Abstract
Platinum-based neoadjuvant chemotherapy followed by interval debulking surgery is an accepted treatment for patients with stage III or IV epithelial ovarian cancer who are not suitable for primary debulking surgery. The identification of suitable adjuvant treatments in these patients is an unmet need. Here, we explore potential genomic characteristics (mutational and immune-associated expression profiles) in a series of patients undergoing neoadjuvant chemotherapy. Tumor samples from biopsy and interval debulking surgery were analyzed for mutational landscape and immune profiling, together with detailed immunohistochemistry using different immune cell markers, and correlated with clinicopathological characteristics and potential response to neoadjuvant chemotherapy. No major differences in the mutational landscape were observed in paired biopsy and surgery samples. Genomic loss of heterozygosity was found to be higher in patients with total/near-total tumor response. The immune gene expression profile after neoadjuvant chemotherapy revealed activation of several immune regulation-related pathways in patients with no/minimal or partial response. In parallel, neoadjuvant therapy caused a significant increase of tumor-infiltrating lymphocyte population abundance, primarily due to an augmentation of the CD8+ T cell population. Remarkably, these changes occurred irrespective of potential homologous recombination defects, such as those associated with BRCA1/2 mutations. Our study strengthens the use of loss of heterozygosity as a biomarker of homologous repair deficiency. The changes of immune states during neoadjuvant chemotherapy reveal the dynamic nature of tumor-host immune interactions and suggest the potential use of immune checkpoint inhibitors or their combination with poly-ADP polymerase inhibitors in high stage and grade epithelial ovarian cancer patients undergoing neoadjuvant therapy.
Highlights
Ovarian cancer represents the seventh most commonly diagnosed cancer and the eighth leading cause of cancer-related death in women worldwide, with an estimated 295,414 new cases and 184,799 deaths annually[1]
From >600 patients with epithelial ovarian cancer (EOC) entered in the Hospital 12 de Octubre Registry from 2000 to 2018, we selected a nonconsecutive cohort of patients treated with neoadjuvant chemotherapy (NACT) followed by Interval debulking surgery
In most of the patients, we observed that CA125 antigen levels Radiological response decreased after NACT and that this reduction is not related to Complete response (CR)
Summary
Ovarian cancer represents the seventh most commonly diagnosed cancer and the eighth leading cause of cancer-related death in women worldwide, with an estimated 295,414 new cases and 184,799 deaths annually[1]. Cancer of the ovary covers a histologically and genetically broad range of tumors, with highgrade serous ovarian cancer (HGSOC) being responsible for 70–80% of all ovarian cancer deaths[2]. HGSOC represents one of the subtypes of the most prevalent ovarian cancer type, epithelial ovarian cancer (EOC), which accounts for approximately 90% of the cases[3]. Endometrioid ovarian carcinoma (EOVC) represents an uncommon subtype of EOC, accounting for approximately 10% of all ovarian tumors[4]. The majority of patients with EOC present with advanced disease and disease management consists of platinumbased chemotherapy and cytoreductive surgery[5]. An alternative option is neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS), which has been shown to be safer and better tolerated than primary debulking surgery for patients with more advanced disease[5,6]. In the hope of emulating the success seen in other tumors, attention has turned to immunotherapy as a new strategy to improve survival in EOC7
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