Lankes, Heather A.

TPS5632 Background: Concurrent chemoradiation therapy (CCRT) is the standard of care for locally advanced cervical cancer (LACC); however, outcomes remain suboptimal in patients with high-risk disease. Recent studies suggest that integration of immunotherapy (IO) with definitive chemoradiation, or induction chemotherapy prior to CCRT improves outcomes. Whether treatment intensification with induction systemic therapy and IO prior to CCRT and IO further improves disease control remains unknown. Induction chemotherapy may reduce tumor burden, eradicate micrometastatic disease, and improve tumor immunogenicity prior to definitive CCRT. Preclinical and clinical data support synergy between systemic therapy or radiotherapy and immune checkpoint blockade, providing the rationale for evaluating an induction strategy incorporating chemotherapy and immunotherapy before standard CCRT with immunotherapy, followed by maintenance immunotherapy. Optional tumor tissue and blood samples will be collected for exploratory correlative analyses, including immune and molecular biomarkers associated with response, resistance, and patterns of failure. Methods: NRG-GY037 is a prospective, multi-institutional phase III randomized trial conducted through NRG Oncology. A total of 336 patients will be enrolled (168 per arm). Patients will be stratified by FIGO stage (III vs. IVA) and presence or absence of para-aortic lymph nodes (N2). The primary endpoint is progression free survival (PFS). The study has 90% power to detect PFS hazard ratio of 0.65 in the experimental arm. Treatment: Patients with previously untreated, high-risk LACC are randomized to receive either induction chemotherapy with pembrolizumab for 6 weeks followed by CCRT with pembrolizumab and pembrolizumab maintenance, or standard CCRT with pembrolizumab followed by pembrolizumab maintenance. Major Eligibility Criteria: Eligible patients have histologically confirmed cervical carcinoma (squamous, adenocarcinoma, or adenosquamous), TNM T3 and T4 disease, N0-2, ECOG performance status 0–1, and no prior definitive therapy for cervical cancer. Current Enrollment Status: The trial is actively accruing patients. No efficacy or safety data are available at the time of submission. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT07061977. Clinical trial information: NCT07061977 .

Abstract Purpose: Our goal was to determine if the HRDefine biomarker combining methylation and mutation assessment of key homologous recombination repair genes identifies BRCA wildtype (BRCAwt) ovarian cancer (OC) with outcomes similar to BRCA mutated (BRCAm) OC within the context of a frontline PARP inhibitor trial for advanced ovarian cancer. Methods: We performed an exploratory biomarker analysis of blood and neoplastic samples from the VELIA trial, a phase 3 study evaluating the PARP inhibitor veliparib as frontline maintenance therapy in OC. We developed a highly sensitive droplet digital PCR assay for quantitative BRCA1 and RAD51C promoter methylation and assessed germline/somatic mutations using the BROCA next generation sequencing platform. Cases were grouped into: BRCAm, HRDefine positive (BRCAwt HRDefine+), and HRDefine negative (BRCAwt HRDefine-). Carcinomas were considered HRDefine+ if quantitative BRCA1 or RAD51C promoter methylation was >/= 60% or if a germline or somatic pathogenic variant (PV) was identified in the following non-BRCA HRR repair genes: RAD51C, RAD51D, PALB2, BARD1. For this analysis, the control group included the two study arms with placebo maintenance compared to the investigational arm of veliparib with chemotherapy and continued as maintenance (veliparib throughout group). HRDefine was compared to the Myriad genomic instability score (GIS) used as HRD assessment in the trial. Progression free survival (PFS) was compared using log rank tests. Results: Among 1140 VELIA participants, biomarker analysis could be performed for 487 cases. Of these, 255 (52%) were BRCAm, 60 (12%) were BRCAwt HRDefine+, and 172 (35%) were BRCAwt HRDefine-. BRCAwt HRDefine+ was driven by promoter methylation (57%), germline (40%), or somatic (3%) PVs. Median PFS (months, all arms combined) was 26 months (BRCAm), 27 months (BRCAwt HRDefine+), and 15 months (BRCAwt HRDefine-), with corresponding hazard ratios (HR) of 0.50 (95% CI: 0.39-0.65) and 0.50 (0.34-0.73) versus HRDefine-. All HRDefine+ molecular subgroups were associated with longer PFS, including RAD51C/D mutations (HR 0.44, 0.25-0.77) and promoter methylation (HR 0.60, 0.36-0.97). HRDefine positivity was significantly associated with improved PFS compared to HRDefine-/GIS low (n=60 vs n=111, median PFS 27 versus 14 months, HR 0.44, 0.30-0.65), while the HRDefine- cases with high GIS demonstrated a trend toward an intermediate PFS (n=56, median 18 months, HR 0.67, 0.45-1.01). When compared by treatment arm, median PFS was significantly longer in the veliparib throughout arm compared to control only for the BRCAm group (32 months vs 23 months, HR 0.61, 0.42-0.87), though the analysis was underpowered for the BRCAwt HRDefine+ sub-group (30 months vs 25 months, HR 0.79, 0.4-1.57). Conclusions: HRDefine identifies BRCAwt OC associated with a PFS that is like that of BRCAm cases and may improve stratification for PARP inhibitor therapy beyond current HRD assays. GIS may have some, albeit reduced, prognostic implication that is independent of HRDefine. Citation Format: Isabel V. Rodriguez, Marc Radke, Ronit Katz, Persephone Miller, Paula Ladd, Nithisha Khasnavis, Jennifer Ochoa, Melanie Dillon, Heather Lankes, Peter Ansell, Carol Aghajanian, Gini Fleming, Michael Birrer, Scott Kaufmann, Charles Leath, Kathleen Moore, Theresa Werner, Linda Van Le, Robert L. Coleman, Elizabeth M. Swisher. Application of HRDefine: a biomarker for identifying root causes of homologous recombination deficiency to a phase 3, randomized, placebo-controlled trial of veliparib in front-line treatment of advanced ovarian cancer (VELIA/GOG-3005) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A044.

Abstract Background There is a critical need to identify patient characteristics associated with long-term ovarian cancer survival. Methods Quality of life (QOL), measured by the Functional Assessment of Cancer Therapy-Ovarian-Trial Outcome Index (FACT-O-TOI), including physical, functional, and ovarian-specific subscales, was compared between long-term survivors (LTS) (8+ years) and short-term survivors (STS) (<5 years) of GOG 218 at baseline; before cycles 4, 7, 13, 21; and 6 months post-treatment using linear and longitudinal mixed models adjusted for covariates. Adverse events (AEs) were compared between survivor groups at each assessment using generalized linear models. All P values are 2-sided. Results QOL differed statistically significantly between STS (N = 1115) and LTS (N = 260) (P < .001). Baseline FACT-O-TOI and FACT-O-TOI change were independently associated with long-term survival (odds ratio = 1.05, 95% confidence interval = 1.03 to 1.06 and odds ratio = 1.06, 95% confidence interval = 1.05 to 1.07, respectively). A 7-point increase in baseline QOL was associated with a 38.0% increase in probability of LTS, and a 9-point increase in QOL change was associated with a 67.0% increase in odds for LTS. QOL decreased statistically significantly with increasing AE quartiles (cycle 4 quartiles: 0-5 vs 6-8 vs 9-11 vs ≥12 AEs, P = .01; cycle 21 quartiles: 0-2 vs 3 vs 4-5 vs ≥6 AEs, P = .001). Further, LTS reported statistically significantly better QOL compared with STS (P = .03 and P = .01, cycles 4 and 21, respectively), with similar findings across higher AE grades. Conclusions Baseline and longitudinal QOL change scores distinguished LTS vs STS and are robust prognosticators for long-term survival. Results have trial design and supportive care implications, providing meaningful prognostic value in this understudied population.

Abstract Background: The influence of sex hormone and insulin/insulin-like growth factor (IGF) axis signaling on endometrial cancer recurrence is unknown. We evaluated these pathways in a prospective cohort of Gynecologic Oncology Group (GOG)0210 trial endometrial adenocarcinoma patients. Methods: Stage II–IV patients (N = 816) were included in this study. Pretreatment specimens were tested for tumor mRNA and protein expression of IGF1, IGF2, IGF-binding proteins (IGFBP)-1 and -3, insulin (IR) and IGF-I receptors (IGF1R), phosphorylated IR/IGF1R (pIGF1R/pIR), and estrogen (ER) and progesterone receptors (PR) using qPCR and IHC. Serum concentrations of insulin, IGF-I, IGFBP-3, estradiol, estrone, and sex hormone binding globulin were measured. HRs and 95% confidence intervals (CI) for progression-free survival were calculated from Cox models adjusting for age, stage, and grade. Results: Recurrence occurred in 280 (34%) cases during a median of 4.6 years of follow-up. ER positivity (HR, 0.67; 95% CI, 0.47–0.95), IR positivity (HR, 0.53; 95% CI, 0.29–0.98), and circulating IGF-I (highest vs. lowest quartile: HR, 0.66; 95% CI, 0.47–0.92) were inversely associated with recurrence risk. Circulating estradiol (highest vs. lowest tertile: HR, 1.55; 95% CI, 1.02–2.36) and pIGF1R/pIR positivity (HR, 1.40; 95% CI, 1.02–1.92) were associated with increased recurrence risk. Conclusions: Circulating estradiol and tumor tissue phosphorylated (activated) IGR1R/IR were independently associated with higher risk of recurrence in patients with endometrial cancer. Impact: This study may inform future clinical trials of endocrine-targeted adjuvant therapies in patients with endometrial cancer that could include baseline assessment of serum and tissue biomarkers of estradiol and insulin signaling pathways.

Abstract Purpose: GOG-0218, a double-blind placebo-controlled phase III trial, compared carboplatin and paclitaxel with placebo, bevacizumab followed by placebo, or bevacizumab followed by bevacizumab in advanced epithelial ovarian cancer (EOC). Results demonstrated significantly improved progression-free survival (PFS), but no overall survival (OS) benefit with bevacizumab. Blood samples were collected for biomarker analyses. Experimental Design: Plasma samples were analyzed via multiplex ELISA technology for seven prespecified biomarkers [IL6, Ang-2, osteopontin (OPN), stromal cell–derived factor-1 (SDF-1), VEGF-D, IL6 receptor (IL6R), and GP130]. The predictive value of each biomarker with respect to PFS and OS was assessed using a protein marker by treatment interaction term within the framework of a Cox proportional hazards model. Prognostic markers were identified using Cox models adjusted for baseline covariates. Results: Baseline samples were available from 751 patients. According to our prespecified analysis plan, IL6 was predictive of a therapeutic advantage with bevacizumab for PFS (P = 0.007) and OS (P = 0.003). IL6 and OPN were found to be negative prognostic markers for both PFS and OS (P < 0.001). Patients with high median IL6 levels (dichotomized at the median) treated with bevacizumab had longer PFS (14.2 vs. 8.7 months) and OS (39.6 vs. 33.1 months) compared with placebo. Conclusions: The inflammatory cytokine IL6 may be predictive of therapeutic benefit from bevacizumab when combined with carboplatin and paclitaxel. Aligning with results observed in patients with renal cancer treated with antiangiogenic therapies, it appears plasma IL6 may also define those patients with EOC more or less likely to benefit from the addition of bevacizumab to standard chemotherapy.

Abstract Purpose: We hypothesized that mutations in homologous recombination repair (HRR) genes beyond BRCA1 and BRCA2 improve outcomes for ovarian carcinoma patients treated with platinum therapy and would impact the relative benefit of adding prolonged bevacizumab. Experimental Design: We sequenced DNA from blood and/or neoplasm from 1,195 women enrolled in GOG-0218, a randomized phase III trial in advanced ovarian carcinoma of bevacizumab added to carboplatin and paclitaxel. Defects in HRR were defined as damaging mutations in 16 genes. Proportional hazards models were used to estimate relative hazards for progression-free survival (PFS) and overall survival (OS). Results: Of 1,195 women with ovarian carcinoma, HRR mutations were identified in 307 (25.7%). Adjusted hazards for progression and death compared with those without mutations were lower for women with non-BRCA HRR mutations [HR = 0.73; 95% confidence interval (CI), 0.57–0.94; P = 0.01 for PFS; HR = 0.67; 95% CI, 0.50–0.90; P = 0.007 for OS] and BRCA1 mutations (HR = 0.80; 95% CI, 0.66–0.97; P = 0.02 for PFS; HR = 0.74; 95% CI, 0.59–0.94; P = 0.01 for OS) and were lowest for BRCA2 mutations (HR = 0.52; 95% CI, 0.40–0.67; P < 0.0001 for PFS; HR = 0.36; 95% CI, 0.25–0.53; P < 0.0001 for OS). A test of interaction showed no difference in the effect of bevacizumab on PFS between cases with and without mutations. Conclusions: HRR mutations, including non-BRCA genes, significantly prolong PFS and OS in ovarian carcinoma and should be stratified for in clinical trials. The benefit of adding bevacizumab was not significantly modified by mutation status. Clin Cancer Res; 24(4); 777–83. ©2017 AACR.

Abstract Purpose: Somatic mosaic mutation in the PPM1D gene have been associated with risk of breast and ovarian cancer. Somatic mosaic mutations in blood cells may be associated with older age and chemotherapy exposure. We wanted to determine if somatic mosaic mutations in PPM1D and in other genes are associated with older age and repeated exposure to chemotherapy, rather than a contributor to risk of disease. Experimental design: We used targeted capture and massively parallel genomic sequencing to sequence DNA from PBMCs from affected patients for PPM1D as well as 60 other DNA repair genes. For a number of samples with PPM1D mutations, we re-sequenced at greater depth on patients where PBMCs that were collected at diagnosis and recurrence. Results: We identified somatic mosaic mutations in exon 6 of PPM1D in 4 out of 474 (0.8%) individuals that were newly diagnosed and had no previous chemotherapy, in 3 out of 29 (10%) individuals newly diagnosed but receiving chemotherapy and in 58 of 274 (21%) individuals with relapsed platinum resistant ovarian cancer (p<0.0001). The presence of PPM1D mutations in exon 6 was strongly associated with more advanced age (p=0.011, Wilcoxon test) and more than one chemotherapy regimen (p=0.026, Fisher's exact test). In paired blood samples from 13 patients, PPM1D mutations present at relapse were either not detected or detected at a lower percentage compared to blood obtained soon after diagnosis. Somatic mosaic mutations were also identified in TP53 in 7 of 274 (2.5%) women with relapsed platinum resistant cancer. In one of these cases, we had an earlier blood sample from diagnosis in which the mutation was not present at time near diagnosis. Conclusion: We found that somatic mosaic PPM1D mutations in PMBCs are associated with advanced age and repeated exposure to chemotherapy. Mosaic mutations in other genes were not confirmed with the exception of TP53, for which mutations are also detectable after extensive treatment. It seems likely that mosaic PPM1D mutations in blood from cancer patients may be a result of selection by chemotherapy of age-induced somatic mutations during exposure to chemotherapy. Further studies are needed to determine the clinical significance of these mutations. Citation Format: Maria I. Harrell, Barbara M. Norquist, Tom Walsh, Mark F. Brady, Ming K. Lee, Robert Hershberg, Kimberly R. Kalli, Heather Lankes, Eric Q. Konnick, Colin C. Pritchard, Bradley J. Monk, John K. Chan, Robert Burger, Scott H. Kaufmann, Michael J. Birrer, Elizabeth M. Swisher. Old age and chemotherapy contribute to the selection of PPM1D somatic mosaic mutations in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B71.