INTRODUCTION:Recent advances in HER2-directed therapies have improved outcomes for patients with HER2+ advanced/metastatic breast cancer (a/mBC), but disease progression ultimately occurs in most cases. Dual targeting of HER2 with tyrosine kinase inhibitors and antibody-drug conjugates has the potential for non-cross-resistant treatments that improve disease control. METHODS:HER2CLIMB-04, a single-arm, open-label, phase 2 study, evaluated tucatinib plus trastuzumab deruxtecan (T-DXd) in patients with HER2+ a/mBC who experienced disease progression on or were intolerant of previous HER2-directed therapy and a taxane. Patients with stable or progressing brain metastases (BMs) were permitted. The primary endpoint was confirmed objective response rate (cORR) by the investigator. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS:A total of 70 patients (median age 57 years, median 2 prior lines for a/mBC) received tucatinib 300 mg orally BID and T-DXd on day 1 of each 21-day cycle. The cORR was 51.4% with a median DOR of 11.9 months (95% CI, 6.0-not estimable); median PFS was 11.5 months, and OS was 28.4 months. The most common treatment-emergent adverse events were diarrhea (80.0%), nausea (77.1%), and fatigue (72.9%). Antidiarrheal prophylaxis, introduced for 44 patients, was associated with reduced any grade diarrhea. Survival outcomes in patients with or without BMs are described. CONCLUSION:Although the addition of tucatinib to T-DXd did not demonstrate a clear benefit compared with previously demonstrated T-DXd monotherapy efficacy, when given with antidiarrheal prophylaxis, the combination was tolerable and showed clinical activity in patients with HER2+ a/mBC. CLINICAL TRIAL NUMBER:NCT04539938.

Strategies are needed to avoid chemotherapy in early stage HER2-positive (HER2 + ) breast cancer (BC). We conducted a neoadjuvant therapy trial with zanidatamab, a dual HER2-directed bispecific antibody, in patients with 1-3 cm, node-negative HER2 + BC. Primary endpoint was pathologic complete response (pCR). Secondary endpoints were radiographic response by ultrasound and magnetic resonance imaging. US and MRI, pathologic response by residual cancer burden (RCB), rate of adverse events, feasibility of accrual and biomarkers of response. Fifteen patients with HER2 IHC 3 + , and 5 with HER2 IHC 2 + /ISH + BC were enrolled. Patients received zanidatamab 20 mg/kg every 2 weeks for 6 (n = 11) or 10 doses (n = 9). Fourteen patients also received endocrine therapy. At 6 weeks, there was a significant decrease in tumor size and volume. At surgery, six patients (30%) had pCR, meeting the prespecified pCR target, and four had limited RCB (RCB-1; 20%). Treatment was well tolerated. All patients with pCR had HER2 IHC 3+ tumors, ERBB2 amplification on WES, PAM50 HER2-high subtype, and a trend towards higher HER2 mRNA expression (p = 0.06). In conclusion, de-escalation to HER2-targeted therapy alone may be feasible. Further research is needed to refine patient selection. This study is registered at ClinicalTrials.gov (NCT05035836). With the improvement of HER2-targeted therapy in patients with breast cancer, there is growing interest in whether chemotherapy can be eliminated from regimens completely. Here, the authors report a phase 2 clinical trial investigating neoadjuvant zanidatamab (HER2-targeting antibody) in patients with early-stage HER2-positive breast cancer.

Treatments for leptomeningeal metastasis (LM) are limited and prognosis is poor. In this phase 2, nonrandomized, single-arm, multicenter study, we evaluated a tucatinib-trastuzumab-capecitabine regimen in patients with newly diagnosed LM and human epidermal growth factor receptor 2-positive (HER2+) breast cancer. The primary endpoint was overall survival; secondary endpoints included central nervous system progression-free survival, LM objective response, neurological symptom improvement, pharmacokinetics and safety. The trial met its prespecified interim efficacy threshold and exceeded the historical control of 4.4 months. Among 17 enrolled women, all had magnetic resonance imaging-confirmed LM, 15 (88%) were symptomatic and 8 (47%) had abnormal cerebrospinal fluid cytology. For a median follow-up of 18 months (range 9.0-26.7 months), 6 of 17 (41%) remained alive. Tucatinib reached therapeutic levels in the cerebrospinal fluid. The median overall survival was 10 months (95% confidence interval 4.1 months, not reached). The median time to central nervous system progression was 6.9 months (95% confidence interval 2.8, 13.8 months). Of 13 response-evaluable patients, 5 (38%) achieved composite LM objective response. Of 12 evaluable patients, 7 (58%) had improved neurological deficits. This prospective study suggests clinical benefit with a systemic regimen for HER2+ LM including objective responses, improved symptoms and extended survival. These data support systemic therapy as an approach in HER2+ breast cancer LM. ClinicalTrials.gov registration: NCT03501979 .

Fam-trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that targets human epidermal growth factor receptor 2 (HER2) and delivers a topoisomerase inhibitor payload. T-DXd has been effectively used to treat metastatic breast cancer but causes pneumonitis in 10–15

Characteristics of patients with both CNS and extracranial response

Background: Brain metastases (BMs) are common in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer, increasing morbidity and mortality. Systemic therapy for BMs can be effective, with the triple combination of trastuzumab, capecitabine, and tucatinib being a potential standard. More recently, intracranial activity of antibodyedrug conjugates has been reported, but the size of individual studies has been small. Therefore, this patient-level pooled analysis was conducted. Patients and methods: This is a patient-level pooled analysis of the prospective phase II DEBBRAH and TUXEDO-1 trials and the retrospective DFCI/Duke/MDACC cohort. Patients with evaluable active BMs (defined as newly diagnosed and untreated or progressing with measurable tumor-related size after previous local therapy) from HER2-positive breast cancer (BC) and treated with trastuzumab deruxtecan (T-DXd) included in these studies were eligible. The primary endpoint was intracranial objective response rate (ORR-IC) by Response Assessment in Neuro-Oncology (RANO)-BM criteria. Results: Overall, 37 patients were assessable for intracranial response assessment. BMs progressing after prior local therapy were present in 64.9% of patients. The median patient age was 49.1 years. All patients had received prior trastuzumab and the median number of prior systemic treatment lines was 3 (0-13). The pooled ORR-IC by RANOBM criteria was 64.9% [95% confidence interval (CI) 47.5% to 79.8%] with low heterogeneity observed between the studies included. The clinical benefit rate by RANO-BM was 81.1% (95% CI 64.8% to 92.0%). The median progression-free survival was 13.3 months (95% CI 8.4-22.6 months) and the median overall survival was 22.5 months (95% CI 14.9 months-not achieved) with high heterogeneity between studies and numerically longer in patients with few prior treatment lines. Quality of life remained stable throughout treatment, with no new safety concerns. Conclusions: This patient-level pooled analysis of DEBBRAH, TUXEDO-1, and the DFCI/Duke/MDACC cohort indicates clinically relevant intracranial activity of T-DXd in patients with active HER2-positive BC, BMs, and extensive systemic pretreatment. The results therefore support the use of T-DXd when clinically indicated irrespective of BMs.

592 Background: Monitoring clinical response by breast ultrasound (US) during neoadjuvant therapy is considered standard of care. We previously demonstrated that suboptimal on-Rx TVR after neoadjuvant doxorubicin and cyclophosphamide (AC) predicts non-pCR after sequential taxane-based chemo. However, it is unknown if on-Rx TVR has the similar predictive value in pts receiving the KN-522 chemo-immunotherapy regimen. Methods: Pts with early stage TNBC planned to receive the KN-522 regimen were enrolled on the prospective ARTEMIS trial (NCT02276443). Breast US was performed at baseline and after 6 weeks of paclitaxel + carboplatin + pembrolizumab. TVR was defined as the percent reduction of tumor volumes calculated using 3 perpendicular measurements of the index breast lesion. Pathological complete response (pCR) was defined as ypT0/isN0. Logistic regression was used to examine associations between covariates and pCR. Receiver operating characteristic (ROC) analyses were utilized to assess the predictive value of TVR and determine an optimal TVR threshold. Results: 150 pts were included. Clinicopathological characteristics are described in Table 1. The pCR rate was 63%. In uni- and multi-variable analyses, TVR was the only covariate to demonstrate statistically significant association with pCR (aOR:1.9 per 10% TVR, p<0.001). In ROC analyses, the area under the ROC curve (AUC-ROC) was 0.74 (95% CI: 0.66-0.82). TVR>50%, selected based on the Youden index, predicted pCR with the following performance characteristics: positive predictive value: 73%; negative predictive value: 79%; sensitivity: 94%; specificity: 41%. Conclusions: Early on-Rx TVR by breast US outperforms clinicopathological covariates in the prediction of pCR in pts with TNBC receiving the KN-522 regimen and should be leveraged for risk stratification and design of response-adapted neoadjuvant clinical trials for pts with TNBC. Clinical trial information: NCT022766443 . pCR (n=95) Non-pCR (n=55) Odds ratio (OR) p value (univariable) Adjusted OR (aOR) p value (multivariable) Median 6w TVR – % (interquartile range [IQR]) 84 (72-90) 69 (38-83) 1.5 <0.001 1.9 <0.001 Median age – years (IQR) 51 (40-61) 51 (43-64) 0.98 0.25 1.0 0.73 N (%) Ethnicity White 50 (53) 33 (60) 1 1 Black 15 (6) 10 (18) 1.1 0.84 0.9 0.91 Hispanic/Latino 25 (26) 6 (11) 2.4 0.08 1.9 0.32 Asian 5 (5) 6 (11) 0.6 0.36 0.2 0.12 T stage T1/2 79 (83) 46 (84) 1 1 T3/4 16 (17) 9 (16) 1.0 0.94 1.2 0.77 Nodal status Positive 31 (33) 24 (44) 1 1 Negative 64 (67) 31 (56) 1.60 0.18 1.4 0.55 Germline BRCA status Mutant 8 (8) 2 (3) 1 1 Wild Type 84 (88) 51 (93) 0.41 0.27 0.3 0.31 Unknown 3 (3) 2 (4) Histology Ductal 87 (92) 48 (87) 1 1 Metaplastic 3 (3) 5 (9) 0.33 0.14 0.3 0.26 Other 4 (4) 2 (4) 1.1 0.91 2.0 0.59 Unknown 1 (1) 0 Histologic grade 2 13 (14) 14 (25) 1 1 3 81 (85) 41 (75) 2.1 0.08 2.0 0.59 Unknown 1 (1) 0 Ki67 ≤35% 5 (5) 8 (15) 1 1 >35% 67 (71) 38 (69) 2.82 0.09 4.6 0.09 Unknown 23 (24) 9 (16)

Representativeness of Study Participants.

PURPOSE:Trastuzumab deruxtecan (T-DXd) is currently approved for treating metastatic breast cancer (MBC) that is HER2 positive [immunohistochemistry (IHC) score of 3+ or in situ hybridization (ISH) positivity] or HER2-low (IHC score of 1+ or IHC 2+/ISH negative), as well as for HER2-positive gastric cancer, HER2-mutant lung cancer, and HER2-overexpressing solid tumors. Given the increasing utilization of T-DXd, we sought to determine how HER2 status might change following T-DXd therapy. EXPERIMENTAL DESIGN:We retrospectively reviewed patients with MBC who received T-DXd at the University of Texas MD Anderson Cancer Center. We included patients with paired pre- and post-treatment biopsies assessed for HER2 status using IHC. RESULTS:We included 41 patients with MBC who received treatment with T-DXd and had paired pre- and post-treatment biopsies assessed for HER2 status using IHC. HER2 loss was observed in 11 patients [32.4% of 34 patients with pre-treatment HER2 expression (1+, 2+, or 3+)] following treatment with T-DXd. In addition to the 11 patients with HER2 loss, another 10 patients (29.4%) had a decrease in HER2 score after treatment with T-DXd. CONCLUSIONS:HER2 loss and decrease in HER2 expression are common in patients with MBC receiving treatment with T-DXd. Reevaluation of HER2 status following T-DXd treatment should be considered prior to alternate HER2-targeted therapies that require HER2 overexpression for efficacy.

Type of Surgery and Adjuvant Therapy Received.

Molecular Subtypes and Pathological Response.

Background: Trastuzumab deruxtecan (T-DXd) is currently approved for treatment of patients with metastatic HER2-positive (immunohistochemistry (IHC) 3+ or ISH positive) or HER2 low (IHC 1+ or IHC 2+/ISH negative) breast cancer in addition to other disease-specific and tissue-agnostic indications. Because of potential clinical implications to treatment selection after exposure to T-DXd, we aimed to evaluate the changes in HER2 status, specifically loss or decrease in HER2 expression, following treatment with T-DXd in patients with metastatic breast cancer. Methods: We retrospectively reviewed patients with metastatic breast cancer who received treatment with T-DXd at The University of Texas MD Anderson Cancer Center (MDACC). We included patients who had post-treatment biopsy (or on-treatment biopsy within the 30 days prior to treatment discontinuation) with IHC re-evaluation of HER2 status at MDACC. We excluded patients who were taken off treatment for toxicity or death after the first cycle of treatment, patients who received T-DXd in addition to another agent concomitantly, and patients who received T-DXd at multiple times interspersed through their medical history. We reviewed pre-treatment HER2 IHC status in the most recent biopsy prior to T-DXd initiation and the biopsy with the highest score of HER2 across patients’ medical history. For patients with multiple testing, the biopsy closest to treatment start- and end date was used to assess the change in HER2 expression status. Treatment dates were extracted from patients’ medical charts and duration on therapy was calculated as the time between cycle 1 day 1 and end of treatment. A decrease in IHC score was defined as any change in IHC score from 3+ to 2+, 1+, or 0; from 2+ amplified to 2+ non-amplified, 1+, or 0; from 2+ non-amplified to 1+ or 0; or from 1+ to 0. HER2 loss was defined as an IHC score of 0 after treatment with any degree of positivity noted in the most recent sample before treatment initiation (1+, 2+, or 3+). Results: We included 45 patients with metastatic breast cancer who started treatment with T-DXd at MDACC between June 2017 and February 2024 and had come off therapy by the time of analysis. The highest HER2 score was 3+ in 14 patients (31%), 2+ in 20 patients (44%; 12 FISH negative, 5 FISH positive, and 3 FISH undetermined), and 1+ in 11 patients (24%). The median duration between pre-treatment biopsy and treatment start date was 355 days (range, 1 to 2663) and the median duration between treatment discontinuation date and post-treatment biopsy was 25 days (range, -14 to 1159). Five patients had HER2 score of 0 in the most recent biopsy before therapy and were excluded from further analysis. In those patients, treatment decision was based on another prior biopsy showing HER2-low or HER2-positive disease and the median time on treatment was 71 days. Out of 40 patients with baseline HER2 expression (1+, 2+, or 3+), almost one third (n=12; 30%) had HER2 loss following treatment with T-DXd. In addition to those 12 patients with HER2 loss, another 11 patients (28%) had a decrease in HER2 score after treatment with T-DXd. Conclusions: HER2 loss and decrease in HER2 expression are common in patients with metastatic breast cancer receiving treatment with T-DXd. Re-evaluation of HER2 status post-therapy should be considered prior to considering alternative HER2 targeted therapy. Citation Format: Mohamed Gouda, Amrit Gonugunta, Ecaterina Dumbrava, Timothy A Yap, Jordi Rodon, Sarina A Piha-Paul, Paula R. Pohlmann, Senthil Damodaran, Rashmi Murthy, Vicente Valero, Jason Mouabbi, Debasish Tripathy, Aysegul Sahin, Hui Chen, Funda Meric-Bernstam. HER2 Loss Following Treatment with Trastuzumab Deruxtecan in Patients with Metastatic Breast Cancer [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 P1-01-27.

Somatic mutations identified by whole exome sequencing. Oncoplot representing the most common somatic mutations assessed by whole exome sequencing (WES) in tumors obtained from patients (n = 23) at the time of diagnosis. Genes with mutations occurring in five or more patients are shown.

Baseline clinicopathologic characteristics and associations with pathologic response

PurposeSleep disturbances are common in patients with breast cancer, but comprehensive evaluations with patient-reported outcomes (PRO) and sleep evaluation with polysomnography (PSG) are lacking. This study describes sleep disruption using PROs and PSG to identify underlying sleep disorders.MethodsA retrospective review of patients with breast cancer undergoing formal sleep evaluation from 4/1/2009 to 7/31/2014 was performed. Clinical characteristics, PROs using Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS), and PSG data were reviewed.Results404 patients were identified with 43% early, 30% locally advanced and 17% metastatic disease. PSQI revealed poor sleep in 75%, and ESS demonstrated daytime sleepiness in 55%. Sleep aid use was reported by 39%, and pain medication use in 22%. Most patients (50.2%) had multiple sleep disorders. Insomnia (54.5%) was the most frequent sleep disorder, followed closely by obstructive sleep apnea (OSA) (53.7%). PSG was performed in 74%. Multivariate analysis linked poor sleep to use of sleep aids [OR 7.7, 95% CI 3.9 to 15.2], anxiety disorder [OR 4.8, 95% CI 1.7 to 14.0], and metastatic disease [OR 2.8, 95% CI 1.1 to 6.6]. Daytime sleepiness correlated with known diagnosis of OSA [OR 1.9, 95% CI 1.0 to 3.3] and sleep aid use [OR 0.6, 95% CI 0.4 to 0.9].ConclusionsPoor sleep was associated with sleep aid use, anxiety disorder and metastatic disease. Insomnia was the most common sleep disorder, followed by OSA (mostly mild). Education about sleep health and proactive screening for sleep symptoms would be beneficial in patients with breast cancer.

2018 Background: Treatment options for patients with leptomeningeal metastasis (LM) are limited and prognosis is poor. Tucatinib is a potent, highly selective HER2-targeted tyrosine kinase inhibitor. The combination of tucatinib-trastuzumab-capecitabine is approved for patients with metastatic HER2+ breast cancer, with or without brain metastases, who have received ≥ 1 prior HER2-based regimens in the metastatic setting. Patients with LM were excluded from HER2CLIMB (NCT02614794). The aim of this study was to determine the benefit of this regimen in patients with HER2+ breast cancer and LM. We previously reported preliminary efficacy data, with a median OS of 10 months and a median time to CNS progression of 6.9 months. Here, we present additional data on LM objective response, provider-rated neurologic clinical exam, and patient-reported outcomes (PRO). Methods: TBCRC049 (NCT03501979) is an investigator-initiated phase 2 study evaluating a tucatinib-trastuzumab-capecitabine regimen in adults with HER2+ breast cancer and newly diagnosed LM. Eligible patients had a Karnofsky performance status > 50 and untreated LM (defined as positive CSF cytology and/or radiographic evidence of LM plus clinical signs/symptoms). In 21-day cycles, patients received PO tucatinib, PO capecitabine, and IV trastuzumab. The primary endpoint was OS. LM objective response was assessed using a composite of neuroaxis imaging, neurologic clinical exam, and CSF cytology, derived from RANO-LM. The clinical exam incorporated the NANO scoring tool and symptom evaluation using MDASI-BT. Up to 4 provider-rated baseline target neuro deficits were monitored. An imaging scorecard was used. PROs were assessed using the LASA and MDASI-BT tools. Results: Enrollment was planned for 30 patients but closed at 17 patients following FDA approval of tucatinib (April 2020). All patients (median age 53 years) had MRI evidence of LM, 15 (88%) were symptomatic, and 8 (47%) had abnormal CSF cytology. At data cutoff (7/20/21), 5 (38%) of 13 response-eligible patients achieved LM objective response per the composite criteria at first response assessment, and all 13 (100%) achieved clinical benefit (SD, PR, or CR). Notably, 7 (58%) of 12 evaluable patients with target neurologic deficits at baseline experienced improvement of deficits. All 17 completed ≥ 75% of LASA and MDASI-BT PRO questionnaires at pre-specified timepoints. The mean improvement in LASA score was 13.5, indicating improved QOL and the mean improvement in MDASI-BT score was 32, indicating improved symptom burden. Conclusions: This is the first prospective evidence of clinically meaningful benefit including objective responses, symptom improvement, and quality of life, along with extended survival, with a systemic regimen for LM from HER2+ BC. These data support the trend toward using systemic therapy as an initial approach in CNS metastases. Clinical trial information: NCT03501979 .

Abstract Background: Many patients develop brain metastasis during the course of their disease and it represents the cause of death in more than half of them. The prognosis and survival of patients with brain metastases remains poor with limited palliative treatment options. Thus, there is a need to develop new strategies for the therapeutic management of patients with brain metastases. Inflammatory stimuli originating from CNS tumors may increase the permeability of the blood-brain barrier and promote immune cell activation and infiltration into tumors. Several studies have demonstrated now the efficacy of immune checkpoint inhibitors in patients with melanoma with active brain metastases. The modulation of VEGF-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. Lenvatinib is an oral, potent multiple receptor tyrosine kinase inhibitor that selectively inhibits VEGFRs, VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other pro-angiogenic and oncogenic pathway-related receptor tyrosine kinases. The combination of lenvatinib and pembrolizumab is approved for patients with metastatic endometrial carcinoma and renal cancer, and it is investigated in other tumor types with promising preliminary results. We hypothesize that pembrolizumab and lenvatinib will be an effective treatment for TNBC, NSCLC, and other solid tumor types with brain metastases by decreasing angiogenic tumor activity and improving antitumor T-cell activity. Methods: This is a single-center, open-label, multi-cohort Phase II study evaluating the efficacy and safety of pembrolizumab in combination with lenvatinib in patients with solid tumors and brain metastases. The study has 3 cohorts: triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and other solid tumor types with established or preliminary clinical evidence of efficacy of programmed cell death-1 (PD-1) and angiogenesis inhibitors. Eligible patients will have at least 1 unirraditated or progressing brain metastasis of 0.5-2 cm on brain MRI. The study is conducted using a Simon’s optimal two-stage design, and approximately 87 patients will be enrolled concurrently (n=29 per cohort). Pembrolizumab (200 mg intravenously on Day 1 of each cycle) and lenvatinib (20 mg orally once daily) are administered in 21-day cycles for a maximum of 24 months. The primary endpoint is intracranial objective response rate at 4 months as assessed by the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Exploratory analyses will include evaluation of tissue and blood-based immune-related correlates of response to the pembrolizumab and lenvatinib combination. The first patient was enrolled in January 2022 and accrual of patients is ongoing (NCT05064280). Citation Format: Ecaterina E. Dumbrava, Emma J. Montazari, Uyen M. Vu, Tiantian Cai, Mehmet Altan, Nuhad K. Ibrahim, Debra N. Yeboa, Jing Li, Frederick F. Lang, Gisela Sanchez, Isabella C. Glitza, Barbara J. O'Brien, Rashmi K. Murthy, Jianbo Wang, Tanisha T. Darko, Denisse Velazquez, Komal Shah, Funda Meric-Bernstam, Hussein Tawbi, Jordi Rodon. Phase II study of pembrolizumab in combination with lenvatinib in patients with triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and other tumor types and brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT292.

BackgroundBreast cancer (BC) with germline BRCA1/2 mutations and their association with triple-negative BC has been thoroughly investigated. However, some carriers of BRCA1/2 mutations have human epidermal growth factor receptor 2 (HER2/neu)-positive BC, which has a different targeted therapy approach, and data are scarce for this patient population. The authors sought to characterize the clinical characteristics and outcomes of patients with HER2/neu-positive BC who had germline BRCA1/2 mutations.MethodsThis was a retrospective analysis of data from 1099 patients diagnosed with HER2/neu-positive BC who were screened for germline BRCA mutations between 1996 and 2022. Clinicopathologic features and survival rates were analyzed by BRCA mutation status. Univariate and multivariable Cox proportional hazards regression models were used to analyze the association between clinical variables and outcomes.ResultsOf 1099 patients with HER2/neu-positive BC, 73 (6.6%) tested positive for BRCA1/2 mutations. Age, race, and tumor characteristics did not differ between BRCA noncarriers and carriers. At a median follow-up of 78.6 months, the 5-year recurrence-free survival rate was 85% in BRCA carriers and 87% in noncarriers (p = .79), and the 5-year overall survival rate was 94% in BRCA carriers and 94% in noncarriers (p = .78). In a multivariable model, BRCA was not associated with recurrence-free survival (hazard ratio, 0.99; 95% confidence interval, 0.51-1.90; p = .96) or overall survival (hazard ratio, 0.83; 95% confidence interval, 0.33-2.07; p = .69).ConclusionsBRCA1/2 mutations occurred in 6.6% of patients with HER2/neu-positive BC and did not affect survival outcomes. Assessing the potential benefits of new treatment strategies, such as combining anti-HER2/neu therapies with poly(ADP-ribose) polymerase inhibitors, may lead to enhanced outcomes for these patients. BRCA1/2 mutations occurred in 6.6% of patients with human epidermal growth factor receptor 2 (HER2/neu)-positive breast cancer. However, BRCA mutation status did not affect survival outcomes in patients who had HER2/neu-positive breast cancer.