High Loss Of Heterozygosity Research Articles

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

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

Immunotherapy outcomes and profile in lung cancer brain metastases.

8646 Background: Brain metastasis (BM) in NSCLCs have a unique tumor micro-environment (TME) characterized by distinct immune-constituents and the presence of blood-brain barrier, differentiating them from primary NSCLC tumors (PT). Despite the high incidence of BM, earlier trials indicated that less than 15% of BM patients benefit from immune checkpoint inhibitors (ICIs). We characterized the TME of BM to potentially identify a subset of patients who may respond favorably to ICIs. Methods: 36,726 NSCLC samples were analyzed by NGS of DNA (592-gene) and RNA (whole transcriptome) at Caris Life Sciences (Phoenix, AZ). TMB-high was defined as >=10mt/MB, PD-L1 was tested by IHC (22c3), and TME by RNA expression (quanTIseq). Real-world overall survival was obtained from insurance claims data and calculated from treatment start on six common ICIs to last contact (IO-OS), while time-on-treatment (TOT) was from first to last of treatment. Hazard ratios (HRs) were calculated using the Cox proportional hazards model and p values (log-rank test). Fisher’s exact tests and Mann-Whiney U were used and adjusted for multiple comparisons (q<0.05). Results: Samples were comprised of 63.5%, PT 4.9% BM, and 31.6% extracranial metastases. High TMB and loss of heterozygosity (LOH) rates were higher in BM vs. PT (55% vs. 35.7%) and (28.0% vs. 14.3%), q<0.05, respectively, while PD-L1+ rate was similar (53.3% BM vs. 55.6% PT). Significant mutational differences in BM vs. PT included TP53 (77.7% vs 65.1%), KEAP1 (19.4% vs. 12.1%), and STK11 (17.5% vs. 12.0%), q<0.05. Immune deconvolution demonstrated the abundance of neutrophils, Tregs, monocytes, and B cells was higher in PT vs. BM (fold-change: 1.35-1.73, q<0.05), while dendritic cells were higher in BM vs. PT (fold-change: 13, q<0.05). BM had significantly longer IO-OS (24.4 vs. 19.7 mo: HR = 0.83, 95% CI 0.76-0.90, p<0.05) and TOT (7.7 vs. 6.0 mo; HR = 0.83, 95% CI 0.77-0.89, p<0.05) compared to PT. PD-L1+ and TMB High were associated with longer IO-OS in BM vs. PT (HR = 0.71, 95% CI 0.63-0.81, p<0.05) and (HR = 0.83, 95% CI 0.74 – 0.93, p<0.05), respectively. By histology, squamous cell carcinoma (SC) was significantly more prevalent in PT compared to BM (25.9% vs. 8.5%, q<0.05). In adenocarcinoma (AD), BM was associated with longer IO-OS (HR = 0.78, 95% CI 0.70-0.87, p<0.05) compared to PT, while in SC, the survival association was not significant. The longer survival seen in AD was still significant after multivariate analysis with TP53, STK11 and KEAP1 (HR = 0.76, 95% CI 0.68-0.86, q<0.05). In BM, PD-L1+ and TMB High were associated with longer IO-OS in AD and may be considered first line treatment in this population, if asymptomatic. Conclusions: Historically BM have been associated with poor outcomes. We demonstrate that BM has higher TMB, increased infiltration of dendritic cells, and higher LOH than PT. After stratifying patients based on PD-L1 and TMB, patients with BM adenocarcinoma histology had improved post ICI survival.

Harvest and decimation affect genetic drift and the effective population size in wild reindeer.

Harvesting and culling are methods used to monitor and manage wildlife diseases. An important consequence of these practices is a change in the genetic dynamics of affected populations that may threaten their long-term viability. The effective population size (N e) is a fundamental parameter for describing such changes as it determines the amount of genetic drift in a population. Here, we estimate N e of a harvested wild reindeer population in Norway. Then we use simulations to investigate the genetic consequences of management efforts for handling a recent spread of chronic wasting disease, including increased adult male harvest and population decimation. The N e/N ratio in this population was found to be 0.124 at the end of the study period, compared to 0.239 in the preceding 14 years period. The difference was caused by increased harvest rates with a high proportion of adult males (older than 2.5 years) being shot (15.2% in 2005-2018 and 44.8% in 2021). Increased harvest rates decreased N e in the simulations, but less sex biased harvest strategies had a lower negative impact. For harvest strategies that yield stable population dynamics, shifting the harvest from calves to adult males and females increased N e. Population decimation always resulted in decreased genetic variation in the population, with higher loss of heterozygosity and rare alleles with more severe decimation or longer periods of low population size. A very high proportion of males in the harvest had the most severe consequences for the loss of genetic variation. This study clearly shows how the effects of harvest strategies and changes in population size interact to determine the genetic drift of a managed population. The long-term genetic viability of wildlife populations subject to a disease will also depend on population impacts of the disease and how these interact with management actions.

Abstract 6568: PTCH1 loss-of-function alterations: Mutational landscape and therapeutic outcomes to hedgehog pathway inhibitors in non-canonical histologies

Abstract Background: Loss-of-function (LOF) alterations of the PTCH1 tumor suppressor gene represent canonical events involved in basal cell carcinoma (BCC) oncogenesis. Hedgehog pathway inhibitors (HPIs) are approved for the treatment of advanced BCC, but genomic characterization and therapeutic outcomes remain limited in tumor agnostic cohorts. Methods: Using the MSK Clinical Sequencing Cohort, we performed a mutational landscape analysis of PTCH1 LOF alterations in non-BCC histologies, including Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) annotation, and analyzed response and progression-free survival (PFS) with HPIs. Results: Out of 115,619 samples, 1972 samples from advanced solid tumors with PTCH1 LOF alterations were identified. Excluding 1306 variants of unknown significance (VUSs) using OncoKB knowledge base as well as 44 BCC samples, a total of 622 samples from 570 patients with oncogenic PTCH1 alterations were identified across histologies. In addition, 124 patients received ≥1 line(s) of HPI at our institution between 2013 and 2023, including 16 patients with non-BCC histologies presenting PTCH1 alterations. At the patient level (n=570), PTCH1 LOF alterations were present across 33 primary sites, including colorectal cancer (CRC; 34%; n=192), endometrial cancer (17%; n=98), gastroesophageal adenocarcinomas (ADC) (8%; n=46), non-small cell lung cancer (NSCLC; 6%; n=34) and soft tissue sarcomas (STS; 4%; n=25). At the sample level (n=622), TMB ≥10 was seen in 83% (n=516), including 324 samples with MSI-high status. PTCH1 alterations most frequently involved frameshift (fs) indels (69%; n=429), followed by nonsense mutations (18%; n=114), splice site mutations (8%; n=47) and fusions (5%; n=32). Recurrent fs events involved S1203Afs*52 (24%; n=150) and R1308Efs*64 (14%; n=89), among others. When comparing monoallelic (monoall) vs biallelic (biall) PTCH1 alterations through FACETS annotation, monoall showed a strong association with higher TMB (p<0.01) whereas biall were associated with higher loss of heterozygosity (LOH; p<0.01). In the 16 non-BCC patients treated with HPIs, histologies included lung squamous cell cancer (SCC; n=4), cutaneous SCC (n=2), medulloblastoma (n=2), carcinosarcoma (n=2), osteosarcoma, chondrosarcoma, chordoma, sebaceous ADC, anal SCC and CRC (each n=1). TMB ≥10 was seen in 31% (n=5), all of which were MSI-low. Tumor regressions on HPI were seen in 50% (n=8), including lung SCC, cutaneous SCC, sebaceous ADC and medulloblastoma, with median time to response of 3.6 months (mo). Median PFS on HPI was 3.9 mo and median OS was 22.7 mo. Median PFS was higher in patients with TMB ≥10 vs TMB <10 (11.8 vs. 1.8 mo, p=0.02). Conclusion: PTCH1 LOF alterations appear actionable in non-BCC cutaneous/adnexal primaries, lung SCC and medulloblastoma, including TMB-high tumors. Citation Format: Antoine Desilets, Matteo Repetto, Soo Ryum Yang, Monica Chen, Dazhi Liu, Nikhil Rizvi, Ezra Rosen, Alan L. Ho, Alexander Drilon, Yonina R. Murciano-Goroff. PTCH1 loss-of-function alterations: Mutational landscape and therapeutic outcomes to hedgehog pathway inhibitors in non-canonical histologies [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 6568.

Abstract C058: Clinical relevance of telomerase upregulation via TERT promoter mutation or TERC amplification in high-grade ovarian cancer

Abstract Background: Increased telomerase activity confers a survival advantage to cancer cells and is considered one of the cancer hallmarks. The two main molecular mechanisms responsible for telomerase upregulation are the amplification of the telomerase RNA component gene (TERCamp) which serves as the template for telomeric repeats, and mutations in the telomerase reverse transcriptasegene promoter (TERTm), which encored the catalytic unit of telomerase. Increased telomerase activity has been detected in more than 90% of ovarian cancer (OC) but the clinical impact of this phenotype remains understudied. Methods: This retrospective analysis included all patients (pts) with high grade OC who underwent large-panel sequencing (Foundation Medicine) from National University Cancer Institute, Singapore and Institut Gustave Roussy, France. TERTm and TERCamp were correlated with clinical, pathological and molecular features as well as progression-free survival (PFS, calculated from histological diagnosis to first progression). Results: Out of the 503 pts with OC analyzed, 15 pts (3.0%) presented TERT mutation and 39 pts (7.8%) had TERC amplification. In the TERTm subgroup, only one hotspot mutation was detected (c.-124C>T). Compared to the wild-type (WT) group, there was significantly higher frequency of FIGO I/II diseases (57% vs 17%, p=0.001) and clear-cell histology (80% vs 14%, p<0.001). Consequently, there were more ARID1A and PIK3CA mutations and median loss of heterozygosity (LOH) score was significantly lower (5.3% vs 16.4%, p=0.006). Interestingly, TERTm were exclusive to P53 and BRCA1/2 mutations. With a follow-up of 64 months, the median PFS was 8.1 months, 18.7 months and 25.5 months for the TERTm, P53m and WT subgroups respectively (p=0.006). In the multivariate analysis, TERTm emerged as an independent negative prognostic biomarker. In the TERCamp subgroup, compared to WT, there was no difference in term of stage (74% of advanced stages vs 82%), or histologic type (77% of high-grade serous vs 71%). TERCamp was associated with a significantly higher tumor mutational load (6.2 mut/mbase vs 4.2, p<0.001), more P53 mutations (90% vs 72%, p=0.014), more BRCA1/2 mutations (33% vs 17%, p=0.016) and higher LOH (22% vs 15%, p=0.023). There were no statistical differences in terms of PFS. Conclusion: This study highlights intriguing heterogeneity in high-grade OC pts with telomerase upregulation. TERTm are associated with a clear-cell phenotype and TERTm and P53m define three prognostic subgroups among OC patients. On the other hand, TERCamp are detected in genomically unstable tumors presenting a higher mutational burden and copy-number alterations. These results emphasize the critical importance of the molecular mechanism underlying increased telomerase activity, which may impact the efficacy of telomerase-targeted therapy. Citation Format: Felix Blanc-Durand, Natalie Ngoi, Damien Vasseur, Patricia Pautier, Judith Michels, Kaissa Ouali, Catherine Genestie, Sophie Cotteret, Etenne Rouleau, Yi Wan Lim, Siew Eng Lim, Diana Lim, Silvana Talisa Wijaya, Alexandra Leary, David SP Tan. Clinical relevance of telomerase upregulation via TERT promoter mutation or TERC amplification in high-grade ovarian cancer [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 C058.

Implementation of Comprehensive Genomic Profiling in Ovarian Cancer Patients: A Retrospective Analysis.

Comprehensive genomic profiling (CGP) allows for the detection of driver alterations at high resolution, but the limited number of approved targeted therapies and their high costs have contributed to its limited clinical utilization. We retrospectively compared data of 946 women with ovarian cancer (11.4% were referred to CGP, and 88.6% served as control) to examine whether CGP provides a prognosis benefit. Patient baseline parameters were similar between the groups. Cox regression analysis adjusted for age, disease stage at diagnosis, and recurrence status showed statistically significantly longer median overall survival (mOS) in the CGP group versus the control (73.4 versus 54.5 months, p < 0.001). Fifty-four patients (52.9%) had actionable mutations with potential treatments; twenty-six (48.2%) were treated with matched targeted therapy, showing a trend for longer mOS than the eighty-six women in the CGP group who were not given a suggested treatment (105.5 versus 63.6 months, p = 0.066). None of the genomic alterations predicted metastasis location. CCNE1 amplification and KRAS mutations were associated with shorter mOS. Patients with tumor mutation burden ≥4 mutations/megabase had longer mOS. High loss of heterozygosity was associated with longer mOS (99.0 versus 48.2 months, p = 0.004). CGP testing may provide both prognostic and predictive insights for treatment of patients with ovarian cancer. Prospective studies of larger cohorts are warranted.

Homologous Recombination Deficiency and Tumor Mutational Burden as Clinical Biomarkers for Melanoma

Abstract Introduction/Objective Homologous recombination deficiency (HRD) cancers have high levels of genetic instability, potentially being targets for platinum agents or poly-ADP ribose polymerase inhibitors. Tumor mutational burden (TMB), which is used to guide immunotherapy, is thought to be associated with HRD. This study aimed to evaluate the frequency of HRD and its correlation with other genomic parameters in melanoma. Methods/Case Report A total of 14 cases with the diagnosis of melanoma were found in the genomic database between March 1, 2021 to July 30, 2021. One case had an EWSR1-ATF1 translocation and was excluded. Copy number variations and absence of heterozygosity detection were analyzed by the NxClinical software (BioDiscovery, El Segundo, CA). HRD was scored by three DNA-based measures of genomic instability (loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale transitions (LST)). HRD-LOH is the number of LOH regions &amp;gt; 15 Mb and do not cross the centromere. HRD-TAI is the number of regions &amp;gt; 10 Mb with allelic imbalance that extend to one of the subtelomeres and do not cross the centromere. HRD-LST is the number of break points between regions &amp;gt; 10 Mb. A high HRD score and LOH percentage were defined as ≥ 42 and ≥ 16%, respectively. Results (if a Case Study enter NA) Of the 13 cases, 10 had a high TMB and 3 had a low TMB. A high HRD score was found in 3 cases; high LOH percentage was found in 4 cases. PDL-1 was expressed in 8 of the 11 cases tested. A high HRD score correlated with high LOH percentage by Pearson’s chi-squared test (p &amp;lt; 0.01). No significant association was found between TMB and HRD score or LOH percentage. Common alterations among cases with high TMB included mutations in NRAS (3/13; 23.1%), CDKN2A (2/13; 15.4%), BRAF (2/13; 15.4%), BRCA2 (2/13; 15.4%), RAF1 (2/13; 15.4%), RET (1/13; 7.7%), IDH1 (1/13; 7.7%), PALB2 (1/13; 7.7%), BRCA1 (1/13; 7.7%), ERBB2 (1/13; 7.7%), NF1 (1/13; 7.7%), MLH1 (1/13; 7.7%), ATM (1/13; 7.7%) and MET (1/13; 7.7%). One case had amplifications in CCND1, FGF 3/4/19 and MET. Among cases with low TMB, alterations included MYC amplification (1/3; 33.3%) and BRAF mutations (2/3; 66.6%). Conclusion In our study, HRD score is not associated with TMB status. There is a strong correlation between HRD score and LOH percentage, suggesting that LOH is a major component in the genomic scarring seen in HRD. HRD may be an independent biomarker of immunogenicity to guide immunotherapy.

Abstract 80: Genomic characterization of PDX models from rare cancer patients in the NCI Patient-Derived Models Repository

Abstract Background: The National Cancer Institute’s Patient-Derived Models Repository (NCI PDMR; https://pdmr.cancer.gov) has developed a large number of patient-derived xenograft (PDX) models from a diverse set of rare cancers. These models have been genomically characterized using whole-exome sequencing (WES) and RNAseq. The resource provides a unique opportunity to explore the genomic features of rare tumor models in NCI PDMR and to understand the oncogenic processes in pre-clinical models to identify biomarkers associated with therapeutic responses. Methods: Genomic characterization was done in 4-6 PDX samples across multiple passages and lineages from each model. As the samples exhibited a high level of genomic stability within each model, consensus mutation and copy number variation (CNV), microsatellite instability (MSI), genomic loss of heterozygosity (LOH), homologous recombination deficiency score (scarHRD), and mutational signature data were generated from WES. Fusions were identified from RNASeq data using Star-Fusion and FusionInspector. Gene set enrichment analysis was conducted from the gene expression data obtained from RNAseq. Results: 1) 233 PDX models have been developed and characterized from more than 45 different rare malignancies. Most frequent cancer types are different sarcomas (n=63), head &amp; neck squamous cell carcinoma (n=61), and malignant fibrous histiocytoma (MFH) (n=11); 2) TP53 was the most frequently altered gene, mutated in 51% of models, followed by NOTCH1 (16%) and PIK3CA (11%). In terms of CNVs, ovarian epithelial cancer (OVT) showed relatively high chromosomal instability, while uterine endometrioid carcinoma (UEC) and synovial sarcoma (SYNS) had low instability; 3) MSI-H was observed in only 7 models. Esophageal adenocarcinoma (ESCA), OVT, and cervical squamous cell carcinoma (CESC) had high scarHRD and genomic LOH scores, while both scores were low in UEC and anal squamous cell carcinoma (ANSC). COSMIC v2 mutational signature 3 is significantly associated with a high scarHRD score (p-value &amp;lt; 0.01, Wilcoxon rank-sum test); 4) Characteristic fusions were observed in certain sarcoma models: SS18-SSX1 and ASPSCR1-TFE3 fusions were observed in SYNS and alveolar soft part sarcoma (ASPS) models respectively. EWSR1-FLI1 fusion was present in 2 out of 3 Ewing sarcoma (ES) models. 5) Gene set enrichment analysis from RNASeq data showed that epithelial-mesenchymal transition score could accurately distinguish carcinoma from sarcoma models, confirming the divergent gene expression programs. Conclusion: Comprehensive genomic characterization of NCI PDMR models generated from rare cancers solves an unmet need in the community. It will serve as a valuable resource for translational researchers interested in pre-clinical drug development and discovery. Citation Format: Li Chen, Rini Pauly, Ting-Chia Chang, Biswajit Das, Yvonne A. Evrard, Chris A. Karlovich, Tomas Vilimas, Alyssa Chapman, Nikitha Nair, Luis Romero, Anna Lee Fong, Amanda Peach, Shahanawaz Jiwani, Nastaran Neishaboori, Lindsay Dutko, Kelly Benauer, Gloryvee Rivera, Erin Cantu, Corinne Camalier, Thomas Forbes, Michelle Gottholm-Ahalt, John Carter, Suzanne Borgel, Chelsea McGlynn, Candace Mallow, Emily Delaney, Tiffanie Miner, Michelle A. Eugeni, Dianne Newton, Melinda G. Hollingshead, P. Mickey Williams, James H. Doroshow. Genomic characterization of PDX models from rare cancer patients in the NCI Patient-Derived Models Repository [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 80.

30P Molecular biomarkers by next generation sequencing predicting oncological outcomes in ovarian cancer patients

BackgroundOvarian cancer (OC) is the most common cause of gynecologic cancer mortality worldwide. Next generation sequencing (NGS) provides molecular biomarkers which can potentially predict oncological outcomes. We performed a retrospective study to examine progonostic biomarkes for ovarian cancer patients treated in our institution.MethodsWe retrospectively evaluated demographic and clinical information of OC patients referred for NGS molecular testing between 2011-2020 at the Tel-Aviv Medical Center. Cox models were used to analyze the clinical impact of molecular biomarkers including LOH and TMB by assessing overall survival (OS) and progression free survival (PFS).ResultsOf 1026 consecutive patients reviewed, 946 were included in the analysis: 108 (11.4%) were referred to NGS and 838 (88.6%) served as control. Patient baseline parameters were similar between the groups. High loss of heterozygosity (LOH) was associated with longer mOS (99.0 vs. 48.2 months, p=0.004). Sixty-six patients had information on TMB status: 75.8% (50/66) had low TMB status (<5) and 24.2% (16/66) had intermediate TMB status (5-15). None had a high TMB status. Analysis of TMB using the Breslow test showed that patients with TMB ≥4 had a statistically significant longer OS compared with patients with TMB<4 (92.8 months [95%CI, 47.1-138.6] vs. 52.77 months [95% CI, 26.4-79.2], p=0.026).ConclusionsWe identified LOH and TMB ≥4 as strong prognostic biomarkers among OC patients. Prospective studies evaluating larger cohorts are necessary to generate a more extensive evaluation of additional prognostic and predictive biomarkers.Legal entity responsible for the studyThe authors.FundingRoche Israel.DisclosureAll authors have declared no conflicts of interest. BackgroundOvarian cancer (OC) is the most common cause of gynecologic cancer mortality worldwide. Next generation sequencing (NGS) provides molecular biomarkers which can potentially predict oncological outcomes. We performed a retrospective study to examine progonostic biomarkes for ovarian cancer patients treated in our institution. Ovarian cancer (OC) is the most common cause of gynecologic cancer mortality worldwide. Next generation sequencing (NGS) provides molecular biomarkers which can potentially predict oncological outcomes. We performed a retrospective study to examine progonostic biomarkes for ovarian cancer patients treated in our institution. MethodsWe retrospectively evaluated demographic and clinical information of OC patients referred for NGS molecular testing between 2011-2020 at the Tel-Aviv Medical Center. Cox models were used to analyze the clinical impact of molecular biomarkers including LOH and TMB by assessing overall survival (OS) and progression free survival (PFS). We retrospectively evaluated demographic and clinical information of OC patients referred for NGS molecular testing between 2011-2020 at the Tel-Aviv Medical Center. Cox models were used to analyze the clinical impact of molecular biomarkers including LOH and TMB by assessing overall survival (OS) and progression free survival (PFS). ResultsOf 1026 consecutive patients reviewed, 946 were included in the analysis: 108 (11.4%) were referred to NGS and 838 (88.6%) served as control. Patient baseline parameters were similar between the groups. High loss of heterozygosity (LOH) was associated with longer mOS (99.0 vs. 48.2 months, p=0.004). Sixty-six patients had information on TMB status: 75.8% (50/66) had low TMB status (<5) and 24.2% (16/66) had intermediate TMB status (5-15). None had a high TMB status. Analysis of TMB using the Breslow test showed that patients with TMB ≥4 had a statistically significant longer OS compared with patients with TMB<4 (92.8 months [95%CI, 47.1-138.6] vs. 52.77 months [95% CI, 26.4-79.2], p=0.026). Of 1026 consecutive patients reviewed, 946 were included in the analysis: 108 (11.4%) were referred to NGS and 838 (88.6%) served as control. Patient baseline parameters were similar between the groups. High loss of heterozygosity (LOH) was associated with longer mOS (99.0 vs. 48.2 months, p=0.004). Sixty-six patients had information on TMB status: 75.8% (50/66) had low TMB status (<5) and 24.2% (16/66) had intermediate TMB status (5-15). None had a high TMB status. Analysis of TMB using the Breslow test showed that patients with TMB ≥4 had a statistically significant longer OS compared with patients with TMB<4 (92.8 months [95%CI, 47.1-138.6] vs. 52.77 months [95% CI, 26.4-79.2], p=0.026). ConclusionsWe identified LOH and TMB ≥4 as strong prognostic biomarkers among OC patients. Prospective studies evaluating larger cohorts are necessary to generate a more extensive evaluation of additional prognostic and predictive biomarkers. We identified LOH and TMB ≥4 as strong prognostic biomarkers among OC patients. Prospective studies evaluating larger cohorts are necessary to generate a more extensive evaluation of additional prognostic and predictive biomarkers.

Efficacy and safety of rucaparib maintenance treatment in patients from ARIEL3 with platinum-sensitive, recurrent ovarian carcinoma not associated with homologous recombination deficiency.

5544 Background: In ARIEL3 (NCT01968213), rucaparib maintenance treatment led to significant improvement vs placebo for the primary endpoint of investigator-assessed progression-free survival (PFS) in patients (pts) with platinum-sensitive, recurrent ovarian carcinoma responsive to the last line of platinum therapy (Coleman et al. Lancet. 2017;390:1949–61). The largest benefit was observed in pts with carcinomas with a BRCA mutation or high loss of heterozygosity (LOH), a marker of homologous recombination deficiency (HRD). However, rucaparib also improved PFS in pts with carcinomas negative by HRD test (ie, BRCA wild-type with low LOH), a subset of pts for which there is no identified molecular mechanism conferring PARP inhibitor sensitivity. Among these pts (rucaparib, n = 107; placebo, n = 54), median PFS was 6.7 vs 5.4 months, respectively (HR, 0.58 [95% CI 0.40–0.85]; P= 0.0049), and 31.8% vs 4.3% were progression-free at 1 yr. In this post hoc exploratory analysis, we further evaluated the efficacy of rucaparib maintenance vs placebo in this subset of pts. Methods: Pts were randomized 2:1 to oral rucaparib (600 mg BID) or placebo. For this analysis, investigator-assessed PFS and safety were evaluated in pts with HRD-negative carcinoma, defined as BRCA wild-type with genomic LOH &lt; 16% using Foundation Medicine’s T5 NGS assay. Results: Visit cutoff dates for efficacy and safety were Apr 15, 2017, and Dec 31, 2019. Across subgroups based on demographic or disease characteristics, the trend of rucaparib benefit vs placebo was consistently observed in pts with HRD-negative carcinoma (Table). The safety profile of rucaparib in the HRD-negative population was consistent with that of the overall safety population reported previously. Conclusions: Rucaparib maintenance reduced risk of progression in pts with ovarian carcinomas, including those not associated with HRD, regardless of clinical prognostic factors. [Table: see text]

Genetic abnormalities and aberrant expression of genes involved in chromosome segregation and mitosis in patients with chromosomally unstable malignant soft tissue tumors haboring extensive somatic loss-of-heterozygosity (LOH).

11576 Background: Malignant soft tissue tumor is a rare cancer with few therapeutic options. Recent genomic analysis of soft tissue sarcoma (STS) revealed a high degree of chromosomal instability (CIN) including genome-wide copy number alteration, aneuploidy, whole genome doubling and chromothripsis. In STS patients, we observed extensive somatic LOH, a hallmark of CIN, which is haploid of germline mutations/variants in cancer-related genes. CIN of STS genome implicates abnormalities in chromosome segregation and mitosis. So far, studies on this issue, however, have not been reported in STS patients. Methods: We recruited 155 patients with metastatic/recurrent malignant soft tissue tumors (135 female and 20 male, mean age 51 at analysis, 100 LMS, 19 LPS, 4 ESS, 3 UPS, 3 AS, 3 MPT, 3 GIST and others) with information of familial cancer burden. Whole exome sequencing and analysis were performed in both blood and tumor samples as described in 2018ASCO. KIF18A expression was assessed by immunohistochemistry. Results: Patients with tumors harboring less than 33% somatic LOH in a total of somatic and LOH mutations/variants in 595 COSMIC genes (n = 54) have a better prognosis than those (34-66%, n = 49, 67-100%, n = 52) with tumors harboring more LOH genes (5-year OS; 71% vs 52% or 46%, p = 0.0299, p = 0.0117, respectively). Neither TMB nor MSI status was associated with LOH. Of the genes involved in chromosome segregation and mitosis, we found that a family of ARHGAP genes which play a role in the spindle assembly and Aurora A kinase activation was frequently mutated in both tumor and germline genomes (n = 81 in a total of 155). Damaging ARHGAP mutations/variants in tumors are correlated with higher LOH values (54±3.4%, n = 81 vs. 39±3.3%, n = 74. mean±SE, p = 0.0021) and poor prognosis of patients (5-year OS; 58% n = 81 vs. 41% n = 74, p = 0.0098). We also found that elevated and robust expression of a mitotic kinesin KIF18A in tumors harboring higher LOH and/or damaging ARHGAP mutations/variants (n = 12) but not in lower LOH tumors without ARHGAP mutations/variants (n = 4). Conclusions: This study, for the first time, demonstrates that genetic abnormalities and aberrant expression of genes involved in chromosome segregation and mitosis in patients with malignant soft tissue tumors. The results reveal a novel target of drug discovery for incurable STS because CIN tumor cells are shown to be particularly vulnerable to KIF18A inhibition, while somatic, diploid cells are not.

Landscape of homologous recombination deficiencies in solid tumours: analyses of two independent genomic datasets

BackgroundDNA repair deficiencies are characteristic of cancer and homologous recombination deficiency (HRD) is the most common. HRD sensitizes tumour cells to PARP inhibitors so it is important to understand the landscape of HRD across different solid tumour types.MethodsGermline and somatic BRCA mutations in breast and ovarian cancers were evaluated using sequencing data from The Cancer Genome Atlas (TCGA) database. Secondly, a larger independent genomic dataset was analysed to validate the TCGA results and determine the frequency of germline and somatic mutations across 15 different candidate homologous recombination repair (HRR) genes, and their relationship with the genetic events of bi-allelic loss, loss of heterozygosity (LOH) and tumour mutation burden (TMB).ResultsApproximately one-third of breast and ovarian cancer BRCA mutations were somatic. These showed a similar degree of bi-allelic loss and clinical outcomes to germline mutations, identifying potentially 50% more patients that may benefit from precision treatments. HRR mutations were present in sizable proportions in all tumour types analysed and were associated with high TMB and LOH scores. We also identified numerous BRCA reversion mutations across all tumour types.ConclusionsOur results will facilitate future research into the efficacy of precision oncology treatments, including PARP and immune checkpoint inhibitors.

A phase 1b study evaluating the safety and preliminary efficacy of berzosertib in combination with gemcitabine in patients with advanced non-small cell lung cancer

ObjectivesBerzosertib (formerly M6620, VX-970) is an intravenous, highly potent and selective, first-in-class ataxia telangiectasia and Rad3-related (ATR) protein kinase inhibitor. We assessed the safety, tolerability, preliminary efficacy, and pharmacokinetics (PK) of berzosertib plus gemcitabine in an expansion cohort of patients with advanced non-small cell lung cancer (NSCLC). The association of efficacy with TP53 status and other tumor markers was also explored. Materials and methodsAdult patients with advanced histologically confirmed NSCLC received berzosertib 210 mg/m2 (days 2 and 9) and gemcitabine 1000 mg/m2 (days 1 and 8) at the recommended phase 2 dose established in the dose escalation part of the study. ResultsThirty-eight patients received at least one dose of study treatment. The most common treatment-emergent adverse events were fatigue (55.3%), anemia (52.6%), and nausea (39.5%). Gemcitabine had no apparent effect on the PK of berzosertib. The objective response rate (ORR) was 10.5% (4/38, 90% confidence interval [CI]: 3.7–22.5%). In the exploratory analysis, the ORR was 30.0% (3/10, 90% CI: 9.0–61.0%) in patients with high loss of heterozygosity (LOH) and 11.0% (1/9, 90% CI: 1.0–43.0%) in patients with low LOH. The ORR was 33.0% (2/6, 90% CI: 6.0–73.0%) in patients with high tumor mutational burden (TMB), 12.5% (2/16, 90% CI: 2.0–34.0%) in patients with intermediate TMB, and 0% (0/3, 90% CI: 0.0–53.6%) in patients with low TMB. ConclusionsBerzosertib plus gemcitabine was well tolerated in patients with advanced, pre-treated NSCLC. Based on the observed clinical efficacy, future clinical trials should involve genomically selected patients.

Rucaparib in patients presenting a metastatic breast cancer with homologous recombination deficiency, without germline BRCA1/2 mutation

BackgroundBreast cancer may present genomic alterations leading to homologous recombination deficiency (HRD). PARP inhibitors have proven their efficacy in patients with HER2-negative (HER2-) metastatic breast cancer (mBC) harbouring germline (g) BRCA1/2 mutations in 3 phases III trials. The single-arm phase II RUBY trial included 42 patients, 40 of whom received at least one dose of rucaparib. RUBY study assessed the efficacy of rucaparib in HER2-mBC with either high genomic loss of heterozygosity (LOH) score or non-germline BRCA1/2 mutation. Patients and methodsThe primary objective was the clinical benefit rate (CBR), and the study was powered to see 20% CBR using a 2-stage Simon design. ResultsThe primary-end point was not reached with a CBR of 13.5%. Two LOH-high patients, without somatic BRCA1/2 mutation, presented a complete and durable response (12 and 28.5 months). Whole-genome analysis was performed on 24 samples, including 5 patients who presented a clinical benefit from rucaparib. HRDetect tended to be associated with response to rucaparib, without reaching statistical significance (median HRDetect responders versus non-responders: 0.465 versus 0.040; p = 0.2135). Finally, 220 of 711 patients with mBC screened for LOH upstream from RUBY presented a high LOH score associated with a higher likelihood of death (hazard ratio = 1.39; 95% CI: 1.11–1.75; p = 0.005). ConclusionOur data suggest that a small subset of patients with high LOH scores without germline BRCA1/2 mutation could derive benefit from PARP inhibitors. However, the RUBY study underlines the need to develop additional biomarkers to identify selectively potential responders.

Characterization of patients with long-term responses to rucaparib treatment in recurrent ovarian cancer

ObjectiveTo describe molecular and clinical characteristics of patients with high-grade recurrent ovarian carcinoma (HGOC) who had long-term responses to the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib. MethodsThis post hoc analysis pooled patients from Study 10 (NCT01482715; Parts 2A and 2B; n = 54) and ARIEL2 (NCT01891344; Parts 1 and 2; n = 491). Patients with investigator-assessed complete or partial response per RECIST were classified based on duration of response (DOR): long (≥1 year), intermediate (6 months to <1 year), or short (<6 months). Next-generation sequencing was used to detect deleterious mutations and loss of heterozygosity (LOH) in tumors. ResultsOverall, 25.3% (138/545) of enrolled patients were responders. Of these, 27.5% (38/138) had long-term responses; 28.3% (39/138) were intermediate- and 34.8% (48/138) were short-term responders. Most of the long-term responders harbored a BRCA1 or BRCA2 (BRCA) mutation (71.1%, 27/38), and BRCA structural variants were most frequent among long-term responders (14.8%; 4/27). Responders with HGOC harboring a BRCA structural variant (n = 5) had significantly longer DOR than patients with other mutation types (n = 81; median not reached vs 0.62 years; HR, 0.21; 95% CI, 0.10–0.43; unadjusted p = 0.014). Among responders with BRCA wild-type HGOC, most long- and intermediate-term responders had high genome-wide LOH: 81.8% (9/11) and 76.9% (10/13), respectively, including 7 with deleterious RAD51C, RAD51D, or CDK12 mutations. ConclusionAmong patients who responded to rucaparib, a substantial proportion achieved responses lasting ≥1 year. These analyses demonstrate the relationship between DOR to PARP inhibitor treatment and molecular characteristics in HGOC, such as presence of reversion-resistant BRCA structural variants.

Abstract 1908: Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes reveals distinct genomic profile of immune excluded phenotype in pan-carcinoma

Abstract Introduction: Immune-excluded phenotype, defined by the existence of tumor-infiltrating lymphocytes (TIL) exclusively confined to cancer-associated stroma (CS) without protruding to tumor nest, has been suggested to be an intrinsic resistance mechanism of immune checkpoint inhibitor. However, little is known about the genomic landscape of immune-excluded phenotype across cancer types. In the current study, we analyzed genomic correlates of immune excluded phenotype in pan-carcinoma, using Lunit SCOPE IO, an artificial intelligence (AI)-powered whole slide image (WSI) software analyzer. Methods: Lunit SCOPE IO has been trained for &amp;gt; 100,000 WSI across &amp;gt; 30 cancer types to detect lymphocyte, cancer epithelium (CE), and CS with &amp;gt; 95% accuracy. WSI was divided into 1 mm2 sized patch and lymphocyte density in CE or its density in CS were calculated to classify immune phenotype as follows: lymphocyte infiltration into CE was considered as inflamed, lymphocyte exclusively enriched in CS as immune-excluded, and sparse lymphocyte infiltration as immune-desert. We analyzed 7,128 The Cancer Genome Atlas (TCGA) pan-carcinoma samples across 20 cancer types excluding those of mesenchymal origin. Results: Lunit SCOPE IO classifies WSI of TCGA pan-carcinoma into three immune phenotypes: inflamed (17.9%), immune-excluded (27.7%), immune-desert (34.2%) and remaining 20.2% of mixed phenotype. Immune-excluded phenotype is highly enriched in lung squamous cell carcinoma (61.5%), lung adenocarcinoma (53.6%), colorectal cancer (51.7%), and pancreatic cancer (42.2%) whereas inflamed phenotype is less dominant in colorectal cancer (3.4%) and pancreatic cancer (3.3%). Tumor mutational burden (TMB) is increased in both inflamed (mean 7.30/Mb) and immune-excluded (7.18/Mb) compared to that in immune-desert (3.28/Mb), however, genomic instability assessed by fraction altered loss-of-heterozygosity (LOH) is only increased in immune-excluded (mean 0.208) compared to that in inflamed (0.143) and immune-desert (0.148, P &amp;lt; 10-16). Consistent with this result, tumors with high TMB (&amp;gt; 10/Mb) and LOH of HLA genes (N = 124) is predominantly enriched by immune-excluded (45.2%), compared to inflamed (23.4%) or immune-desert (8.9%). Interestingly, a majority of oncogenic drivers such as mutations of TP53, KRAS, and KEAP1 are significantly enriched in immune-excluded (fold change &amp;gt; 1.5, P &amp;lt; 10-10), and gene sets associated with epithelial-mesenchymal transition, apical junction, and TGF-beta signaling are enriched in immune-excluded. Conclusion: AI-powered spatial analysis of WSI can classify immune phenotype in pan-carcinoma and it reveals that plausible immune intrinsic resistance pathways including genomic instability, LOH of HLA genes, and alteration of major oncogenic drivers are highly enriched in immune-excluded phenotype. Citation Format: Chan-Young Ock, Changhee Park, Kyunghyun Paeng, Donggeun Yoo, Seokhwi Kim, Sehhoon Park, Se-Hoon Lee, Tony S. Mok, Yung-Jue Bang. Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes reveals distinct genomic profile of immune excluded phenotype in pan-carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1908.

A phase II study of rucaparib in patients with high genomic LOH and/or BRCA 1/2 mutated stage IV non-small cell lung cancer (Lung-MAP Sub-Study, S1900A).

9024 Background: While prior studies have shown robust efficacy leading to FDA approval of PARP inhibitors (PARPi) in BRCA-associated cancers, data in NSCLC are much less clear. S1900A, a LUNG-MAP substudy, evaluated the PARPi rucaparib in advanced stage NSCLC harboring BRCA1/2 mutations or genomic loss of heterozygosity (LOH) as a phenotypic marker of homologous recombination deficiency (HRD). Methods: Eligible patients (pts) were required to have a deleterious mutation in BRCA1/BRCA2 and/or high (≥21%) genomic LOH. Key eligibility criteria: advanced NSCLC patients (pts) with progression on or after platinum based chemotherapy and/or PD-(L)1 antibody and progressed on most recent line of systemic therapy, a Zubrod performance status of 0-1, adequate organ function, no ≥ grade 3 hypercholesterolemia, no previous PARPi exposure and no systemic therapy within 21 days of registration. Pts stratified by histology into two cohorts (squamous [sq] and non-squamous/mixed histology [nsq]). With 40 eligible pts per cohort, the design had 91% power to rule out an ORR of 15% if the true ORR was at least 35% at the 1-sided 5% level. A planned interim analysis on the first 20 pts evaluable for response per cohort required ≥ 3 responses to proceed to full enrollment. Results: 64 pts enrolled (27 sq cohort; 37 nsq cohort) of whom 59 are eligible. Median age 65.7 yrs; M/F 33/26 (56/44%); 98% of the pts received at least 1 prior line of treatment for stage IV disease. Biomarker selection included 36 pts (61%) LOH only, 4 pts (7%) BRCA1 only, 11 pts (19%) BRCA2 only, 4 pts (7%) BRCA1 + LOH high and 4 pts (7%) BRCA2 + LOH high. Both cohorts were closed for futility with insufficient responses in the interim analysis populations. In the full study, 4 responses (3 nsq/1 sq) were reported. ORR was 7% (95% CI: 0-13) (9% nsq/4% sq) and DCR was 62% (95% CI: 50-75) (62% nsq/64% sq); 3 of the 4 responders harbored BRCA1/2 mutations and 1 of 4 high LOH; ORR in BRCA1/2+ pts 3/23 (13%). Median PFS was 3.2 months (95% CI: 1.6-4.6) in nsq cohort and 2.9 months (95% CI 1.6-6.2) in sq cohort. Median OS was 7.8 months in nsq cohort and 7.9 months in sq cohort. The most frequent grade ≥3 adverse events were anemia (22%), lymphopenia (8%), fatigue (8%) and transaminitis (5%). Conclusions: S1900A failed to show the requisite level of efficacy for rucaparib in advanced NSCLC pts with high genomic LOH and/or a BRCA1/2 mutation. There were no new safety signals and hematologic toxicities were the most frequent adverse events. Genomic LOH as a phenotypic marker of HRD does not predict sufficient activity of rucaparib in NSCLC. These results stand in contrast to the high level of efficacy of PARPi in patients with BRCA-associated or high LOH cancers of other tumor types. Underlying biologic differences in the genomic characteristics of these cancers vs. NSCLC may be responsible. Studies examining this premise are ongoing. (NCT03845296). Clinical trial information: NCT03845296.

Next generation sequencing in ovarian cancer patients: Does personalized medicine improve oncological outcomes?

5553 Background: Ovarian cancer (OC) is the second most common gynecologic malignancy and the most common cause of gynecologic cancer mortality in the United States. Homologous recombination deficiency (HRD), including the BRCA mutations, are found in 50% of OC tumors. Next generation sequencing (NGS) provides understanding the underlying molecular and genetic patterns to improve OC treatment. This study examines the prognostic and predictive biomarkers identified with NGS in hopes to improve OC patients outcomes. Methods: The patient cohort included 890 consecutive OC patients treated between 2002 and 2020,at the Tel-Aviv Medical Center. We retrospectively evaluated patients with histopathologically confirmed OC. Cox models were used to analyze the clinical impact of various mutations and biomarkers among OC patients with and without FoundationOne CDx NGS testing, by assessing overall survival (OS), progression free survival (PFS), and physicians' timing preferences for referral to NGS testing. Results: Among the 890 OC patients, 103 (11.57%) completed NGS molecular testing. The median OS among patients with and without NGS testing, adjusted for age, stage and recurrence status, was 73.36 and 68.50 months, respectively (P =.02). The median PFS was 17.23 and 17.43 months, respectively (P =.77). We also evaluated physicians' preferences regarding timing of molecular profiling, upon diagnosis, after first recurrence and at advanced line of treatment in 31.95%, 36.08% and 26.8% of practitioners, respectively. Of the patients who completed NGS, 48 (52.75%) harbored actionable mutations, and 21 patients (43.75%) received matched targeted therapy. Forty-five patients were microsatellite stable (MSS) (45%), 55 with undetermined status (55%) and 0 patients with MSI-H. Forty-one (71.93%) patients had low ( &lt; 5) tumor mutation burden status (TMB), 16 (28.07%) intermediate (5-15) and none with high ( &gt; 15) TMB. There was no noticeable survival difference when comparing low with intermediate TMB (P = 0.3). Loss of heterozygosity (LOH) was a significant prognostic biomarker. Patients with high LOH (hLOH &gt; = 16%) had longer OS compared to low LOH (lLOH &lt; 16%), 99.02 vs. 50.23 months, respectively (P &lt;.005). Patients with hLOH and BRCA mutations (BRCA+) had longer OS compared to hLOH/BRCA WT (BRCA-), lLOH/BRCA+, and lLOH/BRCA-, with an unreached median OS of 91.5 vs. 60.48 vs. 45.21 months, respectively (P =.005). Conclusions: Our work demonstrates the clinical benefit of NGS personalized medicine as a cornerstone of future treatment strategies in OC. Our study suggests an OS benefit among the NGS tested cohort. We identified LOH as a prognostic biomarker. Prospective studies evaluating larger cohorts are necessary to generate a more extensive evaluation of additional prognostic and predictive biomarkers among OC patients.

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Abstract 3548: Loss of heterozygosity (LOH) as a candidate biomarker of PARP inhibitor sensitivity in Chinese solid tumor patients

Abstract Background: Poly (ADP-ribose) polymerase (PARP) plays a vital role in the repair of single-strand DNA breaks through the base excision repair pathway. Several PARP inhibitor approved for advanced BRCA-mutated (BRCAm) ovarian cancer. PARP inhibitors may benefit patients whose tumors are dysfunctional in DNA repair mechanisms unrelated to BRCA1/2. Here we descript the clinical application of LOH score as a candidate biomarker to predicate therapeutic response of PARP inhibitor in Chinese solid tumor patients. Methods: Formalin fixed paraffin embedded (FFPE) samples of 16 Chinese solid tumor patients were collected for next-generation sequencing (NGS) based 450 genes panel assay. Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, gene fusions and rearrangement were assessed. Loss of heterozygosity (LOH) status, Microsatellite stable (MSS) status and TMB (tumor mutational burden) were also acquired by an NGS algorithm. Results: There are 16 patients were analyzed in this retrospective study that most patients having advanced disease stage, Including 9 males and 7 females. The median age is 64 (range, 40-72) years old. The tumor type of these patients including Hepatocellular carcinoma (N=3), Cholangiocarcinoma (N=7), Breast cancer (N=2), Prostate cancer (N=2), Lymphoepithelioma like carcinoma (N=1) and Gallbladder adenocarcinoma (N=1). All 16 patients were treated with PARP inhibitor (Olaparib) including 14 patients harboring BRCA1/2 mutation. 15 patients were evaluable, OS (overall survival) time was calculated until abstract publish. 1 patients achieved complete response (CR), 4 patients achieved partial response (PR), 9 had stable disease (SD) and 1 had progressive disease (PD). Two patients with BRCA wild type achieved SD and the OS time was 13 and 37 months, respectively. LOH status was evaluated all tumors, 25% (4/16) of patients would be considered as having high LOH (LOH-H), including 2 patients without BRCA mutation. 75% (12/16) patients considered as having low LOH (LOH-L). LOH-high group has a longer OS time (P=0.056), median OS time of LOH-H group (N=4) is 25 month (range, 4-42) and LOH-L group (N=11) is 6 month (range, 2-23). Also we explored the association between TMB and OS, identified TMB-H patients (N=6) morel likely has a longer OS (median OS, 11.5 VS 5 month, P=0.017). Conclusion: In patients with advanced solid cancer, High LOH status was associated with good therapeutic response of PARP inhibitor. LOH status may become a potential indicator for the treatment of PARP inhibitors. Due to the limitations of the number and clinical baseline of patients, the results may require further research and validation. Citation Format: Jinwei Hu, Shuirong Zhang, Kai You, Lijuan Chen, Peng Zhang, Junping Shi, Ming Yao, Mo Wang, Kai Wang. Loss of heterozygosity (LOH) as a candidate biomarker of PARP inhibitor sensitivity in Chinese solid tumor patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3548.