Representativeness of Study Participants

Representative multiplex immunofluorescence image with nuclei (blue), CD8 (aqua), PDL1 (green), FOXP3 (yellow), PD1 (orange), CD3 (red), and cytokeratin (white) stains depicted.

601 Background: NCIT improves survival in high-risk eTNBC; however, trial-based data show that most relapses after NCIT are early. Real-world data are lacking. Methods: This retrospective study included pts from the DFCI Multicenter TNBC registry with eTNBC or estrogen receptor (ER)-low (≤10%), HER2-negative breast cancer (BC) treated with NCIT who underwent surgery before 7/1/2025. Aims were to evaluate (1) patterns of relapse; (2) BC–specific event–free survival (BC-EFS) from the first NCIT dose to relapse, contralateral BC, or death; (3) first-line (1L) metastatic systemic treatment patterns, and (4) time to progression (TTP). Results: 220 pts were identified, with median age of 50.1 yrs (IQR: 40.5-60.8). Median follow-up (FU) was 32.7 months (mo) (IQR, 30.4–34.4). At last FU, 29 pts (13.2%) had relapsed (locoregional, n=2; distant, n=27). Among these, 86.2% had not experienced pathologic complete response. Among relapsed pts with PD-L1 assessment (n=16), 43.8% (n=7) had a Combined Positive Score (CPS) <10; 56.2% (n=9) had a CPS ≥10. BC-EFS is shown in the Table. 1L therapy consisted of antibody-drug conjugate (ADC) in 51.7% (n=15), Poly ADP-ribose Polymerase inhibitor (PARPi) in 13.8% (n=4), chemotherapy in 13.8% (n=4), ADC+PARPi in 3.4% (n=1), CIT in 3.4% (n=1), and HER2-directed in 3.4% (n=1); 10.3% (n=3) died before 1L therapy. Median (m)TTP in 1L (n=26) was 7.7 mo (95% CI, 6.0–13.0) and detailed in the Table. Among pts with disease-free interval (DFI) ≤6 mo (n=8), mTTP was 5.1 mos (2.7–NR), with TTP rates of 50.0% (25.0–100.0) at 6 mo and 16.7% (2.9–95.3) at 12 mo. In those with DFI 6–12 mo (n=9), mTTP was 9.7 mo (7.4–NR); TTP rates were 88.9% (70.6–100.0) at 6 mo and 25.4% (7.7–83.8) at 12 mo. For DFI >12 mo (n=9), mTTP was 8.6 mo (5.6–NR), with TTP rates of 71.4% (44.7–100.0) at 6 mo and 28.6% (8.9–92.2) at 12 mo. Among pts treated with 1L ADC (n=16), mTTP was 8.6 mo (7.4–NR); TTP rates were 77.9% (58.4–100.0) at 6 mo and 26.0% (9.9–68.3) at 12 mo. In non-ADC-treated pts (n=10), mTTP was 6.2 mo (3.78–NR), with TTP rates of 60.0% (36.2–99.5) at 6 mo and 20.0% (5.8–69.1) at 12 mo. Median overall survival (from diagnosis) among pts with relapse was 26.3 mo (95% CI, 25.0–NR). Conclusions: Relapse after NCIT was predominantly early with poor metastatic outcomes, underscoring an urgent need for new strategies in this population largely excluded from clinical trials. Any NCIT(n = 216) KEYNOTE-522(n = 176) 1L for metastatic TNBC(n = 26) Time from NCIT start (mo) BC-EFS % (95% CI) Event N BC-EFS % (95% CI) Event N Time from 1L start (mo) TTP survival % (95% CI) Event N 6 100.0(100.0, 100.0) 0 100.0(100.0, 100.0) 0 6 70.8(54.6, 91.7) 7 12 95.4(92.5, 98.4) 9 95.0(91.7, 98.4) 8 12 23.6(11.0, 50.5) 17 18 89.4(84.9, 94.0) 19 89.7(84.9, 94.8) 15 18 14.2(5.0, 40.3) 19 24 86.4(81.3, 91.8) 23 86.0(80.3, 92.2) 19 24 9.4(2.5, 35.2) 20 36 79.9(72.2, 88.3) 27 82.2(74.8, 90.3) 21

Importance:The neoadjuvant combination of paclitaxel, trastuzumab, and pertuzumab (THP) represents a promising abbreviated regimen for early-stage ERBB2-positive breast cancer, but long-term outcomes and the role of ultrasensitive circulating tumor DNA (ctDNA) monitoring remain incompletely defined. Objective:To assess 5-year outcomes and characterize ctDNA dynamics with an ultrasensitive assay in patients with ERBB2-positive breast cancer receiving neoadjuvant THP. Design, Setting, and Participants:This study was a prespecified secondary analysis of the prospective, single-arm, investigator-initiated phase 2 DAPHNe nonrandomized clinical trial. Patients were enrolled in the DAPHNe trial from November 2018 to January 2020. The trial took place at a multicenter academic cancer center and affiliated community practices. Participants included patients with stage II to III ERBB2-positive breast cancer receiving neoadjuvant THP for 12 weeks. Ultrasensitive ctDNA analyses were performed in patients with available tumor tissue and serial plasma samples. The secondary analysis was conducted between between March 2023 and April 2025. Interventions:Neoadjuvant THP administered for 12 weeks, followed by surgery and adjuvant therapy guided by pathologic response. Main Outcomes and Measures:Main outcomes included 5-year event-free survival, recurrence-free interval (RFI), distant RFI, and overall survival. ctDNA detection and clearance were assessed using a whole-genome-based, tumor-informed ultrasensitive assay at 4 predefined time points (baseline, preoperative, postoperative, and late adjuvant). Results:The overall trial cohort included 98 patients (median [IQR] age, 49.5 years [24.0-78.0 years]; 97 female patients [99.0%]; 1 male patient [1.0%]), with mostly stage 2 disease (91 patients [92.9%]) and hormone receptor-positive tumors (65 patients [66.3%]). With a median (IQR) follow-up of 5.2 (5.0-5.4) years, the 5-year event-free survival was 99% (95% CI, 97%-100%), the 5-year RFI was 98% (95% CI, 93%-100%), the 5-year distant RFI was 100% (95% CI, 100%-100%), and the 5-year overall survival was 99% (95% CI, 97%-100%). Among 57 patients included in ctDNA analyses, baseline ctDNA was detected in 51 individuals (89.5%). After neoadjuvant therapy, ctDNA clearance occurred in 49 of 51 patients (96.1%), with only 2 individuals (3.9%) remaining ctDNA-positive preoperatively; detectability remained low (<10%) during postoperative follow-up. One single patient experienced a local recurrence, with ctDNA detected at time of recurrence and cleared following surgical resection. Conclusions and Relevance:In this secondary analysis of the DAPHNe nonrandomized clinical trial, neoadjuvant THP was associated with excellent long-term outcomes in patients with early-stage ERBB2-positive breast cancer. Ultrasensitive ctDNA analyses demonstrated high baseline detection rates and near-universal clearance after abbreviated neoadjuvant therapy, supporting further investigation of ctDNA-guided de-escalation strategies in this setting. Trial Registration:ClinicalTrials.gov Identifier: NCT03716180.

Pearson’s correlation coefficients between tumor-infiltrating lymphocyte subtypes within stroma, with p-values in parentheses.

1083 Background: Pts with HR+ MBC exhibit variable responses to 1L ET + CDKi therapy. We analyzed clinicopathologic features and genomic landscapes of biopsies obtained at the time of the diagnosis of MBC to identify determinants of sensitivity/resistance to 1L CDKi, with a focus on distinguishing endocrine-sensitive from endocrine-resistant (ETR) disease. Methods: A single center cohort included pts with biopsies obtained within 3 months of diagnosis of HR+, HER2-negative MBC (distant recurrent and de-novo [DNIV]), diagnosed between 2013 - 2020. Tumors underwent targeted DNA sequencing (OncoPanel). Clinical data were obtained from the EMBRACE database. Results: The entire cohort included 666 pts, of them 321 (48%) treated with 1L ET + CDKi. Among pts who received adjuvant ET (n = 347), 54 (15.6%) had primary ETR, 140 (40.3%) secondary ETR, and 153 (44.1%) were endocrine-sensitive. Of these pts, 56% (n = 191) received 1L CDKi therapy. The median time to next treatment (TTNT) in pts treated with 1L CDKi differed significantly by disease presentation, with a median of 1.3 years (95% CI, 0.9–1.5) for recurrent MBC and 2.3 years (95% CI, 1.7–3.6) for DNIV (log-rank p = 0.0005). TTNT also varied significantly according to endocrine sensitivity, with median TTNT of 0.6, 0.9, and 1.8 years for primary ETR, secondary ETR, and endocrine-sensitive disease, respectively (p = 0.0005). In the entire cohort, SNVs/indels were most frequent in PIK3CA , TP53 , and CDH1. CCND1 , FGFR1 , and MYC amplifications were most frequent amplifications. TP53 and ESR1 mutations were enriched in ETR tumors, compared with ET sensitive cancers (q < 0.2). ESR1 mutations were detected in 15% of ETR tumors, versus 8% in endocrine-sensitive cancers and 3% in DNIV. Prior adjuvant aromatase inhibitor exposure occurred in 39%, 61%, and 44% of patients with primary ETR, secondary ETR, and ET-sensitive tumors, respectively. When comparing poor and exceptional responders to 1L CDKi, TTNT <6 months versus >36 months, mutations in TP53 and N F1 were significantly enriched in the poor responders (q < 0.2). We also evaluated the association between specific genomic alterations and TTNT on 1L CDKi; mutations in TP53 , NF1 , and ERBB2 , as well as amplifications of RAD21 , FGFR1 and deletions of RB1 , CDKN2A were associated with shorter TTNT on 1L ET plus CDKi (q < 0.2). Conclusions: In our cohort, distinct genomic alterations were associated with ETR and shorter TTNT on 1L CDKi. These findings underscore the biology of ETR and support the clinical relevance of early genomic profiling to refine risk stratification and guide therapeutic decision-making. Notably, the high prevalence of ESR1 alterations in ETR tumors carries important implications for adjuvant and 1L treatment strategies, particularly the potential role of oral selective estrogen receptor degraders in this setting.

Representative multiplex immunofluorescence images with nuclei (blue), CD8 (aqua), FOXP3 (yellow), CD3 (red), and cytokeratin (white) stains depicted.

TPS1147 Background: Due to dramatic improvements in neoadjuvant and adjuvant HER2-directed therapy (tx), most patients (pts) with early HER2+ breast cancer are cured. As a result, over half of pts newly diagnosed with HER2+ metastatic breast cancer (MBC) now present with de novo stage IV disease. Anti-HER2 tx has also significantly extended survival for pts with HER2+ MBC, with a subgroup of exceptional responders alive many years (yrs) after diagnosis. However, the paradigm for HER2+ MBC remains non-curative, and pts receive tx indefinitely with significant toxicities and costs. The SAPPHO study is investigating whether an intensification approach of sequential, non-cross resistant anti-HER2 tx followed by tx discontinuation is associated with long-term disease control in pts with HER2+ MBC. Methods: SAPPHO is an open-label, phase II, single-arm trial testing a sequential regimen of non-cross resistant, HER2-targeted tx with curative intent in pts with de novo HER2+ MBC. Eligible pts must have biopsy-proven, de novo MBC with high HER2 expression (3+ by immunohistochemistry). Pts with brain metastases are eligible upon receipt of local tx. Treatment consists of an induction regimen (trastuzumab-pertuzumab-taxane [THP] x 4 cycles, followed by trastuzumab deruxtecan [TDXd] x 6 cycles, followed by trastuzumab emtansine [TDM1]-tucatinib x 4 cycles), followed by a maintenance regimen (HP-tucatinib for 1 yr). Given results from DESTINY-Breast09, the sequence of TDXd-P x 6 cycles followed by THP x 4 followed by TDM1-tucatinib x 4 can be chosen as alternative induction tx per investigator and patient choice. Pts who remain progression-free after completing maintenance will stop all anti-HER2 tx. Endocrine tx will be continued for pts with hormone receptor+/HER2+ tumors. Tumor specimens from breast and a metastatic site are collected at baseline and the end of induction. Serial plasma samples for ctDNA analysis are collected at baseline, during treatment, and during follow-up. The primary endpoint is the probability of being progression-free and off anti-HER2 tx 4 yrs from the start of induction. With a sample size of 72 pts, the study is designed to have 91% power to reject the null hypothesis that the probability of being off anti-HER2 tx and progression-free is less than 24%, with an alternative hypothesis of 40%. Key secondary endpoints are overall survival, overall response rate by modified RECIST 1.1 after induction, and safety. Correlative endpoints include the relationship between ctDNA dynamics and outcomes. Patient-reported outcomes will be analyzed, including quality of life, illness intrusiveness, financial toxicity, anxiety, distress about cancer progression, perception of benefit and risk of progression. SAPPHO began enrollment in Q3 2024, and the study is open at 4 US sites within the Translational Breast Cancer Research Consortium (NCT05721248). Clinical trial information: NCT05721248 .

Patients with triple-negative breast cancer (TNBC) are encouraged to consider clinical trials given limited treatment options, yet little is known regarding barriers to trial participation in this population. We examined whether patient-level factors, including disease knowledge, were associated with TNBC patients’ participation in trials. From a prospective multicenter registry of patients with newly-diagnosed TNBC, we identified those with stage I-III tumors who completed at least one survey assessing TNBC knowledge, risk perceptions, treatment rationales, and participation in trials. Accuracy of tumor characteristics reported by patients was verified with medical records. Logistic regression was used to identify factors associated with self-reported trial participation. TNBC knowledge varied among patients, with many reporting their tumor characteristics incorrectly and/or underestimating their recurrence risk. Among 116 patients with trial participation responses, 55 (47

Introduction:With recent approvals of multiple targeted therapies for triple-negative breast cancer (TNBC), including antibody-drug conjugates and immunotherapy in biomarker-selected populations, it is critical to define the temporal evolution of cell-surface target expression from early-stage to metastatic disease, the co-expression patterns across these markers, and optimal quantification methodologies. Here we report biomarker expression profiles measured by multi-omics and pathology-based platforms in patients with TNBC using a large cohort of matched longitudinal tumor samples. Methods:Patients who underwent neoadjuvant chemotherapy (NAC) for stage I-III TNBC or were diagnosed with any stage TNBC and developed metastatic recurrence were retrospectively identified from an institutional database and prospective research metastatic biopsy protocol. Tumor samples from diagnosis (DX), residual disease (RD) post-NAC (if applicable), and metastasis/recurrence (MR) were collected. Quantification of HER2, TROP2, and PD-L1 expression was performed by immunohistochemistry (IHC), whole-exome sequencing, transcriptome sequencing, and targeted mass spectrometry (MS). For HER2, TROP2, and stromal tumor-infiltrating lymphocytes (sTILs), both manual pathologist assessment and computational pathology quantification were obtained. HER2 status was categorized as HER2-0 or HER2-low by local (L-IHC) and central (C-IHC) review, TROP2 status was defined as low (H-score <100), medium (H-score 100-200) or high (H-score >200), and PD-L1 as low (tumor area positivity, TAP <5%) or high (TAP ≥5%). Pathologist-assessed sTILs were classified as low (<10%), medium (≥10% and <40%) or high (≥40%). Biomarkers were compared between primary (DX/RD) and MR, and between pre- vs post-NAC (DX-RD) samples. Correlations between markers, quantification methods, inferred PAM50 subtype, and clinical variables of interest were evaluated. Results:A total of 359 samples from 110 patients with TNBC with data available from at least one platform were included in the analysis. HER2-low prevalence at DX, RD, and MR was: 51% (50/98), 40% (21/53), and 27% (16/60); TROP2 high/medium was 90% (47/52), 91% (42/46), and 88% (28/32); PD-L1-high was 51%, 50%, and 38% (9/24); and sTILs-high/medium was 88% (59/67), 80% (40/50), and 49% (17/35), respectively. While TROP2-high/medium vs low remained stable over time, HER2 IHC and sTILs significantly decreased from DX/RD to MR samples, both at the cohort-level (HER2, p=0.0081; sTILs, p=4.6x10e-5) and longitudinal patient-level (HER2, p=0.030; sTILs, p=0.0077), with a similar decreasing trend for PD-L1 that did not reach statistical significance. HER2 concordance (0 vs low) between L-IHC and C-IHC was 78% (91/116). ERBB2 , TACSTD2 and CD274 mRNA expression were significantly correlated with IHC protein levels, though only TACSTD2 had limited overlap in distribution of gene expression between high/medium vs low groups. Strong correlation between protein membrane staining intensity from computational pathology, protein expression measured by MS, and pathologist-assed IHC was observed across all biomarkers tested by each method. In comparisons between biomarkers, pathologist-assessed PD-L1 IHC and sTILs were significantly correlated (p=0.0001); 94% (51/54) of PD-L1-high tumors were classified as sTILs high/medium. PAM50 subtype was not significantly correlated with time point or biomarker status, although there was a trend toward more HER2-enriched tumors in HER2-low (20%, 5/25) vs HER2-0 (6%, 3/52) (p=0.086). Across biomarkers and clinical variables, an association between age and sTILs was observed (p=0.038, FDR=0.42) due to a decrease in sTILs high/medium tumors with age, primarily driven by post-treatment (RD/MR) but not DX samples. Conclusions:Multi-platform and multi-omics profiling in this large unique cohort of longitudinal TNBC samples revealed distinct patterns of expression and dynamic changes of key biomarkers of interest for targeted therapies. Given variability with manual IHC scoring, improved methods for quantification of expression may help optimize treatment selection in an individualized manner.

Multivariate survival analysis by moderate or marked versus absent or mild stromal lymphocytic infiltration, with adjustment for tumor grade, stage, and chemotherapy receipt.

603 Background: Accurate prediction of pathologic complete response (pCR) after preoperative therapy for HER2-positive (HER2+) breast cancer can help triage patients to immediate surgery vs additional preoperative therapy. Pre-surgery (i.e., after neoadjuvant therapy) imaging studies may help estimate the likelihood of pCR. In EA1181, patients (pts) with stage II-IIIA HER2+ breast cancer received four cycles of preoperative taxane, trastuzumab, and pertuzumab (THP×4). Pre-surgery imaging was required, though the specific imaging modality was not mandated. Here, we report the accuracy of pre-surgery breast MRI to predict pCR (ypT0/Tis, ypN0). Methods: Among 2,141 pts treated with THPx4, 1,378 had pre-surgery breast MRI and were representative of the overall cohort, although T3 tumors were more common (16% vs 9%). MRI reports were available for 1,351 pts; all reports were centrally reviewed and classified as radiologic complete response (rCR; no residual tumor enhancement and normalization of lymph nodes, if applicable) or radiologic residual disease (rRD). Reports with indeterminate radiologic response were independently reviewed by two study radiologists blinded to pathology outcomes. Among pts with rCR who had pathologic residual disease (pRD), we also assessed the extent of residual disease by residual cancer burden (RCB) score. Among pts with rRD who had a pCR, we determined the proportion who only had residual ductal carcinoma in situ (DCIS). Results: See Table. Conclusions: After neoadjuvant therapy, preoperative MRI accurately predicted pCR in 86% of patients with HER2+/ER− disease and may help identify patients who can proceed directly to surgery. MRI is insufficient to predict pCR for pts with HER2+/ER+ disease, as only 55% with complete response on MRI had a pCR at surgery. A pre-surgery MRI that indicated residual disease was accurate in 80% of pts with HER2+/ER+ disease, but in only 45% of pts with HER2+/ER- cancer. Accurately predicting residual disease after THPx4 allows for consideration of additional therapy that may increase the chance of pCR. Combining imaging like MRI with other biomarkers, such as tissue-based markers or circulating tumor DNA, may improve prediction of pCR and facilitate personalization of treatment decisions in HER2+ breast cancer. All pts with pre-surgery MRI (n=1351)pCR rate overall in this cohort = 47% MRI result Pathology pCR pRD rCR 70.6% (341/483) 29.4%(142/483) 78% had RCB1 rRD 34%(295/868) 21% of 295 had DCIS only 66.01% (573/868) ER- (n=589)*Overall pCR rate in ER- subset = 68% MRI result Pathology pCR pRD rCR 86.1% (205/238) 13.9% (33/238) 85% had RCB1 rRD 55.3% (194/351) 19% of 194 had only DCIS 44.7% (157/351) ER+ (n= 762)*Overall pCR rate in ER+ subset = 31% MRI result Pathology pCR pRD rCR 55.5% (136/245) 44.5% (109/245) 76% had RCB1 rRD 19.5% (101/517) 26% of 101 had only DCIS 80.5% (416/517)

Importance The neoadjuvant combination of paclitaxel, trastuzumab, and pertuzumab (THP) represents a promising abbreviated regimen for early-stage ERBB2 -positive breast cancer, but long-term outcomes and the role of ultrasensitive circulating tumor DNA (ctDNA) monitoring remain incompletely defined. Objective To assess 5-year outcomes and characterize ctDNA dynamics with an ultrasensitive assay in patients with ERBB2 -positive breast cancer receiving neoadjuvant THP. Design, Setting, and Participants This study was a prespecified secondary analysis of the prospective, single-arm, investigator-initiated phase 2 DAPHNe nonrandomized clinical trial. Patients were enrolled in the DAPHNe trial from November 2018 to January 2020. The trial took place at a multicenter academic cancer center and affiliated community practices. Participants included patients with stage II to III ERBB2 -positive breast cancer receiving neoadjuvant THP for 12 weeks. Ultrasensitive ctDNA analyses were performed in patients with available tumor tissue and serial plasma samples. The secondary analysis was conducted between between March 2023 and April 2025. Interventions Neoadjuvant THP administered for 12 weeks, followed by surgery and adjuvant therapy guided by pathologic response. Main Outcomes and Measures Main outcomes included 5-year event-free survival, recurrence-free interval (RFI), distant RFI, and overall survival. ctDNA detection and clearance were assessed using a whole-genome–based, tumor-informed ultrasensitive assay at 4 predefined time points (baseline, preoperative, postoperative, and late adjuvant). Results The overall trial cohort included 98 patients (median [IQR] age, 49.5 years [24.0-78.0 years]; 97 female patients [99.0%]; 1 male patient [1.0%]), with mostly stage 2 disease (91 patients [92.9%]) and hormone receptor–positive tumors (65 patients [66.3%]). With a median (IQR) follow-up of 5.2 (5.0-5.4) years, the 5-year event-free survival was 99% (95% CI, 97%-100%), the 5-year RFI was 98% (95% CI, 93%-100%), the 5-year distant RFI was 100% (95% CI, 100%-100%), and the 5-year overall survival was 99% (95% CI, 97%-100%). Among 57 patients included in ctDNA analyses, baseline ctDNA was detected in 51 individuals (89.5%). After neoadjuvant therapy, ctDNA clearance occurred in 49 of 51 patients (96.1%), with only 2 individuals (3.9%) remaining ctDNA-positive preoperatively; detectability remained low (<10%) during postoperative follow-up. One single patient experienced a local recurrence, with ctDNA detected at time of recurrence and cleared following surgical resection. Conclusions and Relevance In this secondary analysis of the DAPHNe nonrandomized clinical trial, neoadjuvant THP was associated with excellent long-term outcomes in patients with early-stage ERBB2 -positive breast cancer. Ultrasensitive ctDNA analyses demonstrated high baseline detection rates and near-universal clearance after abbreviated neoadjuvant therapy, supporting further investigation of ctDNA-guided de-escalation strategies in this setting. Trial Registration ClinicalTrials.gov Identifier: NCT03716180

e13776 Background: Growing evidence suggests that overdiagnosis from routine screening may result in overtreatment among older women with indolent breast cancers. Active surveillance has emerged as a potential strategy to reduce treatment-related morbidity without compromising survival outcomes. The use of machine learning (ML) in imaging studies has demonstrated promise in supporting risk stratification and prognostication and may allow for selection of candidates for active surveillance. However, little is known about how older women perceive surveillance-based cancer care or the role of ML in clinical decision-making. Methods: We conducted focus groups to understand patient perceptions on active surveillance and ML-driven risk stratification for low-risk breast cancer. Participants were women aged ≥ 70 either unaffected by or diagnosed with early-stage breast cancer. We used purposive sampling to recruit patients from primary care, oncology, and community-based settings within our catchment area. Focus group transcripts were coded using NVivo qualitative research software. Codes were then analyzed and synthesized into central themes using a deductive approach. Results: We held 4 focus groups with 11 participants (mean age, 75 years). Overall, 64% of participants had a history of breast cancer and 36% reported educational attainment of “Some College” or “High School Degree”. Participants were generally receptive to the concept of active surveillance, though willingness to pursue it varied, and was shaped by perceived cancer risk, prior experiences, desired information, and risk tolerance. Trust in physician recommendations and doctor-patient relationships were central to decision-making about pursuing active surveillance. Participants weighed anticipated long-term outcomes, including treatment burden, quality versus quantity of life, the psychological impact of surveillance, and the perceived value of definitive treatment, while emphasizing autonomy, informed choice, and flexibility to change management over time. Participants favored ML as a supportive tool integrated with human oversight rather than a replacement for clinician judgment. Comfort with ML varied by age, educational attainment, values, previous experiences, and family influences. Accuracy and reliability were viewed as essential for high-stakes decisions. Conclusions: Older women expressed nuanced and conditional acceptance of both active surveillance and ML-supported cancer care. Trust, autonomy, risk tolerance, and human oversight emerged as critical determinants of acceptability. These findings will directly inform the development of a population-based survey and provide a patient-centered foundation for a future prospective trial evaluating ML-driven risk stratification to support active surveillance in older women with indolent breast cancers.

Triple-negative breast cancer (TNBC) patients with brain metastases have a poor prognosis and limited treatment options. Preclinical and clinical evidence suggests that radiotherapy may act synergistically with immune checkpoint inhibitors. We conducted an open-label, single-arm, phase II study of atezolizumab plus stereotactic radiosurgery (SRS) in metastatic TNBC patients with brain metastases. The primary endpoint was progression-free survival (PFS) according to the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) bi-compartmental model. Secondary endpoints included extracranial objective response rate, overall survival (OS), and safety and tolerability. A safety run-in analysis for dose-limiting toxicity (DLT) was performed after the first 6 patients were enrolled and completed the assessment period. Six patients were enrolled into the safety run-in phase between May 11, 2018 and October 24, 2019. No DLTs were observed, but the study was closed early due to slow accrual. Patients received a median of 2 atezolizumab cycles (range: 2—16), and SRS was administered to all 6 patients. Treatment-related adverse events (TRAEs) occurred in 4 participants (66.7 https://www.clinicaltrials.gov NCT03483012. Trial Open to Accrual: 05/01/2018.

Digital breast tomosynthesis (DBT) has demonstrated improved cancer detection compared with digital mammography (DM) in trials of women aged 50–74, identifying more invasive cancers and detecting tumors at smaller sizes. However, its benefits for women over the age of 75 have not been examined. To assess whether DBT versus DM is associated with favorable tumor characteristics and detection of less conspicuous histologic subtypes in women aged ≥ 75 compared with those aged 67–74, thereby informing screening strategies and overdiagnosis risks. We conducted a SEER-Medicare retrospective cohort study of women aged ≥ 67 diagnosed with screen-detected ER+/HER2- breast cancer from 2015 to 2021. The primary exposure was screening modality (DBT vs. DM). Outcomes included tumor size, nodal involvement, grade, and histology (invasive lobular carcinoma [ILC] vs. other). Multivariable logistic regression was used to assess the association between screening modality and tumor characteristics among women aged 67–74 and ≥ 75. Among 17,201 women with screen-detected breast cancer, 43.6

635 Background: Prospective data on efficacy, quality of life, and treatment-related toxicities in older adults with breast cancer are limited. The ATOP trial (NCT03587740) evaluated T-DM1 in older adults and demonstrated favorable 5-year invasive disease-free survival. Here, we report patient-reported adverse events (AEs) and health-related quality of life (HRQOL) findings from ATOP. Methods: ATOP was a single-arm, phase II, multicenter study of adjuvant T-DM1 for those aged 60 with stage I-III HER2+ breast cancer. Protocol therapy included postoperative administration of T-DM1 (3.6 mg/kg) every 21 days for one year (17 cycles). PRO-CTCAE (assessing specific symptoms) and EQ-5D (a measure of HRQOL) surveys were administered electronically or on paper at baseline (pre-treatment), on Day 1 of each treatment cycle, and at a single 6–12-month post-treatment time point. Participants who responded to the baseline and at least one follow-up survey were included in the PRO analysis. EQ-5D changes from baseline were assessed using general linear mixed models. Summary statistics were used to assess PRO-CTCAE scores to evaluate which symptoms developed between baseline and 1 subsequent survey(s) and their severity. Results: Among the 111 patients enrolled on ATOP (median age=71, range 60-88 years), 98 responded to the baseline survey and 1 subsequent survey(s). 1435 surveys were returned that included at least one PRO-CTCAE response, and 1661 surveys were returned that included EQ-5D. The Table displays the % of participants who reported PRO-CTCAE symptoms that worsened from baseline to any severity level (scores >0) or to a severe level (scores ≥3). More than 60% of survey respondents reported new or increased dry mouth, fatigue, muscle aches, decreased appetite, nausea, pain, and/or numbness/tingling at some point during or after treatment, but these were usually not severe. EQ-5D scores did not change significantly from baseline at any time point. Conclusions: In this adjuvant trial for patients aged >60, participation rates for PRO data collection were high. Reassuringly, global HRQOL was not impacted by T-DM1, and though frequently reported, the vast majority of patient-reported symptoms were mild. Future analyses of this trial will focus on duration and predictors (clinical and biomarker-based) of severe AEs, agreement between patient-reported and clinician-reported AEs, and whether sharing PRO reports with clinicians impacted clinician-reported AE grades. Clinical trial information: NCT03587740 . Most common new or worsening symptoms reported via PRO-CTCAE in ATOP (n=95). Symptom % with score >0 n (%) with score 3+ Dry mouth 79% 26% Fatigue 71% 29% Muscle aches 69% 20% Decreased appetite 69% 12% Nausea 67% 6% Pain 66% 21% Numbness/tingling 65% 9% Blurry vision 60% 4% Mouth or throat sores 60% 5%

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

To evaluate the prognostic role of patient-reported outcomes (PROs) in nonmetastatic breast cancer, we conducted secondary analysis of 2763 women in A011502, a randomized trial of adjuvant aspirin vs. placebo. High stress (Perceived Stress Scale) was associated with worse invasive disease-free survival (iDFS) (adjusted hazard ratio (aHR) 2.22) and distant recurrence-free survival (DRFS) (aHR 2.3). Moderate/severe pain (Brief Pain Inventory) predicted worse iDFS (aHR 1.67), DRFS (aHR 1.83), distant recurrence-free interval (aHR 1.53) and overall survival (aHR 2.21). PROs may enhance risk stratification in survivorship care. Trial Registration: ClinicalTrials.gov: NCT02927249.

TPS1164 Background: The use of immunotherapy beyond first-line setting is not yet routine in the treatment arsenal of patients with metastatic triple-negative breast cancer (TNBC), and this opens an opportunity for clinical trials examining whether adding novel immunotherapy agents to standard of care therapies would benefit patients. Prior studies have combined immunotherapy with standard chemotherapy (Cortes J, NEJM 2022), but combining immunotherapies with antibody-drug conjugates (ADCs) is a strategy worth pursuing given improvement of outcomes of ADCs when compared to standard chemotherapy (Bardia A et al, NEJM 2021). Sacituzumab govitecan (SG), a TROP2-ADC, is currently the standard second-line therapy for patients with metastatic TNBC, and in this study it is being combined with either nivolumab (programmed cell death [PD-1] inhibitor) or nivolumab plus relatlimab (lymphocyte activation gene-3 [LAG3]-inhibitor) due to preliminary data showing that simultaneous PD-1 and LAG3 inhibition enhances the anti-tumor immune response and restores the effector function of exhausted T-cells (Woo S-R et al, Cancer Res 2012; Tawbi HA et al, NEJM 2022). Methods: This is an ongoing investigator-initiated randomized, open-label, phase Ib study to assess safety and efficacy of SG plus nivolumab (n= 30 patients) or SG plus a fixed dose combination (FDC) of nivolumab and relatlimab (n = 30 patients) in patients with metastatic TNBC; NCT06963905. The study is accruing patients whose tumors are PD-L1 positive (combined positive score >10) and an amendment in under review to also include patients whose tumors are PD-L1 negative on routine testing, with 1 prior line of cytotoxic chemotherapy with or without prior immunotherapy use in the metastatic setting or within 6 months from completion of curative intent treatment. Study treatment will be continued until progression of disease, unacceptable toxicity, death, or withdrawal of consent. Safety will be monitored, and tumor response will be regularly evaluated by RECIST 1.1 criteria every 9 weeks. The primary endpoint includes safety as the incidence of dose-limiting toxicities (DLT) in 3 weeks after C1D1. Secondary endpoints include objective response rate (defined as either complete response or partial response), duration of response, clinical benefit rate (objective response plus stable disease), progression-free survival, and safety with SG plus nivolumab or SG plus nivolumab + relatlimab FDC. Exploratory endpoints include overall survival, and biomarkers of prediction of response and resistance. There will be a follow-up visit after the last study treatment administration or before starting a new anticancer treatment, whichever occurs first, followed by long-term/survival chart review follow-up every three months for 2 years. Clinical trial information: NCT06963905 .