PURPOSE:In TBCRC 022 (NCT01494662), neratinib and ado-trastuzumab emtansine (T-DM1) demonstrated intracranial activity among patients with HER2-positive breast cancer brain metastases. However, gastrointestinal (GI) toxicities-particularly diarrhea-were common, potentially impacting quality of life. Clinician-reported adverse event (CTCAE) grading may underestimate the patient experience. We report GI toxicities using patient-reported outcomes (PROs) in TBCRC's neratinib-T-DM1 cohort. METHODS:Patients received neratinib (160 mg daily) and T-DM1 (3.6 mg/kg IV every 21 days). A pre-planned analysis assessed patient-reported GI toxicities during Cycles 1-4 using the Patient-reported Outcomes Measurement Information System (PROMIS) GI Diarrhea scale, Systemic Therapy-Induced Diarrhea Assessment Tool (STIDAT), and PRO-CTCAE. Descriptive statistics and linear mixed effects models evaluated symptom trajectories over time. We evaluated agreement for PRO and clinician-reported data. RESULTS:Forty-four patients enrolled; all completed ≥1 PRO. GI symptom burden increased over Cycles 1-3. PROMIS scores worsened significantly by Cycle 2, with a peak mean increase of 6.62 (95% confidence interval (CI): 2.67-10.59; p = 0.002) at Cycle 3. STIDAT scores also worsened by Cycle 3 (mean change 0.50; 95%CI: 0.11-0.90; p = 0.015). Based on maximum PRO-CTCAE scores, moderate-to-severe symptoms were reported by 20.5% (diarrhea), 24.4% (appetite loss), and 41.0% (constipation). Agreement between PRO-CTCAE and clinician-reported CTCAE was low (kappa <0.2) with clinicians reporting less toxicity. PROMIS and STIDAT scores were significantly correlated. CONCLUSION:This GI-focused PRO analysis highlights the value of PROs in capturing patient-experienced toxicities that impact quality of life yet are underestimated by clinicians. Incorporating PROs into clinical trials can inform supportive care and prophylactic strategies.

e22546 Background: Risk-reducing interventions (RRI) reduce cancer risk for patients with pathogenic/likely pathogenic germline variants (PGV) associated with hereditary breast cancer. Uptake varies widely and may be influenced by stage at diagnosis, PGV penetrance, race, and healthcare setting. Data describing RRI utilization by stage and PGV risk, particularly in safety-net systems, remain limited. Methods: We conducted a retrospective cohort study of breast cancer patients with PGV treated at Harris Health System (HHS), a public safety-net hospital, and Baylor St. Luke’s Medical Center (BSLMC), a private academic hospital. Patients diagnosed between October 2009 and September 2019 were included (N = 404; 151 HHS, 253 BSLMC). PGVs were categorized as high-risk (BRCA1, BRCA2, PALB2, PTEN, TP53), or moderate-risk (ATM, CHEK2, other). RRI included risk-reducing breast or gynecologic surgery. Descriptive statistics summarized RRI rates by stage at diagnosis, PGV risk, race, and hospital system. Results: RRI utilization was observed across stages 0 - III, with higher rates among patients diagnosed at earlier stages; no RRIs were observed among stage IV patients. Patients with high-risk PGVs consistently demonstrated higher RRI rates than those with moderate-risk PGVs at all stages. RRI utilization was higher at HHS than at BSLMC, particularly among patients with high-risk PGVs, with variation persisting by stage and PGV risk across hospital systems. Hispanic patients were most likely to undergo RRI and were predominantly treated at HHS. Conclusions: RRI utilization among breast cancer patients with PGVs varies by stage at diagnosis, PGV risk, and healthcare setting. Higher uptake among patients with high-risk PGVs and earlier-stage disease highlights the role of clinical context in RRI decision-making. These findings support further investigation into how access, counseling, and system-level factors influence equitable delivery of risk-reducing care. Percentage of patients utilizing risk-reducing interventions by stage and pathogenic germline variant at safety-net and academic hospital. Overall High-Risk% (Total n) Overall Moderate- Risk% (Total n) Safety-Net High-Risk% (Total n) Safety-Net Moderate- Risk% (Total n) Academic Hospital High-Risk% (Total n) Academic Hospital Moderate- Risk% (Total n) Stage 0 86.67 (15) 23.53 (17) 88.89 (9) 0.00 (2) 83.33 (6) 26.67 (15) Stage I 65.79 (38) 32.26 (31) 75.00 (16) 40.00 (5) 59.09 (22) 30.77 (26) Stage II 70.15 (67) 26.67 (30) 80.49 (41) 50.00 (4) 53.85 (26) 23.08 (26) Stage III 64.71 (51) 31.58 (19) 67.57 (37) 20.00 (5) 57.14 (14) 35.71 (14) Stage 0-1 71.70 (53) 29.17 (48) 80.00 (25) 28.57 (7) 64.29 (28) 29.27 (41) Stage II-III 67.80 (118) 28.57 (49) 74.36 (78) 33.33 (9) 55.00 (40) 27.50 (40) High-risk PGVs include BRCA1, BRCA2, PALB2, PTEN, P53. Medium-risk PGVs include ATM, CHEK2, other.

Supplementary Figure S1. Study design and tissue availability for biomarker analysis.

The diagnosis of metastatic breast cancer (MBC) marks a transition from curative to palliative care, bringing significant psychosocial challenges, often exacerbated by racial and ethnic disparities. This mixed-methods study, grounded in the socioecological model, sought to examine distress levels among MBC patients and caregivers across academic and safety-net healthcare settings and to explore how individual, interpersonal, and system-level factors—shaped by intersecting identities such as race/ethnicity and socioeconomic status—influence unmet supportive care needs and intervention preferences. Surveys and interviews were conducted with a racially and ethnically diverse group of MBC patients (N = 27) and caregivers (N = 19), recruited from a comprehensive cancer center with academic practice and safety-net hospital affiliates. Quantitative analyses found no significant differences in distress levels between patients at safety-net and academic hospitals or between patients and caregivers. Qualitative analysis identified six categories of supportive care needs: personalized supportive care, comprehensive health and symptom management, emotional and psychosocial support, interpersonal and family support, sexual health and intimacy support, and equitable access to care—with patients and caregivers strongly preferring targeted, multilevel interventions to address these needs. Findings underscore the multifaceted nature of MBC care needs and the importance of developing targeted interventions to address the individual, interpersonal, and systemic challenges faced by patients and caregivers.

Supplementary Figure S4. Decision tree algorithm to construct the multiparameter classifier of response in TBCRC023.

Supplementary Figure S3. Distribution of intrinsic subtypes in (A) TBCRC023 and (B) PAMELA cohort.

Supplementary Figure S6. Distribution of HER2 gene ratio in relation to PIK3CA mutation status and HER2-enriched subtype.

Background: Current medications to prevent breast cancer (BC) are the antiestrogens tamoxifen, raloxifene, anastrozole and exemestane which can prevent 50% of ER+ BC. However, because they can have side effects and require 5 years of continuous use, women who are yet cancer-free are often reluctant to take them. Furthermore, antiestrogens do not prevent ER- BC. Therefore, it is urgent that we develop alternative prevention drugs that require only a short-term treatment and are suitable for preventing both ER+ and ER- BC. No prevention strategies have been developed for ER- or HER2+ subtypes, the most virulent forms of the disease. Ruxolitinib is a small molecule which selectively inhibits the activities of Janus Associated Kinases (JAK); activated JAK phosphorylate STATs leading to modulation of gene expression. In animal models, ruxolitinib prevents progression of premalignant breast lesions to invasive BC. Studies in several human tissue types suggest that there are anticancer “barriers,” namely apoptosis and senescence, which are erected in early lesions to prevent the progression to cancer. We hypothesize that the JAK2-STAT5 pathway in human premalignant lesions promotes the progression of these lesions to malignancy by lowering the apoptosis anticancer barrier; therefore, inhibition of this pro-survival pathway could reduce the load of premalignant lesions in the breast and thus lower BC risk. We are conducting a window-of-opportunity trial through the Translational Breast Cancer Research Consortium (TBCRC) to test whether short-term ruxolitinib treatment of subjects with premalignant lesions will result in increased apoptosis. Trial Design: This is a phase II, double-blind, placebo-controlled clinical trial. Our target population consists of patients with premalignant breast lesions requiring surgical excision. Subjects will be randomized 1:1 to receive either ruxolitinib 20 mg twice daily or placebo for ∼15 days after which they will proceed with standard of care surgical excision within 12 hours of the last dose. Key Eligibility Criteria: 1) Breast biopsy showing atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, or ductal carcinoma in situ requiring surgical excision 2) Adequate hematologic and organ function 3) Willing to not use concomitant strong CYP3A4 inhibitors Statistical Methods: The primary endpoint is change in apoptosis, as measured by cleaved caspase-3 staining, in surgical samples relative to baseline biopsy. Lesions of different types will be characterized separately, and the participant’s most advanced lesion present at baseline will be used for the primary analysis. The difference in changes between groups will be evaluated using the Wilcoxon rank sum test. The secondary objectives primarily focused on the effects of ruxolitinib treatment on biomarkers. The secondary endpoints include pre- and post-treatment pSTAT5, TUNEL, Ki67, BCLxL, MCL1, BCL2, PRLR, pSTAT3, and serum prolactin levels. Changes in these markers will be compared between groups using the Wilcoxon rank sum test. Accrual: We expect to enroll 100 subjects from 7 sites in the US in order to obtain 70 evaluable subjects. Currently there are 80 subjects enrolled. Contact Information: For more information on this trial, please visit clinicaltrials.gov NCT02928978 Citation Format: Julie Nangia, Shaun Bulsara, Tao Wang, Amy Ku, Derek Thomas, Ingrid Meszoely, Parijatham S. Thomas, Catherine Parker, Sheldon Feldman, Carla Fisher, Kristalyn Gallagher, Gaorav Gupta, Alastair Thompson, Kristen Otte, Carolina Gutierrez, Chandandeep Nagi, George Miles, Susan Hilsenbeck, Yi Li, C. Kent Osborne, Mothaffar Rimawi. A Randomized Phase II Window-of-opportunity Trial of Ruxolitinib in Patients with High Risk and Premalignant Breast Conditions [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-12-19.

Supplementary Figure S5. Decision tree algorithm to construct the multiparameter classifier of response in PAMELA.

Supplementary Figure S2. Distribution of HER2 gene ratio and protein in the two neoadjuvant cohorts.

Background: Adjuvant endocrine therapy (ET) recommendations for patients (pts) with invasive lobular carcinoma (ILC) are no different than for other breast cancer subtypes. However, due to unique differences in estrogen pathway signaling of ILC, identifying biological markers of ET sensitivity or resistance could have a major impact on its clinical management. Pre-clinical studies suggest that fulvestrant may be more effective than anastrozole or tamoxifen for ILC. Here we test reduction in the proliferation marker Ki67 as a surrogate for treatment response to ET. Methods: This open label, randomized, controlled, multicenter phase 0 window of opportunity trial (NCT02206984) was conducted at 12 TBCRC institutions between 10/8/15 and 7/28/23. Postmenopausal women with previously untreated hormone receptor-positive (HR+), HER2 negative ILC, centrally histologically confirmed on diagnostic core needle biopsy (CNB), measuring ≥ 1 cm, were eligible. Stage IV was excluded. Pts were randomized 1:1:1 to fulvestrant (500 mg IM on days 1 and 15), anastrozole (1mg/day) or tamoxifen (20 mg/day). After 21-27 days of treatment, pts underwent operation (from which a CNB of residual tumor bed was taken) or a post-treatment image-guided CNB. The primary endpoint was change in Ki67 immunohistochemistry at post-treatment compared to baseline. Given the log-normal distribution of Ki67 measurements generally observed in this population, values were log-transformed for statistical analysis [log (post/pre)]. Group medians were compared using a quantile regression linear model adjusting for institutional-level random effects. A linear mixed model (glmmTMB R package) was fit that allowed for treatment level error variance. Post-hoc pairwise comparison of log(post/pre) were performed using Tukey adjustment for multiple comparison. Results: 201 women were randomized, 172 completed the assigned treatment, and 138 (fulvestrant n=37; anastrozole n=49; tamoxifen n=52) had evaluable pre- and post-treatment tissue. No serious adverse events or deaths occurred. Pre-treatment demographic and tumor characteristics were well-balanced between the treatment groups. Median [range] age was 67 [48-86] years. Race was reported as Asian in 2 (1.5%), Black in 15 (10.9%), other in 4 (2.9%) and White in 117 (84.8%). Presenting clinical stage was IA in 54 (39.1%), IB in 4 (2.9%), IIA in 51 (37%), IIB in 19 (13.7%), IIIA in 4 (2.9%), IIIB in 5 (3.6%), and IIIC in 1 (0.7%). Median H-score [IQR] was ER 260 [50], PR 140 [215]. In the fulvestrant, anastrozole and tamoxifen groups respectively, pre-treatment Ki67 [IQR] was 13.8 [13.5], 13.6 [8.7], and 12.6 [11.9]; and post-treatment Ki67 [IQR] was 4.8 [5.4], 4.5 [5.6], and 5.7 [10]. A statistically significant reduction in Ki67 was found favoring fulvestrant vs tamoxifen (p=0.0419). No significant difference after adjustment was seen between anastrozole and tamoxifen (p = 0.2602) or between fulvestrant and anastrozole (p = 0.6643). Conclusions: A greater reduction in Ki67 was seen post-treatment in CNB of pts with ILC treated with fulvestrant vs tamoxifen. Interestingly, tamoxifen treatment resulted in a reduction in Ki67 of a similar magnitude to anastrozole, despite clinical concerns about its reduced efficacy in ILC. Planned correlative studies will determine whether Ki67 reduction is associated with alterations in expression of ER and ER-regulated genes and/or in other novel pathways, potentially opening avenues for improved treatment strategies in ILC. Citation Format: Priscilla McAuliffe, Clark BZ, Hieken TJ, Mukhtar RA, Linden H, Nangia J, Gallagher K, Stringer-Reasor E, Bedrosian I, Feldman S, Nanda R, Boisvert M, Rothman J, Sikora MJ, Atkinson JM, Thorpe H, Tatsuoka C, Lee AV, Thompson A, Davidson NE, Oesterreich S, Jankowitz RC; on behalf of the Translational Breast Cancer Research Consortium (TBCRC). Endocrine Response in Women with Invasive Lobular Carcinoma (TBCRC 037): A Multicenter Randomized Clinical Trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS18-09.

Background: Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinibecapecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. Patients and methods: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A- previously untreated BCBM, cohorts 4B and 4C-BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed. Results: Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%50% experienced stable disease for > 6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months. Conclusions: We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated.

Purpose/Objective(s) This project aims to ensure compliance with Commission on Cancer (CoC) Standard 7.1 by focusing on timely delivery of breast-conserving surgery (BCS) radiation treatment (BCSRT) for patients under 70, acknowledging the impact of delays on patient outcomes. Materials/Methods Utilizing the Institute for Healthcare Improvement (IHI) model, a systematic approach was employed to address delays in initiating radiation therapy (RT) post-breast cancer diagnosis in patients undergoing BCS. Delays were identified through regular BCSRT reports, indicating a significant dead time of almost three weeks after surgery until radiation referrals.1. Modification of health care software radiation referral forms for efficient triage.2. Adjustment of the interdisciplinary referral workflow to initiate radiation oncology referrals at or before surgery.3. Establishment of points of contact from medical, radiation, and surgical oncology disciplines for streamlined communication.4. Integration of internal and external checks to enhance workflow from surgery to radiation, including modifications to the Quality Checklist (QCL) in Moasiq for improved chemotherapy sequencing coordination.BCSRT rate ensuring the time from breast cancer diagnosis to RT initiation is <365 days in ≥90% of BCSRT patients at the end of one year. Process measure: Percentage of referrals made to radiation oncology before surgery (PreSRef), tracking trends in pre-intervention referrals compared to post-intervention. Results Pre-intervention, the median BCSRT rate was 78.24%. Following the first PDSA cycle, PreSRef increased from 20% to 32%. After the second cycle, it improved to 34.4%. Subsequent to the third PDSA cycle, the outcome measure surpassed the goal, achieving a new median BCSRT rate of 100% and BCSRT Mean = 93.08% Limitations: Notably, a lack of communication with rotating clinical medical oncology fellows was identified during the first PDSA cycle, prompting the initiation of biweekly email alerts for early referrals as an additional intervention. Limitations encountered during subsequent cycles included cases where patients proceeded directly to surgery, necessitating surgeons to initiate radiation referrals for these individuals. Conclusion Enhanced referral processes and interdisciplinary collaboration significantly improved BCSRT rates, surpassing goals. Establishing early radiation oncology referrals as a permanent workflow is crucial for our institution. Future plans involve medical oncologists initiating referrals for neoadjuvant therapy, and surgeons for those proceeding directly to surgery. Triple-negative patients with longer chemotherapy durations face additional delays. Institution-specific prediction models will identify at-risk patients based on clinical and social characteristics.

AbstractPurpose: Clinical trials reported 25% to 30% pathologic complete response (pCR) rates in HER2+ patients with breast cancer treated with anti-HER2 therapies without chemotherapy. We hypothesize that a multiparameter classifier can identify patients with HER2-“addicted” tumors who may benefit from a chemotherapy-sparing strategy. Experimental Design: Baseline HER2+ breast cancer specimens from the TBCRC023 and PAMELA trials, which included neoadjuvant treatment with lapatinib and trastuzumab, were used. In the case of estrogen receptor–positive (ER+) tumors, endocrine therapy was also administered. HER2 protein and gene amplification (ratio), HER2-enriched (HER2-E), and PIK3CA mutation status were assessed by dual gene protein assay (GPA), research-based PAM50, and targeted DNA-sequencing. GPA cutoffs and classifier of response were constructed in TBCRC023 using a decision tree algorithm, then validated in PAMELA. Results: In TBCRC023, 72 breast cancer specimens had GPA, PAM50, and sequencing data, of which 15 had pCR. Recursive partitioning identified cutoffs of HER2 ratio ≥ 4.6 and %3+ IHC staining ≥ 97.5%. With PAM50 and sequencing data, the model added HER2-E and PIK3CA wild-type (WT). For clinical implementation, the classifier was locked as HER2 ratio ≥ 4.5, %3+ IHC staining ≥ 90%, and PIK3CA-WT and HER2-E, yielding 55% and 94% positive (PPV) and negative (NPV) predictive values, respectively. Independent validation using 44 PAMELA cases with all three biomarkers yielded 47% PPV and 82% NPV. Importantly, our classifier's high NPV signifies its strength in accurately identifying patients who may not be good candidates for treatment deescalation. Conclusions: Our multiparameter classifier differentially identifies patients who may benefit from HER2-targeted therapy alone from those who need chemotherapy and predicts pCR to anti-HER2 therapy alone comparable with chemotherapy plus dual anti-HER2 therapy in unselected patients.

1. Supplemental Data: Differential of Toxicity and Eligibility Critique.; 2. Supplemental Figure 1: Gene Expression in Patients With Response to Therapy.

OBJECTIVE:Oncology guidelines for distress management recommend use of the single-item distress thermometer (DT) and accompanying Problem List (PL) to identify patients with high distress levels and their potential sources of distress. However, oncology practices have yet to establish standardized protocols to screen and triage caregivers with high distress levels. With an eye toward integrating caregiver-centered support services into cancer care, this mixed-methods study sought to assess caregiver distress and challenges that may contribute to their distress. METHODS:Nineteen caregivers of metastatic breast cancer patients (60% female, 47% ethnic/racial minority) completed an interview and a survey comprised of the DT, the original 39-item PL, and five additional caregiver-specific PL items. RESULTS:Caregivers reported moderate distress levels and more than half exceeded the National Comprehensive Cancer Network (NCCN) cut-off, denoting significant distress. There was no association between caregiver distress and the number of items endorsed on the original PL. Qualitative analysis identified nine problem domains as areas of caregiver unmet need needs (i.e., practical challenges, caregiving responsibilities, social/relationship issues, caregiver and patient emotional well-being, caregiver and patient physical well-being, spiritual well-being, and communication). Two of the problem domains (caregiving responsibilities and communication) were not captured in any way by the original PL. CONCLUSION:With further research and development, the identified domains could serve as the basis for a caregiver-specific PL to facilitate triage and referral when incorporated as part of routine distress screening.

PURPOSE: Treatment options for patients (pts) with HER2+ BCBM remain limited. We previously reported that neratinib monotherapy is associated with a volumetric central nervous system objective response rate (CNS ORR) of 8%, whereas the combination of neratinib and capecitabine resulted in a volumetric CNS ORR of 49% (in lapatinib-naïve pts). Preclinical data suggest that neratinib may overcome resistance to trastuzumab-emtansine (T-DM1) and that the combination has potential CNS efficacy. Here, we report results of neratinib plus T-DM1 in pts with HER2+ BCBM. PATIENTS AND METHODS: In this prospective, multicenter, phase II study, pts with measurable HER2+ BCBM received neratinib 160 mg orally once daily plus T-DM1 3.6 mg/kg IV every 21 days in three parallel-enrolling cohorts. Cohort 4A enrolled pts with previously untreated brain metastases. Cohort 4B enrolled pts with BCBM progressing after prior local CNS-directed therapy without prior exposure to T-DM1. Cohort 4C enrolled pts with BCBM progressing after prior local CNS-directed therapy who had previous exposure to T-DM1. Diarrhea prophylaxis with colestipol and loperamide was required during cycle 1. Cohorts 4A and 4B were single-stage with a planned enrollment of 20 patients; cohort 4C had a two-stage design, with a requirement for at least 1 of the first 9 pts to achieve a response in order to enroll a total of 24 patients. The primary endpoint was Response Assessment in Neuro-Oncology-Brain Metastases (RANO BM) in each cohort separately. Correlative studies included patient-reported outcomes (PROs) for gastrointestinal toxicity. RESULTS: We enrolled 6, 17, and 21 patients to cohorts 4A, 4B, and 4C, during 11/07/2018 – 11/01/2021. Enrollment was stopped prematurely due to slow accrual. Across Cohorts 4A-4C, the median number of prior lines of chemotherapy prior to enrollment was 2 (range 1-10); 25% received prior lapatinib and no patients received prior tucatinib. In cohorts 4B and 4C (prior CNS-treated cohorts), 33% had prior CNS surgery and >94% had prior CNS radiation. Among evaluable patients, CNS ORR in cohorts 4A (n=6), 4B (n=16), and 4C (n=21) was 50.0% (95% CI 18.8- 81.2%), 25.0% (95% CI 8.3-52.6%), and 38.1% (95% CI 19.0-61.3%), respectively. Median (range) number of cycles completed for 4A, 4B, and 4C was 4.5 (1-15), 4 (range 0-49+), and 6 (0-23); three patients on Cohort 4B remain on protocol therapy (cycles 14, 45, and 49). The overall survival at 12-months for cohorts 4A, 4B, and 4C was 83.3% (95% CI, 58.3-100%), 86.2% (95% CI 70-100%), and 83.3% (95% CI 67.6-100%). Diarrhea was the most common grade 3 toxicity (19.0–33.3% across cohorts); one grade 4 liver function event occurred in cohort 4B. Updated efficacy results will be reported at the meeting; PRO analyses are ongoing. CONCLUSION: Intracranial activity was observed for the combination of neratinib plus T-DM1 across all three enrolled cohorts, including those with prior T-DM1 exposure, suggesting synergistic effects of this treatment combination. Our data provide additional evidence for consideration of neratinib-based combinations in pts with HER2+ BCBM. Citation Format: Rachel Freedman, Siyang Ren, Nabihah Tayob, Rebecca Gelman, Karen L. Smith, Raechel Davis, Alyssa Pereslete, Victoria Attaya, Christine Cotter, Wendy Y. Chen, Cesar Augusto Santa-Maria, Catherine Van Poznak, Beverly Moy, Adam M. Brufsky, Michelle Melisko, Ciara C. O’Sullivan, Nadia Ashai, Yasmeen Rauf, Julie Nangia, Dario Trapani, Jennifer Savoie, Robyn Burns, Antonio C. Wolff, Eric Winer, Mothaffar Rimawi, Ian Krop, Nancy U. Lin. Translational Breast Cancer Research Consortium Trial 022: Neratinib and Trastuzumab-Emtansine for HER2+ Breast Cancer Brain Metastases (BCBM) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD7-03.

Clinicopathologic features stratified by treatment arm (RNA-seq analysis population).