeutic agent against metastatic breast cancer and multiple other cancers, it is associated in some patients with neuropathy.

“As an oncologist, it has been very frustrating to have an effective chemotherapy like paclitaxel, which a lot of patients cannot tolerate,” Dr. Umanzor said, noting that, in addition to eliminating the need for intravenous access and the risk of infusion hypersensitivity reactions, oral administration offers a number of potential benefits – particularly patient convenience.

Hypothesizing that the lower peak concentration of oral paclitaxel might result in lower systemic toxicity, Dr. Umanzor and colleagues developed the orally administered paclitaxel regimen used in this study to test that hypothesis. The paclitaxel was made bioavailable through combination with the encequidar, which promotes paclitaxel absorption into the blood stream, he explained, noting that the pharmacokinetic exposure matches that of intravenous paclitaxel when given at 80 mg/m², but with peak concentrations that are approximately one-tenth of those seen with intravenous therapy.

In a phase 2 study of 26 patients with heavily pretreated metastatic breast cancer, the oral therapy was associated with an encouraging 42.3% partial response rate and a 46.2% stable disease rate, he said.

The oral paclitaxel plus encequidar combination used in this pivotal study is the first orally administered taxane to demonstrate improved and durable overall confirmed response rates with minimal clinically meaningful neuropathy, compared with intravenous paclitaxel given every 3 weeks, he said.

“Oral paclitaxel and encequidar provides an important oral therapeutic option for patients with metastatic breast cancer, representing a meaningful improvement in the clinical profile of paclitaxel,” he said.

He further noted in a press release that “[t]his oral form of paclitaxel provides a new therapeutic option for patients, in particular, for those who cannot easily travel. While blood counts still need to be monitored, oral administration allows patients to remain home during therapy, and avoid spending significant time in the chemotherapy unit.”

The next step will be testing the tolerability of oral paclitaxel in patients at high risk of developing peripheral neuropathy, he said, adding that the findings could also open the door for assessing this approach with other taxanes.

During a press briefing on the findings at the symposium, several attendees voiced concerns about patient compliance given the large number of capsules required for oral dosing, but Dr. Umanzor said “there were no complaints at all and no issues with adherence.”

“Patients were so excited that they were getting an oral treatment, and we had very good compliance,” he said.

The study was funded by Athenex, the maker of the oral form of paclitaxel. Dr. Umanzor reported having no conflicts of interest.

SOURCE: Umanzor G et al. SABCS 2019, Abstract GS6-01.

SAN ANTONIO – An oral formulation of paclitaxel given with the P-glycoprotein pump inhibitor encequidar improved outcomes and reduced neuropathy risk, compared with intravenous paclitaxel, in women with metastatic breast cancer in a randomized, open-label, phase 3 study.

Sharon Worcester/MDedge News

The primary study endpoint of radiologically confirmed tumor response rate was 35.8% among 265 patients randomized to receive oral paclitaxel plus encequidar, compared with 23.4% among 137 who received intravenous paclitaxel – a statistically significant 12.4% difference, Gerardo Umanzor, MD, reported at the San Antonio Breast Cancer Symposium.

In the prespecified modified intent-to-treat (mITT) population of patients who had evaluable scans at baseline and who received at least seven doses of oral therapy or one dose of intravenous therapy, the corresponding confirmed tumor response rates were 40.4% and 25.5% (absolute improvement, 14.8%), said Dr. Umanzor, a medical oncologist with Liga Contra el Cancer in San Pedro Sulas, Honduras.

Tumor responses in all clinically important subgroups were consistent with the overall confirmed response profiles, he said, noting that the responses were durable, with ongoing analyses showing median response durations of 39.0 weeks versus 30.1 weeks with oral versus intravenous therapy.

Further, a higher percentage of oral versus intravenous paclitaxel recipients were receiving ongoing treatment at the time of the study endpoint (19% vs. 13%, respectively), he said.

Progression-free survival also showed a trend toward improved outcome with oral therapy in ongoing analyses in the mITT population (9.3 vs. 8.3 months, respectively), and an early analysis of overall survival also showed significant improvement (27.9 vs. 16.9 months; P = .035), he said.

Oral paclitaxel also was associated with a lower incidence of chemotherapy-induced peripheral neuropathy – a “highly debilitating side effect of IV paclitaxel,” he said, adding that “the difference between the arms is quite dramatic.”

The overall rates of neuropathy to week 23 were 17% versus 15% with oral versus intravenous therapy, and the rates of grade 3 neuropathy were 1% versus 8%, he said.

Alopecia incidence was reduced by about 50% with oral versus intravenous therapy, he added.

Toxicity was generally similar in the two groups, although the oral paclitaxel patients experienced higher rates of neutropenia and gastrointestinal effects. “These were low grade and manageable,” Dr. Umanzor said.

Study participants were patients with any type of metastatic breast cancer randomized 2:1 to receive a 15-mg tablet of encequidar followed by 205 mg/m² of oral paclitaxel (about 11 capsules, each containing 30 mg of solubilized paclitaxel) for 3 consecutive days each week for 3 weeks or intravenous paclitaxel at the labeled dose of 175 mg/m² over a 3-hour infusion every 3 weeks.

Confirmed tumor response rates were based on blinded assessment at two consecutive time points, 3-6 weeks apart, by study day 160.

The treatment groups were similar with respect to demographic characteristics and prior taxane therapy, he noted.

The findings have important implications, because while intravenous paclitaxel is an efficacious chemotherapeutic agent against metastatic breast cancer and multiple other cancers, it is associated in some patients with neuropathy.

“As an oncologist, it has been very frustrating to have an effective chemotherapy like paclitaxel, which a lot of patients cannot tolerate,” Dr. Umanzor said, noting that, in addition to eliminating the need for intravenous access and the risk of infusion hypersensitivity reactions, oral administration offers a number of potential benefits – particularly patient convenience.

Hypothesizing that the lower peak concentration of oral paclitaxel might result in lower systemic toxicity, Dr. Umanzor and colleagues developed the orally administered paclitaxel regimen used in this study to test that hypothesis. The paclitaxel was made bioavailable through combination with the encequidar, which promotes paclitaxel absorption into the blood stream, he explained, noting that the pharmacokinetic exposure matches that of intravenous paclitaxel when given at 80 mg/m², but with peak concentrations that are approximately one-tenth of those seen with intravenous therapy.

In a phase 2 study of 26 patients with heavily pretreated metastatic breast cancer, the oral therapy was associated with an encouraging 42.3% partial response rate and a 46.2% stable disease rate, he said.

The oral paclitaxel plus encequidar combination used in this pivotal study is the first orally administered taxane to demonstrate improved and durable overall confirmed response rates with minimal clinically meaningful neuropathy, compared with intravenous paclitaxel given every 3 weeks, he said.

“Oral paclitaxel and encequidar provides an important oral therapeutic option for patients with metastatic breast cancer, representing a meaningful improvement in the clinical profile of paclitaxel,” he said.

He further noted in a press release that “[t]his oral form of paclitaxel provides a new therapeutic option for patients, in particular, for those who cannot easily travel. While blood counts still need to be monitored, oral administration allows patients to remain home during therapy, and avoid spending significant time in the chemotherapy unit.”

The next step will be testing the tolerability of oral paclitaxel in patients at high risk of developing peripheral neuropathy, he said, adding that the findings could also open the door for assessing this approach with other taxanes.

During a press briefing on the findings at the symposium, several attendees voiced concerns about patient compliance given the large number of capsules required for oral dosing, but Dr. Umanzor said “there were no complaints at all and no issues with adherence.”

“Patients were so excited that they were getting an oral treatment, and we had very good compliance,” he said.

The study was funded by Athenex, the maker of the oral form of paclitaxel. Dr. Umanzor reported having no conflicts of interest.

SOURCE: Umanzor G et al. SABCS 2019, Abstract GS6-01.

SAN ANTONIO – An oral formulation of paclitaxel given with the P-glycoprotein pump inhibitor encequidar improved outcomes and reduced neuropathy risk, compared with intravenous paclitaxel, in women with metastatic breast cancer in a randomized, open-label, phase 3 study.

Sharon Worcester/MDedge News

The primary study endpoint of radiologically confirmed tumor response rate was 35.8% among 265 patients randomized to receive oral paclitaxel plus encequidar, compared with 23.4% among 137 who received intravenous paclitaxel – a statistically significant 12.4% difference, Gerardo Umanzor, MD, reported at the San Antonio Breast Cancer Symposium.

In the prespecified modified intent-to-treat (mITT) population of patients who had evaluable scans at baseline and who received at least seven doses of oral therapy or one dose of intravenous therapy, the corresponding confirmed tumor response rates were 40.4% and 25.5% (absolute improvement, 14.8%), said Dr. Umanzor, a medical oncologist with Liga Contra el Cancer in San Pedro Sulas, Honduras.

Tumor responses in all clinically important subgroups were consistent with the overall confirmed response profiles, he said, noting that the responses were durable, with ongoing analyses showing median response durations of 39.0 weeks versus 30.1 weeks with oral versus intravenous therapy.

Further, a higher percentage of oral versus intravenous paclitaxel recipients were receiving ongoing treatment at the time of the study endpoint (19% vs. 13%, respectively), he said.

Progression-free survival also showed a trend toward improved outcome with oral therapy in ongoing analyses in the mITT population (9.3 vs. 8.3 months, respectively), and an early analysis of overall survival also showed significant improvement (27.9 vs. 16.9 months; P = .035), he said.

Oral paclitaxel also was associated with a lower incidence of chemotherapy-induced peripheral neuropathy – a “highly debilitating side effect of IV paclitaxel,” he said, adding that “the difference between the arms is quite dramatic.”

The overall rates of neuropathy to week 23 were 17% versus 15% with oral versus intravenous therapy, and the rates of grade 3 neuropathy were 1% versus 8%, he said.

Alopecia incidence was reduced by about 50% with oral versus intravenous therapy, he added.

Toxicity was generally similar in the two groups, although the oral paclitaxel patients experienced higher rates of neutropenia and gastrointestinal effects. “These were low grade and manageable,” Dr. Umanzor said.

Study participants were patients with any type of metastatic breast cancer randomized 2:1 to receive a 15-mg tablet of encequidar followed by 205 mg/m² of oral paclitaxel (about 11 capsules, each containing 30 mg of solubilized paclitaxel) for 3 consecutive days each week for 3 weeks or intravenous paclitaxel at the labeled dose of 175 mg/m² over a 3-hour infusion every 3 weeks.

Confirmed tumor response rates were based on blinded assessment at two consecutive time points, 3-6 weeks apart, by study day 160.

The treatment groups were similar with respect to demographic characteristics and prior taxane therapy, he noted.

The findings have important implications, because while intravenous paclitaxel is an efficacious chemotherapeutic agent against metastatic breast cancer and multiple other cancers, it is associated in some patients with neuropathy.

“As an oncologist, it has been very frustrating to have an effective chemotherapy like paclitaxel, which a lot of patients cannot tolerate,” Dr. Umanzor said, noting that, in addition to eliminating the need for intravenous access and the risk of infusion hypersensitivity reactions, oral administration offers a number of potential benefits – particularly patient convenience.

Hypothesizing that the lower peak concentration of oral paclitaxel might result in lower systemic toxicity, Dr. Umanzor and colleagues developed the orally administered paclitaxel regimen used in this study to test that hypothesis. The paclitaxel was made bioavailable through combination with the encequidar, which promotes paclitaxel absorption into the blood stream, he explained, noting that the pharmacokinetic exposure matches that of intravenous paclitaxel when given at 80 mg/m², but with peak concentrations that are approximately one-tenth of those seen with intravenous therapy.

In a phase 2 study of 26 patients with heavily pretreated metastatic breast cancer, the oral therapy was associated with an encouraging 42.3% partial response rate and a 46.2% stable disease rate, he said.

The oral paclitaxel plus encequidar combination used in this pivotal study is the first orally administered taxane to demonstrate improved and durable overall confirmed response rates with minimal clinically meaningful neuropathy, compared with intravenous paclitaxel given every 3 weeks, he said.

“Oral paclitaxel and encequidar provides an important oral therapeutic option for patients with metastatic breast cancer, representing a meaningful improvement in the clinical profile of paclitaxel,” he said.

He further noted in a press release that “[t]his oral form of paclitaxel provides a new therapeutic option for patients, in particular, for those who cannot easily travel. While blood counts still need to be monitored, oral administration allows patients to remain home during therapy, and avoid spending significant time in the chemotherapy unit.”

The next step will be testing the tolerability of oral paclitaxel in patients at high risk of developing peripheral neuropathy, he said, adding that the findings could also open the door for assessing this approach with other taxanes.

During a press briefing on the findings at the symposium, several attendees voiced concerns about patient compliance given the large number of capsules required for oral dosing, but Dr. Umanzor said “there were no complaints at all and no issues with adherence.”

“Patients were so excited that they were getting an oral treatment, and we had very good compliance,” he said.

The study was funded by Athenex, the maker of the oral form of paclitaxel. Dr. Umanzor reported having no conflicts of interest.

SOURCE: Umanzor G et al. SABCS 2019, Abstract GS6-01.