Clinical Benefit With PARP Inhibitor for Pathogenic Germline FANCA-mutated Relapsed Epithelial Ovarian Cancer: a Case Report

2021 ◽  
Author(s):  
Bing Qian ◽  
Jin Lu ◽  
Wenshu Leng ◽  
Zhengqing Yan ◽  
Shiqing Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Benefit ◽  
Parp Inhibitor ◽  
Susceptibility Gene ◽  
Radical Resection ◽  
Parp Inhibitors ◽  
Fanconi Anaemia ◽  
Platinum Based Chemotherapy ◽  
Patient Consent ◽  
Recombination Pathway

Abstract Background: PARP inhibitors have been approved as targeted therapy for BRCA-deficient metastatic ovarian cancer (OC). Fanconi anemia complementation group A (FANCA) is one of Fanconi anaemia-related genes and a susceptibility gene to breast and OC. However, whether germline FANCA-mutated relapsed epithelial OC could achieve clinical benefit from the treatment of PARP inhibitor is still unclear. Case presentation: A 49-year-old female patient was diagnosed with epithelial OC and underwent resection and first-line of platinum-based chemotherapy in 2016. After first recurrence, she underwent radical resection and received second-line of platinum-based chemotherapy in 2018. After the second relapse in July 2019, the patient underwent radical resection and the corresponding tumor tissue DNA suffered next generation sequencing (NGS) analysis revealed a germline FANCA mutation. Subsequently, the third-line treatment of liposomal doxorubicin hydrochloride plus lobaplatin was administrated for five cycles with patient consent and then oral niraparib (200 mg daily) was administered for maintenance treatment. During the follow-up, no evidence of tumor recurrence was observed. Currently, the PFS already exceeded 21 months and the treatment is still going on. Conclusions: This case highlighted that OC patients harboring with pathogenic gene alterations in homologous recombination pathway might achieved clinical benefit from PARP inhibitors, which should be confirmed in further studies.

scholarly journals Niraparib in ovarian cancer: results to date and clinical potential

2017 ◽  
Vol 9 (9) ◽  
pp. 579-588 ◽  
Author(s):  
Davide Caruso ◽  
Anselmo Papa ◽  
Silverio Tomao ◽  
Patrizia Vici ◽  
Pierluigi Benedetti Panici ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Repair System ◽  
Gynaecological Malignancy ◽  
Platinum Based Chemotherapy ◽  
Base Excision

Ovarian cancer is the first cause of death from gynaecological malignancy. Germline mutation in BRCA1 and 2, two genes involved in the mechanisms of reparation of DNA damage, are showed to be related with the incidence of breast and ovarian cancer, both sporadic and familiar. PARP is a family of enzymes involved in the base excision repair (BER) system. The introduction of inhibitors of PARP in patients with BRCA-mutated ovarian cancer is correlated with the concept of synthetic lethality. Among the PARP inhibitors introduced in clinical practice, niraparib showed interesting results in a phase III trial in the setting of maintenance treatment in ovarian cancer, after platinum-based chemotherapy. Interestingly, was niraparib showed to be efficacious not only in BRCA-mutated patients, but also in patients with other alterations of the homologous recombination (HR) system and in patients with unknown alterations. These results position niraparib as the first PARP-inhibitor with clinically and statistically significant results also in patients with no alterations in BRCA 1/2 and other genes involved in the DNA repair system. Even if the results are potentially practice-changing, the action of niraparib must be further studied and deepened.

Elucidation of PARP inhibitor activity in BRCAwt recurrent ovarian cancer by hrr mutational gene profile analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5568-5568
Author(s):  
Mansoor Raza Mirza ◽  
Bin Feng ◽  
Ming Shan ◽  
Kaiming Sun ◽  
Ilkar Yalcin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Clinical Benefit ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Gene Mutations ◽  
Recurrent Ovarian Cancer ◽  
Exploratory Analysis ◽  
Platinum Based Chemotherapy ◽  
Biomarker Analysis

5568 Background: Niraparib is an oral, selective poly(ADP-ribose) polymerase inhibitor (PARPi) approved for maintenance treatment of BRCA mutated ( BRCAmut) and BRCA wild-type ( BRCAwt) recurrent ovarian cancer patients (pts) who are in response to platinum-based chemotherapy. In the non-germline BRCA mutated (non-g BRCAmut) cohort of the ENGOT-OV16/NOVA trial, clinical benefit with niraparib vs placebo was seen in pts regardless of their Myriad myChoice HRD test status ( BRCAmut and homologous recombination deficiency [HRD] score), with a hazard ratio (HR) of 0.38 in HRD-positive (HRDpos) and 0.58 in HRD-negative (HRDneg) pts. To determine if treatment benefit in HRDneg pts may result from mutations in other homologous recombination repair ( HRR) genes, we examined the relationship between progression-free survival and other HRR gene mutations in the NOVA non-gBRCAmut cohort. Methods: A retrospective, exploratory biomarker analysis was conducted using all available tumor samples from 331 pts enrolled in the NOVA non-g BRCAmut cohort. Mutation status of HRR genes was evaluated using a 43-gene NGS assay (Myriad Genetics), including BRCA1/2 and 16 additional HRR genes. Results: In this exploratory analysis of the NOVA non-g BRCAmut cohort, niraparib demonstrated clinical benefit in pts with somatic BRCA mutation (HR, 0.27) and in BRCAwt pts (HR, 0.47). In addition, BRCAwt pts with other HRR gene mutations also derived benefit from niraparib (HR, 0.31), as did BRCAwt/ HRRwt pts (HR, 0.49). When BRCAwt/ HRRwt pts were categorized by HRD score, clinical benefit was also observed in both HRDpos and HRDneg pts, with HRs of 0.33 and 0.60, respectively. These results suggest that, although these biomarkers have good positive predictive value, they are not good negative predictors for niraparib benefit in this indication. Conclusions: This retrospective, exploratory analysis of the ENGOT-OV16/NOVA non-g BRCAmut cohort suggests that although pts with somatic BRCA mutation and other HRR mutations benefit from niraparib treatment, clinical benefit is also seen in HRDneg pts without HRR mutations, perhaps related to other genomic, epigenetic, or functional alterations within ovarian tumors yet to be defined.

scholarly journals The Landscape and Therapeutic Implications of Molecular Profiles in Epithelial Ovarian Cancer

2020 ◽  
Vol 9 (7) ◽  
pp. 2239
Author(s):  
Ludivine Dion ◽  
Isis Carton ◽  
Sylvie Jaillard ◽  
Krystel Nyangoh Timoh ◽  
Sébastien Henno ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Genetic Alterations ◽  
High Grade ◽  
Dna Breaks ◽  
Brca Mutations ◽  
Platinum Based Chemotherapy

Epithelial ovarian cancer (EOC) affects 43,000 women worldwide every year and has a five-year survival rate of 30%. Mainstay treatment is extensive surgery and chemotherapy. Outcomes could be improved by molecular profiling. We conducted a review of the literature to identify relevant publications on molecular and genetic alterations in EOC. Approximately 15% of all EOCs are due to BRCA1 or BRCA2 mutations. Four histologic subtypes characterized by different mutations have been described: serous, endometrioid, mucinous, and clear-cell. Between 20–30% of high-grade serous EOCs have a BRCA mutation. Tumors with BRCA mutations are unable to repair double-strand DNA breaks, making them more sensitive to platinum-based chemotherapy and to PolyAdenosine Diphosphate-Ribose Polymerase (PARP) inhibitors. Olaparib is a PARP inhibitor with proven efficacy in BRCA-mutated ovarian cancer, but its effectiveness remains to be demonstrated in tumors with a BRCAness (breast cancer) profile (i.e., also including sporadic tumors in patients with deficient DNA repair genes). A universally accepted molecular definition of BRCAness is required to identify optimal theranostic strategies involving PARP inhibitors. Gene expression analyses have led to the identification of four subgroups of high-grade serous EOC: mesenchymal, proliferative, differentiated, and immunoreactive. These subtypes are not mutually exclusive but are correlated with prognosis. They are not yet used in routine clinical practice. A greater understanding of EOC subtypes could improve patient management.

scholarly journals Overcoming PARP inhibitor resistance in ovarian cancer: what are the most promising strategies?

2020 ◽  
Vol 302 (5) ◽  
pp. 1087-1102
Author(s):  
Daniel Martin Klotz ◽  
Pauline Wimberger
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Multiple Drug Resistance ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Resistance Mechanisms ◽  
Therapeutic Options ◽  
Parp Inhibition ◽  
Multiple Drug ◽  
Platinum Based Chemotherapy

Abstract Purpose Ovarian cancer is the most lethal gynaecological malignancy. Despite the introduction of bevacizumab, standard chemotherapy has remained largely unchanged and the vast majority of patients will relapse within the first two years of diagnosis. However, results from recent clinical trials demonstrating clinical benefits of PARP inhibitor treatment are rapidly changing therapeutic options for many patients with ovarian cancer. Methods Given the introduction of new therapeutic options in the treatment of ovarian cancer, we critically review key clinical trials, areas of scientific research and its clinical relevance. Results Most notably, patients with BRCA1/2 mutant ovarian cancer benefit from maintenance treatment with PARP inhibitors after (complete or partial) response to platinum-based chemotherapy. Here, we discuss the mechanism of PARP inhibition, multiple drug resistance mechanisms, including BRCA reverse mutations, altered PARP expression, changes in DNA repair pathways, kinase activation and additional drug targets that may augment PARP inhibition. Conclusion Although the use of PARP inhibitors is a huge step forward, it is apparent that patients, both with and without BRCA-mutant ovarian cancer, will eventually become resistant to PARP inhibitors. Therefore, novel combination therapies may enhance PARP inhibitor efficacy and overcome resistance mechanisms.

scholarly journals Long-Term Follow-Up of a Female Patient Treated with Olaparib—Hope for a Long Life without Relapse?

2021 ◽  
Vol 18 (7) ◽  
pp. 3430
Author(s):  
Mateusz Kozłowski ◽  
Katarzyna Nowak ◽  
Aneta Cymbaluk-Płoska
Keyword(s):  
Ovarian Cancer ◽  
Parp Inhibitor ◽  
Brca1 Gene ◽  
High Specificity ◽  
Reproductive Organs ◽  
Platinum Based Chemotherapy ◽  
Long Term Follow Up ◽  
History Of ◽  
Advanced Stages

Ovarian cancer is one of the most common cancers of the reproductive organs. As there are no symptoms in the early stages, it is mainly detected in the advanced stages. Even then, the symptoms are non-specific and include, for example, abdominal pain, early satiety, or changes in bowel habits. Both biochemical marker levels and imaging studies are used in the initial diagnosis. However, it should be emphasized that they are not characterized by high specificity. Treatment is multistage, and usually first-line debulking surgery is used followed by platinum-based chemotherapy. Here we present a clinical case of a 56-year-old female, a carrier of a mutation in the BRCA1 gene, with a history of breast cancer and with recurrent epithelial ovarian cancer. The patient was qualified for treatment with a PARP inhibitor and is currently undergoing treatment with olaparib. In the patient’s follow up of 50 months to date, there has been no recurrence of cancer. Few side effects have been observed, and the most serious one that can be effectively treated is anemia. On the basis of the described case, the authors concluded that olaparib treatment is effective, relatively safe, and does not significantly affect daily functioning.

PARP inhibitors decrease response to subsequent platinum-based chemotherapy in patients with BRCA mutated ovarian cancer

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Peter G. Rose ◽  
Meng Yao ◽  
Laura M. Chambers ◽  
Haider Mahdi ◽  
Robert DeBernardo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Parp Inhibitors ◽  
Platinum Based Chemotherapy

scholarly journals Niraparib Maintenance Therapy in Patients With Recurrent Ovarian Cancer After a Partial Response to the Last Platinum-Based Chemotherapy in the ENGOT-OV16/NOVA Trial

2019 ◽  
Vol 37 (32) ◽  
pp. 2968-2973 ◽  
Author(s):  
Josep M. del Campo ◽  
Ursula A. Matulonis ◽  
Susanne Malander ◽  
Diane Provencher ◽  
Sven Mahner ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Partial Response ◽  
Maintenance Therapy ◽  
Clinical Benefit ◽  
Patient Reported Outcomes ◽  
Progression Free Survival ◽  
Recurrent Ovarian Cancer ◽  
Free Survival ◽  
Platinum Based Chemotherapy ◽  
Patient Reported

PURPOSE In the ENGOT-OV16/NOVA trial (ClinicalTrials.gov identifier: NCT01847274 ), maintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, prolonged progression-free survival in patients with platinum-sensitive, recurrent ovarian cancer who had a response to their last platinum-based chemotherapy. The objective of the study was to assess the clinical benefit and patient-reported outcomes in patients who had a partial response (PR) and complete response (CR) to their last platinum-based therapy. PATIENTS AND METHODS A total of 553 patients were enrolled in the trial. Of 203 patients with a germline BRCA mutation (g BRCAmut), 99 had a PR and 104 had a CR to their last platinum-based therapy; of 350 patients without a confirmed g BRCAmut (non–g BRCAmut), 173 had a PR and 177 had a CR. Post hoc analyses were carried out to evaluate safety and the risk of progression in these patients according to g BRCAmut status and response to their last platinum-based therapy. Ovarian cancer–specific symptoms and quality of life were assessed using the Functional Assessment of Cancer Therapy–Ovarian Symptom Index. RESULTS Progression-free survival was improved in patients treated with niraparib compared with placebo in both the g BRCAmut cohort (PR: hazard ratio [HR], 0.24; 95% CI, 0.131 to 0.441; P < .0001; CR: HR, 0.30; 95% CI, 0.160 to 0.546; P < .0001) and the non–g BRCAmut cohort (PR: HR, 0.35; 95% CI, 0.230 to 0.532; P < .0001; CR: HR, 0.58; 95% CI, 0.383 to 0.868; P = .0082). The incidence of any-grade and grade 3 or greater adverse events was manageable. No meaningful differences were observed between niraparib and placebo in PR and CR subgroups with respect to patient-reported outcomes. CONCLUSION Patients achieved clinical benefit from maintenance treatment with niraparib regardless of response to the last platinum-based therapy.

scholarly journals PARP Inhibitor Olaparib Use in a BRCA1-Positive Patient With Metastatic Triple-Negative Breast Cancer, Without the Initial Use of Platinum-Based Chemotherapy, Showing Significant Rapid Near Resolution of Large Liver Metastasis While Patient Experienced Gout-Like Symptoms

2019 ◽  
Vol 7 ◽  
pp. 232470961986498 ◽  
Author(s):  
Trevanne Matthews Hew ◽  
Lara Zuberi
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Management Options ◽  
Federal Drug Administration ◽  
Platinum Based Chemotherapy ◽  
Metastatic Setting

Triple-negative breast cancer (TNBC) accounts for 20% of breast cancers diagnosed worldwide. This subtype of breast cancer tends to behave more aggressively, and unlike other breast cancer subtypes, there are no standard targeted treatments for most patients. However, up to 20% of patients with TNBC harbor a breast cancer gene (BRCA) mutation, particularly in BRCA1. For patients who carry this gene mutation, this opens the door for new management options by the use of newer agents such as polyadenosine diphosphate-ribose polymerase (PARP) inhibitors in the metastatic setting. Given that this is uncommon and that PARP inhibitors have only recently received Federal Drug Administration approval, the experience with these drugs is relatively new. In this article, we present a case of a patient treated in this setting with olaparib who developed an unanticipated side effect as a result of the high efficacy of the drug.

scholarly journals First-line PARP inhibitors in ovarian cancer: summary of an ESMO Open - Cancer Horizons round-table discussion

ESMO Open ◽  
2020 ◽  
Vol 5 (6) ◽  
pp. e001110
Author(s):  
Susana Banerjee ◽  
Antonio Gonzalez-Martin ◽  
Philipp Harter ◽  
Domenica Lorusso ◽  
Kathleen N Moore ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Therapy ◽  
Parp Inhibitor ◽  
Advanced Ovarian Cancer ◽  
Round Table ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
European Medicines Agency ◽  
First Line ◽  
Phase Iii Trials

Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the latest breakthrough in the management of newly diagnosed advanced ovarian cancer. The results of the SOLO-1 trial in 2018 led to European Medicines Agency and Food and Drug Administration approval of olaparib as first-line maintenance therapy in patients with BRCA1/2 mutation, establishing a new standard of care. Subsequently, the results of three phase III trials (PRIMA, PAOLA-1, VELIA) evaluating the use of first-line PARP inhibitors beyond patients with BRCA1/2 mutations and as combination strategies were presented in 2019, leading to the recent approval of maintenance niraparib irrespective of biomarker status and olaparib in combination with bevacizumab in homologous recombination deficiency-positive-associated advanced ovarian cancer. An ESMO Open - Cancer Horizons round-table expert panel discussed the four phase III trials of first-line PARP inhibitor therapy and how they are changing the clinical management of advanced ovarian cancer.

scholarly journals Genome-scale CRISPR knockout screen identifies TIGAR as a modifier of PARP inhibitor sensitivity

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Pingping Fang ◽  
Cristabelle De Souza ◽  
Kay Minn ◽  
Jeremy Chien
Keyword(s):  
Ovarian Cancer ◽  
Metabolic Pathways ◽  
Clinical Utility ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Loss Of Function ◽  
Poor Overall Survival ◽  
Cytotoxic Effects ◽  
Cancer Types ◽  
Genome Scale

Abstract Treatment of cancer with poly (ADP-ribose) polymerase (PARP) inhibitors is currently limited to cells defective in the homologous recombination (HR) pathway. Identification of genetic targets that induce or mimic HR deficiencies will extend the clinical utility of PARP inhibitors. Here we perform a CRISPR/Cas9-based genome-scale loss-of-function screen, using the sensitivity of PARP inhibitor olaparib as a surrogate. We identify C12orf5, encoding TP53 induced glycolysis and apoptosis regulator (TIGAR), as a modifier of PARP inhibitor response. We show that TIGAR is amplified in several cancer types, and higher expression of TIGAR associates with poor overall survival in ovarian cancer. TIGAR knockdown enhances sensitivity to olaparib in cancer cells via downregulation of BRCA1 and the Fanconi anemia pathway and increases senescence of these cells by affecting metabolic pathways and increasing the cytotoxic effects of olaparib. Our results indicate TIGAR should be explored as a therapeutic target for treating cancer and extending the use of PARP inhibitors.

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