Lynce, Filipa

Abstract Background Whether outcomes of germline BRCA1/2 (gBRCA1/2)-associated breast cancer differ compared with sporadic tumors is controversial. We explored the impact of gBRCA1/2 pathogenic variant (PV) status beyond established prognostic features. Methods We conducted 2 retrospective, matched cohort studies comparing gBRCA1/2 PV carriers and noncarriers with HER2-negative, stage I-III breast cancer (Clinical Outcomes Quality Database [COQD] cohort: 185 carriers, 555 noncarriers; Young Women’s Breast Cancer Study [YWS] cohort: 113 carriers, 226 noncarriers). Matching factors were age, stage, hormone receptor status, and year of diagnosis. Clinicopathological features, treatments, and survival outcomes were compared between carriers and noncarriers. Results Most patients in COQD had stage I-II disease (87.2%), and more carriers than noncarriers had genetic testing before diagnosis (33% vs 5.6%, P < .001). In YWS, 22.7% of patients had stage III tumors, and few were tested before diagnosis (14.8% of carriers vs 1.7% of noncarriers; P < .001). Carriers in COQD received chemotherapy more often than noncarriers (81.1 vs 67.0%, P < .001), including platinum (P = .010); the proportion was similar for carriers and noncarriers in YWS. After adjusting for chemotherapy, relapse-free survival was longer in carriers than noncarriers in COQD (adjusted hazard ratio = 0.48 [95% CI = 0.26 to 0.87], P = .016), and a favorable trend was observed for other survival outcomes in both cohorts. Triple-negative tumors appeared to drive the differences. Conclusions We observed a trend toward improved outcomes in gBRCA1/2 PV carriers compared with noncarriers. These findings suggest that carriers should not receive more aggressive treatment solely based on their germline mutation status. Prospective clinical trials in this population are warranted.

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.

TPS1143 Background: Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have revolutionized the treatment of patients (pts) with germline BRCA1/2 (gBRCA)-associated HER2-negative BC. However, resistance eventually occurs in almost all pts. Tumor-associated macrophages (TAMs), a key component of the BC tumor microenvironment, are highly immunosuppressive and associated with poor clinical outcomes. In preclinical immunocompetent models of BRCA-associated BC, PARP inhibition induces suppressive CSF-1R+ TAMs, contributing to resistance, so that combining anti-CSF-1R therapy with PARPi significantly enhances progression free survival (PFS) compared to PARPi monotherapy (190d vs 92d). Axatilimab (SNDX-6352; Ab969.g2), a humanized IgG4 monoclonal antibody targeting CSF-1R, reduces TAMs, potentially slowing tumor growth and enhancing anti-tumor immunity. In the Phase I SNDX-6352-0502 study for advanced solid tumors, axatilimab showed tolerability at the highest dose (6 mg/kg), with biomarker modulation observed at doses as low as 1 mg/kg. Axatilimab is FDA-approved for chronic graft-versus-host disease (cGVHD). Methods: AXALAP (NCT06488378) is a non-randomized open-label, proof-of-concept phase 1 study designed to evaluate axatilimab 1mg/kg or 3mg/kg every 2 weeks in combination with olaparib 300 mg twice daily in pts with somatic or germline BRCA1/2 - and PALB2 -associated HER2-negative metastatic BC. Patients must be PARPi naïve, or have not progressed on prior PARPi, and have received up to 2 prior lines of chemotherapy for metastatic disease. Pts will receive a two-week lead-in of olaparib monotherapy, followed by combined olaparib and axatilimab. Pts will undergo mandatory tumor biopsies pre-treatment, after the 2-week olaparib lead-in, and after 2 cycles of olaparib/axatilimab, with an optional biopsy at time-of-progression. Primary objectives are to establish the maximum tolerated dose (MTD) and recommended phase 2 dose and to assess the safety and tolerability of axatilimab and olaparib. Secondary objectives include assessment of changes in CSF-1R+ CD163+ macrophage levels after olaparib monotherapy and after 2 cycles of combination treatment at the MTD; to determine the objective response rate and the median PFS of the combination per RECIST 1.1 criteria. The MTD will be determined by Bayesian Optimal Interval (BOIN) design. Pts will be treated in cohorts of 3 with a maximum of 10 at each dose. If the MTD is identified as 3mg/kg, we will complete enrollment of 10 pts at 1 mg/kg to assess biological effectiveness and clinical efficacy of the lower dose. We expect to treat up to 20 pts, who will receive study treatment until development of unacceptable toxicity or disease progression. Enrollment began on 5/2024 at Dana-Farber Cancer Institute and the trial will also open at Beth Israel Deaconess Medical Center and Mayo Clinic-Rochester. Clinical trial information: NCT03604692 .

e13808 Background: Cancer is a leading cause of death for Latinos. They experience higher rates than their white peers of preventable, infectious-agent-causing-cancers, such as stomach & liver cancer. Latina women have experienced a 1% rise in cancer cases since 2011 & Latino children & adolescents experience higher rates of leukemia than any other racial/ethnic group. Latinos face disparities in access to healthcare, cancer screening & treatment, medical representation & experience lower rates of survival due to late-stage cancer diagnosis. Methods: To combat these inequities & identify equitable interventions for Latino health, the Institute of Health Promotion Research & the Mays Cancer Center established the Advancing the Science of Cancer in Latinos (ASCL) Conference. The fourth ASCL Conference convened in San Antonio, TX from February 21-23, 2024. The conference objectives were 1) Examine the intersection of health equity & biological underpinnings in cancer control, prevention, and treatment 2) Foster collaborative initiatives among attendees aimed at addressing cancer-related health disparities within the Latino community. The conference hosted 286 participants (speakers, researchers, physicians, healthcare professionals, patient advocates & students). It comprised of 23 sessions (3 keynotes, 6 plenaries, 6 breakouts, 3 general sessions, 1 special session, 1 lunch panel session) featuring insights from 51 speakers, a poster session highlighting 80 research abstracts & a rapid-fire session tailored for early-career investigators. Sessions focused on multiple topics relevant to Latino cancer research, clinical trials, survivorship, patient advocacy, climate change impacts on cancer, precision medicine, health policy & social determinants of health. Results: A post-conference survey from a cohort of 48 respondents underscored high levels of satisfaction, with 90% expressing contentment regarding the conference experience. Nearly all respondents (98%) rated the relevance of conference content to Latino cancer science as excellent, with 93% regarding the conference as an exceptional platform for information exchange. Impressions regarding session quality were positive, with 90% of respondents indicating a high level of satisfaction, & all survey respondents acknowledging the objectivity, balance & absence of commercial bias in the session content. Conclusions: Results showed that the resounding positivity in attendee feedback reflects the conference's success in fostering meaningful engagement among attendees. The ASCL conference facilitated an understanding of cultural nuances and barriers specific to the Latino community, stimulating collaborative efforts aimed at enhancing Latino health outcomes. Overall, this analysis affirms the conference's success in achieving its stipulated objectives and underscores the need of having consistently coordinated research endeavors to reduce Latino health disparities.

Abstract Cancer is the leading cause of mortality within the Latino population. Projections suggest a 142% increase in cancer incidence among Latinos over the next two decades. This trend is concerning given that Latinos, the largest minority group in the United States, are expected to constitute at least 28% of the nation's populace by 2060. To address the need for enhanced comprehension of these trends and to identify equitable interventions targeting Latino health disparities, the Institute of Health Promotion Research and the Mays Cancer Center jointly established the biennial Advancing the Science of Cancer in Latinos (ASCL) Conference. The fourth ASCL Conference convened in San Antonio, TX from February 21-23, 2024. The conference objectives were twofold: 1) Examine the intersection of health equity and biological underpinnings in cancer control, prevention, and treatment; and 2) Foster collaborative initiatives among attendees aimed at addressing cancer-related health disparities within the Latino community. The 2024 conference attracted 286 participants compared to 251 attendees in 2022, encompassing guest speakers, researchers, physicians, healthcare professionals, patient advocates, researchers, and students. It comprised 23 sessions (3 keynotes, 6 plenaries, 6 breakouts, 3 general sessions, 1 special session, 1 lunch panel session) featuring insights from 51 speakers, alongside a poster session highlighting 80 research abstracts and a rapid-fire session tailored for early-career investigators. Sessions encompassed multiple topics relevant to Latino cancer research, spanning health disparities, clinical trials, survivorship, patient advocacy, climate change impacts on cancer, precision medicine, health policy and social determinants of health. A post-conference survey from a cohort of 48 respondents underscored high levels of satisfaction, with 90% expressing pronounced contentment regarding the conference experience, compared to 85% in 2022. Moreover, nearly all respondents (98%) rated the relevance of conference content to Latino cancer science as excellent, with 93% regarding the conference as an exceptional platform for information exchange, compared to 79% in 2022. Impressions regarding session quality were overwhelmingly positive, with 90% of respondents indicating a high level of satisfaction, and all survey respondents acknowledging the objectivity, balance, and absence of commercial bias in the session content. Our results showed that the resounding positivity in attendee feedback reflects the conference's success in fostering meaningful engagement among researchers committed to alleviating Latino cancer health disparities. The ASCL conference facilitated an understanding of cultural nuances and barriers specific to the Latino community, stimulating collaborative efforts aimed at enhancing Latino health outcomes. Overall, this retrospective analysis affirms the conference's success in achieving its stipulated objectives and underscores the need of having consistently coordinated research endeavors to reduce Latino health disparities. Citation Format: Amelie G. Ramirez, Rebecca T. Jones, Matthew P. Banegas, Maria C Camargo, Gerardo Colon-Otero, Cliff Despres, Laura Fejerman, Filipa Lynce, Martin Mendoza, Patricia I. Moreno, Alejandro Recio-Boiles, Barbara Segarra-Vazquez, Sandi Stanford, Mariana Stern, Katherine Y. Tossas, Edward J. Trapido, Nicolette M Orozco. Advancing the science of cancer in Latinos conference [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B032.

PURPOSE To develop recommendations for germline mutation testing for patients with breast cancer. METHODS An ASCO–Society of Surgical Oncology (SSO) panel convened to develop recommendations based on a systematic review and formal consensus process. RESULTS Forty-seven articles met eligibility criteria for the germline mutation testing recommendations; 18 for the genetic counseling recommendations. RECOMMENDATIONS BRCA1/ 2 mutation testing should be offered to all newly diagnosed patients with breast cancer ≤65 years and select patients >65 years based on personal history, family history, ancestry, or eligibility for poly(ADP-ribose) polymerase (PARP) inhibitor therapy. All patients with recurrent breast cancer who are candidates for PARP inhibitor therapy should be offered BRCA1/ 2 testing, regardless of family history. BRCA1/ 2 testing should be offered to women who develop a second primary cancer in the ipsilateral or contralateral breast. For patients with prior history of breast cancer and without active disease, testing should be offered to patients diagnosed ≤65 years and selectively in patients diagnosed after 65 years, if it will inform personal and family risk. Testing for high-penetrance cancer susceptibility genes beyond BRCA1/ 2 should be offered to those with supportive family histories; testing for moderate-penetrance genes may be offered if necessary to inform personal and family cancer risk. Patients should be provided enough pretest information for informed consent; those with pathogenic variants should receive individualized post-test counseling. Variants of uncertain significance should not impact management, and patients with such variants should be followed for reclassification. Referral to providers experienced in clinical cancer genetics may help facilitate patient selection and interpretation of expanded testing, and provide counseling of individuals without pathogenic germline variants but with significant family history. Additional information is available at www.asco.org/breast-cancer-guidelines .

Abstract Background: PARP inhibitor (PARPi) monotherapy has previously demonstrated clinical activity only in patients with a germline BRCA mutation (BRCAmut), while single-agent anti-programmed cell death protein 1 (PD-1) therapy has achieved response rates of only 5–20% in advanced triple negative breast cancer (TNBC). In preclinical studies, PARP inhibition enhanced anti-tumor immunity, increased infiltration of proliferating CD8+ T cells, and synergized with anti-PD-1 agents in BRCA wildtype (wt) tumors. TOPACIO is a fully enrolled, phase I/II trial of niraparib + pembrolizumab (pembro) in advanced TNBC. This combination achieved 28% objective response rate (ORR) and 50% disease control rate (DCR) in evaluable patients. Although activity was highest in patients with BRCAmut (ORR=60%; DCR=80%), durable clinical benefit was also observed in patients without BRCA mutations. In this study, we conducted exploratory biomarker analyses to evaluate their potential correlation with durable clinical benefit (any complete response [CR] or partial response [PR] regardless of duration or stable disease [SD] for ≥16 weeks) beyond BRCA mutations. Method: ORR was assessed by RECIST v1.1. Duration of disease control (DDC) was defined as time from first dose of study treatment to radiologic disease progression or death. Tumor mutational status of homologous recombination repair (HRR) and other DNA damage repair (DDR) pathway genes was determined using an NGS panel. Immunoprofiling was conducted using NanoString IO360 panel complimented with 30 DNA repair spike-ins. Tumor immune micro-environment was characterized using multiplex immuno-fluorescence (CycIF). PD-L1 status was determined using the Agilent/DAKO 22C3 IHC clinical trial assay. Results: Of 46 evaluable patients, 20 achieved durable clinical benefit (any CR/PR or SD≥16 weeks) with niraparib + pembro combination, of which 8 were tumor BRCA wild type (wt), and 1 was BRCA unknown. Of the 9 BRCAwt/unknown patients, 5 had deleterious mutations in HRR/DDR pathway genes, whereas the remaining 4 had no mutations (HRR/DDR wt). Mutations that were associated with response include CHEK1 (CR; DDC=10.3 mos), ATR (CR; DDC=6.4 mos), PALB2 (PR; DDC=3.5 mos), BLM (SD; DDC=8.1 mos), and NBN/RAD51C (SD; DDC=3.7 mos). Of 4 patients that had no identified mutations (HRR/DDR wt), 1 patient had CR; DDC=10.3 mos, and the remaining 3 patients had SD with DDC ranging from ∼4-8 mos. Of note, all 4 HRR/DDR wt patients were also PD-L1-negative. Table:Durable clinical benefit in BRCAwt/unknown patientsHRR/DRR MutationsPD-L1 StatusBest ResponseDDC (Months)CHEK1+CR10.3†ATR+CR6.4PALB2*UnknownPR3.5BLM-SD8.1NBN/RAD51C+SD3.7None-CR10.3†None-SD8.2None-SD4.2None-SD3.9*BRCA status unknown; †Treatment is ongoing. Conclusion: Patients with mutations beyond BRCA achieved durable clinical benefit with niraparib + pembro treatment; five of these patients had DDC >6 mos. Mutations in genes that are associated with the HRR/DDR pathway appear to confer sensitivity to niraparib + anti-PD1. Additional translational analyses, including immunoprofiling and CycIF, will be presented. Funding: TESARO, Inc., Waltham, MA, USA sponsored the study. Citation Format: Vinayak S, Tolaney SM, Schwartzberg L, Mita M, McCann G, Tan AR, Wahner Hendrickson A, Forero A, Anders C, Wulf G, Dillon P, Lynce F, Zarwan C, Erban J, Färkkilä A, Zhou Y, Buerstatte N, Graham JR, Arora S, Dezube B, Telli ML. Durability of clinical benefit with niraparib + pembrolizumab in patients with advanced triple-negative breast cancer beyond BRCA: (TOPACIO/Keynote-162) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-02.