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Abstract Introduction: Analyses of multiple clinical trials have suggested racial and ethnic disparities in outcomes for early-stage, hormone receptor-positive and HER2-negative (HR+HER2-) breast cancer, however, none of these studies examined the use of adjuvant CDK4/6 inhibitors. The objective of this study was to explore racial and ethnic differences in toxicity, treatment duration, and disease outcomes in patients (pts) with early-stage HR+HER2- breast cancer treated with or without adjuvant palbociclib on the PALLAS trial. Methods: The PALLAS phase III, global, open-label trial randomized 5,796 pts with stage II-III HR+HER2- breast cancer to 2 years of palbociclib plus ongoing provider/patient choice adjuvant endocrine therapy (ET+palbo) vs. ET alone (ET). The analytic cohort was limited to pts enrolled in North America with known self-reported race and ethnicity (Non-Hispanic White, Non-Hispanic Black, Hispanic, Asian or Pacific Islander). Descriptive statistics were used to examine treatment characteristics, early discontinuation, and toxicity by race and ethnicity. Kaplan-Meier curves were used to estimate 3-year locoregional recurrence-free survival (LRFS) and invasive disease-free survival (IDFS) stratified by racial and ethnic group. Cox proportional hazards models were used identify predictors of LRFS and IDFS. Results: 2,547 North American pts were randomized and included in the intent-to-treat population with a median follow-up of 59.8 months; 1,996 (78.4%) identified as Non-Hispanic White (NHW), 132 (5.2%) Non-Hispanic Black (NHB), 156 (6.1%) Hispanic, and 134 (5.3%) Asian or Pacific Islander (API). Stage, performance status, type of surgery, and prior radiation were similar across racial and ethnic groups. Age, body mass index, grade, and prior chemotherapy differed by race and ethnicity (p< 0.05). Median age was lowest in API pts and highest in NHW pts (47.5 vs 53.0 years, respectively). Median body mass index was lowest in API and highest in NHB pts (24.4 vs 30.9). NHB pts were most likely to have high-grade disease (40.9% vs 26.9-30.5% in other groups). NHW pts were least likely to have received prior chemotherapy (81.0% vs 87.1-91.0%). Palbociclib early discontinuation was lowest in NHB pts (50.7%) and highest in Hispanic pts (65.9%), p=0.14. ET early discontinuation was similar across all groups (p=0.35). Palbociclib grade 3-4 overall toxicity was variable across groups (NHW 71.6%, NHB 79.1%, Hispanic 69.5%, API 85.2%), but this variation did not reach statistical significance (p=0.07). Neutropenia was highest in API pts (90.0% vs 57.3% in NHW, 58.2% in NHB, and 51.2% in Hispanic pts, p< 0.01). Overall 3-year LRFS was 98% (95% CI 97-98%) and IDFS was 89% (95% CI 88-90%). LRFS and IDFS were statistically similar by race and ethnicity and within each study arm (Table). No differences in LRFS or IDFS were seen by race or ethnicity in adjusted models (p=0.95). Conclusions: In this clinical trial population of HR+HER2- breast cancer patients exposed to similar treatments, no racial/ethnic differences were seen in short-term LRFS or IDFS across study arms. Differences in palbociclib toxicity by racial and ethnic group, particularly neutropenia, were seen with the highest toxicity in API patients; however, this difference did not translate into early discontinuation of palbociclib or ET. Table: 3-year Kaplan-Meier Survival Outcomes Stratified by Race and Ethnicity Citation Format: Olga Kantor, Oluwadamilola (Lola) Fayanju, Amylou Dueck, Michael Gnant, Harold Burstein, Matthew Goetz, Claudine Isaacs, Lois Shepherd, Olwen Hahn, Daniel Anderson, Kathy Miller, Hope Rugo, Tiffany Traina, Zoneddy Dayao, Katherine Clifton, Eric Winer, Antonio Wolff, Norman Wolmark, Dongrui Lu, Patrick O'Brien, Sara Scovil, Angela DeMichele, Erica Mayer. Racial and Ethnic Differences in Clinical Outcomes among North American Patients with Hormone Receptor-Positive, HER2-negative, Early Breast Cancer in the PALLAS Trial (AFT-05) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-02-05.

Abstract Adolescent and young adults (AYAs) (15-39 years) have a heightened risk of developing a second primary malignancy due to extended periods of survivorship, higher incidence of germline cancer predisposing variants, and increased susceptibility to treatment-induced malignancies. Research on survivors of specific AYA cancer types, including breast cancer (BC) survivors, is limited. Among BC survivors, while much survivorship research focuses on risk of locoregional recurrence or contralateral BC, little is known about overall risk, and risk factors, of developing second non-breast primaries. This prospective cohort study examined women diagnosed with BC from 2006-2016 at age ≤40 years enrolled in the Young Women’s BC Study (YWS) (N=1297). Women were excluded from the analytic cohort if initially diagnosed with Stage IV breast cancer (N=64). To enable investigation of how BC treatments may impact second primary risk, women were also excluded if they reported another cancer before primary BC diagnosis (N=3). Patient characteristics, treatment information, and clinical events were collected via serial surveys. Tumor characteristics and detailed treatment data were obtained from medical record review. Five- and 10-year risk of second non-breast primary was estimated via the cumulative incidence function after applying the Fine-Gray competing risks model with time starting at primary BC diagnosis. Death, metastasis, or diagnosis with a second primary BC were considered as competing events. Univariate and multivariate Fine-Gray sub-distribution models were used to estimate sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CI) for second non-breast primary cancer risk. Risk factors considered included age, race, body mass index, smoking, alcohol use, income, family history of cancer, germline pathogenic variant (PV) carrier status, tumor stage, grade, and ER status, primary surgery type, and receipt of radiation, chemotherapy, or endocrine therapy (yes/no). Multivariate models tested individual associations with additional adjustment for radiation therapy and PV carrier status, as both are consistently associated with second primary in the literature. Over a median follow-up of 10.1 years (inter-quartile range (IQR) =7.9-12.1 y), 47 patients (4%) developed a second non-breast primary cancer. Median age at second non-breast primary was 43 years (IQR=39-46), and median time between primary BC and second non-breast primary was 7.3 years (IQR=4.1-9.3). Second primary types included melanoma (n=10), thyroid (n=10), ovarian (n=4), sarcoma (n=4), uterine (n=3), rectal (n=3), bladder (n=2), cervical (n=2), head and neck (n=2), lung (n=2), lymphoma (n=2), pancreatic (n=2), and kidney (n=1). During the study, 22 patients (2%) developed a second primary BC, 167 (19%) developed metastasis, and 15 (1%) died from causes other than BC. Among the patients who developed a second primary BC, two later developed another non-breast cancer (ovarian and brain cancer). When incorporating competing risks, five and 10-year cumulative incidence of second non-breast primary was 1.4% and 3.2%, respectively. No patient or treatment factors were statistically significantly associated with second non-breast primary in univariate or multivariate models, including radiation and PV carrier status. In this population of young BC survivors, 10-year cumulative incidence of second non-breast primary cancer was 3.2%, with the most common second cancers being melanoma and thyroid cancer. Incidence rates of all second primary cancer types in this cohort were higher than population-based incidence rates for healthy women under 50 years of age, highlighting the importance of long-term surveillance for other cancer events in this young population. While risk of second non-breast primary was not associated with primary BC treatment in this study, cases were limited, and the follow-up interval was relatively short. Citation Format: Bessie Zhang, Kristen Brantley, Shoshana Rosenberg, Gregory Kirkner, Laura Collins, Kathryn Ruddy, Rulla Tamimi, Lidia Schapira, Virginia Borges, Ellen Warner, Steven Come, Eric Winer, Ann Partridge. Second primary non-breast cancers in young breast cancer survivors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-11-10.

Abstract Background: Young BC survivors are at risk for impaired QOL in part due to issues that are unique to their life stage. We sought to characterize trajectories of QOL in the 5 years following diagnosis among young BC survivors as well as evaluate patient and clinical characteristics associated with poorer or deteriorating QOL trajectories over time. Methods: Women diagnosed with stage I-III BC at age ≤40 enrolled in the Young Women’s BC Study, a prospective cohort in North America, who completed ≥2 study surveys through 5 years of post-diagnosis follow-up. QOL was evaluated with the Cancer Rehabilitation Evaluation System (CARES) physical, psychosocial, and sexual subscale scores. Demographic, treatment, and clinical characteristics were ascertained through surveys and chart review. Longitudinal trajectories for each CARES subscale were defined using group-based trajectory modeling; associations between patient/clinical characteristics and trajectory group membership were estimated for each subscale using multivariable multinomial logistic regression. Results: Among 900 women, median age at diagnosis was 36 (range: 17-40) 89% were white, 2% Black, and 4% Hispanic. At baseline, 73% were partnered, 61% parous and 49% perceived themselves as financially comfortable. Most had hormone-receptor positive (74%), HER2-negative (70%) BC, and most received chemotherapy (82%); 36% underwent mastectomy with radiation. Physical and psychosocial scores each clustered into 4 trajectories, with >75% of participants clustering in groups reflecting excellent or good QOL that was stable over time and few (6% for physical and 4% for psychosocial) clustering into groups that reflected poorer QOL at baseline that did not improve over time. Sexual health trajectories were more variable, clustering into 5 trajectories, with over half of participants clustered into groups reflecting good (35%) or excellent (20%) QOL that remained relatively stable over time, 22% clustered into a trajectory that was poor at baseline but moderately improved over follow-up, 13% in a group that reflected deteriorating from moderate-to-poor QOL and 11% in a group with poor QOL at baseline that did not improve over time. In multivariable regression analyses (Table), factors associated with clustering in a poorer trajectory (vs. clustering in an excellent trajectory), in multiple QOL domains included baseline financial discomfort (associated with poorer QOL across all 3 domains), mastectomy+radiation (vs. lumpectomy, associated with poorer QOL across all 3 domains); chemotherapy receipt (associated with poorer physical and sexual health trajectories); and baseline BMI >25 (vs. 18.5-24.9, associated with poorer physical and poorer/deteriorating sexual health trajectories). Conclusions: Young BC survivors follow distinct QOL trajectories in survivorship. While most will not experience substantial QOL impairment through the first 5 years following diagnosis, a substantial minority report persistently poor or deteriorating QOL. The association between more extensive local therapy and poorer physical/psychosocial/sexual health trajectories underscores the importance of communicating the potential for negative QOL outcomes when women are making surgical decisions. Additionally, the pervasive impact of financial wellbeing on multiple QOL domains supports the potential value of systematic screening for and addressing of financial distress to prevent or mitigate financial toxicity in survivorship Factors associated with clustering in poorer/deteriorating (vs. excellent) QOL trajectories *Reference trajectory=excellent QOL Citation Format: Tal Sella, Zheng Yue, Kathryn Ruddy, Shari Gelber, Rulla Tamimi, Jeffrey Peppercorn, Lidia Schapira, Virginia Borges, Steven Come, Eric Winer, Ann Partridge, Shoshana Rosenberg. Five-year quality of life (QOL) trajectories among young breast cancer (BC) survivors [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-12-01.

Importance Observational studies of survivors of breast cancer and prospective trials of aspirin for cardiovascular disease suggest improved breast cancer survival among aspirin users, but prospective studies of aspirin to prevent breast cancer recurrence are lacking. Objective To determine whether aspirin decreases the risk of invasive cancer events among survivors of breast cancer. Design, Setting, and Participants A011502, a phase 3, randomized, placebo-controlled, double-blind trial conducted in the United States and Canada with 3020 participants who had high-risk nonmetastatic breast cancer, enrolled participants from 534 sites from January 6, 2017, through December 4, 2020, with follow-up to March 4, 2023. Interventions Participants were randomized (stratified for hormone receptor status [positive vs negative], body mass index [≤30 vs >30], stage II vs III, and time since diagnosis [<18 vs ≥18 months]) to receive 300 mg of aspirin (n = 1510) or placebo once daily (n = 1510) for 5 years. Main Outcomes and Measures The primary outcome was invasive disease–free survival. Overall survival was a key secondary outcome. Results A total of 3020 participants were randomized when the data and safety monitoring committee recommended suspending the study at the first interim analysis because the hazard ratio had crossed the prespecified futility bound. By median follow-up of 33.8 months (range, 0.1-72.6 months), 253 invasive disease–free survival events were observed (141 in the aspirin group and 112 in the placebo group), yielding a hazard ratio of 1.27 (95% CI, 0.99-1.63; P = .06). All invasive disease–free survival events, including death, invasive progression (both distant and locoregional), and new primary events, were numerically higher in the aspirin group, although the differences were not statistically significant. There was no difference in overall survival (hazard ratio, 1.19; 95% CI, 0.82-1.72). Rates of grades 3 and 4 adverse events were similar in both groups. Conclusion and Relevance Among participants with high-risk nonmetastatic breast cancer, daily aspirin therapy did not improve risk of breast cancer recurrence or survival in early follow-up. Despite its promise and wide availability, aspirin should not be recommended as an adjuvant breast cancer treatment. Trial Registration ClinicalTrials.gov Identifier: NCT02927249

Importance Among women diagnosed with primary breast cancer (BC) at or younger than age 40 years, prior data suggest that their risk of a second primary BC (SPBC) is higher than that of women who are older when they develop a first primary BC. Objective To estimate cumulative incidence and characterize risk factors of SPBC among young patients with BC. Design, Setting, and Participants Participants were enrolled in the Young Women’s Breast Cancer Study, a prospective study of 1297 women aged 40 years or younger who were diagnosed with stage 0 to III BC from August 2006 to June 2015. Demographic, genetic testing, treatment, and outcome data were collected by patient surveys and medical record review. A time-to-event analysis was used to account for competing risks when determining cumulative incidence of SPBC, and Fine-Gray subdistribution hazard models were used to evaluate associations between clinical factors and SPBC risk. Data were analyzed from January to May 2023. Main Outcomes and Measures The 5- and 10- year cumulative incidence of SPBC. Results In all, 685 women with stage 0 to III BC (mean [SD] age at primary BC diagnosis, 36 [4] years) who underwent unilateral mastectomy or lumpectomy as the primary surgery for BC were included in the analysis. Over a median (IQR) follow-up of 10.0 (7.4-12.1) years, 17 patients (2.5%) developed an SPBC; 2 of these patients had cancer in the ipsilateral breast after lumpectomy. The median (IQR) time from primary BC diagnosis to SPBC was 4.2 (3.3-5.6) years. Among 577 women who underwent genetic testing, the 10-year risk of SPBC was 2.2% for women who did not carry a pathogenic variant (12 of 544) and 8.9% for carriers of a pathogenic variant (3 of 33). In multivariate analyses, the risk of SPBC was higher among PV carriers vs noncarriers (subdistribution hazard ratio [sHR], 5.27; 95% CI, 1.43-19.43) and women with primary in situ BC vs invasive BC (sHR, 5.61; 95% CI, 1.52-20.70). Conclusions Findings of this cohort study suggest that young BC survivors without a germline pathogenic variant have a low risk of developing a SPBC in the first 10 years after diagnosis. Findings from germline genetic testing may inform treatment decision-making and follow-up care considerations in this population.

AbstractVenetoclax (VEN) combined with hypomethylating agents (HMAs) is the standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive chemotherapy. To date, real‐world data published on HMAs plus VEN have been either single‐center studies or using community‐based electronic databases with limited details on mutational landscape, tolerability, and treatment patterns in elderly patients. Therefore, we conducted a multicenter retrospective study to assess the real‐world experience of 204 elderly patients (≥75 years) with newly diagnosed AML treated with HMAs plus VEN from eight academic centers in the United States. Overall, 64 patients achieved complete remission (CR; 38%) and 43 CR with incomplete count recovery (CRi; 26%) for a CR/CRi rate of 64%, with a median duration of response of 14.2 months (95% CI: 9.43, 22.1). Among responders, 63 patients relapsed (59%) with median overall survival (OS) after relapse of 3.4 months (95% CI, 2.4, 6.7). Median OS for the entire population was 9.5 months (95% CI, 7.85–13.5), with OS significantly worse among patients with TP53‐mutated AML (2.5 months) and improved in patients harboring NPM1, IDH1, and IDH2 mutations (13.5, 18.3, and 21.1 months, respectively). The 30‐day and 60‐day mortality rates were 9% and 19%, respectively. In conclusion, HMAs plus VEN yielded high response rates in elderly patients with newly diagnosed AML. The median OS was inferior to that reported in the VIALE‐A trial. Outcomes are dismal after failure of HMAs plus VEN, representing an area of urgent unmet clinical need.

Importance Adding fulvestrant to anastrozole (A+F) improved survival in postmenopausal women with advanced estrogen receptor (ER)–positive/ERBB2 (formerly HER2)–negative breast cancer. However, the combination has not been tested in early-stage disease. Objective To determine whether neoadjuvant fulvestrant or A+F increases the rate of pathologic complete response or ypT1-2N0/N1mic/Ki67 2.7% or less residual disease (referred to as endocrine-sensitive disease) over anastrozole alone. Design, Setting, and Participants A phase 3 randomized clinical trial assessing differences in clinical and correlative outcomes between each of the fulvestrant-containing arms and the anastrozole arm. Postmenopausal women with clinical stage II to III, ER-rich (Allred score 6-8 or >66%)/ERBB2-negative breast cancer were included. All analyses were based on data frozen on March 2, 2023. Interventions Patients received anastrozole, fulvestrant, or a combination for 6 months preoperatively. Tumor Ki67 was assessed at week 4 and optionally at week 12, and if greater than 10% at either time point, the patient switched to neoadjuvant chemotherapy or immediate surgery. Main Outcomes and Measures The primary outcome was the endocrine-sensitive disease rate (ESDR). A secondary outcome was the percentage change in Ki67 after 4 weeks of neoadjuvant endocrine therapy (NET) (week 4 Ki67 suppression). Results Between February 2014 and November 2018, 1362 female patients (mean [SD] age, 65.0 [8.2] years) were enrolled. Among the 1298 evaluable patients, ESDRs were 18.7% (95% CI, 15.1%-22.7%), 22.8% (95% CI, 18.9%-27.1%), and 20.5% (95% CI, 16.8%-24.6%) with anastrozole, fulvestrant, and A+F, respectively. Compared to anastrozole, neither fulvestrant-containing regimen significantly improved ESDR or week 4 Ki67 suppression. The rate of week 4 or week 12 Ki67 greater than 10% was 25.1%, 24.2%, and 15.7% with anastrozole, fulvestrant, and A+F, respectively. Pathologic complete response/residual cancer burden class I occurred in 8 of 167 patients and 17 of 167 patients, respectively (15.0%; 95% CI, 9.9%-21.3%), after switching to neoadjuvant chemotherapy due to week 4 or week 12 Ki67 greater than 10%. PAM50 subtyping derived from RNA sequencing of baseline biopsies available for 753 patients (58%) identified 394 luminal A, 304 luminal B, and 55 nonluminal tumors. A+F led to a greater week 4 Ki67 suppression than anastrozole alone in luminal B tumors (median [IQR], −90.4% [−95.2 to −81.9%] vs −76.7% [−89.0 to −55.6%]; P < .001), but not luminal A tumors. Thirty-six nonluminal tumors (65.5%) had a week 4 or week 12 Ki67 greater than 10%. Conclusions and Relevance In this randomized clinical trial, neither fulvestrant nor A+F significantly improved the 6-month ESDR over anastrozole in ER-rich/ERBB2-negative breast cancer. Aromatase inhibition remains the standard-of-care NET. Differential NET response by PAM50 subtype in exploratory analyses warrants further investigation. Trial Registration ClinicalTrials.gov Identifier: NCT01953588

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.

Abstract Background: The ATEMPT trial primary analysis found that one year of adjuvant trastuzumab emtansine (T-DM1) achieved a 3-year iDFS of 97.8% for patients with stage I HER2+ breast cancer, but was not associated with fewer clinically relevant toxicities (CRTs) compared with paclitaxel and trastuzumab (TH). In this end-of-study analysis, we report 5-year survival outcomes and correlative analyses from the trial. Methods: Patients with stage I centrally confirmed HER2+ breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for one year or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or paclitaxel 80 mg/m2 IV with weekly trastuzumab IV followed by trastuzumab for 9 months. The co-primary objectives were to compare the incidence of CRTs between the 2 arms and to evaluate iDFS in patients receiving T-DM1. To investigate proteomic correlates of recurrence, spatial proteomic analyses were performed on samples from 13 patients experiencing iDFS events (cases) and 24 matched controls using the NanoString GeoMx Digital Spatial Profiler. The impact of HER2 heterogeneity on outcomes was investigated among 17 cases and 51 matched controls by fluorescence in-situ hybridization (FISH). HER2 genetic heterogeneity was assessed by scrutinizing the whole tumor area and defined as the occurrence of HER2 gene amplification in >5% but < 50% invasive tumor cells. The risk of recurrence was evaluated centrally with the HER2DX genomic assay from 225 primary tumor samples. Germline whole genome sequencing (WGS) was conducted among 55 patients experiencing T-DM1-induced thrombocytopenia and/or bleeding and 55 matched controls to identify genomic correlates for this side effect. Results: A total of 497 patients who initiated protocol therapy were included in this analysis (383 T-DM1 and 114 TH). After a median follow up 5.8 years, among patients receiving T-DM1 there were a total of 11 iDFS events, with 3 distant recurrences. The 5-year iDFS for T-DM1 was 97.0% (95% CI, 95.3-98.8%), the 5-year recurrence-free interval (RFI) was 98.6% (95% CI: 97.4-99.8%) and the 5-year overall survival (OS) for T-DM1 was 97.8 % (95% CI, 96.3-99.3%). Although the study was not powered to evaluate the efficacy of TH, among the 114 patients receiving TH, a total of 9 iDFS events were observed, including 2 distant events; the 5-year iDFS with TH was 91.3% (95% CI: 86.0-96.9%), 5-year RFI was 93.3% (95% CI: 88.6-98.2%) and 5-year OS was 97.9% (95% CI: 95.2-100%). A total of 56 samples were evaluable for heterogeneity analyses, among which 14% (n=8) harbored HER2 genetic heterogeneity. Spatial proteomic analyses found that NF1 (adjusted p=0.72 × 10-6) and CTLA-4 (adjusted p=0.15 × 10-3) were significantly upregulated in primary samples from cases, while cleaved caspase 9, CD25, GITR, ICOS, p53 and PD-L2 were significantly upregulated in controls (all with adjusted p< 0.05). Germline WGS found that the top gene associations with thrombocytopenia and thrombocytopenia or bleeding were ALMS1 (p=0,19 × 10-3) and APBA3 (p=0,23 × 10-3), respectively, although none reaching the threshold for genome wide significance. rs62143195 and rs114169776 were the top single nucleotide polymorphisms associated with thrombocytopenia and thrombocytopenia or bleeding, respectively. Data on the impact of HER2 heterogeneity and of HER2DX score on survival outcomes will be presented. Conclusion: With longer follow-up, adjuvant T-DM1 confirmed outstanding long-term outcomes among patients with stage I HER2+ breast cancer, demonstrating a 5-year RFI of 98.6%. Spatial proteomic analyses identified a potential association between NF1 and CTLA-4 expression with recurrence. Details on the impact of HER2 heterogeneity and HER2DX assay on prognosis will be presented. Citation Format: Paolo Tarantino, Nabihah Tayob, Chau T Dang, Denise Yardley, Steven J. Isakoff, Vicente Valero, Meredith Faggen, Therese Mulvey, Ron Bose, Douglas Weckstein, Antonio C. Wolff, Katherine Reeder-Hayes, Hope Rugo, Bhuvaneswari Ramaswamy, Dan Zuckerman, Lowell Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit Cheng, Audrey Merrill Garrett, Paul K. Marcom, Kathy S. Albain, Patricia DeFusco, Nadine Tung, Blair Ardman, Rita Nanda, Rachel C. Jankowitz, Mothaffar Rimawi, Vandana Abramson, Paula R. Pohlmann, Catherine Van Poznak, Andres Forero-Torres, Minetta C. Liu, Kathryn Ruddy, Yue Zheng, Romualdo Barroso-Sousa, Adrienne Waks, Michelle K. DeMeo, Molly K. DiLullo, Giuseppe Curigliano, Harold Burstein, Ann Partridge, Eric Winer, Giuseppe Viale, Winnie Hui, Elizabeth A. Mittendorf, Bryan P. Schneider, Aleix Prat, Ian Krop, Sara Tolaney. Adjuvant Trastuzumab Emtansine Versus Paclitaxel plus Trastuzumab for Stage I HER2+ Breast Cancer: 5-year results and correlative analyses from ATEMPT (TBCRC033) [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 PD18-01.

Abstract 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.