Effect of genomic loss of heterozygosity and homologous recombination deficiency on platinum sensitivity and clinical course in women with epithelial ovarian cancer (175)

Abstract

Objectives: Genomic loss of heterozygosity (gLOH) and homologous recombination deficiency (HRD) genomic alterations confer an improved response to PARP inhibitors (PARPi) in the management of women with epithelial ovarian cancer (OC). Whether these mutations also confer a significantly improved response to platinum-based chemotherapy is unknown. Chemotherapy with platinum-based agents is the first-line systemic chemotherapy for OC. We sought to evaluate the role of gLOH and HRD mutations in the treatment of OC at our institution. Methods: Tumor tissue was collected from 137 women with OC at our institution and was analyzed for genetic alterations by hybrid-capture, next-generation sequencing for up to 324 genes. Validated algorithms evaluated gLOH (high ≥ 16%), HRD mutation status, and tumor mutations burden (mutations/Mb). Clinical data were abstracted from the medical record for 103 patients with complete information. Thirty-four patients were excluded due to a lack of clinical data. Genomic status was compared with clinical factors, including platinum sensitivity (PS defined as progression-free survival [PFS] > 6 months after treatment), use of neoadjuvant chemotherapy, use of PARPi maintenance, and bevacizumab maintenance, PFS, and overall survival (OS). Statistical analysis was performed using the Chi-square test and log-rank test with p < 0.05 deemed significant. Results: All 103 patients received platinum-based chemotherapy in the neoadjuvant and adjuvant first-line setting. Patients defined as gLOH high were significantly more likely to be PS (77% vs 51%, p < 0.05); however, this did not translate to confer an improved PFS or OS in this cohort (p > 0.05). Patients with alterations in the HRD pathway did not show a significant difference in PS, but the increased response approached significance (80.8% vs 56.5%, p = 0.052). Patients with alterations in the HRD pathway had no difference in PFS (p > 0.05); however, they had a significantly longer OS (p < 0.05). Patients who had optimal cytoreduction in the primary or interval setting demonstrated an improved OS (p < 0.05). Women who received neoadjuvant chemotherapy and underwent interval cytoreduction did not have a significantly different PFS or OS when compared to those who underwent primary cytoreduction (p > 0.05). Conclusions: gLOH was a significant predictor of PS in women with OC. However, this did not translate into improved PFS or OS in this cohort of women with advanced-stage OC. The utility of gLOH for predicting platinum sensitivity may prove useful in other contexts. Patients with HRD alterations showed a trend toward a significant improvement in PS with a significantly longer OS. These data support larger studies that may extend the predictive utility of gLOH and HR mutation status biomarkers. Larger sample size is required to predict the therapeutic advantages of gLOH and HRD mutations in OC during systemic chemotherapy and maintenance therapy. Objectives: Genomic loss of heterozygosity (gLOH) and homologous recombination deficiency (HRD) genomic alterations confer an improved response to PARP inhibitors (PARPi) in the management of women with epithelial ovarian cancer (OC). Whether these mutations also confer a significantly improved response to platinum-based chemotherapy is unknown. Chemotherapy with platinum-based agents is the first-line systemic chemotherapy for OC. We sought to evaluate the role of gLOH and HRD mutations in the treatment of OC at our institution. Methods: Tumor tissue was collected from 137 women with OC at our institution and was analyzed for genetic alterations by hybrid-capture, next-generation sequencing for up to 324 genes. Validated algorithms evaluated gLOH (high ≥ 16%), HRD mutation status, and tumor mutations burden (mutations/Mb). Clinical data were abstracted from the medical record for 103 patients with complete information. Thirty-four patients were excluded due to a lack of clinical data. Genomic status was compared with clinical factors, including platinum sensitivity (PS defined as progression-free survival [PFS] > 6 months after treatment), use of neoadjuvant chemotherapy, use of PARPi maintenance, and bevacizumab maintenance, PFS, and overall survival (OS). Statistical analysis was performed using the Chi-square test and log-rank test with p < 0.05 deemed significant. Results: All 103 patients received platinum-based chemotherapy in the neoadjuvant and adjuvant first-line setting. Patients defined as gLOH high were significantly more likely to be PS (77% vs 51%, p < 0.05); however, this did not translate to confer an improved PFS or OS in this cohort (p > 0.05). Patients with alterations in the HRD pathway did not show a significant difference in PS, but the increased response approached significance (80.8% vs 56.5%, p = 0.052). Patients with alterations in the HRD pathway had no difference in PFS (p > 0.05); however, they had a significantly longer OS (p < 0.05). Patients who had optimal cytoreduction in the primary or interval setting demonstrated an improved OS (p < 0.05). Women who received neoadjuvant chemotherapy and underwent interval cytoreduction did not have a significantly different PFS or OS when compared to those who underwent primary cytoreduction (p > 0.05). Conclusions: gLOH was a significant predictor of PS in women with OC. However, this did not translate into improved PFS or OS in this cohort of women with advanced-stage OC. The utility of gLOH for predicting platinum sensitivity may prove useful in other contexts. Patients with HRD alterations showed a trend toward a significant improvement in PS with a significantly longer OS. These data support larger studies that may extend the predictive utility of gLOH and HR mutation status biomarkers. Larger sample size is required to predict the therapeutic advantages of gLOH and HRD mutations in OC during systemic chemotherapy and maintenance therapy.