ctDNA pathogenic variants (PVs) in homologous recombination repair (HRR) genes in patients with metastatic CRPC.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 138-138
Author(s):  
Ellen Jaeger ◽  
Elisa Marie Ledet ◽  
Marcus W. Moses ◽  
Charlotte Manogue ◽  
Brian E. Lewis ◽  
...  
Keyword(s):  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Cancer Center ◽  
Small Subset ◽  
Published Data ◽  
Pathogenic Variants ◽  
Recombination Repair ◽  
Brca1 Brca2 ◽  
Allelic Fraction ◽  
Germline Testing

138 Background: HRR PVs can serve as predictive biomarkers and two PARP inhibitors are approved for metastasic CRPC (mCRPC) pts. Published data are predominantly focused on tissue-based assays, but obtaining tissue from mCRPC pts is problematic. In a large tissue based series (PROfound), 4047 mCRPC pts had tumor samples submitted for genomic testing but only 69% had interpretable results. No data were published from PROfound enumerating pts without available tissue to submit. Herein we assess frequency of PVs from selected HRR genes using a ctDNA assay. Methods: 292 mCRPC pts at Tulane Cancer Center were assessed for detectable HRR ctDNA changes using the Guardant 360 assay (which assesses the HRR genes BRCA1, BRCA2, and ATM). Results: 20/292 (6.8%) pts had a PV in ATM. However only 4/292 (1.4%) had > 1% mutant allelic fraction. Germline testing occurred in 18/20 of the ctDNA ATM PV pts and 0/18 had a germline PV. The PROfound series had 6.3% somatic PVs in ATM. 18/292 pts (6.2%) had a PV in BRCA2 and 12/292 (4.1%) had a mutant allelic fraction of > 1%. Germline testing was performed in 17/18 with BRCA2 ctDNA PVs and 9/17 had germline PVs. The PROfound series had 9.7% somatic BRCA2 PVs. BRCA1 PVs were detected in 6/292 (2.1%) pts and 3/292 (1%) had a mutant allelic fraction > 1%. 6/6 of the ctDNA PVs has germline testing and 1/6 had a BRCA1 PV. The PROfound series had 1.3% somatic PVs in BRCA1. Conclusions: Using ctDNA essay, it is feasible to measure PVs in only a small subset of HRR genes in mCRPC pts. These assays fail to detect deep deletions, a known and important mechanism of HRR gene loss. The ctDNA mutant allelic fractions are often low. The ability of ctDNA PVs using this assay to predict treatment effects are unknown.

Germline BRCA1/2, PALB2, and ATM mutations in 3,030 patients with pancreatic adenocarcinoma: Survival analysis of carriers and noncarriers.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 280-280
Author(s):  
Pashtoon Murtaza Kasi ◽  
Fergus Couch ◽  
William R Bamlet ◽  
Chunling Hu ◽  
Steven Hart ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Pancreatic Adenocarcinoma ◽  
Final Analysis ◽  
Parp Inhibitors ◽  
P Value ◽  
Pathogenic Variants ◽  
Kaplan Meier ◽  
Hazard Ratios ◽  
Before And After ◽  
Brca1 Brca2

280 Background: Patients with pancreatic adenocarcinoma (PDAC) can have mutations in breast cancer associated genes ( BRCA1/2) and other homologous recombination (HR) pathway genes. The therapeutic significance of these mutations for PDAC patients is not yet established. We performed a comprehensive survival analysis of 3,030 unselected PDAC patients comparing non-carriers and carriers of BRCA1/2, PALB2, and ATM mutations. Methods: We analyzed germline DNA samples and outcomes from confirmed PDAC patients recruited from 1999-2014 into the Mayo Clinic SPORE in Pancreatic Cancer registry. A total of 3,046 genomic DNA samples were analyzed by next generation sequencing. All pathogenic variants were validated by Sanger sequencing. Survival analysis of PDAC patients with and without BRCA1, BRCA2, PALB2, or ATM germline mutations was performed using the Kaplan-Meier method and log-rank tests. Hazard ratios (HR) were calculated using Cox proportional hazard modeling adjusted for co-variates including age, sex, and stage. A p-value < 0.05 was considered statistically significant. Pre- and post-FOLFIRINOX eras were defined as before and after June 1, 2011. Results: A total of 139 (4.6%) patients were noted to have deleterious mutations in BRCA1, BRCA2, PALB2, or ATM genes. After exclusion of patients with missing data, final analysis was restricted to 2,452 PDAC patients. Overall survival was slightly better (14.2 months versus 11.3 months) in patients with mutations as compared to those without mutations, although this finding was not statistically significant (p = 0.07). When stratified by FOLFIRINOX era, 40 patients with these mutations in the post-FOLFIRINOX era had better outcomes than 668 non-carriers (adjusted HR 0.62; 95% CI 0.43-0.89; p = 0.0062). Conclusions: Deleterious germline BRCA1/2, PALB2, and ATM mutations were seen in approximately 5% of patients with PDAC. Post-FOLFIRINOX era patients with these mutations had improved outcomes, possibly secondary to exposure to DNA-damaging chemotherapies. Germline screening of PDAC patients and development of trials incorporating this information (e.g., PARP inhibitors) has potential value for PDAC patients.

Prospective assessment for pathogenic germline alterations (PGA) in pancreas cancer (PAC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4102-4102 ◽  
Author(s):  
Emmet Jordan ◽  
Maeve Aine Lowery ◽  
Winston Wong ◽  
Yelena Kemel ◽  
Semanti Mukherjee ◽  
...  
Keyword(s):  
Cancer Predisposition ◽  
Small Subset ◽  
Ashkenazi Jewish ◽  
Time To Progression ◽  
Degree Relative ◽  
Brca Mutations ◽  
Pathogenic Variants ◽  
The Us ◽  
Prospective Assessment ◽  
Germline Testing

4102 Background: Cancer predisposition syndromes are identified in a subset of PAC. Identifying PGA has implications for therapy as well as for cancer predisposition in blood relatives. Germline testing (GT) in the US is currently performed in a small subset of PAC patients according to NCCN/other guidelines. At MSKCC, we have implemented an ‘opt in’ strategy to perform germline testing in all patients evaluated in PAC clinics at MSKCC. Methods: PAC pts consented prospectively for GT had samples analyzed for pathogenic or likely pathogenic variants using the MSK-IMPACT germline platform (NCT01775072). All pts first had somatic profiling of tumor samples for > 340 genes by MSK-IMPACT. Clinicopathological features, time to progression on platinum (TTPP) and overall survival (OS) were collated. Results: N = 305 PAC pts consented for GT between 9/2015-11/2016.164/305 (54%) were male, 70/305 (23%) were Ashkenazi Jewish. 242 pts (79%) had a family hx of cancer. 67/305 (22%) had a GA identified, 45/67 (67%) were stage III/IV at dx. Median age at PAC dx for all GA carriers was 60 years (y) (range 29-81) compared to 66 y (18-69) without GA. Median age at dx was 54 y (32-68) for BRCA1 and 61 y (37-77) for BRCA2 GA. 3/9 and 3/20 pts with BRCA1/2 GA had a PAC dx < 50 y. 2/63 pts (3%) with no family hx had a GA (CDKN2A, PMS2). N = 5/22 pts (23%) with a 1st degree relative (DR) with PAC had a GA. N = 13/45 pts (29%) had a GA with either a 1st or 2nd DR with PAC. 19/84 pts (23%) with ≥2 1stDR with cancer had a GA detected. For median OS and TTP on platinum therapy, see Table. Pts with BRCA1/2, ATM and those with coexisting GA tended to have a better median OS as well as longer TTP on platinum therapy (Table). Conclusions: GA’s are significantly under identified in PAC using current practices with a high, frequency (22%) observed in this relatively unselected cohort. BRCA mutations are the most frequent GA noted. There are significant implications of these observations for therapy and for blood relatives. [Table: see text]

Characteristics of colorectal cancer (CRC) patients with BRCA1 and BRCA2 mutations.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 606-606 ◽  
Author(s):  
Madiha Naseem ◽  
Joanne Xiu ◽  
Mohamed E. Salem ◽  
Richard M. Goldberg ◽  
Ari M. Vanderwalde ◽  
...  
Keyword(s):  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Brca1 And Brca2 ◽  
Chi Square ◽  
Statistical Correlations ◽  
Pathogenic Variants ◽  
Tumor Mutational Burden ◽  
Brca2 Mutations ◽  
Brca1 And Brca2 Mutations ◽  
Next Generation Sequencing Ngs

606 Background: Between 3-5% of CRC patients have BRCA1/2 pathogenic mutations. This study aims to identify associations between BRCA1 and BRCA2 mutations and clinical characteristics in CRC. Methods: A total of 6396 CRC tumor samples were tested with Next-Generation Sequencing (NGS) on a 592-gene panel, pathogenic or presumed pathogenic variants were counted as mutations (mt). Microsatellite instability (MSI) and tumor mutational burden (TMB) were tested by NGS. Statistical correlations were investigated using ANOVA, Chi-square and t-test. Results: Among tumors sampled, 53% derived from male patients and median age was 60 years. BRCA1 mt were detected in 1.1% (n = 72) of tumors, while BRCA2 in 2.8% (n = 179). BRCA1 mt were more frequent in women (W;65%) than men (M;35%) (p = 0.0019) while no relationship with sex was seen for BRCA2 mt (42% F vs. 58% M). No significant associations with age were noticed. Majority of pathogenic mt in BRCA1 (52%; n = 34) and BRCA2 (62%; n = 103) occurred in MSI-High (MSI-H) cases. MSI-H pts had more frameshift mt in both BRCA1/2 than MSS pts. MSS cases had lower rates of BRCA1 and 2 pathogenic mt (44% and 37%, respectively). Right-sided tumors were significantly associated with BRCA1 (p = 0.0056) and BRCA2 (p < 0.0001) mt in MSI-H cases only. BRCA1/2 mt were associated with higher TMB in all CRCs, including MSI-H and MSS cases (p < 0.001). POLE mt (n = 31) were associated with higher BRCA1/2 mt rates (9.6%, 55% respectively). Among MSS cases with POLE wild-type status, BRCA1 (p = 0.0269) and BRCA2 (p = 0.0151) mt were associated with high TMB and combining both BRCA1/2 mutations led to an even higher TMB (3.6%; p = 0.001). Conclusions: This is the first study to show that BRCA1/2 mutations are more frequent in MSI-H, and independently associated with higher TMB, pathogenic POLE mutations, and right-sided tumors in MSI-H CRCs. Given their relationship with TMB, the presence of BRCA1/2 mutations may be potential predictive biomarkers for checkpoint or PARP inhibitors in CRC, a finding that should be prospectively evaluated.

Somatic alterations in a seven-gene DDR gene panel predicts platinum sensitivity in advanced prostate cancer patients.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 283-283
Author(s):  
Panagiotis J. Vlachostergios ◽  
Jyothi Manohar ◽  
Muhammad Junaid Niaz ◽  
Aileen Lee ◽  
Amy Hackett ◽  
...  
Keyword(s):  
Single Gene ◽  
Brca2 Gene ◽  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Kaplan Meier ◽  
Platinum Based Chemotherapy ◽  
Somatic Alterations ◽  
Brca1 Brca2 ◽  
Tissue Specimens ◽  
The Impact

283 Background: Genomic alterations in the DNA damage response and repair (DDR) pathways are common in advanced PC. Platinum compounds are active in CRPC pts. DDR-defective PC tumors have increased sensitivity to PARP inhibitors (PARPi); the mechanisms involved in sensitivity to platinum and PARPi may be similar but not identical. This study aimed to assess the impact of somatic DDR alterations on clinical outcome of platinum-treated patients with advanced PC. Methods: We reviewed records of advanced PC patients, who received platinum-based chemotherapy with available tumor tissue specimens. We used next generation sequencing (whole exome or targeted) to assess for mutations and copy number alterations in a selected panel of DDR genes, including BRCA1, BRCA2, ATM, ERCC3, ERCC5, TP53 and RB1. We used Kaplan Meier curves to predict PFS and OS after initiation of platinum chemotherapy. Results: Our cohort included 50 men, median age 69.5 years (45-91), median PSA 0.81 (0.008-2291.25), median LDH 264 (109-6714). 39 had visceral metastases (38 liver, 15 lung, 2 adrenal, 2 peritoneal, 1 brain). The majority or pts (33/50) received carboplatin, 17 received cisplatin (2 subsequently also received carbo with initial platinum used for data analysis). Most pts received chemotherapy doublets, and platinum was most frequently combined with etoposide (N=27) and paclitaxel (N=9). 39 pts had tumors harboring at least one DDR alteration. Somatic deletions in BRCA2 gene (N=18) were associated with a significantly longer PFS compared to men with wild-type BRCA2 (median PFS: 6 versus 3 months, P=0.019). No significant associations were identified between somatic DDR alterations and OS. Presence of ≥2 concomitant DDR somatic alterations predicted a favorable PFS compared to single-gene alterations or lack thereof (6 vs 3 months, P=0.006). Conclusions: Our study suggests that presence of ≥2 concomitant DDR somatic alterations from a 7-gene DDR panel, including BRCA1, BRCA2, ATM, ERCC3, ERCC5, TP53, and RB1, may predict longer PFS in pts with advanced PC treated with platinum-based chemotherapy. Further studies are needed to clinically qualify multiplex predictive biomarkers of DDR-defective PCs.

scholarly journals Considerations on the identification and management of metastatic prostate cancer patients with DNA repair gene alterations in the Canadian context

2021 ◽  
Vol 16 (4) ◽  
Author(s):  
Michael P. Kolinsky ◽  
Karen Y. Niederhoffer ◽  
Edmond M. Kwan ◽  
Sebastien J. Hotte ◽  
Zineb Hamilou ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Testing ◽  
Patient Population ◽  
Metastatic Prostate Cancer ◽  
Parp Inhibitors ◽  
Circulating Tumor Dna ◽  
Brca1 Brca2 ◽  
Tumor Dna ◽  
Germline Testing ◽  
Gene Alterations

Olaparib is the first Health Canada-approved agent in metastatic prostate cancer to use a companion diagnostic to identify alterations in BRCA1, BRCA2, or ATM. As olaparib is introduced, clinicians must learn to access and interpret germline and somatic next-generation sequencing (NGS) results, and how to manage affected patients who appear to have distinct clinical features. The traditional model of referring patients to a hereditary cancer clinic (HCC) for germline testing is likely impractical in this disease, as the metastatic prostate cancer patient population would be overwhelming. Alternate approaches to this are clinician-ordered genetic testing (so-called “mainstreaming”), out-of-pocket payment for third-party private company genetic testing, or germline testing done in conjunction with somatic testing, particularly cell free circulating tumor DNA (ctDNA). Germline testing alone is not sufficient for identifying Olaparib-eligible patients, as less than half of BRCA1, BRCA2, or ATM alterations are germline in origin, but it is critically important to identify family members who are carriers so that risk-reduction measures can be undertaken. Somatic testing is not widely available in Canada, but some patients can access it through research protocols or by paying out-of-pocket. Somatic testing can be performed on archival or fresh solid tissue biopsy samples, or through whole blood samples to access plasma-derived circulating tumor DNA (ctDNA). Both testing approaches have relative advantages and disadvantages, but neither may be informative in all patients and, therefore, ideal somatic NGS pathways should provide options for both tissue and ctDNA testing. We advocate that clinicians begin discussions with their provincial lab formularies, HCC, and molecular pathology labs to highlight the importance of germline and somatic testing in this population and identify pathways for patient access. While olaparib has approval for use in BRCA1, BRCA2, and ATM-altered mCRPC, emerging evidence suggests that PARP inhibitors have variable activity in these three genes, with BRCA2 alterations appearing to be the most responsive. Retrospective and prospective series have reported varying outcomes to standard of care therapies, such as ARATs and taxane-based chemotherapy, in metastatic castration-resistant prostate cancer (mCRPC) patients with DNA damage repair (DDR) gene alterations, such as BRCA2. In the absence of high-level evidence showing a lack of benefit, we believe this patient population should still be considered for these treatments. In addition, platinum-based chemotherapy appears to have activity in DDR gene-altered mCRPC and should be considered another option when access to olaparib is not possible. At present, there is no evidence to support an optimal treatment sequence in this patient population, therefore, physician and patient preferences will need to be taken into consideration when selecting therapies. As olaparib and other PARP inhibitors are tested in different disease states and in combination with other therapies, we will likely see a more refined approach to use of these agents and management of this new biomarker-defined patient population.

scholarly journals Evaluation of Germline Genetic Testing Criteria in a Hospital-Based Series of Women With Breast Cancer

2020 ◽  
Vol 38 (13) ◽  
pp. 1409-1418 ◽  
Author(s):  
Siddhartha Yadav ◽  
Chunling Hu ◽  
Steven N. Hart ◽  
Nicholas Boddicker ◽  
Eric C. Polley ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Cancer Center ◽  
Brca1 And Brca2 ◽  
Breast Cancer Predisposition ◽  
Pathogenic Variants ◽  
Predisposition Genes ◽  
American Society ◽  
Brca1 Brca2 ◽  
Testing Criteria

PURPOSE To determine the sensitivity and specificity of genetic testing criteria for the detection of germline pathogenic variants in women with breast cancer. MATERIALS AND METHODS Women with breast cancer enrolled in a breast cancer registry at a tertiary cancer center between 2000 and 2016 were evaluated for germline pathogenic variants in 9 breast cancer predisposition genes ( ATM , BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53). The performance of the National Comprehensive Cancer Network (NCCN) hereditary cancer testing criteria was evaluated relative to testing of all women as recommended by the American Society of Breast Surgeons. RESULTS Of 3,907 women, 1,872 (47.9%) meeting NCCN criteria were more likely to carry a pathogenic variant in 9 predisposition genes compared with women not meeting criteria (9.0% v 3.5%; P < .001). Of those not meeting criteria (n = 2,035), 14 (0.7%) had pathogenic variants in BRCA1 or BRCA2. The sensitivity of NCCN criteria was 70% for 9 predisposition genes and 87% for BRCA1 and BRCA2, with a specificity of 53%. Expansion of the NCCN criteria to include all women diagnosed with breast cancer at ≤ 65 years of age achieved > 90% sensitivity for the 9 predisposition genes and > 98% sensitivity for BRCA1 and BRCA2. CONCLUSION A substantial proportion of women with breast cancer carrying germline pathogenic variants in predisposition genes do not qualify for testing by NCCN criteria. Expansion of NCCN criteria to include all women diagnosed at ≤ 65 years of age improves the sensitivity of the selection criteria without requiring testing of all women with breast cancer.

Indirect treatment comparison of the efficacy of olaparib 300 mg tablets BID and cabazitaxel 25 mg/m2 every 3 weeks plus daily prednisolone and granulocyte colony-stimulating factor in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5051-5051
Author(s):  
Tim Reason ◽  
Charles McCrea ◽  
Robert Hettle ◽  
Sameer Ghate ◽  
Christian Heinrich Poehlein ◽  
...  
Keyword(s):  
Fixed Effects ◽  
Published Data ◽  
Castration Resistant Prostate Cancer ◽  
Indirect Treatment Comparison ◽  
Treatment Comparison ◽  
Hazard Ratios ◽  
Alternative Treatment Option ◽  
Recombination Repair ◽  
Indirect Treatment ◽  
Brca1 Brca2

5051 Background: In PROfound, olaparib demonstrated improved radiological PFS (rPFS) and overall survival (OS) versus new hormonal agent (NHA) in patients with homologous recombination repair mutated (HRRm) mCRPC that had progressed on prior NHA. This efficacy was observed across prespecified subgroups including patients treated with prior taxane therapy and for whom intravenous cabazitaxel is an alternative treatment option. The relative efficacy of olaparib versus cabazitaxel has not been assessed in head-to-head studies. An indirect treatment comparison (ITC) was performed to simulate the comparative efficacy of olaparib and cabazitaxel in patients with HRRm mCRPC after prior taxane and NHA. Methods: Fixed-effects frequentist ITCs were conducted using efficacy data from the prior taxane subgroup of PROfound (NCT02987543) and published data from the Phase IV CARD study of cabazitaxel versus NHA after prior NHA and taxane treatment (NCT02485691). Baseline variables feasible for comparison across studies were assessed for effect modification. Efficacy analyses were performed on the hazard ratios (HR) of rPFS by independent central review and OS. The OS analysis was performed using the final PROfound OS results, which included switching from NHA to olaparib after progression, and using results that were adjusted for switching. In the absence of biomarker subgroup data, the efficacy results of the overall population in CARD were assumed generalizable to the HRRm biomarker population of PROfound, such that mutation status is not a modifier of relative treatment effect for cabazitaxel versus NHA. Results were presented for the comparison of olaparib with cabazitaxel in the BRCA1-/BRCA2-mutated (BRCAm) and BRCAm/ATM populations. Results: The ITC HR for rPFS was 0.36 (95% confidence interval 0.20–0.64) in BRCAm and 0.51 (0.31–0.84) for the BRCAm/ATM population. Without adjustment for switching in PROfound, the ITC HRs for OS in the BRCAm population and BRCAm/ATM population were 0.99 (0.55–1.78) and 0.88 (0.52–1.47), respectively; after switch adjustment, the OS HRs were 0.47 (0.12–1.79) and 0.44 (0.17–1.10), respectively. Conclusions: The ITC results suggest that olaparib is associated with significantly improved rPFS versus cabazitaxel in the treatment of BRCAm and BRCAm/ATM patients who have progressed on taxane and NHA therapy. After removing the effect of switching from NHA to olaparib in PROfound, olaparib appears associated with a non-significant OS improvement versus cabazitaxel in both populations. The results require confirmation in comparative studies. Analysis limitations include uncertainty over the efficacy of cabazitaxel versus NHA in HRRm mCRPC patients, and heterogeneity in prior taxane and NHA therapy. Clinical trial information: NCT02987543.

Genomic characterization of ATM alterations in advanced pancreatic ductal adenocarcinoma (PDAC).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 396-396
Author(s):  
Sheron Perera ◽  
Robert Edward Denroche ◽  
Spring Holter ◽  
Deirdre Kelly ◽  
Amy Zhang ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Large Scale ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Parp Inhibitors ◽  
Ductal Adenocarcinoma ◽  
Parp Inhibition ◽  
Germline Variants ◽  
Pathogenic Variants

396 Background: BRCA1/2 and PALB2 are genes critical to the faithful repair of double strand breaks through the homologous recombination repair (HRR) pathway. Alterations in these genes serve as predictive biomarkers to both platinum and PARP inhibitors. Ataxia-telangiectasia mutated ( ATM) is also indirectly involved in HRR; however, its role as a predictive biomarker to DNA damage response agents is debated. Herein we evaluated the genomic characteristics and clinical outcomes of patients with ATM alterations on the Comprehensive Molecular Characterization of Advanced Ductal Pancreas Adenocarcinoma for Better Treatment Selection (COMPASS) trial. Methods: Patients on this study undergo a biopsy for whole genome sequencing (WGS) and RNA sequencing prior to chemotherapy; those with germline variants in ATM were reviewed by a genetics counsellor and defined as pathogenic, likely pathogenic, variant of unknown significance (VUS) or benign/likely benign. Genomic characteristics were reviewed and published classifiers of homologous recombination deficiency (HRD) were applied to all cases and included the percentage of substitution base signature (SBS) 3, the HRDetect score, the computed algorithm of large scale transitions, telomeric allelic imbalances and loss of heterozygosity (LOH), otherwise known as the genomic instability score (GIS). Results: As of January 2020, 304 patients were enrolled and 245 patients had both WGS and clinical data available. 86 germline variants in ATM were present in 70 patients. The majority of these (80%) were classified as benign or likely benign. 10 VUS were detected and 4 patients (2%) had pathogenic/likely pathogenic variants (PV). Of these 4 patients, LOH or a second somatic hit was evident in 1 case. Upon review of the PVs and VUS, SBS were consistent with typical PDAC and tumour mutational burden was low. HRDetect scores were low ( < 0.1) for 13/14 cases with either a VUS or PV; one VUS without biallelic loss, had a high HRDetect score, with presence of SBS 3 and a high GIS. This particular case was also found to have a tandem duplicator phenotype. None of the 4 cases with PV had evidence of HRD. Furthermore all four were treated with platinum based regimens without evidence of response. Conclusions: In a large series of sequenced pancreatic cancers, the presence of pathogenic germline variants in ATM was rare, with none of the cases demonstrating evidence of HRD. This suggests that this population is unlikely to benefit from PARP inhibition.

Case series examining somatic test results for patients with hereditary cancer syndromes associated with gastrointestinal cancer risk.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 680-680
Author(s):  
Kristen Pauley ◽  
Cathryn Koptiuch ◽  
Samantha Greenberg ◽  
Gammon Amanda ◽  
Christopher Nevala-Plagemann ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Treatment Options ◽  
Case Series ◽  
Parp Inhibitors ◽  
Cancer Genes ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Test Criteria ◽  
Uncertain Significance ◽  
Germline Testing

680 Background: Somatic tumor testing may identify germline pathogenic variants (PV) associated with cancer predisposition syndromes. Labs differ whether they offer somatic only or paired germline analysis. Methods used by somatic testing labs, even those that include germline analysis, differ from designated germline labs that have optimized the identification of germline PV. Methods: Chart reviews were performed for patients who had testing through both somatic and designated germline laboratories. Cases with discrepant results in which germline PV were not detected by the somatic laboratory are summarized. Results: Nine cases with discrepant results. Five had paired germline testing and 4 somatic testing only. All 9 patients met the criteria to undergo designated germline testing, either for Lynch syndrome (3) or BRCA1/2 testing (6), based on personal and/or family history. Designated germline testing identified 4 MLH1, 1 BRCA1, 2 ATM, 1 MUTYH and 1 RAD50 PV not reported by the somatic labs’ tumor or germline analysis; 2 MLH1 PV were called variants of uncertain significance by somatic testing but classified as PV by ClinVar and designated germline labs. Three PV identified by designated germline labs are targets for PARP inhibitors and resulted in different treatment options. Three of the MLH1 PV were identified in patients meeting Lynch Syndrome test criteria while 1 was identified in a patient meeting BRCA1/2 criteria. Among the 5 other patients meeting BRCA1/2 test criteria, 3 had PV in breast cancer genes (2 ATM, 1 BRCA1) and 2 had PV in other cancer genes ( MUTYH and RAD50) not reported by the somatic labs, highlighting the importance of panel testing. Conclusions: Methods used by somatic labs, regardless of inclusion of germline analysis, are not equivalent to those of designated germline labs. Overlooked germline PV may miss identification of hereditary syndromes and targeted therapy opportunities (e.g. Anti-PD1 immunotherapy, PARP inhibitors). Patients meeting criteria for genetic evaluation should be referred for designated germline testing regardless of somatic testing outcomes.

Frequency of homologous recombination repair alterations in ovarian cancer in Chinese population.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17531-e17531
Author(s):  
Tongtong Yang ◽  
Huanhuan Liu ◽  
Mingwei Li ◽  
Yanrui Zhang ◽  
Yun Zhang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Chinese Population ◽  
Parp Inhibitors ◽  
Homologous Recombination Repair ◽  
Non Invasive ◽  
Recombination Repair ◽  
The Difference ◽  
Brca1 Brca2 ◽  
Tumor Dna

e17531 Background: Ovarian Cancer (OC) is the most lethal cancer of all gynecological malignancies.Circulating tumor DNA (ctDNA) has received substantial attention in recent years resulting from the non-invasive, safe and effective method with considerable potential for clinical diagnosis and treatment management in patients with OC. Here, we assessed the mutational feature in homologous recombination repair (HRR) using ctDNA in OC. Methods: Plasma ctDNA was isolated from blood of patients and then was analyzed by AcornMed Biotechnology NGS-based assay for 808 genes panel for genomic alterations. The somatic and germline pathogenic mutations were identified in 12 HRR genes (ATM, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, PALB2, RAD51B, RAD51C, RAD51D, RAD54L). Results: At our institution, 85 patients underwent NGS analysis of ovarian cancer specimens. The median age was 57 (range from 26 to 83). Twenty-six patients(42.34%) harbored a mutation in at least 1 of the HRR genes in their tumor. The most commonly altered HRR gene was BRCA1 (18.25%), followed by BRCA2 (8.76%), ATM (5.84%), RAD51D(3.65%), CHEK2 (2.92%), FANCA(2.19%) and RAD51C (0.73%). To determine the difference of mutation landscape in HRR between Chinese and western populations, we compared prevalence and spectrum in cases between our cohort and the cohort of Heeke et al 1(Table). Prevalence of HRR were different from the Western cases(42.34% vs 20%, P＜0.05). Of note, BRCA1, BRCA2, ATM and CHEK2 alterations rate was higher in our cohort, and BRIP1 and PALB2 were only detected in the western cohort. Conclusions: CtDNA can characterize the mutational feature of HRR in OC. Around 42.3% of patients with OC harbour germline or somatic HRR mutations. The expanded use of PARP inhibitors in HRR deficient tumours using a signature of HRR by ctDNA in clinical practice requires validation.[Table: see text]

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