Partridge, A. H.

Abstract Background Central nervous system (CNS) metastases are a major clinical concern in patients with HER2-positive metastatic breast cancer (MBC). The PATINA phase III study showed improved PFS with palbociclib added to maintenance anti-HER2/endocrine therapy (44.3 vs. 29.1 months; hazard ratio 0.75; 95% CI 0.59-0.96; 1-sided P=0.0109). Preclinical and early clinical data suggest palbociclib may have CNS activity. We conducted a pre-specified secondary analysis to evaluate the incidence and timing of CNS progression. Methods CNS progression was defined as the emergence of new intracranial lesions per investigator assessment. Baseline CNS imaging was not mandated but recommended if symptomatic. Competing risks analyses evaluated time from registration to first CNS progression or death (CNS PFS), treating non-CNS progression as a competing event. All randomized patients were included in the primary analysis, regardless of known baseline CNS involvement. Patients with baseline CNS metastases were not censored if progression involved the CNS. A secondary analysis excluded patients with CNS metastases present at baseline. Cumulative incidence functions were estimated and compared using 2-sided Gray’s test. Results Data cutoff for this analysis was on October 15, 2024. 518 participants were enrolled between June 2017 and July 2021, 261 to the palbociclib arm and 257 to the control arm. CNS metastases at baseline were present in 11 patients in the palbociclib arm and 9 patients in the control arm. Among all randomized patients, CNS progression occurred in 35 of 261 (13.4%; 95% CI: 9.5-18.2) in the palbociclib arm and 50 of 257 (19.5%; 95% CI: 14.8-24.8) in the control arm. When excluding patients with CNS metastases at baseline, CNS progression was observed in 32 of 250 (12.8%; 95% CI: 8.9-17.6) in the palbociclib arm and 47 of 248 (19.0%; 95% CI: 14.3-24.4) in the control arm. The median follow-up for patients who were alive and progression-free was 53.5 months. At 36 months, the cumulative incidence of CNS PFS was 13.4% vs. 19.9% for palbociclib versus control (Gray’s test p=0.0386). Importantly, when the analysis was restricted to pts without evidence of CNS disease at baseline (Table 1), —the CNS benefit with palbociclib was maintained (13.0% vs. 19.2% at 36 months, Gray’s test p = 0.0378). Conclusion The addition of palbociclib to anti-HER2 and endocrine therapy was associated with a lower incidence of CNS metastases. Among patients without known baseline CNS involvement, the absolute reduction in CNS progression at 36 months was 6.2% in favor of palbociclib. This benefit was observed at 12 months and sustained over 3 years (Table 1). These findings suggest that palbociclib may help delay or prevent CNS involvement in HR+/HER2+ MBC, warranting confirmation in future studies. Citation Format: O. Metzger, S. Mandrekar, T. Dockter, L. Gianni, E. Ciruelos, A. De Michele, J. Gligorov, E. Lim, S. Loibl, X. Gonzàlez Farré, F. Lynce, J. Lanzillotti, L. Carey, S. Goel, A. Partridge, E. Winer. Central Nervous System Outcomes from the Phase III PATINA Trial (AFT-38) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr RF4-01.

Abstract BACKGROUND: Obesity is prevalent in Hispanic patients (pts) with breast cancer (BC), but this population is often underrepresented in studies of weight loss interventions (WLIs). The BWEL trial (Alliance A011401; NCT02750826) is a phase III randomized trial testing the impact of a 2-year (yr) telephone-based WLI on invasive disease-free survival in pts with stage II-III HER2-negative BC and a body mass index (BMI) > 27 kg/m2. At 12 months (mo), Hispanic pts lost less weight than White pts on the WLI. Here, we evaluate differences in intervention engagement over the first 12 mo by language preference and ethnicity among BWEL pts on the WLI. METHODS: BWEL randomized pts 1:1 to WLI + health education (HE) or HE alone. WLI +HE pts received semi-structured telephone-based health coaching in English or Spanish, in addition to access to an activity monitor, wireless scale and meal replacement shakes. Pts self-reported ethnicity and their preferred language for the WLI. Kruskal Wallis and chi-square tests were used to assess language and ethnicity differences in demographic and treatment factors for continuous and categorical variables, respectively. Percent weight change and mean values for intervention attrition, number of calls, call duration, number of shake shipments, and frequency of activity monitor use and weight tracking over 12 mo were compared between Spanish-preferred Hispanic pts (SH), English-preferred Hispanic (EH) pts and non-Hispanic (NH) pts using ANOVA. Pts with missing language, ethnicity or 12 mo weight data were excluded from analysis. RESULTS: 1591 pts were randomized to the WLI + HE from 08/2018 to 02/2021. 80.5% of pts were White, 12.8% Black and 7.1% Hispanic. 1190 pts had 12 mo weight and language available. Among the 87 WLI + HE pts who had available data and identified as Hispanic, 34% were SH and 66% EH. SH WLI pts were younger (in yrs: 49.5 SH, 51.1 EH, 53.9 NH, p=0.006) and had lower BMI (32.2 SH, 35.1 EH, 34.5 NH, p=0.007). At 12 mo, SH WLI pts lost 2.4% of baseline body weight vs 3.3% in EH and 5.1% in NH (p=0.051) (Table). Compared with EH and NH WLI pts, SH WLI pts participated in fewer calls (15.7 SH, 21.1 EH, 24.3 NH, p< 0.0001), had fewer days of activity monitor use (134.2 SH, 177.3 EH, 205.3 NH, p=0.015) and fewer days of weight tracking (65.3 SH, 96.8 EH, 148.2 NH, p<0.0001), but had more shake shipments (3.9 SH, 3.5 EH, 3.0 NH, p=0.015). There were no significant differences in attrition rate or call duration by language preference or ethnicity. CONCLUSIONS: In a large phase III WLI study in breast cancer patients, engagement with the WLI appeared lower in SH pts, despite provision of the intervention in Spanish. More work is needed to improve accessibility and efficacy of WLI studies among non-English speaking populations. Support: U10CA180821, U10CA180882, UG1CA189823; https://acknowledgments.alliancefound.org. Citation Format: A. Odai-Afotey, K. V. Ballman, L. M. McCall, C. Cao, C. Alfano, V. Bernstein, T. E. Crane, L. M. Delahanty, L. Frank, P. J. Goodwin, O. Hahn, D. L. Hershman, J. O. Hopkins, M. Irwin, E. L. Mayer, L. Minasian, L. Nebeling, M. Neuhouser, E. D. Paskett, P. A. Spears, V. Stearns, C. A. Thomson, T. A. Wadden, A. Weiss, J. White, C. Hudis, E. P. Winer, L. Carey, A. H. Partridge, J. Ligibel. Variation in weight loss and intervention engagement in the Breast Cancer Weight Loss (BWEL) trial by language and ethnicity (Alliance) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-09-29.

Abstract Background: Microtubule inhibitors remain a standard chemotherapy in the management of HER2-negative metastatic breast cancer (MBC). CALGB (Alliance) 40502 was a phase 3 randomized study involving 799 patients with MBC receiving first-line chemotherapy, to determine the optimal chemotherapeutic agent among paclitaxel, nab-paclitaxel, or ixabepilone (with or without bevacizumab). Secondary analysis suggested inferior PFS with nab-paclitaxel specifically among patients with hormone receptor positive (HR+)/HER2-negative breast cancer. Correlative analysis demonstrated significant association of stromal tumor infiltrating lymphocytes (sTILs) with improved progression-free (PFS) and overall survival (OS) in CALGB40502. We hypothesized that immune activation would be associated with differential benefit among distinct microtubule agents. To address this, we evaluated the sTILs and RNA-based immune features association with clinical outcomes, including evaluation of nab-paclitaxel versus paclitaxel. Methods: To limit heterogeneity, analyses focused on pre-treatment primary tumor breast samples with central review/pathologist-enumerated sTILs in accordance with International TILs Working Group methods and RNAseq (n = 280). PAM50 molecular subtypes were assigned based on transcriptomic features. RNAseq data were used to generate immune deconvolution estimates from 5 distinct algorithms (CIBERSORT, xCell, ABIS, ConsensusTME, ImmuCellAI). 1,018 curated breast cancer gene expression signatures GES) were derived from previously published studies. Associations between sTILs and GES were evaluated with sTILs being a categorical variable with the thresholds <5% (low) and (≥5%) high. Results: In the evaluable population, basal-like PAM50 subtype was enriched for high sTILs category (p=1e-4), as anticipated. T-cell and B-cell immune signatures and immune deconvolution estimates were among most highly associated with sTILs. In addition to the expected prognostic association of high T-cell GES, high B-cell-related IgG signature score was also significantly associated with improved overall survival (OS) among triple-negative breast cancer (TNBC) in CALGB 40502 (HR = 0.50,95% CI:0.30-0.86, log-rank p=0.01) but not in HR+/HER2-. In an exploratory analysis of young patients (age at study entry <50 years), high sTILs were associated with improved OS among TNBC patients but worse OS among those with HR+/HER2- MBC (HR = 2.19, 95% CI:1.10-4.36, log-rank p=0.022). High (above median) RNA-based Xcell total immune score was significantly associated with worse OS in both CALGB 40502 and a validation dataset of primary breast cancers, METABRIC (OS HR = 2.12, 95% CI:1.01-4.45, log-rank p=0.042). To further investigate the clinical trial finding of inferior PFS for nab-paclitaxel compared with paclitaxel in patients with HR+/HER2- MBC, there was a significant enrichment of T-cell signatures associated with poor outcome in patients receiving nab-paclitaxel (Fisher exact p<0.001). Conclusion: In this translational analysis of sTILs and RNAseq from a large phase III clinical trial, sTILs and immune signatures were not uniformly associated with better outcome. Rather, high sTILs or immune signatures were associated with worse OS in young patients with HR+/HER2- breast cancer and higher T-cell signatures were associated with inferior PFS with nab-paclitaxel among HR+/HER2- MBC patients. These data reinforce the importance of context/subtype-specific interrogation of the tumor-immune microenvironment Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. Bristol Myers Squibb (BMS); Clinicaltrials.gov Identifier: NCT00785291 Citation Format: E. K. Blige, K. V. Ballman, A. Michmerhuizen, M. Vater, L. A. Carey, A. H. Partridge, W. F. Symmans, M. A. Watson, C. M. Perou, D. G. Stover, H. S. Rugo. Rna-based immune features associated with benefit from distinct microtubule inhibitor therapy for metastatic her2-negative breast cancer: a post hoc analysis of the calgb 40502 (alliance) phase iii randomized clinical trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-13-17.

Abstract Background: In the treatment of ER+/HER2- metastatic breast cancer (MBC), randomized phase II/III trials testing selective estrogen receptor degraders (SERDs), proteolysis-targeting chimeras (PROTACs), complete estrogen receptor antagonists (CERANs) and selective ER modulators (SERMs) (mostly compared to fulvestrant) have demonstrated modest (1-2 months) improvements in progression-free survival (PFS), mainly limited to patients with ESR1-mutated MBC. In these studies, the median PFS (mPFS) ranges from 3 to 6 months, with shorter mPFS in patients with prior progression on CDK 4/6 inhibitor (CDK 4/6i). Here we report the final results of a randomized phase II study that compared Z-endoxifen (Endx) 80 mg/day with tamoxifen (Tam) 20 mg/day in postmenopausal women with estrogen receptor (ER)- positive/ HER2-negative MBC, and report outcomes according to ESR1, PIK3CA, PTEN and AKT alterations (Alliance A011203; NCT02311933). Methods: Postmenopausal women with unlimited prior endocrine regimens (including CDK 4/6i) and up to two chemotherapy regimens for MBC, with tumor biopsy confirmation of ER+ (>10% nuclear staining) and negative for HER2 amplification/overexpression were eligible. Prior adjuvant Tam was allowed if relapse was > 1 year following Tam completion. Patients randomized to Tam could cross over to Endx at progression. The primary end point was PFS analyzed by the interval censored data analytic approach. ctDNA was analyzed for ESR1 and PIK3CA/PTEN/AKT alterations using Guardant360 CDx 74-gene next-generation sequencing-based assay (Guardant Health). Results: Among 108 women who preregistered, 76 (Endx: 40; Tam: 36) were randomized and eligible. Patients were heavily pretreated; all patients had prior exposure to an aromatase inhibitor (AI), 50% had ≥ 2 AI based regimens in the metastatic setting and 50% in each arm had received fulvestrant. Approximately half on each arm received at least one chemotherapy regimen in the metastatic setting. Prior CDK 4/6i therapy was imbalanced (48% on Endx and 28% on Tam). Endx did not significantly prolong PFS compared to Tam (median PFS [mPFS] 4.3 vs 1.7 months; HR 0.72, p=0.168). Because arms were imbalanced according to prior CDK 4/6i exposure, we performed an unplanned analysis demonstrating that Endx improved PFS relative to Tam in CDK 4/6i-naïve patients (mPFS 8.3 vs 2.1 months; HR 0.39, p=0.0097) but not in patients treated with prior CDK 4/6i (mPFS 3.0 vs 1.5 months). In the subset of patients who consented for ctDNA testing (n=28), the mPFS for those with either an activating alteration in the PIK3CA/PTEN/AKT pathway or with an ESR1 mutation was similar as the overall trial. For the 24 patients who progressed on Tam and crossed-over to Endx, the median PFS was 3.5 months (range 1.5-15.0 months) with a 6-month clinical benefit rate of 33.3% (8/24; 90% CI: 17.8-52.1%). Conclusions: Endx did not meet the prespecified threshold for concluding that it significantly improved PFS relative to Tam in a cohort of heavily pretreated MBC. However, the observations of a > 6-month improvement in mPFS in CDK 4/6i-naïve patients, anti-tumor activity following crossover to Tam, and mPFS estimates similar to other novel endocrine agents in development all support the ongoing development of Endx. Support: U10CA180821, U10CA180882, U24CA196171, U10CA180820 (ECOG-ACRIN) and 5P50CA116201. Clinicaltrials.gov Id: NCT02311933. https://acknowledgments.alliancefound.org. Citation Format: M. P. Goetz, V. Suman, J. Reid, T. Dockter, C. Strand, W. F. Symmans, J. Hawse, A. Storniolo, J. Doroshow, J. M. Collins, H. Streicher, M. M. Ames, A. Tarnower, O. M. Hahn, J. N. Ingle, L. Carey, A. Partridge. Final results from the Randomized Phase II study of Z-Endoxifen and Tamoxifen in Endocrine Refractory, Estrogen Receptor Positive, HER2 negative Metastatic Breast Cancer (Alliance A011203) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-08-07.

Abstract Background: Obesity is a poor prognostic factor in early breast cancer (BC). The BWEL trial (Alliance A011401; NCT02750826) is a phase 3 randomized trial testing the impact of a weight loss intervention (WLI) on invasive disease-free survival in women with stage II-III BC and a body mass index (BMI) ≥27 kg/m2. Here we report trajectories of weight change in BWEL WLI participants (pts). Methods: Eligible pts were within 16 months of diagnosis of stage II-III HER2-negative BC, had completed chemotherapy (chemo) and radiation (if given), and were randomized 1:1 to a telephone-based WLI, focused on caloric restriction and exercise, plus health education (HE) or to an HE-alone control group. WLI pts were assigned a trained coach at the BWEL call center and received 42 phone calls over the 2-year (yr) WLI period. Weight and height at baseline, 6 and 24 months were collected by study staff. All WLI pts were provided with a Fitbit wireless scale. Fitbit weight records (FWRs) were automatically imported to the BWEL portal for pts with wireless access and self-reported in the portal for pts without wireless access. FWRs were averaged (avg) by week (wk) from the WLI start date up to 104 wks. Baseline pt factors were self-reported; treatment history was abstracted from the medical record. Linear mixed-effect models were used to evaluate trajectories of weight change over the 104-wk WLI. Principal component analysis and multinomial models were used to examine distinct clusters of weight trajectories. Results: 3180 pts were enrolled from 637 sites between 8/2016 and 2/2021. FWRs were available from 1508 of 1591 WLI pts, with a total of 366,294 FWRs collected during the 2-yr WLI period. In pts with FWRs, mean baseline BMI was 34.4 ± 5.6 kg/m2, mean age was 53.2 ± 10.3 yrs, 10.8% self-identified as Non-Hispanic (NH) Black and 6.1% as Hispanic, 81.1% received chemo and 56.9% were postmenopausal. No statistically significant differences in baseline factors were observed between pts with and without FWRs. Intraclass correlation coefficient of baseline weights collected by study staff and by Fitbit scales was 0.99. In the WLI cohort, avg weekly weight (kg) decreased from 91.4 (95% CI: 90.6-92.3) at baseline to 85.6 (95% CI: 84.8-86.5) by wk 40, corresponding to a peak loss of 6.1% (95% CI: 5.7-6.4) of baseline weight. Weight remained stable until wk 52 and then gradually increased to 87.0 kg (95% CI: 86.2-87.9) at wk 104, corresponding to a 4.4% (95% CI: 4.0-4.8) loss at wk 104 vs. baseline. Principal component analysis identified 3 distinct weight trajectories: 67.6% of pts experienced peak weight loss of 6.6% (95% CI: 6.3-6.9) of baseline weight, 10.0% experienced peak loss of 17.5% (95% CI: 16.8-18.2) of baseline weight, and 22.4% did not achieve weight loss, gaining on avg 2.2% (95% CI: 1.7-2.6) of baseline weight. Pts with college (relative risk ratio [RRR]=1.41, 95% CI: 1.03-1.92) and post-graduate education (RRR= 1.58, 95% CI: 1.13-2.20) and those who were premenopausal (RRR=1.70, 95% CI: 1.28-2.26) were more likely to be in the cluster that did not lose weight. Pts who were NH White (RRR=3.60, 95% CI: 1.95-6.68), postmenopausal (RRR=1.94, 95% CI: 1.28-2.95), had no alcohol use (RRR=1.49, 95% CI: 1.03-2.16), had not received chemo (RRR=1.76, 95% CI: 1.15-2.72), and had <3 chronic conditions (RRR: 2.12, 95% CI: 1.23-3.66) were more likely to be in the cluster with the highest weight loss. Conclusion: Longitudinal weight data from BWEL demonstrate peak weight loss of 6.1% in the WLI cohort at 40 wks, with distinct trajectories indicating differential responses to the WLI. This work demonstrates the feasibility of using digital health tools to track outcomes in the setting of a large-scale weight loss intervention study and informs future precision behavioral interventions in oncology. Support: U10CA180821, U10CA180882, UG1CA189823; U10CA180863. https://acknowledgments.alliancefound.org. Citation Format: C. Cao, K. Ballman, L. McCall, C. Alfano, V. Bernstein, T. Crane, L. Delahanty, L. Frank, P. Goodwin, O. Hahn, D. Hershman, J. Hopkins, M. Irwin, E. Mayer, L. Minasian, L. Nebeling, M. Neuhouser, E. Paskett, P. Spears, V. Stearns, C. Thomson, T. Wadden, A. Weiss, J. White, C. Hudis, E. Winer, A. Partridge, L. Carey, J. Ligibel. Weight Trajectories in the Breast Cancer Weight Loss (BWEL) Trial (Alliance) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD8-01.

Abstract Background Young age is a known risk factor for breast cancer recurrence and mortality, particularly in hormone receptor-positive disease. However, no specific evidence exists on whether age at diagnosis influences clinical behavior and outcomes among carriers of germline BRCA pathogenic or likely pathogenic variants (PVs). Methods The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study including women with germline BRCA1 and/or BRCA2 PVs and diagnosed with stage I-III breast cancer at the age of 40 years or younger between January 2000 and December 2020. The present analysis aimed to evaluate clinical features and outcomes of breast cancer in young BRCA carriers according to age at diagnosis, by comparing patients aged ≤30 years with those aged 31-35 and 36-40 years at breast cancer diagnosis. The primary endpoint was disease-free survival (DFS). Overall survival (OS) was a secondary endpoint. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs), adjusting for risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) (time-dependent), and stratifying by country, year of diagnosis, tumor size, nodal involvement, tumor grade and hormone receptor status. Results From 109 centers in 5 continents, 5350 young BRCA carriers were included, of whom 1106 (20.7%) were ≤30 years of age, 1945 (36.4%) were 31-35 years and 2299 (43.0%) were 36-40 years at the time of breast cancer diagnosis. Compared to patients aged 31-35 and 36-40 years, those aged ≤30 years were more likely to harbor BRCA1 PVs (71.3%, 62.4%, 61.1%, respectively), to present with high-grade (G3 in 71.3%, 66.6%, 65.0%, respectively), triple-negative breast cancer (56.3%, 48.1%, 46.6%, respectively), and less frequently smaller tumor size (T1: 31.7%, 36.6% and 39.5%, respectively). Consequently, chemotherapy was administered more frequently among patients aged ≤30 years (94.4%, 92.6%, 89.7%, respectively). At a median follow-up of 8.2 years (IQR, 4.7-12.8), 8-year DFS rate was 65.0% among patients aged ≤30 years, 64.7% in the 31-35 years group, and 65.8% in the 36-40 years group. No significant association between age at diagnosis and DFS outcome was observed (31-35 vs. ≤30 years: aHR 1.03, 95% CI 0.89-1.19; 36-40 vs. ≤30 years aHR 1.00, 95% CI 0.87-1.16). Similarly, no significant association between age at diagnosis and OS was observed (31-35 vs. ≤30 years: aHR 1.10, 95% CI 0.86-1.41; 36-40 vs. ≤30 years: aHR 1.11, 95% CI 0.87-1.43). Subgroup analyses by specific BRCA gene, tumor subtype, tumor size, nodal status, and chemotherapy use revealed no statistically significant interaction with age at diagnosis in terms of DFS or OS (all p for interaction > 0.05). Specifically, no significant differences between age groups were observed among patients with luminal-like tumors for both DFS and OS. Conclusions In this unique international cohort of BRCA carriers diagnosed with breast cancer at a young age (≤40 years), we found no significant differences in DFS nor OS across different age groups. Notably, very young age (≤30 years) at diagnosis was not associated with worse outcomes compared to 31-35 years or 36-40 years. Age per se should not be considered a negative prognostic factor in BRCA carriers when appropriate treatment is provided. Citation Format: E. Blondeaux, A. Meacci, M. Fragío Gil, E. Klocker, F. Coussy, H. Kim, R. Bernstein Molho, F. Hilbers, A. Di Meglio, A. Kwong, K. Pogoda, J. Bajpai, H. Wildiers, E. Agostinetto, J. Balmana, H. C. Moore, K. Phillips, A. H. Partridge, C. Rousset-Jablonski, F. A. Peccatori, A. Toss, T. Renaud, C. Anghelone, A. Benitez Cruz, S. Paluch-Shimon, J. Lee, R. Fruscio, W. Cui, S. M. Wong, M. Lee, M. Rozenblit, C. Vernieri, C. Villarreal-Garza, A. Matikas, M. Dieci, L. De Marchis, J. K. Plichta, K. J. Ruddy, D. Can Guven, F. Puglisi, Z. Kemp, P. A. Meireles, L. Del Mastro, V. Delucchi, M. Lambertini. Association between age at diagnosis and survival among young BRCA carriers with breast cancer: results from an international multicenter hospital-based cohort study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD4-07.

Abstract Background: Despite its widespread adoption, there is a lack of data as to whether breast MRI for local staging and surgical planning of newly diagnosed breast cancer patients improves oncologic outcomes. The Alliance A011104 phase III trial was designed to test the hypothesis that MRI detection of mammographically occult disease helps to tailor surgical intervention thereby reducing local recurrence and improving local regional control. Here we report on the primary outcome of 5-year local regional recurrence. Methods: Patients with newly diagnosed clinical stage I-II, ER/PR- and HER2- negative (triple- negative) or ER/PR-negative and HER2-positive breast cancer, deemed eligible for breast- conserving surgery (BCS) based on clinical exam, mammography +/- ultrasound were randomized to undergo staging breast MRI or no further local staging. Patients with multifocal tumors that could be encompassed in a single operative resection were eligible. Patients who were carriers of gBRCA 1/2, or who had bilateral breast cancer, or a prior history of breast cancer were excluded. Initial eligibility was limited to patients not scheduled to receive neoadjuvant chemotherapy; however, a subsequent amendment allowed for enrollment after completion of neoadjuvant chemotherapy. Categorical variables were compared between arms with a chi-square or Fisher’s exact test. LRR, distant recurrence and overall survival (OS) were estimated with Kaplan-Meier point estimates and 95% confidence intervals (CIs). Hazard ratios (HRs) and 95% CIs were obtained from Cox proportional hazards models. Results: Of 319 patients enrolled from 2/2014-12/2019,161 were randomized to undergo breast MRI and 158 to no breast MRI evaluation. The mean age at enrollment was 58.9 years (range 29-85). Most patients (72.1%) had T1 tumors, 93.4% were cN0 and 19.7% were HER2 positive. Systemic chemotherapy was utilized in 85% with 17.6% receiving treatment neoadjuvantly; receipt of systemic therapy was unknown for 15 patients (4.7%). Two hundred and ninety-eight patients (93.4%) underwent surgical intervention; 91.9% underwent BCS as initial surgical procedure with no significant differences noted between groups (92.7% in the no MRI group and 91.9% in the MRI group [p=0.62]). Of patients who underwent breast surgery, 293 underwent axillary evaluation with the majority (270 patients, 92%) undergoing sentinel lymph node biopsy as the only axillary intervention. Among patients who received neoadjuvant chemotherapy, the overall pathologic complete response rate was 39.3%, 29.0%in the MRI arm vs. 52.0% no MRI arm (p=0.10). Receipt of adjuvant radiation was comparable between arms, 85.4% and 85.0% receiving radiation in the no MRI and MRI arms, respectively. Among 298 patients evaluable for the primary endpoint, with median follow-up of 61.1 months (0.2, 68.1), there were no differences in rates of LRR; 5-year local regional control was 93.2% (89.0-97.6%) in the MRI group and 95.7% (92.3-99.1%) in the no MRI group (HR: 1.1, 95% CI: 0.3, 3.9). For the entire cohort, 5-year distant recurrence-free rate and OS were 94.3% (91.7, 97.1) and 92.2% (89.1, 95.4), respectively, with no differences between groups. Conclusions: With multimodality therapy, rates of 5-year LRR in patients with early stage triple- negative and HER2-positive breast cancer are very low. Breast MRI for local staging and surgical planning in this setting does not result in improved local regional control. Support: U10CA180821, U10CA180882; UG1CA189823; U10CA180868 (NRG Oncology); ClinicalTrials.gov Identifier: NCT01805076; https://acknowledgments.alliancefound.org Citation Format: I. Bedrosian, K. Ballman, L. M. McCall, C. E. Comstock, G. W. Unzeitig, T. Yen, A. Weiss, B. G. Haffty, J. M. Bensenhaver, S. M. DeSnyder, J. J. Liu, A. H. Partridge, L. A. Carey, K. K. Hunt.Effect of Preoperative Breast MRI Staging on Local Regional Recurrence (LRR) in Early Stage Breast cancer: Alliance A011104/ACRIN 6694 [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS2-07.

Abstract Background: The association of TILs with pathologic complete response (pCR) and survival in HER2+ breast cancer is not well established with several prior studies showing inconsistent results. In this secondary analysis of EA1181, we evaluated the association between stromal TILs (sTILs) and pCR rates. Methods: EA1181 (NCT04266249) enrolled patients (pts) with anatomic clinical stage II/III HER2+ breast cancer who preoperatively received 4 cycles of trastuzumab and pertuzumab with 12 weeks of paclitaxel or docetaxel q3w x 4 (THP), followed by surgery. sTILs density was assessed on full-face hematoxylin and eosin (H&E)-stained tumor biopsy sections. sTILs scores were analyzed per protocol as a continuous variable (every 10% increment) and as a categorical variable (<10% vs 10-60% vs >60% as per Denkert et al, 2018), and also with an exploratory 30% cutoff commonly used in TNBC. Cox proportional hazards models were used to examine the association between sTILs and pCR, adjusting for available baseline factors. The associations between sTILs (by category) and clinicopathologic characteristics were examined using Fishers’ exact test. Results: Among 2141 pts with HER2+ BC treated on EA1181, H&E slides were available for 1328 (62%). The study population evaluated for sTILs was comparable to the overall population. pCR rates were 44.5% overall, 64% for HER2+/ER- and 33% for HER2+/ER+ disease. sTILs distribution was: 623 (47%) <10%, 698 (52%) 10-60%, and 7 (0.5%) >60%, which led us to merge the latter two groups (705 [53%] had ≥10% sTILs). In univariable and multivariable analyses, increasing sTILs (as a continuous variable) were associated with increasing pCR rates in both HER2+/ER+ and HER2+/ER- disease (p<0.001; Table). sTILs analyzed as a categorical variable (<10% vs ≥10%) were significantly associated with pCR for all patients (combined) and for those with HER2+/ER+ disease. In exploratory analysis using a cutoff of <30% vs ≥30% sTILs, an association with pCR was also seen in univariable analysis for both HER2+/ER+ disease (p<0.001) and HER2+/ER- disease (p=0.045), though in multivariable analysis with clinical factors, sTILs >30% remained a significant predictor for pCR only in HER2+/ER+ disease. Additional exploratory analysis with other molecular biomarkers, intrinsic subtypes, and immune signatures will be presented. Conclusion: sTILs were associated with pCR after THP, further supporting the important role of immune mechanisms in HER2+ breast cancer, and highlighting a potentially robust predictive tool to assess pathologic response. Baseline sTILs could potentially inform the preoperative design of future trials of therapy optimalization. Association of baseline sTILs with recurrence free survival in EA1181 will be reported in the future. Citation Format: S. S. Badve, F. Zhao, N. Tung, Y. Gokmen-Polar, C. C. O'Sullivan, A. Prat, E. P. Winer, J. L. Wright, A. Recht, A. C. Weiss, J. A. Tjoe, S. M. Feldman, G. B. Rocque, M. Smith, N. Unni, S. Sardesai, S. Tang, S. Modi, W. J. Irvin, P. Villagrassa, C. Battelli, A. K. Krie, N. Bagegni, M. A. George, M. L. Telli, V. F. Borges, N. D’Abreo, P. Shah, K. D. Miller, A. H. Partridge, L. A. Carey, A. M. DeMichele, A. C. Wolff, ECOG-ACRIN.Tumor infiltrating lymphocytes (TILs) and pathologic complete response (pCR) in stage II/III HER2+ breast cancer treated with taxane, trastuzumab, and pertuzumab (THP): secondary results from the ECOG-ACRIN EA1181/CompassHER2 pCR trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS1-04.