Homologous Recombination Deficient Patients Research Articles

Abstract 3726: Absence of synergistic effects for PARPi and immunotherapy combinations in ex vivo 3D micro tumor assay for ovarian cancer patients

Abstract Introduction: 50% of ovarian cancers are homologous recombination deficient (HRD), with 15% of the patients carrying a BRCA mutation. PARP inhibitors (PARPi) are designed to improve survival in HRD patients, but clinical responses to PARPi often do not match HRD status. In this study, a 3D ex vivo tumor testing platform was applied to quantify patient-specific drug responses to (combinations of) PARPi, chemo- and immunotherapies. Material and Methods: 81 patients with ovarian cancer eligible for chemotherapy were included in the trial between 2019 and 2022 in the Netherlands (IRB P18.032). Tumor clusters were isolated from ascites and solid tissue, seeded and exposed to three PARPi, standard-of-care chemotherapies and immunotherapies, both single agent and in combination. Ex vivo drug sensitivity was quantified using high-throughput 3D imaging and extraction of morphological features. Bliss scores were calculated for synergy analysis. Results: Results were generated in two weeks after sample collection. Ex vivo patient-specific response profiles were observed for all drug classes, with a small percentage of patients (7%) showing strong PARPi sensitivity reflected by strong tumor cluster shrinkage upon treatment. Significant correlation of drug sensitivity profiles was observed comparing the different PARPi between themselves, but also comparing PARPi and platinum responses. Interestingly, ex vivo sensitivity to olaparib and immunotherapy combinations demonstrated additive, but no synergistic effects (21 patients, 79 tests). In addition, olaparib responses were shown to be independent of immune responses (SEA). Conclusion: This study applied a predictive ex vivo 3D micro tumor testing platform to classify patient-specific sensitivity to (a combination of) PARPi, chemo- and immunotherapies in over 80 patients. The current dataset demonstrates the potential of ex vivo testing to identify patients that are responsive to PARPi. No synergistic effects were observed for these drugs in combination with immunotherapies. Discussion: Evaluation of PARPi responses in a functional 3D micro tumor assay could support identification of responsive patients prior to treatment. Distinct responses were observed for PARPi and immunotherapies. No synergistic but additive effects were measured, suggesting that ovarian cancer patients could benefit from PARPi and immunotherapies. Correlation of clinical and ex vivo drug responses to PARPi in combination with available HRD tests will further validate the platform for predicting patient clinical outcome. Citation Format: Lieke J. Ceton, Esmee Koedoot, Timothy J. Sijsenaar, Dieudonné J. van der Meer, Marta Montero Garcia, Jurrian van der Valk, Kristofer Maad, Cor de Kroon, Anne van Altena, Willemijn Vader, Judith Kroep, Nelleke Ottevanger. Absence of synergistic effects for PARPi and immunotherapy combinations in ex vivo 3D micro tumor assay for ovarian cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3726.

Abstract IA008: Targeting homologous recombination deficiency (HRD) using optimized ionizing radiation and drug combinations

Abstract Homologous recombination deficiency (HRD) is found not only in germline mutation carriers of HR genes but is also observed in sporadic cancers when both copies of the HR gene are inactivated. Recognition of HRD is facilitated by using genomic landscape alterations in addition to target gene sequencing. In addition, HR function can be established by measuring RAD51 foci in tumor specimens, particularly if they are irradiated ex-vivo to reveal the HR pathway function more clearly. Triple negative breast cancer (TNBC) is highly enriched for HRD constituting ~45% of primary tumors and over 50% of locally recurrent or metastatic cancers. In a clinical trial of recurrent TNBC, we used the combination of ionizing radiation (IR) with low-dose weekly cisplatin (cis) to study the clinical response according to HRD status. The combination of IR + cis has been shown in HRD cells to be more sensitizing than either agent alone. In the clinical study of 49 TNBC patients, there were imaging responses in 22/29 (75%) HRD patients, but only in 4/20 (20%) HR-proficient patients. We have followed this study by investigating the combination of the PARP-inhibitor with radiotherapy in an ongoing clinical trial as well as with detailed cell-based studies. HRD cells have elevated PARP activity at baseline, as observed by the extent of PARylated proteins, plus the lower baseline levels of NAD. When PARP-inhibitors are combined with radiotherapy, there is demonstrable supra-additive sensitization at 6Gy of IR and up to 100nM talazoparib (TZ). However, when the dose of TZ is above 1 µM, there is paradoxical recovery from the combination therapy, due to rescue of NAD depletion in HRD cells. The threshold for seeing this paradoxical recovery effect in HR-proficient cells was not reached. One of the mechanisms of cell killing in HRD cells is enhanced parthanatos, which higher doses of TZ will prevent, particularly in conjunction with IR. The implication of this work is that the optimal combination of radiotherapy with PARP-inhibitor may not be the maximum tolerated dose, but rather a tuned level of the combination to maximize radiosensitization without exceeding the threshold for PARP-inhibitor mediated protection of cell death. It is already observed that the maximum tolerated dose of PARP-inhibitor in the setting of curative doses of IR have to be modified by 3-10-fold. Further optimization of the combination dosing to achieve the maximal therapeutic ratio will be discussed including the development of biomarkers to achieve this goal. Additional radiation combinations with synthetic lethal targets of HRD will be discussed. Citation Format: Simon N. Powell, Niamh McDermott, Robert Delsite. Targeting homologous recombination deficiency (HRD) using optimized ionizing radiation and drug combinations [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA008.

Correlation of homologous recombination deficiency (HRD) score with response to the first-line treatment of immune checkpoint inhibitors plus chemotherapy in non-small cell lung cancer.

e21121 Background: Homologous recombination (HR) gene mutations were reported to be associated with efficiency of immune checkpoint inhibitors (ICIs). However, up to date, no recognized standard has been set up for definition of HR mutation (+), which limited its clinical application. Homologous recombination deficiency (HRD) score reflects genomic scar induced by HR genes alteration and disfunction. Thus, it may be worth to explore whether HRD score could predict the efficacy of ICIs-based therapy. Methods: We collected tumor tissues from metastatic non-small cell lung cancer (NSCLC) patients who received first-line treatment of ICIs combined with platinum-based chemotherapy. HRD score testing were carried by BGI genomic scar analysis kit, which calculates the sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), large-scale state transitions (LST) scores, and corrected by ploidy of tumor samples, through next generation sequencing(NGS) data. The association of HRD score and response to ICIs plus chemotherapy were analyzed. Results: 22 EGFR/ALK wild-type metastatic NSCLC patients were included. The average HRD score was 24.57, varying from -26.37 to 92.34. Threshold traversal was performed based on analysis of the progression free survival (PFS) data from the included NSCLC patients. HRD score 31 or more were define as HRD (+). Kaplan-Meier PFS Survival analysis showed prolonged median PFS (mPFS) in HRD (+) versus HRD (-) NSCLC patients (N/A vs. 7.0 ms, Log-rank P = 0.029; HR 0.20, 95%CI 0.04-0.96, likelihood-ratio P = 0.03). The objective response rate (ORR) was 45.5% (5/11) in HRD(+) versus 27.2% (3/11) in HRD(-) patients. In patients with PD-L1 TPS≥1% (22C3), the mPFS was N/A vs. N/A, and the ORR was 75.0% (3/4) vs. 37.5% (3/8), in HRD (+) vs. HRD(-) patients. In patients with PD-L1 TPS < 1% (22C3), the mPFS was 8.5 ms vs.2.0 ms (Log-rank P = 0.0085; HR 0.08, 95%CI 0.01-0.82, likelihood-ratio P = 0.02), and the ORR were 28.6% (2/7) vs. 0%(0/3), in HRD (+) vs. HRD(-) patients. Conclusions: In addition to PD-L1 expression level, HRD score would be a potential promising biomarker for predicting the efficiency of ICIs plus platinum-based chemotherapy in NSCLC patients.

Genomic and molecular landscape of homologous recombination deficiency across multiple cancer types

Homologous recombination deficiency (HRD) causes faulty double-strand break repair and is a prevalent cause of tumorigenesis. However, the incidence of HRD and its clinical significance in pan-cancer patients remain unknown. Using computational analysis of Single-nucleotide polymorphism array data from 10,619 cancer patients, we demonstrate that HRD frequently occurs across multiple cancer types. Analysis of the pan-cancer cohort revealed that HRD is not only a biomarker for ovarian cancer and triple-negative breast cancer, but also has clinical prognostic value in numerous cancer types, including adrenocortical cancer and thymoma. We discovered that homologous recombination–related genes have a high mutation or deletion frequency. Pathway analysis shows HRD is positively correlated with the DNA damage response and the immune-related signaling pathways. Single cell RNA sequencing of tumor-infiltrating lymphocytes reveals a significantly higher proportion of exhausted T cells in HRD patients, indicating pre-existing immunity. Finally, HRD could be utilized to predict pan-cancer patients’ responses to Programmed cell death protein 1 immunotherapy. In summary, our work establishes a comprehensive map of HRD in pan-cancer. The findings have significant implications for expanding the scope of Poly ADP-ribose polymerase inhibitor therapy and, possibly, immunotherapy.

PARPi monotherapy as first-line maintenance following chemotherapy + bevacizumab in advanced ovarian cancer.

e17601 Background: Chemotherapy (CT) + bevacizumab is a standard-of-care option for first-line (1L) treatment for patients with advanced ovarian cancer (AOC). Real-world approaches to 1L maintenance (1LM) treatment include, among others, bevacizumab monotherapy or switching to poly(ADP-ribose) polymerase inhibitor (PARPi) monotherapy after completing 6–9 cycles of induction CT + bevacizumab. Methods: We identified 61 patients with AOC from the US-based, deidentified Integra PrecisionQ database who received 1LM bevacizumab monotherapy (n=27) or PARPi monotherapy (n=34) after 1L CT + bevacizumab initiated between July 1, 2019, and March 31, 2021, and followed them until the data cut-off of March 31, 2022. Using the start of 1LM therapy as the index date, we examined patient characteristics, time to next treatment or death (TTNT; often used as a real-world proxy for progression-free survival), and overall survival (OS) for these two treatment groups. Results: For patients who received 1LM bevacizumab, the median age was 69 years, 89% had Eastern Cooperative Oncology Group (ECOG) performance status 0–1, 63% had Stage III disease at index, and only 1 (4%) had a recorded/documented homologous recombination deficiency (HRd)-positive tumor. Of the 34 patients who switched to 1LM PARPi monotherapy, 21 (62%) received olaparib, 12 (35%) niraparib, and 1 (3%) rucaparib. The median age of these patients was 63.5 years, 94% had ECOG performance status 0–1, 62% had Stage III disease at index date, and 47% had HRD+ tumors. For patients who switched to 1LM PARPi monotherapy, the median TTNT was 10.8 months (mo) and 97% were still alive at the 12-month mark. For patients who continued with 1LM bevacizumab, the median TTNT was 4.9 mo and 81% remained alive at the 12-month mark. Conclusions: This study suggests that switching to maintenance with PARPi monotherapy following induction CT + bevacizumab is a viable option for the treatment of AOC. A higher prevalence of HRd patients switching to PARPi monotherapy may indicate clinician preference for PARPi monotherapy in biomarker-selected subgroups, and further analysis is needed to examine which patients are most likely to benefit from switch maintenance. Funding: GSK215281. [Table: see text]

Copy number alteration features in pan-cancer homologous recombination deficiency prediction and biology

Homologous recombination deficiency (HRD) renders cancer cells vulnerable to unrepaired double-strand breaks and is an important therapeutic target as exemplified by the clinical efficacy of poly ADP-ribose polymerase (PARP) inhibitors as well as the platinum chemotherapy drugs applied to HRD patients. However, it remains a challenge to predict HRD status precisely and economically. Copy number alteration (CNA), as a pervasive trait of human cancers, can be extracted from a variety of data sources, including whole genome sequencing (WGS), SNP array, and panel sequencing, and thus can be easily applied clinically. Here we systematically evaluate the predictive performance of various CNA features and signatures in HRD prediction and build a gradient boosting machine model (HRDCNA) for pan-cancer HRD prediction based on these CNA features. CNA features BP10MB[1] (The number of breakpoints per 10MB of DNA is 1) and SS[ > 7 & <=8] (The log10-based size of segments is greater than 7 and less than or equal to 8) are identified as the most important features in HRD prediction. HRDCNA suggests the biallelic inactivation of BRCA1, BRCA2, PALB2, RAD51C, RAD51D, and BARD1 as the major genetic basis for human HRD, and may also be applied to effectively validate the pathogenicity of BRCA1/2 variants of uncertain significance (VUS). Together, this study provides a robust tool for cost-effective HRD prediction and also demonstrates the applicability of CNA features and signatures in cancer precision medicine.

Loss of HRD functional phenotype impedes immunotherapy and can be reversed by HDAC inhibitor in ovarian cancer.

In recent years, homologous recombination deficiency (HRD) has not achieved the expected substantial promotion of immunotherapeutic efficacy in ovarian cancer. This study aims to explore the role of HRD functional phenotype as a powerful biomarker in identifying HRD patients who may benefit from immunotherapy. HRD functional phenotype, namely HRD-EXCUTE, was defined as the average level of the 15 hub genes upregulated in HRD ovarian cancer. A decision tree was plotted to evaluate the critical role of HRD-EXCUTE in HRD patients. Agents inducing HRD-EXCUTE were identified by CMAP web (Connectivity Map). The mechanisms and immunotherapeutic effect of PARPi and HDACi in promoting HRD-EXCUTE was examined in vitro and in vivo. The decision tree plotted on the basis of HRD and HRD-EXCUTE indicated the HRD patients without the HRD functional phenotype were largely unresponsive to immunotherapy, which was validated by the immunotherapeutic cohorts. Furthermore, loss of HRD-EXCUTE in the HRD patients attenuated immunogenicity and inhibited immune cells in tumor microenvironment. Moreover, Niraparib combined with Entinostat induced HRD-EXCUTE by activating the cGAS-STING pathway and increasing the histone acetylation. The combination therapy could enhance the cytotoxicity of immune cells, and promote pro-immune cells infiltrating into ascites, resulting in inhibited ovarian cancer growth. The HRD functional phenotype HRD-EXCUTE was set up as a potent biomarker to identify whether HRD patients can benefit from immunotherapy. Loss of HRD-EXCUTE in HRD patients were largely insensitive to immunotherapy. The combination of PARPi with HDACi could improve the efficacy of the PARPi-based immunotherapy in ovarian cancer by augmenting the HRD functional phenotype.

Alternative academic approaches for testing homologous recombination deficiency in ovarian cancer in the MITO16A/MaNGO-OV2 trial

BackgroundThe detection of homologous recombination deficiency (HRD) can identify patients who are more responsive to platinum and poly ADP ribose polymerase inhibitors (PARPi). MyChoice CDx (Myriad) is the most used HRD test in ovarian cancer (OC). However, some limitations of commercial tests exist, because of the high rate of inconclusive results, costs, and the impossibility of evaluating functional resistance mechanisms.Patients and methodsTwo academic genomic tests and a functional assay, the RAD51 foci, were evaluated to detect HRD. One hundred patients with high-grade OC enrolled in the MITO16A/MaNGO-OV2 trial and treated with first-line therapy with carboplatin, paclitaxel, and bevacizumab were analyzed.ResultsThe failure rate of the two genomic assays was 2%. The sensitivity in detecting HRD when compared with Myriad was 98.1% and 90.6%, respectively. The agreement rate with Myriad was 0.92 and 0.87, with a Cohen’s κ coefficient corresponding to 0.84 and 0.74, respectively. For the RAD51 foci assay, the failure rate was 30%. When the test was successful, discordant results for deficient and proficient tumors were observed, and additional HRD patients were identified compared to Myriad; sensitivity was 82.9%, agreement rate was 0.65, and Cohen’s κ coefficient was 0.18. The HRD detected by genomic assays and residual tumor at primary surgery and stage was correlated with progression-free survival at multivariate analysis.ConclusionsResults suggest the feasibility of academic tests for assessing HRD status that show robust concordance with Myriad and correlation with clinical outcome. The contribution of the functional information related to the RAD51 foci test to the genomic data needs further investigation.

Cost-utility analysis of management strategies after frontline treatment of women with epithelial ovarian cancer (339)

<b>Objectives:</b> Performed a cost-utility analysis comparing maintenance therapies for advanced epithelial ovarian cancer to surveillance based on genetic mutation. <b>Methods:</b> We developed Markov models of post-frontline treatment disease course until death for women diagnosed with stage III-IV epithelial ovarian cancer to compare niraparib, olaparib, bevacizumab, and olaparib+bevacizumab with active surveillance. Four subgroups were analyzed: <i>(1)</i> all-comers, <i>(2) BRCA, (3) non-BRCA</i> homologous recombination deficiency (HRD), and <i>(4)</i> homologous recombination proficient (HR proficient). Transition probabilities for progression-free survival and adverse events were derived from randomized controlled trials, for all-cause mortality from US life tables, and for disease-specific mortality after recurrence from SEER. Utilities for maintenance treatment, grade 3-4 adverse events, disease-free off treatment, recurrence, and death were derived from ovarian cancer-specific time trade-off studies. Costs of treatment, adverse events, recurrence, and death were obtained from Centers for Medicare & Medicaid Services (CMS) fee schedules and published studies. Analysis was conducted from CMS's perspective. We considered a 3-month cycle length, a lifetime time horizon and applied a 3% annual discount rate. The primary outcome of interest was the incremental cost-effectiveness ratio (ICER), defined as the ratio of incremental cost to incremental quality-adjusted life-year (QALY). Uncertainty was evaluated using deterministic and probabilistic sensitivity analyses and represented by cost-effectiveness at willingness-to-pay (WTP) thresholds up to $200K/QALY. <b>Results:</b> For all-comers, surveillance and olaparib+bevacizumab were undominated (more effective and less costly), and the ICER of olaparib+bevacizumab in reference to surveillance was $182,823/ QALY. The probability of cost-effectiveness of olaparib+bevacizumab at a WTP threshold of $100K/QALY was 20%. For <i>BRCA</i> patients, surveillance and olaparib were nominated, and the ICER of olaparib was $49,896/QALY. The probability of olaparib being cost-effective at a WTP threshold of $100K/QALY was 71%. For non-<i>BRCA</i> HRD patients, surveillance and olaparib+bevacizumab were both undominated, and the ICER of olaparib+bevacizumab was $98,685/QALY. At a WTP threshold of $100,000/QALY, olaparib+bevacizumab had a higher probability of being cost-effective (48%) than niraparib (6%) or bevacizumab alone (4%). For HR proficient patients, surveillance was undominated and had the highest probability of being cost-effective at all WTP thresholds. <b>Conclusions:</b> Compared to active surveillance, olaparib+bevacizumab was the most cost-effective maintenance strategy for all-comers and non-<i>BRCA</i> HRD patients. At the same time, olaparib was most costeffective for women with <i>BRCA</i> mutations. The likelihood of any maintenance therapy being cost-effective for women with HR proficient disease was low.

Abstract 794: Pan-cancer proteogenomic analysis reveals functional mechanisms underlying DNA repair deficiencies

Abstract Emerging classifiers that leverage recent advances in the characterization of mutational signatures have identified a broader range of cancer patients with DNA repair deficiencies, many of whom do not harbor mutations or epigenetic silencing of canonical DNA repair genes. Investigating the various mechanisms underlying dysfunctional DNA damage response (DDR) and heterogeneity across patients will be crucial to understand disparate responses to therapy, including to PARP1 inhibitors and to immunotherapy. In this study, we integrate genomic, transcriptomic, proteomic, and post-translational modification (PTM) data across 11 cancer types to elucidate the diverse functional mechanisms of DNA repair deficiencies and their therapeutic implications through an in-depth proteogenomic analysis. We first characterized the landscape of mutational signatures in 1110 patients by applying SignatureAnalyzer, a tool that uses a Bayesian non-negative matrix factorization method to discover patterns of somatic mutations. Our analysis identified 144 homologous recombination-deficient (HRD) and 60 mismatch repair-deficient (MMRD) patients. Multi-omic (mRNA, protein, PTMs) signature based hierarchical clustering revealed two distinct clusters of HRD patients defined by either (i) acute or (ii) chronic hypoxic states. The acute hypoxia cluster exhibited typical HRD phenotypes, including a preference for non-homologous end joining (NHEJ) and enrichment in PARP1 activity, as well as phosphorylation patterns driven by DNA-PKcs, ATM, and ATR. In contrast, tumors under chronic hypoxia exhibited a halting of replication and silencing of DDR, suggesting that patients with these tumors may respond poorly to common HRD treatments that exploit alternative error-prone repair and PARP1 activation. Notably, these tumors were enriched in signatures representative of highly active kinases involved in cellular stress responses, potentially providing additional avenues for therapy. Additional analysis of both HRD and MMRD tumors revealed groups of highly immunogenic DNA repair-deficient tumors that may respond well to some types of immunotherapy given their increased mutagenesis. Moreover, differences in inflammation-related kinase activities offer further insight into the interaction between faulty DDR and the innate immune response (e.g., alterations in the cGAS-STING DNA sensing pathway). Overall, our multi-omic signature analysis provides insights into the mechanisms underlying DDR and its crosstalk with other cancer-related pathways that remain unexplained by evaluating genomic and transcriptomic data alone. Our characterization of the heterogeneity within the population of patients with DNA repair deficiency shows promise for improved prediction of treatment response, as well as identifying additional potential therapeutic targets. Citation Format: Yo Akiyama, Yifat Geffen, Shankara Anand, Tomer Yaron, Jared L. Johnson, Emily Huntsman, David Heiman, Chet Birger, Karl Clauser, Özgün Babur, Mendy Miller, Karsten Krug, D R Mani, Lewis C. Cantley, Steven A. Carr, PanCancer Oncogenic Drivers and Pathways Group, Clinical Proteomic Tumor Analysis Consortium (CPTAC), Francois Aguet, Li Ding, Gad Getz. Pan-cancer proteogenomic analysis reveals functional mechanisms underlying DNA repair deficiencies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 794.

Abstract P1-08-32: Homologous recombination deficiency predicts the response to platinum-based neoadjuvant chemotherapy in patients with early-stage triple-negative breast cancer: A meta-analysis

Abstract Background: Recent studies have explored the potential role of homologous recombination deficiency (HRD) as a biomarker and shown that the HRD status may be related to the pCR rate. However, does HRD specifically predict the efficacy of platinum chemotherapy, or only predict the benefit of the pCR, irrespective of the treatment regimen? Is there any difference in the efficacy of platinum supplementation between gBRCA1/2 carriers and HRD tumors without gBRCA mutations? Does the addition of platinum to neoadjuvant chemotherapy for patients without HRD bring no curative effects but only increase adverse reactions? We developed this meta-analysis and included all qualified relevant clinical trials to answer these research questions. Materials and methods: Eligible studies were systematically searched from inception to June 1, 2021, in the PubMed, Embase, Medline, Web of Science, and Cochrane databases, and in the abstracts of the European Society for Medical Oncology Congress and the American Society of Clinical Oncology Annual Meeting. The primary outcome was the pathological complete response (pCR, defined as ypT0/is ypN0) after neoadjuvant chemotherapy. Secondary outcomes included clinical response rates and grade 3 or higher adverse events. Classic forest plots were generated using standard techniques to present the meta-analysis results. Results: A total of 1404 patients were included in the present meta-analysis, of which the HRD status was measurable in 1142 (81.3%) patients, and 723 (51.5%) were confirmed to have HRD. Regardless of the HRD status, platinum-based neoadjuvant treatment was statistically associated with better pCR rates than platinum-free neoadjuvant regimens (51.3% vs. 37.6%, OR 1.93, 95% CI 1.13 - 3.30, p = 0.02). The pCR was higher in HRD patients receiving platinum than those without platinum exposure (56.7% vs. 39.4%, OR 1.95, 95% CI 1.17 - 3.23, p = 0.01), while no significant differences were identified between the platinum and control groups in non-HRD patients (36.5% vs. 20.5%, OR 1.82, 95% CI 0.61 - 5.40, p = 0.28). Irrespective of the treatment arm, the odds ratio of achieving the pCR was 3.35 times higher in patients with HRD than in non-HRD patients (51.6% vs. 27.4%, OR 3.35, 95% CI 1.93 - 5.81, p &amp;lt; 0.01). Moreover, among patients on platinum-based regimens, HRD patients had a significant pCR benefit compared to the non-HRD group (58.3% vs. 33.3%, OR 3.40, 95% CI 1.86 - 6.24, p &amp;lt; 0.01). For those without platinum exposure, the results revealed no difference in pCR rates, irrespective of the HRD status (34.3% vs. 20.5%, OR 1.89, 95% CI 0.81 - 4.43, p = 0.14). Among patients with HRD who received platinum-containing therapy, pooled results demonstrated no statistically significant difference between patients with BRCA mutations and those with BRCA wild-type (70.4% vs. 57.8%, OR 1.84, 95% CI 0.84 - 4.02, p = 0.12). With respect to clinical response rates, while more benefit was observed with the use of platinum in HRD and non-HRD patients, the difference was not statistically significant in the forest plot (85.1% vs. 76.1%, OR 1.97, 95% CI 0.91 - 4.27, p = 0.08). Additionally, our results revealed that grade 3 or higher adverse events were more frequently observed in patients on platinum-based regimens. Conclusion: Platinum-based neoadjuvant chemotherapy is associated with significantly higher pCR rates in early-stage triple-negative breast cancer patients with HRD, irrespective of BRCA status. Adding platinum to neoadjuvant treatment in the non-HRD population increases adverse reactions rather than improving the therapeutic effect. Citation Format: Yuanqi Chen, Liulu Zhang, Minyi Cheng, Xiaosheng Zhuang, Ci-Qiu Yang, Fei Ji, Hong-Fei Gao, Mei Yang, Teng Zhu, Jieqing Li, Kun Wang. Homologous recombination deficiency predicts the response to platinum-based neoadjuvant chemotherapy in patients with early-stage triple-negative breast cancer: A meta-analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-32.

Examining the prevalence of homologous recombination repair defects in ER+ breast cancers.

Homologous recombination deficiency (HRD) is well characterized in triple-negative breast cancer (TNBC), but its prevalence in the hormone-receptor-positive breast cancer subtypes is not as clearly defined. It is estimated that around 50-60% of TNBC cases are deficient in HR. We sought to identify HRD cases in ER+/Her2- patients using various mutational HRD signatures. We abstracted published HRD genomic signatures from the Pan-Cancer Analysis of Whole Genomes (PCAWG) database and compared the prevalence of HRD in ER+/Her2- breast cancer, comparing this to the control of set of triple-negative breast cancers. In 78 patients with ER+/Her2- breast cancer, 13 patients have over a 70% probability of being HRD as measured by HRDetect, while 18 qualify as HRD based on HRD score, with an approximate prevalence of HRD ranging between 14 and 20% of cases. Our analyses suggest that 14% of ER+/Her2- patients may be HRD and therefore potentially eligible for treatments with HRD-directed therapies such as platinum agents and PARP inhibitors. As the ER+/Her2- subtype is the most common breast cancer subtype, thisgroup of HRD patients is likely more sizable than that of HRD TNBC patients.

Quality-adjusted time without symptoms of disease or toxicity and quality-adjusted progression-free survival with niraparib maintenance in first-line ovarian cancer in the PRIMA trial.

Background:The PRIMA phase 3 trial showed niraparib significantly prolongs median progression-free survival (PFS) versus placebo in patients with advanced ovarian cancer (OC) responsive to first-line platinum-based chemotherapy, including those who had tumors with homologous recombination deficiency (HRd). This analysis of PRIMA examined the quality-adjusted PFS (QA-PFS) and quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) of patients on maintenance niraparib versus placebo.Methods:Patients were randomized 2:1 to receive once-daily maintenance niraparib (n = 487) or placebo (n = 246). QA-PFS was defined as the PFS of patients adjusted for their health-related quality of life (HRQoL) prior to disease progression, measured using European Quality of Life Five-Dimension (EQ-5D) questionnaire index scores from the PRIMA trial. Q-TWiST was calculated by combining data on PFS, duration of symptomatic grade ⩾2 adverse events (fatigue or asthenia, nausea, vomiting, abdominal pain, and abdominal bloating) prior to disease progression, and EQ-5D index scores. Analyses used data collected up to the last date of PFS assessment (May 17, 2019).Results:The restricted mean QA-PFS was significantly longer with niraparib versus placebo in the HRd (n = 373) and overall intention-to-treat (ITT; n = 733) populations (mean gains of 6.5 [95% confidence interval; CI, 3.9–8.9] and 4.1 [95% CI, 2.2–5.8] months, respectively). There were also significant improvements in restricted mean Q-TWiST for niraparib versus placebo (mean gains of 5.9 [95% CI, 3.5–8.6] and 3.5 [95% CI, 1.7–5.6] months, respectively) in the HRd and ITT populations.Conclusions:In patients with advanced OC, first-line niraparib maintenance was associated with significant gains in QA-PFS and Q-TWiST versus placebo. These findings demonstrate that niraparib maintenance treatment is associated with a PFS improvement and that treatment benefit is maintained even when HRQoL and/or toxicity data are combined with PFS in a single measure.Trial registration:ClinicalTrials.gov: NCT02655016; trial registration date: January 13, 2016Plain language summaryBackground: In a large clinical trial called PRIMA, patients with advanced cancer of the ovary (ovarian cancer) were given either niraparib (a type of cancer medicine) or placebo (a pill containing no medicine/active substances) after having chemotherapy (another type of cancer medicine). Taking niraparib after chemotherapy is called maintenance therapy and aims to give patients more time before their cancer returns or gets worse than if they were not given any further treatment. In the PRIMA trial, patients who took niraparib did have more time before their cancer progressed than if they took placebo. However, it is important to consider patients’ quality of life, which can be made worse by cancer symptoms and/or side effects of treatment. Here, we assessed the overall benefit of niraparib for patients in PRIMA.Methods: Both the length of time before disease progression (or survival time) and quality of life were considered using two different analyses:● The first analysis was called quality-adjusted PFS (QA-PFS) and looked at how long patients survived with good quality of life.● The second analysis was called quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) and looked at how long patients survived without cancer symptoms or treatment side effects.Results: The PRIMA trial included 733 patients; 487 took niraparib and 246 took placebo. Around half of the patients in both groups had a type of ovarian cancer that responds particularly well to drugs like niraparib – they are known as homologous recombination deficiency (HRd) patients.● When information on quality of life (collected from patient questionnaires) and survival was combined in the QA-PFS analysis, HRd patients who took niraparib had approximately 6.5 months longer with a good quality of life before disease progression than those who took placebo. In the overall group of patients (including HRd patients and non-HRd patients), those who took niraparib had approximately 4 months longer than with placebo.● Using the second analysis (Q-TWiST) to combine information on survival with cancer symptoms and treatment side effects, the HRd patients taking niraparib had approximately 6 months longer without cancer symptoms or treatment side effects (such as nausea or vomiting) than patients taking placebo. In the overall group of patients, those taking niraparib had approximately 3.5 months longer without these cancer symptoms/side effects than patients receiving placebo.Conclusions: These results show that the survival benefits of niraparib treatment remain when accounting for patients’ quality of life. These benefits were seen not only in HRd patients who are known to respond better to niraparib, but in the overall group of patients who took niraparib.

Ovarian Cancer Treatments Strategy: Focus on PARP Inhibitors and Immune Check Point Inhibitors.

Simple SummaryOvarian cancer treatment is the deadliest of gynecological cancers but the introduction of target therapies in its therapeutic algorithm has significantly improved outcomes. The aim of this article was to provide a review of completed and ongoing clinical trials involving the use of PARP inhibitors and/or immune checkpoint inhibitors for the treatment of ovarian cancer in front line and relapse settings. We confirmed the role of bevacizumab and PARP inhibitors which have transformed OC into a chronic disease while almost all trials involving immunotherapy were disappointing. Ovarian cancer treatment strategy is mainly based on three pillars: cytoreductive surgery, platinum-based chemotherapy, and targeted therapies. The latter in the last decade has provided a remarkable improvement in progression free patients and, hopefully, in overall survival. In particular, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors exploit BRCA 1/2 mutations and DNA damage response deficiencies, which are believed to concern up to 50% of high grade epithelial ovarian cancer cases. While these agents have an established role in ovarian cancer treatment strategy in BRCA mutated and homologous recombination deficient patients, an appropriate predictive molecular test to select patients is lacking in clinical practice. At the same time, the impressive results of immunotherapy in other malignancies, have opened the space for the introduction of immune-stimulatory drugs in ovarian cancer. Despite immune checkpoint inhibitors as a monotherapy bringing only modest efficacy when assessed in pretreated ovarian cancer patients, the combination with chemotherapy, anti-angiogenetics, PARP inhibitors, and radiotherapy is believed to warrant further investigation. We reviewed literature evidence on PARP inhibitors and immunotherapy in ovarian cancer treatment.

Cost-effectiveness of various maintenance therapies based on mutation status following first-line treatment of primary epithelial ovarian cancer in the United States

The recent SOLO1, PRIMA, and PAOLA trials all reported positive efficacy results, making it difficult to determine optimal upfront maintenance therapy for patients with primary, advanced ovarian cancer. We evaluated the cost-effectiveness of the maintenance strategies outlined in these trials for BRCA-positive patients, homologous-recombination deficient patients without a BRCA mutation (HRD-positive), and homologous-recombination proficient (HRD-negative) patients.

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.

Niraparib maintenance in frontline management of ovarian cancer: a cost effectiveness analysis

ObjectivesNiraparib maintenance after frontline chemotherapy for advanced ovarian cancer extends progression free survival. The objective of this study was to determine the cost effectiveness of niraparib maintenance therapy in patients...

Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection.

Genomic methods can identify homologous recombination deficiency (HRD). Rigorous evaluation of their outcome association to DNA damage response-targeted therapies like platinum in pancreatic ductal adenocarcinoma (PDAC) is essential in maximizing therapeutic outcome. We evaluated progression-free survival (PFS) and overall survival (OS) of patients with advanced-stage PDAC, who had both germline- and somatic-targeted gene sequencing. Homologous recombination gene mutations (HRm) were evaluated: BRCA1, BRCA2, PALB2, ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, and RTEL1 HRm status was grouped as: (i) germline versus somatic; (ii) core (BRCAs and PALB2) versus non-core (other HRm); and (iii) monoallelic versus biallelic. Genomic instability was compared using large-scale state transition, signature 3, and tumor mutation burden. Among 262 patients, 50 (19%) had HRD (15% germline and 4% somatic). Both groups were analyzed together due to lack of difference in their genomic instability and outcome. Median [95% confidence interval (CI)] follow-up was 21.9 (1.4-57.0) months. Median OS and PFS were 15.5 (14.6-19) and 7 (6.1-8.1) months, respectively. Patients with HRD had improved PFS compared with no HRD when treated with first-line (1L) platinum [HR, 0.44 (95% CI: 0.29-0.67); P < 0.01], but not with 1L-non-platinum. Multivariate analysis showed HRD patients had improved OS regardless of their first-line treatment, but most had platinum exposure during their course. Biallelic HRm (11%) and core HRm (12%) had higher genomic instability, which translated to improved PFS on first-line platinum (1L-platinum) versus 1L-non-platinum. Pathogenic HRm identifies HRD in patients with PDAC with the best outcome when treated with 1L-platinum. Biallelic HRm and core HRm further enriched benefit from 1L-platinum from HRD.

Dysregulation in nucleic acid-sensing pathway genes is associated with cancer patients' prognosis.

The innate immune system, the first line of defense against pathogens, is activated by nucleic acids from microbial invaders that are recognized by nucleic acid‐sensing receptors. Recent evidence affirms the ability of these receptors to respond to nucleic acids released by damaged cancer cells. The innate immune system is also involved in cancer immunosurveillance, and could be modulated for devising effective antitumor therapies by targeting nucleic acid‐sensing pathways. A systematic, comprehensive analysis of dysregulation in nucleic acid‐sensing pathways in cancer is required to fully understand its role. Based on multidimensional data of The Cancer Genome Atlas pan‐cancer cohort, we revealed that upregulation of cytosolic DNA‐sensing genes like AIM2 and CGAS was common in tumor tissues. We used 15 genes in the nucleic acid‐sensing pathway to cluster all tumor patients into 2 subgroups and found that the subgroup with higher expression of nucleic acid‐sensing pathway genes was associated with poorer prognosis across cancer types. However, in homologous recombination deficient patients, the nucleic acid recognition activated subgroup was associated with better prognosis, which confirms the therapeutic effect of nucleic acid recognition. This study contributes to a better understanding of the functions and mechanisms of nucleic acid recognition in cancer, lays the foundation for new therapeutic strategies, and enlarges the scope of development of new drugs.

An integrative molecular framework to predict homologous recombination deficiency.

e15664 Background: Homologous recombination deficiency (HRD) is the primary biomarker for sensitivity to PARP inhibitors, but identifying the genetic and transcriptomic characteristics that fully capture all HRD patients has remained difficult. For example, DNA-based approaches are limited to patients with pathogenic mutations and loss of heterozygosity (LOH) events, and can fail to properly classify patients with variants of unknown significance. To capture more dynamic cellular processes that arise immediately upon induction of HRD through silencing or loss of BRCA 1/2, a more integrated approach that includes both RNA and DNA based models is necessary. Methods: Using DNA sequencing we developed a genome-wide LOH score that combines pathogenic mutation status and LOH at the BRCA1/2 loci, and the proportion of bases sequenced in the Tempus xT panel that undergo LOH. We also developed three independent RNA-based models to predict BRCA deficiency: 1) An elastic net transcriptome model to predict DNA-based HRD scores derived from exome and SNP array data for each tumor type represented in TCGA; 2) A logistic model to detect BRCA1 promoter hypermethylation from the transcriptome in TCGA data; 3) A model that leveraged the mSigDB annotated gene sets to conduct single sample gene set enrichment analysis (ssGSEA) on Tempus-sequenced patients, selecting over a hundred gene sets that were predictive of BRCA-deficiency. These 4 features were combined to develop a stacked, linear-regression model to distinguish BRCA-intact from BRCA-deficient patients. Results: We found that the genome-wide LOH score alone is predictive of BRCA deficiency. However, our integrated model was highly accurate at distinguishing between BRCA-intact and BRCA-deficient patients and outperformed any single RNA- or DNA-based model. Using this model, we identified many patients that are likely to respond to PARP inhibitors that would have been overlooked using RNA or DNA-based inferences alone. Conclusions: Our approach highlights the strength of integrating diverse molecular features to refine diagnosis and enable oncologists to deliver the most effective therapies to patients.