Abstract
In the era of personalized medicine, where transition from organ-based to individualized genetic diagnosis takes place, the tailoring of treatment in cancer becomes increasingly important. This is particularly true for high-grade, advanced FIGO stage serous adenocarcinomas of the ovary (OC), fallopian tube (TC), and peritoneum (PC), which are currently all treated identically. We analyzed three independent patient cohorts using histopathologically classified diagnosis and various molecular approaches (transcriptomics, immunohistochemistry, next-generation sequencing, fluorescent and chromogenic insitu hybridization). Using multivariate Cox regression model, we found that PC is more aggressive compared with advanced-stage OC independent of residual disease as shown by an earlier relapse-free survival in two large cohorts (HR: 2.63, CI: 1.59-4.37, P<0.001, and HR: 1.66, CI: 1.04-2.63, P<0.033). In line with these findings, transcriptomic data revealed differentially expressed gene signatures identifying PC as high stromal response tumors. The third independent cohort (n=4054) showed a distinction between these cancer types for markers suggested to be predictive for chemotherapy drug response. Our findings add additional evidence that ovarian and peritoneal cancers are epidemiologically and molecularly distinct diseases. Moreover, our data also suggest consideration of the tumor-sampling site for future diagnosis and treatment decisions.
Highlights
High-grade serous adenocarcinomas are typically TP53 mutation-harboring cancers, classified as primary ovarian (OC), fallopian tube (TC), or peritoneal (PC) carcinomas
All three diseases share many histopathological and clinical characteristics, ovarian cancer (OC) is supposed to arise from the ovarian surface epithelium [12] and the fallopian tube [13], tubal cancer (TC) from the fimbrial end of the fallopian tube epithelium [14,15], and peritoneal cancer (PC) presumably from the peritoneal mesothelium [16]
In cohort 1, which was comprised of 78.2% poorly differentiated and 21.8% moderately differentiated tumors of the ovary and peritoneum with 87.7% diagnosed at advanced FIGO (III/IV) stages, patients with PC showed a shorter relapse-free survival and a trend toward a shorter disease-specific survival in the entire cohort (Figure 1A,B)
Summary
High-grade serous adenocarcinomas are typically TP53 mutation-harboring cancers, classified as primary ovarian (OC), fallopian tube (TC), or peritoneal (PC) carcinomas. Niraparib monotherapy is currently being studied in patients with high-grade serous adenocarcinomas treated with at least three prior chemotherapy regimens [4]. It is difficult to classify the disease when the primary site of origin cannot be precisely determined. It is unclear whether the different phenotype occurs based on the origin or the site of development of the individual cancer. The clinical benefits of distinguishing between these diseases are evident, as shown previously in the case of TC, which has been linked to frequent BRCA mutations [5,6,7]. All three diseases share many histopathological and clinical characteristics, OC is supposed to arise from the ovarian surface epithelium [12] and the fallopian tube [13], TC from the fimbrial end of the fallopian tube epithelium [14,15], and PC presumably from the peritoneal mesothelium [16]
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