Citations

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: Women with a pathogenic variant in the BRCA1 or BRCA2 gene (carriers) are at a high risk of developing ovarian cancer and recommended to undergo bilateral salpingo-oophorectomy at an early age resulting in surgical menopause. Menopausal hormone therapy (MHT) is the most effective way to mitigate the adverse outcomes of early menopause; however, the safety of MHT on breast cancer risk in this population has not been established. Methods: We conducted a prospective matched analysis of MHT use following menopause (predominantly surgical) and breast cancer risk in BRCA carriers using a matched prospective analysis to emulate a randomized clinical trial. Women without a history of any cancer or bilateral mastectomy and who were enrolled in a longitudinal study with detailed data collection were eligible for inclusion. Women who initiated MHT (exposed) after menopause were matched one-to-one to women who had not initiated MHT (unexposed) by gene, year of birth, and age at menopause, resulting in 676 matched pairs. Cox proportional hazards regression to estimate the hazard ratios (HR) and 95%CIs (CI) of incident breast cancer associated with MHT use. Results: After a mean follow-up of 5.6 years from the date of first MHT use in the exposed woman, there were 87 incident breast cancer cases in the exposed group (12·9%) and 128 cases in the unexposed group (18·9%) (P = 0·002). Compared to their unexposed match, women who used estrogen (E) experienced a significant decrease in the risk of breast cancer (HR = 0·37; 95%: CI 0·24-0·57). There was no protective (or adverse) effect associated with the use of E plus progestogen (E+P) (HR = 0·94; 95%CI 0·54-1·63), with progestogen alone (P) (HR = 1·14; 95%CI: 0·21-6·22) or with tibolone (HR = 0·57; 95%CI: 0·19-1·69). There were no diagnoses of breast cancer in the 43 women who used a CEE + bazedoxifene. Findings were similar for carriers of either gene mutation. Conclusion: To our knowledge, this represents the largest prospective report of MHT use and breast cancer risk in BRCA1 and BRCA2 carriers. Our findings showed no increase in the risk of breast cancer with the use of MHT, irrespective of gene mutation or formulation. These findings provide an evidence-based approach for the management of women at high-risk of breast cancer who are facing the acute and chronic effects of early surgical menopause. The safe use of MHT by BRCA carriers will continue to be an important research topic as formulations continue to evolve. Citation Format: J. Kotsopoulos, M. Seca, G. Jacek, T. Huzarski, P. Møller, R. H. Kim, C. Singer, B. Karlan, A. Aeilts, T. Ramon y Cajal, T. Pal, A. Eisen, L. Bordeleau, W. Foulkes, N. Tung, F. Couch, S. Neuhausen, D. Zakalik, C. Cybulski, O. Olopade, K. Metcalfe, R. Fruscio, P. Sun, J. Lubinski, S. Narod, Hereditary Breast Cancer Clinical Study Group. Menopausal Hormone Therapy and the Risk of Breast Cancer in Women with a Pathogenic Variant in BRCA1 or BRCA2 [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 GS3-01.

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.

Background: Carriers of a pathogenic variant (PV) in BRCA1 face a high risk of breast cancer. This study estimated the risk of developing breast cancer according to mutation type and location. Methods: BRCA1 carriers with no personal history of breast cancer or bilateral mastectomy were included. Detailed information on clinical and family history was collected by questionnaire. Survival analysis was used to estimate 15-year cumulative risk according to PV type and location. Results: A total of 3677 BRCA1 carriers were followed for a mean of 7.2 years (range 0.1–15.0 years); 481 incident breast cancers were documented. Overall, the 15-year cumulative incidence was 25%. Risk estimates varied by exon, ranging from 9% (exon 21) to 19% (exon 12) to 36% (exon 15); however, strata were small. Carriers of four founder mutations common in Eastern Europe (c.5263_5264insC, c.181T > G, c.66_67delAG and c.4034delA) experienced a lower-than-expected cancer risk (15.9–24.4%) compared to other PVs (28.8%) (p = 0.02). Conclusions: Although our data suggests some variability in penetrance based on specific BRCA1 PV, this was based on a large number of founder mutations. Breast cancer management strategies should continue to be based on comprehensive risk assessment.

Abstract Background Women with a pathogenic variant in BRCA1 or BRCA2 are at high risk of developing ovarian cancer, and it is often recommended that they undergo bilateral salpingo-oophorectomy at an early age, resulting in surgical menopause. Menopausal hormone replacement therapy (HRT) is an effective way to mitigate the adverse outcomes of early menopause; however, the safety of menopausal HRT on breast cancer risk in this population has not been established. Methods We conducted a prospective matched analysis of HRT use following menopause and breast cancer risk in BRCA carriers. Women who initiated HRT were matched one-to-one with women who had not initiated menopausal HRT by gene, year of birth, and age at menopause, resulting in 676 matched pairs. Menopausal HRT use collected by questionnaire included formulation and mode of administration. Results After a mean of 5.6 years, there were 87 (12.9%) incident breast cancer cases in the 676 exposed women and 128 (18.9%) cases in the 676 unexposed women (P = .002). Compared with unexposed matched control individuals, women who used estrogen alone experienced a statistically significantly decreased risk of breast cancer (hazard ratio = 0.37, 95% CI = 0.24 to 0.57). No protective or adverse effect was associated with the use of estrogen plus progestogen (hazard ratio = 0.94, 95% CI = 0.54 to 1.63). Conclusions Our findings suggest no substantial increase in the risk of breast cancer in BRCA carriers with the use of HRT and that estrogen alone might be protective.

Abstract Introduction Down-sized inflatable penile prosthesis (IPP) cylinders are useful in cases with substantial penile fibrosis such as history of priapism or prior infection. Although down-sized IPP cylinders have a clear role in fibrotic corpora, their role in primary implant cases is unclear. Objective To identify factors associated with the use of down-sized cylinders in men undergoing primary IPP placement. Methods We conducted a retrospective analysis of 4,389 patients undergoing primary IPP placement from our multicenter database. Patients were categorized by down-sized (AMS 700 CXR, Coloplast NB) vs. standard sized cylinders (AMS 700 CX, AMS 700 LGX, Coloplast Titan). We collected demographic, intraoperative, and postoperative data. A multivariable analysis was performed to identify factors associated with use of down-sized cylinders Results A total of 4,389 men undergoing primary inflatable penile prosthesis (IPP) placement were included in the study, with a mean age of 62.3 ± 10.3 years. Among them, 1,485 (34%) had diabetes and 2,131 (49%) had hypertension. A total of 406 down-sized cylinders and 3,983 standard cylinders were implanted. Non-infectious complications occurred more frequently with the use of down-sized cylinders (odds ratio [OR] = 2.0, p < 0.001). Specifically, non-infectious complications were reported in 44 out of 185 men (23.8%) with down-sized cylinders, compared to 192 out of 2,727 men (10.9%) with standard cylinders. Cylinder complications constituted 13.9% and 13.0% of the non-infectious complications in the down-sized and standard cylinder groups, respectively. Conclusions The rate of cylinder-related complications were similar between the down-sized cylinder and standard cylinder groups. Urologists should be prepared to place down-sized cylinders during IPP placement in diabetic men and in men requiring serial dilation due to fibrosis. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Intuitive Surgical, Fidelis, Urofill, Boston Scientific, Coloplast, Cynosure, Antares Pharma, Clarus Pharmaceuticals, Acerus Pharma; Endo Pharma.

Background: Endometriosis affects an estimated 10% of reproductive-aged women and is associated with increased ovarian cancer risk. While BRCA1/2 mutations are established risk factors for ovarian cancer, their association with endometriosis remains unclear. This study aimed to characterize the prevalence and clinical features of endometriosis within a large cohort of BRCA mutation carriers. Methods: A descriptive analysis was conducted using data from a multi-center longitudinal cohort of women with pathogenic BRCA variants. Reproductive history and related factors were collected through self-reported questionnaires and compared. Results: Among 16,950 BRCA carriers, the prevalence of endometriosis was 2.4%. Compared to BRCA carriers without endometriosis, those with endometriosis were more likely to carry a BRCA2 mutation, have post-secondary education, and experience earlier menarche. BRCA carriers with endometriosis had a lower ovarian cancer prevalence than those without (10% vs. 15%, p < 0.001). Conclusions: This is the first study of this scale to report the prevalence of endometriosis among BRCA mutation carriers, which was lower than previously reported in the general population. The association between endometriosis and ovarian cancer does not appear to be generalizable to this population. Further prospective studies are warranted to clarify this association among BRCA mutation carriers.