Older adult participation in cancer clinical trials: A systematic review of barriers and interventions.

Cancer is a disease of aging and, as the world's population ages, the number of older persons with cancer is increasing and will make up a growing share of the oncology population in virtually every country. Despite this, older patients remain vastly underrepresented in research that sets the standards for cancer treatments. Consequently, most of what we know about cancer therapeutics is based on clinical trials conducted in younger, healthier patients, and effective strategies to improve clinical trial participation of older adults with cancer remain sparse. For this systematic review, the authors evaluated published studies regarding barriers to participation and interventions to improve participation of older adults in cancer trials. The quality of the available evidence was low and, despite a literature describing multifaceted barriers, only one intervention study aimed to increase enrollment of older adults in trials. The findings starkly amplify the paucity of evidence-based, effective strategies to improve participation of this underrepresented population in cancer trials. Within these limitations, the authors provide their opinion on how the current cancer research infrastructure must be modified to accommodate the needs of older patients. Several underused solutions are offered to expand clinical trials to include older adults with cancer. However, as currently constructed, these recommendations alone will not solve the evidence gap in geriatric oncology, and efforts are needed to meet older and frail adults where they are by expanding clinical trials designed specifically for this population and leveraging real-world data.

Falls prechemotherapy and toxicity-related hospitalization during adjuvant chemotherapy for breast cancer in older women: Results from the prospective multicenter HOPE trial.

BACKGROUND: Older women with breast cancer frequently experience toxicity-related hospitalizations during adjuvant chemotherapy. Although the geriatric assessment can identify those at risk, its use in clinic remains limited. One simple, low-cost marker of vulnerability in older persons is fall history. Here, the authors examined whether falls prechemotherapy can identify older women at risk for toxicity-related hospitalization during adjuvant chemotherapy for breast cancer. METHODS: In a prospective study of women >65 years old with stage I-III breast cancer treated with adjuvant chemotherapy, the authors assessed baseline falls in the past 6 months as a categorical variable: no fall, one fall, and more than one fall. The primary end point was incident hospitalization during chemotherapy attributable to toxicity. Multivariable logistic regression was used to examine the association between falls and toxicity-related hospitalization, adjusting for sociodemographic, disease, and geriatric covariates. RESULTS: Of the 497 participants, 60 (12.1%) reported falling before chemotherapy, and 114 (22.9%) had one or more toxicity-related hospitalizations. After adjusting for sociodemographic, disease, and geriatric characteristics, women who fell more than once within 6 months before chemotherapy had greater odds of being hospitalized from toxicity during chemotherapy compared to women who did not fall (50.0% vs. 20.8% experienced toxicity-related hospitalization, odds ratio, 4.38; 95% confidence interval, 1.66-11.54, p = .003). CONCLUSIONS: In this cohort of older women with early breast cancer, women who experienced more than one fall before chemotherapy had an over 4-fold increased risk of toxicity-related hospitalization during chemotherapy, independent of sociodemographic, disease, and geriatric factors.

Racial disparities in outcomes of patients with stage I-III triple-negative breast cancer after adjuvant chemotherapy: a post-hoc analysis of the E5103 randomized trial.

PURPOSE: Breast cancer mortality is higher in Black women than other racial groups. This difference has been partially attributed to a higher proportion of triple-negative breast cancer (TNBC). However, it is uncertain if survival disparities exist in racially diverse TNBC patients receiving similar treatments. Here, we examine racial differences in disease-related outcomes in TNBC patients treated on the E5103 clinical trial. METHODS: From 2007 to 2011, 4,994 patients with stage I-III HER2-negative breast cancer were randomized to adjuvant chemotherapy with or without bevacizumab. This analysis was limited to the subset of 1,742 TNBC patients with known self-reported race. Unadjusted Kaplan-Meier curves and adjusted Cox-Proportional Hazards models were used to determine breast cancer events and survival outcomes. RESULTS: Of the analysis population, 51 (2.9%) were Asian, 269 (15.4%) Black, and 1422 (81.6%) White. Median age was 51 years. Patient characteristics, treatment arm, and local therapies were similar across racial groups. White women were more commonly node-negative (56% vs. 49% and 44% in Asian and Black women, respectively; p < 0.01). At a median follow-up of 46 months, unadjusted Kaplan-Meier locoregional and distant recurrence, and disease-free and overall survival, did not differ significantly by race. In Cox models adjusted for patient and tumor characteristics and treatment arm, race was not associated with any disease event. Larger tumor size and nodal involvement were consistently associated with breast cancer events. CONCLUSION: This clinical trial population of similarly treated TNBC patients showed no racial differences in breast cancer outcomes. Disease extent, rather than race, was associated with disease events.

Trends in Locoregional Therapy in Older Women with Early-Stage Hormone Receptor-Positive Breast Cancer by Frailty and Life Expectancy.

BACKGROUND: In women ≥ 70 years of age with T1N0 hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, breast surgery type and omission of axillary surgery or radiation therapy (RT) do not impact overall survival. Although frailty and life expectancy ideally factor into therapy decisions, their impact on therapy receipt is unclear. We sought to identify trends in and factors associated with locoregional therapy type by frailty and life expectancy. METHODS: Women ≥ 70 years of age with T1N0 HR+/HER2- breast cancer diagnosed in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database between 2010 and 2015 were stratified by validated claims-based frailty and life expectancy measures. Therapy trends over time by regimen intensity ('high intensity': lumpectomy + axillary surgery + RT, or mastectomy + axillary surgery; 'moderate intensity': lumpectomy + RT, lumpectomy + axillary surgery, or mastectomy only; or 'low intensity': lumpectomy only) were analyzed. Factors associated with therapy type were identified using generalized linear mixed models. RESULTS: Of 16,188 women, 21.8% were frail, 22.2% had a life expectancy < 5 years, and only 12.3% fulfilled both criteria. In frail women with a life expectancy < 5 years, high-intensity regimens decreased significantly (48.8-31.2%; p < 0.001) over the study period, although in 2015, 30% still received a high-intensity regimen. In adjusted analyses, frailty and life expectancy < 5 years were not associated with breast surgery type but were associated with a lower likelihood of axillary surgery (frailty: odds ratio [OR] 0.86, 95% confidence interval [CI] 0.76-0.96; life expectancy < 5 years: OR 0.22, 95% CI 0.20-0.25). Life expectancy < 5 years was also associated with a lower likelihood of RT receipt in breast-conserving surgery patients (OR 0.30, 95% CI 0.27-0.34). CONCLUSIONS: Rates of high-intensity therapy are decreasing but overtreatment persists in this population. Continued efforts aimed at appropriate de-escalation of locoregional therapy are needed.

Breast cancer treatment receipt and the role of financial stress, health literacy, and numeracy among diverse breast cancer survivors.

PURPOSE: Disparities in breast cancer treatment for low-income and minority women are well documented. We examined economic hardship, health literacy, and numeracy and whether these factors were associated with differences in receipt of recommended treatment among breast cancer survivors. METHODS: During 2018-2020, we surveyed adult women diagnosed with stage I-III breast cancer between 2013 and 2017 and received care at three centers in Boston and New York. We inquired about treatment receipt and treatment decision-making. We used Chi-squared and Fisher's exact tests to examine associations between financial strain, health literacy, numeracy (using validated measures), and treatment receipt by race and ethnicity. RESULTS: The 296 participants studied were 60.1% Non-Hispanic (NH) White, 25.0% NH Black, and 14.9% Hispanic; NH Black and Hispanic women had lower health literacy and numeracy and reported more financial concerns. Overall, 21 (7.1%) women declined at least one component of recommended therapy, without differences by race and ethnicity. Those not initiating recommended treatment(s) reported more worry about paying large medical bills (52.4% vs. 27.1%), worse household finances since diagnosis (42.9% vs. 22.2%), and more uninsurance before diagnosis (9.5% vs. 1.5%); all P < .05. No differences in treatment receipt by health literacy or numeracy were observed. CONCLUSION: In this diverse population of breast cancer survivors, rates of treatment initiation were high. Worry about paying medical bills and financial strain were frequent, especially among non-White participants. Although we observed associations of financial strain with treatment initiation, because few women declined treatments, understanding the scope of impact is limited. Our results highlight the importance of assessments of resource needs and allocation of support for breast cancer survivors. Novelty of this work includes the granular measures of financial strain and inclusion of health literacy and numeracy.

Racial Disparities in Locoregional Recurrence in Postmenopausal Patients with Stage I-III, Hormone Receptor-Positive Breast Cancer Enrolled in the NSABP B-42 Clinical Trial.

BACKGROUND: There are limited data examining racial disparities in locoregional recurrence (LRR) among women with access to high-quality care. We aimed to examine differences in late LRR by race in patients with stage I-IIIA, hormone receptor-positive (HR+) breast cancer enrolled in the National Surgical Adjuvant Breast and Bowel (NSABP) B-42 trial. METHODS: From 2006 to 2010, 3966 postmenopausal women with stage I-IIIA HR+ breast cancer who were disease-free after 5 years of endocrine therapy were randomized to an additional 5 years of endocrine therapy or placebo. Patients were excluded if multi-racial or if race was unknown. Kaplan-Meier curves were used to estimate 6-year LRR from the time of trial registration and according to race. Cox proportional hazards models were used for adjusted survival analyses. RESULTS: Overall, 3929 NSABP B-42 patients were included: 3688 (93.9%) White, 151 (3.8%) Black, and 90 (2.3%) Asian patients. Median follow-up was 75.2 months. Overall estimated 6-year LRR from trial registration was 1.8% and differed by race: LRR rates were 1.7% in White women, 4.9% in Black women, and 0% in Asian women (p = 0.046). Adjusted Cox proportional hazards analysis found Black race to be independently associated with LRR (hazard ratio [HzR] 2.36, 95% confidence interval [CI] 1.01-5.49; p = 0.047). Node-positivity was also associated with increased LRR (HzR 1.75, 95% CI 1.07-2.86; p = 0.025). Adjusted Cox analysis found LRR (HzR 2.32, 95% CI 1.33-4.06; p = 0.003) to be associated with increased overall mortality; however, race was not independently associated with mortality. CONCLUSION: Among postmenopausal patients with stage I-IIIA HR+ breast cancer in the NSABP B-42 trial, racial differences in late LRR were present, with the highest LRR in Black women.

Racial and Ethnic Disparities in Outcomes After Breast-Conserving Therapy and Endocrine Therapy for DCIS: A Post-Hoc Analysis of the NSABP B-35 Randomized Clinical Trial.

BACKGROUND: Racial and ethnic disparities in outcomes after treatment for ductal carcinoma in situ (DCIS) are largely unknown. The objective of this study was to examine breast cancer outcomes by race and ethnicity in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-35 clinical trial. PATIENTS AND METHODS: The NSABP B-35 trial randomized postmenopausal women with hormone receptor-positive DCIS treated with breast-conserving therapy to 5 years of tamoxifen or anastrozole. In total, 3104 women were enrolled between 2003 and 2006. For this analysis, patients without complete self-reported race and ethnicity or with immediate trial dropout were excluded. Kaplan-Meier curves and adjusted Cox-proportional hazards models were used for analyses. RESULTS: Of the 3061 women included, 2614 (85.4%) were non-Hispanic white (NHW), 255 (8.3%) were non-Hispanic Black (NHB), 95 (3.1%) were Hispanic, and 96 (3.1%) were Asian or Pacific Islander (API). Endocrine therapy assignment and duration were well balanced between racial and ethnic groups. Median follow-up was 9 years; unadjusted Kaplan-Meier curves did not show any racial differences in disease events. Adjusted Cox-proportional hazards models found API (versus NHW) race to be associated with higher local recurrence [hazard ratio (HzR) 2.45, p = 0.035] and NHB race to be associated with higher distant recurrence (HzR 5.03, p = 0.020) and breast cancer mortality (HzR 3.83, p = 0.046). CONCLUSIONS: Despite similar locoregional treatments and standard endocrine therapy in a clinical trial population, racial and ethnic disparities exist in long-term outcomes for hormone-receptor-positive DCIS. These findings suggest that factors outside of access and treatment may impact DCIS outcomes by race and ethnicity.

Development of a workflow process mapping protocol to inform the implementation of regional patient navigation programs in breast oncology.

BACKGROUND: Implementing city-wide patient navigation processes that support patients across the continuum of cancer care is impeded by a lack of standardized tools to integrate workflows and reduce gaps in care. The authors present an actionable workflow process mapping protocol for navigation process planning and improvement based on methods developed for the Translating Research Into Practice study. METHODS: Key stakeholders at each study site were identified through existing community partnerships, and data on each site's navigation processes were collected using mixed methods through a series of team meetings. The authors used Health Quality Ontario's Quality Improvement Guide, service design principles, and key stakeholder input to map the collected data onto a template structured according to the case-management model. RESULTS: Data collection and process mapping exercises resulted in a 10-step protocol that includes: 1) workflow mapping procedures to guide data collection on the series of activities performed by health care personnel that comprise a patient's navigation experience, 2) a site survey to assess program characteristics, 3) a semistructured interview guide to assess care coordination workflows, 4) a site-level swim lane workflow process mapping template, and 5) a regional high-level process mapping template to aggregate data from multiple site-level process maps. CONCLUSIONS: This iterative, participatory approach to data collection and process mapping can be used by improvement teams to streamline care coordination, ultimately improving the design and delivery of an evidence-based navigation model that spans multiple treatment modalities and multiple health systems in a metropolitan area. This protocol is presented as an actionable toolkit so the work may be replicated to support other quality-improvement initiatives and efforts to design truly patient-centered breast cancer treatment experiences. LAY SUMMARY: Evidence-based patient navigation in breast cancer care requires the integration of services through each phase of cancer treatment. The Translating Research Into Practice study aims to implement patient navigation for patients with breast cancer who are at risk for delays and are seeking care across 6 health systems in Boston, Massachusetts. The authors designed a 10-step protocol outlining procedures and tools that support a systematic assessment for health systems that want to implement breast cancer patient navigation services for patients who are at risk for treatment delays.

Breast cancer knowledge and understanding treatment rationales among diverse breast cancer survivors.

PURPOSE: The degree to which breast cancer survivors know about their tumors and understand treatment rationales is not well understood. We sought to identify information gaps within a diverse sample and explore whether knowledge about breast cancer and treatment may impact care. METHODS: We conducted a one-time, interviewer-administered survey of women who were diagnosed with breast cancer during 2013-2017 and received care at one of three centers in Boston, MA, and New York, NY. We examined knowledge of breast cancer and treatment rationales, information preferences, and treatment receipt. RESULTS: During 2018-2020, we interviewed 313 women (American Association for Public Opinion Research Cooperation Rates 58.4-76.5% across centers) who were 56.9% White, 23.6% Black, 14.1% Hispanic, and 5.4% other. Among the 296 included in analyses, we observed high variability in knowledge of breast cancer and treatment rationales, with a substantial number demonstrating limited knowledge despite feeling highly informed; > 25% actively avoided information. Black and Hispanic (vs. White) women consistently knew less about their cancers. Lack of understanding of treatment rationales for chemotherapy, radiation, and hormonal therapy was common but not consistently different by race and ethnicity. Understanding treatment rationale (but not cancer knowledge) was associated with treatment initiation, but small sample sizes limited in-depth examination. CONCLUSIONS: Our study highlights the need for enhanced informational support for breast cancer survivors, who are challenged with complex information during the decision-making process and beyond. More research is needed to understand how to further educate and empower diverse populations of patients with breast cancer.

Surveillance mammography after treatment for male breast cancer.

PURPOSE: To identify the practice patterns related to use of surveillance mammography in male breast cancer (MaBC) survivors. METHODS: Using administrative claims data from OptumLabs Data Warehouse, we identified men who underwent surgery for breast cancer during 2007-2017. We calculated the proportion of men who had at least one mammogram (a) within 13 months for all patients and (b) within 24 months amongst those who maintained their insurance coverage for at least that length of time after surgery. Multivariate logistic regression modeling was used to identify factors associated with mammography within each timeframe. RESULTS: Out of 729 total MaBC survivors, 209 (29%) underwent mammography within 13 months after surgery. Among those who had lumpectomy, 41% underwent mammography, whereas among those who had mastectomy, 27% had mammography. Amongst 526 men who maintained consistent insurance coverage for 24 months after surgery, 215 (41%) underwent mammography at least once during that 24-month period. In this cohort, the proportion who had at least one mammogram during the 24-month period was 49% after lumpectomy and 40% after mastectomy. In a multivariate logistic regression model, more recent diagnosis (2015+) and older age at diagnosis were associated with lower odds of undergoing mammography, while receipt of radiation was associated with higher odds of undergoing mammography. CONCLUSIONS: Although recent ASCO guidelines recommend surveillance mammography after lumpectomy, a minority of MaBC survivors undergo surveillance mammography, even after lumpectomy. This is likely due to the paucity of data regarding the true benefits and harms of surveillance/screening mammography for MaBC.

Acceptability of a companion patient guide to support expert consensus guidelines on surveillance mammography in older breast cancer survivors.

PURPOSE: To support shared decision-making, patient-facing resources are needed to complement recently published guidelines on approaches for surveillance mammography in breast cancer survivors aged ≥ 75 or with < 10-year life expectancy. We created a patient guide to facilitate discussions about surveillance mammography in older breast cancer survivors. METHODS: The "Are Mammograms Still Right for Me?" guide estimates future ipsilateral and contralateral breast (in-breast) cancer risks, general health, and the potential benefits/harms of mammography, with prompts for discussion. We conducted in-clinic acceptability testing of the guide by survivors and their clinicians at a National Cancer Institute-designated comprehensive cancer center, including two community practices. Patients and clinicians received the guide ahead of a clinic visit and surveyed patients (pre-/post-visit) and clinicians (post-visit). Acceptability was defined as ≥ 75% of patients and clinicians reporting that the guide (a) should be recommended to others, (b) is clear, (c) is helpful, and (d) contains a suitable amount of information. We also elicited feedback on usability and mammography intentions. RESULTS: We enrolled 45 patients and their 21 clinicians. Among those responding in post-visit surveys, 33/37 (89%) patients and 15/16 (94%) clinicians would recommend the guide to others; 33/37 (89%) patients and 15/16 (94%) clinicians felt everything/most things were clear. All other pre-specified acceptability criteria were met. Most patients reported strong intentions for mammography (100% pre-visit, 98% post-visit). CONCLUSION: Oncology clinicians and older breast cancer survivors found a guide to inform mammography decision-making acceptable and clear. A multisite clinical trial is needed to assess the guide's impact mammography utilization. TRIAL REGISTRATION: ClinicalTrials.gov-NCT03865654, posted March 7, 2019.

Variation in Deescalated Axillary Surgical Practices in Older Women with Early-Stage Breast Cancer.

BACKGROUND: Randomized controlled trials show that certain axillary surgical practices can be safely deescalated in older adults with early-stage breast cancer. Hospital volume is often equated with surgical quality, but it is unclear whether this includes performance of low-value surgeries. We sought to describe how utilization of two low-value axillary surgeries has varied by time and hospital volume. METHODS: Women aged ≥ 70 years diagnosed with breast cancer from 2013 to 2016 were identified in the National Cancer Database. The outcomes of interest were sentinel lymph node biopsy (SLNB) in cT1N0 hormone receptor-positive cancer patients and axillary lymph node dissection (ALND) in cT1-2N0 patients undergoing breast-conserving surgery with ≤ 2 pathologically positive nodes. Time trends in procedure use and multivariable regression with restricted cubic splines were performed, adjusting for patient, disease, and hospital factors. RESULTS: Overall, 83.4% of 44,779 women eligible for omission of SLNB underwent SLNB and 20.0% of 7216 patients eligible for omission of ALND underwent ALND. SLNB rates did not change significantly over time and remained significantly different by age group (70-74 years: 93.5%; 75-79 years: 89.7%, 80-84 years: 76.7%, ≥ 85 years: 48.9%; p < 0.05). ALND rates decreased over the study period across all age groups included (22.5 to 16.9%, p < 0.001). In restricted cubic splines models, lower hospital volume was associated with higher likelihood of undergoing SLNB and ALND. CONCLUSIONS: ALND omission has been more widely adopted than SLNB omission in older adults, but lower hospital volume is associated with higher likelihood of both procedures. Practice-specific deimplementation strategies are needed, especially for lower-volume hospitals.

Racial and Socioeconomic Disparities in Breast Cancer Outcomes within the AJCC Pathologic Prognostic Staging System.

BACKGROUND: Non-Hispanic black (NHB) women and those of lower socioeconomic status (SES) have inferior breast cancer outcomes compared with non-Hispanic white (NHW) women and those of higher SES. We examined racial and SES disparities in breast cancer survival within the AJCC 8th edition pathologic prognostic staging system. METHODS: Using the Surveillance, Epidemiology and End Results Program, we identified patients diagnosed with invasive breast cancer from 2010 to 2015, with follow-up through 2016. Census tract-level SES (cSES) data were available as a composite index and analyzed in quintiles. Cox proportional-hazards survival analyses adjusted for age, race, cSES, insurance, marital status, histology, pathologic prognostic stage, and treatment were used to estimate disease-specific survival (DSS). RESULTS: A total of 259,852 patients were included: 176,369 (67.9%) NHW; 28,510 (11.0%) NHB; 29,737 (11.4%) Hispanic; and 22,887 (8.8%) Asian. NHB race and lower cSES were associated with increased incidence of triple-negative disease compared with NHW (p < 0.01). NHB race, lower cSES, public insurance, lower education, and increased poverty were associated with lower DSS. Survival analyses adjusting for cSES, tumor, and treatment characteristics demonstrated that NHB patients had inferior DSS within each AJCC pathologic prognostic stage (hazard ratio [HR] 1.25, 95% confidence interval [CI] 1.20-1.30) compared with NHW patients. Fully adjusted models also showed patients residing in lower SES counties had inferior DSS. CONCLUSIONS: Racial and cSES disparities in breast cancer-specific mortality were evident across all stages, even within the pathologic prognostic staging system which incorporates tumor biology. Future efforts should assess the biological, behavioral, social, and environmental determinants that underlie racial and SES inequities in outcomes.

Risks of subsequent primary cancers among breast cancer survivors according to hormone receptor status.

BACKGROUND: This study was aimed at examining the risks of subsequent primary cancers (SPCs) among breast cancer survivors by hormone receptor (HR) status and age at diagnosis. METHODS: Data from 12 Surveillance, Epidemiology, and End Results registries were used to identify 431,222 breast cancer survivors (at least 1 year) diagnosed between the ages of 20 and 84 years from 1992 to 2015. Risks of SPCs were measured as the standardized incidence ratio (SIR) and the excess absolute risk (EAR) per 10,000 person-years. Poisson regression was used to test the difference in SIRs by HR status. RESULTS: In comparison with the general population, the risk of new cancer diagnoses among survivors was 20% higher for those with HR-positive cancers (SIR, 1.20; 95% confidence interval [CI], 1.19-1.21; EAR, 23.3/10,000 person-years) and 44% higher for those with HR-negative cancers (SIR, 1.44; 95% CI, 1.41-1.47; EAR, 45.2/10,000 person-years), with the risk difference between HR statuses statistically significant. The higher risk after HR-negative cancer was driven by acute nonlymphocytic leukemia and breast, ovarian, peritoneal, and lung cancers. By age at diagnosis, the total EAR per 10,000 person-years ranged from 15.8 (95% CI, 14.1-17.5; SIR, 1.11) among late-onset (age, 50-84 years) HR-positive survivors to 69.4 (95% CI, 65.1-73.7; SIR, 2.24) among early-onset (age, 20-49 years) HR-negative survivors, with subsequent breast cancer representing 73% to 80% of the total EAR. After breast cancer, the greatest EARs were for ovarian cancer among early-onset HR-negative survivors, lung cancer among early- and late-onset HR-negative survivors, and uterine corpus cancer among late-onset HR-positive survivors. CONCLUSIONS: Risks of SPCs after breast cancer differ substantially by subtype and age. This suggests that more targeted approaches for cancer prevention and early-detection strategies are needed in survivorship care planning.

Tumor subtypes and survival in male breast cancer.

PURPOSE: Male breast cancer is an uncommon disease, and population-based information regarding prognostic factors is limited. Most cases are hormone receptor (HR) positive; however, the association of tumor subtype with overall survival (OS) and breast cancer-specific survival (BCSS) is unclear. METHODS: Using SEER data, we identified men with invasive breast cancer between 2010 and 2017 with known HR and HER2 status. We examined tumor subtypes by patient characteristics and performed multivariate Cox proportional hazards analyses to determine the associations of each variable with OS and BCSS. RESULTS: We included 2389 men with a median follow-up of 43 months (IQR 19-68). Median age was 66 years. Tumor subtype distribution was 84.1% HR+/HER2-, 12.7% HR+/HER2+ , 0.8% HR-/HER2+, and 2.3% triple-negative (TN). In univariate analysis, OS at 5 years was 76.5% for HR+/HER2-, 65.1% for HR+/HER2+ , 84.2% for HR-/HER2+, and 48.1% for TN (p < 0.0001). Of all subtypes, TN had the worst BCSS (p < 0.0001). Stage, tumor subtype and race were significantly associated with OS and BCSS in multivariate analysis. Adjusted Cox hazard ratios for OS by tumor subtype with HR+/HER2- as reference were 1.55 for HR+/HER2+ (p = 0.001), 1.1 for HR-/HER2+ (p = 0.888), and 3.59 for TN (p < 0.001). CONCLUSION: We observed significant differences in survival outcomes by tumor subtype. Poor outcomes among men with HER2+ and TN disease suggest possible under-treatment, aggressive tumor biology, and/or more advanced disease at presentation. Studies to better understand the inferior survival for men with these subtypes are warranted and will likely require international collaboration.

Twenty-year risks of breast cancer-specific mortality for stage III breast cancer in the surveillance, epidemiology, and end results registry.

PURPOSE: We aimed to report the 20-year risk of breast cancer-specific mortality (BCSM), report the risk of BCSM conditional on having survived 5 years, and identify factors associated with late deaths in stage III breast cancer. METHODS: Using Surveillance, Epidemiology, and End Results data, we included women with stage III breast cancer diagnosed from 1990 to 2005. We excluded women with unknown hormone receptor (HR) status, women who did not undergo resection of the primary tumor or axillary nodes, or unknown cause of death. We estimated risks of BCSM using cumulative incidence function and used Fine and Gray regression to identify factors associated with late deaths. RESULTS: Final sample was 36,500 patients with 14 years of median follow-up. For each stage subgroup, the risk of BCSM at 20 years was significantly higher for HR-negative vs HR-positive tumors (IIIA: 49.8% vs 43.2%, P < 0.0001; IIIB: 60.9% vs 47.6%, P < 0.0001; IIIC: 68.7% vs 63.1%, P < 0.0001). Compared with the risks of non-BCSM, the risks of BCSM at 20 years were four times higher in stage IIIC HR-positive disease and seven times higher in stage IIIC HR-negative disease. Risks of BCSM conditional on having survived 5 years depended on tumor size, nodal status, race, and tumor grade for HR-positive disease and depended on tumor size, nodal status, and age for HR-negative disease. CONCLUSIONS: In stage III breast cancer, the risk of BCSM at 20 years is very high and remains important even beyond the first 5 years in both HR-positive and HR-negative disease. Late BCSM depends on traditional clinicopathologic factors.

Oncotype DX testing in node-positive breast cancer strongly impacts chemotherapy use at a comprehensive cancer center.

PURPOSE: In 2016, we initiated standardized "reflex" Oncotype DX Recurrence Score (RS) testing for patients ≤ 65 years with pT1-2N0-1 HR+/HER2- breast cancer. Here, we examine RS testing patterns, RS distribution, and factors associated with chemotherapy use in patients with pN1 breast cancer. METHODS: Patients with stage I-III HR+/HER2- pN1 breast cancer treated with upfront surgery from February 2016 to March 2019 were identified. Clinical characteristics were compared between patients meeting reflex RS testing criteria, those with RS ordered outside of reflex criteria, and those without RS testing. RS was categorized as low (< 18), intermediate (18-30), and high (≥ 31). Multivariate logistic regression was performed to identify factors associated with adjuvant chemotherapy receipt. We examined 3-year recurrence-free survival (RFS) and overall survival (OS) stratified by chemotherapy use. RESULTS: We identified 347 HR+/HER2- pN1 patients; 272 (78.4%) received RS testing, and 194 (71.3%) met reflex criteria. RS was < 18 in 164 (61.4%) patients, 18-30 in 89 (32.7%) patients, and ≥ 31 in 16 (5.9%) patients. On multivariate analysis, RS < 18 (OR 0.47, 95% CI 0.24-0.92) was associated with lower odds of chemotherapy use, whereas presence of lymphovascular invasion (OR 1.77, 95% CI 1.03-3.07) and lobular subtype (OR 2.40, 95% CI 1.21-4.78) were associated with higher odds. No differences in 3-year RFS (p = 0.97) or OS (p = 0.19) based on chemotherapy receipt were observed. CONCLUSION: Most RS-tested HR+/HER2- pN1 patients at our center had low genomic risk. A low RS independently influenced chemotherapy omission and in RS-tested patients, short-term outcomes were excellent. Our study demonstrates increased use of RS in guiding adjuvant treatment decisions in node-positive disease.

Factors associated with late risks of breast cancer-specific mortality in the SEER registry.

PURPOSE: Most reports describing the risk of late relapse in breast cancer (BC) have been based on selected patients enrolled into clinical trials. We examined population-based long-term risks of BC-specific mortality (BCSM), the risks of BCSM conditional on having survived 5 years, and factors associated with late BCSM. METHODS: Using SEER, we identified women diagnosed with BC (T1-T2, N0-N2, M0) between 1990 and 2005 with known hormone receptor (HR) status. Kaplan-Meier analyses determined cumulative risks of BCSM. We performed Fine and Gray regression stratified by HR status. RESULTS: We included 202,080 patients (median follow-up of 14.17 years). Of all BC deaths, the proportion that occurred after 5 years was 65% for HR-positive vs 28% for HR-negative (p < 0.001) BC. In HR-positive BC, the cumulative risks of BCSM during years 5-20 were 9.9%, 21.9%, and 38% for N0, N1, and N2 disease. For HR-negative BC, the risks were 7.9%, 12.2%, and 19.9%, respectively. For T1a/b, N0, HR-positive BC, the risk of BCSM was 6 times lower than the risk of non-BCSM. In N2, HR-positive BC, the risk of BCSM was 43% higher than the risk of non-BCSM. In adjusted Fine and Gray models stratified by HR status, the risks of BCSM conditional on having survived 5 years for both HR-positive and HR-negative depended on T-N status, age, and year of diagnosis. In HR-positive, the risks also depended on race and grade. CONCLUSION: The risks of BCSM beyond 5 years, although different, remain important for both HR-positive and HR-negative BC. Strategies to prevent early and late recurrences are warranted.

A dynamic portrait of adverse events for breast cancer patients: results from a phase II clinical trial of eribulin in advanced HER2-negative breast cancer.

PURPOSE: Adverse events (AE) during oncology clinical trials are typically reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), which provides information about the frequency and severity of AEs from the provider's perspective. Instruments that track patient-reported outcomes (PRO) complement the CTCAE and provide additional patient-centered information about the toxicity profile of an anti-cancer drug. METHODS: We conducted a single-arm, open-label phase II study of eribulin as first- or second-line therapy for metastatic hormone receptor-positive/HER2-negative (HR+/HER2-) or triple-negative breast cancer (TNBC). Patients were recruited simultaneously into each cohort by tumor subtype. The primary endpoint was overall response rate (ORR). Secondary endpoints included evaluation of toxicity by CTCAE and PRO instruments and agreement between CTCAE and PRO. The study also investigated single-nucleotide polymorphisms (SNPs) associated with treatment-induced neurotoxicity. RESULTS: 83 patients were enrolled: 45 into the HR+/HER2- cohort and 38 into the TNBC cohort. The ORR was 35.6% (90% CI 24-39%) in the HR+/HER2- cohort and 13.2% (90% CI 5-26%) in the TNBC cohort. Stable disease as the best response was recorded in 55.1% of patients with HR+/HER2- disease and 60.5% with TNBC. Toxicity analysis revealed a discordance between CTCAE and PRO assessment in many patients, with a focus on fatigue, alopecia, and neuropathy. Pharmacogenomic analysis identified SNPs associated with treatment-induced peripheral neuropathy. CONCLUSIONS: Eribulin is active in HER2- breast cancer. This study reveals that provider-assessed AEs can vary greatly from patient experiences. Future studies should incorporate CTCAE and PRO instruments to improve reporting of treatment-related AEs. ClinicalTrials.gov Registration: NCT01827787.

A phase II study of efficacy, toxicity, and the potential impact of genomic alterations on response to eribulin mesylate in combination with trastuzumab and pertuzumab in women with human epidermal growth factor receptor 2 (HER2)+ metastatic breast cancer.

PURPOSE: There are limited data on trastuzumab-pertuzumab (HP)-based treatments beyond the first-line, HER2+ metastatic breast cancer (MBC) setting. We conducted a phase II study of eribulin mesylate, which extends survival in MBC, with HP in patients with previously treated HER2+ MBC to evaluate efficacy, toxicity, and genomic alterations driving therapeutic response. METHODS: After a run-in phase for eribulin dosing, two cohorts were enrolled (Cohort A-no prior pertuzumab; Cohort B-prior pertuzumab). All patients received eribulin 1.4 mg/m2 on days 1, 8 with standard-dose HP on day 1 (21-day cycles). The primary endpoint was objective response rate (ORR). Genomic characterization via whole exome sequencing (WES) was completed on tumor DNA and matched germline DNA from 19 patients. RESULTS: The six-patient run-in established a dose of eribulin 1.4 mg/m2 with HP. Cohorts A and B enrolled 17 and 7 patients, respectively. Accrual stopped early due to an evolving treatment landscape and slow enrollment. The ORR was 26.3% (95% Confidence Interval [CI] 9.2-51.2%) in Cohort A and 0% in Cohort B (95% CI 0-41.0%). WES revealed more frequent alterations in TP53 (p < 0.05, q > 0.05) in patients without clinical benefit (disease control for < 24 weeks) which was not significant after multiple hypothesis correction. CONCLUSION: Eribulin-HP had manageable toxicity and modest clinical activity in patients without prior pertuzumab exposure. This study provides a preliminary landscape of somatic alterations in this patient cohort. Our data add to the literature on how genomic alterations may predict for therapy response/resistance, as we work to individualize choices in a quickly evolving HER2+ MBC treatment landscape. TRIAL REGISTRATION: www.clinicaltrials.gov , NCT01912963. Registered 24 July 2013.