Citations

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.

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: 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 Introduction: Hormone receptor positive (HR+), HER2- breast cancer (BC) is the most common subtype of BC. Despite advances in chemotherapy and endocrine therapy optimization, local and systemic recurrences frequently occur, especially for patients with node-positive disease. Recent data suggest a subset of patients with this tumor phenotype may benefit from the addition of anti-Programmed Death-1(aPD1) to neoadjuvant chemotherapy. However, T-cell infiltration (TCI), a biomarker of response to aPD1 and chemotherapy, is typically low in this BC subtype. Preclinical models show that combining preoperative radiation therapy (preop RT) with immune checkpoint inhibitors can enhance TCI and anti-tumor immunity. We conducted the first randomized trial to test whether no-, low- or high-dose RT combined with aPD1 increases TCI and improves responses in non-irradiated, metastatic lymph nodes in HR+/HER2- BC (NCT04443348). Materials & Methods: Eligible patients had ER and/or PR≥10%, HER2 negative invasive BC with clipped and biopsy-proven positive axillary node(s), cT1c-T4c, cN1-3, and at least one of the following criteria: grade 3 or grade 1-2 with cN2-N3, Ki67 >20%, or high genomic assay score. Between 2022-2024, 51 patients from 10 centers were randomized to no (0Gy; control arm), low (9Gy) or high (24Gy) doses of preop RT to the primary tumor with concurrent pembrolizumab followed by a 2-week tumor biopsy. Stratification factors were T1c vs. T2-4 and N1 vs. N2-3. Patients subsequently received pembrolizumab with 12 weeks of paclitaxel, followed by 4 cycles of adriamycin-cyclophosphamide (q2wk or q3wk) with pembrolizumab (200 mg q3 wks or 400 mg q6 wks). Surgery and adjuvant therapy followed standard-of-care. Dual co-primary endpoints were 2wk tumor TCI and nodal pathologic complete response (ypN0) at time of definitive surgery. TCI was assessed by multiplex immunofluorescence (pan-cytokeratin, CD3, CD8), using a rank-based Immunoscore (range 0-1), compared to baseline reference biopsies via two-tailed Mann-Whitney test. ypN0 was evaluated non-comparatively. Secondary endpoints included pCR and Residual Cancer Burden (RCB) 0/1. Results: Among 51 patients enrolled, 49 were evaluable for TCI and 48 for the ypN0 endpoint. Median age was 49.5 years (range 23-78). The cohort had a high-risk clinical profile: 92% had cT2-4, 50% N2-3, and 62% grade 3 tumors. Median ER and PR positivity were 90% (20-100) and 68% (1-98), respectively. Multifocal or multicentric tumors were present in 32%. TCI was assessed at 2 weeks post-treatment. The proportion of tumors with TCI in the upper quartile increased with RT dose escalation: 31% (0Gy), 40% (9Gy), and 53% (24Gy). Median TCI scores at 2 weeks were 0.60 (0Gy), 0.56 (9Gy), and 0.82 (24Gy), compared to a median baseline value of 0.50 from untreated reference samples. A statistically significant increase in TCI was observed only in the 24Gy cohort relative to the untreated group (p=0.027). 70.8% underwent mastectomy, with 39.6% receiving immediate reconstruction. 8% experienced G2/3 wound complications, balanced across arms. Median number of lymph nodes removed was 6.5 (1-42). The overall ypN0 rate was 29%, and 24%(0Gy), 29%(9Gy) and 33%(24Gy) per arm. pCR/RCB 0-1 rates were 18%/27% in the entire cohort and 6%/18%(0Gy), 29%/29%(9Gy), and 19%/33%(24Gy), respectively. Conclusion: The addition of 24Gy preop RT to aPD1 significantly increased tumor TCI in HR+/HER2- early-stage BC. Non-irradiated nodal response rates were promising despite over one-third of the study population with grade 1/2 tumors and high disease burden, laying the foundation for a future randomized trial comparing the efficacy of this novel approach against standard of care for node-positive HR+/HER2- BC. Citation Format: G. Gupta, A. Y. Ho, F. Gharibpoor, Y. Abdou, J. D. Anampa, R. C. Blitzblau, B. C. Calhoun, D. L. Casey, S. F. Dent, L. A. Carey, J. R. Bellon, L. E. Warren, J. Lu, T. J. Hieken, A. G. Taghian, A. Bardia, T. Traina, G. Plitas, K. Gallagher, K. Daugherty, A. Thompson, I. Krop, A. Wolff, E. Mittendorf, J. Fox, H. Garber, E. Hwang, A. J. Khan, J. P. Loene, R. Mutter, S. Patil, C. Santa-Maria, B. V. Vincent, J. L. Wright, L. Spring.Primary Results from the HR+/HER2- Cohort of TBCRC-053 (P-RAD): A Randomized Trial of No, Low, or High Dose Preoperative RADiation with Pembrolizumab and Chemotherapy in Node-Positive, HER2-Negative 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 GS2-05.

Abstract Background: TheTAILORx trial established that adjuvant endocrine therapy (ET) is non-inferiorto chemotherapy plus ET (CET) in T1-2N0 HR+/HER2-negative early breast cancer(EBC) with an Oncotype DX (ODX) 21-gene recurrence score (RS) of 11-25, RS 0-10is associated with low distant recurrence (DR) rates with ET alone, and RS26-100 is associated with higher DR rates despite CET. Although ODX isprognostic for 10-year DR, it has limited value for late DR >5 years. Inorder to develop improved DR risk prognostication, we developed multimodal AImodels integrating clinical, molecular, and histopathology features to provideprognostic information for early (<5years), late (>5 years), and overall DR at 15 years using primary tumorsamples and clinical data from volunteers who participated in TAILORx. Methods: DigitizedH&E slides were generated and nucleic acids extracted and sequenced from∼5000 primary tumor samples using Caris MI Tumor Seek-Hybrid, of which 2,808(56%) were used for model training and 5-fold nested cross validation (60/20/20split). Models included single-modality (clinical [C], image [I], molecular [M:ODX genes]), dual-modality (CM, IC), and multimodal (ICM). An expandedmolecular model (M+) model was also derived from expanded molecular inputsderived from whole transcriptome sequencing (WTS) data, including 5 commercialgene signatures (ODX, MammaPrint, Prosigna, EndoPredict, BCI) and 57 high-variancegenes; only EndoPredict, BCI, and ODX gene signatures were retained for model M+.Model-CM+ combined clinical plus expanded molecular features, while ICM/ICM+integrated image, clinical, and (expanded) molecular inputs. Risk scores were dichotomized into high vs. low risk groups usingthresholds chosen to yield risk group proportions closely matching thosedefined by the ODX RS cutoff of 25 for distinguishing high vs. low genomicrisk. Theprimary endpoint was distant recurrence (DR). Prognostic performance wasassessed using truncated concordance index (C-index, 90th percentile of eventtimes), hazard ratios (HRs), and log-rank tests. DNA-level whole exomesequencing (WES) features were also tested but did not provide additionalprognostic information and thus excluded from final models. Results: Theactual ODX continuous RS achieved a C-index of 0.625 for overall DR and 0.743early DR, but no prognostic value for late DR (0.52). Similar results for theC-index were observed for ODX+C for overall DR (0.619), early DR (0.724), andlate DR (0.514). Of all modelsevaluated, model-ICM+ gave the best overall prognostic accuracy for overall DR (C-index0.713; hazard ratio [HR] 3.56 for comparison of high vs. low risk, p<0.001)and late DR (C-index 0.655; HR 2.36, p<0.001), and ranked second for earlyDR (C-index 0.772; HR 6.59, p<0.001) behind the CM+ model (C-index 0.782). Amongsingle-modality models, Model-M+ improved early DR prognostication comparedwith a molecular model including only ODX genes(C-index 0.767 vs 0.744 for M),whereas Model-I was strongest for late DR prognostication (C-index 0.635). Conclusions: Molecularfeatures primarily drove prognostic accuracy for early DR within 5 years,whereas histopathology features strengthened the prognostic accuracy for lateDR after 5 years. Multimodal models captured these complementary signals, withICM+ giving the best overall accuracy for individualized prognostic assessment.Additional validation of the optimized ICM+ model and other models is beingperformed in an intendent validation sample of 2000 TAILORx volunteers, withresults to be presented at the meeting.Supported by the Breast CancerResearch Foundation and the U.S. NIH/NCI U10CA180820 and 5U24CA196172, and theU.S. Postal Service Breast Cancer Stamp Fund. Citation Format: J. A. Sparano, V. Wang, R. J. Gray, D. F. Makower, K. S. Albain, D. F. Hayes, C. E. Geyer, E. C. Dees, M. P. Goetz, J. A. Olson, S. S. Badve, T. J. Saphner, T. J. Whelan, M. Radovich, V. G. Kaklamani, G. W. Sledge. Multimodal artificial intelligence (AI) models integrating image, clinical, and molecular data for predicting early and late breast cancer recurrence in TAILORx [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 GS1-08.

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.

Abstract Background: The current standard of care for first-line (1L) treatment of human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) consists of induction chemotherapy combined with trastuzumab (TRAS) and pertuzumab (PERT) followed by maintenance therapy with TRAS + PERT. Although this regimen has been associated with sustained disease control, most patients eventually experience disease progression. The HER2CLIMB-05(NCT05132582) study is investigating the efficacy and safety of adding tucatinib to TRAS + PERT as maintenance therapy in patients with HER2+ MBC after completion of 1L chemotherapy-based induction therapy. Methods: Patients with centrally confirmed HER2+MBC without evidence of progression after 1L induction therapy with 4 to 8cycles of a taxane combined with TRAS + PERT, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, and no or asymptomatic brain metastases (BM) were enrolled in HER2CLIMB-05. Contrast-enhanced brain magnetic resonance imaging was performed at screening and regular intervals during the study. Patients were randomly assigned 1:1 to receive either tucatinib 300 mg or placebo twice daily, in combination with either TRAS (6 mg/kg IV or 600 mg SC) plus PERT (420 mg/kg IV) or a SC fixed-dose combination of TRAS, PERT, and hyaluronidase administered every 21 days. Endocrine therapy was permitted for patients with hormone receptor-positive tumors. The primary endpoint is investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints include overall survival (OS), PFS by blinded independent central review, investigator-assessed central nervous system (CNS)-PFS, and safety. Results: Between March 2022 and July 2024, 654 patients were randomly assigned to receive tucatinib (n = 326) or placebo (n = 328) with1L maintenance therapy. All patients were female (median age: 54 years [range, 24-83]);45.0% were White, 35.2% were Asian, 2.9% were Black/African American, and 19.3%were Hispanic/Latino(a)/Spanish origin. Most patients had ECOG PS of 0 (64.1%)and de novo metastatic disease (69.3%). At baseline, 12.4% of patients had presence or history of BM and 52.6% had hormone receptor-positive MBC. As of September5, 2025, PFS was statistically significantly improved with the addition of tucatinib versus placebo to 1L maintenance therapy (hazard ratio [HR] = 0.641 [95%confidence interval (CI), 0.514-0.799]; 2-sided P < 0.0001). All prespecified patient subgroups demonstrated a PFS benefit with tucatinib combination 1L maintenance therapy consistent with the overall population and regardless of presence or absence of BM at baseline or hormone-receptor status. OS is still immature (observed number of deaths = 51;tucatinib arm versus control arm HR = 0.539 [95% CI, 0.303-0.957; 2-sided P= 0.032]). In the safety analysis set, the most common treatment-emergent adverse events (TEAEs) in the tucatinib arm (n = 326) were diarrhea (72.7%), nausea (33.1%), and elevated liver enzymes (alanine aminotransferase: 28.2%; aspartate aminotransferase:25.8%), of which 6.1%, 0.9%, 13.5%, and 7.1% were, respectively, grade ≥ 3. In the tucatinib arm, 13.5% of patients discontinued tucatinib due to TEAEs. Conclusions: In the HER2CLIMB-05 trial, the addition of tucatinib to TRAS + PERT as 1L maintenance therapy demonstrated a statistically significant and clinically meaningful improvement in PFS with a manageable safety profile in patients with HER2+ MBC. Citation Format: E. Hamilton, G. Curigliano, M. Martin, F. Lerebours, J. Tsurutani, M. Savard, K. Jerzak, X. Hu, L. Martins de Aquino Pimentel, C. O'Sullivan, E. Tokunaga, A. Okines, C. Huang, W. Jacot, J. Sohn, E. Cronemberger Silva, V. Mueller, S. Yang, G. Granata, Q. Shen, L. Santarpia, V. Dieras Her2climb-05: a randomized, double-blind, phase 3 study of tucatinib versus placebo in combination with trastuzumab and pertuzumab as maintenance therapy for her2+ metastatic 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 GS1-01.

Background: Lithium, the gold standard treatment of bipolar disorder (BD), is thought to cause nephropathy in long-term users. However, the role of confounding variables linked to BD in exerting this adverse effect remains unclear. Objectives: This paper evaluates kidney function in patients with affective disorders who are taking lithium compared to patients not on lithium treatment. Design: This article is a systematic review and meta-analysis. Data sources and methods: A comprehensive search of publications up to October 2023 within Cochrane, Embase, PubMed, Scopus, Web of Science, and CINAHL databases was performed. Three assessors screened and extracted data from eligible observational studies. Risk of bias assessment was done with the ROBINS-E tool. Eligible studies were comparative studies of adult patients with diagnoses of affective disorders, including BD on lithium, with control groups not on lithium, reporting kidney function outcomes. Results: Mean estimated Glomerular filtration rate (eGFR) showed less favorable outcomes in the lithium group compared to the non-lithium group ( n = 1622, MD = −11.14 ml/min/1.73 m 2 , 95% CI: −16.61, −5.68, I 2 = 86%). The mean annual eGFR decline comparison favored the non-lithium group ( n = 13,280, MD = 0.13 ml/min/1.73 m 2 , 95% CI: 0.06, 0.20, I 2 = 0%). Serum creatinine concentration (mg/dl) was found to be higher in the lithium compared to non-lithium groups ( n = = 1704, MD = 0.05, 95% CI: 0.03, 0.07, I 2 = 3%). New or progressing chronic kidney disease events were not found to be statistically different between the lithium and control groups ( n = = 17,740, OR = 2.16, 95% CI: 0.59, 7.94, I 2 = 99%). The high heterogeneity in this meta-analysis limits the reliability and interpretability of our results. Conclusion: Kidney function, as measured by eGFR, was decreased in the lithium-taking groups versus the non-lithium groups. Continuous monitoring and discussion of risks and benefits with patients, especially those with a baseline of reduced kidney function, is imperative. Trial registration: This review was registered prospectively with PROSPERO (CRD42024517414).

Freezing of gait (FOG) is a complex and highly disabling motor symptom that frequently affects patients with Parkinson’s disease (PD), especially in the middle and late stages. Although traditionally associated with motor deficits, accumulating evidence suggests that FOG is also strongly influenced by non-motor domains, including cognitive dysfunction and emotional disturbances. The prefrontal cortex (PFC), a key hub for executive functions, attention, and emotional regulation, has been increasingly implicated in the pathophysiology of FOG. Structural and functional abnormalities in the PFC, particularly in the dorsolateral prefrontal cortex (DLPFC) and medial prefrontal cortex (MPFC), have been reported in PD patients with FOG. This narrative review aims to summarize current evidence on the role of the prefrontal cortex in the development and modulation of freezing episodes, focusing on neuroimaging findings. Clarifying the contribution of frontal lobe dysfunction to FOG may inform therapeutic strategies targeting frontostriatal circuits to improve mobility and quality of life in PD patients. This is a narrative review and does not employ formal systematic review methodology.