Highlights
Checkpoint inhibitor therapy affecting PD-L1 as treatment for advanced solid tumors.
Success in trial pembrolizumab therapy in multiresistant metastatic choriocarcinoma.
Long-term remission after pembrolizumab therapy in multiresistant choriocarcinoma.
Only six reported cases, one with comparable follow-up and outcome.
The introduction of checkpoint inhibitors (CPI) has set a paradigm shift within the therapies for a variety of advanced solid tumors. By altering key regulators of cellular immune response, so-called immune checkpoints, CPIs modulate peripheral cancer immune tolerance to induce cancer-targeted immune reactions. Response rates, however, vary significantly between different solid tumor types. A certain efficacy of CPIs has been described for gynecological malignancies, as the KEYNOTE-028 study reported an objective response rate (ORR) of 13.0% (95% confidence interval [CI] 2.8-33.6) for endometrial and the Check-Mate-358 study an ORR of 26.3% (95% CI 9.1-51.2) for cervical cancer. With respect to epithelial ovarian cancer (EOC), recent evidence suggests only modest response, as the largest study to date by Matulonis et al. reported in 2019 that pembrolizumab induced an ORR of only 8.0% in 376 patients with EOC. Thus, latest clinical data indicate EOC to be rather "immunologically cold", most likely due to both an inherently low tumor mutational burden (TMB) and a subsequently limited cellular antigen presentation.
SummarySince the introduction of poly-ADP-ribose polymerase (PARP) inhibitor therapy for epithelial ovarian cancer (EOC) patients, testing for aberrations of homologous recombination (HR) repair as a predictive biomarker of therapy response has become an area of particular clinical interest. As HR represents a crucial repair pathway of otherwise possibly lethal DNA double strand breaks, its deficiency triggers a phenotypic behavior of tumor cells resulting in the accumulation of genetic damage. PARP inhibitors target this emerging genomic instability by fostering DNA strand breaks. Whereas testing for mutations of the tumor-suppressor genes BRCA 1 and BRCA 2 as a pivotal part of the HR apparatus has entered clinical routine, approximately 30% more high-grade EOC patients harbor aberrations of the HR pathway other than BRCA mutations and may therefore respond to PARP inhibition therapy. In recent years, several double-blind, placebo-controlled trials investigating sizeable patient cohorts have reported positive results of PARP inhibitor therapy response in HR-positive patient subgroups. Therefore, introducing HR testing in both the primary and recurrent setting as a biomarker for PARP inhibitor response may expand the range of patients who may profit from this therapeutic option beyond BRCA-mutated tumors.
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