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PURPOSE EA1181 (ClinicalTrials.gov identifier: NCT04266249 ) is a single-arm trial evaluating neoadjuvant taxane, trastuzumab, and pertuzumab (THP) in patients with clinical stage II/IIIa human epidermal growth factor receptor 2 (HER2)–positive breast cancer. This report focuses on the secondary end points of pathologic complete response (pCR) rates and associated factors. The primary end point—3-year recurrence-free survival among patients achieving a pCR (ypT0/Tis, ypN0)—will be reported when data mature. METHODS Patients received four cycles of trastuzumab and pertuzumab (HP) with either once per week paclitaxel (12 weeks) or docetaxel (every 3 weeks for four cycles), followed by surgery. Clinicopathologic characteristics were assessed in all patients. The HER2DX pCR score was determined using diagnostic biopsy samples in a representative subset. Logistic regression models identified factors associated with pCR. RESULTS A total of 2,175 patients were enrolled (781 HER2+/estrogen receptor‑negative [ER–]; 1,394 HER2+/ER+). Of 2,141 patients who initiated THP, the overall pCR rate was 43.8%: 63.7% in HER2+/ER– and 32.4% in HER2+/ER+ tumors. Higher pCR rates were observed in tumors that were ER-negative or low ER expressing, progesterone receptor-negative or low expressing, HER2 immunohistochemistry (IHC) 3+, and in patients treated with once per week paclitaxel. T3 disease was associated with a lower pCR rate in HER2+/ER– tumors; otherwise, tumor (T) and nodal (N) stage did not significantly affect pCR. Among 569 patients assessed for HER2DX pCR scores, a high score was independently associated with higher pCR rates, after adjustment for clinicopathologic variables. CONCLUSION Neoadjuvant THP achieved pCR in nearly two-thirds of patients with HER2+/ER– and one third with HER2+/ER+ breast cancer. Low hormone receptor expression, HER2 IHC 3+ status, once per week paclitaxel use, and a high HER2DX pCR score were independent predictors of pCR. These findings should help optimize risk stratification and treatment personalization for patients with HER2-positive breast cancer.

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 .

e13730 Background: Financial toxicity, the burden of treatment cost, affects up to half of people with cancer and can affect survival. Financial toxicity is a health equity issue, disproportionately affecting Black patients. This cross-sectional study used baseline data from the Discussions of Cost (DISCO) Trial, an RCT to improve patient-provider treatment cost discussions and, in turn, mitigate financial toxicity, to examine whether Black and White patients differed in patient-provider communication perceptions and financial toxicity correlates. Methods: Data were collected from 2021-2025 at an NCI-designated comprehensive cancer center. Participants were Black or White patients diagnosed with solid tumor cancers. At baseline, patients completed demographic measures; communication measures of self-efficacy in patient-provider interactions (e.g., “I am confident I know what questions to ask a provider”); self-efficacy in managing cancer treatment costs (e.g., “I am confident I can understand treatment costs”); and whether they have a provider- or patient-centered approach (e.g., “the provider should decide what gets talked about”); and financial measures including economic burden (e.g., “it’s difficult to live on my income”); treatment cost distress (e.g., “worries about paying for my cancer treatment keep me up at night”); and anticipated material hardship (e.g., “I worry about the financial problems I will have in the future as a result of my treatment”). Comparisons were conducted by patient race. Results: A total of 202 patients participated (116 Black patients, 86 White patients). White patients were more likely to have advanced degrees, a higher annual income, and less likely to have Medicaid compared to Black patients. Black patients reported higher self-efficacy for managing treatment costs ( p = .002) and a higher provider-focused orientation to the patient-provider relationship ( p = .001), than White patients. Black patients reported greater levels of financial burden ( p < .001), cost distress ( p = .005), and anticipated material hardship ( p = .003). There was no difference in self-efficacy for interacting with providers. Conclusions: These results suggest that a communication intervention for patients may help mitigate the experience of financial toxicity, especially for Black patients. Clinical trial information: NCT04766190 . Patient characteristics. Black Patients White Patients p -value Race 116 86 Education < High School High School/GED Some College 2 or 4-year College Degree Graduate/Professional College Trade/Technical/Vocational School 10352626712 0141631187 < .001 Annual Household Income 0 - $19,999 $20,000 - 39,999 $40,000 - 59,999 $60,000 - 79,999 $80,000 - 99,999 $100,000 - 149,999 $150,000 + 53201611431 51215991716 <.001 Insurance Type* Medicaid Medicare Medicare supplement Private None 604911330 113726393 <.001>.99<.001.20.15 *Patients could select more than one

e13729 Background: Financial toxicity, the burden of treatment cost, affects up to half of people with cancer and can affect survival. Financial toxicity is a health equity issue, disproportionately affecting Black patients. Patient education about cost and patient-provider cost discussions are recommended to mitigate financial toxicity but occur infrequently. The Discussions of Cost (DISCO) App, designed to mitigate financial toxicity through a tailorable education and communication intervention, was assessed for efficacy in an RCT with Black and White patients. Here we describe the DISCO App's feasibility and acceptability. Methods: Data were collected from 2021 to 2025 at an NCI-designated comprehensive cancer center. Participants were Black or White patients diagnosed with solid tumor cancers. While waiting to see their provider, patients randomized to the intervention arm used the DISCO App on a tablet. The DISCO App includes a video about treatment costs, ways to manage costs, and the importance of discussing costs with providers. Once patients enter their socio-demographic information (e.g., employment) and financial concerns, they receive a tailored list of cost questions to ask their provider. Patients responded to measures immediately after using the DISCO App. Feasibility was assessed by patient reports of how much time they needed to use the DISCO App and if they were able to use the DISCO App before the provider entered the exam room. Acceptability was measured by items assessing patient perceptions of the DISCO App (1 = strongly disagree; 5 = strongly agree). Descriptive statistics summarized results and mean comparisons were used to assess perceptions by patient self-identified race. Results: Of the 202 patients recruited, 124 were randomized to the intervention arm (67 Black patients; 57 White patients). All patients completed using the DISCO App prior to their provider entering the exam room and 80% of patients needed 15 minutes or less to use the DISCO App, with no difference by patient race. Black patients ( M = 4.4) reported finding the DISCO App more helpful than White patients ( M = 3.9; p = .02) and it brought up cost issues they had not considered (Black patients = 3.5; White patients = 3.0; p = .05). Patients reported the questions were easy to understand ( M = 4.4), helped them feel it was okay to talk with their provider about cost ( M = 4.0), that it prompted cost questions ( M = 3.3), that they learned what costs to consider (55%), and learned ways to manage cost (62%) with no differences by patient race. Conclusions: The DISCO App was feasible and acceptable to Black and White patients with cancer, with Black patients reporting more favorable perceptions than White patients. Next steps include assessing effectiveness in improving outcomes including prompting patient-provider treatment cost discussions and related financial toxicity outcomes (e.g., treatment adherence). Clinical trial information: NCT04766190 .

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%

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)

12010 Background: BWEL (Alliance A011401; NCT02750826) is a Phase III trial that randomizes patients (pts) with stage II-III breast cancer and body mass index (BMI) ≥27 kg/m 2 1:1 to a 24-month (mo) lifestyle-based WLI + health education (HE) or HE alone. Here we report prespecified secondary outcomes of the impact of the WLI on patient-reported QOL and symptoms. Methods: The first 540 BWEL pts (randomized between 9/2016 and 7/2017) were included in this substudy that collected PROMIS 29 Profile 2.0 and Global Health scores at enrollment, 6 and 24 mos. Adjusting for baseline scores, mean physical function (predefined substudy primary outcome), global physical and mental health, fatigue and other scores were compared at 6 and 24 mos using analysis of covariance (ANCOVA). P-values <0.05 were considered significant. Positive differences in positive attributes (e.g., physical function) and negative differences in negative attributes (e.g., anxiety) represented better outcomes in the WLI arm. Results: At baseline, median BMI was 32.9 kg/m 2 (26.5 – 69.1), median age was 53 (25 - 78) years; 83.9% of pts were non-Hispanic White, 10.7% were Black and 5.9% were Hispanic. At 6 mos, the WLI (vs HE) arm had significantly better physical function (ANCOVA-based mean difference between arms 1.9 [95% CI 0.8, 3.0]; p<0.001), global physical health (2.0 [95% CI 0.9, 3.0]; p<0.001), global mental health (1.30 [95% CI 0.2, 2.4], p=0.03), social roles and activities (2.3 [95% CI 1.1, 3.6]; p<0.001), and fatigue (-1.7 [95% CI -3.1, -0.4], p=0.01) (Table). Improvements were generally maintained at 24 mos. Similar findings were seen in analyses using longitudinal mixed modeling. Conclusions: The BWEL WLI demonstrated QOL benefits for patients with breast cancer, resulting in significantly better physical function, global physical and mental health, and symptoms. Future analyses will evaluate which populations experienced the most benefit, as well as the relationships among QOL, symptoms, and weight loss. Support: U10CA180821, U10CA180882, UG1CA189823; U10CA180820; U10CA180868; U10CA180863, CCS 707213; U10CA180888; UG1CA189858; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02750826 . Analysis of covariance-adjusted least squares means values at 6-mos adjusted for baseline scores. QOL/Symptom Attributes HE WLI Between arm difference (95% CI)* P value Physical Function 47.1 49.0 1.9 (0.8, 3.0) <0.001 Global Physical Health 46.2 48.1 2.0 (0.9, 3.0) <0.001 Global Mental Health 48.6 49.9 1.3 (0.2, 2.4) 0.03 Social Roles and Activities 52.7 55.0 2.3 (1.1, 3.6) <0.001 Anxiety 50.2 50.0 -0.2 (-1.6, 1.2) 0.77 Depression 47.5 47.5 -0.0 (11.2, 1.2) 0.96 Fatigue 50.6 48.9 -1.7 (-3.1, -0.4) 0.01 Sleep Disturbance 51.0 51.1 0.1 (-0.6, 0.8) 0.80 Pain Interference 51.3 50.3 -1.0 (-2.4, 0.4) 0.15 *Positive differences in positive attributes and negative differences in negative attributes favor WLI arm.

Abstract Background Breast cancer (BC) diagnosed during pregnancy or postpartum often presents with aggressive features, potentially influenced by hormonal, immunological, and tissue remodeling changes. Studies have suggested that postpartum BC may be associated with worse outcomes, though most evidence is retrospective and constrained by methodological limitations. This study evaluated associations between pregnancy history, recency of childbirth, and long-term outcomes in a prospective cohort of young patients with early-stage BC. Patients and Methods Patients aged ≤40 years with stage I–III BC enrolled in the Young Women’s Breast Cancer Study were categorized at diagnosis as nulligravid, nulliparous, pregnant, or parous (≤5 vs 5 to 10 years postpartum). Analyses were stratified by BC subtype (estrogen receptor-positive [ER+]/HER2−, HER2+, and triple-negative [TNBC]), with distant recurrence-free survival (DRFS) as the primary endpoint. Results Among 859 patients, 257 (29.9%) were nulligravid, 50 (5.8%) nulliparous, 37 (4.3%) pregnant, and 515 (60.0%) parous. Pregnant patients had proportionally more TNBC, nodal involvement, T3/T4, and grade 3 tumors. After 11.1 years median follow-up, pregnancy or postpartum status was not independently associated with DRFS in multivariable models adjusted for age, tumor characteristics, and treatment, with consistent findings across ER+/HER2−, HER2+, and TNBC subtypes. Sensitivity analyses, including further categorization of postpartum diagnoses (&lt;2 vs 2 to 5 years), yielded consistent results. Conclusions Pregnancy history and recency of childbirth were not independently associated with long-term DRFS. Despite more aggressive features at diagnosis, patients diagnosed during or after pregnancy had comparable outcomes after adjustment, suggesting no adverse prognostic impact. Clinical trial registration NCT01468246 (https://clinicaltrials.gov/study/NCT01468246? term=NCT01468246&rank=1).

Abstract Background: Pyrimidine synthesis is a therapeutic vulnerability in cancer but inhibition results in toxicity to normal cells. Differential targeting of CTP synthase 1 (CTPS1), sparing the CTPS2 isoenzyme, is a therapeutic strategy in lymphoid cancers, supported by human genetic studies, that can potentially avoid toxicity; however, CTPS2 activity may compensate in epithelial tumours. Loss of CTPS2 protein expression characterises 25% of solid tumours and is predicted to expose a synthetic lethal vulnerability to CTPS1 inhibition. Dencatistat (STP938) is a first in class oral CTPS1 inhibitor showing &gt;1,300-fold selectivity over CTPS2. In preclinical studies, CTPS2 expression was confirmed as a key modulator of response to CTPS1 inhibition, and dencatistat induced tumour regression in an in vivo model of CTPS2 negative ovarian cancer. Study design: The study comprises a standard 3+3 phase 1a dose escalation design, in which intra-patient dose escalation is encouraged, followed by a phase 1b safety expansion. The dose escalation study is recruiting participants with high grade advanced tumours who have exhausted standard of care therapy (excluding haematological cancers, salivary gland tumours and low grade tumours of any tissue). In addition, participants with high grade serous ovarian cancer whose tumours lack expression of CTPS2 (per central laboratory testing by immunohistochemistry) are eligible for backfill into cleared cohorts during dose escalation. The recommended phase 2 dose (RP2D) will be nominated based on safety, tolerability, target engagement and early signs of clinical efficacy. The phase 1b safety expansion study will recruit participants with CTPS2 negative ovarian, lung or endometrial cancer who will receive treatment at the RP2D. Standard inclusion criteria apply; patients with ECOG performance score &gt;2 (&gt;1 for phase 1a in France) or active/symptomatic CNS metastases are not eligible. The primary objectives of the study are to evaluate the safety and tolerability of single agent dencatistat and to determine the RP2D for further development. Secondary objectives comprise evaluation of pharmacokinetic properties and preliminary clinical activity. Exploratory endpoints include evaluation of target engagement, molecular features associated with response, and determination of drug metabolites. The study opened to enrolment in the UK, France and USA in September 2024 and is currently in dose escalation (NCT06297525). The phase 1b study is expected to commence mid-2026 and will include additional centres in Spain. Citation Format: Donna M. Graham, David Sommerhalder, Douglas Orr, Rowan Miller, Neeharika Makani, David O'Malley, Ira Winer, Philip A. Beer, Karen Smith, Maureen Higgins, John R. Hawse, Xiyin Wang, Saravut J. Weroha, Christophe Massard, Patricia Roxburgh. Lack of CTPS2 expression exposes synthetic lethal vulnerability to selective CTPS1 inhibition: A phase 1 dose escalation study of dencatistat (STP938) with safety expansion in biomarker selected cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT075.

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