Does the primary site really matter? Profiling mucinous ovarian cancers of uncertain primary origin (MO-CUP) to personalise treatment and inform the design of clinical trials

Abstract Objective Advanced stage mucinous ovarian cancers are diagnostically and therapeutically challenging. Histotype specific trials have failed due to low recruitment after excluding non-ovarian primaries. Mucinous ovarian cancers are commonly metastatic from other sites however lack definitive diagnostic markers. We suggest a classification of mucinous ovarian cancers of uncertain primary origin ‘MO-CUPs' in clinical trials. This study aims to identify drug targets to guide treatment and future trials. Methods We analyzed a large de-identified, multi-platform tumor profiling dataset of MO-CUPs enriched for advanced stage and recurrent cases submitted to Caris Life Sciences. Available data included a 45-gene next-generation sequencing (NGS) panel, gene amplification of HER2 and cMET and 18 immunohistochemical (IHC) markers of drug sensitivity/resistance. Results Mucinous tumors from 333 patients were analyzed, including 38 borderline tumors and 295 invasive cancers. The most common mutations in a subset (n = 128) of invasive cancers were KRAS (60%), TP53 (38%), PIK3CA (13%) and PTEN (9%). Borderline tumors had higher rates of BRAF mutations, and PGP and TOP2A overexpression than invasive cases. KRAS mutant invasive cancers had lower expression of thymidylate synthase (p = 0.01) and higher expression of TUBB3 (p = 0.01) than KRAS wildtype tumors. Conclusions To our knowledge, this is the largest series profiling mucinous ovarian cancers and almost certainly includes cases of ovarian and non-ovarian origin. Given the difficulty recruiting patients to histotype-specific trials in rare subsets of ovarian cancer, it may be more important to focus on identifying potential treatment targets and to personalise treatment and design clinical trials in MO-CUPS agnostic of primary site to overcome these issues.