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Objective Mutations in the MAP kinase pathway (KRAS, NRAS, BRAF) are common in low grade serous ovarian carcinoma (LGSOC). The effect of these and other mutations on RNA transcription in this disease is poorly understood. Our objective was to describe patterns of somatic mutations and gene transcription in a racially diverse population with LGSOC. Methods Utilizing an institutional tumor registry, patients with LGSOC were identified and charts were reviewed. RNA was extracted from available tumor tissue. Commercial tumor profiling results were analyzed with PanCancer pathway nanoString mRNA expression data. Along with nanoString n-Solver software, Chi-squared, Fishers Exact, and Cox proportional hazards models were used for statistical analysis, with significance set at p Results 39 patients were identified—20% Black, 43% Hispanic, and 36% non-Hispanic White. 18 patients had commercial somatic DNA test results, and 23 had available tumor tissue for RNA extraction and nanoString analysis. The most common somatic alterations identified was KRAS (11 patients, 61%), followed by ERCC1 and TUBB3 (9 each, 50%). KRAS mutations were less common in smokers (14.3% vs 90.9%, p = 0.002). RNA expression analysis demonstrated a greater than two-fold decrease in expression of HRAS in tumors from older patients (p = 0.04), and a greater than two-fold decrease in the expression of HRAS in recurrent tumors (p = 0.007). No significant differences were seen in somatic testing results, RNA expression analysis, or progression free survival between different racial and ethnic cohorts. Conclusions Somatic deficiencies in ERCC1, TUBB3, and KRAS are common in LGSOC in a population of minority patients. HRAS demonstrates decreased expression in tumors from older patients and recurrent tumors.

Objectives: Uterine serous carcinoma (USC) is a rare but aggressive histologic variant of endometrial cancer that accounts for less than 10% of cases but 80% of endometrial cancer deaths. Initial treatment strategies have remained largely unchanged over the years, with the mainstay of treatment being primary cytoreductive surgery (PCS) followed by adjuvant chemotherapy with or without tailored radiotherapy. More recent strategies have incorporated the use of neoadjuvant chemotherapy (NAC) in certain cases with bulky nodal disease or stage IV disease. This study compares survival outcomes between PCS and neoadjuvant chemotherapy followed by an interval cytoreductive surgery (ICS). Methods: Retrospective data spanning 7 years was collected for patients with stage III or IV USC in a large academic institution. PCS was categorized as initial surgical treatment for stage III or IV disease. This was further stratified into microscopic and bulky disease at the time of surgery. ICS was defined as initial treatment with NAC with interval cytoreductive surgery. Overall survival (OS) and progression free survival (PFS) were calculated for each group with Kaplan-Meier estimation and analyzed using the Chi-Square test. Results: Forty-seven patients were identified to have stage III or IV disease at the time of diagnosis. 35 patients underwent PCS and 12 underwent ICS. The PCS and ICS groups were matched for race, age and BMI. Among the PCS patients, 52% had bulky disease. OS was 82.1 months compared to 40.1 months for PCS and ICS respectively (p=0.23). PFS of PCS patients was 42.9 months compared to 18.1 months of ICS patients (p=0.03). PCS of non-bulky disease, PCS of bulky disease and ICS had OS of 82.1, 40.9, and 31.8 months respectively (p=0.47) while PFS was 42.9, 19.6 and 13.8 months for PCS of non-bulky disease, PCS of bulky disease and ICS respectively (p=0.02). For patients with non-bulky disease and bulky disease, OS was 82.1 vs 40.1 months respectively (p=0.23) while PFS was 42.9 and 18.1 months respectively (p=0.32). Patients with bulky disease who had PCS had an OS of 40.9 months compared to 31.8 months for ICS (p=0.86) and PFS of 19.7 months vs 13.9 months (p=0.13). Conclusions: While no statistical difference in OS was observed between the groups, there was a significant improvement in PFS in the PCS patients compared to ICS patients. PFS was significantly longer after PCS regardless of bulky disease. PFS appears to favor PCS over ICS. This study is limited by the small sample size. Additional studies are needed to better determine optimal treatment strategies for patients with advance stage USC.

Objectives: Standard of care treatment for advanced stage EOC is a combination of chemotherapy and surgery. Despite this approach, the majority of women remain incurable, underscoring the need for novel therapeutics. This study assessed the pathologic objective response rate (pORR), historically reported as 6-10% and tumor transcriptomic changes in women with advanced stage EOC treated with neoadjuvant pembrolizumab, paclitaxel, and carboplatin. Methods: This was an open-label, single-arm, phase II trial for women with newly diagnosed biopsy proven EOC dispositioned to receive carboplatin, paclitaxel and pembrolizumab 200mg/m2 every 21 days. Patients received 3-4 cycles prior to interval debulking surgery followed by another 3-4 cycles of adjuvant therapy. A planned interim analysis to assess futility (based on reported historic response with NACT, required 1 pORR) was completed after enrollment of 20 of planned 40 evaluable patients. Transcriptomic analyses of bulk RNA to identify functional genes and significant pathways from matched specimens from treatment naive tumor, and tumor after 3-4 cycles of NACT plus immune checkpoint inhibitor, (ICI) were completed. Strand-specific RNA libraries were sequenced using single-end reads (50 bp, average 40 million reads per sample) on the DNBSeq platform. Differentially expressed genes (DEG) with a false discovery rate q 1.5 were used. Results: Interim data for the first 20 patients evaluable for pORR are reported. Most women were White (95%) and had high grade serous histology (100%). In 11 cases (55%), R0 (complete) cytoreduction was achieved. There have been no surgical complications related to combination treatment. Treatment was generally well tolerated, with mostly grade 1/2 toxicity: 30% pruritic rash, 10% thyroid abnormalities. One patient had grade 3 nephritis that recovered with treatment. A total of 6 patients achieved a pathologic complete response (pCR, 30%) and another 4 (25%) pathologic partial response (pPR) for a 55% pORR. There were 4 pts with deleterious genetic mutation in the homologous recombination pathway (20%) and 2 patients with Fanconi anemia somatic mutations (10%). There were 863 DEGs between the chemonaive and ICI+NACT matched tumors. ICI+NACT induced activation of PI3K-Akt pathway, myeloid differentiation, AGE-RAGE signaling, and focal adhesion kinase pathways which included upregulation of FXR, NLRP11 and FOXL2 expression, known regulators of inflammation and immune responses. Conclusions: Interim analysis demonstrates an increase in pORR compared to previously reported in literature (6-10%) and is generally well tolerated. Transcriptomic analyses revealed specific ICI induced gene signatures when combined with NACT. Further characterization of complete and partial responders are needed to improve patient selection for ICI therapies.