Exceptional Response to Olaparib in a Patient With Recurrent Ovarian Cancer and an Entire BRCA1 Germline Gene Deletion

Abstract

PARP inhibitors are known to be effective in patients with ovarian cancer (OC) and germline mutations in BRCA1 and BRCA2 genes (BRCA mutations). Little is known, however, about any correlation between the deletion size and location of the BRCA mutation and the response to PARP inhibitors. Women with OC commonly undergo genetic testing because the presence of a germline BRCA mutation impacts therapeutic decisions and is important for cancer surveillance in patients and their family members. This report presents a case of a rare entire germline BRCA1 gene deletion and an exceptional response to a PARP inhibitor, olaparib, in a heavily pretreated patient with OC. Her disease course was also remarkable for complete responses to platinum-based chemotherapy and long chemotherapy-free intervals. Interestingly, the deletion of the entire BRCA1 gene was found after previously negative BRCA test results and is associated with a deletion of 6 adjacent genes without known clinical significance. She has remained progression-free and asymptomatic for >3 years on olaparib, with an overall survival of >12 years. We postulate that this unusually favorable response and prolonged overall survival is related to the cancer cells’ inability to reverse the entire gene deletion to wild-type (a common mechanism of resistance to PARP inhibition). This case shows the value of genetic testing for patients with OC and highlights the utility of additional testing with previously negative results and limited genetic testing. It also provides insight into a potential mechanism of an exceptional response to PARP inhibition.

Clinical Benefits of Olaparib in Mexican Ovarian Cancer Patients With Founder Mutation BRCA1-Del ex9-12

“…In this way, BRCA1 9–12 exon deletion represents the loss of more than 60% of the gene-coding region, so it would be complex to opt for a mutational reversion resistance mechanism to restore the wild-type allele and thus correlate with the better response and survival. Similar observations have been reported in patients with BRCA LGRs and their response to platinum and PARPi ( Randall et al, 2020 ; Wang et al, 2022 ).…”

Cytotoxic and targeted therapy for BRCA1/2-driven cancers

“…The analysis of tumors exposed to platinum therapy or PARPi revealed instances of the rescue of BRCA1/2 function, which is achieved by the second mutation in the affected gene, and, consequently, by the restoration of BRCA1/2 open reading frame [ 24 , 28 ]. These data are supported by clinical observations of extraordinarily good response in patients with deletion of large fragments of BRCA1/2 genes, i.e., in instances where BRCA1/2 function cannot be restored by the secondary mutation [ 51 , 77 ]. Studies on BRCA1 -mutated ovarian carcinomas demonstrated the persistence of a small fraction of BRCA1-proficient cells even in chemonaive tumors; these cells rapidly repopulate tumor mass during the first weeks of platinum-based therapy thus explaining the phenomenon of inevitable emergence of platinum-resistance [ 78 , 79 ].…”

In Silico Molecular Dynamics Docking of Drugs to the Inhibitory Active Site of SARS-CoV-2 Protease and Their Predicted Toxicology and ADME

“…Figure 4 shows the top 20 approved drugs, and the top 10 are described in detail as follows. Olaparib (Rank 35, BE=-8.7, B09074) is a PARP inhibitor primarily indicated for the treatment of ovarian cancer, but has been useful for pancreatic cancer, advanced solid tumors, and gallbladder cancer [87][88][89][90][91][92] . Etoposide (Rank 56, BE=-8.6, B00773) is for use in combination with other chemotherapeutic agents in the treatment of refractory testicular tumors and as first line treatment in patients with small cell lung cancer.…”