Background: Despite treatment advances in mTNBC, most patients presenting for first-line therapy will require cytotoxic chemotherapy (CT). Sacituzumab govitecan (SG) is an antibody-drug conjugate to the Trop-2 antigen that is expressed in the majority of TNBCs. SG is approved as second- or third-line therapy for patients with mTNBC per the phase III ASCENT trial, but its utility as a first-line treatment is unknown. ctDNA correlates with cancer burden and response to local and systemic therapies, but there is not an approved use for quantitatively monitoring patients’ ctDNA levels during treatment. Previous studies showed a direct correlation between a patient’s ctDNA mean variant allele frequency (VAF) and tumor burden as well as response or resistance to treatment. We hypothesize that a lack of a significant decrease in ctDNA VAFs shortly after initiating a first-line CT for mTNBC could serve as a biomarker of de novo resistance and could warrant a change of therapy earlier than conventional imaging studies would normally dictate. This study therefore evaluates switching to SG in mTNBC patients without a 50% decrease in ctDNA VAFs less than one month after starting a first-line CT with the goal of improving progression-free survival (PFS) and overall survival (OS) and of decreasing toxicity by stopping an ineffective treatment earlier. Methods: In this two-arm randomized clinical trial, 120 patients will receive standard of care (SOC) physician’s choice CT. Patients will be randomized 1:1; one group will undergo SOC treatment with conventional staging imaging to guide treatment decisions, while the other group will undergo ctDNA evaluation on cycle (C) 1 days (D) 1 and 15 of treatment. If the mean ctDNA VAF on-treatment does not decrease by 50% on C1D15, patients will change SOC CT to SG. Both groups will undergo radiological assessment every 9 weeks. ctDNA will be banked on C4D1, C7D1, and at the end of treatment. Patients with a biopsy-confirmed new diagnosis of mTNBC that is PD-L1 negative (CPS <10) or who are otherwise not eligible for immune checkpoint inhibitor therapy are eligible for this study. Patients will not have received prior treatment for mTNBC and must have an ECOG PS of 0-2 as well as measurable disease by RECIST. The primary endpoint is PFS. This study has 80% power to detect a 2-month difference in PFS between patients treated with a ctDNA-guided therapeutic approach compared to patients assessed by conventional imaging alone (one-sided type 1 error of 10%). Key secondary endpoints include evaluating the overall response rate (RECIST v1.1), PFS2, and OS. Correlative studies include assessing ctDNA-defined clonal mutation profiles and their predictive value and correlating changes in ctDNA with standard imaging. This study (NCT05770531) is open at Vanderbilt University Medical Center and will open at 7 other sites through the ACCRU network. Six patients have been enrolled as of 6/2024. Citation Format: Jessica Sharpe, Ben H. Park, Vandana G. Abramson. A randomized clinical trial comparing ctDNA-directed therapy change with standard of care in patients with metastatic triple negative breast cancer (mTNBC) [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 P2-12-29.

BACKGROUND:Tumor-infiltrating lymphocytes (TILs), assessed by visual examination, are prognostic and predictive in early-stage triple-negative breast cancer. Computational assessment may provide a complementary approach. We evaluated the prognostic value of TILs by visual examination and computational assessment. METHODS:Cisplatin vs Paclitaxel for Triple Negative Breast Cancer (TBCRC030; ClinicalTrials.gov identifier NCT01982448) was a randomized phase 2 trial enrolling patients with BRCA1/2-proficient stage I to III triple-negative breast cancer to receive preoperative cisplatin or paclitaxel. The primary endpoint was pathological response at surgery. The TILs were visually scored on digitized pretreatment biopsies per International TILS Working Group recommendations. Computational assessment used the 4D Path QPOR platform to generate TILs, an immune heterogeneity index, and a combined immune/cell cycle biomarker (CmbI). Predictive performance for residual cancer burden 0/1 was assessed using receiver operating characteristic curves and odds ratios (ORs) with 95% CIs; all statistical tests were 2-sided. RESULTS:Of 139 response-evaluable patients, 121 had matched visual examination and computational assessment data (59 on cisplatin, 62 on paclitaxel). Median visual examination TILs were higher in responders (40.0% vs. 10.0%; P = .002) and predicted response (OR = 1.86, 95% CI = 1.24 to 2.87; area under the curve = 0.69, 95% CI = 0.57 to 0.80). Computational assessment CmbI differed by response group and predicted residual cancer burden 0/1 (OR = 3.20, 95% CI = 1.05 to 11.07; area under the curve = 0.62, 95% CI = 0.51 to 0.73). Computational assessment TILs and immune heterogeneity index were not predictive. Visual examination TILs and computational assessment CmbI predicted response to paclitaxel (OR = 2.91, 95% CI = 1.56 to 6.14; OR = 9.17, 95% CI = 2.01 to 66.39, respectively) but not to cisplatin. CONCLUSION:Visual examination TILs and computational assessment CmbI were each associated with response to neoadjuvant chemotherapy in triple-negative breast cancer in the overall cohort and the paclitaxel arm. Computational assessment CmbI did not outperform visual assessment. Further validation is needed before clinical implementation of computational approaches.

The NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget's disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The panel convenes annually to update recommendations based on a review of recently published clinical trials. This selection from the NCCN Guidelines for Breast Cancer focuses on the recommendations for the management of recurrent or stage IV (M1) metastatic breast cancer. It summarizes the treatment strategies stratified by tumor biology, including hormone receptor status and HER2 expression, as well as clinical factors such as prior therapy and disease-free interval. Throughout all treatment lines, supportive care, quality of life preservation, toxicity minimization, and clinical trial participation are emphasized as integral components of patient care.

Gedatolisib is a pan phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor and was evaluated in a multicenter, open-label, phase 1b dose-escalation and dose-expansion trial in combination with palbociclib and endocrine therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) -breast cancer with varying categories of prior therapy (ClinicalTrials.gov NCT02684032). The primary objective of the dose-escalation cohorts was safety while the primary endpoint of the dose-expansion cohorts was investigator-assessed objective response. Median progression-free survival at 12 months was 72.1%, 54.5%, 23.6%, and 53.2% for Arms A, B, C, and D, respectively, as defined in the methods. In the dose-expansion cohorts gedatolisib triplet therapy achieved overall response rates (ORR) of 85%, 77%, 36% and 63% in Arm A, B, C and D respectively. Based on the promising ORR of the phase 1b trial, further follow-up was warranted to analyze survival outcomes. Here we report survival results of patients who received gedatolisib combined with palbociclib plus letrozole or fulvestrant.

Background: PARP inhibitors (PARPi) have an approved role in treating patients (pts) with germline BRCA1/2 mutated (gBRCAm) breast cancer in the advanced and early settings, with activity also seen in pts with gPALB2m. Preclinical data suggest PARPi exposure leads to intratumoral activation of the proinflammatory cGAS/STING pathway, recruiting CD8+ T cells, and sensitizing gBRCAm cancers to immune-targeted therapy. Preoperative treatment with PARPi monotherapy has demonstrated notable pathologic complete response (pCR) rates. TBCRC 056, an open-label randomized phase II study, evaluates the PARPi niraparib (N) with the anti-PD-1 antibody dostarlimab (D) in the neoadjuvant treatment of gBRCAm or gPALB2mHER2-negative breast cancer, with cohorts for both triple negative breast cancer (TNBC, Arms A and B) and hormone receptor positive (HR+) disease (Arm C). Results from Arm C are being presented. Methods: Eligible pts in Arm C had a gBRCAm or gPALB2m and a tumor size of >1.0 cm, ER and/or PR+ (>10%). All pts in Arm C received 18 weeks of combination N 200 mg orally once daily and D 500 mg IV every 3 weeks (1 cycle = 3 weeks), with mandatory baseline (BL) and week 3 core tumor biopsies. After 18 weeks, pts either underwent surgery or received additional preoperative systemic therapy (per physician’s choice) if residual disease was present on imaging. The primary study objectives are to evaluate pCR at surgery as well as change in stromal tumor infiltrating lymphocytes (sTILs) from BL to 3 weeks in Arms A and B. Evaluation of pCR and change in sTILs in Arm C are secondary study objectives, with pCR to be reported with a two-sided exact 90% confidence interval without hypothesis testing. Change in sTILs between BL and 3 weeks was evaluated using a Wilcoxon signed-rank test, and the association between sTILs and pCR was assessed using a Wilcoxon rank sum test. Results: Accrual to Arm C was completed after 18 pts with HR+/HER2- breast cancer were enrolled and treated between April 2021 and May 2024 (5 gBRCA1m (27.8%), 13 gBRCA2m (72.2%), 0 gPALB2m). Median age was 41.8 years (range 28.8-61.9), 14 were self-reported White (77.8%), 4 (22.2%) Black, and none Hispanic. Stage distribution was 38.9% stage I, 44.5% stage II, and 16.7% stage III. All 18 pts had ER+ >10% disease. Sixteen of 18 pts have completed protocol therapy through surgery, with results pending for 2 pts. Among evaluable pts, 10 (62.5%) completed 6 cycles of D with mean number of cycles received 4.7. Six pts discontinued D early (1 progressive disease, 1 withdrawal of consent, 4 unacceptable adverse events (AE)). Thirteen pts (81.2%) completed 6 cycles of N with mean number of cycles received 5.4. Three pts discontinued N early (1 progressive disease, 1 withdrawal of consent, 1 unacceptable AE). The most common AE (> grade 2) with D+N were rash (25.0%), elevated liver function tests (18.8%), diarrhea (12.5%), and hypertension (12.5%). Of the 16 pts evaluable for response at this time, 3 had pCR at surgery (18.8%, (90% CI 5.3% - 41.7%)), 11 (68.8%) had residual disease (3 RCB-I, 4 RCB-II, 4 RCB-III), and 2 (12.5%) received additional chemotherapy before surgery. Among 12 pts with evaluable sTILs at BL and 3 weeks, mean sTILs at BL was 11.9% (range 1.0% – 35.0%), mean sTILs at week 3 was 23.8% (range 5.0% - 90.0%), with a mean absolute increase of 11.9%; Wilcoxon signed rank p=0.09). Higher sTILs (as a continuous variable) at BL was associated with pCR (odds ratio 1.09, 95% CI 1.00 – 1.19, Wilcoxon rank sum p = 0.03). Conclusions: In pts with gBRCAm HR+/HER2- breast cancer, 18 weeks of PARPi and anti-PD1 resulted in a pCR rate of 18.8%, and a mean absolute increase of sTILs of 11.9% at 3 weeks. Further data from the TNBC cohort of this study are awaited. Given the reported activity of PD-1 inhibitors in the preoperative management of HR+ breast cancer, additional exploration of targeted non-chemotherapy approaches is of great interest in this pt population. Citation Format: Erica Mayer, Noah Graham, Roberto A. Leon-Ferre, Mariya Rozenblit, Cesar Santa-Maria, Steven Isakoff, Jennifer Specht; Nadine Tung, Vandana Abramson, Jennifer Desrosiers, Beyza Koca, Sara M. Tolaney, Eric P. Winer, Ian E. Krop, Antonio C. Wolff, Geoffrey I. Shapiro, Nabihah Tayob, Jennifer L. Guerriero. TBCRC 056: A Phase II Study of Neoadjuvant Niraparib with Dostarlimab for Patients with BRCA- or PALB2-mutated Breast Cancer: Results From the ER+/HER2- Cohort [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 RF3-01.

The treatment landscape of invasive early-stage and metastatic breast cancer is evolving constantly. These NCCN Guidelines Insights focus on recent updates included in the most recent version (version 5.2025) of the NCCN Guidelines for Breast Cancer specific to workup, locoregional therapy, surveillance, and systemic neoadjuvant/adjuvant therapy recommendations for invasive, nonmetastatic breast cancer.

Background: PARP inhibitors are associated with improved progression free survival (PFS) and patient quality of life in germline BRCA1/2 mutant MBC, leading to their approval in this setting, but their applicability is limited as germline BRCA1/2 mutations are present in 5% of breast cancer. We previously demonstrated that a subset of patients with MBC who are not germline BRCA1/2 carriers may harbor pathogenic somatic BRCA1/2 mutations that are identified by cell-free DNA and/or tumor tissue genotyping. We developed a circulating tumor cell culture from a patient with MBC harboring a pathogenic somatic BRCA1 mutation, and demonstrated that a PARP inhibitor induced cell growth inhibition similar to a germline BRCA1/2 mutant culture. Thus, we hypothesize that a PARP inhibitor may be effective in treating somatic BRCA1/2 mutant MBC. In this clinical trial, we are studying the efficacy of a PARP inhibitor in somatic BRCA1/2 mutant MBC. Our work may expand the clinical application of PARP inhibitors in MBC. Trial Design: This phase II investigator-initiated clinical trial is enrolling 30 patients with MBC with a pathogenic somatic BRCA1/2 mutation identified by a CLIA certified cell-free DNA and/or tumor tissue genotyping assay. Patients are treated with the PARP inhibitor talazoparib 1 mg/day until progression of disease. Imaging (CT chest, abdomen and pelvis, and bone scan) occurs for disease assessment at baseline and every 3 months. Cell-free DNA is collected at baseline and then monthly to evaluate changes in the genomic environment. Patients also undergo Cancer Risk B (CR-B) assay, a novel flow variant test to identify double-strand break repair mutations in circulating blood cells, at baseline. Eligibility Criteria: Patients must have MBC with a pathogenic somatic BRCA1/2 mutation identified in a cell-free DNA and/or tumor tissue genotyping assay, with pathogenicity confirmed by a genetics counselor using validated genomic databases such as ClinVar. Patients may have triple-negative (receipt of at least 1 prior chemotherapy) or hormone receptor positive/HER2- (receipt of at least 1 prior hormone therapy) MBC. Patients must not be known germline BRCA1/2 carriers. Any number of prior therapies including a prior platinum (in absence of progressive disease on a platinum) are allowed, but patients should not have received a prior PARP inhibitor. Patients must have adequate organ function and performance status. Specific Aims: The primary aim is to determine PFS (RECIST 1.1). Secondary aims include determining the objective response rate and toxicity (NCI CTCAE v 5.0). Exploratory aims include evaluating serial changes in BRCA1/2 mutant allelic frequency in cell-free DNA, understanding the impact of BRCA1/2 reversion mutations in cell-free DNA, comparing pre- and post-treatment cell-free DNA results to understand changes in the genomic environment, studying the CR-B assay positivity rate, and correlating these biomarker analyses with treatment response. Statistical Methods: This study has 81% power to demonstrate that the 12-week PFS is 53% or higher. In contrast, there is a 4% (alpha) probability of concluding that the 12-week PFS is ≥ 53% if the true 12-week PFS is 30% or lower. If 14 or more of 30 total patients achieve PFS > 12 weeks, the null hypothesis (12-week PFS ≤ 30%) will be rejected. Present accrual and target accrual: This study (NCT03990896) is open at Massachusetts General Hospital, MD Anderson, University of California San Francisco, Emory, Northwestern, Vanderbilt, and Cornell. As of 7/2024, 21/30 patients are enrolled. Funding: A Pfizer ASPIRE award and Conquer Cancer Foundation of ASCO–Breast Cancer Research Foundation- Career Development Award fund this study. Citation Format: Neelima Vidula, Senthil Damodaran, Manali Bhave, Erica Blouch, Ogadinma Ogbenna, Vandana Abramson, Ami Shah, Lisa Flaum, Massimo Cristofanilli, Joseph Sparano, Harry Ostrer, Nora Horick, Hope S. Rugo, Aditya Bardia. Phase II study of talazoparib, a PARP inhibitor, in HER2- metastatic breast cancer (MBC) with a somatic BRCA1/2 mutation identified in cell-free DNA or tumor tissue genotyping [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 P3-10-20.

BACKGROUND:Early metabolic change on PET/CT was predictive of response to neoadjuvant trastuzumab/pertuzumab (HP) in TBCRC026. We hypothesized that a composite biomarker incorporating PET/CT and HER2 tissue-based biomarkers could improve biomarker performance. METHODS:83 patients with estrogen receptor-negative/HER2-positive breast cancer received neoadjuvant HP alone [pathologic complete response (pCR) 22 %]. PET/CT was performed at baseline and 15 days post initiation of therapy (C1D15). Promising imaging biomarkers included ≥40 % SULmax decline between baseline and C1D15, and C1D15 SULmax ≤3. Baseline tissue-based biomarkers included HER2-enriched intrinsic subtype (72 %, 46/64; NanoString), tumor HER2 protein abundance (median log2 13.5, range log2 7.1-15.9; NanoString DSP), and HER2 3+ (83 %, 64/77; immunohistochemistry). Logistic regressions were fitted to predict pCR with HER2/PET-CT biomarkers. The C statistic assessed overall prediction power. The optimal composite score cut-off was determined by maximizing Youden's index. RESULTS:Factors most predictive for pCR in single predictor models included C1D15 SULmax (OR 0.43; p = 0.007, c = 0.77), % reduction in SULmax (OR 1.03, p = 0.006, c = 0.72) and tumor HER2 protein abundance (OR 1.75; p = 0.01, c = 0.76). The composite of C1D15 SULmax and % reduction in SULmax and their interaction term, had improved probability (c = 0.89 from c = 0.78), with high sensitivity (100 %) and negative predictive value (100 %). The addition of tumor HER2 protein did not further improve prediction power (c = 0.90). CONCLUSION:The HER2/PET-CT biomarker had high prediction power for pCR, however was not superior to the prediction power of PET/CT alone. Non-invasive PET/CT biomarkers may facilitate a response-guided approach to neoadjuvant therapy, allowing intensification and de-intensification of treatment, pending further evaluation.

PURPOSE:Predictive biomarkers to better tailor therapy for patients with early-stage human epidermal growth factor 2 (HER2)-positive breast cancer are a priority. We hypothesized that HER2 and immune-based biomarkers would be predictive of pathologic complete response (pCR) to preoperative trastuzumab/pertuzumab (HP). MATERIALS AND METHODS:Patients with stage II/III, estrogen receptor (ER)-negative, HER2-positive breast cancer received neoadjuvant HP in the TBCRC026 clinical trial. The pCR after receiving HP alone was 22% (18/83). Tumor biopsies were performed at baseline. Secondary correlative objectives were to determine the relationship between HER2-based biomarkers and immune processes with pCR. NanoString code sets BC360 and IO360 were used to compare differential gene expression in baseline tumors that underwent pCR versus no pCR. NanoString GeoMx digital spatial profiling was used to assess immune protein abundance in intraepithelial and stromal segments. Stromal tumor-infiltrating lymphocytes and Ki67 were evaluated by hematoxylin and eosin and immunohistochemistry, respectively. RESULTS:Intraepithelial HER2 protein abundance was significantly associated with pCR (P = .001). Low HER2 abundance tumors were primarily basal-like, and essentially all (19/20) failed to achieve pCR. High HER2 abundance tumors that achieved pCR (14/51) exhibited a high degree of immune cell activity, whereas high HER2 abundance tumors that failed to achieve pCR tumors (37/51) were enriched for M-phase processes and epidermal growth factor receptor signaling. Baseline Ki67 was significantly higher in nonresponders (P = .04). CONCLUSION:ER-negative, HER2-positive breast cancer has unique molecular and immunologic features that may predict pCR after neoadjuvant HP. Validation of these potential biomarkers and composite biomarker analyses may guide design of future clinical trials.

Background: Gedatolisib is a pan PI3K/mTOR inhibitor and was evaluated in a multicenter, open-label, phase 1b dose-escalation and dose-expansion trial in combination with palbociclib and endocrine therapy in patients with hormone receptor-positive/HER-2 negative (HR+/HER2-) breast cancer with varying categories of prior therapy (ClinicalTrials.gov NCT02684032). The primary objective of the dose-escalation cohorts was safety while the primary endpoint of the dose-expansion cohorts was investigator-assessed objective response. Median progression-free survival at 12 months was 72.1%, 54.5%, 23.6%, and 53.2% for Arms A, B, C, and D, respectively, as defined in the methods. In the dose-expansion cohorts gedatolisib triplet therapy achieved overall response rates (ORR) of 85%, 77%, 36% and 63% in Arms A, B, C and D respectively. Based on the promising ORR of the phase 1b trial, further follow-up was warranted to analyze survival outcomes. Here we report survival results of patients who received gedatolisib combined with palbociclib plus letrozole or fulvestrant. Methods: Female patients aged at least 18 years from 17 sites across the USA with HR+/HER2- advanced breast cancer and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 were enrolled in the phase 1b trial. There were 2 dose-escalation arms that assessed safety of gedatolisib 180 mg/week plus standard doses of palbociclib with endocrine therapy of letrozole or fulvestrant. The dose expansion portion had 4 patient cohorts based on prior treatment history, with Arm A comprising patients with no prior systemic treatment for breast cancer, Arm B with patients with 1-2 prior endocrine therapies but no history of CDK4/6 inhibitor, and Arms C and D with patients with one or more prior lines of therapy, including a CDK4/6 inhibitor. Gedatolisib 180 mg was administered intravenously weekly in 28-day treatment cycles for Arms A-C, and on days 1, 8, and 15 for Arm D. Endocrine therapy with letrozole or fulvestrant and CDK4/6 inhibition with palbociclib were administered at standard dose. Participating sites were asked to collect patient outcome for survival analysis. Results: As of the phase 1b study data lock on June 29, 2022, the median overall survival was not reached in any group. The sponsor has initiated overall survival follow up for all patients that will be presented at the conference which provides at least 2 years of additional follow-up time. Conclusions: Gedatolisib in combination with palbociclib and letrozole demonstrated promising overall response rates and progression-free survival in patients with HR+/HER2- advanced breast cancer that warrants further evaluation of overall survival outcomes./ Citation Format: Rachel Layman, Hope S. Rugo, Robert Wesolowski, Hyo Han, Jennifer M. Specht, E. Claire Dees, Erica M. Stringer-Reasor, Peter Kabos, Vandana Abramson, Anthony Shields, Charlotte Moser, Igor Gorbatchevsky, Pratima Nayak, Samuel Suzuki, Sarah Mutka. Overall survival in patients with HR+/HER2- advanced breast cancer treated in a phase 1b trial evaluating gedatolisib in combination with palbociclib and endocrine therapy [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 P4-08-25.

PURPOSE The time required for in-clinic drug administration can substantially affect breast cancer patients' quality of life. Subcutaneous (SC) drug administration, as opposed to intravenous (IV), may reduce this time commitment. This study sought to estimate the difference in time burden between IV and SC administration of trastuzumab and pertuzumab (HP). METHODS We prospectively enrolled a subcohort of patients participating in the ADEPT trial (ClinicalTrials.gov identifier: NCT04569747, investigating adjuvant HP plus endocrine therapy for stage I human epidermal growth factor receptor 2-positive breast cancer) to this single-arm crossover time and motion substudy. Patients received two cycles of IV HP followed by two cycles of SC HP. During each cycle, time points in drug preparation and administration were captured. The primary end point was total patient time in the treatment chair. Additional end points included total patient treatment experience time and total pharmacy workflow time. A sample size of 22 patients was estimated to provide 90.7% power with two-sided alpha .05 to detect a difference of 70 minutes in the primary end point by treatment arm (IV v SC). RESULTS Twenty-two patients were enrolled. The mean total patient time in the treatment chair was 61.8 minutes shorter with SC versus IV HP (22.5 v 84.3 minutes; P < .0001). The mean total patient treatment experience time (incorporating time spent waiting for treatment initiation and time spent in the treatment chair) was 81.8 minutes shorter for SC administration (96 v 177.8 minutes; P < .0001). The pharmacy workflow time was 78.2 minutes shorter for SC versus IV formulation (41 v 119.2 minutes; P < .0001). CONCLUSION SC administration of HP shortened patient time burden by approximately 1 hour. SC drug administration can facilitate faster workflows for health care professionals and improve patients' breast cancer treatment experience.

TPS1143 Background: PARP inhibitors are approved for germline BRCA1/2mutant MBC but the applicability of these well-tolerated oral targeted therapies is limited, as germline BRCA1/2mutations account for 5% of breast cancer. We demonstrated that pathogenic somatic BRCA1/2mutations are detectable in cell-free DNA and tumor tissue genotyping assays in a subset of HER2- MBC, in patients who are not known germline BRCA1/2carriers. In a circulating tumor cell culture model derived from a patient with a pathogenic somatic BRCA1 mutation, we demonstrated that the growth inhibitory effect of a PARP inhibitor paralleled germline BRCA1/2mutant cultures. We hypothesize that somatic BRCA1/2mutations may be amenable to PARP inhibition. In this study, we are evaluating the efficacy of a PARP inhibitor in somatic BRCA1/2mutant MBC. The results may expand the population of patients who benefit from PARP inhibitors. Methods: In this phase II investigator-initiated clinical trial, 30 patients with HER2- MBC with pathogenic somatic BRCA1/2mutations (in the absence of a known germline BRCA1/2mutation) identified in a CLIA certified cell-free DNA or tumor tissue genotyping assay are being enrolled at 7 academic centers. Mutations are vetted for pathogenicity by genetic counselors using validated genomic databases such as ClinVar. Patients with metastatic triple-negative or hormone receptor positive (HR)+/HER2- breast cancer who received ≥1 prior therapy in the metastatic setting are eligible. Any number of prior therapies are acceptable, including a prior platinum (in absence of disease progression). Patients must have adequate baseline performance status and organ function. Patients are treated with talazoparib 1 mg/day until disease progression. Disease assessments occur at baseline and every 3 months via CT chest, abdomen, and pelvis, and bone scan. The primary endpoint is progression free survival (PFS) via RECIST 1.1. This study has 81% power to demonstrate the 12-week PFS is ≥53% (4% alpha). Secondary endpoints include objective response rate and toxicity (NCI CTCAE v 5.0). Exploratory endpoints, determined using serial cell-free DNA collected at baseline and monthly, include identifying resistance mutations, and evaluating the impact of mutant allele fraction and BRCA1/2reversion mutations on response. The Cancer Risk B (CR-B) assay, a novel method to identify double-strand break repair mutations in circulating blood cells, will be correlated with response. The study (NCT03990896) is open at Massachusetts General Hospital, University of California San Francisco, MD Anderson, Emory, Northwestern, and Vanderbilt and will open at Cornell, with 17 patients enrolled as of 2/2024. Clinical trial information: NCT03990896 .

The treatment landscape of invasive early-stage and metastatic breast cancer is evolving constantly. These NCCN Guidelines Insights focus on recent updates included in the most recent version (version 5.2025) of the NCCN Guidelines for Breast Cancer specific to workup, locoregional therapy, surveillance, and systemic neoadjuvant/adjuvant therapy recommendations for invasive, nonmetastatic breast cancer.

We evaluated the feasibility, safety, and efficacy of adjuvant bevacizumab, alone or in combination with chemotherapy, in early-stage breast cancer patients with residual invasive disease after neoadjuvant chemotherapy. Feasibility was demonstrated only for bevacizumab with flat-dosed capecitabine. The 36-month recurrence-free survival (RFS) ranged from 58.0% with bevacizumab monotherapy to 75.0% with bevacizumab plus body surface area-dosed capecitabine. Background: Breast cancer patients with residual disease after neoadjuvant therapy have increased risk of recurrence. Novel therapies to decrease this risk are urgently needed. Methods: Two clinical trials (05-055 and 09-134) offered adjuvant bevacizumab-based therapy to stage I-III breast cancer patients with residual disease after neoadjuvant chemotherapy. Study 05-055 evaluated four treatment regimens: bevacizumab (cohort A); bevacizumab with metronomic cyclophosphamide and methotrexate (CM) (cohort B); and bevacizumab with body surface area-dosed capecitabine (cohorts C); or flat-dosed capecitabine (cohort D). The primary endpoint was feasibility and tolerability. In 09-134, patients were randomized to bevacizumab with or without CM; the primary endpoint was recurrence-free survival (RFS). Study 09-134 closed prematurely for lack of accrual. A pooled survival analysis with participants from 05-055 and 09-134 was conducted. Results: Among 213 total patients (05-055, n = 163; 09-134, n = 50), the most common adverse events (AEs) of any grade were headache (49.3%) and fatigue (57.3%). Grade 3-4 AEs were highest in cohorts C (71.4%) and D (72.5%). The 36-month RFS was 58.0% with bevacizumab monotherapy, 62.3% with bevacizumab plus CM, and 72.7%-75.0% with bevacizumab plus capecitabine (depending on schedule). Treatment with capecitabine was independently associated with improved RFS in triple-negative breast cancer (TNBC) (HR: 0.47; 95% CI, 0.23-0.96). Conclusion: This pooled analysis demonstrates that postneoadjuvant bevacizumab plus capecitabine may be associated with improved RFS, especially in TNBC. Each regimen carries moderate toxicity, and despite these treatments, patients with residual disease after neoadjuvant therapy still experience high rates of recurrence, indicating that new strategies are warranted. Clinical Trial Registration: clinicaltrials.gov, NCT00121134 (DFCI Protocol Number: 05-055); NCT00925652 (DFCI Protocol Number: 09-134).

Nanostring and flow cytometry immune profiling analysis

B7-H4 expression does not correlate with resistance to chemotherapy + immunotherapy in human breast tumors. Patients were from the I-SPY2 clinical trial (paclitaxel control and pembrolizumab arms) or the TBCRC 043 clinical trial (carboplatin control and atezolizumab arms). A, In breast tumors from the I-SPY2 clinical trial (control and pembrolizumab arms), B7-H4 expression is higher in TNBC tumors compared with HR+ tumors. Data were analyzed by unpaired t test. B, In the same patient cohort, B7-H4 expression is not higher in grade III tumors compared with grade I (orange dots) or II. Data analyzed by unpaired t test. C and D, B7-H4 expression is not correlated with pCR in tumors regardless of HR status, treated with either paclitaxel or paclitaxel + pembrolizumab (ICI). Data analyzed by unpaired t test. E, EFS in HR+ (n = 89) and TNBC (n = 62) tumors from the I-SPY2 cohort. Tumors with high B7-H4+ expression (top 33% of patients) have worse EFS when treated with paclitaxel alone and no survival benefit when treated with paclitaxel + ICI. Data were analyzed by log-rank Mantel–Cox test. F, In the metastatic setting, PFS stratified by B7-H4 expression (top and bottom 33% of cohort) from primary breast biopsy or metastatic lesion in patients from the TBCRC 043 trial does not correlate with B7-H4 expression in either control or carboplatin + atezolizumab (ICI) groups. Data were analyzed by log-rank Mantel–Cox test. G and H, We also assessed survival by treatment status. Metastatic tumors (H) from TBCRC 043 with high B7-H4 expression had significantly improved PFS to ICI, and nonmetastatic tumors (I-SPY2) had minimal improvement to ICI (G). Data were analyzed by log-rank Mantel–Cox test. n = 151 patients for A–E and G; n = 91 patients for F and H.

PURPOSELong-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need.METHODSIn the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia.RESULTSAfter a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively.CONCLUSIONAdjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.

Abstract Despite the success of immune checkpoint inhibition (ICI) in treating cancer, patients with triple-negative breast cancer (TNBC) often develop resistance to therapy, and the underlying mechanisms are unclear. MHC-I expression is essential for antigen presentation and T-cell–directed immunotherapy responses. This study demonstrates that TNBC patients display intratumor heterogeneity in regional MHC-I expression. In murine models, loss of MHC-I negates antitumor immunity and ICI response, whereas intratumor MHC-I heterogeneity leads to increased infiltration of natural killer (NK) cells in an IFNγ-dependent manner. Using spatial technologies, MHC-I heterogeneity is associated with clinical resistance to anti-programmed death (PD) L1 therapy and increased NK:T-cell ratios in human breast tumors. MHC-I heterogeneous tumors require NKG2A to suppress NK-cell function. Combining anti-NKG2A and anti–PD-L1 therapies restores complete response in heterogeneous MHC-I murine models, dependent on the presence of activated, tumor-infiltrating NK and CD8+ T cells. These results suggest that similar strategies may enhance patient benefit in clinical trials. Significance: Clinical resistance to immunotherapy is common in breast cancer, and many patients will likely require combination therapy to maximize immunotherapeutic benefit. This study demonstrates that heterogeneous MHC-I expression drives resistance to anti–PD-L1 therapy and exposes NKG2A on NK cells as a target to overcome resistance. This article is featured in Selected Articles from This Issue, p. 201