Homologous Recombination Repair Genes Research Articles

Untapped Potential of Poly(ADP-Ribose) Polymerase Inhibitors: Lessons Learned From the Real-World Clinical Homologous Recombination Repair Mutation Testing.

Testing for homologous recombination deficiency (HRD) mutations is pivotal to assess individual risk, to proact preventive measures in healthy carriers and to tailor treatments for cancer patients. Increasing prominence of poly(ADP-ribose) polymerase (PARP) inhibitors with remarkable impact on molecular-selected patient survival across diverse nosologies, ingrains testing for BRCA genes and beyond in clinical practice. Nevertheless, testing strategies remain a question of debate. While several pathogenic BRCA1/2 gene variants have been described as founder pathogenic mutations frequently found in patients from Russia, other homologous recombination repair (HRR) genes have not been sufficiently explored. In this study, we present real-world data of routine HRR gene testing in Russia. We evaluated clinical and sequencing data from cancer patients who had germline/somatic next-generation sequencing (NGS) HRR gene testing in Russia (BRCA1/2/ATM/CHEK2, or 15 HRR genes). The primary objectives of this study were to evaluate the frequency of BRCA1/2 and non-BRCA gene mutations in real-world unselected patients from Russia, and to determine whether testing beyond BRCA1/2 is feasible. Data of 2,032 patients were collected from February 2021 to February 2023. Most had breast (n = 715, 35.2%), ovarian (n = 259, 12.7%), pancreatic (n = 85, 4.2%), or prostate cancer (n = 58, 2.9%). We observed 586 variants of uncertain significance (VUS) and 372 deleterious variants (DVs) across 487 patients, with 17.6% HRR-mutation positivity. HRR testing identified 120 (11.8%) BRCA1/2-positive, and 172 (16.9%) HRR-positive patients. With 51 DVs identified in 242 formalin-fixed paraffin-embedded (FFPE), testing for variant origin clarification was required in one case (0.4%). Most BRCA1/2 germline variants were DV (121 DVs, 26 VUS); in non-BRCA1/2 genes, VUS were ubiquitous (53 DVs, 132 VUS). In silico prediction identified additional 4.9% HRR and 1.2% BRCA1/2/ATM/CHEK2 mutation patients. Our study represents one of the first reports about the incidence of DV and VUS in HRR genes, including genes beyond BRCA1/2, identified in cancer patients from Russia, assessed by NGS. In silico predictions of the observed HRR gene variants suggest that non-BRCA gene testing is likely to result in higher frequency of patients who are candidates for PARP inhibitor therapy. Continuing sequencing efforts should clarify interpretation of frequently observed non-BRCA VUS.

Alterations in the expression of homologous recombination repair (HRR) genes in breast cancer tissues considering germline BRCA1/2 mutation status.

Homologous recombination (HR) is a crucial DNA-repair mechanism, and its disruption can lead to the accumulation of mutations that initiate and promote cancer formation. The key HR genes, BRCA1 and BRCA2, are particularly significant as their germline pathogenic variants are associated with a hereditary predisposition to breast and/or ovarian cancer. The study was performed on 45 FFPE breast cancer tissues obtained from 24 and21 patients, with and without the germline BRCA1/2 mutation, respectively. The expression of 11 genes: BRCA1, BRCA2, ATM, BARD1, FANCA, FANCB, FANCI, RAD50, RAD51D, BRIP1, and CHEK2 was assessed using Custom RT2 PCR Array (Qiagen), and results were analysed using R. Cancer tissues from patients with BRCA1 or BRCA2 germline mutations displayed no significant differences in the expression of the selected HR genes compared to BRCA1 or BRCA2 wild-type cancer tissues. In BRCA1mut cancer tissues, BRCA1 expression was significantly higher than in BRCA2mut and BRCA wild-type cancer tissues. In cancer tissues harbouring either BRCA1 or BRCA2 germline mutations, no significant differences in expression were observed at the mRNA level of any tested HR genes, except BRCA1. However, the significant differences observed in BRCA1 expression between germline BRCA1mut,germline BRCA2mut and BRCA1/2wttissues may indicate a compensatory mechanism at the mRNA level to mitigate the loss of BRCA1 function in the cells.

Somatic and germline aberrations in homologous recombination repair genes among Chinese high-risk breast cancer patients by multi-gene next-generation sequencing.

Recently, genes involved in homologous recombination repair (HRR) pathway have been extensively studied. However, the landscapes of HRR gene mutations remain poorly defined in Chinese high-risk breast cancer (BC) patients. Our study aims to identify the status of germline and somatic HRR gene mutations and their association with clinicopathological features in these patients. A total of 100 high-risk BC patients from our institution who underwent paired peripheral blood germline and BC tissues somatic 26 genes next-generation sequencing (NGS) from January 2018 to July 2023 were enrolled for retrospective analysis. Out of 100 high-risk BC patients, 55 (55%) had at least one germline or somatic mutation in HRR genes. Among them, 22% carried germline pathogenic variants (19 BRCA1/2 and 3 non-BRCA genes), 9% harbored somatic pathogenic mutations (3 BRCA1/2 and 6 non-BRCA genes). Among high-risk factors, family history and early onset BC showed a correlation with HRR gene mutations (p < 0.05). BRCA1 germline and HRR gene somatic mutations showed a correlation with TNBC, but BRCA2 germline mutations were associated with Luminal B/HER2-negative BC (p < 0.05). Patients with HRR gene somatic pathogenic variant more likely had a lympho-vascular invasion and distant metastasis (p < 0.05). The prevalence of HRR gene germline and somatic mutations were higher in Chinese BC patients with high risk factors. We strongly recommend that these high-risk BC patients receive comprehensive gene mutation testing, especially HRR genes, which are not only related to genetic consultation for BC patients and provide a theoretical basis for necessary prevention and individualized treatment.

Prevalence of homologous recombination biomarkers in multiple tumor types: an observational study.

Aim: To determine the prevalence of deleterious mutations in BRCA1 and BRCA2 and in 13 genes involved in homologous recombination repair (HRR), the prevalence of genomic loss of heterozygosity and the allelic and hereditary status of BRCA1, BRCA2 and other HRR gene mutations in multiple solid tumor types. Patients & methods: This was a retrospective observational study of patients with an advanced/metastatic diagnosis in one of 15 solid tumor types, who were identified in a real-world clinico-genomic database. Results: Tumor tissue samples from 9457 patients were analyzed, among which 4.7% had known or suspected deleterious BRCA1/2 mutations. The prevalence (range) of mutations in HRR genes was 13.6% (2.4%-26.0%) and genomic loss of heterozygosity ≥16% was 20.6% (2.6-34.4%) across all tumor types. Conclusion: The prevalence of mutations varied significantly depending on the type of tumor.

The pathologic and clinical outcomes of risk-reducing salpingo-oophorectomy in asymptomatic carriers of homologous recombination repair gene mutation.

To investigate the prevalence of pathological findings and clinical outcomes of risk-reducing salpingo-oophorectomy (RRSO) in asymptomatic carriers with germline homologous recombination repair (HRR) gene pathogenic/likely pathogenic variants (PV/LPV). This retrospective study enrolled asymptomatic carriers with germline HR gene PV/LPV who underwent RRSO between 2006 and 2022 at the National Cancer Center in Korea. Clinical characteristics, including history of breast cancer, family history of ovarian/breast cancer, parity, and oral contraceptive use, were analyzed. Of the 255 women who underwent RRSO, 129 (50.6%) had PV/LPV in BRCA1, 121 (47.5%) in BRCA2, and 2 (0.7%) had both BRCA1 and BRCA2 PV/LPV. In addition, 1 carried PV/LPV in RAD51D, and 2 in BRIP1. Among the BRCA1/2 PV/LPV carriers, occult neoplasms were identified in 3.5% of patients: serous tubal intraepithelial carcinoma (1.1%, n=3), fallopian tubal cancers (0.8%, n=2), ovarian cancer (1.2%, n=3), and breast cancer (0.4%, n=1). Of the 9 patients with occult neoplasms, 5 (2.0%) were identified from the 178 breast cancer patients, and 4 (1.6%) were detected in 65 healthy mutation carriers. During the median follow-up period of 36.7 months (interquartile range, 25.9-71.4), 1 (0.4%) BRCA1 PV carrier with no precursor lesions at RRSO developed primary peritoneal carcinomatosis after 30.1 months. Women with HRR gene mutations PV/LPV who undergo RRSO are at a risk of detecting occult neoplasms, with a of 3.5%. Even in the absence of precursor lesions during RRSO, there was a cumulative risk of peritoneal carcinomatosis development, emphasizing the need for continued surveillance.

Is the Homologous Recombination Repair Mutation Defined by a 15-Gene Panel Associated with the Prognosis of Epithelial Ovarian Cancer?

There is no consensus regarding the specific genes included in the homologous recombination repair (HRR) gene panel for identifying the HRR deficiency (HRD) status and predicting the prognosis of epithelial ovarian cancer (EOC) patients. We aimed to explore a 15-gene panel involving the HRR pathway as a predictive prognostic indicator in Chinese patients newly diagnosed with EOC. We reviewed the previously published reports about different HRR gene panels and prespecified the 15-gene panel. The genetic testing results in a 15-gene panel from 308 EOC patients diagnosed between 2014 and 2022 from six centers were collected. The association of clinicopathologic characteristics, the use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) and progression-free survival (PFS) with 15-gene panel HRR mutations (HRRm) status was assessed. 43.2% (133/308) of patients were determined to carry 144 deleterious HRRm, among which68.1% (98/144) were germline mutations and 32.8% (101/308) were BRCA1/2gene lethal mutations. The hazard ratio (HR) (95% confidence interval, CI) for PFS (HRRmvHRR wild type, HRRwt) using the 15-gene panel HRRm was 0.42 (0.28-0.64) at all stages and 0.42 (0.27-0.65) at stages IIIC-IV. However, a prognostic difference was observed only between the BRCA mutation group and the HRRwt group, not between the non-BRCA HRRm group and the HRRwt group. For the subgroups of patients not using PARPis, the HR (95% CI) was 0.41 (0.24-0.68) at stages IIIC-IV. This study provides evidence that 15-gene panel HRRm can predict the prognosis of EOC, of these only the BRCA1/2 mutations, not non-BRCA HRRm, contribute to prognosis prediction. Among patients without PARPis, the HRRm group presented a better PFS. This is the first study of this kind in the Chinese population.

BRCA functional domains associated with PARP-inhibitors in patients with prostate cancer: The PROGRESS study.

10543 Background: Homologous recombination repair (HRR) defects are driver mutational imprints and actionable biomarkers in prostate cancer (PrC) patients. However, recent research provides evidence of PrC onset also in the context of mismatch repair deficiency (MMRd). In the current report, we investigated whether the position of pathogenic variants (PVs) in the functional domains (FDs) of HRR genes could be associated with reduced or increased sensitivity to PARP-inhibitors (PARPis). We also questioned whether the HRR FDs had a prognostic significance and affected the development of second primary tumor (SPT) in males with a genetic predisposition. Methods: This was a real-world, observational, study including PrC patients undergoing germline, somatic, and liquid biopsy testing between January 2020 and December 2023. Prognostic factors, SPT history, and PARPi benefit were evaluated according to mutated genes ( BRCA1, BRCA2,No- BRCAHRR), PV location within the FDs, and germline (g) or somatic (s) PV. The BRCA1FDs were RING, DNA-binding domain (DBD), BRCA1 C terminus (BRCT), or other location, and the BRCA2 FDs were RAD51-BD, DBD, or other location. Results: A total of 833 metastatic PrC patients, aging 40 to 91, were included in this study; 169 (20.3%) were carriers of germline (n.48, 5.8%) or somatic (n.121, 14.5%) PVs in HRR genes: 17 in BRCA1 (g BRCA1: n.4, 2.4%; s BRCA1: n.13, 7.7% ), 102 in BRCA2 (g BRCA2: n.33, 19.5%; s BRCA2: n.69, 40.8% ), and 53 in no- BRCA HRR genes (gHRR: n.11, 6.5%; sHRR: n.42, 24.8%). CHEK2was the HRR gene most frequently affected by germline PVs (27.3%), while the most frequent somatic PVs were in the ATM (40.5%). Liquid biopsy identified PVs in 33 patients out of 185 tested, including n.10 (5.4%) not detected through somatic and germline testing, considerably expanding the therapeutic window for the use of PARPi. Notably, differences in PFS rates at 48 months were observed when comparing sub-groups according to PV location in the FDs of BRCA2.Surprisingly, when we investigated the SPT in the cohorts of patients with and without germline PVs, the difference was not significant (14.5% vs 12.4%, respectively) and, in the subgroup without germline PVs, the sites of SPT were predominantly colorectal, gastric, bladder or other tumors classically dominated by MMRd and recognized as Lynch Syndrome-spectrum tumors. This observation may result in unexplored forms of hypermutable tumor phenotypes, potentially impacting cancer risk management and increasing therapeutic opportunities. Conclusions: Our results suggest preliminary evidence that not all BRCA2-mutated PrC are equally sensitive to PARPis, and the response could depend on the PV location within FDs. The study of SPT in patients with no-HRR-associated PrC highlights the need to expand the genes in multigene panel testing, including MMR along with HRR genes, to capture unrecognized constitutional predisposition.

Clinical homologous recombination repair gene reversion analysis identifies mechanisms of resistance to PARP inhibitors and platinum‐chemotherapy

AbstractIdentifying mechanisms underlying cancer resistance to therapy is vital for advancing treatment strategies. Pathogenic mutations of homologous recombination repair (HRR) genes are known biomarkers for platinum (Pt)‐based chemotherapy and poly ADP ribose polymerase inhibitors (PARPi) effectiveness. Yet, the dynamics of HRR reversion mutations, which may herald therapy resistance, are not fully elucidated. Addressing this gap, our study analyzed secondary HRR gene mutations in a comprehensive pan‐cancer data set of approximately 13,000 patients who underwent targeted next‐generation sequencing. We identified a subset of patients harboring secondary mutations, which were further categorized into three tiers based on their nature, and occur in the presence of a primary pathogenic mutation, notably in BRCA1, BRCA2, PALB2, and RAD51D genes. Here we show that secondary BRCA2 mutations, indicative of adaptive resistance, emerge post‐Pt/Olaparib treatment. This challenges the prevailing notion that pathogenic HRR mutations uniformly predict therapeutic sensitivity, highlighting a nuanced genetic interplay that impacts treatment success. This investigation enriches our understanding of cancer's adaptive mechanisms against therapy, suggesting a pivotal shift towards more personalized, dynamic treatment strategies. It underscores the imperative of adapting to cancer's genetic evolution, aiming for a step ahead in the ongoing battle against this disease.

Deleterious alterations in homologous recombination repair genes and efficacy of platinum-based chemotherapy in biliary tract cancers.

Platinum-based chemotherapy represents the standard first-line treatment for biliary tract cancers (BTC). Deficits in genes involved in the homologous recombination (HR) and DNA damage response (DDR) may confer higher sensitivity to platinum agents. We retrospectively included patients affected by BTC from 2 Italian institutions. Inclusion criteria consist of the receipt of platinum-based chemotherapy in the metastatic setting and the availability of comprehensive genomic profiling using next-generation sequencing (NGS). Patients were included in the HRD-like group if demonstrated oncogenic or likely oncogenic alterations in HR-/DDR-genes. Clinical endpoints were compared between the HRD-like group and the non-HRD-like group. Seventy-four patients were included, of whom 25 (33%) in the HRD-like group and 49 (66%) in the non-HRD group. With a median follow-up of 26.04 months (interquartile-range [IQR] 9.41-29.27) in the HRD-like group and of 22.48 months (IQR 16.86-40.53) in the non-HRD group, no PFS difference emerged, with a mPFS of 5.18 months in the HRD-like group compared to 6.04 months in the non-HRD group (hazard ratio [HR], 1.017, 95% CI 0.58-1.78; P = .95). No differences were observed in DCR (64% [95 CI 45%-83%] vs 73% [95 CI 61%-86%]; P = .4), and CBR (45% [95% CI 28%-73%] vs 50% [95% CI, 37%-68%]; P = .9) between the HRD-like group and non-HRD groups, respectively. Median OS did not statistically differ between the HRD-like group and non-HRD group (26.7 vs 18.0 months, respectively; HR, 0.670, 0.33 to 1.37, P = .27). HR-/DDR-genes, when assessed with regular tumor-only NGS panels, provide limited clinical validity to identify patients with BTC more likely to benefit from platinum-based chemotherapy.

Exploring the correlation between high HRD status and immunotherapy response in melanoma.

e21541 Background: Homologous recombination deficiency (HRD) status demonstrates DNA instability in tumor cells and has been implicated as a response marker for immune checkpoint inhibitors (ICI). Here, we explore the correlation between high HRD status and ICI response biomarkers, homologous recombination repair (HRR) mutations, and the prognostic advantage of high HRD status following ICI in cutaneous melanoma patients. Methods: Melanoma samples (N = 2158) were profiled for genomic loss of heterozygosity (LOH) by NGS at Caris Life Sciences (Phoenix, AZ). As a surrogate for HRD, LOH-high was defined as LOH at ≥ 16% of the segments analyzed (up to 552). PD-L1 expression was assessed using IHC (SP142; positive (+): ≥ 1%). Mismatch repair deficiency/microsatellite instability-high (dMMR/MSI-H) was tested by IHC/NGS.Tumor mutational burden (TMB)-high was defined as ≥ 10 mutations/Mb. interferon gamma (IFN-g) and T-cell inflamed scores. Real-world overall survival (rw-OS) information was obtained from insurance claims data, with Kaplan-Meier estimates calculated from the start of immunotherapy until the last date of contact. Mann-Whitney U, Chi-square, and Fisher exact tests were applied where appropriate, with p-values adjusted for multiple comparisons. Results: Melanoma patient samples include - cutaneous: 1853; acral: 130; mucosal: 175, with LOH-high observed in 8.3% of cutaneous specimens, 13.1% of acral, and 30.9% of mucosal. Firstly, most biomarkers associated with response to ICI (PD-L1, TMB-high, total neoantigen load, IFN-g score, T-cell inflamed level, and dMMR/MSI-H) were not significantly different between LOH-high and LOH-low cohorts in all melanoma subtypes. However, TMB-high was significantly more prevalent in LOH-low cutaneous melanoma patients (54.9% vs 63.3%, p = 0.039). Prevalence of HRR gene mutations was not significantly different between high and low LOH groups in all cohorts, except for the ATRX gene which exhibited a significantly higher prevalence in the high LOH cutaneous (8.6% vs 1.3%, p &lt; 0.001) and mucosal (28.8% vs 2.5%, p &lt; 0.00001) melanoma specimens. Analysis of rw-OS showed no improvement in the treatment of LOH-high cutaneous melanoma patients with ICI compared to LOH-low (HR: 1.397 [95% CI: 0.759- 2.569], p = 0.281). Conclusions: This study demonstrates that HRDness reflected by the high-LOH status in melanoma did not correlate with mutations in HRR genes. In addition, melanoma specimens with high HRD status did not exhibit an overall higher prevalence of biomarkers associated with ICI response. Our study did not demonstrate improved survival outcomes in patients with high HRD status following anti-PD1 therapies. Future investigation is needed to assess other therapeutic approaches for these patients such as PARP inhibitors.

Inherited Germline Variants in Urinary Tract Cancer: A Multicenter Whole-Exome Sequencing Analysis and Correlation With Clinical Features and Tumor Genomics.

This study investigates a real-world multicenter cohort of patients with urinary tract cancer (UTC), with primary disease sites including the bladder, urethra, and upper tract, who enrolled for research molecular testing of their germline and tumor. The purpose of this study was to evaluate factors that could affect the likelihood of identifying a clinically actionable germline pathogenic variant (PV). Patients with UTC were identified from 10 cancer institutes of the Oncology Research Information Exchange Network consortium. The data set comprised abstracted clinical data with germline and tumor genomic data, and comparative analyses were conducted. Clinically actionable germline PVs in cancer predisposition genes were identified in 16 (4.5%) of 354 patients. A higher proportion of patients with the urethra and the upper tract as the primary sites of disease had PVs with a prevalence of 11% (5/45), compared with only 3.6% (11/308) in those with the bladder as the primary site of disease (P = .04). There were no significant differences in markers of genomic instability (such as tumor mutational burden, microsatellite instability [MSI], and loss of heterozygosity, copy number, and chromosomal instability) between those with PVs and those without (P > .05). Of the PVs identified, 10 (62%) were in homologous recombination repair (HRR) genes, three (19%) in mismatch repair (MMR) genes, and three (19%) in genes associated with other pathways. Tissue-based assessment of genomic instability, such as MSI, does not reliably indicate germline PV. A comprehensive clinical germline testing approach that includes HRR genes in addition to MMR genes is likely to yield PVs in approximately one of 10 patients with nonbladder primary disease sites such as the upper tract and the urethra.

Somatic tissue testing in prostate cancer using the Oncomine V3 panel: A single-institution retrospective analysis.

e17002 Background: Approximately 20-30% of prostate cancer (PC) patients have a mutation in the homologous recombination repair or mismatch repair genes, 50% of which are somatic. These mutations have prognostic and predictive implications. Somatic tissue testing (STT) was implemented at Sunnybrook Health Sciences Centre using the Oncomine V3 panel, which includes 161 genes, but only four genes (BRCA1/2, ATM, PALB2) are reported due to funding restrictions. We describe our centre’s testing experience and the utility of reporting beyond these four genes. Methods: Sixty-two PC patients between May 1, 2021 - January 31, 2023 were included. Clinical characteristics were gathered via chart review. Somatic variants of genes of interest (GOI) within the Oncomine V3 panel were extracted by an annotation specialist. Results: STT was ordered at diagnosis in 69.4% of cases (n=42) vs. at progression in 27.4% (n=17), 3 cases were external and lacked clinical context. Tests were ordered in the locoregional disease setting in 46.8% (n=29), 37.1% (n=23) in the metastatic castrate-sensitive setting, 8.1% (n=5) in the metastatic castrate-resistant (CR) setting and 3.2% (n=2) in the non-metastatic CR setting. Tests were ordered by Urology or Pathology (reflex testing) in 64.5% (n=40), by Medical Oncology in 16% (n=10), by Radiation Oncology in 13% (n=8) and by others in 6.5% (n=4). Fifty-one samples (82.2%) were of the prostate and 11 (17.7%) were of metastatic sites. The median sample age was 8 days (range 0-5781). The median test turn-around time was 28.5 days (range 5-57). There were 378 variants within the GOI and meeting the limit of detection [1] , of which 63 (16.7%) were tier 1 or 2 and are listed by gene in the table. Eight of 63 variants (12.7%) were within the four funded genes whereas 55/63 (87.3%) were within unfunded genes of clinical significance. CDK12, FANCA, NBN (n=7, 11.2%) are investigated in poly (ADP-ribose) polymerase inhibitor trials and PMS2 deficiency (n=1, 1.6%) can select for immune checkpoint inhibitors. PIK3R1/PIK3CA/AKT1-mutated tumors (n=11, 17.7%) have shown response to AKT-inhibitors. SPOP-mutated tumors (n=6, 9.7%) are associated with prolonged response to androgen receptor blockade whereas PTEN/TP53/RB1-negative tumors (n=12, 19.4%) are associated with anti-androgen resistance and worse prognosis. Conclusions: The majority of STT variants identified were beyond the currently funded genes in Ontario, and many have important prognostic and predictive implications. This highlights that STT early in the disease course using expanded gene panels may help in delivering personalized PC care. [Table: see text]

Association of homologous recombination repair mutation defined with a 15-gene panel with the prognosis of epithelial ovarian cancer: A Chinese multicenter retrospective study.

e17556 Background: There was no consensus regarding the optimal homologous recombination repair (HRR) gene panel to predict prognosis of epithelial ovarian cancer (EOC). Methods: The genetic testing results in a 15-gene panel from 308 EOC patients diagnosed between 2014 and 2022 from six centres were collected. The association of clinicopathologic characteristics, the use of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors and progression-free survival (PFS) with 15-gene panel mutation status was assessed. Results: 43.2% (133/308) of patients were determined to carry 144 deleterious HRR mutations (HRRm), among which 68.1% (98/144) were germline mutations and 32.8% (101/308) were BRCA1/2 gene lethal mutations. Patients who received PARP inhibitors (PARPis) were 29.1% (37/127) and 50.5% (46/91) in the HRR wild-type (HRRwt) group and HRRm group at IIIC-IV stages, respectively. A prognostic difference was observed only between the BRCA mutation group and the HRRwt group, not between the non-BRCA HRRm group and the HRRwt group. In univariate analysis, significant predictors of relapse included nonresidual status (HR, 0.62; 95% CI, 0.39-0.98; P = 0.0287), 15-gene panel mutation (HR, 0.42; 95% CI, 0.28-0.64; P = 0.0001), platinum sensitivity (HR, 0.07; 95% CI, 0.02-0.22; P &lt; 0.001) and maintenance therapy (PARPi) (HR, 0.48; 95% CI, 0.31-0.74; P = 0.0028) (Figure 5). In multivariate Cox analysis, nonresidual (HR, 0.63; 95% CI, 0.40-0.99; P = 0.046), 15-gene panel mutation (HR, 0.49; 95% CI, 0.28-0.88; P = 0.016) and platinum sensitivity (HR, 0.02; 95% CI, 0.01-0.05; P &lt; 0.001) remained independent prognostic factors. Conclusions: This study provides evidence that HRRm with a 15-gene panel can predict the prognosis of EOC, among which only BRCA1/2 mutations contribute to prognosis prediction. [Table: see text]

Association of homologous recombination repair mutation defined with a 15-gene panel with the prognosis of epithelial ovarian cancer: A Chinese multicenter retrospective study.

e17556 Background: There was no consensus regarding the optimal homologous recombination repair (HRR) gene panel to predict prognosis of epithelial ovarian cancer (EOC). Methods: The genetic testing results in a 15-gene panel from 308 EOC patients diagnosed between 2014 and 2022 from six centres were collected. The association of clinicopathologic characteristics, the use of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors and progression-free survival (PFS) with 15-gene panel mutation status was assessed. Results: 43.2% (133/308) of patients were determined to carry 144 deleterious HRR mutations (HRRm), among which 68.1% (98/144) were germline mutations and 32.8% (101/308) were BRCA1/2 gene lethal mutations. Patients who received PARP inhibitors (PARPis) were 29.1% (37/127) and 50.5% (46/91) in the HRR wild-type (HRRwt) group and HRRm group at IIIC-IV stages, respectively. A prognostic difference was observed only between the BRCA mutation group and the HRRwt group, not between the non-BRCA HRRm group and the HRRwt group. In univariate analysis, significant predictors of relapse included nonresidual status (HR, 0.62; 95% CI, 0.39-0.98; P = 0.0287), 15-gene panel mutation (HR, 0.42; 95% CI, 0.28-0.64; P = 0.0001), platinum sensitivity (HR, 0.07; 95% CI, 0.02-0.22; P &lt; 0.001) and maintenance therapy (PARPi) (HR, 0.48; 95% CI, 0.31-0.74; P = 0.0028) (Figure 5). In multivariate Cox analysis, nonresidual (HR, 0.63; 95% CI, 0.40-0.99; P = 0.046), 15-gene panel mutation (HR, 0.49; 95% CI, 0.28-0.88; P = 0.016) and platinum sensitivity (HR, 0.02; 95% CI, 0.01-0.05; P &lt; 0.001) remained independent prognostic factors. Conclusions: This study provides evidence that HRRm with a 15-gene panel can predict the prognosis of EOC, among which only BRCA1/2 mutations contribute to prognosis prediction. [Table: see text]

Utilization of genetic and genomic data and correlation to outcomes of treatment with PARP inhibitors in advanced or metastatic castrate-resistant prostate cancer.

e17034 Background: Prostate cancer is the second-leading cause of cancer death in men in the United States, with aggressive forms associated with mutations in homologous recombination repair (HRRm) genes. PARP inhibitors (PARPi) (olaparib, rucaparib, niraparib, and talazoparib) are FDA approved for treatment of HRRm metastatic castration-resistant prostate cancer (mCRPC). Previous data have shown PARPi has the greatest benefit in patients with HRRm, but the responses in HRR genes other than BRCA1/2 and ATM are less robust based on available data. Methods: This retrospective study utilized the electronic health record to identify adult patients diagnosed with prostate cancer and treated at Avera Cancer Institute from 1/1/2018 to 12/31/2022 who received somatic (tumor and/or ctDNA) and/or germline genetic testing. Testing results were reviewed for pathogenic HRRm (BRCA1, BRCA2, ATM, ATR, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C) and treatment histories were reviewed to identify PARPi use. Data about PARPi received, duration, and biochemical response (decline in PSA during therapy) were collected. Results: 191 patients were included in the final analysis. Of these, 88 (46%) patients had germline only testing, 31 (16%) had somatic only testing, and 72 (38%) had both germline and somatic testing completed. 45 patients had HRRm of which 22 were somatic and 33 were germline. The average patient age at time of testing was 70 years. Thirteen of the patients in this cohort received treatment with a PARPi . Twelve of these patients received treatment with olaparib monotherapy, and one patient received olaparib in combination with abiraterone. Average progression free survival was 26 months (range 5-92 months) and the median PFS was 11 months. Four patients were biochemical non-responders, with an average PFS of 8 months, compared to 33 months for the 9 biochemical responders (p=0.04). Gene alterations present in non-responders included germline BRCA1 (n=1), germline CHEK2 (n=2), and somatic ATM (n=1). Germline alterations present in responders included BRCA2 (n=7) and PALB2 (n=2). In patients who received PARPi therapy, the average age of testing was 73 years. Conclusions: The patients found to have HRRm that were treated with a PARPi showed similar responses to previously described data in that the BRCA2 mutated group showed best response, followed by PALB2 mutated tumors. The overall proportion of patients with HRRm that were ultimately treated with PARPi was smaller than expected warranting further investigation. New FDA approvals of PARPi combined with next generation hormonal agents in the first line mCRPC setting are expected to increase utilization of PARPi. Additional outcomes data for individual HRR genes are needed to improve patient selection, outcomes, and reduce unnecessary toxicity due to PARPi therapy.

Efficacy of first line (1L) poly ADP-ribose polymerase inhibitors (PARPi) in combination with androgen pathway inhibitors (API) by homologous recombination repair (HRR) genes in metastatic castration-resistant prostate cancer (mCRPC): A living meta-analysis.

e17059 Background: It is unclear if patients with different HRR gene-mutated mCRPC derive consistent benefit from treatment with PARPi and API combination. Approval labels for PARPi+API are inconsistent across regulatory bodies in the US (Food and Drug Administration, FDA) and Europe (European Medical Agency, EMA), adding to confusion among practicing clinicians. Therefore, we aimed to assess the differential efficacy of PARP+API therapy by different genes using up-to-date trial evidence. Methods: We maintain a living meta-analysis on mCRPC treatments that is updated when new data becomes available. Here, we report data from phase III randomized control trials (RCTs) assessing PARPi+API in 1L mCRPC. The outcomes of interest included radiographic progression-free survival (rPFS) and overall survival (OS). Hazard ratios (HR) for rPFS and OS by different genes were summarized using random effects meta-analysis via inverse variance approach. Results: We have screened 27376 references since the inception of this living review. Here, we report data from three trials (15 references) with a total of 1618 patients. Frequently reported HRR gene mutations in the included trials were BRCA2 (35%), ATM (21%), CDK12 (12.2%), CHEK2 (12.2%), BRCA1 (4.6%), and PALB2 (3.4%). In terms of rPFS, statistical benefit was observed in BRCA (0.28; 95% CI: 0.13-0.59) and CDK12 (0.58; 95% CI: 0.35-0.95) subgroups, whereas no statistically significant benefit was seen in PALB2 (0.53; 95% CI: 0.21-1.32), ATM (0.93; 95% CI, 0.57-1.53), and CHEK2 (0.92; 95% CI: 0.53-1.61) subgroups. For OS, benefit was observed in BRCA (0.47; 95%CI: 0.31-0.71) subgroup. While not statistically significant, a signal of meaningful OS benefit was observed in PALB2 (0.33; 95%CI: 0.10-1.16) but no OS benefit was observed in ATM (0.97; 95% CI: 0.57-1.67), CDK12 (0.80; 95% CI: 0.36-1.78), and CHEK2 (0.81; 95% CI: 0.37-1.75) subgroups. Conclusions: Current results show that mCRPC patients with BRCA and CDK12 alterations had delayed disease progression with PARPi+API as 1L therapy. BRCA mutations are also associated with improved OS, while patients with CHEK2 and ATM derived no significant benefit with PARPi+API combination. [Table: see text]

Prevalence of pathogenic genetic variants in patients with gastric cancer ascertained through multi-gene panel testing.

10578 Background: Gastric cancer (GC) is the fourth leading cause of cancer-related deaths worldwide. The role of pathogenic/likely pathogenic variants (PVs) in cancer predisposition genes is not well understood. We aimed to assess the prevalence of PVs in GC patients undergoing germline genetic testing (GGT) via multi-gene panel testing (MGPT) at a large commercial laboratory. Methods: Retrospective review of MGPT (&gt;10 genes) in GC patients at a large commercial laboratory (Invitae Corp.) from March 2015 to July 2023 was performed. GC included diffuse type, intestinal type or unspecified type, as provided by ordering clinicians. Association of patient characteristics with positive GGT results was assessed with logistic regression with a significance threshold of p &lt; 0.05. Results: 3,706 GC patients underwent GGT(Table). Overall, 495 (13.4%) patients were found to carry ≥1 PV, including 29 patients with 2 PVs and 3 patients with 3 PVs. GGT was negative in 1,890 (51.0%) patients, 1,199 (32.4%) had a variant of uncertain significance-only and 121 (3.3%) carried a single PV in a gene associated with autosomal recessive inheritance. PVs were identified in 38 genes; 77.7% (385/495) were in a gene previously associated with GC, primarily the homologous recombination repair genes ( BRCA1, BRCA2, PALB2and ATM, 34.9%), the Hereditary Diffuse Gastric Cancer genes ( CDH1and CTNNA1, 19.6%) and mismatch repair genes ( MLH1, MSH2, MSH6, PMS2and EPCAM, 17.4%). Males were more likely to carry a PV than females (OR 1.4, 95% CI 1.1-1.7) and having a personal history of another cancer increased the odds of carrying a PV (OR 1.3, 95% CI 1.0-1.7). Age, number of genes tested and histology were not significantly associated with PV. Conclusions: In this large study of GGT in GC patients, the prevalence of PVs in cancer associated genes was 13.4%, higher than previous estimates of 3-5%. PVs were predominantly in genes associated with GC. Male sex and history of other cancers were associated with a PV. Limitations include incomplete histologic data, varying panel size, and ascertainment bias as patients may have had additional personal/family history that prompted GGT. These results support consideration of GGT in all GC patients as prevalence of PVs is similar to other cancer types for which guidelines recommend universal genetic testing.[Table: see text]

A molecular glue RBM39-degrader induces synthetic lethality in cancer cells with homologous recombination repair deficiency

E7820 and Indisulam (E7070) are sulfonamide molecular glues that modulate RNA splicing by degrading the splicing factor RBM39 via ternary complex formation with the E3 ligase adaptor DCAF15. To identify biomarkers of the antitumor efficacy of E7820, we treated patient-derived xenograft (PDX) mouse models established from 42 patients with solid tumors. The overall response rate was 38.1% (16 PDXs), and tumor regression was observed across various tumor types. Exome sequencing of the PDX genome revealed that loss-of-function mutations in genes of the homologous recombination repair (HRR) system, such as ATM, were significantly enriched in tumors that responded to E7820 (p = 4.5 × 103). Interestingly, E7820-mediated double-strand breaks in DNA were increased in tumors with BRCA2 dysfunction, and knockdown of BRCA1/2 transcripts or knockout of ATM, ATR, or BAP1 sensitized cancer cells to E7820. Transcriptomic analyses revealed that E7820 treatment resulted in the intron retention of mRNAs and decreased transcription, especially for HRR genes. This induced HRR malfunction probably leads to the synthetic lethality of tumor cells with homologous recombination deficiency (HRD). Furthermore, E7820, in combination with olaparib, exerted a synergistic effect, and E7820 was even effective in an olaparib-resistant cell line. In conclusion, HRD is a promising predictive biomarker of E7820 efficacy and has a high potential to improve the prognosis of patients with HRD-positive cancers.

Homologous Recombination Repair Gene Mutations in Prostate Cancer: Prevalence and Clinical Value.

Despite advances in our understanding of the molecular landscape of prostate cancer and the development of novel biomarker-driven therapies, the prognosis of patients with metastatic prostate cancer that is resistant to conventional hormonal therapy remains poor. Data suggest that a significant proportion of patients with metastatic castration-resistant prostate cancer (mCRPC) have mutations in homologous recombination repair (HRR) genes and may benefit from poly(ADP-ribose) polymerase (PARP) inhibitors. However, the adoption of HRR gene mutation testing in prostate cancer remains low, meaning there is a missed opportunity to identify patients who may benefit from targeted therapy with PARP inhibition, with or without novel hormonal agents. Here, we review the current knowledge regarding the clinical significance of HRR gene mutations in prostate cancer and discuss the efficacy of PARP inhibition in patients with mCRPC. This comprehensive overview aims to increase the clinical implementation of HRR gene mutation testing and inform future efforts in personalized treatment of prostate cancer.

Familial and hereditary pancreatic cancer in Japan.

As in Western countries, familial pancreatic cancer accounts for 5-7% of pancreatic cancer (PC) in Japan. Opportunities for diagnosing hereditary pancreatic cancer (HPC) are increasing owing to the coverage of companion diagnostics and cancer genomic profiling by national health insurance in patients with unresectable or recurrent PC refractory to standard chemotherapies. HPC is recognized in 7% of PCs and 15% of familial pancreatic cancer, including germline variants of BRCA1/2, ATM, PALB2, APC, and mismatch repair genes. Individuals with 5-fold or greater inherited risks of PC are recommended to undergo pancreatic surveillance according to Japanese guidelines. The imaging modalities for this surveillance include endoscopic ultrasound, magnetic resonance cholangiopancreatography, abdominal ultrasound, and enhanced computed tomography. Currently, a nationwide prospective surveillance study is ongoing in Japan. Platinum-based chemotherapy is an effective pancreatic cancer treatment in patients with variants of homologous recombination repair genes (BRCA1/2 and PALB2); however, the use of platinum regimens solely based on familial/personal cancer history remains controversial. The efficacy of olaparib maintenance therapy, as confirmed by the POLO study, has significantly impacted the clinical treatment of advanced PC patients in Japan. Since the initiation of precision cancer medicine in 2019, genetic medicine for PC patients has expanded in Japan.