Homologous Recombination Deficiency Mutation Research Articles

Abstract B019: Deciphering the role of homologous recombination deficiency mutations in the response to combined immune checkpoint and PARP inhibitors

Abstract Background: Over 2 million women develop breast cancer globally every year despite immense advances in disease biology, diagnostic strategies and novel treatment options. The deeper knowledge of disease biology and genomic landscape has fostered a broader mechanistic approach to patients and their therapeutic choices. Many preclinical and clinical studies suggest a benefit of combining PARP inhibitors (PARPi) and immune checkpoint inhibitors (ICPi) in patients with homologous recombination deficiency (HRD) intact and mutated cancers. However, similar to the varied benefits of either drug class based on tissue and mutational context, the benefits of such combination are strongly variable based on tumor type, tissue and mutation context. Methods: To study how select HRD mutations respond to a combination of a PARPi inhibitor with an ICPi, we used CRISPR engineering to functionally impair or repress BRCA1, BRCA2, ATM, CHEK2, PALB2 in different mouse breast cancer cell lines. EMT6 and 4T1 cells were engineered to expressed deactivated cas9 nuclease (dcas9) fused to the repressor domain Kruppel-associated- box (KRAB) and mcherry florescent protein. The dcas9-KRAB-mcherry breast cancer cells were further engineered to express BFP-tagged guide RNAs targeting selected genes under a doxycycline inducible tet-on system. After establishing functional loss/repression of the targeted HRD mutations, cells were then implanted in the mammary fat pad of balb/cJ mice and treated with PARPi and ICPi to determine the ICPi, PARPi and their combination induced changes in inflammatory signals and their association with therapy response. Results: Induced suppression of BRCA1 and PALB2 in these breast cancer cells showed exquisite sensitivity to PARPi (IC50 0.01 uM and 0.098 uM) and diminishing sensitivity to PARPi in BRCA2 and ATM (IC50 0.16 uM and IC50 0.28 uM). In contrast, inducible suppression of CHEK2 showed resistance to PARPi versus parental EMT6 cells (IC50 13.9 uM versus 5.3 uM). Evaluation of changes in expression levels of PDL1 and select chemokines including CCL2, CCL5, CXCL9, CXCL10 and CXCL11 suggest a differential response to PARPi depending on specific HRD mutations. HRD mutations and tissue-context will be further characterized in combination therapy of ICPi and PARPi. Conclusion: Using inducible suppression of HRD function in an immune competent mouse breast cancer model helps to understand the differential role of individual HRD mutations (BRCA1, BRCA2, ATM, CHEK2, PALB2) in altering inflammatory signals in response to PARPi and ICI. This data may guide the clinical development of such combination in breast cancer and other cancers. Citation Format: Sibapriya Chaudhuri, Scott Thomas, Luika Timmerman, Pamela Munster. Deciphering the role of homologous recombination deficiency mutations in the response to combined immune checkpoint and PARP inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B019.

Survival impact of homologous recombination deficiency in veterans with cholangiocarcinoma including mutual exclusivity with pathogenic KRAS and TP53.

546 Background: Cholangiocarcinoma (CCA) has poor prognosis and limited treatment options. The US Veteran Health Administration’s (VHA) National Precision Oncology Program (NPOP) was established to characterize pathogenic drivers across the integrated VA network. Here, we summarize an important subgroup of CCA with homologous recombination deficiency (HRD) and its impact on overall survival (OS). Methods: Next-generation sequencing (NGS) was performed using FoundationOne CDx Analysis included clinicopathological, molecular alterations including, single nucleotide variants, gene amplification/loss, and gene fusion/rearrangements obtained from centralized data of the VHA’s Corporate Data Warehouse. Homologous recombination deficiency was defined by pathogenic variant mutations (MT) in ARID1A, ATM, ATR, BAP1, BRCA1, BRCA2, CDK12, CHEK2, FANC, NBN, PALB2, and RAD51. Statistical analysis was performed using Chi-squared test for concurrent gene enrichment and log-rank Kaplan-Meier analysis. Results: 483 CCA samples underwent tissue NGS as standard of care. Pathogenic variants in HRD genes included ARID1A (15.5%, n=75), BAP1 (9.5%, n=46), ATM (2.7%, n=13), PALB2 (2.3%, n=11) and BRCA (2.0%, n=10), representing 31.7% (n=153) of the population. HRD mutations were found in similar proportions of localized (31.8%) and metastatic (31.5%) clinical presentations at diagnosis. OS was not significantly different between CCA with HRD mutations (12.3 mo WT vs. 13.8 months with HRD MT, p=64). KRAS MT (n=77, 15.9% of population) did not impact OS (WT 12.3 mo v. MT 13.1 mo) including subgroup analysis stratified by HRD status. There was increased frequency in KRAS MT with HRD WT 18.5% versus HRD MT10.4% (p<0.03). Additionally, there was increased frequency in TP53 MT with HRD WT 54.8% versus HRD MT 28.1% (p<0.00001). TP53 MT (n=224, 46.3% of population) conferred inferior OS (WT 12.3 mo v. MT 13.1 mo) including subgroup analysis stratified by HRD status. Subgroup analysis of TP53 MT had worsened OS with concurrent HRD MT (n=39, 4.1 mo) v. HRD WT (n=158, 9.0 mo; p<0.04). Conclusions: Across a diverse integrated healthcare system of Veterans, mutations associated with HRD were found to be common, however, not prognostic in OS across a diverse patient population of CCA. Further work is needed to clarify exposure to platinum containing chemotherapy. TP53 MT CCA remains a critical unmet need that drives worsened outcomes including here in patients with mutations in HRD. Future analysis should consider mutation signatures of HRD, loss in heterozygosity of HRD, and platinum exposure to further define the subgroups of CCA with mutations in HRD. [Table: see text]

Abstract B040: NCI 10129: A Phase 2 Study of the PARP inhibitor Olaparib (AZD2281) in IDH1 and IDH2 mutant advanced solid tumors

Abstract Introduction: Cholangiocarcinoma (CCA) is a highly aggressive malignancy with mutations in Isocitrate dehydrogenase (IDH) identified in approximately 15% of patients. Neomorphic mutations in IDH 1/2 result in accumulation of the oncometabolite 2-hydroxyglutarate (2G), which has been implicated in tumor progression via inhibitory effects on alpha ketoglutarate. Moreover, the mutant IDH dependent accumulation of 2HG results in homologous recombination deficiency (HRD) and renders these cells exquisitely sensitive to Poly (ADP-Ribose) polymerase (PARP) inhibitors. NCI 10129 evaluated the efficacy of olaparib for IDH mutated solid tumors, and here we present the CCA cohort. Methods: NCI 10129 is a 3 arm, open label phase 2 clinical trial performed in the NCI National Clinical Trials Network evaluating olaparib 300 mg twice daily for IDH mutated solid tumors refractory to standard treatment. Patients with CCA were enrolled in 2 cohorts 1) IDHi pre-treated CCA and 2) IDHi untreated CCA. The primary endpoint was overall response rate (ORR) and secondary endpoints includes progression-free survival (PFS), and overall survival (OS). An exploratory analysis measured the impact of circulating 2HG levels, circulating tumor DNA, and tumor genomics on patient outcomes.  Results: Thirty patients with CCA enrolled on NCI10129 (15 each IDHi pre-treated and IDHi treatment naïve), 18 patients received ≥ 2 prior systemic treatments, and 23 patients had IDH1 mutations and 7 patients IDH2 mutations. There were no objective responses seen in the first 15 CCA patients in either cohort and enrollment was closed. The median PFS was 2.4 months 95% CI (1.9 - 6.5) and median OS 12.9 months 95% CI (6.3 – not reached). The IDHi pre-treated cohort had improved median OS compared to IDHi treatment naïve (15.3 vs 7.3, P = 0.04). There were 8/30 (27%) patients with clinical benefit (CB) as defined by PFS > 6 months. Patients with CB had lower baseline mean D-2HG levels compared to those without CB (1.4 umol/L vs 5.9 umol/L, p = 0.02). Whole exome sequencing revealed the study population to be enriched for HRD by sum scores and HRD mutational signatures without alternative HRD mutations other than IDH1/2. No improvement in survival was noted based on HRD status. RNA sequencing Gene Set Enrichment Analysis revealed that cell cycle and interferon alpha pathways were activated in patients with CB (p < 0.01). Olaparib was tolerable with the majority of adverse events grade 1-2. Conclusion: Olaparib did not result in objective responses in IDH mutated CCA. However, a subgroup of patients did demonstrate prolonged PFS comparable to historical controls for refractory CCA as well that seen with targeted agents such as IDHi. Exploratory analysis revealed this subgroup to be enriched for lower baseline 2HG levels. Serial ctDNA analysis is ongoing and will be presented. Given the CB subgroup and OS data, additional clinical trials leveraging the HRD properties of IDH mutations is warranted. Future studies may benefit from DNA damage combination therapies thereby enhancing potency. Citation Format: Michael Cecchini, Mary Jo Pilat, Nataliya Uboha, Nilofer S Azad, May Cho, Elizabeth J Davis, Jordi Rodon Ahnert, Gabriel Tinoco, Geoff I Shapiro, Simon Khagi, Benjamin Powers, Roman Groisberg, Jan Drappatz, Li Chen, Biswajit Das, Xun Bao, Jing Li, Abhijit Patel, Monica Niger, Deborah Doroshow, Diane Durecki, Scott Boerner, Ranjit Bindra, Percy Ivy, Yu Shyr, Patricia LoRusso. NCI 10129: A Phase 2 Study of the PARP inhibitor Olaparib (AZD2281) in IDH1 and IDH2 mutant advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B040.

Comprehensive genomic analysis for homologous recombination deficiency in pancreatic cancer.

e15168 Background: Although homologous recombination deficiency (HRD) has been heavily studied in oncology, HRD in pancreatic cancer remains poorly understood beyond germline alterations in BRCA1, BRCA2 and PALB2. Methods: We performed whole exome sequencing (WES) on 205 patients with pancreatic cancer. Germline and somatic mutations in HRD genes were evaluated: (1) canonical HRD mutation ( BRCA1, BRCA2 and PALB2); and (2) non-canonical HRD mutation ( ATM, ATR, ATRX, CHEK2, BAP1, BARD1, BLM, BRIP1, NBN, RAD51 genes, RAD54 genes, FANC genes and ERCC genes). In addition, signature-based HRD classifiers were also applied: (1) the genomic instability score (GIS); (2) substitution base signature 3 (SBS3); and (3) small insertion and deletions 83B (ID83B). The frequency of HRD mutations and signatures-based HRD in pancreatic cancer were evaluated and their clinical utility were assessed by confirming the association with the response to platinum-containing chemotherapy. Results: Among the 205 patients, 41 patients (20.0%) were identified to harbor HRD mutations. Germline and somatic HRD mutations were identified in 19 (9.3%) and 24 (11.7%) patients, respectively. Mutations in canonical genes and non-canonical genes were found in 12 (5.9%) and 37 (18.1%) patients, respectively. Using signature-based HRD classifier, additional 45 (22.0%) patients were determined to be HRD. Among patients who received first-line FOLFIRINOX ( N = 113), canonical HRD mutation and signature-based HRD group showed higher response rate than non-canonical HRD and non-HRD group (75.0% and 57.1% vs. 31.3% and 33.3%, respectively). In the survival analysis of patients treated with FOLFIRINOX, canonical HRD and signature-based HRD group tended to have better overall survival than non-HRD group. Conclusions: Comprehensive genomic analysis could identify a significant number of HRD pancreatic cancer beyond germline BRCA1,2 and PALB2 mutation, and it would be helpful to choose the appropriate chemotherapy regimen.

Hereditary breast and ovarian cancer syndrome: A misnomer?

10594 Background: Germline pathogenic gene variants (PGV) in homologous recombination deficiency (HRD) genes are traditionally associated with breast, ovarian, pancreatic, prostate and melanoma skin cancer. Recent evidence suggests other cancers may also be associated with these genes. We analyzed the prevalence of somatic HRD mutations in common, traditionally non-hereditary breast and ovarian cancer (HBOC) associated incident cancers in the US. Methods: Data were collected from the American Association for Cancer Research’s (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database version 13.0 via cBioPortal (http://genie.cbioportal.org). This is a publicly available, multi-institutional database of next-generation sequencing (NGS) genomic profiles of tumor samples. The database was queried for all cancers with at least 20,000 incident cases in 2022, as reported by the American Cancer Society, excluding well established HBOC associated cancers – breast, ovarian, prostate, pancreatic, melanoma. Frequencies of somatic PGVs were reported for nine HRD genes currently included in National Comprehensive Cancer Network (NCCN) management guidelines for HBOC: ATM , BARD1, BRCA1, BRCA2, BRIP1, CHEK2, PALB2, RAD51C and RAD51D. Results: A total of 78,285 tumor samples across 12 cancer types were included. At least 1 somatic HRD was found in 6.8% of all included tumors. At least 1 HRD PGV was most common in: Uterine Cancer (694/5,760, 12.1%), Non-Melanoma Skin Cancer (127/1,209, 10.5%), Bladder Cancer (462/4,605, 10.0%), Colorectal Cancer (1306/14,625, 8.9%) Non-Hodgkin’s Lymphoma (5/58, 8.6%), Esophagogastric Cancer (356/4,649, 7.7%), Hepatobiliary Cancer (219/3,325, 6.6%), Lung Cancer (1,480/23,621, 6.3%), Kidney Cancer (113/2,564, 4.4%), Brain Cancer (420/10,206, 4.1%), Thyroid Cancer (89/2,246, 4.0%) and Leukemia (80/5,417, 1.5%). The most common PGVs across all cancer types were BRCA1/2 and ATM (Table). Conclusions: A pan-cancer analysis using NGS data demonstrates a substantial rate of somatic HRD PGVs in common, traditionally non-HBOC associated cancers in the US. These data raise the possibility that germline pathogenic variants in HRD genes could be associated with several more cancers than currently known, underscoring the need for studies evaluating risks of the aforementioned cancers in germline PGV carriers. Additionally, these findings present opportunities for trials evaluating the efficacy of HRD-targeting therapies in these cancers. [Table: see text]

Abstract 4258: Racial and ethnic differences in the mutational landscape of low-grade serous ovarian cancer

Abstract Objective To characterize the mutational landscape of low grade serous ovarian cancer (LGSOC) with racial/ethnic stratification. Methods The AACR Project GENIE database version 12.0 was queried via cBioPortal (http://genie.cbioportal.org) for low-grade serous ovarian cancer (LGSOC) samples. This is a publicly available, de-identified, multi-institutional database of next-generation sequencing genomic profiling results for tumor samples. Mutation frequencies for 9 homologous recombination deficiency (HRD) genes, 4 MAP-Kinase (MAP-K) pathway genes and 6 mismatch-repair (MMR) deficiency genes were reported and compared between racial/ethnic groups using chi-squared or Fischer’s exact tests. The threshold used for statistical significance was a two-sided alpha of 0.05. Results Among 317 tumor samples of LGSOC, there were high rates of MAP-K pathway gene mutations but low rates of HRD, MMR and TP53 gene mutations (Table 1). Non-Hispanic Black patients had significantly higher rates of KRAS mutations compared to non-Hispanic White patients (6/7, 86% vs 48/178, 27%, p<0.01). There was no difference in KRAS mutation frequency among Asian (6/17, 35%), Hispanic (7/24, 29%) and Native American (2/2, 100%) patients when compared to non-Hispanic White patients. BRAF mutations were less common compared to KRAS mutations (32/317, 10%), with no racial/ethnic differences in mutation frequency. Conclusion High rates of MAP-K pathway mutations in LGSOC support development and trials of drugs targeting this pathway, such as MEK protein inhibitors. Furthermore, prior literature has demonstrated the prognostic advantage of KRAS and BRAF mutations in LGSOC as well as the association of KRAS mutations with progression of serous borderline tumors to LGSOC. These racial/ethnic differences in frequencies of these mutations are thus hypothesis generating for clinical research to evaluate the impact of race/ethnicity on the development and prognosis of this rare ovarian cancer. Mutation frequencies of HR, MAP-kinase, MMR and TP53 genes in low-grade serous ovarian cancer Gene No. of samples with ≥1 mutation No. of samples profiled for mutation Mutation frequency BRCA1 3 287 1.05 BRCA2 7 287 2.44 BRIP1 5 271 1.85 CHEK2 2 278 0.72 BARD1 2 239 0.84 RAD51B - - - RAD51C - - - RAD51D 2 246 0.81 PALB2 2 279 0.72 KRAS 93 317 29.34 NRAS 29 317 9.15 BRAF 32 317 10.09 EIF1AX 14 144 9.72 MSH2 3 275 1.09 MSH3 1 113 0.88 MSH6 6 286 2.10 MLH1 1 317 0.32 MLH3 3 96 3.13 PMS2 1 270 0.37 TP53 12 317 3.79 Citation Format: Muhammad Danyal Ahsan, Emily M. Webster, Sarah R. Levi, Natalie T. Nguyen, Juan R. Cubillos-Ruiz, Evelyn Cantillo, Eloise Chapman-Davis, Melissa K. Frey, Kevin Holcomb. Racial and ethnic differences in the mutational landscape of low-grade serous ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4258.

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.

Effect of genomic loss of heterozygosity and homologous recombination deficiency on platinum sensitivity and clinical course in women with epithelial ovarian cancer (175)

Objectives: Genomic loss of heterozygosity (gLOH) and homologous recombination deficiency (HRD) genomic alterations confer an improved response to PARP inhibitors (PARPi) in the management of women with epithelial ovarian cancer (OC). Whether these mutations also confer a significantly improved response to platinum-based chemotherapy is unknown. Chemotherapy with platinum-based agents is the first-line systemic chemotherapy for OC. We sought to evaluate the role of gLOH and HRD mutations in the treatment of OC at our institution. Methods: Tumor tissue was collected from 137 women with OC at our institution and was analyzed for genetic alterations by hybrid-capture, next-generation sequencing for up to 324 genes. Validated algorithms evaluated gLOH (high ≥ 16%), HRD mutation status, and tumor mutations burden (mutations/Mb). Clinical data were abstracted from the medical record for 103 patients with complete information. Thirty-four patients were excluded due to a lack of clinical data. Genomic status was compared with clinical factors, including platinum sensitivity (PS defined as progression-free survival [PFS] > 6 months after treatment), use of neoadjuvant chemotherapy, use of PARPi maintenance, and bevacizumab maintenance, PFS, and overall survival (OS). Statistical analysis was performed using the Chi-square test and log-rank test with p < 0.05 deemed significant. Results: All 103 patients received platinum-based chemotherapy in the neoadjuvant and adjuvant first-line setting. Patients defined as gLOH high were significantly more likely to be PS (77% vs 51%, p < 0.05); however, this did not translate to confer an improved PFS or OS in this cohort (p > 0.05). Patients with alterations in the HRD pathway did not show a significant difference in PS, but the increased response approached significance (80.8% vs 56.5%, p = 0.052). Patients with alterations in the HRD pathway had no difference in PFS (p > 0.05); however, they had a significantly longer OS (p < 0.05). Patients who had optimal cytoreduction in the primary or interval setting demonstrated an improved OS (p < 0.05). Women who received neoadjuvant chemotherapy and underwent interval cytoreduction did not have a significantly different PFS or OS when compared to those who underwent primary cytoreduction (p > 0.05). Conclusions: gLOH was a significant predictor of PS in women with OC. However, this did not translate into improved PFS or OS in this cohort of women with advanced-stage OC. The utility of gLOH for predicting platinum sensitivity may prove useful in other contexts. Patients with HRD alterations showed a trend toward a significant improvement in PS with a significantly longer OS. These data support larger studies that may extend the predictive utility of gLOH and HR mutation status biomarkers. Larger sample size is required to predict the therapeutic advantages of gLOH and HRD mutations in OC during systemic chemotherapy and maintenance therapy. Objectives: Genomic loss of heterozygosity (gLOH) and homologous recombination deficiency (HRD) genomic alterations confer an improved response to PARP inhibitors (PARPi) in the management of women with epithelial ovarian cancer (OC). Whether these mutations also confer a significantly improved response to platinum-based chemotherapy is unknown. Chemotherapy with platinum-based agents is the first-line systemic chemotherapy for OC. We sought to evaluate the role of gLOH and HRD mutations in the treatment of OC at our institution. Methods: Tumor tissue was collected from 137 women with OC at our institution and was analyzed for genetic alterations by hybrid-capture, next-generation sequencing for up to 324 genes. Validated algorithms evaluated gLOH (high ≥ 16%), HRD mutation status, and tumor mutations burden (mutations/Mb). Clinical data were abstracted from the medical record for 103 patients with complete information. Thirty-four patients were excluded due to a lack of clinical data. Genomic status was compared with clinical factors, including platinum sensitivity (PS defined as progression-free survival [PFS] > 6 months after treatment), use of neoadjuvant chemotherapy, use of PARPi maintenance, and bevacizumab maintenance, PFS, and overall survival (OS). Statistical analysis was performed using the Chi-square test and log-rank test with p < 0.05 deemed significant. Results: All 103 patients received platinum-based chemotherapy in the neoadjuvant and adjuvant first-line setting. Patients defined as gLOH high were significantly more likely to be PS (77% vs 51%, p < 0.05); however, this did not translate to confer an improved PFS or OS in this cohort (p > 0.05). Patients with alterations in the HRD pathway did not show a significant difference in PS, but the increased response approached significance (80.8% vs 56.5%, p = 0.052). Patients with alterations in the HRD pathway had no difference in PFS (p > 0.05); however, they had a significantly longer OS (p < 0.05). Patients who had optimal cytoreduction in the primary or interval setting demonstrated an improved OS (p < 0.05). Women who received neoadjuvant chemotherapy and underwent interval cytoreduction did not have a significantly different PFS or OS when compared to those who underwent primary cytoreduction (p > 0.05). Conclusions: gLOH was a significant predictor of PS in women with OC. However, this did not translate into improved PFS or OS in this cohort of women with advanced-stage OC. The utility of gLOH for predicting platinum sensitivity may prove useful in other contexts. Patients with HRD alterations showed a trend toward a significant improvement in PS with a significantly longer OS. These data support larger studies that may extend the predictive utility of gLOH and HR mutation status biomarkers. Larger sample size is required to predict the therapeutic advantages of gLOH and HRD mutations in OC during systemic chemotherapy and maintenance therapy.

Homologous recombination deficiency (HRD) alterations as a predictor of responsiveness to combination pancreatic cancer in advanced pancreatic ductal adenocarcinoma (PDAC).

e16259 Background: Advanced PDAC is associated with a poor prognosis and median survivals of less than one year. FOLFIRINOX and Gemcitabine/Nab-Paclitaxel are both considered standard of care in the first line setting, though there is considerable variability among oncologists regarding sequencing of these regimens. Pre-clinical and clinical data support the use of platinum therapy in HRD+ PDAC, but little is known about how this translates into best practices regarding sequencing of treatment or clinical benefit relevant to Gemcitabine based therapies in this population. Methods: Using the cancer registry and Inova molecular tumor board database, we retrospectively reviewed all patients from January 2015 until November 2021 with unresectable PDAC who had NGS performed and stratified by the presence or absence of HRD mutation. HRD mutations included by BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, ARID1A, FANCA, FANCL. We analyzed for RR to Folfirinox/Folfox and Gemcitabine based therapies, adjusted time to progression on Folfirinox/Folfox (time from first dose of oxaliplatin based combination to first dose of gemcitabine to account for those who stopped oxaliplatin early for neuropathy or received maintenance therapy), and time on gemcitabine based therapy. Results: 142 consecutive patients with advanced PDAC were examined, including 20 with HRD variants. When excluding those who eventually received surgery and those who never received platinum therapy, we were left with 87 (74 in Control and 13 in HRD) for analysis. RR to Folfirinox/Folfox was 60% in HRD+ and 31.25% in control (p = 0.71) (Table). Mean adjusted time to progression on Folfirinox/Folfox was 320.0 days in HRD+ group and 252.9 in the control group (p = 0.57) (Table 2). The time on treatment for gemcitabine based combination therapy was 260.7 in HRD+ and 165.1 in control group. Conclusions: HRD+ patients had longer durations of treatment on both 5-FU based therapy and Gemcitabine based combinations. These data challenges the importance of first line platinum therapy in HRD+ patients, and further exploration should be considered.[Table: see text]

Optimized molecular classification of endometrial carcinoma-based on the combination of POLE mutations with homologous recombination deficiency (HRD).

e17628 Background: Molecular analysis of endometrial carcinoma (EC) has identified four clinically significant molecular subgroups with different prognoses: POLE mutations, microsatellite instability-high (MSI-H/dMMR), copy number low (CN-L/p53-normal), and copy number high (CN-H/p53-aberrant). However, the convenience and repeatability of detection methods for molecular classification, as well as the evaluation of their prognostic significance, need to be further explored. Recently, homologous recombination deficiency (HRD) has been studied to show the prognostic value in EC. Here, we aimed to establish a next-generation sequencing (NGS)-based one-stop method with the combination of HRD and POLE mutations for molecular classification of EC. Methods: Paraffin-embedded tissues of 143 eligible EC patients were collected from Beijing Cancer Hospital between 2011 and 2020 and sequenced using a panel of 520 cancer-related genes which could also detect MSI status (OncoScreen Plus, Burning Rock Biotech). HRD score was calculated as the sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST) scores based on the sequencing data. Results: The median follow-up time in this cohort was 38.77 months. We firstly classified EC patients into four subgroups: POLE mutations (mut) (n = 9, 6.3%), MSI-H (n = 45, 31.5%), TP53 wildtype (wt) (n = 67, 46.9%), and TP53 mut (n = 22, 15.4%). POLE mut subgroup had the excellent prognosis as no patient in this subgroup relapsed after surgical resection. Compared with TP53 mut subgroup, the other two subgroups had better prognosis [disease free survival (DFS): TP53 wt: hazard ratio (HR), 0.2, 95% CI, 0.07-0.57, P = 0.003; MSI-H: HR, 0.2, 95% CI, 0.06-0.68, P = 0.01; overall survival (OS): TP53 wt: HR; 0.11, 95% CI, 0.02-0.56, P = 0.008; MSI-H: HR, 0.25, 95% CI, 0.06-1.03, P = 0.055]. Except for the patients with POLE mut, the others were then further optimized and divided into two groups based on HRD score with the cutoff of 13: HRD-high (n = 15, 11.5%) and HRD-low (n = 116, 88.5%). Patients in HRD-low subgroup showed much improved survival than those in HRD-high subgroup (DFS: HR, 0.06, 95% CI, 0.02-0.15, P &lt; 0.001; OS: HR, 0.06, 95% CI, 0.02-0.21, P &lt; 0.001). Most notably, the postoperative recurrence rate was 36.4% in the TP53 mut subgroup with the worst prognosis in the traditional classification, and 66.7% in the HRD-high subgroup with the worst prognosis in the optimized classification. Conclusions: The method of classifying EC patients into four subgroups by NGS large panel provides similar clinical features to previous reports classified by other methods but is more convenient and stable. Furthermore, the method of combination of POLE mutations with HRD offers more accurate disease risk stratification and demonstrates the potential for directing therapy for EC patients.

PARP-remmers bij gemetastaseerde prostaatkanker: een systematische review

PARP inhibitors in metastatic prostate cancer: a systematic review Background. Poly ADP-ribose polymerase (PARP) inhibitors provide a novel therapeutic approach for the treatment of metastatic prostate cancer. They act on the homologous recombination DNA repair mechanism. In metastatic prostate cancer, 20-25% of the patients harbour a homologous recombination repair deficiency. This review investigates the current evidence for the use of PARP inhibitors in clinical practice. Methods. The databases MEDLINE, CENTRAL and EMBASE were searched, as well as the clinical trial registries EudraCT and Clinicaltrials.gov. Randomised controlled trials with PARP inhibitors were included. The outcomes of interest were: overall survival (OS), progression-free survival (PFS), objective response rate (ORR), adverse events and quality of life. The data were analysed according to Cochrane methodology. Results. Three controlled trials were included, all in a castration-resistant setting. Five phase 2 trials were excluded; these data are presented in a narrative form. One study of olaparib in monotherapy versus enzalutamide or abiraterone found a benefit in OS and PFS in patients with a BRCA1, BRCA2 or ATM mutation, though not in patients with other HRD (‘homologous recombination deficiency’) mutations. Two studies investigated a PARP inhibitor in combination with abiraterone versus abiraterone in monotherapy. The combination with olaparib showed a modest PFS benefit, whereas the veliparib combination showed no OS or PFS benefit. Conclusion. At present, the role of PARP inhibitors is limited to BRCA1, BRCA2 and ATM mutation carriers. Combination therapy with other agents could provide a synergistic advantage and is being researched. Fourteen ongoing trials meet the inclusion criteria and will clarify the role of PARP inhibitors in the treatment of prostate cancer.

Genomic profiles and clinical outcomes in primary versus secondary metastatic hormone-sensitive prostate cancer.

Clinical outcomes may differ among patients presenting with primary (de novo) metastatic hormone-sensitive prostate cancer (mHSPC) versus secondary (metachronous) mHSPC occurring after local therapy. It is unknown what molecular features distinguish these potentially distinct presentations. A single-center retrospective study of mHSPC patients classified as primary mHSPC (n = 121) or secondary mHSPC (n = 106). A targeted set of genes was analyzed: BRCA2, PTEN, RB1, TP53, SPOP, CDK12, any two out of PTEN/RB1/TP53 alterations, and homologous recombination deficiency mutations. TP53 mutations were categorized as loss-of-function (LOF) versus dominant-negative (DN). The impacts of genetic features on progression-free survival (PFS) and overall survival (OS) were assessed using univariate and multivariate Cox proportional hazards regression. Median PFS was 15 and 30 months for men with primary and secondary mHSPC, respectively (hazard ratio: 0.57, 95% confidence interval: 0.41-0.78; p < .01). OS did not show a significant difference between groups. There were more men with Gleason 8-10 disease in the primary versus secondary mHSPC groups (83% vs. 68%;p < .01). In univariate and multivariate analyses, TP53 DN mutations showed a statistically significant association with OS for the entire mHSPC population. Conversely, SPOP mutations were associated with improved OS. Additionally, TP53 mutations (DN and LOF) were associated with worse OS for secondary mHSPC. A combination of PTEN/RB1/TP53 mutations was associated with worse OS and PFS for secondary mHSPC, while no genomic alteration affected outcomes for primary mHSPC. TP53 DN mutations, but not all TP53 alterations, were the strongest predictor of negative outcomes in men with mHSPC, while SPOP mutations were associated with improved outcomes. In subgroup analyses, specific alterations were prognostic of outcomes in secondary, but not primary, mHSPC.

31P Accurate detection of HRD status in multiple cancer types using somatic mutation pattern

Homologous Recombination Deficiency (HRD) is caused by various molecular alterations in genes that participate in HR repair. However, HR is a complicated biological process and it is unlikely that all HRD causing alterations have been uncovered so far. We hypothesized that HRD detection based on mutation pattern can accurately detect HRD status with better patient stratification. We retrieved mutations of ovarian cancer from TCGA repository. Samples treated with platinum chemotherapy were selected for further analysis. Mutation pattern were profiled using negative matrix factorization (NMF) method. Samples were tiered based on weight of HRD-related mutation signature. Cox model was applied to compare survival of samples of each tier against non-HRD samples separately. To test the feasibility of our method on targeted sequencing data, mutation profile was shrunk to selected genomic region composed of 825 genes (∼ 2.2Mb). We retrieved 192 in-house clinical samples and labeled HRD status based on known HRD causing variants. We applied our method on these samples to inspect the consistency. 375 samples were profiled for HRD status and were divided into four tiers based on the weight of HRD-related mutation pattern. Cox model showed significant survival difference (p-value = 0.001) proportional to the weight of HRD mutation pattern with higher weight being the longest survival and vice versa. 223 and 152 samples were categorized as HRD and non-HRD based on optimized threshold and survival difference remains significant (p-value = 0.0017). Similar survival difference was observed (p-value=0.0013) suggesting the validity of the method on targeted sequencing. Out of 124, 49 and 19 breast, ovarian and prostate cancer samples, 13, 11 and 4 of them were labeled as HRD positive based on known HRD causing variants. All but one HRD positive samples were consistently classified by our method. Our results showed that NMF method is able to faithfully detect HRD samples. The method can be applied to WES as well as targeted sequencing and achieve equally significant survival difference between samples with different HR status. Upon detecting HRD, this method can identify additional HRD patients and therefore make better patient stratification.

Abstract B105: The impact of ancestry on mutational and immune signatures in triple-negative breast cancers

Abstract Background: Oncologist found that Androgen Receptor (AR) therapies work in 10% of Triple Negative Breast Cancer (TNBC) patients. Recently we published that women with AR- TNBC, Quadruple Negative Breast Cancer (QNBC), have an Immune basal Signature that’s particularly prevalent in AA women. AA women at a similar mean age of incidence as QNBC AA (47) have increased chances of methylation as a Homologous Recombination Deficiency (HRD) compared to white women. For this reason, we explored QNBC patients to see what correlation may exist between AR, ancestry, immune signatures, and HRD. Methods: We analyzed mRNA expression and HRD events in 987 tumors from The Cancer Genome Atlas. Samples were dichotomized as AR positive or negative using mean gene expression cutoff. Global Ancestry was calculated using Structure. Immune signatures were obtained from TIMER. Mutational Signatures were determined from COSMIC. Linear regression models, forest plots, and Correlation Plots were made using R packages. Pathway analysis was done using the Hallmarks geneset in GSEA and Pathway Studio. Results: Our analysis found significant upregulation of PD-1 (p = 0.001), PD-L1 (p = 0.037), and CTLA-4 (p&amp;lt;0.0001) in QNBC vs non-QNBC patients, as well as upregulated PD-1 (p = 0.017), PD-L1 (p = 0.011), and CTLA-4 (p = 0.0114) in AA QNBC vs CA QNBC using linear regression models adjusted for age and stage. We also found an upregulation in TH-1(p &amp;lt; 0.0001) and TH-17(p &amp;lt;0.0001) differentiation pathways in AA QNBC patients compared to CA QNBC patients found through pathway studio. We also observed that of the 20 AA patients that had an HRD only 2 were mutations while the other 18 were caused by Epigenetic Silencing. We found that West African global ancestry is associated with lower expression of BRCA1 (p = 0.0113), BRCA2 (p &amp;lt; 0.001), RAD51C (p = 0.0208) and, PALB2 (p &amp;lt; 0.001). We also found that within QNBC patients European global ancestry was inversely associated with the APOBEC mutational signature (p = 0.027) and West African global ancestry was inversely associated with the “Aging” mutational signature (p = 0.0256). There was no significant association with global ancestry and the HRD signature. Conclusion: The use of AR as a biomarker may lead to better diagnosis of aggressiveness for breast cancer patients especially for AA women and women with TNBC. QNBC patients may be receptive to immune therapies in particular patients of African Ancestry. Most patients with HRD are likely to be QNBC. West African global ancestry was associated with lower levels of the Aging signature and European global ancestry was associated with lower levels of APOBEC mutational Signature. Also, Women of African Ancestry are more likely to have epigenetically silenced DNA repair mechanism compared to Mutations in it while women of European descent have similar chances of having both. Despite this neither groups global ancestry had a significant association with the HRD mutation signature. Further research is needed to determine the impact of local ancestry on the HRD signature. Citation Format: Raymond W Hughley, Clayton Yates, Paz Polak. The impact of ancestry on mutational and immune signatures in triple-negative breast cancers [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B105.

Identification of SLX4 as the most frequently mutated gene in homologous recombination deficiency in Asian gastric cancer.

4570 Background: Gastric cancer is the third most common malignancy worldwide. Homologous recombination (HR) is a type of genetic recombination, and homologous recombination deficiency (HRD) is highly involved in multiple types of cancers and can predict response to anticancer therapies. However, homologous recombination deficiency is not well characterized in patients with Asian gastric cancer. Methods: 196 Asian patients with gastric cancer were analyzed in this study. A list of 102 genes related to HRD was compiled based on previous literature. Haplox 605-gene panel was used to capture the sequencing library. Mutations related to HRD were analyzed following next-generation sequencing. In addition, tumor mutational burden (TMB) was calculated by dividing the total number of mutations by the size of the coding region. The correlation analysis between HRD and TMB was also conducted. Results: In total, 43 (21.94%) of 196 Asian patients with gastric cancer harbored at least one HRD gene. The top 10 mutant HRD genes included SLX4 (3.57%), ATR (2.04%), RECQL (1.53%), NBN (1.53%), ERCC4 (1.53%), BAP1 (1.53%), ATM (1.53%), RAD54L (1.02%), BRCA1 (1.02%) and PARP1 (1.02%). In addition, the occurrence of HRD mutations was significantly correlated with a higher TMB. The median TMB of HRD group (8.28 muts/Mb) was significantly higher than that of the Non-HRD group (3.07 muts/Mb) (p &lt; 0.01). The overall upper quantile value (4.80 muts/Mb) was used to screen patients with high TMB (TMB-H). The TMB-H in HRD group was significantly higher than the Non-HRD group (44.19% VS 17.92%, p &lt; 0.01). Conclusions: Our study described that SLX4 was the most frequently mutated HR-related gene in Asian gastric cancer. Moreover, the positive correlation with homologous recombination deficiency (HRD) and tumor mutational burden (TMB) was observed in these patients.

MiST1: A phase IIa trial of rucaparib in patients harbouring BAP1/BRCA1 deficient relapsed malignant mesothelioma.

9057 Background: Malignant Mesothelioma (MM) remains an incurable cancer lacking effective treatments in the relapsed setting. Personalised therapy is still in its infancy. Homologous recombination (HR) deficiency associated with BRCA1 mutation has been shown to predict sensitivity to inhibition of poly-ADP ribose. In MM, BRCA1 associated protein 1 carboxy-terminal hydrolase (BAP1) is frequently mutated. It regulates both HR, and BRCA1 expression which is lost in 38% of mesotheliomas. Mesothelioma Stratified Therapy 1 (MiST1) was designed to test the hypothesis that BAP1/BRCA1 negative mesotheliomas would exhibit defective HR and exhibit sensitivity to PARP inhibition. Methods: MiST1 was a single centre, open label single arm phase IIa design with prospective molecular stratification; cytoplasmic/negative BAP1 or BRCA1 deficient MM was deemed eligible. Treatment was 600mg BD rucaparib (R) PO daily every 28 days for 6 cycles or until disease progression, unacceptable toxicity, withdrawal or death. Primary outcome was disease control rate at 12 weeks (DCR12w); secondary outcomes safety and toxicity profile, objective response rate (ORR) and DCR at 24 weeks (DCR24w). The null hypothesis states the true DCR12w is less than or equal to 25% and was tested against a one-sided alternative hypothesis that the DCR12w will be equal to or greater than 50%. Results: Between February 2019 and June 2019, 26 patients (pts) were eligible and consented to MiST1, median age 65.5 years, 85% are male and 15% female. Of these pts 15% had an ECOG performance status (PS) of 0 and 85% had an ECOG PS of 1. Molecular eligibility was 89% for BAP1 alone, 50% BRCA1 alone, and 39% BAP1+BRCA1. Primary tumour site was thoracic (96%) and subtype epithelioid (81%). DCR12w was 57.7% (95% CI, 36.9 - 76.7), DCR24w was 23.1% (95% CI, 9.0 – 43.7) and ORR was 11.5% (95%CI, 2.5 – 30.2). R was well tolerated with 9% (15/166) grade (G) 3/4 toxicities seen in 10 pts (38%), with no G5 toxicities. The most common adverse events were nausea occurring in 18 pts (69%), fatigue in 14 pts (54%), and decreased appetite in 10 pts (38%). Six cycles of R was received by 8 pts (30.8%). Dose reductions occurred in 9 pts (n = 8; 1 dose and n = 1; 2 doses). Dose delays occurred in 14 pts. Conclusions: MiST1 using the PARP inhibitor R met its primary endpoint of disease control rate at 12 weeks, showing promising efficacy with manageable toxicity. HR deficiency mutation signature enrichment is being investigated to refine the identification of responders to PARP inhibition. PARP inhibition warrants further investigation in MM. Clinical trial information: NCT03654833.

The prognostic value of HRD mutations in liver cancer.

e13546 Background: Liver cancer is the sixth most common cancer in the world and the fourth most common cause of cancer mortality. Genomic alterations including homologous recombination deficiency (HRD) mutations often lead to aberrant regulations of signaling pathways, which play an important role in tumorigenesis. The prognostic value of HRD mutation and its correlation with overall survival in liver cancer is unclear. Methods: We used cBioPortal platform to analyze a cohort of 978 liver cancer samples. Mutations in 13 genes (BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, ABRAXAS1, MRE11, NBN, PALB2, RAD51C, RAD51D) were screened due to the fact that they are the most common indication of deficiency in the homologous recombination (HR) DNA repair pathway. We define overall survival (OS) as the time between the sample collection (surgical) date and the date of death or the last follow-up visit. We conducted Kaplan-Meier survival analysis, and the statistical differences were compared by log-rank tests. Results: 228 of the cases harbored at least one mutation of the HRD-indicator genes. Based on the result, patients were divided into the HRD and non-HRD group. The median OS of the HRD group was 45.47, which is significantly shorter than the OS of the non-HRD group (log-rank test p = 1.6196e-4, Table). Conclusions: HRD mutations are significantly associated with a shorter OS in liver cancer patients. HRD mutation was a negative prognostic factor for overall survival in liver cancer, but the underlying mechanisms remain to be explored. [Table: see text]

Phase I study of rucaparib and irinotecan in advanced solid tumors with homologous recombination deficiency (HRD) mutations.

3513 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for multiple tumor types with HRD mutations. In efforts to prolong durations of response, combination treatments of PARPi and chemotherapy are being explored. However, expected overlapping toxicities have previously limited the tolerability of PARPi-chemotherapy combinations. Preclinical studies suggest that the inhibition of PARP will prevent the repair of topoisomerase induced DNA strand breaks. In this Phase I trial, we test whether pulse dosing and alternate treatment schedules of rucaparib and irinotecan are safe and tolerable. Methods: Rucaparib and irinotecan were dose escalated in a 3+3 design. Patients with advanced solid tumors and somatic or germline known or suspected pathogenic mutations in HRD were accepted on trial. 15 patients have been enrolled in 3 cohorts and treated with rucaparib 400 mg BID (days 1-7) and irinotecan 65 mg/m2 (cohort 1) or 100 mg/m2 (cohort 2) every 2 weeks or 100 mg/m2 every 3 weeks (cohort 2i). Results: Tumor types on trial are heterogeneous and include pancreatic ductal adenocarcinoma (PDAC: 3), cholangiocarcinoma, neuroendocrine carcinoma of the pancreas, ovarian cancer/primary peritoneal carcinoma (3), prostate cancer, small bowel carcinoma, squamous cell carcinoma of the tonsil, testicular cancer, triple negative breast cancer, and urothelial carcinoma. 14/15 patients had 3+ prior lines of therapy. Mutation types include: 7 ATM, 3 BRCA1, 3 BRCA2, 1 CHEK2, and 1 PALB2. All patients were previously exposed to platinum chemotherapies; 8/15 had progressive disease while on platinum. 5/15 patients had prior PARPi with progression. There were 3 DLT events, all of which were related to grade 3 or 4 neutropenia. Of the 13 patients evaluable for response, there was one confirmed partial response (PR). 5 patients have remained on study for longer than 6 months and 3 patients with ATM mutations have remained on study for longer than one year (primary peritoneal cancer, small bowel carcinoma, PNET). 4/5 patients with clinical benefit had prior platinum progression and 1/5 had previously progressed on a PARPi. Our current recommended phase 2 dose is rucaparib 400 mg BID days 1-7 and irinotecan 100 mg/m2 every 3 weeks. Conclusions: The pulse dosing schedule of rucaparib and irinotecan has allowed for long term tolerability and exposure to both agents with encouraging efficacy in patients with ATM mutations. Further testing of PARPi and topoisomerase inhibitors at this schedule in patients with ATM mutations is planned. Clinical trial information: NCT03318445 .

Association between homologous recombination deficiency and tumor mutational burden in lung cancer.

e21043 Background: Homologous recombination (HR) is an important repair method for DNA double-strand damage. HR is involved with complex signaling pathways and multiple steps, including BRCA1/2. Homologous Recombination Deficiency (HRD) can be caused by the loss of function of BRCA1/2 proteins due to gene mutation. Tumor mutational burden (TMB) was indicated to involved with HRD, which is critical to the guidance of immunotherapy. Methods: Patients available with tumor specimen genomic testing for lung cancer were enrolled in this study. The sequencing library was captured using a 605-gene panel. Homologous recombination (HR)-related gene list included 102 genes. Genomic alterations of HR-related genes were assessed by next-generation sequencing assay, including nonsense, nonstop, frameshift, splice site, damaging missense mutations in somatic variants and pathogenic germline variants. Then, TMB was calculated by dividing the total number of mutations counted by the size of the coding region. Results: A total of 741 patients was enrolled and 182 of them (25.6%) had at least one genomic alteration of the HR genes. The top mutant HR genes included ATM (4.1%), DNMT3A (2.8%), ATR (1.8%), CHEK2 (1.5%), BRCA2 (1.5%), ABL1 (1.4%), FANCA (1.2%), RIF1 (1.1%), FANCI (1.1%), RAD50 (0.9%), BRCA1 (0.9%), and MRE11A (0.9%). The most common mutational type was missense mutation (69.2%), followed by frameshift (15.6%), and nonsense mutation (15.2%). The median age was 62 in the HRD group (age &lt; 45:5.4%, 45-65:59.6%, &gt; 65:34.9%) compared to 60 in the rest of the patients (age &lt; 45:11.3%, 45-65:61.3%, &gt; 65:27.4%). There were overall 57.5% males and 42.5% females in terms of gender. HRD group had a significantly higher rate than Non-HRD group in males (72.1% vs 52.8%, p &lt; 0.01). The occurrence of HRD mutations was significantly correlated with a high level of TMB (p &lt; 0.01). The median TMB of HRD group (7.9 muts/Mb, 95%CI:7.1-9.2 muts/Mb) was significantly higher than that of Non-HRD group (3.8 muts/Mb, 95%CI:3.3-4.2 muts/Mb). In addition, the upper quantile value (7.5 muts/Mb) was used to identify patients with high TMB. HRD group had a significantly higher rate of TMB-high patients than Non-HRD group (51.1% vs 17.0%, p &lt; 0.01). Conclusions: Our study demonstrated genomic alterations of the HR genes in about one fourth’s lung cancer. Besides, there was a significant positive correlation between HRD mutations and TMB level. The significance of HRD genomic mutation on predicting the efficacy of immunotherapy deserves further study.

Genomic and clinical characterization of pulmonary-only metastatic prostate cancer: A unique molecular subtype.

Isolated pulmonary involvement is uncommon in metastatic hormone-sensitive prostate cancer (mHSPC). To characterize outcomes and molecular alterations of this unique patient subset, we conducted a retrospective review of patients with hormone-naïve prostate cancer presenting with lung-only metastases. This was a retrospective single-institution study. Medical records of 25 patients presenting with pulmonary-only metastases before receiving androgen deprivation therapy (ADT) were analyzed. Germline and/or somatic genomic results, where available (n = 16), were documented. Tumor tissue was analyzed using clinical-grade next-generation DNA sequencing assays. Clinical endpoints included complete prostate-specific antigen (PSA) response to ADT (<0.1 ng/mL), median overall survival (OS) from time of ADT initiation, median PSA progression-free survival (PSA-PFS), and failure-free survival (FFS) at 4 years. Baseline characteristics were notable for 48% of men (12 of 25) having first or second-degree relatives with prostate cancer, compared with 20% expected. Complete PSA responses to ADT were noted in 52% of men, with a median PSA-PFS of 66 months, a 4-year FFS rate of 72%, and a median OS that was not reached after 190 months. In evaluable patients, molecular drivers were enriched for mismatch repair mutations (4 of 16, 25%) and homologous-recombination deficiency mutations (4 of 16, 25%). These results are limited by the small sample size and retrospective nature of this analysis. This exploratory study represents one of the largest cohorts of lung-only mHSPC patients to-date. The prevalence of actionable DNA-repair gene alterations was higher than anticipated (any DNA-repair mutation: 8 of 16, 50%). Compared to historical data, these patients appear to have exceptional and durable responses to first-line ADT. This study suggests that pulmonary-tropic mHSPC biology may be fundamentally different from nonpulmonary mHSPC.