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Purpose: Patients with HER2-positive breast cancer brain metastases have few effective systemic therapy options. In a prior study, pertuzumab with high-dose trastuzumab demonstrated a high clinical benefit rate (CBR) in the central nervous system (CNS) in patients with brain metastases. The current trial evaluated whether the addition of atezolizumab to this regimen would produce further improvements in CNS response., Patients and Methods: This was a single-arm, multi-center, phase II trial of atezolizumab, pertuzumab, and high-dose trastuzumab for patients with HER2-positive breast cancer brain metastases. Participants received atezolizumab 1200 mg IV every 3 weeks (q3w), pertuzumab (loading dose 840 mg IV, then 420 mg IV q3w), and high-dose trastuzumab (6 mg/kg IV weekly for 24 weeks, then 6 mg/kg IV q3w). The primary endpoint was CNS overall response rate (ORR) per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Key secondary endpoints included CBR, overall survival (OS), and safety and tolerability of the combination., Results: Among 19 enrolled participants, two had a confirmed intracranial partial response for a CNS-ORR of 10.5% (90% CI: 1.9%-29.6%). The study did not meet the prespecified efficacy threshold and was terminated early. The CBR was 42.1% at 18 weeks and 31.6% at 24 weeks. Seven patients (36.8%) required a dose delay or hold, and the most frequent any-grade adverse events were diarrhea (26.3%) and fatigue (26.3%)., Conclusions: The addition of atezolizumab to pertuzumab plus high-dose trastuzumab does not result in improved CNS responses in patients with HER2-positive breast cancer brain metastases.

Association of stromal tumor-infiltrating lymphocytes (sTILs) with survival outcomes among patients with metastatic breast cancer (MBC) remains unclear. The primary objective was to evaluate the association of sTILs with progression-free survival in randomized phase III trial CALGB 40502. sTILs were associated with progression-free and overall survival in chemotherapy-treated MBC when controlling for treatment arm; however, this effect did not remain significant after additional adjustment for hormone receptor status. CALGB is now part of the Alliance for Clinical Trials in Oncology. Trial Registration: ClinicalTrials.gov: NCT00785291., (© 2024. The Author(s).)

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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is) are an important component of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), but it is not known if patients might derive benefit from continuation of CDK4/6i with endocrine therapy beyond initial tumor progression or if the addition of checkpoint inhibitor therapy has value in this setting., Methods: The randomized multicenter phase II PACE trial enrolled patients with hormone receptor-positive/HER2- MBC whose disease had progressed on previous CDK4/6i and aromatase inhibitor (AI) therapy. Patients were randomly assigned 1:2:1 to receive fulvestrant (F), fulvestrant plus palbociclib (F + P), or fulvestrant plus palbociclib and avelumab (F + P + A). The primary end point was investigator-assessed progression-free survival (PFS) in patients treated with F versus F + P., Results: Overall, 220 patients were randomly assigned between September 2017 and February 2022. The median age was 57 years (range, 25-83 years). Most patients were postmenopausal (80.9%), and 40% were originally diagnosed with de novo MBC. Palbociclib was the most common previous CDK4/6i (90.9%). The median PFS was 4.8 months on F and 4.6 months on F + P (hazard ratio [HR], 1.11 [90% CI, 0.79 to 1.55]; P = .62). The median PFS on F + P + A was 8.1 months (HR v F, 0.75 [90% CI, 0.50 to 1.12]; P = .23). The difference in PFS with F + P and F + P + A versus F was greater among patients with baseline ESR1 and PIK3CA alterations., Conclusion: The addition of palbociclib to fulvestrant did not improve PFS versus fulvestrant alone among patients with hormone receptor-positive/HER2- MBC whose disease had progressed on a previous CDK4/6i plus AI. The increased PFS seen with the addition of avelumab warrants further investigation in this patient population.

Background: N-terminal pro-brain natriuretic peptide (NT-proBNP) is a cardiac biomarker associated with the risk of heart failure and death in the general population, but it has not been explored in cancer survivors., Methods: Using a US nationally representative sample of adults 20 years of age and older from the National Health and Nutrition Examination Survey from 1999 to 2004, this study compared NT-proBNP levels between adults without cancer (n = 12 574) and adult cancer survivors (n = 787). It examined the association of NT-proBNP with all-cause and cause-specific mortality among cancer survivors., Results: Cancer survivors had higher NT-proBNP levels than adults without cancer (median [interquartile range] = 125.4 pg/mL [52.4-286.0] vs 43.2 pg/mL [20.3-95.0]). In particular, survivors of breast, prostate, and colorectal cancers had higher NT-proBNP levels than adults without cancer (multivariable-adjusted P < .05). In total, 471 survivors died (141 from cancer; 95 from cardiac disease) during a median follow-up period of 13.4 years (9393 person-years). Among cancer survivors, higher NT-proBNP levels were statistically associated with increased risks of all-cause death (hazard ratio [HR] = 1.31, 95% confidence interval [CI] = 1.18 to 1.46) and cardiac death (HR = 1.55, 95% CI = 1.21 to 2.00) but not with death from cancer (HR = 1.10, 95% CI = 0.92 to 1.32]). Higher NT-proBNP levels were associated with elevated overall mortality in survivors of prostate cancer (HR = 1.49, 95% CI = 1.22 to 1.81) and colorectal cancer (HR = 1.78, 95% CI = 1.00 to 3.16) (P = .169 for interaction). Nonlinear dose-response relationships were observed between NT-proBNP and mortality, with statistically significant relationships emerging above 125 pg/mL., Conclusions: Cancer survivors had higher NT-proBNP levels than adults without cancer, and elevated NT-proBNP levels were associated with higher risks of all-cause and cardiac mortality in cancer survivors., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Patient-reported outcomes (PROs) are a better tool for evaluating the experiences of patients who have symptomatic, treatment-associated adverse events (AEs) compared with clinician-rated AEs. The authors present PROs assessing health-related quality of life (HRQoL) and treatment-related neurotoxicity for adjuvant capecitabine versus platinum on the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) EA1131 trial (ClinicalTrials.gov identifier NCT02445391)., Methods: Participants completed the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index (NFBSI-16) and the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group neurotoxicity subscale (platinum arm only) at baseline, cycle 3 day 1 (C3D1), 6 months, and 15 months. Because of early termination, power was insufficient to test the hypothesis that HRQoL, as assessed by the NFBSI-16 treatment side-effect (TSE) subscale, would be better at 6 and 15 months in the capecitabine arm; all analyses were exploratory. Means were compared by using t-tests or the Wilcoxon rank-sum test, and proportions were compared by using the χ 2 test., Results: Two hundred ninety-six of 330 eligible patients provided PROs. The mean NFBSI-16 TSE subscale score was lower for the platinum arm at baseline (p = .02; absolute difference, 0.6 points) and for the capecitabine arm at C3D1 (p = .04; absolute difference, 0.5 points), but it did not differ at other times. The mean change in TSE subscale scores differed between the arms from baseline to C3D1 (platinum arm, 0.15; capecitabine arm, -0.72; p = .03), but not from baseline to later time points. The mean decline in Functional Assessment of Cancer Therapy-Gynecologic Oncology Group neurotoxicity subscale scores exceeded the minimal meaningful change (1.38 points) from baseline to each subsequent time point (all p < .05)., Conclusions: Despite the similar frequency of clinician-rated AEs, PROs identified greater on-treatment symptom burden with capecitabine and complemented clinician-rated AEs by characterizing patients' experiences during chemotherapy., (© 2024 American Cancer Society.)

Background: Overall survival (OS) is a universally accepted measure of clinical benefit; however, prolonged follow-up is needed to observe sufficient events. Disease-free survival (DFS) has been widely adopted as a primary endpoint for early breast cancer (EBC) trials, as follow-up is comparatively shorter. Here, we present an analysis evaluating DFS as a surrogate for OS for adjuvant treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) EBC., Methods: A systematic literature review which included randomized controlled trials (RCTs) with ≥80% of adult patients with HR+/HER2- EBC was conducted. The RCTs evaluated various systemic therapeutic categories; key inclusion criteria included reporting of DFS and OS hazard ratios (HRs) and mature OS data. Spearman rank correlation and weighted linear regression analyses evaluated DFS and OS HR correlation. A scenario analysis tested base-case analysis robustness, and a parallel analysis using patient-level data was conducted., Results: The base case (N = 14 RCTs) showed an unweighted Spearman coefficient of 0.81 between OS and DFS (weighted: 0.81), with 84% of the variability in OS explained by DFS differences (R 2 from weighted regression). The surrogate threshold effect (Burzykowski T, Buyse M. Pharm Stat. 2006;5:173-186) was 0.82 for DFS/OS HR. Scenario analysis (n = 9 RCTs), which excluded chemotherapy trials, and patient-level analysis using FACE trial data were consistent with the base-case analysis., Conclusions: These analyses support DFS as a reliable surrogate endpoint for OS in adjuvant HR+/HER2- EBC trials. Using DFS as a surrogate measure will permit timelier access to novel treatments for patients with HR+/HER2- EBC., Competing Interests: Declaration of Competing Interest Representatives of the sponsor were responsible for trial design, data compilation, and confirming the accuracy of the analyses. All authors had access to the data and vouch for the completeness and accuracy of the data as well as the fidelity of the trial to the protocol. All authors participated in the writing and review of all manuscript drafts and contributed to the interpretation of the data. Medical writing support and editorial support were paid for by Novartis., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The addition of taxanes to anthracycline-based chemotherapy is considered standard of care in the treatment of breast cancer. However, there are insufficient data regarding the safety of taxanes during pregnancy. The aim of this study was to describe the incidence of obstetric and neonatal adverse events associated with the use of taxane-containing chemotherapy regimens for the treatment of breast cancer during pregnancy., Methods: This is a multicenter, international cohort study of breast cancer patients treated with taxanes during pregnancy. A descriptive analysis was undertaken to synthetize available data., Results: A total of 103 patients were included, most of whom were treated with paclitaxel and anthracyclines given in sequence during gestation (90.1%). The median gestational age at taxane initiation was 28 weeks (range = 12-37 weeks). Grade 3-4 adverse events were reported in 7 of 103 (6.8%) patients. The most common reported obstetric complications were intrauterine growth restriction (n = 8 of 94, 8.5%) and preterm premature rupture of membranes (n = 5 of 94, 5.3%). The live birth rate was 92 of 94 (97.9%), and the median gestational age at delivery was 37 weeks (range = 32-40 weeks). Admission to an intensive care unit was reported in 14 of 88 (15.9%) neonates, and 17 of 70 (24.3%) live births resulted in small for gestational age neonates. Congenital malformations were reported in 2 of 93 (2.2%)., Conclusion: Obstetric and neonatal outcomes after taxane exposure during pregnancy were generally favorable and did not seem to differ from those reported in the literature with standard anthracycline-based regimens. This study supports the use of taxanes during gestation when clinically indicated., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Metronomic chemotherapy has the potential to offer tumor control with reduced toxicity when compared to standard dose chemotherapy in patients with metastatic breast cancer. As metronomic chemotherapy may target the tumor microvasculature, it has the potential for synergistic effects with antiangiogenic agents such as the VEGF-A inhibitor bevacizumab., Methods: In this randomized phase II study, patients with metastatic breast cancer were randomized to receive metronomic oral cyclophosphamide and methotrexate (CM) combined with bevacizumab (Arm A) or CM alone (Arm B). The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety and tolerability., Results: A total of 55 patients were enrolled, with 34 patients treated on Arm A and 21 patients treated on Arm B. The ORR was modestly higher in Arm A (26%) than in Arm B (10%); neither met the 40% cutoff for further clinical evaluation. The median time to progression (TTP) was 5.52 months (3.22-13.6) on Arm A and 1.82 months (1.54-6.70) on Arm B (log-rank p = 0.008). The median OS was 29.6 months (17.2-NA) on Arm A and 16.2 months (15.7-NA) on Arm B (log-rank p = 0.7). Common all-grade adverse events in both arms included nausea, fatigue, and elevated AST., Conclusion: The combination of metronomic CM with bevacizumab significantly improved PFS over CM alone, although there was no significant difference in OS. Oral metronomic chemotherapy alone has limited activity in advanced breast cancer., Clinicaltrials: gov Identifier: NCT00083031. Date of Registration: May 17, 2004., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2023. Society of Surgical Oncology.)

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., (© 2023. Society of Surgical Oncology.)

Purpose: BMI affects breast cancer risk and prognosis. In contrast to cytotoxic chemotherapy, CDK4/6 inhibitors are given at a fixed dose, irrespective of BMI or weight. This preplanned analysis of the global randomized PALLAS trial investigates the impact of BMI on the side-effect profile, treatment adherence, and efficacy of palbociclib., Methods: Patients were categorized at baseline according to WHO BMI categories. Neutropenia rates were assessed with univariable and multivariable logistic regression. Time to early discontinuation of palbociclib was analyzed with Fine and Gray competing risk models. Unstratified Cox models were used to investigate the association between BMI category and time to invasive disease-free survival (iDFS). 95% CIs were derived., Results: Of 5,698 patients included in this analysis, 68 (1.2%) were underweight, 2,082 (36.5%) normal weight, 1,818 (31.9%) overweight, and 1,730 (30.4%) obese at baseline. In the palbociclib arm, higher BMI was associated with a significant decrease in neutropenia (unadjusted odds ratio for 1-unit change, 0.93; 95% CI, 0.91 to 0.94; adjusted for age, race ethnicity, region, chemotherapy use, and Eastern Cooperative Oncology Group at baseline, 0.93; 95% CI, 0.92 to 0.95). This translated into a significant decrease in treatment discontinuation rate with higher BMI (adjusted hazard ratio [HR] for 10-unit change, 0.75; 95% CI, 0.67 to 0.83). There was no significant improvement in iDFS with the addition of palbociclib to ET in any weight category (normal weight HR, 0.84; 95% CI, 0.63 to 1.12; overweight HR, 1.10; 95% CI, 0.82 to 1.49; and obese HR, 0.95; 95% CI, 0.69 to 1.30) in this analysis early in follow-up (31 months)., Conclusion: This preplanned analysis of the PALLAS trial demonstrates a significant impact of BMI on side effects, dose reductions, early treatment discontinuation, and relative dose intensity. Additional long-term follow-up will further evaluate whether BMI ultimately affects outcome.

Purpose: A 3-biomarker homologous recombination deficiency (HRD) score is a key component of a currently FDA-approved companion diagnostic assay to identify HRD in patients with ovarian cancer using a threshold score of ≥ 42, though recent studies have explored the utility of a lower threshold (GIS ≥ 33). The present study evaluated whether the ovarian cancer thresholds may also be appropriate for major breast cancer subtypes by comparing the genomic instability score (GIS) distributions of BRCA1/2-deficient estrogen receptor-positive breast cancer (ER + BC) and triple-negative breast cancer (TNBC) to the GIS distribution of BRCA1/2-deficient ovarian cancer., Methods: Ovarian cancer and breast cancer (ER + BC and TNBC) tumors from ten study cohorts were sequenced to identify pathogenic BRCA1/2 mutations, and GIS was calculated using a previously described algorithm. Pathologic complete response (pCR) to platinum therapy was evaluated in a subset of TNBC samples. For TNBC, a threshold was set and threshold validity was assessed relative to clinical outcomes., Results: A total of 560 ovarian cancer, 805 ER + BC, and 443 TNBC tumors were included. Compared to ovarian cancer, the GIS distribution of BRCA1/2-deficient samples was shifted lower for ER + BC (p = 0.015), but not TNBC (p = 0.35). In the subset of TNBC samples, univariable logistic regression models revealed that GIS status using thresholds of ≥ 42 and ≥ 33 were significant predictors of response to platinum therapy., Conclusions: This study demonstrated that the GIS thresholds used for ovarian cancer may also be appropriate for TNBC, but not ER + BC. GIS thresholds in TNBC were validated using clinical response data to platinum therapy., (© 2023. The Author(s).)

Background: The expansion of hematopoietic stem cells carrying recurrent somatic mutations, termed clonal hematopoiesis (CH), is common in elderly individuals and is associated with increased risk of myeloid malignancy and all-cause mortality. Though chemotherapy is a known risk factor for developing CH, how myelosuppressive therapies affect the short-term dynamics of CH remains incompletely understood. Most studies have been limited by retrospective design, heterogeneous patient populations, varied techniques to identifying CH, and analysis of single timepoints., Methods: We examined serial samples from 40 older women with triple-negative or hormone receptor-positive breast cancer treated on the prospective ADjuVANt Chemotherapy in the Elderly trial to evaluate the prevalence and dynamics of CH at baseline and throughout chemotherapy (6 and 12 weeks)., Results: CH was detected in 44% of patients at baseline and in 53% at any timepoint. Baseline patient characteristics were not associated with CH. Over the course of treatment, mutations exhibited a variety of dynamics, including emergence, expansion, contraction, and disappearance. All mutations in TP53 (n = 3) and PPM1D (n = 4), genes that regulate the DNA damage response, either became detectable or expanded over the course of treatment. Neutropenia was more common in patients with CH, particularly when the mutations became detectable during treatment, and CH was significantly associated with cyclophosphamide dose reductions and holds (P = .02)., Conclusions: Our study shows that CH is common, dynamic, and of potential clinical significance in this population. Our results should stimulate larger efforts to understand the biological and clinical importance of CH in solid tumor malignancies., Trial Registration: ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03858322). Clinical trial registration number: NCT03858322., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Importance: Whether racial and ethnic disparities in locoregional recurrence (LRR) exist among patients with similar access to care treated in randomized clinical trials is unknown., Objective: To examine racial and ethnic differences in LRR among patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (ERBB2 [formerly HER2 or HER2/neu])-negative, node-negative breast cancer enrolled in the Trial Assigning Individualized Options for Treatment (TAILORx)., Design, Setting, and Participants: This unplanned retrospective post hoc analysis examined a prospective multicenter clinical trial population of women with breast cancer enrolled between 2006 and 2010, with 9 years of follow-up. The TAILORx investigators randomized patients to treatment based on their Oncotype DX recurrence score, including endocrine therapy alone (recurrence score <11), endocrine therapy alone vs chemotherapy followed by endocrine therapy (recurrence score 11-25), or chemotherapy followed by endocrine therapy (recurrence score >25). Patients with unknown race and ethnicity or lack of follow-up were excluded from this analysis. Data analysis was performed between December 2021 and March 2022., Main Outcome and Measures: Locoregional recurrence was defined as ipsilateral in breast, skin, chest wall, or regional nodal recurrence without concurrent distant recurrence, and was stratified by racial and ethnic group. Unadjusted Kaplan-Meier and adjusted Cox proportional hazards regression models were used for survival analyses., Results: Of the 10 273 women enrolled in TAILORx, this analysis included 9369 with T1-2N0 HR-positive, ERBB2-negative breast cancer. Of these patients, 428 (4.6%) were Asian, 886 (9.4%) were Hispanic, 676 (7.2%) were non-Hispanic Black (hereinafter Black), and 7406 (78.8%) were non-Hispanic White (hereinafter White). Assigned treatment receipt was high, with a 9.3% (n = 870) crossover of treatment groups and a median endocrine therapy duration of longer than 60 months, ranging from 61.1 to 65.9 months, across racial and ethnic groups. A total of 6818 patients (72.6%) received radiation (6474 [96.1%] after breast-conserving surgery and 344 [13.0%] after mastectomy). At a median follow-up of 94.8 months (range, 1-138 months), 8-year LRR rates were 3.6% (95% CI, 1.6%-5.6%) in Asian patients, 3.9% (95% CI, 2.2%-5.4%) in Black patients, 3.1% in Hispanic patients (95% CI, 1.7%-4.5%), and 1.8% (95% CI, 1.5%-2.3%) in White patients (P < .001). In survival analyses adjusted for patient, tumor, and treatment factors, Asian race (hazard ratio, 1.91 [95% CI, 1.12-3.29]) and Black race (1.78 [1.15-2.77]) were independently associated with LRR. In adjusted survival analyses for breast cancer mortality, LRR was independently associated with increased breast cancer mortality (hazard ratio, 5.71 [95% CI, 3.50-9.31])., Conclusions and Relevance: In this post hoc analysis, racial and ethnic differences in LRR were observed among patients with T1-2N0 HR-positive, ERBB2-negative breast cancer despite high rates of treatment receipt in this clinical trial population, with the highest LRR rates in Asian and Black patients. Further study is needed to understand whether failure to rescue after LRR may contribute to racial disparities in breast cancer mortality., Trial Registration: ClinicalTrials.gov Identifier: NCT00310180.

Opinion Statement: For high-risk early-stage hormone-receptor-positive, HER2-negative breast cancer (HR + /HER2 - EBC), short- and long-term recurrence risks remain substantial despite local control with surgery and radiation and systemic treatment with chemotherapy and endocrine therapy (ET). Recent trials have provided new strategies for reducing recurrence. The monarchE trial demonstrated that adding 2 years of adjuvant abemaciclib to ET improves invasive disease-free survival (iDFS) and distant recurrence-free survival (DRFS). In the OlympiA trial for high-risk disease in patients with germline BRCA1/BRCA2 mutations, adding 1 year of olaparib to ET improved iDFS, DRFS, and overall survival (OS). In addition, for premenopausal women with high-risk tumors, long-term follow-up of the SOFT, ASTRRA, TEXT, ABCSG-12, and HOBOE trials supports the role of ovarian function suppression (OFS), in combination with adjuvant tamoxifen or aromatase inhibition (AI). For postmenopausal women with high-risk tumors, extended-duration AI for at least 7 years should be used with zoledronic acid. Given the remaining recurrence risk even with these interventions and with the ongoing development of new strategies for HR + disease, patients with high-risk EBC should be encouraged to participate in clinical trials, such as trials of immunotherapy, novel oral estrogen receptor alpha (ERα)-targeting agents, antibody-drug conjugates (ADCs), and trials guided by measurements of minimal residual disease (MRD)., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: Aurora A kinase (AURKA) activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor (ER) α expression, endocrine resistance, and implicated in cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance. Alisertib, a selective AURKA inhibitor, upregulates ERα and restores endocrine sensitivity in preclinical metastatic breast cancer (MBC) models. The safety and preliminary efficacy of alisertib was demonstrated in early-phase trials; however, its activity in CDK 4/6i-resistant MBC is unknown., Objective: To assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC., Design, Setting, and Participants: This phase 2 randomized clinical trial was conducted through the Translational Breast Cancer Research Consortium, which enrolled participants from July 2017 to November 2019. Postmenopausal women with endocrine-resistant, ERBB2 (formerly HER2)-negative MBC who were previously treated with fulvestrant were eligible. Stratification factors included prior treatment with CDK 4/6i, baseline metastatic tumor ERα level measurement (<10%, ≥10%), and primary or secondary endocrine resistance. Among 114 preregistered patients, 96 (84.2%) registered and 91 (79.8%) were evaluable for the primary end point. Data analysis began after January 10, 2022., Interventions: Alisertib, 50 mg, oral, daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle (arm 1) or alisertib same dose/schedule with standard-dose fulvestrant (arm 2)., Main Outcomes and Measures: Improvement in ORR in arm 2 of at least 20% greater than arm 1 when the expected ORR for arm 1 was 20%., Results: All 91 evaluable patients (mean [SD] age, 58.5 [11.3] years; 1 American Indian/Alaskan Native [1.1%], 2 Asian [2.2%], 6 Black/African American [6.6%], 5 Hispanic [5.5%], and 79 [86.8%] White individuals; arm 1, 46 [50.5%]; arm 2, 45 [49.5%]) had received prior treatment with CDK 4/6i. The ORR was 19.6%; (90% CI, 10.6%-31.7%) for arm 1 and 20.0% (90% CI, 10.9%-32.3%) for arm 2. In arm 1, the 24-week clinical benefit rate and median progression-free survival time were 41.3% (90% CI, 29.0%-54.5%) and 5.6 months (95% CI, 3.9-10.0), respectively, and in arm 2 they were 28.9% (90% CI, 18.0%-42.0%) and 5.4 months (95% CI, 3.9-7.8), respectively. The most common grade 3 or higher adverse events attributed to alisertib were neutropenia (41.8%) and anemia (13.2%). Reasons for discontinuing treatment were disease progression (arm 1, 38 [82.6%]; arm 2, 31 [68.9%]) and toxic effects or refusal (arm 1, 5 [10.9%]; arm 2, 12 [26.7%])., Conclusions and Relevance: This randomized clinical trial found that adding fulvestrant to treatment with alisertib did not increase ORR or PFS; however, promising clinical activity was observed with alisertib monotherapy among patients with endocrine-resistant and CDK 4/6i-resistant MBC. The overall safety profile was tolerable., Trial Registration: ClinicalTrials.gov Identifier: NCT02860000.

Detecting mutations from single DNA molecules is crucial in many fields but challenging. Next-generation sequencing (NGS) affords tremendous throughput but cannot directly sequence double-stranded DNA molecules ('single duplexes') to discern the true mutations on both strands. Here we present Concatenating Original Duplex for Error Correction (CODEC), which confers single duplex resolution to NGS. CODEC affords 1,000-fold higher accuracy than NGS, using up to 100-fold fewer reads than duplex sequencing. CODEC revealed mutation frequencies of 2.72 × 10 -8 in sperm of a 39-year-old individual, and somatic mutations acquired with age in blood cells. CODEC detected genome-wide, clonal hematopoiesis mutations from single DNA molecules, single mutated duplexes from tumor genomes and liquid biopsies, microsatellite instability with 10-fold greater sensitivity and mutational signatures, and specific tumor mutations with up to 100-fold fewer reads. CODEC enables more precise genetic testing and reveals biologically significant mutations, which are commonly obscured by NGS errors., (© 2023. The Author(s).)

ESR1 mutation ( ESR1 m) is a frequent cause of acquired resistance to aromatase inhibitor (AI) plus cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i), which is a first-line therapy for hormone-receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Camizestrant is a next-generation oral selective estrogen receptor degrader (SERD) that in a phase II study significantly improved progression-free survival (PFS) over fulvestrant (also a SERD) in ER+/HER2- ABC. SERENA-6 (NCT04964934) is a randomized, double-blind, phase III study evaluating the efficacy and safety of switching from an AI to camizestrant, while maintaining the same CDK4/6i, upon detection of ESR1 m in circulating tumor DNA before clinical disease progression on first-line therapy for HR+/HER2- ABC. The aim is to treat ESR1 m clones and extend the duration of control of ER-driven tumor growth, delaying the need for chemotherapy. The primary end point is PFS; secondary end points include chemotherapy-free survival, time to second progression event (PFS2), overall survival, patient-reported outcomes and safety.

Introduction: Older adults with breast cancer receiving neo/adjuvant chemotherapy are at high risk for poor outcomes and are underrepresented in clinical trials. The ADVANCE (ADjuVANt Chemotherapy in the Elderly) trial evaluated the feasibility of two neo/adjuvant chemotherapy regimens in parallel-enrolling cohorts of older patients with human epidermal growth factor receptor 2-negative breast cancer: cohort 1-triple-negative; cohort 2-hormone receptor-positive., Materials and Methods: Adults age ≥ 70 years with stage I-III breast cancer warranting neo/adjuvant chemotherapy were enrolled. Cohort 1 received weekly carboplatin (area under the curve 2) and weekly paclitaxel 80 mg/m 2 for twelve weeks; cohort 2 received weekly paclitaxel 80 mg/m 2 plus every-three-weekly cyclophosphamide 600 mg/m 2 over twelve weeks. The primary study endpoint was feasibility, defined as ≥80% of patients receiving ≥80% of intended weeks/doses of therapy. All dose modifications were applied per clinician discretion., Results: Forty women (n = 20 per cohort) were enrolled from March 25, 2019 through August 3, 2020 from three centers; 45% and 35% of patients in cohorts 1 and 2 were age > 75, respectively. Neither cohort achieved targeted thresholds for feasibility. In cohort 1, eight (40.0%) met feasibility (95% confidence interval [CI] = 19.1-63.9%), while ten (50.0%) met feasibility in cohort 2 (95% CI = 27.2-72.8). Neutropenia was the most common grade 3-4 toxicity (cohort 1-65%, cohort 2-55%). In cohort 1, 80% and 85% required ≥1 dose holds of carboplatin and/or paclitaxel, respectively. In cohort 2, 10% required dose hold(s) for cyclophosphamide and/or 65% for paclitaxel., Discussion: In this pragmatic pilot examining chemotherapy regimens in older adults with breast cancer, neither regimen met target goals for feasibility. Developing efficacious and tolerable regimens for older patients with breast cancer who need chemotherapy remains an important goal., Clinicaltrials: gov Identifier: NCT03858322., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: The identification of patients with homologous recombination deficiency (HRD) beyond BRCA1/2 mutations is an urgent task, as they may benefit from PARP inhibitors. We have previously developed a method to detect mutational signature 3 (Sig3), termed SigMA, associated with HRD from clinical panel sequencing data, that is able to reliably detect HRD from the limited sequencing data derived from gene-focused panel sequencing., Experimental Design: We apply this method to patients from two independent datasets: (i) high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) from a phase Ib trial of the PARP inhibitor olaparib in combination with the PI3K inhibitor buparlisib (BKM120; NCT01623349), and (ii) TNBC patients who received neoadjuvant olaparib in the phase II PETREMAC trial (NCT02624973)., Results: We find that Sig3 as detected by SigMA is positively associated with improved progression-free survival and objective responses. In addition, comparison of Sig3 detection in panel and exome-sequencing data from the same patient samples demonstrated highly concordant results and superior performance in comparison with the genomic instability score., Conclusions: Our analyses demonstrate that HRD can be detected reliably from panel-sequencing data that are obtained as part of routine clinical care, and that this approach can identify patients beyond those with germline BRCA1/2mut who might benefit from PARP inhibitors. Prospective clinical utility testing is warranted., (©2022 The Authors; Published by the American Association for Cancer Research.)

Breast cancer is the most common malignancy and the second leading cause of cancer-related mortality in the United States (US). Most patients are diagnosed with early-stage disease; however, there is still a need to prevent recurrences that often present as incurable metastatic disease. The treatment landscape of early-stage breast cancer is evolving rapidly. The immune checkpoint inhibitor pembrolizumab is approved in combination with neoadjuvant chemotherapy for the treatment of high-risk triple-negative breast cancer (TNBC). The cyclin-dependent kinase (CDK) 4 and 6 inhibitor abemaciclib is approved for adjuvant treatment of patients with high-risk hormone receptor (HR)-positive disease. While adjuvant olaparib has shown significant improvement in outcomes for patients with pathogenic/likely pathogenic BRCA1/2 mutations and high-risk human epidermal growth factor receptor 2 (HER2)-negative breast cancer, and is approved in this setting. For the HER2-positive subtype, the post-neoadjuvant therapy can be tailored based on the response to neoadjuvant chemotherapy and HER2-targeted agents. In this narrative review, we summarize the most recent approvals for early-stage breast cancer as well as frequently encountered clinical challenges utilizing these medications., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Guidelines support comparable treatment for women diagnosed with breast cancer during pregnancy (PrBC) and nonpregnant women with limited case-specific modifications to ensure maternal-fetal safety. Experience during pregnancy with modern agents, such as taxanes or granulocyte colony-stimulating factors (GCSF), is limited., Patients and Methods: We retrospectively identified a multi-institutional cohort of PrBC between 1996 and 2020. Propensity score analyses with multiple imputation for missing variables were applied to determine the associations between chemotherapy exposures during pregnancy, with or without taxanes or GCSF, and a compound maternal-fetal outcome including spontaneous preterm birth, preterm premature rupture of membranes, chorioamnionitis, small for gestational age newborns, congenital malformation, or 5-min Apgar score < 7., Results: Among 139 PrBC pregnancies, 82 (59.0%) were exposed to chemotherapy, including 26 (31.7%) to taxane and 18 (22.0%) to GCSF. Chemotherapy use, in general, and inclusion of taxane and/or GCSF, specifically, increased over time. Pregnancies resulting in live singleton births (n = 123) and exposed to chemotherapy were as likely to reach term as those that were not (59.5% vs. 63.6%, respectively, p unadjusted  = 0.85). Among women treated with chemotherapy, propensity score-matched odds ratios (OR) for the composite maternal-fetal outcome were not significantly increased with taxane (OR 1.24, 95% CI 0.27-5.72) or GCSF (OR 2.11, 95% confidence interval (CI) 0.48-9.22) with similar effects in multiple imputation and sensitivity models., Conclusion: The judicious increased use of taxane chemotherapy and/or growth factor support during pregnancy was not associated with unfavorable short-term maternal-fetal outcomes. While these findings are reassuring, case numbers remain limited and continued surveillance of these patients and progeny is warranted., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To update recommendations on appropriate use of breast cancer biomarker assay results to guide adjuvant endocrine and chemotherapy decisions in early-stage breast cancer., Methods: An updated literature search identified randomized clinical trials and prospective-retrospective studies published from January 2016 to October 2021. Outcomes of interest included overall survival and disease-free or recurrence-free survival. Expert Panel members used informal consensus to develop evidence-based recommendations., Results: The search identified 24 studies informing the evidence base., Recommendations: Clinicians may use Onco type DX, MammaPrint, Breast Cancer Index (BCI), and EndoPredict to guide adjuvant endocrine and chemotherapy in patients who are postmenopausal or age > 50 years with early-stage estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative (ER+ and HER2-) breast cancer that is node-negative or with 1-3 positive nodes. Prosigna and BCI may be used in postmenopausal patients with node-negative ER+ and HER2- breast cancer. In premenopausal patients, clinicians may use Onco type in patients with node-negative ER+ and HER2- breast cancer. Current data suggest that premenopausal patients with 1-3 positive nodes benefit from chemotherapy regardless of genomic assay result. There are no data on use of genomic tests to guide adjuvant chemotherapy in patients with ≥ 4 positive nodes. Ki67 combined with other parameters or immunohistochemistry 4 score may be used in postmenopausal patients without access to genomic tests to guide adjuvant therapy decisions. BCI may be offered to patients with 0-3 positive nodes who received 5 years of endocrine therapy without evidence of recurrence to guide decisions about extended endocrine therapy. None of the assays are recommended for treatment guidance in individuals with HER2-positive or triple-negative breast cancer. Treatment decisions should also consider disease stage, comorbidities, and patient preferences.Additional information is available at www.asco.org/breast-cancer-guidelines., Competing Interests: Fabrice AndreStock and Other Ownership Interests: PegacsyResearch Funding: AstraZeneca (Inst), Novartis (Inst), Pfizer (Inst), Lilly (Inst), Roche (Inst), Daiichi (Inst).Travel, Accommodations, Expenses: Novartis, Roche, GlaxoSmithKline, AstraZeneca Nofisat IsmailaEmployment: GlaxoSmithKline (I)Stock and Other Ownership Interests: GlaxoSmithKline (I) Kimberly H. AllisonConsulting or Advisory Role: MammotomeExpert Testimony: Kaiser Permanente William E. BarlowResearch Funding: Merck (Inst), AstraZeneca (Inst). Deborah E. CollyarHonoraria: PfizerConsulting or Advisory Role: Parexel, MaxisIT, Kinnate BiopharmaTravel, Accommodations, Expenses: Parexel Senthil DamodaranResearch Funding: EMD Serono (Inst), Guardant Health (Inst), Taiho Pharmaceutical (Inst), Novartis (Inst), Sermonix Pharmaceuticals (Inst) N. Lynn HenryResearch Funding: Blue Note Therapeutics (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/27894/summary Komal JhaveriConsulting or Advisory Role: Novartis, Pfizer, AstraZeneca, Jounce Therapeutics, Synthon, Intellisphere, Bristol Myers Squibb, Genentech, AbbVie, Lilly, BluePrint Medicines, Seattle Genetics, Daiichi Sankyo, Biotheranostics, SunPharma Pvt Ltd, Taiho Oncology, SanofiResearch Funding: Novartis (Inst), Genentech (Inst), Debiopharm Group (Inst), ADC Therapeutics (Inst), Pfizer (Inst), Novita Pharmaceuticals (Inst), Clovis Oncology (Inst), Lilly (Inst), Zymeworks (Inst), Immunomedics (Inst), Puma Biotechnology (Inst), VelosBio/Merck (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: Taiho Pharmaceutical, Jounce Therapeutics, Pfizer, AstraZeneca, Intellisphere Kevin KalinskyStock and Other Ownership Interests: Array BioPharma, Pfizer, GRAILConsulting or Advisory Role: bioTheranostics, Lilly, Pfizer, Novartis, Eisai, AstraZeneca, Genentech/Roche, Immunomedics, Ipsen, Merck, Seattle Genetics, Cyclacel, Oncosec, 4D Pharma, Daiichi Sankyo/Astra Zeneca, Puma BiotechnologySpeakers' Bureau: LillyResearch Funding: Incyte (Inst), Novartis (Inst), Genentech/Roche (Inst), Lilly (Inst), Pfizer (Inst), Calithera Biosciences (Inst), Immunomedics (Inst), Acetylon Pharmaceuticals (Inst), Seattle Genetics (Inst), Amgen (Inst), Zeno Pharmaceuticals (Inst), CytomX Therapeutics (Inst)Travel, Accommodations, Expenses: Lilly, AstraZeneca, PfizerOther Relationship: Immunomedics, Genentech Nicole M. KudererEmployment: Self-employedConsulting or Advisory Role: Janssen, BeyondSpring Pharmaceuticals, Invitae, Bristol Myers Squibb, Samsung Bioepis, G1 Therapeutics, Sandoz-Novartis, BeyondSpring Pharmaceuticals, Teva, MerckResearch Funding: AmgenTravel, Accommodations, Expenses: Janssen, Mylan, Agendia, Bayer, Spectrum Pharmaceuticals Anna LitvakConsulting or Advisory Role: Bristol Myers Squibb, bioTheranostics Erica L. MayerConsulting or Advisory Role: Lilly, Novartis, AstraZeneca, Gilead SciencesResearch Funding: Pfizer (Inst) Lajos PusztaiHonoraria: bioTheranostics, Natera, OncoCyte, AthenexConsulting or Advisory Role: H3 Biomedicine, Merck, Novartis, Seattle Genetics, Syndax, AstraZeneca, Roche/Genentech, Bristol Myers Squibb, Clovis Oncology, Immunomedics, Eisai, Almac Diagnostics, PfizerResearch Funding: Merck (Inst), Genentech (Inst), Seattle Genetics (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst), Pfizer (Inst)Travel, Accommodations, Expenses: AstraZenecaUncompensated Relationships: NanoString Technologies, Foundation MedicineOpen Payments Link: https://openpaymentsdata.cms.gov/physician/110878 Antonio C. WolffThis author is an Associate Editor for Journal of Clinical Oncology. Journal policy recused the author from having any role in the peer review of this manuscript.Consulting or Advisory Role: Ionis PharmaceuticalsPatents, Royalties, Other Intellectual Property: Antonio Wolff has been named as inventor on one or more issued patents or pending patent applications relating to methylation in breast cancer, and has assigned his rights to JHU, and participates in a royalty sharing agreement with JHUOpen Payments Link: https://openpaymentsdata.cms.gov/physician/357301/summary Vered StearnsConsulting or Advisory Role: NovartisResearch Funding: AbbVie (Inst), Pfizer (Inst), Novartis (Inst), Puma Biotechnology (Inst), Biocept (Inst)Other Relationship: Immunomedics, AstraZenecaNo other potential conflicts of interest were reported. Fabrice AndreStock and Other Ownership Interests: PegacsyResearch Funding: AstraZeneca (Inst), Novartis (Inst), Pfizer (Inst), Lilly (Inst), Roche (Inst), Daiichi (Inst).Travel, Accommodations, Expenses: Novartis, Roche, GlaxoSmithKline, AstraZeneca Nofisat IsmailaEmployment: GlaxoSmithKline (I)Stock and Other Ownership Interests: GlaxoSmithKline (I) Kimberly H. AllisonConsulting or Advisory Role: MammotomeExpert Testimony: Kaiser Permanente William E. BarlowResearch Funding: Merck (Inst), AstraZeneca (Inst). Deborah E. CollyarHonoraria: PfizerConsulting or Advisory Role: Parexel, MaxisIT, Kinnate BiopharmaTravel, Accommodations, Expenses: Parexel Senthil DamodaranResearch Funding: EMD Serono (Inst), Guardant Health (Inst), Taiho Pharmaceutical (Inst), Novartis (Inst), Sermonix Pharmaceuticals (Inst) N. Lynn HenryResearch Funding: Blue Note Therapeutics (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/27894/summary Komal JhaveriConsulting or Advisory Role: Novartis, Pfizer, AstraZeneca, Jounce Therapeutics, Synthon, Intellisphere, Bristol Myers Squibb, Genentech, AbbVie, Lilly, BluePrint Medicines, Seattle Genetics, Daiichi Sankyo, Biotheranostics, SunPharma Pvt Ltd, Taiho Oncology, SanofiResearch Funding: Novartis (Inst), Genentech (Inst), Debiopharm Group (Inst), ADC Therapeutics (Inst), Pfizer (Inst), Novita Pharmaceuticals (Inst), Clovis Oncology (Inst), Lilly (Inst), Zymeworks (Inst), Immunomedics (Inst), Puma Biotechnology (Inst), VelosBio/Merck (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: Taiho Pharmaceutical, Jounce Therapeutics, Pfizer, AstraZeneca, Intellisphere Kevin KalinskyStock and Other Ownership Interests: Array BioPharma, Pfizer, GRAILConsulting or Advisory Role: bioTheranostics, Lilly, Pfizer, Novartis, Eisai, AstraZeneca, Genentech/Roche, Immunomedics, Ipsen, Merck, Seattle Genetics, Cyclacel, Oncosec, 4D Pharma, Daiichi Sankyo/Astra Zeneca, Puma BiotechnologySpeakers' Bureau: LillyResearch Funding: Incyte (Inst), Novartis (Inst), Genentech/Roche (Inst), Lilly (Inst), Pfizer (Inst), Calithera Biosciences (Inst), Immunomedics (Inst), Acetylon Pharmaceuticals (Inst), Seattle Genetics (Inst), Amgen (Inst), Zeno Pharmaceuticals (Inst), CytomX Therapeutics (Inst)Travel, Accommodations, Expenses: Lilly, AstraZeneca, PfizerOther Relationship: Immunomedics, Genentech Nicole M. KudererEmployment: Self-employedConsulting or Advisory Role: Janssen, BeyondSpring Pharmaceuticals, Invitae, Bristol Myers Squibb, Samsung Bioepis, G1 Therapeutics, Sandoz-Novartis, BeyondSpring Pharmaceuticals, Teva, MerckResearch Funding: AmgenTravel, Accommodations, Expenses: Janssen, Mylan, Agendia, Bayer, Spectrum Pharmaceuticals Anna LitvakConsulting or Advisory Role: Bristol Myers Squibb, bioTheranostics Erica L. MayerConsulting or Advisory Role: Lilly, Novartis, AstraZeneca, Gilead SciencesResearch Funding: Pfizer (Inst) Lajos PusztaiHonoraria: bioTheranostics, Natera, OncoCyte, AthenexConsulting or Advisory Role: H3 Biomedicine, Merck, Novartis, Seattle Genetics, Syndax, AstraZeneca, Roche/Genentech, Bristol Myers Squibb, Clovis Oncology, Immunomedics, Eisai, Almac Diagnostics, PfizerResearch Funding: Merck (Inst), Genentech (Inst), Seattle Genetics (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst), Pfizer (Inst)Travel, Accommodations, Expenses: AstraZenecaUncompensated Relationships: NanoString Technologies, Foundation MedicineOpen Payments Link: https://openpaymentsdata.cms.gov/physician/110878 Antonio C. WolffThis author is an Associate Editor for Journal of Clinical Oncology. Journal policy recused the author from having any role in the peer review of this manuscript.Consulting or Advisory Role: Ionis PharmaceuticalsPatents, Royalties, Other Intellectual Property: Antonio Wolff has been named as inventor on one or more issued patents or pending patent applications relating to methylation in breast cancer, and has assigned his rights to JHU, and participates in a royalty sharing agreement with JHUOpen Payments Link: https://openpaymentsdata.cms.gov/physician/357301/summary Vered StearnsConsulting or Advisory Role: NovartisResearch Funding: AbbVie (Inst), Pfizer (Inst), Novartis (Inst), Puma Biotechnology (Inst), Biocept (Inst)Other Relationship: Immunomedics, AstraZenecaNo other potential conflicts of interest were reported.

Purpose: We had previously reported on the safety and the recommended phase 2 dose (RP2D) of olaparib in combination with the PI3Kα-specific inhibitor alpelisib in patients with high-grade serous ovarian cancer as studied in a phase 1b trial (NCT01623349). Here, we report on the breast cancer cohort from that study., Patients and Methods: Eligible patients had recurrent triple-negative breast cancer (TNBC) or recurrent breast cancer of any subtype with a germline BRCA mutation and were enrolled to a dose-escalation or -expansion cohort. After definition of the RP2D, secondary end points included safety and objective response rate (ORR). Exploratory analyses were performed using circulating-free DNA (cfDNA)., Results: Seventeen patients with TNBC were enrolled with a median of three prior lines of chemotherapy. The most common treatment-related grade 3-4 adverse events were hyperglycemia (18%) and rash (12%). The ORR was 18% (23% for patients treated at the RP2D) and 59% had disease control. The median duration of response was 7.4 months. Analysis of cfDNA tumor fractions (TFx) revealed that patients with TFx < 15% after completion of the first cycle had a longer progression-free survival compared with those with TFx ≥ 15% (6.0 vs. 0.9 months; P = 0.0001)., Conclusions: Alpelisib in combination with olaparib is tolerable in patients with pre-treated TNBC, with evidence of activity in non-BRCA carriers. cfDNA provided important prognostic information. Results highlight potential synergistic use of a PI3K inhibitor to sensitize HR-proficient (BRCA wild-type) TNBC to PARP inhibition and suggest the potential to expand the use of PARP inhibition beyond BRCA-mutant tumors., (©2022 American Association for Cancer Research.)

Objective: Breast cancer is one of the most frequently diagnosed cancers in pregnancy and is commonly treated with chemotherapy. To date, studies examining effects of chemotherapy during pregnancy on fetal growth have yielded conflicting results, and most are limited by small sample sizes or are nonspecific with respect to cytotoxic regimen or type of cancer treated. We sought to evaluate the effect of chemotherapy for breast cancer in pregnancy on birthweight and small for gestational age infants., Study Design: This is a retrospective cohort study of 74 women diagnosed with pathologically confirmed breast cancer during pregnancy between 1997 and 2018 at one of three academic medical centers, who had a singleton birth with known birthweight. Forty-nine received chemotherapy and 25 did not receive chemotherapy. Linear regression modeling was used to compare birthweight (by gestational age and sex-specific z -score) by chemotherapy exposure. Subanalyses of specific chemotherapy regimen and duration of chemotherapy exposure were also performed. Placental, neonatal, and maternal outcomes were also analyzed by chemotherapy exposure., Results: In the adjusted model, chemotherapy exposure was associated with lower birthweight (Δ z -score = -0.49, p  = 0.03), but similar rates of small for gestational age (defined as birthweight <10th percentile for gestational age) infants (8.2 vs. 8.0%, p  = 1.0; Fisher's exact test). Each additional week of chemotherapy (Δ z -score = -0.05, p  = 0.03) was associated with decreased birthweight, although no association was found with specific chemotherapy regimen. Chemotherapy exposure was associated with lower median placental weight percentile by gestational age (9th vs. 75th, p  < 0.05). Secondary maternal outcomes were similar between the group that did and did not receive chemotherapy., Conclusion: Chemotherapy for breast cancer in pregnancy in this cohort is associated with lower birthweight but no difference in the rate of small for gestational age infants., Key Points: · Chemotherapy for breast cancer in pregnancy is associated with decreased birthweight but similar rates of small for gestational age infants.. · Birthweight did not differ according to chemotherapy regimen.. · There is no difference in the rate of small for gestational age infants.., Competing Interests: None declared., (Thieme. All rights reserved.)

Competing Interests: ELM reports personal fees from Eisai, Lilly, and Novartis outside the submitted work. SL reports honoraria from Abbvie, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, DSI, Eirgenix, GlaxoSmithKline, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Prime–Medscape, Puma, Roche, Samsung, and Seagen; a consulting or advisory role for Abbvie, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, DSI, Eirgenix, GlaxoSmithKline, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Prime–Medscape, Puma, Roche, and Seagen; a speaker's bureau for AstraZeneca, DSI, Novartis, Pfizer, Pierre Fabre, Prime–Medscape, Roche, and Samsung; research funding from Abbvie, Amgen, AstraZeneca, Celgene, Cepheid, DSI, Immunomedics, Novartis, Pfizer, and Roche; and a patent or an intellectual property interest with VM Scope, all outside the submitted work. GC served as consultant or advisor for Roche, Lilly, and Bristol Myers Squibb; served on the speaker's bureau for Roche, Pfizer, and Lilly; received travel funding from Pfizer and Roche; and received honoraria from Roche, Pfizer, Lilly, Novartis, and SEAGEN, all outside the submitted work. GA and CV declare no competing interests.

Purpose: The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS., Methods: Patients with stage II-III HR+, HER2- disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS., Results: Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non-protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11)., Conclusion: Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies., Competing Interests: Erica L. MayerConsulting or Advisory Role: Lilly, Novartis, AstraZeneca, Gilead SciencesResearch Funding: Pfizer (Inst) Christian FeslResearch Funding: Pfizer (Inst) Dominik HlauschekResearch Funding: Pfizer (Inst) Laura Garcia-EstevezConsulting or Advisory Role: Daiichi Sankyo/Astra Zeneca, Palex, Seattle GeneticsResearch Funding: Roche/Genentech (Inst) Nicholas ZdenkowskiHonoraria: Roche, Pfizer, EisaiConsulting or Advisory Role: Lilly, AstraZeneca, EisaiResearch Funding: Roche (Inst), Pfizer (Inst)Travel, Accommodations, Expenses: Roche, Amgen, Novartis Kathy D. MillerThis author is the Senior Deputy Editor of Journal of Clinical Oncology. Journal policy recused the author from having any role in the peer review of this manuscript.Consulting or Advisory Role: Merck, Genentech/Roche, Athenex, AstraZeneca, Bristol Myers Squibb/CelgeneResearch Funding: Taiho Pharmaceutical (Inst), Novartis (Inst), Seattle Genetics (Inst), Pfizer (Inst), Astex Pharmaceuticals (Inst), British Biotech (Inst), CytomX Therapeutics (Inst), Alphamab (Inst) Marija BalicConsulting or Advisory Role: Amgen, AstraZeneca, Daiichi Sankyo/Astra Zeneca, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, SamsungSpeakers' Bureau: Amgen, AstraZeneca, Daiichi Sankyo/Astra Zeneca, Lilly, Novartis, Pierre Fabre, Pfizer, Roche, Seattle GeneticsResearch Funding: Lilly (Inst), Novartis (Inst), Pfizer (Inst)Travel, Accommodations, Expenses: MSD Ingrid A. MayerConsulting or Advisory Role: Novartis, AstraZeneca, Lilly, Genentech, GlaxoSmithKline, Immunomedics, Macrogenics, Pfizer, AbbVie, Seattle Genetics, Puma Biotechnology, Cyclacel, Blueprint Medicines, SanofiResearch Funding: Novartis (Inst), Pfizer (Inst), Genentech (Inst) David CameronConsulting or Advisory Role: Lilly (Inst), Novartis (Inst), Novartis (Inst), Research Triangle Institute RTI Health Solutions (Inst), Daiichi Sankyo (Inst), Prima BioMed (Inst), Merck Sharp & Dohme (Inst), Zymeworks (Inst), Eisai (Inst), Puma Biotechnology (Inst), Pfizer (Inst), Oncolytics (Inst), Roche (Inst), Roche (Inst), Samsung Bioepis (Inst), Seattle Genetics (Inst), Synthon (Inst), Clarity Pharmaceuticals (Inst), Bexon/Zymeworks (Inst), Sanofi (Inst)Research Funding: Roche (Inst), Novartis (Inst), AstraZeneca (Inst) Eric P. WinerHonoraria: Genentech/Roche, Genomic HealthConsulting or Advisory Role: Leap Therapeutics, Seattle Genetics, Jounce Therapeutics, GlaxoSmithKline, Carrick Therapeutics, Lilly, G1 Therapeutics, Syros Pharmaceuticals, Genentech/Roche, Gilead Sciences, Zymeworks, AthenexResearch Funding: Genentech (Inst)Other Relationship: InfiniteMD José Juan Ponce LorenzoHonoraria: Seattle Genetics, Novartis, Pfizer, AstraZeneca/Daiichi Sankyo, Lilly, RocheConsulting or Advisory Role: Seattle Genetics, Novartis, AstraZeneca/Daiichi Sankyo, Roche Tufia C. HaddadResearch Funding: Takeda (Inst) Hiroji IwataHonoraria: Chugai Pharma, AstraZeneca, Eisai, Pfizer, Daiichi Sankyo, Lilly Japan, Kyowa Hakko Kirin, Taiho PharmaceuticalConsulting or Advisory Role: Chugai Pharma, Daiichi Sankyo, Pfizer, AstraZeneca, Lilly Japan, Kyowa Hakko Kirin, NovartisResearch Funding: MSD (Inst), AstraZeneca (Inst), Kyowa Hakko Kirin (Inst), Daiichi Sankyo (Inst), Chugai Pharma (Inst), Nihonkayaku (Inst), Lilly Japan (Inst), Novartis (Inst), Bayer (Inst), Pfizer (Inst), Boehringer Ingelheim (Inst), Sanofi (Inst) Matthew GoetzConsulting or Advisory Role: Lilly, bioTheranostics, Genomic Health, Novartis, Eisai, Sermonix Pharmaceuticals, Context Therapeutics, Pfizer, BiovicaResearch Funding: Lilly (Inst), Pfizer (Inst), Sermonix Pharmaceuticals (Inst)Patents, Royalties, Other Intellectual Property: Methods and Materials for Assessing Chemotherapy Responsiveness and Treating Cancer, Methods and Materials for Using Butyrylcholinesterases to Treat Cancer, Development of Human Tumor Xenografts from Women with Breast Cancer Treated with Neoadjuvant Chemotherapy (Inst)Travel, Accommodations, Expenses: Lilly Fatima CardosoConsulting or Advisory Role: Roche, Novartis, Pfizer, AstraZeneca, Teva, Astellas Pharma, Merus, Celgene, Eisai, Daiichi Sankyo, Genentech, Merck Sharp & Dohme, Sanofi, Pierre Fabre, Macrogenics, Amgen, GE Healthcare, GlaxoSmithKline, Mylan, Mundipharma, Seattle Genetics, Samsung Bioepis, Medscape, Prime OncologyTravel, Accommodations, Expenses: Pfizer, Roche, AstraZeneca Tiffany A. TrainaConsulting or Advisory Role: Genentech/Roche, Pfizer, AstraZeneca, Merck, Puma Biotechnology, Athenex, Daiichi Sankyo, Ionis Pharmaceuticals, Seattle Genetics, Eisai, Exact Sciences, Foundation Medicine, Ayala Pharmaceuticals, Gilead Sciences, Blueprint Medicines, Ellipses Pharma, Fuji Pharma, ITeos Therapeutics, AgendiaResearch Funding: Eisai (Inst), Pfizer (Inst), Novartis (Inst), Innocrin Pharma (Inst), AstraZeneca (Inst), Astellas Pharma (Inst), Immunomedics (Inst), Genentech/Roche (Inst), Daiichi Sankyo (Inst), Carrick Pharm (Inst), Ayala Pharmaceuticals (Inst) Urs BreitensteinConsulting or Advisory Role: AstraZeneca (Inst), Elie Lilly (Inst), Novartis (Inst), Pierre Fabre (Inst), Roche (Inst) Kerstin AckerlResearch Funding: Pfizer (Inst) Otto Metzger FilhoHonoraria: Grupo Oncoclinicas, RocheResearch Funding: Susan G. Komen for the Cure (Inst), Pfizer (Inst), Roche/Genentech (Inst), Eisai (Inst), Cascadian Therapeutics (Inst), AbbVie (Inst)Travel, Accommodations, Expenses: Grupo Oncoclinicas Karin ZehetnerResearch Funding: Pfizer (Inst) Kadine SolomonEmployment: Alliance Foundation TrialsStock and Other Ownership Interests: Pfizer, Merck, Moderna Therapeutics Sarra El-AbedEmployment: Astellas Pharma (I), argenx (I)Research Funding: Novartis (Inst), Roche/Genentech (Inst), Pfizer (Inst) Kathy Puyana TheallEmployment: Pfizer (I)Stock and Other Ownership Interests: Pfizer (I)Honoraria: PfizerTravel, Accommodations, Expenses: Pfizer Dongrui Ray LuEmployment: PfizerStock and Other Ownership Interests: Pfizer Amylou DueckPatents, Royalties, Other Intellectual Property: Royalties from licensing fees for a patient symptom questionnaire (MPN-SAF) Michael GnantEmployment: Sandoz (I)Honoraria: Amgen, Novartis, AstraZeneca, LillyConsulting or Advisory Role: Daiichi-Sankyo, Veracyte, Tolmar, LifeBrain, Lilly Angela DeMicheleResearch Funding: Pfizer (Inst), Genentech (Inst), Calithera Biosciences (Inst), Novartis (Inst)No other potential conflicts of interest were reported.

Objective: The Healthy Living and Eating After Cancer Trial demonstrated that a clinic-based weight loss program reduced body weight, as compared with a waitlist control group, over 15 weeks. Here we report the impact of the weight loss intervention on health-related quality-of-life outcomes at week 15, and maintenance of weight loss to week 30., Methods: This trial randomized cancer survivors of solid tumors and hematologic malignancies (breast cancer: 76.7%) to a 15-week group-based weight loss program (n = 30) or a waitlist control group (n = 30). Participants were not blinded to group assignment. Participants completed a variety of health-related quality-of-life outcome measures at baseline and week 15. From week 15 to week 30, participants initially randomized to the weight loss program were followed with no additional intervention, and participants initially randomized to the waitlist control group commenced the weight loss program., Results: Over the 15 weeks, the weight loss program improved physical functioning (6.2 ± 2.9; p = 0.02; d = 0.31) and reduced insomnia symptoms (-17.1 ± 7.4; p = 0.03; d = -0.30) as measured by the EORTC QLQ-C30, and sleep disturbance (-4.9 ± 1.6; p = 0.005; d = -0.40) as measured by PROMIS, compared to waitlist control. After a weight loss of 4.6 ± 3.9 kg, from week 15 to week 30, participants who were initially randomized to the weight loss program maintained their prior weight loss (+0.6 ± 3.5 kg) and participants who were initially randomized to the waitlist control group lost weight (-3.4 ± 2.9 kg; p < 0.001)., Conclusions: In cancer survivors with overweight or obesity, a 15-week clinic-based weight loss program improved health-related quality-of-life outcomes and produced sustained weight loss to week 30., (© 2022 John Wiley & Sons Ltd.)

Competing Interests: GP reports personal fees from Novartis, Roche, AstraZeneca, Eli Lilly, and Amgen; and grants and personal fees from Pfizer, outside the submitted Comment. AD reports grants from the Alliance Foundation for Clinical Trials, during the conduct of the study; personal fees from Pfizer and Context Therapeutics; grants from Novartis, Pfizer, Genentech, Calithera, and Johnson and Johnson, outside the submitted Comment; and that their spouse is on a data safety monitoring board for a Pfizer drug not for use in oncology. CF reports grants from Pfizer, during the conduct of the study. MG reports personal fees from Amgen, Daiichi Sankyo, AstraZeneca, Eli Lilly, LifeBrain, Nanostring, Novartis, and TLC Biopharmaceuticals, all outside the submitted Comment; and that an immediate family member is employed by Sandoz. ELM reports personal fees from Eisai, Eli Lilly, and Novartis, outside the submitted work. ACD declares no competing interests. We received support from Alliance Foundation Trials, Austrian Breast and Colorectal Cancer Study Group, and the Breast International Group. The trial (including these analyses) was funded by Pfizer, who provided the study drug and financial support.

Purpose: Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor-positive breast cancer has not been confirmed., Patients and Methods: In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer-free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival., Results: Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial., Conclusion: At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor-positive breast cancer., Competing Interests: Michael GnantEmployment: Sandoz (I)Honoraria: Amgen, Novartis, AstraZeneca, LillyConsulting or Advisory Role: Daiichi Sankyo, Veracyte, Tolmar¸ LifeBrain, Lilly Amylou C. DueckPatents, Royalties, Other Intellectual Property: Royalties from licensing fees for a patient symptom questionnaire (MPN-SAF) Miguel MartinHonoraria: Roche/Genentech, Lilly, Pfizer, Novartis, Pierre FabreConsulting or Advisory Role: Roche/Genentech, Novartis, Pfizer, Lilly, AstraZeneca, Taiho Pharmaceutical, PharmaMarSpeakers' Bureau: Lilly/ImClone, Roche/Genentech, Pierre FabreResearch Funding: Novartis (Inst), Roche (Inst)¸ Puma Biotechnology (Inst)Other Relationship: Roche, Novartis Hal J. BursteinThis author is an Associate Editor for Journal of Clinical Oncology. Journal policy recused the author from having any role in the peer review of this manuscript. Richard GreilHonoraria: Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, MSD¸ Sandoz, AbbVie, Gilead Sciences, Daiichi SankyoConsulting or Advisory Role: Celgene, Novartis, Roche, Bristol Myers Squibb, Takeda, AbbVie, AstraZeneca, Janssen, MSD, Merck, Gilead Sciences, Daiichi SankyoResearch Funding: Celgene (Inst), Merck (Inst), Takeda (Inst), AstraZeneca (Inst), Novartis (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), MSD (Inst), Sandoz (Inst), Gilead Sciences (Inst), Roche (Inst)Travel, Accommodations, Expenses: Roche, Amgen, Janssen-Cilag, AstraZeneca, Novartis, MSD, Celgene, Gilead Sciences, Bristol Myers Squibb, AbbVie, Daiichi Sankyo Antonio C. WolffThis author is an Associate Editor for Journal of Clinical Oncology. Journal policy recused the author from having any role in the peer review of this manuscript.Consulting or Advisory Role: Ionis PharmaceuticalsPatents, Royalties, Other Intellectual Property: A.C.W. has been named as an inventor on one or more issued patents or pending patent applications related to methylation in breast cancer, has assigned his rights to JHU, and participates in a royalty sharing agreement with JHUOpen Payments Link: https://openpaymentsdata.cms.gov/physician/357301/summary Arlene ChanHonoraria: Novartis, LillyConsulting or Advisory Role: LillyResearch Funding: Eisai Eric P. WinerHonoraria: Genomic Health, Genentech/RocheConsulting or Advisory Role: Leap Therapeutics, Seattle Genetics, Jounce Therapeutics, GlaxoSmithKline, Carrick Therapeutics, Lilly, G1 Therapeutics, Syros Pharmaceuticals, Genentech/Roche, Gilead Sciences, Zymeworks, AthenexResearch Funding: Genentech (Inst)Other Relationship: InfiniteMD Georg PfeilerHonoraria: Amgen, Roche/Genentech, Pfizer¸ Lilly, AstraZeneca/Merck, AstraZeneca/Daiichi Sankyo, Novartis, UCB, Accord HealthcareConsulting or Advisory Role: Pfizer¸ Amgen¸ Lilly, Novartis, AstraZeneca/Merck, AstraZeneca/Daiichi Sankyo, UCB, Roche/GenentechSpeakers' Bureau: Roche/Genentech, Pfizer, Lilly, Novartis, UCB, AstraZeneca/Merck, AstraZeneca/Daiichi Sankyo, Accord Healthcare, Amgen, Accord HealthcareResearch Funding: Pfizer, Roche/GenentechTravel, Accommodations, Expenses: Novartis, Lilly, Roche/Genentech, Lilly, AstraZeneca/Daiichi Sankyo Kathy MillerThis author is an Associate Editor for Journal of Clinical Oncology. Journal policy recused the author from having any role in the peer review of this manuscript.Consulting or Advisory Role: Merck, Genentech/Roche, Athenex, AstraZeneca, Bristol Myers Squibb/CelgeneResearch Funding: Taiho Pharmaceutical (Inst), Novartis (Inst), Seattle Genetics (Inst), Pfizer (Inst), Astex Pharmaceuticals (Inst), British Biotech (Inst), CytomX Therapeutics (Inst), Alphamab (Inst) Marco ColleoniResearch Funding: Roche (Inst) Gabor RubovskyConsulting or Advisory Role: Pfizer, Novartis, Roche, Gilead SciencesTravel, Accommodations, Expenses: Amgen Judith M. BlissResearch Funding: AstraZeneca (Inst), Merck Sharp & Dohme (Inst), Puma Biotechnology (Inst), Pfizer (Inst), Roche (Inst), GlaxoSmithKline/Novartis (Inst), Lilly (Inst), Janssen-Cilag (Inst), Clovis Oncology (Inst)Travel, Accommodations, Expenses: Pfizer Ingrid A. MayerConsulting or Advisory Role: Novartis, AstraZeneca, Lilly, Genentech, GlaxoSmithKline, Immunomedics, MacroGenics, Pfizer, AbbVie, Seattle Genetics, Puma Biotechnology, Cyclacel, Blueprint Medicines, SanofiResearch Funding: Novartis (Inst), Pfizer (Inst), Genentech (Inst) Christian SingerHonoraria: Novartis, AstraZeneca/MedImmune, Daiichi Sankyo Europe GmbHConsulting or Advisory Role: AstraZeneca/MedImmune, Daiichi-Sankyo, Gilead Sciences, Sanofi/Aventis, NovartisSpeakers' Bureau: Novartis, AstraZeneca/MedImmuneResearch Funding: Novartis, Sanofi, Myriad Genetics, Roche, AstraZeneca/MedImmuneTravel, Accommodations, Expenses: Roche, Novartis Zbigniew NoweckiTravel, Accommodations, Expenses: Roche/Genentech Olwen HahnLeadership: Via OncologyStock and Other Ownership Interests: Teleflex MedicalHonoraria: Cardinal Health (I)Consulting or Advisory Role: Pfizer, hmpglobal.comTravel, Accommodations, Expenses: Cardinal Health (I) Jacqui ThomsonHonoraria: MSD Oncology, Roche/Genentech Norman WolmarkOpen Payments Link: https://openpaymentsdata.cms.gov/physician/159597 Hope S. RugoHonoraria: Puma Biotechnology, MylanConsulting or Advisory Role: SamsungResearch Funding: MacroGenics (Inst), OBI Pharma (Inst), Eisai (Inst), Pfizer (Inst), Novartis (Inst), Lilly (Inst), Genentech (Inst), Merck (Inst), Immunomedics (Inst), Odonate Therapeutics (Inst), Daiichi Sankyo (Inst), Seattle Genetics (Inst), Sermonix Pharmaceuticals (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: Pfizer, Novartis, Mylan, AstraZeneca Spain, MerckOpen Payments Link: https://openpaymentsdata.cms.gov/summary Guenther G. StegerHonoraria: Pfizer, Lilly, Novartis, Roche, AstraZeneca/Daiichi Sankyo, Teva, Pfizer, Lilly, NovartisTravel, Accommodations, Expenses: Roche, Teva Blanca Hernando Fernández de AránguizHonoraria: GlaxoSmithKline, PharmaMar, Clovis OncologyTravel, Accommodations, Expenses: Pfizer, MSD Oncology, Roche Tufia C. HaddadResearch Funding: Takeda (Inst) Meritxell Bellet EzquerraConsulting or Advisory Role: Pfizer, Lilly, NovartisSpeakers' Bureau: Lilly, Pfizer, Novartis Hannes FohlerEmployment: Takeda (I)Research Funding: Pfizer (Inst) Otto MetzgerHonoraria: Grupo Oncoclinicas, RocheResearch Funding: Susan G. Komen for the Cure (Inst), Pfizer (Inst), Roche/Genentech (Inst), Eisai (Inst), Cascadian Therapeutics (Inst), AbbVie (Inst)Travel, Accommodations, Expenses: Grupo Oncoclinicas Anita Jallitsch-HalperResearch Funding: Pfizer (Inst) Kadine SolomonEmployment: Alliance Foundation TrialsStock and Other Ownership Interests: Pfizer, Merck, Moderna Therapeutics Céline SchurmansResearch Funding: Pfizer (Inst), Roche/Genentech (Inst), AstraZeneca (Inst), Novartis (Inst), Servier (Inst), Pfizer (Inst), Sanofi (Inst)Patents, Royalties, Other Intellectual Property: My organization receives royalties from Agendia Kathy P. TheallEmployment: PfizerStock and Other Ownership Interests: PfizerHonoraria: PfizerTravel, Accommodations, Expenses: Pfizer Dongrui R. LuEmployment: PfizerStock and Other Ownership Interests: Pfizer Kathleen TennerStock and Other Ownership Interests: Merck Christian FeslResearch Funding: Pfizer (Inst) Angela DeMicheleResearch Funding: Pfizer (Inst), Genentech (Inst), Calithera Biosciences (Inst), Novartis (Inst) Erica L. MayerConsulting or Advisory Role: Lilly, Novartis, AstraZeneca, Gilead SciencesResearch Funding: Pfizer (Inst)No other potential conflicts of interest were reported.

Background: Audio recordings of oncology clinic discussions can help patients retain and understand information about their disease and treatment decisions. Access to this tool relies on acceptance of recordings by oncologists. This is the first study to evaluate experience and attitudes of oncologists toward patients recording clinic visits., Methods: Medical, radiation, and surgical oncologists from 5 US cancer centers and community affiliates were surveyed to evaluate clinicians' experience, beliefs, and practices regarding patient-initiated recordings., Results: Among 360 oncologists (69% response rate), virtually all (93%) have experienced patients seeking to record visits. Although 75% are comfortable with recording, 25% are uncomfortable and 56% report concerns ranging from less thorough discussions to legal liability. Most (85%) always agree when patients ask to record, but 15% never or selectively allow recording. Although 51% believe recording is positive for the patient-physician relationship, a sizable minority report that it can lead to less detailed conversations (28%) or avoidance of difficult topics, including prognosis (33%). Views did not vary based on subspecialty, practice setting, or geographic region, but older age and years in practice were associated with more positive views of recording. The majority of clinicians (72%) desire institutional policies to govern guidelines about recordings., Conclusions: Most oncologists are comfortable with patient requests to record visits, but a sizable minority remain uncomfortable, and access to recording varies solely on physician preference. This difference in care delivery may benefit from institutional policies that promote access while addressing legitimate physician concerns over privacy and appropriate use of recordings., (© 2021 American Cancer Society.)

Purpose: While chemotherapy remains the standard treatment for triple-negative breast cancer (TNBC), identifying and managing chemoresistant tumors has proven elusive. We sought to discover hallmarks and therapeutically actionable features of refractory TNBC through molecular analysis of primary chemoresistant TNBC specimens., Experimental Design: We performed transcriptional profiling of tumors from a phase II clinical trial of platinum chemotherapy for advanced TNBC (TBCRC-009), revealing a gene expression signature that identified de novo chemorefractory tumors. We then employed pharmacogenomic data mining, proteomic and other molecular studies to define the therapeutic vulnerabilities of these tumors., Results: We reveal the RAS-GTPase-activating protein (RAS-GAP) RASAL2 as an upregulated factor that mediates chemotherapy resistance but also an exquisite collateral sensitivity to combination MAP kinase kinase (MEK1/2) and EGFR inhibitors in TNBC. Mechanistically, RASAL2 GAP activity is required to confer kinase inhibitor sensitivity, as RASAL2-high TNBCs sustain basal RAS activity through suppression of negative feedback regulators SPRY1/2, together with EGFR upregulation. Consequently, RASAL2 expression results in failed feedback compensation upon co-inhibition of MEK1/2 and EGFR that induces synergistic apoptosis in vitro and in vivo . In patients with TNBC, high RASAL2 levels predict clinical chemotherapy response and long-term outcomes, and are associated via direct transcriptional regulation with activated oncogenic Yes-Associated Protein (YAP). Accordingly, chemorefractory patient-derived TNBC models exhibit YAP activation, high RASAL2 expression, and tumor regression in response to MEK/EGFR inhibitor combinations despite well-tolerated intermittent dosing., Conclusions: These findings identify RASAL2 as a mediator of TNBC chemoresistance that rewires MAPK feedback and cross-talk to confer profound collateral sensitivity to combination MEK1/2 and EGFR inhibitors., (©2021 The Authors; Published by the American Association for Cancer Research.)

The coronavirus disease (COVID)-19 pandemic has affected graduate medical education training programs, including hematology-oncology fellowship programs, both across the United States and abroad. Within the Dana-Farber Cancer Institute/Mass General Brigham hematology-oncology fellowship program, fellowship leadership had to quickly reorganize the program's clinical, educational, and research structure to minimize the risk of COVID-19 spread to our patients and staff, allow fellows to assist in the care of patients with COVID-19, maintain formal didactics despite physical distancing, and ensure the mental and physical well-being of fellows. Following the first wave of patients with COVID-19, we anonymously surveyed the Dana-Farber Cancer Institute/Mass General Brigham first-year fellows to explore their perceptions regarding what the program did well and what could have been improved in the COVID-19 response. In this article, we present the feedback from our fellows and the lessons we learned as a program from this feedback. To our knowledge, this represents the first effort in the hematology-oncology literature to directly assess a hematology-oncology program's overall response to COVID-19 through direct feedback from fellows., Competing Interests: M. Dror MichaelsonEmployment: Jounce Therapeutics, Cullinan OncologyStock and Other Ownership Interests: Jounce TherapeuticsHonoraria: Pfizer, Exelixis, Merck, EisaiConsulting or Advisory Role: Pfizer, Exelixis, Eisai, MerckResearch Funding: Pfizer, Eisai, Millennium, Exelixis, Merck, Bristol-Myers Squibb Erica L. MayerConsulting or Advisory Role: Lilly, Novartis, Sanofi, EisaiResearch Funding: Pfizer Aric D. ParnesConsulting or Advisory Role: Sigilon Therapeutics, Uniqure, Takeda, Shire, Sunovion, I-mAbResearch Funding: Genentech, Takeda Ann S. LaCasceConsulting or Advisory Role: Forty Seven, Bristol-Myers Squibb, Seattle Genetics, HumanigenSpeakers' Bureau: Research to PracticeResearch Funding: Sanofi, Forty Seven, Celgene, Seattle GeneticsPatents, Royalties, Other Intellectual Property: Up to Date royaltiesNo other potential conflicts of interest were reported.

Purpose: Patients with triple-negative breast cancer (TNBC) and residual invasive disease (RD) after completion of neoadjuvant chemotherapy (NAC) have a high-risk for recurrence, which is reduced by adjuvant capecitabine. Preclinical models support the use of platinum agents in the TNBC basal subtype. The EA1131 trial hypothesized that invasive disease-free survival (iDFS) would not be inferior but improved in patients with basal subtype TNBC treated with adjuvant platinum compared with capecitabine., Patients and Methods: Patients with clinical stage II or III TNBC with ≥ 1 cm RD in the breast post-NAC were randomly assigned to receive platinum (carboplatin or cisplatin) once every 3 weeks for four cycles or capecitabine 14 out of 21 days every 3 weeks for six cycles. TNBC subtype (basal v nonbasal) was determined by PAM50 in the residual disease. A noninferiority design with superiority alternative was chosen, assuming a 4-year iDFS of 67% with capecitabine., Results: Four hundred ten of planned 775 participants were randomly assigned to platinum or capecitabine between 2015 and 2021. After median follow-up of 20 months and 120 iDFS events (61% of full information) in the 308 (78%) patients with basal subtype TNBC, the 3-year iDFS for platinum was 42% (95% CI, 30 to 53) versus 49% (95% CI, 39 to 59) for capecitabine. Grade 3 and 4 toxicities were more common with platinum agents. The Data and Safety Monitoring Committee recommended stopping the trial as it was unlikely that further follow-up would show noninferiority or superiority of platinum., Conclusion: Platinum agents do not improve outcomes in patients with basal subtype TNBC RD post-NAC and are associated with more severe toxicity when compared with capecitabine. Participants had a lower than expected 3-year iDFS regardless of study treatment, highlighting the need for better therapies in this high-risk population., Competing Interests: Ingrid A. MayerConsulting or Advisory Role: Novartis, AstraZeneca, Lilly, Genentech, GlaxoSmithKline, Immunomedics, Macrogenics, Pfizer, AbbVie, Seattle Genetics, Puma Biotechnology, Cyclacel, Blueprint MedicinesResearch Funding: Novartis, Pfizer, Genentech Carlos L. ArteagaLeadership: American Association for Cancer ResearchStock and Other Ownership Interests: Provista Diagnostics, Y-Trap IncConsulting or Advisory Role: Novartis, Lilly, Sanofi, Radius Health, Taiho Pharmaceutical, Puma Biotechnology, Merck, H3 Biomedicine, Symphogen, Origimed, Petra Pharma, Third Rock Ventures, Immunomedics, Daiichi Sankyo, Athenex, G1 Therapeutics, Clovis OncologyResearch Funding: Puma Biotechnology, Pfizer, Lilly, Radius Health, Takeda, BayerOther Relationship: Susan G. Komen for the Cure William F. SymmansStock and Other Ownership Interests: ISIS Pharmaceuticals, Nuvera Biosciences, Delphi Diagnostics, Eiger BioPharmaceuticalsConsulting or Advisory Role: Merck, Almac DiagnosticsPatents, Royalties, Other Intellectual Property: Intellectual Property, Intellectual Property (expired)Travel, Accommodations, Expenses: Luminex, MerckUncompensated Relationships: Delphi Diagnostics Ben H. ParkLeadership: LoxoStock and Other Ownership Interests: Loxo, CelcuityHonoraria: AstraZenecaConsulting or Advisory Role: Horizon Discovery, Foundation Medicine, Loxo, Casdin Capital, H3 Biomedicine, Jackson Laboratory for Genomic Medicine, Lilly, Celcuity, Sermonix Pharmaceuticals, PathovaxResearch Funding: AbbVie, Pfizer, GE Healthcare, LillyPatents, Royalties, Other Intellectual Property: Royalties paid through inventions at Johns Hopkins University by Horizon Discovery LtdTravel, Accommodations, Expenses: Lilly, LoxoUncompensated Relationships: Tempus Amye J. TevaarwerkOther Relationship: Epic Systems Karen L. SmithStock and Other Ownership Interests: AbbVie, Abbott LaboratoriesHonoraria: ASiM CMEResearch Funding: Pfizer Margaret BlockConsulting or Advisory Role: Theranostics Health Bernard TawfikOther Relationship: Ipsen Lisa E. FlaumConsulting or Advisory Role: Seattle Genetics, NovartisSpeakers' Bureau: Seattle Genetics, Novartis, AstraZeneca Erica L. MayerConsulting or Advisory Role: Lilly, Novartis, Sanofi, Eisai, AstraZenecaResearch Funding: Pfizer William M. SikovHonoraria: UpToDateSpeakers' Bureau: Lilly, Daiichi Sankyo, Eisai, Seagen Lynne I. WagnerStock and Other Ownership Interests: Johnson & Johnson, Lilly, Gilead SciencesConsulting or Advisory Role: Celgene, AthenexTravel, Accommodations, Expenses: Celgene Angela M. DeMicheleResearch Funding: Pfizer, Genentech, Calithera Biosciences, Novartis Joseph A. SparanoStock and Other Ownership Interests: MetastatConsulting or Advisory Role: Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, Merrimack, Adgero Biopharmaceuticals, Cardinal Health, GlaxoSmithKline, CStone Pharmaceuticals, Epic Sciences, Daiichi Sankyo, BMSiSpeakers' Bureau: Eisai, CertaraResearch Funding: Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, Merrimack, Radius Health, Olema PharmaceuticalsTravel, Accommodations, Expenses: Menarini Silicon Biosystems, Roche/Genentech, Adgero Biopharmaceuticals, Myriad Genetics, Pfizer, AstraZeneca, Rhenium Medical Antonio C. WolffConsulting or Advisory Role: Ionis PharmaceuticalsPatents, Royalties, Other Intellectual Property: Antonio Wolff has been named as inventor on one or more issued patents or pending patent applications relating to methylation in breast cancer, and has assigned his rights to JHU, and participates in a royalty sharing agreement with JHUOpen Payments Link: https://openpaymentsdata.cms.gov/physician/357301/summary Kathy D. MillerConsulting or Advisory Role: Merck, Genentech/Roche, Athenex, AstraZeneca, Bristol Myers Squibb/CelgeneResearch Funding: Taiho Pharmaceutical, Novartis, Seattle Genetics, Pfizer, Astex Pharmaceuticals, British Biotech, CytomX TherapeuticsNo other potential conflicts of interest were reported.

Vaccination-associated adenopathy is a frequent imaging finding after administration of COVID-19 vaccines that may lead to a diagnostic conundrum in patients with manifest or suspected cancer, in whom it may be indistinguishable from malignant nodal involvement. To help the medical community address this concern in the absence of studies and evidence-based guidelines, this special report offers recommendations developed by a multidisciplinary panel of experts from three of the leading tertiary care cancer centers in the United States. According to these recommendations, some routine imaging examinations, such as those for screening, should be scheduled before or at least 6 weeks after the final vaccination dose to allow for any reactive adenopathy to resolve. However, there should be no delay of other clinically indicated imaging (eg, for acute symptoms, short-interval treatment monitoring, urgent treatment planning or complications) due to prior vaccination. The vaccine should be administered on the side contralateral to the primary or suspected cancer, and both doses should be administered in the same arm. Vaccination information-date(s) administered, injection site(s), laterality, and type of vaccine-should be included in every preimaging patient questionnaire, and this information should be made readily available to interpreting radiologists. Clear and effective communication between patients, radiologists, referring physician teams, and the general public should be considered of the highest priority when managing adenopathy in the setting of COVID-19 vaccination., (© RSNA, 2021.)

Purpose: Preclinical studies support the JAK2-STAT3 signaling pathway as a key driver in CD44+ CD24- "stem-cell-like" breast cancer cells. Ruxolitinib is an orally bioavailable JAK1/2 inhibitor. We aimed to identify the recommended phase 2 dose (RP2D) of ruxolitinib in combination with paclitaxel in patients with HER2-negative metastatic breast cancer (MBC)., Methods: Eligible patients had HER2-negative MBC and had received ≤ 3 chemotherapy regimens for advanced disease. Patients received oral ruxolitinib (10-25 mg bid) in a 3 + 3 dose escalation design in combination with weekly paclitaxel 80 mg/m 2 in a 3-week cycle. The primary objective was to determine the maximum tolerated dose (MTD) and the RP2D., Results: Nineteen patients received protocol therapy (mean age 52 years). Eight (42%) had triple-negative breast cancer and 11 (58%) had hormone receptor-positive disease; 12 (63%) had visceral disease. Ten (53%) patients had not received prior treatment for advanced disease. Patients received a median number of 5 cycles of combination therapy (range 1-12) and five patients continued single-agent ruxolitinib. The MTD of ruxolitinib was 25 mg bid when combined with paclitaxel, and the RP2D for the combination was 15 mg bid. Thirteen (68%) patients required dose reductions or holds. Most frequent toxicities reported of any grade were neutropenia (50%) and anemia (33%). There were no grade 4/5 toxicities attributed to study drug. Four (21%) patients had PR, 12 (63%) had SD and three (16%) had PD as their best response., Conclusion: The combination of ruxolitinib and weekly paclitaxel was well tolerated with evidence of clinical activity. Further analysis of this combination is ongoing (NCT02041429)., Trial Registration: NCT02041429. Date of registration: January 22, 2014.

Background: Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer., Methods: PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II-III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30)., Findings: Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9-29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2-90·6) for palbociclib plus endocrine therapy and 88·5% (85·8-90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76-1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3-4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths., Interpretation: At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing., Funding: Pfizer., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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.

Purpose: Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1,000-fold lower error rate than conventional sequencing., Experimental Design: We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2- metastatic breast cancer (MBC) sampled within 6 months following metastatic diagnosis and 142 patients with stage 0 to III breast cancer who received curative-intent treatment with most sampled at surgery and 1 year postoperative. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples., Results: Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median = 57; range = 2-346). Clinical sensitivity was 81% ( n = 13/16) in newly diagnosed MBC, 23% ( n = 7/30) at postoperative and 19% ( n = 6/32) at 1 year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at 1 year was strongly associated with distant recurrence [HR = 20.8; 95% confidence interval, 7.3-58.9]. Median lead time from first positive sample to recurrence was 18.9 months (range = 3.4-39.2 months)., Conclusions: Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track., (©2020 American Association for Cancer Research.)

Purpose: Platinum compounds have activity in triple-negative breast cancer (TNBC) in germline BRCA mutation carriers ( BRCA carriers). Limited data exist for estrogen receptor (ER)-positive (+) breast cancer among BRCA carriers. INFORM is a randomized, multicenter, phase II trial comparing pathologic complete response (pCR) rates (ypT0/is, N0) after neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin-cyclophosphamide (AC) in BRCA carriers with stage I-III human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Secondary objectives included residual cancer burden scores (RCB) of 0 or 1 (combined) and toxicity. The goal was to determine whether pCR was ≥ 20% higher with CDDP than AC., Patients and Methods: BRCA carriers with cT1-3 (≥ 1.5 cm), cN0-3 HER2-negative breast cancer were randomly assigned to preoperative CDDP (75 mg/m 2 every 3 weeks × 4 doses) or AC (doxorubicin 60 mg/m 2 ; cyclophosphamide 600 mg/m 2 every 2-3 weeks × 4 doses) followed by surgery. Pathologic responses were confirmed by central review., Results: A total of 118 patients were randomly assigned; 117 were included in outcome analyses. Mean age was 42 years (range, 24-73 years); 69% were BRCA1 +, 30% were BRCA2 +, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% had nodal involvement at baseline. Seventy percent had TNBC. Clinical and tumor characteristics were well matched between treatment arms. The pCR rate was 18% with CDDP and 26% with AC, yielding a risk ratio (RR) of 0.70 (90% CI, 0.39 to 1.2). The risk of RCB 0 or 1 (RCB 0/1) was 33% with CDDP and 46% with AC (RR, 0.73; 90% CI, 0.50 to 1.1). Both regimens were generally well tolerated without unexpected toxicities., Conclusion: pCR or RCB 0/1 is not significantly higher with CDDP than with AC in BRCA carriers with stage I-III HER2-negative breast cancer for both TNBC and ER+/HER2-negative disease.

Purpose: Preclinical data demonstrating androgen receptor (AR)-positive (AR + ) triple-negative breast cancer (TNBC) cells are sensitive to AR antagonists, and PI3K inhibition catalyzed an investigator-initiated, multi-institutional phase Ib/II study TBCRC032. The trial investigated the safety and efficacy of the AR-antagonist enzalutamide alone or in combination with the PI3K inhibitor taselisib in patients with metastatic AR + (≥10%) breast cancer., Patients and Methods: Phase Ib patients [estrogen receptor positive (ER + ) or TNBC] with AR + breast cancer received 160 mg enzalutamide in combination with taselisib to determine dose-limiting toxicities and the maximum tolerated dose (MTD). Phase II TNBC patients were randomized to receive either enzalutamide alone or in combination with 4 mg taselisib until disease progression. Primary endpoint was clinical benefit rate (CBR) at 16 weeks., Results: The combination was tolerated, and the MTD was not reached. The adverse events were hyperglycemia and skin rash. Overall, CBR for evaluable patients receiving the combination was 35.7%, and median progression-free survival (PFS) was 3.4 months. Luminal AR (LAR) TNBC subtype patients trended toward better response compared with non-LAR (75.0% vs. 12.5%, P = 0.06), and increased PFS (4.6 vs. 2.0 months, P = 0.082). Genomic analyses revealed subtype-specific treatment response, and novel FGFR2 fusions and AR splice variants., Conclusions: The combination of enzalutamide and taselisib increased CBR in TNBC patients with AR + tumors. Correlative analyses suggest AR protein expression alone is insufficient for identifying patients with AR-dependent tumors and knowledge of tumor LAR subtype and AR splice variants may identify patients more or less likely to benefit from AR antagonists., (©2019 American Association for Cancer Research.)

Background: Signaling through the cyclin-dependent kinase 4 and 6 (CDK4/6) pathway can mediate therapeutic resistance in HER2-positive breast cancer. Preclinical studies have demonstrated that CDK4/6 inhibitors can resensitize resistant HER2-positive breast cancer to anti-HER2 therapies., Patients and Methods: We conducted a phase 1b/2 study of ribociclib (400 mg per day on a continuous schedule) plus trastuzumab (6 mg/kg every 3 weeks) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. There were no restrictions on the number of prior therapy lines. Primary objective was clinical benefit rate at 24 weeks, and secondary objectives included safety, objective response, rate and progression-free survival. The study was enrolled at ClinicalTrials.gov as NCT02657343., Results: From March 2016 to March 2017, 13 patients were enrolled. One patient was found to have HER2-negative disease and did not receive treatment. Median number of prior lines in the metastatic setting was 5 (range, 0-14); 67% had hormone receptor-positive disease. No dose-limiting toxicities were observed during the safety run-in phase, and ribociclib was thus dosed at 400 mg per day continuously for the expansion cohort. Grade 3 adverse events were observed in 4 patients (33.3%) and included neutropenia (n = 2) as well as fatigue and pain in 1 patient each. No grade 4/5 adverse events or QTc prolongation were observed. One patient (8.3%) experienced stable disease > 24 weeks; no objective responses were observed, and median progression-free survival was 1.33 months (95% confidence interval, 0.92-2.57)., Conclusion: Continuous low-dose ribociclib (400 mg) plus trastuzumab is safe, with no new safety concerns. The limited activity observed in this study suggests that further study of CDK4/6 inhibitor/anti-HER2 combinations should focus on a less pretreated population., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The incidence of breast cancer diagnosed during pregnancy is increasing. We sought to characterize patient, treatment, pregnancy and lactation factors among young women with newly diagnosed breast cancer during pregnancy in a prospective cohort study. We identified all women who were pregnant when diagnosed with invasive breast cancer among those enrolled in the Young Women's Breast Cancer Study (NCT01468246), and collected details on pregnancy, birth and lactation from surveys, and treatment information medical record review. Of 1302 enrolled participants, 976 women with invasive breast cancer completed full baseline surveys, among whom 39 (4.0%) patients reported being pregnant at diagnosis. Median age at diagnosis was 34 years (range: 25-40), with stage distribution: I, 28%; II, 44%; III, 23%; and IV, 5%. 74% of patients (29/39) had grade 3 tumors, 59% (23/39) ER-positive, and 31% (12/39) HER2-positive disease. 23 (59%) had surgery during pregnancy, 4 (17%) during the first trimester. Among the women who had surgery during pregnancy, 61% (14/23) underwent lumpectomy, 35% (8/23) unilateral, and 4% (1/23) bilateral mastectomy. All patients who had chemotherapy (51%, 20/39) received it in second and third trimesters, and had ACx4. There were 31 live births, 2 spontaneous, and 5 therapeutic abortions. Among live births, 16 (41%) were before 37 weeks of gestation. Three women reported breastfeeding. Within 6 months after delivery, comprehensive staging in 13 patients showed upstaging in four patients. In a contemporary cohort of young women with breast cancer, pregnancy at diagnosis is relatively uncommon. Treatment during pregnancy can generally be consistent with standard surgical and chemotherapy approaches, with attention to timing of therapies. Longer-term outcomes including effects of some timing issues including delayed use of anti-HER2 therapy on patient outcomes warrant further research., (© 2019 Wiley Periodicals, Inc.)

Background: Based on preclinical work, we found that combination of poly (ADP-ribose) polymerase (PARP) inhibitors with drugs that inhibit the homologous recombination repair (HRR) pathway (such as PI3K inhibitors) might sensitise HRR-proficient epithelial ovarian cancers to PARP inhibitors. We aimed to assess the safety and identify the recommended phase 2 dose of the PARP inhibitor olaparib in combination with the PI3K inhibitor alpelisib in patients with epithelial ovarian cancer and in patients with breast cancer., Methods: In this multicentre, open-label, phase 1b trial following a 3 + 3 dose-escalation design, we recruited patients aged 18 years or older with the following key eligibility criteria: confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of high-grade serous histology; confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of any histology with known germline BRCA mutations; confirmed diagnosis of recurrent breast cancer of triple-negative histology; or confirmed diagnosis of recurrent breast cancer of any histology with known germline BRCA mutations. Additional patients with epithelial ovarian cancer were enrolled in a dose-expansion cohort. Four dose levels were planned: the starting dose level of alpelisib 250 mg once a day plus olaparib 100 mg twice a day (dose level 0); alpelisib 250 mg once a day plus olaparib 200 mg twice a day (dose level 1); alpelisib 300 mg once a day plus olaparib 200 mg twice a day (dose level 2); and alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Both drugs were administered orally, in tablet formulation. The primary objective was to identify the maximum tolerated dose and the recommended phase 2 dose of the combination of alpelisib and olaparib for patients with epithelial ovarian cancer and patients with breast cancer. Analyses included all patients who received at least one dose of the study drugs. The trial is active, but closed to enrolment; follow-up for patients who completed treatment is ongoing. This trial is registered with ClinicalTrials.gov, number NCT01623349., Findings: Between Oct 3, 2014, and Dec 21, 2016, we enrolled 34 patients (28 in the dose-escalation cohort and six in the dose-expansion cohort); two in the dose-escalation cohort were ineligible at the day of scheduled study initiation. Maximum tolerated dose and recommended phase 2 dose were identified as alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Considering all dose levels, the most common treatment-related grade 3-4 adverse events were hyperglycaemia (five [16%] of 32 patients), nausea (three [9%]), and increased alanine aminotransferase concentrations (three [9%]). No treatment-related deaths occurred. Dose-limiting toxic effects included hyperglycaemia and fever with decreased neutrophil count. Of the 28 patients with epithelial ovarian cancer, ten (36%) achieved a partial response and 14 (50%) had stable disease according to Response Evaluation Criteria in Solid Tumors 1.1., Interpretation: Combining alpelisib and olaparib is feasible with no unexpected toxic effects. The observed activity provides preliminary clinical evidence of synergism between olaparib and alpelisib, particularly in epithelial ovarian cancer, and warrants further investigation., Funding: Ovarian Cancer Dream Team (Stand Up To Cancer, Ovarian Cancer Research Alliance, National Ovarian Cancer Coalition), Breast Cancer Research Foundation, Novartis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)