Yadav, Siddhartha

Abstract Importance: The poly-adenosine diphosphate–ribose polymerase (PARP) enzymes are important for DNA single-strand break repair and PARP inhibitors (PARPi) cause an accumulation of unresolved DNA damage in tumors with BRCA1/2 mutations, resulting in cell death. However, because platinum salts also ultimately cause double-strand DNA breaks and may have overlapping mechanisms of resistance with PARPi, the efficacy of PARPi in patients with prior platinum therapy is unknown. Objective We sought to evaluate the efficacy of PARPi in patients with BRCA1/2-related breast cancer and previous platinum exposure. Data Sources: PubMed, Embase, and Cochrane Central Register of Controlled Trials databases were searched for papers up to June 26, 2022. Study Selection: We performed a systematic review and meta-analysis of studies that evaluated the efficacy of PARPi in patients with advanced or metastatic breast cancer and germline BRCA1/2 mutations. Two independent investigators identified double-blind, randomized controlled trials (RCTs) that included the subgroup of previous exposure to platinum. Data Extraction and Synthesis: Data extraction from published reports and quality assessment were performed under Cochrane recommendations. The software Review Manager 5.3 was selected for conducting the statistical analyses. Main Outcome(s) and Measure(s): The primary endpoint of interest was progression-free survival (PFS). Hazard ratios (HRs) with a 95% confidence interval (CI) were pooled, and a p-value of < 0.05 was considered statistically significant. Results From 2,069 database results (487 on PubMed; 1,376 on Embase; and 206 on Cochrane), 42 studies were fully reviewed, and 4 RCTs (total of 249 patients) were included in the final investigation. The PARPi included were Olaparib, Talazoparib, Niraparib, and Veliparib. Pooled analysis showed that PARPi improved PFS in breast cancer patients with prior treatment with platinum-based therapy compared to the control group [HR = 0.72; 95% CI, 0.53–0.97; p = 0.03]. For comparison, the population without previous platinum exposure had a similar magnitude of benefit from PARPi [HR = 0.68; 95% CI, 0.52–0.89; p = 0.005]. Conclusions and Relevance: Despite the concerns about cross-resistance between PARPi and platinum agents, patients with advanced breast cancer and previous exposure to platinum therapy have a longer PFS with PARPi when compared to standard chemotherapy.

10585 Background: The 21-gene recurrence score assay (Oncotype DX, Genomic Health Inc., CA) is prognostic, quantifies predicted benefit of adjuvant chemotherapy, and informs clinical decisions for patients with early-stage, hormone receptor-positive (HR+) breast cancer (BC). Differences in Oncotype recurrence scores (RS) in individuals with and without BRCA1 and BRCA2 pathogenic variants (PV) have been demonstrated, but the results of this assay in patients with BC and germline CHEK2 or ATM PV have not previously been described. This is of particular relevance as CHEK2 BC have been associated with a worse prognosis. Methods: Prospective Registry of MultiPlex Testing (PROMPT) is an online research registry for individuals who have had multigene panel testing for inherited cancer susceptibility. We retrospectively evaluated Oncotype DX recurrence scores from PROMPT participants (pts) with PV or likely PV in CHEK2 or ATM. Mood’s median tests were used to compare median RS, and Yates corrected Chi-square tests were used to compare RS distributions between carriers and a genetically unselected reference population. Results: Oncotype DX reports were reviewed for 75 pts with 77 BC (n = 50 pts with CHEK2 PV with 51 BC; n = 24 with ATM PV; n = 1 with CHEK2 and ATM PV with 2 BC). Among CHEK2 carriers, median RS was 17 (range 2-43) overall, 17 (2-36) for pts < age 50, and 18.5 (8-43) for pts ≥age 50 (p-value 0.47), with distributions not significantly different than reference ( < 50, p = 0.70; ≥50, p = 0.93). Ten pts had low penetrance CHEK2 alleles (p.S428F or p.I157T) with median RS 16 (9-28) compared to 18 (2-43) in those with other CHEK2 alleles (p = 0.35). Among ATM carriers, median RS was 17 (1-35) overall, 17 (1-35) for pts < age 50, and 16 (11-32) for pts ≥age 50 (p = 0.51), with distributions also not significantly different ( < 50, p = 0.78; ≥50, p = 0.79). Conclusions: Unlike data seen in BC associated with BRCA1 and BRCA2, Oncotype DX RS in individuals with CHEK2 and ATM-associated BC are similar to the published genetically unselected commercial database median RS of 16, with no clear difference based on penetrance of CHEK2 allele. Proportions of patients < 50 and ≥50 with CHEK2 and ATM PV with RS within the range for chemoendocrine therapy consideration are also similar to the historical reference. The inferior prognosis that has been suggested in CHEK2 BC is not reflected in Oncotype DX RS. [Table: see text]

10501 Background: Greater than 90% of missense variants in BRCA2 are classified as variants of uncertain significance (VUS). In addition, among the few known missense pathogenic variants (PVs) in BRCA2, breast cancer risk has been reported to be lower compared to pathogenic truncating variants (PTVs) (Li et al., 2022) . Herein, we aim to reclassify several missense variants in BRCA2 and investigate the associated breast cancer risk. Methods: A total of 450 BRCA2 missense variants in the C-terminal DNA binding domain (DBD) were evaluated for functional effect utilizing a previously validated homology-directed DNA double-strand repair (HDR) assay. The results of the functional evaluation along with clinical, structural, and in-silico data were applied to the rules-based ACMG/AMP criteria for variant classification to identify pathogenic/likely pathogenic (P/LP) variants and benign/likely benign (B/LB) variants. A pooled case-control analysis was performed comparing the frequency of reclassified P/LP missense variants among 82,372 women with breast cancer within the Ambry Genetics database as cases and 174,167 unaffected women within gnomAD, CARRIERS, and BRIDGES datasets as controls to evaluate associated breast cancer risk. Separate case-control analysis and comparisons with BRCA2 DBD PTVs, exon 11 PTVs, and known missense PV standards in ENIGMA were also performed. Results: From the 450 missense variants in the DBD, 137 (30.4%) were noted to be functionally deleterious and 313 (69.6%) were functionally neutral by the HDR assay. Incorporation of the functional and other data into an ACMG/AMP model led to the reclassification of 439 (97.6%) variants, with 131 as P/LP and 308 as B/LB variants. In a pooled case-control analysis, reclassified BRCA2 missense P/LP variants were associated with clinically significant increased risks of breast cancer (Odds Ratio (OR):5.6, 95%CI:3.9–8.0), whereas B/LB missense variants were not (OR:1.1, 95%CI:1.1–1.2). Similarly elevated risks of breast cancer were observed for BRCA2 PTVs in the DBD (OR:6.8, 95%CI:5.1–9.0) and missense PV standards in ENIGMA (OR:7.8, 95%CI:4.1–14.7). However, PTVs in exon 11 of BRCA2 were associated with a lower risk of breast cancer (OR:4.4, 95%CI:3.8–4.9) compared to PTVs in DBD, confirming the ovarian cancer cluster region effect in BRCA2. Conclusions: The study demonstrates that the HDR functional assay in conjunction with other clinical and genomic data can be a powerful tool that can aid in the reclassification of > 95% of missense variants in BRCA2. In addition, missense PVs in DBD were noted to have a similarly elevated risk of breast cancer as PTVs. The reclassification of the BRCA2 missense VUS and identification of associated breast cancer risk in this study will significantly influence breast cancer risk assessment and management strategies among carriers of these missense variants.

6557 Background: Trials that inadequately include underrepresented minority (URM) populations widen inequities in cancer care. We assessed reporting patterns, representation, and trends of URM representation in breast cancer (BC) trials. Methods: We analyzed all phase 2/3 trials for age disparity and trials recruiting from the US for racial/ethnic disparity amongst BC RCTs (1990-2021). Enrollment-incidence ratios (EIR), which compare trial proportions (TP) from age subgroups against global estimates of incidence in the corresponding age group (from Global Burden of Disease) and racial/ethnic subgroups against US-population-based incidence in the corresponding racial/ethnic group (from SEER 22), were calculated. Individual-trial EIRs were pooled using random-effects meta-analyses. EIRs of <0.80 indicated meaningful underrepresentation, while EIRs >1.20 indicated meaningful overrepresentation. Meta-regression was used to explore associations between key trial characteristics and EIR, and trends in EIR over the last three decades. Results: Of 842 global trials with 490,657 participants, 232 (27.6%) reported the number of participants in specific age strata and 144 (17.1%) reported outcomes by age. Only 60 trials recruited exclusively from the US. Of these, 41 (68.3%) reported race and 24 (40.0%) reported ethnicity, and 2 (3.3%) analyzed outcomes by race. Older adults aged ≥65 years (TP: 24.3%; EIR: 0.53 [95% CI: 0.47-0.60]) and Hispanic women (TP: 5.3%; 0.54; 0.40-0.75) were underrepresented across global trials and US-only trials respectively. Black women were significantly underrepresented in trials that led to FDA approval (0.38; 0.25-0.58) but not in US-only trials. Stratified analysis by BC subtype (with subtype-specific population incidence) showed underrepresentation of Black women in US-only trials for HER2+ BC (0.66; 0.47-0.93), Hispanic women in ER+ BC (0.42; 0.20-0.90), Asians in triple-negative BC (0.24; 0.11-0.53), and older women in HER2+ BC (0.35; 0.31-0.40) and triple-negative BC (0.36; 0.29-0.45). From 1990-2021, the representation of older women declined significantly (meta-regression coefficient for EIR: -0.4 per 10 years), while Black and Hispanic representation showed no significant change. Black (p = 0.02) and Hispanic representation (p = 0.05) worsened significantly in larger trials. Conclusions: Published reports of BC trials do not consistently report the inclusion of URM. Older and Hispanic women were consistently underrepresented, whereas Black women were underrepresented in large, practice-changing trials. [Table: see text]

e15050 Background: Molecular tumour boards (MTB) facilitate discussions among medical professionals, scientists, bioinformaticians and geneticists for clinical application of precision oncology, via interpretation of various genomic sequencing studies, most commonly Next Generation Sequencing (NGS). NGS test vendor recommendation may differ from the MTB recommendations. We aim to study the discordance rate between these recommendations. Methods: MTB discussions between April 1, 2021 and December 31, 2021, were retrospectively evaluated. MTBs which assessed NGS reports with or without significant genetic mutations but with drug recommendations were included. NGS testing was done with multiple vendors. Patients from all over India, Nepal, Bangladesh, Dubai and Abu Dhabi were discussed. We excluded MTBs which assessed NGS data without any drug recommendations. We compared therapeutic recommendations provided in the NGS report with the first-choice recommendation in the MTB discussion. Recommendation discordance was defined as disagreement between the NGS recommendation and the first MTB recommendation that either instructed its implementation either immediately or on disease progression. Results: 70 MTB data was studied. 49 MTBs assessing NGS reports of 49 unique patients (median age 54 years; range, 32-82) were included in the study. 13 patients had lung cancer, 10 colorectal, 6 breast, 7 hepatopancreatobiliary, 4 carcinoma of unknown primary and 9 others. 17 did not provide any treatment recommendations and hence were excluded. 4 were discussions based on NGS reports previously discussed in an MTB that was already included in the study, hence were excluded. Recommendation discordance rate was 49% (24 of 49). Conclusions: To our knowledge, this is the first study that assessed discordance rate in recommendations between NGS report and MTB from a low- and middle-income country setting. Accurate clinical translation of complex genomic data is at the forefront of personalized cancer care.

Abstract Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C−/− cells identified 30 nonfunctional (deleterious) variants, including 18 in a hotspot within the ATP-binding region. The deleterious variants conferred sensitivity to cisplatin and olaparib and disrupted formation of RAD51C/XRCC3 and RAD51B/RAD51C/RAD51D/XRCC2 complexes. Computational analysis indicated the deleterious variant effects were consistent with structural effects on ATP-binding to RAD51C. A subset of the variants displayed similar effects on RAD51C activity in reconstituted human RAD51C-depleted cancer cells. Case–control association studies of deleterious variants in women with breast and ovarian cancer and noncancer controls showed associations with moderate breast cancer risk [OR, 3.92; 95% confidence interval (95% CI), 2.18–7.59] and high ovarian cancer risk (OR, 14.8; 95% CI, 7.71–30.36), similar to protein-truncating variants. This functional data supports the clinical classification of inactivating RAD51C missense variants as pathogenic or likely pathogenic, which may improve the clinical management of variant carriers. Significance: Functional analysis of the impact of a large number of missense variants on RAD51C function provides insight into RAD51C activity and information for classification of the cancer relevance of RAD51C variants.

Abstract Introduction: ATRi and PARPi combinations kill tumor cells via synergistic modulation of complementary DDR pathways but clinical utility is limited by overlapping toxicities. A genome-wide CRISPR-Cas9 screen identified DDR alterations that sensitize tumors to the ATRi camonsertib (cam) plus PARPi. Based on preclinical models, tolerability and efficacy of cam plus PARPi given intermittently at low doses in pts with solid tumors with DDR alterations, including BRCA-mutated PARPi-resistant cancers, was evaluated. Methods: Pts (≥ 18 yrs) with relapsed/refractory (r/r) solid tumors with DDR alterations were treated with cam plus talazoparib (tala), niraparib (nira), or olaparib (ola) in 2 phase I trials (NCT04497116, NCT04972110). An adaptive BOIN design was used to optimize dose/schedule. Endpoints were safety, recommended phase II dose (RP2D), pharmacokinetics (PK), response (RECIST v1.1 [confirmed/unconfirmed], CA 125, or PSA), clinical benefit rate (CBR; RECIST/tumor marker response or treatment duration ≥ 16 wk), and ctDNA molecular response rate (MRR; best reduction in mean variant allele frequency [mVAF] ≥ 50%). Results: As of Nov 2022, 99 pts were enrolled (61 with ≥ 3 prior lines of therapy, 36 PARPi-pretreated); 43, 27, 29 pts in tala, nira, and ola combinations, respectively. Tumors included ovarian (n=20), prostate (n=13), breast (n=17), bile duct (n=3); most common genotypes were ATM (n=26), BRCA1 (n=19), and BRCA2 (n=33). Grade 3+ toxicities included reversible myelosuppression (neutropenia, anemia, and thrombocytopenia in 35%, 28%, and 14% of pts overall; 33%, 16%, and 11% at preliminary RP2Ds), fatigue (3%), and alkaline phosphatase increase (2%). Two pts discontinued treatment due to drug-related toxicity. Forty pts remain on therapy, up to 63 wks. Preliminary RP2Ds: cam 80 mg QD (d 5-7) + tala 0.25 mg QD, 1 wk on/1 wk off; cam 80 mg QD + nira 100 mg QD, 2 d on/5 d off; cam 50 mg QD + ola 100 mg BID, 3 d on/4 d off. As of abstract submission, response rate was 13% in 85 evaluable pts; CBR was 49%. Responders included pts with ovarian (n=6), bile duct (n=2), and breast, pancreatic, and carcinoma of unknown primary (n=1 each) cancers harboring alterations in BRCA1/2 (n=9), IDH1 (n=1), and ATM (n=1). Of 30 evaluable PARPi-pretreated pts, response rate was 23% and CBR was 52%. MRR was 64% (14/22 evaluable); change in mVAF correlated with a change in target lesion size (r=0.63, P=0.001). PK of each drug in the combination was consistent with respective monotherapy PK. Conclusion: Combination of cam plus PARPi at low doses on intermittent schedules was generally well-tolerated with clinical activity in DDR-aberrant tumors, including those pretreated with PARPi. RP2D optimization and translational correlative studies are ongoing. Citation Format: Timothy A. Yap, Siddhartha Yadav, Benjamin Herzberg, Benedito A. Carneiro, Elisa Fontana, Martin Højgaard, Michael J. Pishvaian, Ruth Plummer, Theresa L. Werner, Vaibhav Sahai, Stephanie Lheureux, Elizabeth K. Lee, Niharika B. Mettu, Gregory M. Cote, Joseph D. Schonhoft, Victoria Rimkunas, Ian M. Silverman, Marisa Wainszelbaum, Gerson Peltz, Adrian J. Fretland, Kezhen Fei, Danielle Ulanet, Insil Kim, Maria Koehler, Ezra Rosen, Michael Cecchini. Safety and efficacy of three PARP inhibitors (PARPi) combined with the ataxia telangiectasia- and Rad3-related kinase inhibitor (ATRi) camonsertib in patients (pts) with solid tumors harboring DNA damage response (DDR) alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT018.

Abstract Two recent studies have defined population-based risk of breast cancer (BC) due to pathogenic variants (PVs) in well-established BC susceptibility genes. Prior studies in high-risk BC cohorts identified variable BC risks based on the position and type of mutation in BRCA1 and BRCA2, and based on the type of mutation in ATM, CHEK2, and PALB2. Whether this variability holds true in the general population has not been evaluated. To determine the BC risks associated with mutations of different types and in different locations in BC susceptibility genes in the general population, we carried out case-control analyses of 32247 cases and 32544 controls in the CARRIERS study, including 12 US population-based studies, and case-control analyses, subset to mutation carriers. We used age-adjusted logistic regression to estimate odds ratios (OR), relative OR (rOR), and 95% confidence intervals (CI) for PVs in BRCA1, BRCA2, ATM, CHEK2, and PALB2. ORs were estimated using the full population of mutation carriers and noncarriers while rORs were estimated within subsets of individual gene mutation carriers. We identified 273 BRCA1, 421 BRCA2, 253 ATM, 351 CHEK2, and 148 PALB2 in women with BC and 35 BRCA1, 84 BRCA2, 139 ATM, 139 CHEK2, and 38 PALB2 variant carriers in those without BC. For BRCA1, we did not find differences in risk by mutation type or location. However, variants leading to nonsense mediated decay (NMD) predicted to have re-initiation at p.M128 had a non-statistical 3-fold higher risk for BC compared to those leading to NMD without re-initiation (rOR 3.1, 0.99-13.52, p = 0.0826). BRCA2 loss of function (LoF) mutations in exons 1-10 had a higher BC risk compared to LoF mutations in the exon 11 (rOR 2.7, 1.1-7.9, p=0.048) ovarian cancer cluster region (OCCR). We did not detect any differences in risk by mutation type or location in ATM, CHEK2, or PALB2. CHEK2 missense variants p.I157T (rOR 0.5, 0.4-0.7, p &lt;0.001) and p.T476M (rOR 0.5, 0.3 - 0.8, p=0.005) were associated with lower BC risk relative to CHEK2 c.1100delC (OR 2.5, 2.0-3.3, p&lt;0.001). The CHEK2 c.444+1G&gt;A splicing variant was associated with highest BC risk among common CHEK2 variants (OR 4.2, 1.9-10.5, p&lt;0.001), but was not statistically significantly different from c.1100delC (rOR 1.7, 0.8-4.3, p=0.230). In summary, we identified a higher BC risk for LoF variants in BRCA2, lower risk for CHEK2 missense mutations, and non-statistical higher risk for NMD/re-initiation BRCA1 variants and CHEK2 c.444+1G&gt;A in this population-based study. Despite the large numbers included in the overall CARRIERS study, the number of PV carriers was relatively small, which may have limited the detection of associations. Nonetheless, we were able to detect genotype-risk associations that have implications for counseling women about their BC risk, and certainly for the development of individualized risks. Citation Format: Mwangala P. Akamandisa, Nicholas Boddicker, Chunling Hu, Siddhartha Yadav, Jeffrey N. Weitzel, Peter Kraft, Susan M. Domchek, Fergus J. Couch, Katherine L. Nathanson, for the CARRIERS Consortium . Mutation type and location in breast cancer susceptibility genes are associated with differential risk in the general population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1183.