The population-level effects of omitting chemotherapy guided by a 21-gene expression assay in node-positive breast cancer: a simulation modeling study.

BACKGROUND: A recent trial showed that postmenopausal women diagnosed with hormone receptor-positive, human epidermal growth factor receptor-2 (HER2)-negative, lymph node-positive (1-3 nodes) breast cancer with a 21-gene recurrence score of ≤ 25 could safely omit chemotherapy. However, there are limited data on population-level long-term outcomes associated with omitting chemotherapy among diverse women seen in real-world practice. METHODS: We adapted an established, validated simulation model to generate the joint distributions of population-level characteristics of women diagnosed with early-stage breast cancer in the U.S. Input parameters were derived from cancer registry, meta-analyses, and clinical trial data. The effects of omitting chemotherapy on 10-year distant recurrence-free survival, life-years, and quality adjusted life-years (QALYs) were modeled for premenopausal and postmenopausal women. QALYs were discounted at 3%. Results were evaluated for subgroups stratified by race and ethnicity. Sensitivity analyses included testing results across a range of inputs. The model was validated using the published RxPONDER trial data. RESULTS: In premenopausal women, the 10-year distant recurrence-free survival rates were 85.3% with chemo-endocrine and 80.1% with endocrine therapy. The estimated life-years and QALYs gained with chemotherapy in premenopausal women were 2.1 and 0.6, respectively. There was no chemotherapy benefit in postmenopausal women. There was no variation in the absolute benefit of chemotherapy across racial or ethnic subgroups. However, there were differences in distant recurrence-free survival rates, life-years, and QALYs across groups. Sensitivity analysis showed similar results. The model closely replicated the RxPONDER trial. CONCLUSIONS: Modeled population-level outcomes show a small chemotherapy benefit in premenopausal women, but no benefit among postmenopausal women. Simulation modeling provides a useful tool to extend trial data and evaluate population-level outcomes.

Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer-Cyclin-Dependent Kinase 4 and 6 Inhibitors: ASCO Guideline Rapid Recommendation Update.

ASCO Rapid Recommendation Updates highlight revisions to select ASCO guideline recommendations as a response to the emergence of new and practice-changing data. The rapid updates are supported by an evidence review and follow the guideline development processes outlined in the ASCO Guideline Methodology Manual. The goal of these articles is to disseminate updated recommendations, in a timely manner, to better inform health practitioners and the public on the best available cancer care options. Guidelines and updates are not intended to substitute for independent professional judgment of the treating provider and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix 1 and Appendix 2, online only).

Collaborative Modeling to Compare Different Breast Cancer Screening Strategies: A Decision Analysis for the US Preventive Services Task Force.

Importance: The effects of breast cancer incidence changes and advances in screening and treatment on outcomes of different screening strategies are not well known. Objective: To estimate outcomes of various mammography screening strategies. Design, Setting, and Population: Comparison of outcomes using 6 Cancer Intervention and Surveillance Modeling Network (CISNET) models and national data on breast cancer incidence, mammography performance, treatment effects, and other-cause mortality in US women without previous cancer diagnoses. Exposures: Thirty-six screening strategies with varying start ages (40, 45, 50 years) and stop ages (74, 79 years) with digital mammography or digital breast tomosynthesis (DBT) annually, biennially, or a combination of intervals. Strategies were evaluated for all women and for Black women, assuming 100% screening adherence and "real-world" treatment. Main Outcomes and Measures: Estimated lifetime benefits (breast cancer deaths averted, percent reduction in breast cancer mortality, life-years gained), harms (false-positive recalls, benign biopsies, overdiagnosis), and number of mammograms per 1000 women. Results: Biennial screening with DBT starting at age 40, 45, or 50 years until age 74 years averted a median of 8.2, 7.5, or 6.7 breast cancer deaths per 1000 women screened, respectively, vs no screening. Biennial DBT screening at age 40 to 74 years (vs no screening) was associated with a 30.0% breast cancer mortality reduction, 1376 false-positive recalls, and 14 overdiagnosed cases per 1000 women screened. Digital mammography screening benefits were similar to those for DBT but had more false-positive recalls. Annual screening increased benefits but resulted in more false-positive recalls and overdiagnosed cases. Benefit-to-harm ratios of continuing screening until age 79 years were similar or superior to stopping at age 74. In all strategies, women with higher-than-average breast cancer risk, higher breast density, and lower comorbidity level experienced greater screening benefits than other groups. Annual screening of Black women from age 40 to 49 years with biennial screening thereafter reduced breast cancer mortality disparities while maintaining similar benefit-to-harm trade-offs as for all women. Conclusions: This modeling analysis suggests that biennial mammography screening starting at age 40 years reduces breast cancer mortality and increases life-years gained per mammogram. More intensive screening for women with greater risk of breast cancer diagnosis or death can maintain similar benefit-to-harm trade-offs and reduce mortality disparities.

Analysis of Breast Cancer Mortality in the US-1975 to 2019.

Importance: Breast cancer mortality in the US declined between 1975 and 2019. The association of changes in metastatic breast cancer treatment with improved breast cancer mortality is unclear. Objective: To simulate the relative associations of breast cancer screening, treatment of stage I to III breast cancer, and treatment of metastatic breast cancer with improved breast cancer mortality. Design, Setting, and Participants: Using aggregated observational and clinical trial data on the dissemination and effects of screening and treatment, 4 Cancer Intervention and Surveillance Modeling Network (CISNET) models simulated US breast cancer mortality rates. Death due to breast cancer, overall and by estrogen receptor and ERBB2 (formerly HER2) status, among women aged 30 to 79 years in the US from 1975 to 2019 was simulated. Exposures: Screening mammography, treatment of stage I to III breast cancer, and treatment of metastatic breast cancer. Main Outcomes and Measures: Model-estimated age-adjusted breast cancer mortality rate associated with screening, stage I to III treatment, and metastatic treatment relative to the absence of these exposures was assessed, as was model-estimated median survival after breast cancer metastatic recurrence. Results: The breast cancer mortality rate in the US (age adjusted) was 48/100 000 women in 1975 and 27/100 000 women in 2019. In 2019, the combination of screening, stage I to III treatment, and metastatic treatment was associated with a 58% reduction (model range, 55%-61%) in breast cancer mortality. Of this reduction, 29% (model range, 19%-33%) was associated with treatment of metastatic breast cancer, 47% (model range, 35%-60%) with treatment of stage I to III breast cancer, and 25% (model range, 21%-33%) with mammography screening. Based on simulations, the greatest change in survival after metastatic recurrence occurred between 2000 and 2019, from 1.9 years (model range, 1.0-2.7 years) to 3.2 years (model range, 2.0-4.9 years). Median survival for estrogen receptor (ER)-positive/ERBB2-positive breast cancer improved by 2.5 years (model range, 2.0-3.4 years), whereas median survival for ER-/ERBB2- breast cancer improved by 0.5 years (model range, 0.3-0.8 years). Conclusions and Relevance: According to 4 simulation models, breast cancer screening and treatment in 2019 were associated with a 58% reduction in US breast cancer mortality compared with interventions in 1975. Simulations suggested that treatment for stage I to III breast cancer was associated with approximately 47% of the mortality reduction, whereas treatment for metastatic breast cancer was associated with 29% of the reduction and screening with 25% of the reduction.

Chemotherapy Regimens Received by Women With BRCA1/2 Pathogenic Variants for Early Stage Breast Cancer Treatment.

BACKGROUND: Genetic testing is widespread among breast cancer patients; however, no guideline recommends using germline genetic testing results to select a chemotherapy regimen. It is unknown whether breast cancer patients who carry pathogenic variants (PVs) in BRCA1 and/or 2 (BRCA1/2) or other cancer-associated genes receive different chemotherapy regimens than noncarriers. METHODS: We linked Surveillance, Epidemiology, and End Results registry records from Georgia and California to germline genetic testing results from 4 clinical laboratories. Patients who 1) had stages I-III breast cancer, either hormone receptor (HR) positive and HER2 negative or triple negative (TNBC), diagnosed in 2013-2017; 2) received chemotherapy; and 3) were linked to genetic results were included. Chemotherapy details were extracted from Surveillance, Epidemiology, and End Results text fields completed by registrars. We examined whether PV carriers received more intensive regimens (HR-positive,HER2-negative: ≥3 drugs including an anthracycline; TNBC: ≥4 drugs including an anthracycline and platinum) and/or less standard breast cancer agents (a platinum). All statistical tests were 2-sided. RESULTS: Among 2293 patients, 1451 had HR-positive, HER2-negative disease, and 842 had TNBC. On multivariable analysis of women with HR-positive, HER2-negative disease, receipt of a more intensive chemotherapy regimen varied statistically significantly by genetic results (P = .02), with platinum receipt more common among BRCA1/2 PV carriers (odds ratio = 2.44, 95% confidence interval = 1.36 to 4.38; P < .001). Among women with TNBC, chemotherapy agents did not vary significantly by genetic results. CONCLUSION: BRCA1/2 PV carriers with HR-positive, HER2-negative breast cancer had twofold higher odds than noncarriers of receiving a platinum, as part of a more intensive chemotherapy regimen. This likely represents overtreatment and emphasizes the need to monitor how genetic testing results are managed in oncology practice.

Genetic and immunohistochemical profiling of small cell and large cell neuroendocrine carcinomas of the breast.

Neuroendocrine carcinomas (NEC) of the breast are exceedingly rare tumors, which are classified in the WHO system as small cell (SCNEC) and large cell (LCNEC) carcinoma based on indistinguishable features from their lung counterparts. In contrast to lung and enteropancreatic NEC, the genomics of breast NEC have not been well-characterized. In this study, we examined the clinicopathologic, immunohistochemical, and genetic features of 13 breast NEC (7 SCNEC, 4 LCNEC, 2 NEC with ambiguous small versus large cell morphology [ANEC]). Co-alterations of TP53 and RB1 were identified in 86% (6/7) SCNEC, 100% (2/2) ANEC, and 50% (2/4) LCNEC. The one SCNEC without TP53/RB1 alteration had other p53 pathway aberrations (MDM2 and MDM4 amplification) and was immunohistochemically RB negative. PIK3CA/PTEN pathway alterations and ZNF703 amplifications were each identified in 46% (6/13) NEC. Two tumors (1 SCNEC, 1 LCNEC) were CDH1 mutated. By immunohistochemistry, 100% SCNEC (6/6) and ANEC (2/2) and 50% (2/4) LCNEC (83% NEC) showed RB loss, compared to 0% (0/8) grade 3 neuroendocrine tumors (NET) (p < 0.001) and 38% (36/95) grade 3 invasive ductal carcinomas of no special type (IDC-NST) (p = 0.004). NEC were also more often p53 aberrant (60% vs 0%, p = 0.013), ER negative (69% vs 0%, p = 0.005), and GATA3 negative (67% vs 0%, p = 0.013) than grade 3 NET. Two mixed NEC had IDC-NST components, and 69% (9/13) of tumors were associated with carcinoma in situ (6 neuroendocrine DCIS, 2 non-neuroendocrine DCIS, 1 non-neuroendocrine LCIS). NEC and IDC-NST components of mixed tumors were clonally related and immunophenotypically distinct, lacking ER and GATA3 expression in NEC relative to IDC-NST, with RB loss only in NEC of one ANEC. The findings provide insight into the pathogenesis of breast NEC, underscore their classification as a distinct tumor type, and highlight genetic similarities to extramammary NEC, including highly prevalent p53/RB pathway aberrations in SCNEC.

Patient perspectives on window of opportunity clinical trials in early-stage breast cancer.

PURPOSE: Window of opportunity trials (WOT) are increasingly common in oncology research. In WOT participants receive a drug between diagnosis and anti-cancer treatment, usually for the purpose of investigating that drugs effect on cancer biology. This qualitative study aimed to understand patient perspectives on WOT. METHODS: We recruited adults diagnosed with early-stage breast cancer awaiting definitive therapy at a single-academic medical center to participate in semi-structured interviews. Thematic and content analyses were performed to identify attitudes and factors that would influence decisions about WOT participation. RESULTS: We interviewed 25 women diagnosed with early-stage breast cancer. The most common positive attitudes toward trial participation were a desire to contribute to research and a hope for personal benefit, while the most common concerns were the potential for side effects and how they might impact fitness for planned treatment. Participants indicated family would be an important normative factor in decision-making and, during the COVID-19 pandemic, deemed the absence of family members during clinic visits a barrier to enrollment. Factors that could hinder participation included delay in standard treatment and the requirement for additional visits or procedures. Ultimately, most interviewees stated they would participate in a WOT if offered (N = 17/25). CONCLUSION: In this qualitative study, interviewees weighed altruism and hypothetical personal benefit against the possibility of side effect from a WOT. In-person family presence during trial discussion, challenging during COVID-19, was important for many. Our results may inform trial design and communication approaches in future window of opportunity efforts.

Breast cancer diagnosis and treatment during the COVID-19 pandemic in a nationwide, insured population.

PURPOSE: The early months of the COVID-19 pandemic led to reduced cancer screenings and delayed cancer surgeries. We used insurance claims data to understand how breast cancer incidence and treatment after diagnosis changed nationwide over the course of the pandemic. METHODS: Using the Optum Research Database from January 2017 to March 2021, including approximately 19 million US adults with commercial health insurance, we identified new breast cancer diagnoses and first treatment after diagnosis. We compared breast cancer incidence and proportion of newly diagnosed patients receiving pre-operative systemic therapy pre-COVID, in the first 2 months of the COVID pandemic and in the later part of the COVID pandemic. RESULTS: Average monthly breast cancer incidence was 19.3 (95% CI 19.1-19.5) cases per 100,000 women and men pre-COVID, 11.6 (95% CI 10.8-12.4) per 100,000 in April-May 2020, and 19.7 (95% CI 19.3-20.1) per 100,000 in June 2020-February 2021. Use of pre-operative systemic therapy was 12.0% (11.7-12.4) pre-COVID, 37.7% (34.9-40.7) for patients diagnosed March-April 2020, and 14.8% (14.0-15.7) for patients diagnosed May 2020-January 2021. The changes in breast cancer incidence across the pandemic did not vary by demographic factors. Use of pre-operative systemic therapy across the pandemic varied by geographic region, but not by area socioeconomic deprivation or race/ethnicity. CONCLUSION: In this US-insured population, the dramatic changes in breast cancer incidence and the use of pre-operative systemic therapy experienced in the first 2 months of the pandemic did not persist, although a modest change in the initial management of breast cancer continued.

Spatial proteomic characterization of HER2-positive breast tumors through neoadjuvant therapy predicts response.

The addition of HER2-targeted agents to neoadjuvant chemotherapy has dramatically improved pathological complete response (pCR) rates in early-stage, HER2-positive breast cancer. Nonetheless, up to 50% of patients have residual disease after treatment, while others are likely overtreated. Here, we performed multiplex spatial proteomic characterization of 122 samples from 57 HER2-positive breast tumors from the neoadjuvant TRIO-US B07 clinical trial sampled pre-treatment, after 14-21 d of HER2-targeted therapy and at surgery. We demonstrated that proteomic changes after a single cycle of HER2-targeted therapy aids the identification of tumors that ultimately undergo pCR, outperforming pre-treatment measures or transcriptomic changes. We further developed and validated a classifier that robustly predicted pCR using a single marker, CD45, measured on treatment, and showed that CD45-positive cell counts measured via conventional immunohistochemistry perform comparably. These results demonstrate robust biomarkers that can be used to enable the stratification of sensitive tumors early during neoadjuvant HER2-targeted therapy, with implications for tailoring subsequent therapy.

Performance of the IBIS/Tyrer-Cuzick model of breast cancer risk by race and ethnicity in the Women's Health Initiative.

BACKGROUND: The IBIS/Tyrer-Cuzick model is used clinically to guide breast cancer screening and prevention, but was developed primarily in non-Hispanic White women. Little is known about its long-term performance in a racially/ethnically diverse population. METHODS: The Women's Health Initiative study enrolled postmenopausal women from 1993-1998. Women were included who were aged <80 years at enrollment with no prior breast cancer or mastectomy and with data required for IBIS/Tyrer-Cuzick calculation (weight; height; ages at menarche, first birth, and menopause; menopausal hormone therapy use; and family history of breast or ovarian cancer). Calibration was assessed by the ratio of observed breast cancer cases to the number expected by the IBIS/Tyrer-Cuzick model (O/E; calculated as the sum of cumulative hazards). Differential discrimination was tested for by self-reported race/ethnicity (non-Hispanic White, non-Hispanic Black, Hispanic, Asian or Pacific Islander, and American Indian or Alaskan Native) using Cox regression. Exploratory analyses, including simulation of a protective single-nucleotide polymorphism (SNP), rs140068132 at 6q25, were performed. RESULTS: During follow-up (median 18.9 years, maximum 23.4 years), 6783 breast cancer cases occurred among 90,967 women. IBIS/Tyrer-Cuzick was well calibrated overall (O/E ratio = 0.95; 95% CI, 0.93-0.97) and in most racial/ethnic groups, but overestimated risk for Hispanic women (O/E ratio = 0.75; 95% CI, 0.62-0.90). Discrimination did not differ by race/ethnicity. Exploratory simulation of the protective SNP suggested improved IBIS/Tyrer-Cuzick calibration for Hispanic women (O/E ratio = 0.80; 95% CI, 0.66-0.96). CONCLUSIONS: The IBIS/Tyrer-Cuzick model is well calibrated for several racial/ethnic groups over 2 decades of follow-up. Studies that incorporate genetic and other risk factors, particularly among Hispanic women, are essential to improve breast cancer-risk prediction.

Treatment and Monitoring Variability in US Metastatic Breast Cancer Care.

PURPOSE: Treatment and monitoring options for patients with metastatic breast cancer (MBC) are increasing, but little is known about variability in care. We sought to improve understanding of MBC care and its correlates by analyzing real-world claims data using a search engine with a novel query language to enable temporal electronic phenotyping. METHODS: Using the Advanced Cohort Engine, we identified 6,180 women who met criteria for having estrogen receptor-positive, human epidermal growth factor receptor 2-negative MBC from IBM MarketScan US insurance claims (2007-2014). We characterized treatment, monitoring, and hospice usage, along with clinical and nonclinical factors affecting care. RESULTS: We observed wide variability in treatment modality and monitoring across patients and geography. Most women received first-recorded therapy with endocrine (67%) versus chemotherapy, underwent more computed tomography (CT) (76%) than positron emission tomography-CT, and were monitored using tumor markers (58%). Nearly half (46%) met criteria for aggressive disease, which were associated with receiving chemotherapy first, monitoring primarily with CT, and more frequent imaging. Older age was associated with endocrine therapy first, less frequent imaging, and less use of tumor markers. After controlling for clinical factors, care strategies varied significantly by nonclinical factors (median regional income with first-recorded therapy and imaging type, geographic region with these and with imaging frequency and use of tumor markers; P < .0001). CONCLUSION: Variability in US MBC care is explained by patient and disease factors and by nonclinical factors such as geographic region, suggesting that treatment decisions are influenced by local practice patterns and/or resources. A search engine designed to express complex electronic phenotypes from longitudinal patient records enables the identification of variability in patient care, helping to define disparities and areas for improvement.

Pathologic and molecular responses to neoadjuvant trastuzumab and/or lapatinib from a phase II randomized trial in HER2-positive breast cancer (TRIO-US B07).

In this multicenter, open-label, randomized phase II investigator-sponsored neoadjuvant trial with funding provided by Sanofi and GlaxoSmithKline (TRIO-US B07, Clinical Trials NCT00769470), participants with early-stage HER2-positive breast cancer (N = 128) were recruited from 13 United States oncology centers throughout the Translational Research in Oncology network. Participants were randomized to receive trastuzumab (T; N = 34), lapatinib (L; N = 36), or both (TL; N = 58) as HER2-targeted therapy, with each participant given one cycle of this designated anti-HER2 therapy alone followed by six cycles of standard combination chemotherapy with the same anti-HER2 therapy. The primary objective was to estimate the rate of pathologic complete response (pCR) at the time of surgery in each of the three arms. In the intent-to-treat population, we observed similar pCR rates between T (47%, 95% confidence interval [CI] 30-65%) and TL (52%, 95% CI 38-65%), and a lower pCR rate with L (25%, 95% CI 13-43%). In the T arm, 100% of participants completed all protocol-specified treatment prior to surgery, as compared to 69% in the L arm and 74% in the TL arm. Tumor or tumor bed tissue was collected whenever possible pre-treatment (N = 110), after one cycle of HER2-targeted therapy alone (N = 89), and at time of surgery (N = 59). Higher-level amplification of HER2 and hormone receptor (HR)-negative status were associated with a higher pCR rate. Large shifts in the tumor, immune, and stromal gene expression occurred after one cycle of HER2-targeted therapy. In contrast to pCR rates, the L-containing arms exhibited greater proliferation reduction than T at this timepoint. Immune expression signatures increased in all arms after one cycle of HER2-targeted therapy, decreasing again by the time of surgery. Our results inform approaches to early assessment of sensitivity to anti-HER2 therapy and shed light on the role of the immune microenvironment in response to HER2-targeted agents.

Chromatin regulators mediate anthracycline sensitivity in breast cancer.

Anthracyclines are a highly effective component of curative breast cancer chemotherapy but are associated with substantial morbidity1,2. Because anthracyclines work in part by inhibiting topoisomerase-II (TOP2) on accessible DNA3,4, we hypothesized that chromatin regulatory genes (CRGs) that mediate DNA accessibility might predict anthracycline response. We studied the role of CRGs in anthracycline sensitivity in breast cancer through integrative analysis of patient and cell line data. We identified a consensus set of 38 CRGs associated with anthracycline response across ten cell line datasets. By evaluating the interaction between expression and treatment in predicting survival in a metacohort of 1006 patients with early-stage breast cancer, we identified 54 CRGs whose expression levels dictate anthracycline benefit across the clinical subgroups; of these CRGs, 12 overlapped with those identified in vitro. CRGs that promote DNA accessibility, including Trithorax complex members, were associated with anthracycline sensitivity when highly expressed, whereas CRGs that reduce accessibility, such as Polycomb complex proteins, were associated with decreased anthracycline sensitivity. We show that KDM4B modulates TOP2 accessibility to chromatin, elucidating a mechanism of TOP2 inhibitor sensitivity. These findings indicate that CRGs mediate anthracycline benefit by altering DNA accessibility, with implications for the stratification of patients with breast cancer and treatment decision making.

Publisher Correction: Clonal replacement and heterogeneity in breast tumors treated with neoadjuvant HER2-targeted therapy.

The original version of this Article omitted from the Author Contributions statement that 'R.S. and J.G.R contributed equally to this work.' This has been corrected in both the PDF and HTML versions of the Article.