Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer

Abstract

High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. In this Opinion article, we outline a set of research priorities that we believe will reduce incidence and improve outcomes for women with this disease. This 'roadmap' for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015.

Figure 1. Clinical and molecular features of HGSOC at a glance

a | High-grade serous ovarian cancer (HGSOC) is thought to arise predominately from the secretory cells of the fallopian tube, from where there is no barrier to peritoneal spread. HGSOCs have a tropism for omental fat, which they use as an energy source. b | HGSOC is characterized by an initial favourable response to platinumbased therapy but then cycles of relapse and the development of acquired resistance to chemotherapy, as depicted by this plot of CA125 levels in a representative patient showing a typical clinical course. Triangles and diamonds indicate administration of different lines of chemotherapy. c | TP53 mutations are a near-invariant feature of HGSOC but somatic point mutations in other driver genes occur at a low frequency. The data shown here were taken from 300 HGSOC tumours in The Cancer Genome Atlas database. d | The frequency of key driver mutations in HGSOC, including point mutations, amplifications or gene loss through structural variation (generated from data posted on the cBio Cancer Genomics Portal, Memorial Sloan-Kettering Cancer Center (MSKCC) and REF. 17). Approximately half of all HGSOCs show mutational and functional evidence of putative homologous recombination (HR) deficiency, including germline mutations in BRCA1 or BRCA2 in 15–17% of patients. Cyclin E1 (CCNE1) amplification represents an important subset of HR-intact tumours, and recent data increases the proportion of tumours with NF1 (neurofibromin 1) and RB1 loss. Somatic and germline mutations in components of HR are generally mutually exclusive, as are CCNE1, BRCA1 and BRCA2 mutations; however, other mutations can co-occur such that individual tumours can have more than one of the driver events represented here. e | Graph showing cancer types dominated by either mutations (M class) or copy number changes (C class). HGSOC is one of the most chromosomally structurally variant malignancies. AML, acute myeloid leukaemia; BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CRC, colorectal carcinoma; GBM, glioblastoma; HNSCC, head and neck squamous cell carcinoma; KIRC, kidney clear-cell carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; UCEC, uterine carcinoma. Part e of the figure is from REF , Nature Publishing Group.

Figure 2. Fallopian tube origins of HGSOC

Animal modelling of high-grade serous ovarian carcinoma (HGSOC) by targeting the fallopian tube and reflecting known mutations in human tumours. a | Different stages of HGSOC development in the human fallopian tube marked by p53 staining and cellular morphology. A substantial proportion of HGSOC arises from the fallopian tube, most likely PAX8-positive fallopian tubes secretory epithelial cells (FTSECs). p53 staining marks clonal expansion of cells (signatures) in the absence of morphological transformation of the fallopian tube epithelium. Piling up of cells and loss of epithelial architecture occurs in early lesions (tubal intraepithelial carcinoma (TIC)), finally leading to invasive cancer. b | Crossing strategy to generate a conditional, Cre-recombinase driven model of HGSOC in mice with Trp53 missense mutation, mutation in Brca1 or Brca2, and dysregulation of the PI3K–PTEN pathway. c | The histological appearance of mouse tumours parallels what is seen in human HGSOC. H and E, haematoxylin and eosin; rtTA, reverse tetracycline-controlled transactivator; TetO-Cre, tetracycline-driven Cre recombinase. Part a of the figure is in part reproduced with permission from REF. , Elsevier. Figure parts b and c are adapted with permission from REF. , Elsevier.

Figure 3. The complex tumour microenvironment of HGSOC

Immunohistochemical staining of high-grade serous ovarian cancer showing diversity and architectural features of immune cell infiltration. a | CD8⁺ cytotoxic T cell, CD4⁺ T helper cell and CD20⁺ B cell infiltration among tumour cells. b | Tertiary lymphoid structure resembling a lymph node, embedded in tumour, with defined T cell and B cell zones and associated high endothelial venules (HEVs). Tumour-infiltrating lymphocytes (TILs) are found in the adjacent tumour. c | CD8⁺ T cells are often surrounded by immunosuppressive elements such as programmed cell death protein 1 ligand 1 (PDL1)-expressing macrophages and tumour cells. d–f | Range of CD4⁺ and CD8⁺ T cell responses in different patient samples in terms of density and association with B cell infiltrate. High TIL density (part f) is most likely to be associated with therapeutic response to immune checkpoint inhibition. Images are courtesy of K. Milne, D. Kroeger and B.H.N..