Rozenblit, M.

Abstract Background PARP inhibitors (PARPi) are active in patients (pts) with germline BRCA1/2 or PALB2 mutated (gBRCA1/2; gPALB2m) breast cancer (BC). Preclinical data suggest PARPi leads to intratumoral activation of the proinflammatory cGAS/STING pathway, recruiting CD8+ T cells, and sensitizing gBRCAm cancers to immune-targeted therapy. Prolonged preoperative treatment with PARPi monotherapy has demonstrated notable pathologic complete response (pCR) rates. The randomized phase II TBCRC 056 study evaluates the PARPi niraparib (N) with the anti-PD-1 antibody dostarlimab (D) as neoadjuvant treatment of gBRCAm or gPALB2mHER2-negative BC, with cohorts for both triple negative BC (TNBC, Arms A and B) and estrogen receptor positive (ER+) BC (Arm C). Results from Arms A and B are being presented. Methods Eligible pts (gBRCA1/2m/gPALB2m BC, T >1.0 cm, ER- (<10%), HER2-) were randomized to either Arm A: upfront combination N 200 mg orally QD and D 500 mg IV every 3 weeks (wks) for 18 wks (1 cycle = 3 wks), or Arm B: N monotherapy for 3 wks, followed by combination N plus D for 15 wks, with baseline (BL) and wk 3 tumor biopsies. After 18 wks, pts either underwent surgery or received additional preoperative systemic therapy (per MD choice) after an end of treatment biopsy if residual disease present. The primary study objectives are to evaluate pCR in Arms A and B combined, as well as change in stromal tumor infiltrating lymphocytes (sTILs) from BL to 3 wks in each Arm separately; 46 pts and a target pCR rate of 50% provides 85% power to reject the null hypothesis of pCR < 30%. Results A total of 46 pts with TNBC enrolled to Arms A and B (38 gBRCA1m (82.6%), 8 gBRCA2m (17.4%), 0 gPALB2m). Median age was 39.3 years (range 24.8-72.8); 84.8% self-reported White, 6.5% Black, 4.3% Asian, and 8.7% Hispanic. Clinical stage distribution was 37.0% stage I, 45.7% stage II, and 17.4% stage III; most had ER- BC (42 ER <1%, and 4 ER 1-10%). Among all pts, 38 (82.6%) completed the target number of cycles of D, with mean cycles received 5.1. Five pts discontinued D early (3 inadequate response/progression, 2 unacceptable AE: LFTs, rash). A total of 38 pts (82.6%) completed 6 cycles of N, with mean cycles received 5.7. Seven pts discontinued N early (3 inadequate response/progression, 4 unacceptable AE: LFTs, anemia, rash (2)). Most common AEs (> grade 2) with D+N were anemia (26.1%), fatigue (21.7%), hypertension (15.2%), hypothyroidism (15.2%), and neutropenia (15.2%). Most common Grade >3 AEs with D+N were anemia (17%) and neutropenia (6.5%). Among all pts, 23 (50%) had a pCR at surgery (90% CI 37.1% - 62.9%), 12 (26.1%) had residual disease (4 RCB-I, 5 RCB-II, 2 RCB-III, 1 RCB not calculable), and 11 (23.9%) crossed over to additional preoperative therapy. The pCR rate exceeded the protocol efficacy criterion of >43%, a significant increase over null hypothesis. pCR rates were the same on Arms A (50%, 90% CI 31.1% - 68.9%) and B (50%, 90% CI 31.9% - 68.1%). Among 15 pts on Arm A with evaluable sTILs at BL and 3 wks, mean sTILs at BL was 16% (range 1% - 40%), and at 3 wks was 27.4% (range 0.5% - 60%), for an average increase of 11.4% (p=0.009). Among 22 pts on Arm B with evaluable sTILs at BL and 3 wks, mean sTILs at BL was 19.5% (range 1% - 75%), and at 3 wks was 42.1% (range 1% - 85%), for an average increase of 22.7% (p=0.0003). Among all pts, BL sTILs (continuous) were significantly higher among those who achieved pCR than those who did not (median 15% vs. 5%, p=0.03). There was no relationship between pCR and BL PD-L1 score, or pCR and ER-0 vs. ER-low. Conclusions In pts with gBRCAm early TNBC, 18 wks of targeted therapy using PARPi and anti-PD1 agents, with or without 3-week PARPi lead-in, resulted in a pCR rate of 50%, and a statistically significant increase in sTILs from BL to 3 wks. Further ongoing correlative work may identify best candidates for this non-chemotherapy-based approach. Citation Format: E. L. Mayer, N. Graham, R. A. Leon-Ferre, M. Rozenblit, C. A. Santa-Maria, S. Isakoff, J. Specht, N. Tung, V. Abramson, J. Desrosiers, A. Schubert, B. Koca, S. M. Tolaney, E. P. Winer, I. E. Krop, A. C. Wolff, G. I. Shapiro, N. Tayob, J. L. Guerriero. Tbcrc 056: a phase 2 study of neoadjuvant niraparib with dostarlimab for patients with BRCA- or PALB2-mutated breast cancer: results from the TNBC cohorts [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 RF5-02.

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: Young BRCA carriers may undergo breast conserving surgery (BCS) or mastectomy with or without contralateral risk reducing mastectomy at the time of an index breast cancer diagnosis. A variety of factors may influence surgical decision making. Methods: The BRCA BCY Collaboration (NCT03673306) is an international, hospital-based, retrospective cohort study conducted at 109 centres across 5 continents including women with germline pathogenic or likely pathogenic variants (PV) in BRCA1/2 diagnosed between 2000 and 2020 with invasive stage I-III breast cancer prior to or at age 40 years. The primary objective of the present analysis was to evaluate surgical management in these patients. Breast surgery was defined as BCS, unilateral mastectomy, or bilateral mastectomy administered as part of primary treatment for a first diagnosis of invasive breast cancer. Multivariable logistic regression was used to determine factors associated with receipt of bilateral mastectomy. Results: Of 5660 eligible BRCA1/2 carriers, 4715 had unilateral stage I-III breast cancer with surgical treatment details available. The median age of the cohort was 35 years (IQR, 31-38 years). Overall, 1805 (38.3%) patients underwent BCS, 1752 (37.2%) underwent unilateral mastectomy, and 1158 (24.6%) underwent bilateral mastectomy. The proportion of young BRCA1/2 carriers undergoing BCS decreased over the study period (55.7% in 2000 vs. 27.0% in 2020), whereas the use of bilateral mastectomy significantly increased (8.0% in 2000 vs. 44.4% in 2020). Bilateral mastectomy was more common in women who had genetic testing performed before (57.0%) or within 6 months of a breast cancer diagnosis (38.5%), compared to those tested after diagnosis (5.1%, p<0.001). On multivariable analysis, compared to those tested after diagnosis, earlier genetic testing remained the strongest predictor of bilateral mastectomy receipt (testing prior to diagnosis: OR 20.7 [95% CI 15.3-28.1]; testing at diagnosis: OR 6.8 [95% CI 5.4-8.7]). Other predictors of bilateral mastectomy receipt included geographic region, later year of diagnosis, smaller tumor size, node negative disease, and neoadjuvant treatment. In subgroup analysis including 2327 patients who had genetic testing performed before or within 6 months of diagnosis, 42.0% underwent bilateral mastectomy, with the lowest rates reported in Asia/Africa (26.1%) and the highest rates reported in North America (66.4%, p<0.001). In adjusted subgroup analyses, BRCA1 PV, later year of diagnosis, smaller tumor size, node negative disease, neoadjuvant treatment, and geographic region remained independently associated with bilateral mastectomy. Conclusions: In this large, international study of young affected BRCA carriers, geographic region and timing of genetic testing strongly impacted surgical management. These data support early genetic testing for young women with breast cancer to help optimize local therapy decisions. Citation Format: S. M. Wong, E. Blondeaux, V. Delucchi, F. Coussy, R. Bernstein Molho, S. Linn, A. Di Meglio, A. Kwong, K. Pogoda, E. Agostinetto, I. Nevelsteen, J. Balmana, H. C. Moore, A. Toss, A. Ferrari, C. Rousset-Jablonski, T. Renaud, K. Phillips, F. A. PeccatorI, M. Agustina Ipina, S. Paluch-Shimon, J. Ryu, W. Kui, M. Lee, R. Fruscio, M. Rozenblit, C. Vernieri, A. Matikas, M. Dieci, F. J. Couch, L. De Marchis, S. E. Hwang, D. Aguilar-y Mendez, D. Can Guven, M. Swain, C. Gianni, S. Spinaci, G. Montagna, M. Lambertini, H. Kim. Surgical management of young BRCA1/2 carriers with early onset breast cancer [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 PD12-01.

Abstract BACKGROUND: EOP is an I-SPY2 sub-study designed to test novel endocrine-based strategies in patients (pts) predicted to have modest benefit from chemotherapy. Vepdegestrant is a selective oral PROTAC estrogen receptor (ER) degrader that has demonstrated efficacy in mutant ER+ HER2-negative MBC. METHODS: EOP eligibility included pts with Stage 2/3 HR+ HER2-negative, MammaPrint (MP) Low Risk BC. Patients with MP High1 signatures were eligible if clinically node-negative or SET 2,3 High. Pts were randomized to one of 3 oral treatment (tx) arms: vepdegestrant 200 mg/d (V), vepdegestrant 200 mg/d +letrozole (VL), vepdegestrant 200 mg/d + abemaciclib 150 mg bid (VA). Pts received tx for six 28-day cycles followed by surgery. Premenopausal (PreMN) pts received ovarian function suppression (OFS) starting C1D1 in the VL arm, and C2D1 in the V and VA arms. The primary endpoint was feasibility, defined as >75% of pts completing >75% of study therapy. Breast MRI functional tumor volume (FTV) and ctDNA (tumor-informed assay) were assessed at baseline (T0), 3 weeks (T1), 12 weeks (T2), and 6 months (T3). Ki67 and ER/PR by IHC were centrally assessed from tumor biopsies at T0, T1, and the surgical specimen. Results: Between 4/2023 and 1/2025, 121 pts were enrolled: 40 in V, 41 in VL, and 40 in VA. Median age was 54 years, 50% preMN. 60% of pts had ductal, 35% lobular, 5% mixed histology. 55% were cN+, and 59% were not breast conservation surgery (BCS) candidates at baseline. Mean baseline Ki67 was 12.5%, 85.1% had MP Low Risk signature, 79.3% were SET 2,3 High. All 3 tx arms met the primary endpoint with 88%, 88%, and 83% completing > 75% study therapy in V, VL, and VA (thus far), respectively. Most common all grade (AG) TRAEs in V and VL arms include fatigue (53% V, 71% VL), hot flashes (48% V, 71% VL), arthralgias (33% V, 49% VL), all G1 or G2 except for 1 G3 fatigue in VL arm. G2 and G3 neutropenia was seen in 1 pt each in V and VL arms. The most common AG TRAEs in VA include diarrhea (80%), fatigue (65%), nausea (58%), hot flashes (50%), neutropenia (43%). High grade TRAEs in VA include neutropenia (23% G3, 5% G4), ovarian cyst requiring surgery (5% G3), diarrhea (15% G3), nausea (3% G3), transaminitis (3% G3), thromboembolic event (8% G3), acute kidney injury (3% G3). Table 1 summarizes key response endpoints by tx arm. CONCLUSION: Six months of neoadjuvant vepdegestrant, alone or in combination with letrozole or abemaciclib, is feasible and demonstrates robust ER/PR degradation. Encouraging anti-tumor activity through reduction of Ki67 and MRI FTV, ctDNA clearance, and achievement of BCS was seen in pre- and postMN women. The neoadjuvant setting provides a rich platform to identify the dynamic range of response and non-response using a multi-modal approach and can be leveraged to inform future trial design and adjuvant therapy. Citation Format: J. Chien, R. M. Mukhtar, C. Yau, A. D. Elias, A. M. Wallace, N. Chan, C. Omene, N. Chen, J. Tseng, M. S. Trivedi, E. Stringer-Reasor, D. Yee, A. S. Clark, A. Thomas, H. Han, M. Arora, C. Nangia, K. Albain, C. Falkson, C. Isaacs, A. Zimmer, M. Rozenblit, L. van't Veer, L. Brown Swigart, G. Hirst, W. Symmans, A. D. Borowsky, N. Onishi, N. Hylton, S. Alkhafaji, K. V. Giridhar, C. Vaklavas, M. Wei, M. P. Goetz, O. Olopade, L. Huppert, C. Wu, L. J. Esserman. I- SPY2 Endocrine Optimization Pilot (EOP): Neoadjuvant vepdegestrant monotherapy or in combination with letrozole or abemaciclib in molecularly selected patients with stage 2/3 HR+ HER2-negative breast cancer (BC) [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 PD10-02.