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Abstract Background Transcriptomic immune-related gene signatures have been associated with achievement of pathologic complete response (pCR) and prognosis in the neoadjuvant setting. I-SPY 2 is a multicenter, phase 2 platform trial using response-adaptive randomization within subtypes defined by receptor status (HR/HER2) and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. Given racial disparities in mortality from breast cancer and the paucity of racial demographic data from clinical trials, we aimed to evaluate the association between racial groups and baseline characteristics, including expression-based subtypes and immune signatures, treatment response, and prognosis of patients enrolled in the I-SPY 2 TRIAL. Methods Our study population included 990 I-SPY 2 patients. 15 patients identified as part of a racial group with <10 patients enrolled in the trial and were excluded from analysis. Pre-treatment expression data was available for 971 patients. Follow-up data was available for 907 patients; median follow-up time of 4.4 yrs. Chi-square test was used to assess associations between racial groups and pre-treatment SBR grade, HR/HER2 defined subtypes, intrinsic subtype (defined by BluePrint 80-gene molecular subtyping) and residual cancer burden (RCB) class. Logistic regression was used to evaluate race association with pCR. Cox proportional hazard modeling was used to assess the association between racial groups and event free survival (EFS) in a univariate setting, adjusting for pCR status. Association between racial groups and 28 expression signatures related to immune, proliferation, ER and HER2 pathway was analyzed using ANOVA with post-hoc Tukey test in the overall population and in each receptor subtype. Results Of 975 patients included in our analysis, 787 (81%) were White, 68 (7%) were Asian, and 120 (12%) were Black or African American. No significant associations between race and pre-treatment SBR grade (p=0.49), HR/HER2 defined subtypes (p=0.09), or expression-based subtypes (p=0.25) were observed. pCR rates do not significantly differ by racial groups (Odds ratio of pCR relative to White: 1.00 for Asian and 0.89 for Black or African American); and no significant differences in RCB class distribution by race was observed (p=0.88). Event free survival was not associated with patient racial group in a univariate Cox model (Hazard ratio relative to White: 1.10, p=0.73 for Asian and 1.37, p=0.13 for Black or African American). Among the 28 expression signatures evaluated, four were differentially expressed among racial groups within the overall population (F-test p<0.05): IFN module, B cell signature, Dendritic cell signature, and Mitotic score. Pairwise comparisons between racial groups with post-hoc Tukey test identified significant differences in IFN module expression between Black or African American vs. White (p=0.019) and Dendritic cell signature expression between Asian vs White (p=0.047). Among patients in the TNBC subtype, three signatures (dendritic cell signature, macrophage signature and ERBB2 module) were differentially expressed between Black or African American and White patients (p=0.002, 0.016 and 0.007). Conclusion Our analysis demonstrates that among women with high risk breast cancer, race does not affect subtype specific response rates nor event free survival. Distribution of subtypes previously shown to be associated with pCR in the I-SPY2 trial did not significantly differ among racial groups indicating race is less likely than tumor biology to predict response. The decreased expression of immune signatures observed in Black or African American women with TNBC suggests possible differential sensitivity to immunotherapy plus combination chemotherapy. Tumor immune multiplex studies are underway to further investigate. Citation Format: Beverly Kyalwazi, Christina Yau, Olufunmilayo Olopade, A. Jo Chien, Anne Wallace, Andres Forero-Torres, Lajos Pusztai, Erin Ellis, Kathy Albain, Anne Blaes, Barbara Haley, Judy Boughey, Anthony Elias, Amy Clark, Claudine Isaacs, Rita Nanda, Hyo Han, Rachel Yung, Debu Tripathy, Kristen Edmiston, Rebecca Viscusi, Donald Northfelt, Qamar Khan, Ashish Sanil, Scott Berry, Smita Asare, Amy Wilson, Gillian Hirst, Nola Hylton, Michelle Melisko, Jane Perlmutter, Hope Rugo, Fraser Symmans, Laura van ‘t Veer, Donald Berry, Laura Esserman. Analysis of clinical outcomes and expression-based immune signatures by race in the I-SPY 2 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-02.

Abstract Background Advances in the multidisciplinary care of hormone-receptor positive (HR+) early breast cancer (eBC) have markedly improved clinical outcomes: however, disease recurrence may still occur, particularly in patients (pts) with moderate or high-risk cancers at the time of diagnosis. The use of CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) is a standard of care for advanced breast cancer, supporting the rationale to study CDK4/6i in the eBC setting. Here we present the final protocol-planned analyses of the global phase III PALLAS trial investigating whether the addition of the CDK4/6i palbociclib (P) to adjuvant ET improves outcomes over ET alone for HR+/HER2- eBC. Methods PALLAS (PALbociclib CoLlaborative Adjuvant Study, NCT02513394) is a randomized phase III open-label trial in which pts with stage II-III HR+/HER2- eBC were randomized to receive either 2 years of P with adjuvant ET (P+ET) or ET alone. The primary endpoint is invasive disease-free survival (iDFS); secondary endpoints include distant recurrence-free survival (DRFS), locoregional recurrence-free survival (LRRFS), overall survival (OS), and safety. Mandatory biospecimen collection has supported the creation of an expansive translational science program, and long-term follow-up is planned. Revised sample size calculations required recruitment of 5600 pts in order to detect a 25% iDFS improvement in patients receiving P+ET with 85% power; this final protocol-planned analysis was planned after 469 iDFS events. Results From September 1, 2015 to November 30, 2018, 5,761 pts (median age 52 years, range 22-90) were randomized in 406 centers in 21 countries worldwide. 1,014 (17.6%) had stage IIA disease (capped) and 4,728 (82.1%) stages IIB/III. 4,754 (82.5%) had received prior (neo)adjuvant chemotherapy. After a protocol-planned 2nd interim analysis in May 2020 crossed the futility threshold, 349 P+ET pts still on active treatment stopped P and were transferred to follow-up. At the time of final analysis cutoff date (November 20, 2020), after a median follow-up of 31 months and 516 events recorded, iDFS was similar between the two arms, with 3-year iDFS of 89.3% (95% CI: 87.8-90.6%) for Palbo+ET, and 89.4% (88.0-90.7%) for ET alone (hazard ratio 0.96, 95% CI: 0.81-1.14). There was no statistically significant difference in secondary outcome endpoints. Subgroup analyses revealed no significant interactions between treatment effect and other factors (including risk category). The safety profile of P was as expected, with grade 3 or 4 neutropenia the most common side effect (safety population: 1759/2841 [61.9%] vs 11/2902 [0.4%]). Overall 42% of pts. discontinued P prior to the planned 2-year duration, 28.2% of Palbo+ET pts discontinued therapy due to adverse events, without an observed impact on survival outcomes. Conclusions Now with the full number of events, this analysis of the PALLAS trial shows that the addition of 2 years of P to ongoing adjuvant ET did not improve survival endpoints for pts with stage II-III HR+/HER2- eBC. Whether P is beneficial in the adjuvant setting for certain sub-groups of pts will be further evaluated with longer-term follow-up and by the ongoing translational science program. Support: ABCSG; AFT; Pfizer; ClinicalTrials.gov Identifier: NCT02513394; https://www.abcsg.org; https://acknowledgments.alliancefound.org Citation Format: Michael Gnant, Amylou C Dueck, Sophie Frantal, Miguel Martin, Hal Burstein, Richard Greil, Peter Fox, Antonio C Wolff, Arlene Chan, Eric Winer, Christian Singer, Kathy Miller, Marco Colleoni, Michelle Naughton, Gabor Rubovszky, Judith Bliss, Ingrid A Mayer, Guenther G Steger, Zbigniew Nowecki, Olwen Hahn, Norman Wolmark, Hope Rugo, Georg Pfeiler, Hannes Fohler, Otto Metzger, Céline Schurmans, Kathy P Theall, Dongrui R Lu, Kathleen Tenner, Christian Fesl, Angela DeMichele*, Erica L Mayer, *shared last authorship. Adjuvant palbociclib in HR+/HER2- early breast cancer: Final results from 5,760 patients in the randomized phase III PALLAS trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-07.

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.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor–positive, HER2-negative breast cancer.

Hematopoietic growth factors, including erythrocyte stimulating agents (ESAs), granulocyte colony-stimulating factors, and thrombopoietin mimetics, can mitigate anemia, neutropenia, and thrombocytopenia resulting from chemotherapy for the treatment of cancer. In the context of pandemic SARS-CoV-2 infection, patients with cancer have been identified as a group at high risk of morbidity and mortality from this infection. Our subcommittee of the NCCN Hematopoietic Growth Factors Panel convened a voluntary group to review the potential value of expanded use of such growth factors in the current high-risk environment. Although recommendations are available on the NCCN website in the COVID-19 Resources Section (https://www.nccn.org/covid-19/), these suggestions are provided without substantial context or reference. Herein we review the rationale and data underlying the suggested alterations to the use of hematopoietic growth factors for patients with cancer in the COVID-19 era.

Abstract Background: In MONARCH 2, abemaciclib plus fulvestrant significantly improved median progression-free survival (PFS, 16.4 vs 9.3 months, hazard ratio [HR], 0.553) and overall survival (OS, 46.7 vs 37.3 months; HR, 0.757) compared with placebo plus fulvestrant in hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) advanced breast cancer (ABC) patients who were endocrine therapy (ET) resistant, regardless of menopausal status. Here, we report findings in the premenopausal subgroup of the MONARCH 2 trial. Methods: The premenopausal subgroup included patients with natural menstrual bleeding who received a gonadotropin-releasing hormone agonist at least 4 weeks prior to study treatment start date and for the entire study duration. Of the 669 patients enrolled in the MONARCH 2 trial, 114 were premenopausal (abemaciclib plus fulvestrant, n=72; placebo plus fulvestrant, n=42), and were included in this analysis. The primary objective was investigator-assessed PFS and secondary objectives were OS, objective response rate, and safety and tolerability. Exploratory analyses included time to second disease progression (PFS2), time to chemotherapy (TTC), and chemotherapy-free survival (CFS). Results: At the primary objective cutoff (14 February, 2017), median PFS was not reached for the abemaciclib plus fulvestrant arm versus 10.52 months for the placebo plus fulvestrant arm (HR, 0.415; 95% CI, 0.246-0.698). At the pre-specified OS interim cutoff (20 June, 2019), median PFS was 28.6 months in the abemaciclib plus fulvestrant arm compared with 10.26 months in the placebo plus fulvestrant arm (HR, 0.477; 95% CI, 0.302-0.755). OS benefit was observed in the abemaciclib plus fulvestrant compared to fulvestrant alone (HR, 0.689; 95% CI, 0.379-1.252, median, not reached vs 47.3 months). Improvements were also observed for the exploratory outcomes of PFS2 (HR, 0.599), TTC (HR, 0.674), and CFS (HR, 0.642) with the addition of abemaciclib to fulvestrant. The safety profile was generally consistent with results disclosed previously. Conclusions: Results of the premenopausal subgroup in the MONARCH 2 trial were consistent with the improved clinical outcomes observed in the intent-to-treat population. The analysis provides support for the use of abemaciclib plus fulvestrant (with ovarian suppression) as an effective treatment option for premenopausal patients with HR+, HER2- ABC who are ET-resistant. Clinical trial registration: NCT02107703. Registered 08 April 2014- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02107703

PURPOSE The ATEMPT trial was designed to determine if treatment with trastuzumab emtansine (T-DM1) caused less toxicity than paclitaxel plus trastuzumab (TH) and yielded clinically acceptable invasive disease-free survival (iDFS) among patients with stage I human epidermal growth factor receptor 2–positive (HER2+) breast cancer (BC). METHODS Patients with stage I centrally confirmed HER2+ BC were randomly assigned 3:1 to T-DM1 or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or T 80 mg/m 2 IV with H once every week × 12 weeks (4 mg/kg load →2 mg/kg), followed by H × 39 weeks (6 mg/kg once every 3 weeks). The co-primary objectives were to compare the incidence of clinically relevant toxicities (CRTs) in patients treated with T-DM1 versus TH and to evaluate iDFS in patients receiving T-DM1. RESULTS The analysis population includes all 497 patients who initiated protocol therapy (383 T-DM1 and 114 TH). CRTs were experienced by 46% of patients on T-DM1 and 47% of patients on TH ( P = .83). The 3-year iDFS for T-DM1 was 97.8% (95% CI, 96.3 to 99.3), which rejected the null hypothesis ( P < .0001). Serially collected patient-reported outcomes indicated that patients treated with T-DM1 had less neuropathy and alopecia and better work productivity compared with patients on TH. CONCLUSION Among patients with stage I HER2+ BC, one year of adjuvant T-DM1 was associated with excellent 3-year iDFS, but was not associated with fewer CRT compared with TH.

TPS1111 Background: Chest wall recurrence is a subtype of breast cancer that is challenging to treat, and associated with a short duration of response to treatment and an increased risk of development of distant metastases. Given the inflammatory nature of this disease and the association of chest wall disease with lymphovascular invasion, which is correlated with higher programmed cell death 1 (PD-1) expression, we hypothesized that immunotherapy may be beneficial as treatment. Combinations of immunotherapy and chemotherapy have a synergistic effect and demonstrated efficacy in the treatment of metastatic triple negative breast cancer (TNBC). This study is evaluating the efficacy of pembrolizumab, an anti-PD-1 antibody, in combination with carboplatin, in patients with chest wall infiltration from breast cancer. This drug combination has shown efficacy in advanced lung cancer. Methods: This is a multicenter, 2:1 randomized phase II study of pembrolizumab/carboplatin (Arm A, 56 patients) vs. carboplatin (Arm B, 28 patients) in 84 patients with chest wall disease from breast cancer, with or without distant metastases. Patients may have TNBC, hormone receptor positive/HER2 negative (following receipt of 2 prior hormone therapies), or HER2 positive breast cancer (with option to continue trastuzumab on study). Pembrolizumab is administered as 200 mg IV every 3 weeks, and carboplatin as AUC 5 IV every 3 weeks. Patients on Arm A may continue pembrolizumab +/- carboplatin (Arm Ax) after completion of 6 cycles of treatment, while patients in Arm B can cross-over to pembrolizumab (+/- carboplatin) on progression (Arm Bx). Patients must have adequate organ function, performance status ≤ 2, and may have received any number of lines of prior chemotherapy. Patients undergo serial chest wall photography and imaging (CT chest, abdomen, and pelvis, and bone scan) at baseline and every 6 weeks, as well as blood collection for correlative studies and chest wall biopsies at baseline and after 2 cycles of treatment. The primary endpoint is disease control rate (RECIST 1.1) at 18 weeks of treatment, and the study is powered to determine a 20% difference in disease control rates between arms (HR 0.52, a = 0.10, ß = 0.20). An interim analysis will occur for Arm B after 18 patients are enrolled, with a stopping rule for futility. Secondary endpoints include progression-free survival, toxicity (NCI CTCAE), and response based on irRECIST and tumor programmed death ligand 1 (PD-L1) expression. Exploratory objectives include evaluating changes in soluble PD-L1, tumor and peripheral blood immune composition, circulating tumor cells and cell-free DNA, and MYC oncogene expression. This study (NCT03095352) is open at 7 sites in the Translational Breast Cancer Research Consortium (TBCRC). 52 patients are enrolled. Grant funding is provided by Merck and UCSF. Clinical trial information: NCT03095352 .