Targeted Next Generation Sequencing Identifies Potential Novel Therapeutic Options In Chinese HGSOC Patients

Background High-grade serous ovarian cancer(HGSOC)is very sensitive to platinum-based chemotherapy,however,most patients with intermediate and advanced stages will eventually develop resistance to platinum-based chemotherapy and relapse.Platinum resistance is an unavoidable serious problem in the course of ovarian cancer treatment,limiting the use of platinum-based chemotherapy.Targeted therapy and next generation sequencing(NGS)provide a new treatment option for ovarian cancer patients,and provides new hope for prolonging survival time and improving the quality of life for patients with ovarian cancer platinum-resistant.In the past few years,targeted therapy,especially Poly(adenosine diphosphate ribose)polymerase(PARP)inhibitors(PARPi),has improved the outcome of patients with ovarian cancer.However,most ovarian cancer patients may be still not response or low-response to PARPi,which mechanism is still not fully understood.It is necessary to identify the possible genetic alteration of low-response and resistance to PARPi and the potential novel targets for other available targeted drugs.In this study,a broad,hybrid capture-based NGS assay was used to identify actionable genetic alterations from ovarian cancer tissues.Methods We collected 21 patients with advanced HGSOC from Jan 1,2014 to Nov 1,2021 at the Department of Oncology,Affiliated Hospital of Qingdao University.In order to expand the sample,we collected 47 patients with early and mid-term HGSOC by medical records screening system from Jan 1,2014 to Nov 1,2021,all those patients had a radical operation at the Affiliated Hospital of Qingdao University,and the tissue was collected during the operation for pathological examination.68 cases of ovarian cancer were analyzed,including 6 International Federation of Gynecology and Obstetrics(FIGO)stage I,15 FIGO stage II,37 FIGO stage III and 10 FIGO stage IV,all the patients signed the informed consent.We assessed 7708 exons of 508 tumorrelated genes and 78 introns of 19 frequently rearranged genes for base substitutions,INDELs,copy number alterations,and gene fusions.Results In our study,14.7%(10/68)of the tumors harbored actionable genetic alterations in BRCA1.25.0%(17/68)patients without BRCA1 mutations harbored other actionable genetic alterations,such as homologous-recombination repair(HRR)pathway-related genes(ATM,CDK12,FANCA,FANCD2),PI3K/AKT/mTOR pathway genes(NF1,FBXW7,PIK3 CA,PTEN,TSC1,TSC2),and some other genes(ARID1A,FGFR1,KRAS,NRAS).Those genes identified by NGS associated with the PARPi clinical effect,and related to potential novel therapeutic options for ovarian cancer.Clinical follow-up shows that some targetable gene alterations such as ARID1 A and NF1 can guide potential treatment options for HGSOC.ARID1 A mutations may predict the efficacy of immunotherapy,and patients with NF1 mutations may benefit from everolimustargeted therapy.Bioinformatics analysis showed that ARID1 A expression was closely related to the immune microenvironment.Conclusions In our study,39.7%(27/68)patients had at least one actionable genetic alterations,14.7%(10/68)of ovarian cancers harbored BRCA1 actionable genetic alterations,and 25.0%(17/68)patients without BRCA1 actionable genetic alterations had other somatic mutations or copy number variations associated with potential treatment options and may benefit from other targeted therapies or immunotherapy.Therefore,NGS testing in ovarian cancer tissues is necessary to identify actionable genetic alteration in patients to guide personalized and precise treatment.