Abstract 5373: The Oxford Ovarian Cancer Predict Chemotherapy Response (OXO-PCR) study: Understanding the genomic drivers of primary chemotherapy-resistant microscopic residual disease
Authors: Artibani Mara , Mallett Garry , Sunanda Dhar , KaramiNejadRanjbar Mohammad , Morotti Matteo , ElSahhar Salma , Sauka-Spengler Tatjana , Ahmed Ahmed A. 
Published: August 2018

In spite of excellent clinical response to primary chemotherapy, more than 70% of patients with high grade serous ovarian cancer (HGSOC) suffer from recurrence within 12 months of completion of treatment. Moreover, clinical and biochemical response are poor surrogates for survival outcomes: patients with complete clinical response following primary treatment usually suffer from recurrence, which can occur as early as within the first six months after treatment. The reason for this paradoxical disconnect between response and survival is unclear. Results from patients treated with neoadjuvant chemotherapy (NACT) suggest that, while complete clinical response following primary treatment is common, complete pathological response is highly unusual in HGSOC. The characterization of microscopic residual disease (MRD) following NACT is required to advance our understanding about the key mechanisms of primary chemotherapy resistance. Accurate and comprehensive characterization of MRD, however, has been very difficult because of the minute nature of these samples. Here we report our results from a prospective phase 0 translational clinical study (OXO-PCR) for the comprehensive genomic characterization of MRD. Twenty women with at least stage IIIC HGSOC were prospectively recruited to this study. All patients had paired samples collected at the time of diagnostic laparoscopy prior to chemotherapy and following at least three cycles of NACT. Chemotherapy response was evaluated using CT and CA125, while site-specific response was assessed through laparoscopy, which was conducted before and after chemotherapy. Laser capture microdissection was then used to obtain MRD which were analyzed through RNA-seq and whole genome sequencing. Our results show that, in contrast to sites where only partial clinical response was observed, complete clinical response and MRD are characterized by differential expression of specific gene signatures related to cell adhesion, actin binding and RNA processing. Most notably, MRD is characterized by the upregulation of a large number of ATP-binding cassette transporters (n = 12). For one patient, recurrence samples were also collected and analyzed: PCA of RNA-seq data from this patient shows that the recurrence resembles the pre-chemotherapy samples, suggesting that MRD represents a distinct cell state that is capable of resisting chemotherapy. Such state is lost following repopulation and emergence of recurrence. Our results show that the approach of comprehensive analysis of MRD is a powerful method for the early characterization of tumor resistance. This has important implications for future design of appropriate maintenance therapies to prevent recurrence.

Citation Format: Mara Artibani, Garry Mallett, Dhar Sunanda, Mohammad KaramiNejadRanjbar, Matteo Morotti, Salma ElSahhar, Tatjana Sauka-Spengler, Ahmed A. Ahmed. The Oxford Ovarian Cancer Predict Chemotherapy Response (OXO-PCR) study: Understanding the genomic drivers of primary chemotherapy-resistant microscopic residual disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5373.