Germline Mutations In BRCA1 Research Articles

1298P Extended overall survival results from the POLO study of active maintenance olaparib in patients with metastatic pancreatic cancer and a germline BRCA mutation

1298P Extended overall survival results from the POLO study of active maintenance olaparib in patients with metastatic pancreatic cancer and a germline BRCA mutation

Maintenance therapy with a poly(ADP-ribose) polymerase inhibitor in patients with newly diagnosed advanced epithelial ovarian cancer: individual patient data and trial-level meta-analysis

BackgroundWe synthesize the efficacy and toxicity of poly(ADP-ribose) polymerase inhibitors (PARPis) in patients with newly diagnosed advanced ovarian cancer.Patients and methodsWe manually extracted individual patient data (IPD) for progression-free survival (PFS) from published survival curves of randomized controlled trials (RCTs) that compared PARPi versus placebo as maintenance therapy in first-line treatment, for whole study populations and subgroups, based on BRCA1/BRCA2 mutation (germline and/or somatic) and homologous recombination deficiency (HRD) status, using WebPlotDigitizer software. The respective PFS curves for each study and combined population were reconstructed from extracted IPD. The primary outcome was PFS in combined whole population and subgroups.ResultsIn IPD analysis of combined population from three RCTs, with 2296 patients and 1287 events, PFS was significantly longer in PARPi versus placebo [median 20.4 (95% confidence interval (CI) 18.6-21.9) versus 14.9 (95% CI 13.9-16.5) months, respectively; hazard ratio (HR) 0.67, 95% CI 0.60-0.75; P < 0.001]. In IPD subgroup analyses from four eligible RCTs (2687 patients and 1485 events), median PFS was significantly longer in PARPi versus placebo arm, in the BRCA-mutated (45.7 versus 17.7 months, respectively; HR 0.38, 95% CI 0.32-0.46; P < 0.001), HRD-positive including BRCA-mutated (34.7 versus 17.9 months, respectively; HR 0.45, 95% CI 0.38-0.54; P < 0.001), and HRD positive excluding BRCA-mutated (22.3 versus 13.1 months, respectively; HR 0.47, 95% CI 0.34-0.65; P < 0.001) subgroups, but not in the HRD-negative (15.0 versus 11.3 months, respectively; HR 0.90, 95% CI 0.76-1.05; P = 0.75) subgroup. Results of trial-level meta-analysis were concordant with IPD analysis in whole population and subgroups.ConclusionsAmong newly diagnosed ovarian cancer patients, PARPi maintenance therapy significantly improves PFS in those with germline and/or somatic BRCA mutation and/or HRD-positive tumor but not in those with HRD-negative tumor.

Brca1L63X /+ rat is a novel model of human BRCA1 deficiency displaying susceptibility to radiation-induced mammary cancer.

Women who are heterozygous for deleterious BRCA1 germline mutations harbor a high risk of hereditary breast cancer. Previous Brca1‐heterozygous animal models do not recapitulate the breast cancer phenotype, and thus all currently used knockout models adopt conditional, mammary‐specific homozygous Brca1 loss or addition of Trp53 deficiency. Herein, we report the creation and characterization of a novel Brca1 mutant rat model harboring the germline L63X mutation, which mimics a founder mutation in Japan, through CRISPR‐Cas9–based genome editing. Homozygotes (Brca1 L63X/L63X) were embryonic lethal, whereas heterozygotes (Brca1 L63X/+) showed apparently normal development. Without carcinogen exposure, heterozygotes developed mammary carcinoma at a comparable incidence rate with their wild‐type (WT) littermates during their lifetime. Intraperitoneal injection of 1‐methyl‐1‐nitrosourea (25 or 50 mg/kg) at 7 weeks of age induced mammary carcinogenesis at comparable levels among the heterozygotes and their littermates. After exposure to ionizing radiation (0.1–2 Gy) at 7 weeks of age, the heterozygotes, but not WT littermates, displayed dose‐dependent mammary carcinogenesis with 0.8 Gy−1 excess in hazard ratio during their middle age; the relative susceptibility of the heterozygotes was more prominent when rats were irradiated at 3 weeks of age. The heterozygotes had tumors with a lower estrogen receptor α immunopositivity and no evidence of somatic mutations of the WT allele. The Brca1 L63X/+ rats thus offer the first single‐mutation, heterozygous model of BRCA1‐associated breast cancer, especially with exposure to a DNA break‐inducing carcinogen. This implies that such carcinogens are causative and a key to breast cancer prevention in individuals who carry high‐risk BRCA1 mutations.

BRCA Mutations in Ovarian and Prostate Cancer: Bench to Bedside.

Simple SummaryDNA damage is one of the hallmarks of cancer. Epithelial ovarian cancer (EOC) —especially the high-grade serous subtype—harbors a defect in at least one DNA damage response (DDR) pathway. Defective DDR results from a variety of lesions affecting homologous recombination (HR) and nonhomologous end joining (NHEJ) for double strand breaks, base excision repair (BER), and nucleotide excision repair (NER) for single strand breaks and mismatch repair (MMR). Apart from the EOC, mutations in the DDR genes, such as BRCA1 and BRCA2, are common in prostate cancer as well. Among them, BRCA2 lesions are found in 12% of metastatic castration-resistant prostate cancers, but very rarely in primary prostate cancer. Better understanding of the DDR pathways is essential in order to optimize the therapeutic choices, and has led to the design of biomarker-driven clinical trials. Poly(ADP-ribose) polymerase (PARP) inhibitors are now a standard therapy for EOC patients, and more recently have been approved for the metastatic castration-resistant prostate cancer with alterations in DDR genes. They are particularly effective in tumours with HR deficiency.DNA damage repair (DDR) defects are common in different cancer types, and these alterations can be exploited therapeutically. Epithelial ovarian cancer (EOC) is among the tumours with the highest percentage of hereditary cases. BRCA1 and BRCA2 predisposing pathogenic variants (PVs) were the first to be associated with EOC, whereas additional genes comprising the homologous recombination (HR) pathway have been discovered with DNA sequencing technologies. The incidence of DDR alterations among patients with metastatic prostate cancer is much higher compared to those with localized disease. Genetic testing is playing an increasingly important role in the treatment of patients with ovarian and prostate cancer. The development of poly (ADP-ribose) polymerase (PARP) inhibitors offers a therapeutic strategy for patients with EOC. One of the mechanisms of PARP inhibitors exploits the concept of synthetic lethality. Tumours with BRCA1 or BRCA2 mutations are highly sensitive to PARP inhibitors. Moreover, the synthetic lethal interaction may be exploited beyond germline BRCA mutations in the context of HR deficiency, and this is an area of ongoing research. PARP inhibitors are in advanced stages of development as a treatment for metastatic castration-resistant prostate cancer. However, there is a major concern regarding the need to identify reliable biomarkers predictive of treatment response. In this review, we explore the mechanisms of DDR, the potential for genomic analysis of ovarian and prostate cancer, and therapeutics of PARP inhibitors, along with predictive biomarkers.

Emerging Role of PARP Inhibitors in Metastatic Prostate Cancer.

We highlight the clinical development of Poly (ADP-Ribose) polymerase (PARP) inhibitors in prostate cancer. Approximately 10 to 30% of metastatic prostate cancer patients carry germline or somatic mutations in DNA repair pathways. BRCA2 is the most commonly mutated gene in DNA damage repair pathways. Because of its critical function in homologous recombination repair (HRR) machinery, deleterious BRCA2 mutation enables synthetic lethality to a PARP inhibitor. Olaparib demonstrated clinical benefit in patients with deleterious mutations in HRR-related genes and most clearly in patients with BRCA2 mutations. Olaparib received the US FDA approval or mCRPC patients with a qualifying HRR gene mutation in May 2020. Rucaparib received an accelerated FDA approval for patients with BRCA1- or BRCA2-mutated mCRPC based on 43% objective response rate in a phase II study. To expand the application of a PARP inhibitor, several trials have evaluated various combination strategies with an androgen receptor signaling inhibitor, immunotherapy, radium-223, and others. While no PARP inhibitor combination regimen has been approved, promising data from a PARP inhibitor and an ASI combination have been reported. PARP inhibitor represents a standard treatment for patient with mCRPC with germline or somatic mutations in BRCA2 and other HRR pathway genes.

Germline and somatic genetic testing trends among women with epithelial ovarian cancer (197)

Objectives: Identifying homologous recombination deficiency (HRD) mutations has significant treatment implications for women with epithelial ovarian cancer (EOC). While germline testing strategies have been well cataloged in clinical practice, and the American Society for Clinical Oncology recommends somatic testing if germline testing is negative, best-practice strategies for obtaining somatic, germline, or combination testing remain unclear. We aimed to trend rates and temporal relationships of germline and somatic genetic testing at an academic institution to identify gaps in equitable access to precision testing. Methods: All patients with EOC were identified from the electronic medical record (EMR) using diagnostic codes at a single urban academic gynecologic oncology group from January 2015 to December 2020. IRB approval was obtained and an EMR review was performed to analyze trends in germline and somatic genetic testing. Descriptive statistics and Chi-square tests were performed. Results: A total of 431 women with EOC were identified. Patients were predominantly White (88%), older women (mean age 68) who had insurance (97%). Most patients had advanced stage disease (80%) with high-grade serous histology (77%). Eighty percent of patients underwent germline testing with 15% having BRCA1/2 mutations identified. The somatic testing rate was 50% with rates increasing each contact year (Figure 1A) and a detection rate of 29.5% for HRD mutations. Combination testing rates also increased per contact year (Figure 1B). Patients with negative germline testing were more likely to undergo somatic testing (60%) compared to those with germline BRCA1 (29%) or BRCA2 (37%) mutations (p = 0.0012). About 12.5% of patients with negative germline testing had a somatic mutation in either BRCA1/2 or loss of heterozygosity. Of patients without germline genetic testing, only 27% had somatic testing performed (22/81). Thirty percent had somatic testing performed after a recurrence; however, 36% of patients experiencing a recurrence never underwent somatic testing. Sixty-nine percent had somatic testing performed on a current tissue specimen as opposed to archived tissue. Conclusions: Somatic testing resulted in actionable HRD mutations in one in three patients in this cohort, with one in eight patients having somatic HRD mutations despite negative germline testing. This illustrates the therapeutic potential of comprehensive genetic profiling and represents how variations in practice may result in missed therapeutic interventions. As somatic testing rates continue to increase, efforts to define barriers and create streamlined, guideline-based strategies for universal testing are warranted to better align with current clinical practice guidelines. Objectives: Identifying homologous recombination deficiency (HRD) mutations has significant treatment implications for women with epithelial ovarian cancer (EOC). While germline testing strategies have been well cataloged in clinical practice, and the American Society for Clinical Oncology recommends somatic testing if germline testing is negative, best-practice strategies for obtaining somatic, germline, or combination testing remain unclear. We aimed to trend rates and temporal relationships of germline and somatic genetic testing at an academic institution to identify gaps in equitable access to precision testing. Methods: All patients with EOC were identified from the electronic medical record (EMR) using diagnostic codes at a single urban academic gynecologic oncology group from January 2015 to December 2020. IRB approval was obtained and an EMR review was performed to analyze trends in germline and somatic genetic testing. Descriptive statistics and Chi-square tests were performed. Results: A total of 431 women with EOC were identified. Patients were predominantly White (88%), older women (mean age 68) who had insurance (97%). Most patients had advanced stage disease (80%) with high-grade serous histology (77%). Eighty percent of patients underwent germline testing with 15% having BRCA1/2 mutations identified. The somatic testing rate was 50% with rates increasing each contact year (Figure 1A) and a detection rate of 29.5% for HRD mutations. Combination testing rates also increased per contact year (Figure 1B). Patients with negative germline testing were more likely to undergo somatic testing (60%) compared to those with germline BRCA1 (29%) or BRCA2 (37%) mutations (p = 0.0012). About 12.5% of patients with negative germline testing had a somatic mutation in either BRCA1/2 or loss of heterozygosity. Of patients without germline genetic testing, only 27% had somatic testing performed (22/81). Thirty percent had somatic testing performed after a recurrence; however, 36% of patients experiencing a recurrence never underwent somatic testing. Sixty-nine percent had somatic testing performed on a current tissue specimen as opposed to archived tissue. Conclusions: Somatic testing resulted in actionable HRD mutations in one in three patients in this cohort, with one in eight patients having somatic HRD mutations despite negative germline testing. This illustrates the therapeutic potential of comprehensive genetic profiling and represents how variations in practice may result in missed therapeutic interventions. As somatic testing rates continue to increase, efforts to define barriers and create streamlined, guideline-based strategies for universal testing are warranted to better align with current clinical practice guidelines.

Optimal Choice of Neoadjuvant Chemotherapy for HER2-Negative Breast Cancer: Clinical Insights.

The neoadjuvant setting provides immense opportunities for translational research and drug development. The acceptance of pathological complete response (pCR) as a surrogate endpoint for clinical benefit has led to the widespread use of neoadjuvant treatment. Optimal neoadjuvant therapies are determined based on their ability to achieve the highest rates of pCR. Predicted rates of pCR for triple negative breast cancer (TNBC) treated with sequential taxane/anthracycline regimens range from 35% to 48%. With the addition of a platinum agent pCR rates of 55% are predicted. Further increases have been observed with the addition of immune checkpoint inhibitors to this standard chemotherapy backbone. In the pivotal KEYNOTE-522 clinical trial pCR rates of 65% and 69% were reported for chemotherapy plus pembrolizumab in the overall and PD-L1-positive subgroup respectively. The role of the neoadjuvant chemotherapy is less clear in hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer. In general, HR–positive cancers have the least chance of achieving a pCR after neoadjuvant chemotherapy, especially if they are low-grade. If neoadjuvant chemotherapy is given for high-risk HR-positive, HER2-negative breast cancer, standard adjuvant anthracycline/taxane regimens are appropriate. Optimum endocrine therapy is the standard-of-care in the adjuvant setting regardless of pCR. There are several genomic signatures available to guide decisions regarding adjuvant chemotherapy use however these assays are not routinely used in the neoadjuvant setting. For high-risk patients meeting the criteria for the monarchE trial adjuvant abemaciclib in addition to endocrine therapy is associated with an improvement in disease free survival (DFS) at 3 years. Based on the OlympiA trial patients with germline BRCA mutations should be considered for adjuvant olaparib therapy. In this article we review neoadjuvant clinical trials that guide optimum treatment options for TNBC and HR-positive, HER2-negative breast cancer.

Germline BRCA mutations are associated with an increased likelihood of secondary cytoreductive surgery in ovarian cancer patients (116)

<b>Objectives:</b> <i>BRCA</i> mutations have been associated with improved outcomes in ovarian cancer patients, specifically with delayed recurrences. This study aimed to compare the secondary cytoreduction rates and eligibility among ovarian cancer patients by <i>BRCA</i> mutation status. <b>Methods:</b> The study was retrospective and included high-grade serous ovarian cancer patients from one Canadian center and two Israeli centers from January 1999 to December 2018, with the first disease recurrence 12 months or more from the last cycle of platinum-based chemotherapy. Demographic and genetic data, tumor characteristics, pattern of recurrence, and surgical and medical treatments were obtained from electronic charts. Eligibility for secondary cytoreduction was defined as recurrence 12 months or longer from completion of adjuvant treatment, up to three lesions at recurrence, and absence of ascites, in line with DESKTOP criteria. Patients were grouped according to <i>BRCA</i> mutation status. Continuous variables were compared using the student's t-test and categorical variables using the Chi-square test. Regression analysis was used to identify predictors of eligibility for and performance of secondary cytoreduction. <b>Results:</b> One hundred forty-seven patients were enrolled, including 97 from Canada and 50 from Israel. Forty-seven patients (32%) had a <b>Conclusions:</b> Germline <i>BRCA</i> mutation carriers are more likely to undergo secondary cytoreduction, most likely due to lower volume disease at recurrence. This observation should be considered when planning the follow-up for these patients after first-line treatment.

RNAseq correlative biomarkers IFIT1B and VSTM5 predict progression free survival and clinical benefit in a multi-site Phase I/II trial of Olaparib and Tremelimumab for gBRCAm recurrent ovarian cancer (LBA 11)

<b>Objectives:</b> Although ovarian cancer is a rational target for immune therapy, immune checkpoint blockade has not demonstrated the efficacy seen in other solid tumors. In preclinical studies, PARP inhibition (PARPi) synergized with CTLA4 immune checkpoint blockade, resulting in durable anti-tumor immunity and long-term survival in ovarian cancer models. This combination was tested in women with germline BRCA1 or BRCA2 mutations (gBRCAm) and recurrent ovarian cancer in a phase I/II clinical trial (NCT0257125). Correlative studies were performed to identify predictive biomarkers of response. <b>Methods:</b> Women with recurrent ovarian cancer, confirmed gBRCAm, and measurable disease were eligible for participation. There were no restrictions on the number or type of prior treatment regimens. Prior PARPi treatment was allowed. Subjects received olaparib at 300mg BID and the CTLA4 antibody tremelimumab at 10mg/kg IV every 4 weeks for six doses followed by maintenance dosing every 12 weeks. Treatment continued for up to two years. The Phase I lead-in allowed dose modifications for toxicity. The phase II component used Simon's 2-stage design based on the primary endpoint of overall response rate. RNAseq was performed on archived formalin-fixed, paraffin embedded pre-treatment tumor samples from 30 subjects, and candidate biomarkers were selected based on differential expression in subjects with and without clinical benefit. <b>Results:</b> Forty-nine patients received study treatment (mean age 56 yrs, range 39-79) at five sites. Twenty-eight subjects had received ≥3 prior chemotherapy regimens, and 29 were previously treated with a PARPi. After 14 patients received the study regimen, the recommended phase 2 schedule for tremelimumab was changed to 10mg/kg infusions every 4 weeks for four doses followed by maintenance dosing every 12 weks due to immune-related adverse events, primarily colitis. Fifty-nine percent of subjects experienced at least one non-hematologic ≥ grade 3 toxicity. Among 44 evaluable patients, the overall response rate was 39%, with a clinical benefit rate of 48%. The median PFS was 3.4 months (95% CI 2.7-6.1). In a curated analysis of interferon response genes, lack of IFIT1B expression was associated with significantly enhanced PFS (median 11.4 vs 2.7 months; log-rank p=0.009; Fig 1). In an unbiased analysis of all genes, VSTM5 was the most differentially expressed marker (AUC=0.852), and lack of VSTM5 expression was significantly associated with PFS (8.12 vs 2.56 months; log-rank p=0.001). <b>Conclusions:</b> The combination of olaparib and tremelimumab achieved durable treatment benefit in a subset of gBRCAm recurrent ovarian cancer patients. Immune toxicity was moderate. Biomarkers based on gene expression in archived tumor samples were associated with clinical benefit. Future studies are needed to assess the utility of these biomarkers to identify candidates for immune therapy.

Tissue is the issue: Chemotherapy response score (CRS) is most predictive of response to neoadjuvant chemotherapy in advanced, high grade serous ovarian cancer (HGSOC) (488)

Tissue is the issue: Chemotherapy response score (CRS) is most predictive of response to neoadjuvant chemotherapy in advanced, high grade serous ovarian cancer (HGSOC) (488)

Streamline of the gene line: Implementation of reflex homologous recombination deficiency (HRD) tumor testing in newly diagnosed ovarian cancer patients (593)

Streamline of the gene line: Implementation of reflex homologous recombination deficiency (HRD) tumor testing in newly diagnosed ovarian cancer patients (593)

Single-cell analysis of the tubal transcriptome in germline BRCA1 mutation carriers: Exploring early events in carcinogenesis (123)

<b>Objectives:</b> Loss of ciliated cells in the fallopian tube has been proposed to be a primary step in tumor initiation in high-grade serous ovarian cancer (HGSOC). Our objective was to identify single-cell transcriptional networks related to ciliated cell function in the fallopian tubes of women with germline <i>BRCA1</i> mutations who are at high risk of developing HGSOC. <b>Methods:</b> Four women aged 38-44 years with pathogenic germline <i>BRCA1</i> mutations underwent risk-reducing surgery at an urban, academic tertiary care center. Under the supervision of a pathologist, fallopian tube ampullae were collected, digested and primary cells were reconstituted in a single-cell suspension. Single-cell RNA-sequencing libraries were prepared using the Chromium Next GEM Single Cell 3' kit with a cell recovery target of 2000-8000 cells. Libraries were sequenced on an Illumina NovaSeq 6000. Seurat v3 and Harmony were used for data dimensionality reduction, cell cluster identification, and classification. Ancestry-based cluster analysis and pseudo-time trajectory analysis were performed using Harmony and Monocle 3. <b>Results:</b> Integrated analysis of 6015 cells from four <i>BRCA1</i> tubal epithelia samples identified ten cell clusters with unique transcriptional profiles. Of these, clusters 4 and 10 had features of ciliated cells. Cluster 4 cells expressed <i>PAX8, RFX2, RFX3,</i> and <i>FOXJ1</i> associated with an intermediate phase ciliated and secretory cell phenotype. Gene ontology analysis showed upregulation of cilia-related genes and stemness pathways, including an upregulation of the gene, <i>SNAI2,</i> belonging to stem-cell development pathway (Enrichment score [ES]: 6.30, p=1.83 x 10^-3). Cluster 10 cells expressed <i>RFX2</i> and <i>RFX3</i> associated with early progenitor ciliated cells, and gene ontology analysis showed upregulation of stemness pathways, with <i>SOX17, SOX18,</i> and <i>NOTCH1</i> regulating stem-cell proliferation (ES: 7.45, p=5.79 x10^-4). Trajectory analysis identified an early progenitor ciliated cell population and a late-stage ciliated cell population with stem-cell populations intermediate to the two populations. Cells belonging to Cluster 4 showed transitionary features and are identified at all branch points along the trajectory. <b>Conclusions:</b> Single-cell RNA sequencing analysis of the tubal epithelia from <i>BRCA1</i> mutation carriers identified select clusters having progenitor and stem-like transcriptional profiles of secretory and ciliated cells, with the <i>SOX18, PAX8, RFX2,</i> and <i>RFX3</i> genes defining these cell populations. Trajectory analysis indicated the differential potential of the ciliated cells to be involved in malignant transformation. The implications of these findings will be further explored by comparison to wild-type and HGSOC transcriptomes.

Prognostic significance of germline BRCA mutations in patients with HER2-POSITIVE breast cancer

BackgroundHER2-positive breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinicopathological characteristics and prognosis of this subgroup of patients. Materials and methodsUsing a retrospective matched cohort design, we collected data from 700 women who were diagnosed with operable invasive breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinicopathological features and survival rates were analyzed by BRCA and HER2 status. ResultsOne hundred and fifteen HER2-positive/BRCA mutated cases were evaluated in comparison to the three control groups: HER2-positive/BRCA wild type (n = 129), HER2-negative/BRCA mutated (n = 222), HER2-negative/BRCA wild type (n = 234). HER2-positive breast cancers were more likely to have high histologic grade and high proliferation rate than HER2-negative neoplasms, regardless of BRCA mutation status. An interaction between BRCA mutations and HER2-positive status was found to correlate with worse survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3–16.7). ConclusionsCo-occurrence of BRCA mutations and HER2-positive status is a poor prognostic factor in patients with early or locally advanced breast cancer. This finding may be a proof of concept that a combined pharmacological intervention directed to these targets could be synergistic.

Novel Germline Mutations in a Cohort of Men with Familial Prostate Cancer.

Simple SummaryIn this study, we identified germline mutations that contribute to prostate cancer development in men who have multiple relatives with prostate cancer (and other cancers). We correlated the genetic mutations found in each patient with the resulting prostate cancer characteristics. Mutations found in ATM and CHEK2 genes were associated with aggressive prostate cancer. More data is needed to confirm the prevalence and impact of these germline mutations in prostate cancer.Background: Germline mutations in BRCA2 are associated with aggressive prostate cancer. Additional information regarding the clinical phenotype of germline pathogenic variants in other prostate cancer predisposition genes is required. Clinical testing has been limited by evidence, further restricting knowledge of variants that contribute to prostate cancer development. Objective: Prostate cancer patients who were first- and second-degree relatives from multi-case prostate cancer families underwent a gene panel screen to identify novel (non-BRCA) germline pathogenic variants in cancer predisposition genes and define clinical phenotypes associated with each gene. Methods: The germline genomic DNA (gDNA) of 94 index cases with verified prostate cancer from families with a minimum of two verified prostate cancer cases was screened with an 84-cancer-gene panel. Families were recruited for multi-case breast/ovarian cancer (n = 66), or multi-case prostate cancer (n = 28). Prostate cancer characteristics associated with each gene were compared with prostate cancer cases of confirmed non-mutation carriers (BRCAX), also from multi-case prostate cancer families (n = 111), and with data from the Prostate Cancer Outcomes Registry (PCOR). Results: Ninety-four prostate cancer index cases underwent gene panel testing; twenty-two index cases (22/94; 23%) were found to carry a class 4–5 (C4/5) variant. Six of twenty-two (27%) variants were not clinically notifiable, and seven of twenty-two (31.8%) variants were in BRCA1/2 genes. Nine of twenty-two (40.9%) index cases had variants identified in ATM (n = 4), CHEK2 (n = 2) and HOXB13G84 (n = 3); gDNA for all relatives of these nine cases was screened for the corresponding familial variant. The final cohort comprised 15 confirmed germline mutation carriers with prostate cancer (ATM n = 9, CHEK2 n = 2, HOXB13G84 n = 4). ATM and CHEK2-associated cancers were D’Amico intermediate or high risk, comparable to our previously published BRCA2 and BRCAX prostate cancer cohort. HOXB13G84 carriers demonstrated low- to intermediate-risk prostate cancer. In the BRCAX cohort, 53.2% of subjects demonstrated high-risk disease compared with 25% of the PCOR cohort. Conclusions: ATM and CHEK2 germline mutation carriers and the BRCAX (confirmed non-mutation carriers) cohort demonstrated high risk disease compared with the general population. Targeted genetic testing will help identify men at greater risk of prostate-cancer-specific mortality. Data correlating rare variants with clinical phenotype and familial predisposition will strengthen the clinical validity and utility of these results and establish these variants as significant in prostate cancer detection and management.

Rare germline variants in PALB2 and BRCA2 in familial and sporadic chordoma.

Chordoma is a rare bone tumor with genetic risk factors largely unknown. We conducted a whole-exome sequencing (WES) analysis of germline DNA from 19 familial chordoma cases in five pedigrees and 137 sporadic chordoma patients and identified 17 rare germline variants in PALB2 and BRCA2, whose products play essential roles in homologous recombination (HR) and tumor suppression. One PALB2 variant showed disease cosegregation in a family with four affected people or obligate gene carrier. Chordoma cases had a significantly increased burden of rare variants in both genes when compared to population-based controls. Four of the six PALB2 variants identified from chordoma patients modestly affected HR function and three of the 11 BRCA2 variants caused loss of function in experimental assays. These results, together with previous reports of abnormal morphology and Brachyury expression of the notochord in Palb2 knockout mouse embryos and genomic signatures associated with HR defect and HR gene mutations in advanced chordomas, suggest that germline mutations in PALB2 and BRCA2 may increase chordoma susceptibility. Our data shed light on the etiology of chordoma and support the previous finding that PARP-1 inhibitors may be a potential therapy for some chordoma patients.

Treatment of metastatic pancreatic cancer

Pancreatic cancer is the 4th most common cause of cancer death in Germany and continues to be associated with apoor prognosis. Aprerequisite for chemotherapy or radiotherapy is always the pathohistological (or cytological) confirmation of the tumor disease. Molecular diagnostics include analysis of DNA mismatch repair in the tumor and of the germline mutations in BRCA 1/2 (gBRCA mutation). Systemic chemotherapy remains the mainstay in the management of locally advanced and metastatic disease. If agBRCA mutation is detected, platinum-based therapy should be used. Patients with good performance status benefit from second-line therapy. Immunotherapy with checkpoint inhibitors (not yet approved) may be considered in pretreated patients with evidence of deficient DNA mismatch repair or microsatellite instability.

PSY8-6 Current status and issues in the management of prostate cancer with BRCA gene mutation

Men with a family history of hereditary breast and ovarian cancer syndrome are at increased risk of developing prostate cancer, especially men with germline BRCA2 mutations. Prostate cancer with germline BRCA2 mutations is known to have a younger age of onset, higher grade, and lower survival after curative treatment. In addition, prostate cancer with BRCA2 mutations is characterized by genomic instability and is pathologically associated with intraductal carcinoma of the prostate. Therefore, counseling and prostate-specific antigen testing starting at age 40 should be suggested for men with germline BRCA2 mutations.

Management Strategies of Breast Cancer Patients with BRCA1 and BRCA2 Pathogenic Germline Variants.

Most of breast cancer cases are sporadic; however, 15–20% are associated with family history, and some are inherited. Among those, deleterious mutations in BRCA1 and BRCA2 tumor suppressor genes are the most commonly encountered pathogenic germline variants (PGVs). Given the availability and affordability of multi-gene panel sequencing technologies, testing for PGVs is commonly practiced. With our enhanced understanding of cancer genetics and specific molecular alterations, the better acceptance of risk-directed screening and prevention, and the recent introduction of novel targeted therapies, management of BRCA-positive breast cancers is taking a new direction, focusing more on risk-reducing interventions, including mastectomy and salpingo-oophorectomy, and incorporating special treatment regimens, including platinum-based chemotherapy, and the recently-introduced PARP (poly (ADP)-ribose polymerase) inhibitors. Given the recent advances in reproductive technology and molecular medicine, younger women with PGVs may have the option of embryo selection through preimplantation genetic testing and diagnosis, thus preventing the potential transmission of the implicated genes to the next generations. In this review, we cover the clinical implications of identifying a pathogenic germline mutation in BRCA1 and BRCA2 genes in breast cancer patients, and their relatives, across the continuum of care – from cancer prevention and early detection, through active treatment and up to survivorship issues.

SY23-3 Clinical development of PARP inhibitors in ovarian cancer

Initial clinical development of PARP inhibitor (PARPi) started for ovarian patients with germline BRCA mutation (gBRCAm) based on the mechanistic assumptions. The first large phase 3 trial, SOLO2, focused on the patient with platinum-sensitive recurrent ovarian cancer known to have gBRCAm. On the other hand, the NOVA trial tested the innovative study design. The investigators challenged to include patients with not only gBRCAm but also with non-gBRCAm, which included HRD+ (tBRCAm only and BRCAwt) and HRD-negative population.

PSY8-3 PARP inhibitors for hereditary breast cancer with germline BRCA mutation

BRCA1 and BRCA2 mutations (mt) are responsible genes which give an autosomal-dominant inherited trait predisposing women to hereditary breast cancer and ovarian cancer(HBOC). BRCA-mt cancer cells have abnormal homologous recombination (HR) repair of DNA. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are effective in causing cell death in BRCA-mt cells while sparing normal cells-a concept called synthetic lethality. PARPi are the first cancer therapy designed to exploit synthetic lethality.