Germline Mutation Status Research Articles

Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers.

Pathogenic variants in homologous recombination repair (HRR) genes other than BRCA1/2 have been associated with a high risk of ovarian cancer (OC). In current clinical practice, genetic testing is generally limited to BRCA1/2. Herein, we investigated the mutational status of both BRCA1/2 and 5 HRR genes in 69 unselected OC, evaluating the advantage of multigene panel testing in everyday clinical practice. We analyzed 69 epithelial OC samples using an NGS custom multigene panel of the 5 HRR pathways genes, beyond the genetic screening routine of BRCA1/2 testing. Overall, 19 pathogenic variants (27.5%) were detected. The majority (21.7%) of patients displayed a deleterious mutation in BRCA1/2, whereas 5.8% harbored a pathogenic variant in one of the HRR genes. Additionally, there were 14 (20.3%) uncertain significant variants (VUS). The assessment of germline mutational status showed that a small number of variants (five) were not detected in the corresponding blood sample. Notably, we detected one BRIP1 and four BRCA1/2 deleterious variants in the low-grade serous and endometrioid histology OC, respectively. We demonstrate that using a multigene panel beyond BRCA1/2 improves the diagnostic yield in OC testing, and it could produce clinically relevant results.

Comprehensive characterization of CRC with germline mutations reveals a distinct somatic mutational landscape and elevated cancer risk in the Chinese population.

Objective:Hereditary colorectal cancer (CRC) accounts for approximately 5%–10% of all CRC cases. The full profile of CRC-related germline mutations and the corresponding somatic mutational profile have not been fully determined in the Chinese population.Methods:We performed the first population study investigating the germline mutation status in more than 1,000 (n = 1,923) Chinese patients with CRC and examined their relationship with the somatic mutational landscape. Germline alterations were examined with a 58-gene next-generation sequencing panel, and somatic alterations were examined with a 605-gene panel.Results:A total of 92 pathogenic (P) mutations were identified in 85 patients, and 81 likely pathogenic (LP) germline mutations were identified in 62 patients, accounting for 7.6% (147/1,923) of all patients. MSH2 and APC was the most mutated gene in the Lynch syndrome and non-Lynch syndrome groups, respectively. Patients with P/LP mutations had a significantly higher ratio of microsatellite instability, highly deficient mismatch repair, family history of CRC, and lower age. The somatic mutational landscape revealed a significantly higher mutational frequency in the P group and a trend toward higher copy number variations in the non-P group. The Lynch syndrome group had a significantly higher mutational frequency and tumor mutational burden than the non-Lynch syndrome group. Clustering analysis revealed that the Notch signaling pathway was uniquely clustered in the Lynch syndrome group, and the MAPK and cAMP signaling pathways were uniquely clustered in the non-Lynch syndrome group. Population risk analysis indicated that the overall odds ratio was 11.13 (95% CI: 8.289–15.44) for the P group and 20.68 (95% CI: 12.89–33.18) for the LP group.Conclusions:Distinct features were revealed in Chinese patients with CRC with germline mutations. The Notch signaling pathway was uniquely clustered in the Lynch syndrome group, and the MAPK and cAMP signaling pathways were uniquely clustered in the non-Lynch syndrome group. Patients with P/LP germline mutations exhibited higher CRC risk.

Brief family history questionnaire to screen for Lynch syndrome in women with newly diagnosed non-serous, non-mucinous ovarian cancers

ObjectivesWhile ovarian cancer is the third most common Lynch syndrome-associated cancer in women, there is no established screening strategy to identify Lynch syndrome in this population. The objective of this...

Effects of Neoadjuvant Chemotherapy in Ovarian Cancer Patients With Different Germline BRCA1/2 Mutational Status: A Retrospective Cohort Study.

BackgroundWhether neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) against primary debulking surgery (PDS) has a differential effect on prognosis due to Breast Cancer Susceptibility Genes (BRCA)1/2 mutations has not been confirmed by current studies.MethodsAll patients included in this retrospective study were admitted to Qilu Hospital of Shandong University between January 2009 and June 2020, and germline BRCA1/2 mutation were tested. Patients in stage IIIB, IIIC, and IV, re-staged by International Federation of Gynecology and Obstetrics (FIGO) 2014, were selected for analysis. All patients with NAC received 1-5 cycles of platinum-containing (carboplatin, cisplatin, or nedaplatin) chemotherapy. Patients who received maintenance therapy after chemotherapy were not eligible for this study. All relevant medical records were collected.ResultsA total of 322 patients were enrolled, including 112 patients with BRCA1/2 mutations (BRCAmut), and 210 patients with BRCA1/2 wild-type (BRCAwt). In the two groups, 40 BRCAmut patients (35.7%) and 69 BRCAwt patients (32.9%) received NAC. The progression-free survival (PFS) of BRCAmut patients was significantly reduced after NAC (median: 14.9 vs. 18.5 months; p=0.023); however, there was no difference in overall survival (OS) (median: 75.1 vs. 72.8 months; p=0.798). Whether BRCAwt patients received NAC had no significant effect on PFS (median: 13.5 vs. 16.0 months; p=0.780) or OS (median: 54.0 vs. 56.4 months; p=0.323). Multivariate analyses in BRCAmut patients showed that the predictors of prolonged PFS were PDS (p=0.001), the absence of residual lesions (p=0.012), and FIGO III stage (p=0.020); Besides, PARP inhibitor was the independent predictor for prolonged OS in BRCAmut patients (p=0.000), for BRCAwt patients, the absence of residual lesions (p=0.041) and history of PARP inhibitors (p=0.000) were beneficial factors for OS prolongation.ConclusionsFor ovarian cancer patients with FIGO IIIB, IIIC, and IV, NAC-IDS did not adversely affect survival outcomes due to different BRCA1/2 germline mutational status.

Clonal Hematopoiesis-Associated Gene Mutations in a Clinical Cohort of 448 Patients With Ovarian Cancer.

Cancer patients are at risk of secondary therapy-related myeloid neoplasms (t-MNs). Acquired blood-specific mutations in clonal hematopoiesis (CH)-associated genes are t-MN risk factors, and their occurrence associated with cancer therapy and age. Patients with ovarian cancer (OC) showed a particularly high prevalence of CH-associated gene mutations, which may additionally be explained by the high proportion of a hereditary disease cause in this cancer entity. We performed a retrospective analysis of 448 OC patients enrolled in the AGO-TR1 study; 249 were enrolled at primary diagnosis and 199 at platinum-sensitive recurrence. Analyses included the most frequently altered CH-associated genes (ASXL1, DNMT3A, GNAS, JAK2, PPM1D, SF3B1, SH2B3, SRSF2, TET2, TP53). Results were analyzed according to the BRCA1/2 germline (gBRCA1/2) mutation status. All statistical tests were 2-sided. Advanced age at blood draw and a high number of prior platinum-based chemotherapy lines were risk factors to acquire CH-associated gene mutations, with gene-specific effects observed. Binomial logistic regression suggested increased probabilities for gBRCA1/2 mutation carriers to acquire CH-associated PPM1D and TP53 gene mutations (PPM1D: odds ratio = 4.30, 95% confidence interval = 1.48 to 12.46, P = .007; TP53: odds ratio = 6.20, 95% confidence interval = 0.98 to 53.9, P = .06). This observation was due to a statistically significantly increased number of platinum-based chemotherapy lines in gBRCA1/2 mutation carriers vs noncarriers (PPM1D: mean [SD] = 2.04 [1.27] vs 1.04 [0.99], P < .001; TP53: mean [SD] = 2.83 [1.33] vs 1.07 [1.01], P < .001). No interaction between platinum-based chemotherapy and gBRCA1/2 mutation status with the occurrence of CH-associated gene mutations was observed. A positive gBRCA1/2 mutation status is not a risk factor to acquire CH-associated gene mutations. OC patients may benefit from monitoring CH-associated gene mutations, especially following carboplatin exposure. Future clinical studies are required to assess whether treatment regimen should be adapted according to individual t-MN risks.

Germline Mutation Landscape and Associated Clinical Characteristics in Chinese Patients With Renal Cell Carcinoma.

BackgroundRenal cell carcinoma (RCC) is a disease of genomic alterations, of which the complete panorama helps in facilitating molecular-guided therapy. Germline mutation profiles and associated somatic and clinical characteristics remains unexplored in Chinese RCC patients.MethodsWe retrospectively profiled the germline and somatic mutations of 322 unselected RCC patients using a panel consisting of 808 cancer-related genes. We categorized patients into three groups based on germline mutation status and compared the somatic mutation spectrum among different groups.ResultsApproximately one out of ten (9.9%) RCC patients were identified to carry pathogenic/likely pathogenic (P/LP) germline variants (PGVs), of which 3.7% were variants in syndromic RCC-associated genes and 6.2% were other cancer-predisposition genes. The most common PGV was found in VHL (2.2%), followed by FH, TSC2, ATM, BRCA1, NBN, and BLM (0.6% each). Young patients (≤46 years) were more likely to harbor PGVs. Variants in syndromic RCC-associated genes were predominant identified in young patients, while variants in other cancer-predisposition genes were found in patients >46 years more frequently. Furthermore, 39.3% (11/28) of patients carrying PGVs were detected to have somatic “second hit” events. Germline and somatic sequencing, including microsatellite instability (MSI) status analysis, provided potentially actionable therapeutic targets in 17.1% of patients in the whole cohort.ConclusionsOur results revealed that approximately 10% of RCC patients carried clinically significant germline mutations. Current guidelines recommendation for genetic testing seemed not sensitive enough to identify patients with hereditary RCC susceptibility. It is rational to promote genetic testing in RCC population.

Phase 2 Study of Olaparib in Malignant Mesothelioma and Correlation of Efficacy With Germline or Somatic Mutations in BAP1 Gene

IntroductionPARP inhibition may enhance antitumor responses in BAP1-associated mesothelioma by inducing synthetic lethality. MethodsA single-center, nonrandomized, phase 2 trial was conducted, in which patients with refractory mesothelioma were given olaparib 300 mg twice daily in a 21-day cycle until disease progression or intolerable toxicity. The primary objective was to determine the objective response rate on the basis of somatic or germline mutation status of DNA repair genes. The secondary objectives were to assess safety and tolerability and to determine progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing was performed on blood and tumor. ResultsA total of 23 previously treated patients with pleural and peritoneal mesothelioma were enrolled and treated (germline BAP1, n = 4; germline MRE11A, n = 1; somatic BAP1, n = 8 mutations). There was one (4%) partial response, 18 (78%) with stable disease at 6 weeks, and four (17%) with progressive disease. The median overall PFS and OS were 3.6 months (95% confidence interval [CI]: 2.7–4.2 mo) and 8.7 months (95% CI: 4.7 mo–not estimable), respectively. The median PFS of germline BAP1 mutants (n = 4) was 2.3 months (95% CI: 1.3–3.6 mo) versus 4.1 months (95% CI: 2.7–5.5 mo) for wild-type (n = 19; p = 0.019). The median OS was 4.6 months (95% CI: 3.1–4.9 mo) for germline BAP1 mutation versus 9.6 months (95% CI: 5.5 mo–not estimable) in no germline mutation (p = 0.0040). Olaparib was safe with no new safety concerns. ConclusionsOlaparib has limited activity in previously treated mesothelioma including patients with BAP1 mutations. Germline BAP1 mutations were associated with decreased PFS and OS.

Transcriptome of Male Breast Cancer Matched with Germline Profiling Reveals Novel Molecular Subtypes with Possible Clinical Relevance.

Simple SummaryBreast cancer in men is a rare disease; however, morbidity and mortality in male breast cancer (MBC) patients is a serious concern. The identification of specific molecular features in MBC is essential for developing more appropriate and targeted therapeutic strategies for MBC patients. In this study, by transcriptome analysis of 63 MBCs characterized for germline mutations in the most relevant BC susceptibility genes, mainly BRCA1/2, we highlighted possible differences in the molecular pathways underlying MBC pathogenesis in relation to germline mutation status. Furthermore, we identified two distinct subgroups of MBCs of clinical relevance, which are characterized by different biological features and prognosis. Overall, our results showed that transcriptome profiling by RNA sequencing is a valuable approach to dissect the molecular heterogeneity of MBC and suggest that the transcriptome matched with germline profiling may lead to the identification of MBC subtypes with possible relevance in the clinical setting, which is a primary step to improve the clinical management of MBC patients.Male breast cancer (MBC) is a rare and understudied disease compared with female BC. About 15% of MBCs are associated with germline mutation in BC susceptibility genes, mainly BRCA1/2 and PALB2. Hereditary MBCs are likely to represent a subgroup of tumors with a peculiar phenotype. Here, we performed a whole transcriptome analysis of MBCs characterized for germline mutations in the most relevant BC susceptibility genes in order to identify molecular subtypes with clinical relevance. A series of 63 MBCs, including 16 BRCA2, 6 BRCA1, 2 PALB2, 1 RAD50, and 1 RAD51D germline-mutated cases, was analyzed by RNA-sequencing. Differential expression and hierarchical clustering analyses were performed. Module signatures associated with central biological processes involved in breast cancer pathogenesis were also examined. Different transcriptome profiles for genes mainly involved in the cell cycle, DNA damage, and DNA repair pathways emerged between MBCs with and without germline mutations. Unsupervised clustering analysis revealed two distinct subgroups, one of which was characterized by a higher expression of immune response genes, high scores of gene-expression signatures suggestive of aggressive behavior, and worse overall survival. Our results suggest that transcriptome matched with germline profiling may be a valuable approach for the identification and characterization of MBC subtypes with possible relevance in the clinical setting.

1506MO Incorporating genetic and non-genetic risk factors in breast cancer risk prediction for healthy women with non-informative genetic test result

Calculating breast cancer (BC) risks is becoming increasingly accurate and important in the care of healthy women with a cancer family history. Clinical recommendations are commonly based on cancer family history and germline mutation status. More recently, risk-modifying single- nucleotide polymorphisms (SNPs) which can be used to calculate polygenic risk score (PRS) as well as non-genetic risk factors (NGRF) have been incorporated into established risk prediction tools. We evaluated the impact of personalized BC risk calculation incorporating PRS and NGRF on clinical recommendations for intensified breast surveillance (IBS), based on the 10-year BC risk with a threshold of ≥5% for IBS indication (German Guideline) and a lifetime risk of ≥20 % (French/Dutch), respectively.

Metabolomics as a Tool for Biomarker Discovery in Gastric Cancer.

Globally, early detection and interception of gastric cancer remains limited by the lack of a broad screening paradigm for individuals with the exception of those at established hereditary risk (e.g., hereditary diffuse gastric cancer or CDH1 germline mutation status). The path forward will likely rely on establishment of biomarkers using multiple -omic approaches to detect molecular profiles associated with gastric cancer risk that can in turn be leveraged to identify individuals who may benefit from more intensive evaluation, such as screening endoscopy. In this issue, Shu and colleagues describe the results of a case-control cohort study of Asian individuals that demonstrates baseline metabolite levels are predictive of future gastric cancer risk above and beyond lifestyle and demographic risk factors. We discuss the promise and limitations of these exemplar circulating biomarkers and emphasize the need for a multifactorial risk assessment to advance precision prevention and early detection of gastric cancer.See related article by Shu et al., p. 1634.

Recommendations for a More Organized and Effective Approach to the Early Detection of Pancreatic Cancer From the PRECEDE (Pancreatic Cancer Early Detection) Consortium

Recommendations for a More Organized and Effective Approach to the Early Detection of Pancreatic Cancer From the PRECEDE (Pancreatic Cancer Early Detection) Consortium

Discoidin Domain Receptor 2 (DDR2) expression in combination with mutation status is predictive of survival in patients with ovarian cancer

<h3>Objectives:</h3> Dicoidin Domain Receptor 2 (DDR2) is a tyrosine kinase receptor which binds the most common extracellular matrix protein, fibrillar collagen type 1. Expression of DDR2 is critical for invasion and migration of ovarian cancer tumor cells. Clinically, high DDR2 expression has been shown to be associated with advanced stage disease and decreased survival. It is not known how <i>BRCA</i> mutation status, a known marker for treatment sensitivity, impacts this relationship between DDR2 expression and survival. This study aimed to determine whether DDR2 expression was correlated with <i>BRCA</i> mutation status and to quantify the effects of this relationship on survival. <h3>Methods:</h3> Immunohistochemical (IHC) analysis of DDR2 expression in two ovarian cancer tissue microarrays (TMA) was performed. DDR2 staining on the membrane of tumor cells was scored microscopically according to the intensity and percentage of cells positive for DDR2 expression compared to controls. High DDR2 staining was defined as >70% and low staining <69%. Clinical information, including germline mutational status and survival data, was abstracted from the electronic medical record. Statistical analysis was performed using descriptive statistics and unpaired t-tests. Survival analysis was performed using the Kaplan-Meier method with statistical significance determined using the log-rank test. <h3>Results:</h3> The cohort included 164 patients diagnosed between 2/1994 and 1/2017. The majority had advanced stage disease (79%) and high-grade serous histology (76%). Germline mutation status was known in 93 patients (57%). <i>BRCA1</i> was the most common mutation in 38 patients (64%) followed by <i>BRCA2</i> in 20 patients (34%). 34 patients had negative germline testing. DDR2 expression was significantly associated with mutational status. Patients without a germline mutation had significantly higher DDR2 expression (64%) compared to <i>BRCA1</i> (37%) (p=0.002) and <i>BRCA2</i> had significantly higher DDR2 expression (55%) compared to <i>BRCA1</i> (37%) (p=0.03). DDR2 expression did not vary by stage, grade or platinum sensitive status. In survival analysis, patients with high DDR2 expression had significantly lower overall survival (33mo vs 83mo, HR 1.94, p=0.002) and progression free survival (17mo vs 34mo, HR 1.668, p=0.04) compared to patients with low DDR2 expression. When survival analysis was stratified by mutation status and DDR2 expression, survival differences were seen. In patients without a germline mutation, high DDR2 expression was associated with worse overall survival (42mo vs 147mo, HR=2.818, p=0.04) compared to low DDR2 expression. <h3>Conclusions:</h3> Tumor DDR2 expression is correlated with mutation status and when combined, provides useful prognostic information. Studies are ongoing to identify additional <i>BRCA</i> deficient tumors for further survival analysis.

Performance characteristics of brief family history questionnaire to screen for Lynch syndrome in women with newly diagnosed ovarian cancers

<h3>Objectives:</h3> Ovarian cancer (OC) is the third most common Lynch syndrome (LS)-associated cancer in women but there is no established screening strategy to identify LS in this population. In centers without access to universal tumor immunohistochemistry (IHC) testing for mismatch repair (MMR) deficiency, family history may identify patients with OC suspected of LS, prompting a referral to genetic counseling. We have previously developed and shown that patient-administered 4-item brief Family History Questionnaire (bFHQ) can effectively identify women with confirmed LS in those with newly diagnosed endometrial cancers. The objective of this study was to assess whether bFHQ can be used as a screening tool to identify women with OC at high risk of LS. <h3>Methods:</h3> Prospective cohort study recruited women with newly diagnosed non-serous/non-mucinous OC from three cancer centers in Ontario, Canada. Participants completed bHFQ, extended Family History Questionnaire (eFHQ; encompassing Amsterdam II criteria, Society of Gynecologic Oncology 20-25% criteria and Ontario Ministry of Health criteria), IHC for MMR proteins and universal germline testing (reference standard) for LS. The sensitivity, specificity, positive and negative predictive values (PPV, NPV) were compared between the family history screening strategies and MMR IHC to identify LS. <h3>Results:</h3> Of 215 women, 169 (79%) were evaluable with both bFHQ and germline mutation status; 12 of these 169 were confirmed to have LS (7%). Median age was 53 years (range 21-71), and for all 12 patients with LS, OC was their sentinel malignancy (100%). Nine of 12 patients (75%) with LS were correctly identified by bFHQ, compared to 6 of 11 (55%) by eFHQ and 11 of 13 (85%) by IHC. The sensitivity, specificity, PPV and NPV values of bFHQ were 75%, 66%, 15% and 98%, compared to 55%, 92%, 35% and 96% for eFHQ and 85%, 90%, 39% and 99% for IHC respectively (Table 1). IHC was the most sensitive and specific approach. The 4-item bFHQ was more sensitive than eFHQ and took less than 10 minutes for each patient to complete. <h3>Conclusions:</h3> Patient-administered bFHQ may serve as an adequate screening tool to triage women with OC for further genetic assessment for LS, especially in centers without access to universal tumor testing for IHC for MMR or microsatellite instability.

PMS2 is the most frequently mutated Lynch syndrome (LS) gene in women with endometrial cancer (EC): what is the role that low penetrance LS genes play in EC?

Objectives: To determine the frequency and spectrum of LS pathogenic variants in EC patients using upfront germline testing for cancer susceptibility. Secondary objectives included determining the sensitivity and specificity of current LS screening. Methods: Women diagnosed with EC were prospectively enrolled at 9 institutions. Clinical germline testing (panel testing for common cancer susceptibility genes) was performed for 840 unselected EC patients between 10/1/2017 and 10/1/2020. Mismatch repair (MMR) IHC, MLH1 methylation status and relevant clinicopathologic data were abstracted from patients’ records. Detailed family history data were obtained for all subjects. Results: Germline testing revealed 26 of 840 EC patients (3.1%) had a pathogenic/likely pathogenic MMR gene mutation. Mutations in PMS2 were most frequent (10/26, 38%), followed by MSH6 (8/26, 31%), MSH2 (6/26, 23%), and MLH1 (2/26, 8%). Mean BMI for PMS2 carriers was greater than other mutation carriers (31.3 vs 27.8). Age at diagnosis was also higher for PMS2 carriers (59 vs 52). IHC combined with MLH1 methylation correctly predicted LS for all MLH1 and MSH2 mutation carriers. For MSH6 and PMS2, IHC and germline mutation status concordance was lower. Only 4/9 (44%) PMS2 carriers had isolated PMS2 loss. IHC was not completed for one PMS2 carrier (insufficient tumor). IHC correctly predicted MSH6 mutations in 7/8 (88%) carriers. Family history did not predict LS for PMS2 carriers: using PREMM5 (LS prediction model), all had low ( Conclusions: This is the largest cohort of prospectively enrolled EC patients to undergo germline genetic testing in an unselected manner, irrespective of patient age, family history or tumor results. It shows that a majority of LS mutations in EC are in the low-penetrance genes, MSH6 and PMS2. PMS2 mutations were the most common, 10/840 (1.2%). Universal screening with IHC would have missed three PMS2 carriers and one MSH6 carrier. Accurate identification of patients with MMR defects is critical not only for identification of LS, but potentially in consideration of treatment options. In the past, ascertainment of LS relied largely on a strong family cancer history, which is most often seen with MLH1 and MSH2 mutations. For all PMS2 carriers in our study, family history was not predictive of LS and the proband's EC diagnosis was the sentinel event leading to a LS diagnosis in the family. Our study may highlight an evolving LS phenotype in which gene/environment interactions are changing. The observation that EC patients with PMS2 mutations have higher BMIs leads us to hypothesize the existence of an obesity-mediated pathway important in PMS2-associated EC. It may be that in the general population, PMS2 mutation carriers face higher risks for EC than colon cancer.

Performance characteristics of brief family history questionnaire to screen for Lynch syndrome in women with newly diagnosed ovarian cancers.

e22525 Background: Ovarian cancer (OC) is the third most common Lynch syndrome (LS)-associated cancer in women but there is no established screening strategy to identify LS in this population. An adequate family history may identify patients suspected of LS, prompting a referral to genetic assessment. We have previously validated the 4-item brief Family History Questionnaire (bFHQ) in endometrial cancers. The objective of this study was to assess whether bFHQ can be used as a screening tool to identify women with OC at risk of LS. Methods: Prospective cohort study recruited women with newly diagnosed non-serous/non-mucinous OC from three cancer centers in Ontario, Canada. Participants completed bHFQ, extended Family History Questionnaire (eFHQ; encompassing Amsterdam II criteria, Society of Gynecologic Oncology 20-25% criteria and Ontario Ministry of Health criteria), immunohistochemistry (IHC) for mismatch repair (MMR) proteins and universal germline testing for LS. The performance characteristics were compared between bFHQ, eFHQ, and IHC. Results: Of 215 participants, 169 (79%) were evaluable with both bFHQ and germline mutation status; 12 of these 169 were confirmed to have LS (7%). Nine of 12 patients (75%) with LS were correctly identified by bFHQ, compared to 6 of 11 (55%) by eFHQ and 11 of 13 (85%) by IHC. The sensitivity, specificity, positive predictive values and negative predictive values of bFHQ were 75%, 66%, 15% and 98%, compared to 55%, 92%, 35% and 96% for eFHQ and 85%, 90%, 39% and 99% for IHC respectively. IHC was the most sensitive and specific approach. The 4-item bFHQ was more sensitive than eFHQ and took less than 10 minutes for each patient to complete. Conclusions: Patient-administered bFHQ may serve as an adequate screening tool to triage women with OC for further genetic assessment for LS, especially in centers without access to universal tumor testing for IHC for MMR.[Table: see text]

Real-life data of niraparib maintenance treatment in patients with recurrent platinum-sensitive ovarian cancer.

5560 Background: PARP (poly adenosine diphosphate [ADP]–ribose polymerase) inhibitors are the new standard for maintenance treatment in platinum sensitive recurrent ovarian cancer (PSROC), independent of germline (g-BRCA) or somatic BRCA mutation status. Real-life data after the introduction of new anti-neoplastic agents are needed to evaluate whether the benefit observed in phase III trials can be translated into clinical practice. The aim of this study was to provide real-life data on efficacy and safety of niraparib in non-gBRCA PSROC. Methods: This retrospective multi-center cohort study included patients with PSROC who were enrolled in a national individual patient access program in Norway. Efficacy and safety data were collected from the patients´ electronic medical records. The primary outcome was time from start of niraparib treatment to first subsequent treatment (TFST). Secondary endpoints included prevalence of dose interruption and -reduction, as well as adverse events. Results: The study included 106 patients with median age of 64 years (range 38-81). After median follow up of 15.3 months (95% CI 12.1-18.5), 71 patients (67%) had progressed, 64 (60%) had started a new line of treatment, and 25 (24%) had died. 25 (24%) patients were still receiving niraparib. Median duration of niraparib treatment was 7.6 months (0.4 to 27.3 months). Median TFST was 11.7 months (95% CI 9.2 -14.2). Patients with elevated CA125 after chemotherapy prior to start of niraparib had shorter progression-free survival (PFS) compared to patients with complete serological response (6.5 months (95% CI 5.7 – 7.3) vs 12 months (95% CI 6.2 – 17.9, (p &lt; 0.001)). Grade 3-4 hematologic and non-hematologic events occurred in 25% and 17% of the patients, respectively. The most common grade 3/4 hematologic events were anemia (15%), thrombocytopenia (11%) and neutropenia (8%). Adverse events led to dose interruption in 38% and dose reduction in 44% of the patients. Patients with individualized dosing based on baseline weight and platelet counts had fewer dose reductions (p &lt; 0.001) and -interruptions (p = 0.042) than patients whose dose was not adjusted to those baseline values. Conclusions: In a real-life setting, niraparib maintenance treatment in patients with non-gBRCA PSROC showed efficacy comparable with the published phase III data and an acceptable safety profile. Individualized dosing at start of treatment minimized adverse events. The prolonged PFS in patients with CA125 normalization after last chemotherapy, suggests that these patients in particular benefit from maintenance treatment but warrants confirmation in a larger sample.[Table: see text]

The correlation between BRCA status and surgical cytoreduction in high-grade serous ovarian carcinoma.

5543 Background: High grade serous ovarian cancers (HGSC) with BRCA mutation are biologically unique, with distinct molecular and clinical behaviour from sporadic cases. It is unclear if these biological differences translate to favorable outcomes at the time of primary cytoreductive surgery (PCS). The aim of this study is to compare the amount of residual disease following PCS in BRCA-mutated (BRCAm) and wildtype (BRCAwt) HGSC, and to assess whether BRCA status is an independent predictor of residual disease. Methods: We conducted a retrospective analysis of patients with HGSC with known germline and somatic BRCA mutation status, treated with PCS from 2000 to 2017. We compared the cytoreduction outcomes between the BRCAm and the BRCAwt cohorts and built a predictive model to assess whether BRCA status was associated with amount of residual disease at the time of PCS. Results: Of 355 women, 144 harbored germline or somatic BRCA mutations (41%) and 211 were BRCAwt (59%). BRCAm women tended to be younger (54 vs. 59; p &lt; 0.001), but there were no differences between the two groups in stage, disease burden at presentation, surgical complexity score, length of surgery, or perioperative complications. The BRCAm group had a higher rate of complete cytoreduction to no residual disease (0mm) [75% vs. 54%], and a lower rate of optimal cytoreduction (1-9mm) [16% vs. 34%] or suboptimal cytoreduction (≥10mm) [9% vs. 12%] (p &lt; 0.001). In our predictive model, after accounting for length of surgery, CA-125 level, stage, disease scores and surgical complexity scores, BRCAm status was predictive of complete cytoreduction to 0mm residual disease (OR 4.78; 95% CI 2.32-9.85; p &lt; 0.001). Conclusions: BRCA status is predictive of complete cytoreduction at time of PCS in HGSC. Timely availability of BRCA testing is paramount as it may aid in the therapeutic decision making between PCS or neoadjuvant chemotherapy in women with newly diagnosed HGSC.

Neoadjuvant talazoparib (TALA) in patients (pts) with germline BRCA1/2 (gBRCA1/2) mutation-positive, early HER2-negative breast cancer (BC): Exploration of tumor BRCA mutational status and zygosity and overall mutational landscape in a phase 2 study.

554 Background: TALA is a poly(ADP-ribose) polymerase inhibitor approved as monotherapy for adult pts with g BRCA1/2-mutated HER2-negative locally advanced/metastatic BC. We report biomarker analyses from a phase 2, nonrandomized, single-arm, open-label study (NEOTALA; NCT03499353) evaluating the efficacy and safety of TALA in the neoadjuvant setting for pts with early g BRCA1/2-mutated HER2− BC. Efficacy and safety results are presented separately. Methods: The biomarker analysis population was all pts treated with TALA for whom biomarker results are available. To support molecular eligibility, blood was tested using BRCAnalysis CDx (Myriad Genetics). Baseline tumor tissue was retrospectively tested using FoundationOne CDx, with BRCA1/2 zygosity assessed using somatic-germline-zygosity (SGZ; Sun et al. JCO PO, 2018). Germline mutational status of 14 non- BRCA DNA damage response (DDR) genes was retrospectively assessed in baseline saliva samples using Ambry CustomNext-Cancer. Mutations were defined as known/likely pathogenic/deleterious variants, including copy number alterations (CNAs). Association between mutational status of MYC or RAD21 and primary endpoint pathological complete response (pCR) as per Independent Central Review was investigated with logistic regression. Results: Of 52 evaluable tumor samples from 61 treated pts, 39 (75%) and 13 (25%) pts exhibited BRCA1 and BRCA2 mutations, respectively; 1 (2%) pt exhibited mutations in both genes, and 1 (2%) pt had mutations in neither. BRCA loss of heterozygosity (LOH) was seen in 42/43 (98%) evaluable BRCA-mutant tumors. Of 45 pts evaluable centrally for both germline and tumor, 44/45 (98%) pts exhibited the same BRCA mutation in tumor as originally detected in germline, with the remaining pt exhibiting a g BRCA1 mutation, but lacking a tumor BRCA mutation. None of 49 saliva-evaluable pts exhibited non- BRCA germline DDR mutations. TP53 (51 [98%] pts) was the most frequently mutated gene in tumors. MYC and RAD21 (each 14 [27%] pts) were the most frequent CNAs. No evidence of association between mutational status of MYC or RAD21 and pCR was found (odds ratio=0.39, 95% CI 0.12-2.30). Based on a cutoff of ≥16%, genomic LOH was elevated in 24/27 (89%) tumors evaluable for both gLOH and pCR, precluding assessment of the potential association of gLOH high/low status with pCR. Conclusions: Tumor BRCA mutations were evident in nearly all pts in the biomarker analysis population, with BRCA LOH evident in all but 1 BRCA-mutated tumor. No pts had non- BRCA germline DDR gene mutations; tumor TP53 mutations were near-universal. MYC and RAD21 each exhibited CNAs in 27% of tumors, with no association with pCR. These results support the central role of BRCA mutations in tumor pathobiology in this indication. Clinical trial information: NCT03499353.

Characterization and Clinical Outcomes of DNA Mismatch Repair-deficient Small Bowel Adenocarcinoma.

The prevalence and clinical characteristics of small bowel adenocarcinomas (SBA) in the setting of Lynch syndrome have not been well studied. We characterized SBA according to DNA mismatch repair and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes. A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via IHC staining. Germline DNA was analyzed for mutations in known cancer predisposition genes, including MMR (MLH1, MSH2, MSH6, PMS2, and EPCAM). Clinical variables were correlated with MMR/MSI status. Twenty-six percent (26/100; 95% confidence interval, 18.4-35.4) of SBAs exhibited MMR deficiency (MMR-D). Lynch syndrome prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-Lynch syndrome MMR-D versus MMR-proficient (MMR-P) SBAs (65 vs. 61; P = 0.75), but significantly younger in Lynch syndrome (47.5 vs. 61; P = 0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P versus 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in Lynch syndrome (P = 0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared with 23.1% (6/26) in the MMR-D group (P = 0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared with 18.2% (2/11) in the MMR-D group (P = 0.0002). When compared with MMR-P SBA, MMR-D SBA was associated with earlier stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline Lynch syndrome testing in MMR-D SBA is warranted.

Abstract PS13-10: Impact of BRCA mutation status on immune infiltration, chemosensitivity, and prognosis of breast cancer patients treated with neoadjuvant chemotherapy

Abstract Context: The majority of BRCA mutation carriers diagnosed with breast cancer (BC) are treated with chemotherapy. The effectiveness of standard neoadjuvant chemotherapy (NAC) in BRCA associated BC compared to noncarriers has been poorly explored. Objectives: To assess whether the BRCA mutation status modifies the immune infiltration, chemosensitivity, and prognosis of breast cancer. Methods: We retrospectively identified in our institutional database all consecutive patients with BRCA germline mutation status available treated with NAC between 2002 and 2012. Microbiopsy specimens and paired surgical samples were evaluated for pre-NAC and post-NAC immune infiltration (stromal TILs, str TILs; intratumoral TILs, IT TILs). Response to chemotherapy was assessed by pathological complete response (pCR) rates. Association of clinical and pathological factors with pCR, overall survival (OS), and relapse free survival (RFS) was assessed by univariate and multivariate analyses. Results: Overall, 267 patients were included in this study (46 BRCA carriers and 221 BRCA noncarriers). The median age at BC diagnosis was 40 years old, and most of the patients (n=227, 85%) were premenopausal. Patients repartition by subtype was as follows: luminal (n=90, 33.7%), TNBC (n=110, 41.2%), HER2-positive (n=67, 25.1%). BRCA mutation carriers were likely to have familial history of BC (73.9% vs. 52.3%, p = 0.012), and be diagnosed with TNBC (58.7% vs 37.6%; p = 0.006), than noncarriers. No pattern was significantly different between BRCA mutation subgroups regarding age, body mass index, histology, tumor size, grade or Ki67. TIL levels were available in 192 patients. Neither pre-NAC stromal TIL levels nor IT TILs were significantly different by BRCA status in the whole population, nor in each BC subtype. PCR rates were significantly higher in BRCA mutation carriers (p= 0.035), and this association remained statistically significant only in the luminal BC subtype (p=0.006) after stratification by BC subtype (Pinteraction= 0.056). After multivariate analysis, only BC subtype and pre-NAC str TILs were independent predictors of pCR. Post-NAC stromal and intra-tumoral TIL levels were significantly higher luminal subtype (p=0.009 and p=0.019, respectively). After a median follow-up of 90 months, RFS and OS were not different between BRCA carriers and noncarriers, neither in the whole population nor after stratification by BC subtype. Discussion: In our study, BRCA status was associated with an enhanced response to standard NAC, particularly in luminal BC patients, in addition to higher post-NAC TIL levels. Whether patients with luminal BC and BRCA mutation derive benefit from second line immunotherapy after NAC completion remains to determine. Citation Format: Beatriz Grandal, Clémence Evrevin, Eric Daoud, Elise Dumas, Nadir Sella, Clara Sebbag, Sonia Rozette, Isabelle Jardin, Lucie Laot, Florence Coussy, Claire Saule, Dominique Stoppa-Lyonnet, Sophie Franck, Claire Sénéchal, Enora Laas, Marick Lae, Diane De Croze, Fabien Reyal, Anne-Sophie Hamy. Impact of BRCA mutation status on immune infiltration, chemosensitivity, and prognosis of breast cancer patients treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-10.