The major clinical challenge in the treatment of high-grade serous ovarian cancer (HGSOC) is the development of progressive resistance to platinum-based chemotherapy. The objective of this study was to determine whether intra-tumour genetic heterogeneity resulting from clonal evolution and the emergence of subclonal tumour populations in HGSOC was associated with the development of resistant disease.
Methods and Findings
Evolutionary inference and phylogenetic quantification of heterogeneity was performed using the MEDICC algorithm on high-resolution whole genome copy number profiles and selected genome-wide sequencing of 135 spatially and temporally separated samples from 14 patients with HGSOC who received platinum-based chemotherapy. Samples were obtained from the clinical CTCR-OV03/04 studies, and patients were enrolled between 20 July 2007 and 22 October 2009. Median follow-up of the cohort was 31 mo (interquartile range 22–46 mo), censored after 26 October 2013. Outcome measures were overall survival (OS) and progression-free survival (PFS). There were marked differences in the degree of clonal expansion (CE) between patients (median 0.74, interquartile range 0.66–1.15), and dichotimization by median CE showed worse survival in CE-high cases (PFS 12.7 versus 10.1 mo, p = 0.009; OS 42.6 versus 23.5 mo, p = 0.003). Bootstrap analysis with resampling showed that the 95% confidence intervals for the hazard ratios for PFS and OS in the CE-high group were greater than 1.0. These data support a relationship between heterogeneity and survival but do not precisely determine its effect size. Relapsed tissue was available for two patients in the CE-high group, and phylogenetic analysis showed that the prevalent clonal population at clinical recurrence arose from early divergence events. A subclonal population marked by a NF1 deletion showed a progressive increase in tumour allele fraction during chemotherapy.
This study demonstrates that quantitative measures of intra-tumour heterogeneity may have predictive value for survival after chemotherapy treatment in HGSOC. Subclonal tumour populations are present in pre-treatment biopsies in HGSOC and can undergo expansion during chemotherapy, causing clinical relapse.
In this study, James Brenton and colleagues demonstrate that quantitative measures of intratumoural heterogeneity may have predictive value for survival after chemotherapy treatment in high-grade serous ovarian cancer.
Every year, nearly 250,000 women develop ovarian cancer, and about 150,000 die from the disease. Ovarian cancer occurs when a cell on the surface of the ovaries (two small organs in the pelvis that produce eggs) or in the Fallopian tubes (which connect the ovaries to the womb) acquires genetic changes (mutations) that allow it to grow uncontrollably and to spread around the body (metastasize). For women whose ovarian cancer is diagnosed when it is confined to its site of origin, the outlook is good. About 90% of these women survive for at least five years. However, ovarian cancer is rarely diagnosed this early. Usually, by the time the cancer causes symptoms (often only vague abdominal pains and mild digestive disturbances), it has spread into the peritoneal cavity (the space around the gut, stomach, and liver) or has metastasized to distant organs. Patients with advanced ovarian cancer are treated with a combination of surgery and platinum-based chemotherapy, but only a quarter of such women are still alive five years after diagnosis, and the overall five-year survival rate for ovarian cancer is less than 50%.
Why Was This Study Done?
The major clinical challenge in the treatment of high-grade serous ovarian cancer (HGSOC; the most common type of ovarian cancer) is the development of resistance to platinum-based chemotherapy. If we knew how this resistance develops, it might be possible to improve the treatment of HGSOC. Tumors are thought to arise from a single mutated cell that accumulates additional mutations as it grows and divides. This process results in the formation of subpopulations of tumor cells, each with a different set of mutations. Experts think that this “intra-tumor heterogeneity” gives rise to tumor subclones that possess an evolutionary advantage over other subclones (they might, for example, grow faster or be resistant to chemotherapy) and that eventually dominate the tumor (“clonal expansion”). Here, the researchers investigate whether clonal evolution and the emergence of subclonal tumor populations explains the development of chemotherapy-resistant HGSOC by undertaking evolutionary inference and phylogenetic quantification of the heterogeneity of samples taken from women with HGSOC at different times and from different places in their body. Evolutionary inference and phylogenetic quantification are analytical approaches that can be used to reconstruct the evolutionary history (“family tree”) of a tumor.
What Did the Researchers Do and Find?
The researchers used an algorithm (a step-by-step procedure for data processing) called MEDICC to analyze detailed genetic data obtained from 135 spatially and temporally separated samples taken from 14 patients with HGSOC who had received platinum-based chemotherapy. The researchers report that there were marked differences in the degree of clonal expansion among the patients. When they split the patients into two groups based on the degree of clonal expansion in their tumors (CE-high and CE-low), patients with tumors classified as CE-high had a shorter progression-free survival time than patients with tumors classified as CE-high (10.1 months compared to 12.7 months) and a shorter overall survival time (23.5 months compared to 42.6 months). Moreover, a type of statistical analysis called bootstrap analysis, which tests for the robustness of the result, indicated that having CE-high tumors was likely to increase a patient’s risk of a poor outcome. Finally, phylogenetic analysis of samples taken from two patients before and after relapse and analysis of a NF1 deletion (NF1 encodes neurofibromin 1, a tumor suppressor protein that prevents uncontrolled cell growth; NF1 is frequently mutated in HGSOC) indicated that a resistant subclonal population was already present in the patients’ tumors before treatment began.
What Do These Findings Mean?
These findings show that clonal expansion occurs between diagnosis and relapse in HGSOC, that there are marked differences in the degree of clonal expansion among patients, and that a high degree of clonal expansion may have a negative effect on survival. The accuracy of these findings is limited by the small number of patients included in the study, and it is likely that the analyses reported here overestimate the effect of clonal expansion on patient outcomes. Nevertheless, the researchers suggest that, provided larger patient studies yield similar results, quantitative measures of intra-tumor heterogeneity might be useful as patient-specific prognostic markers in HGSOC. That is, measures of intra-tumor heterogeneity might eventually help clinicians to predict which of their patients with ovarian cancer are likely to have the best outcomes after platinum-based chemotherapy.
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001789.
The US National Cancer Institute provides information about cancer and how it develops (in English and Spanish), including detailed information about ovarian cancer
Cancer Research UK, a not-for-profit organization, provides general information about cancer and how it develops, and detailed information about ovarian cancer
The UK National Health Service Choices website has information and personal stories about ovarian cancer
The not-for-profit organization Healthtalk.org provides personal stories about dealing with ovarian cancer; Eyes on the Prize, an online support group for women who have had cancers of the female reproductive system, also includes personal stories; the not-for-profit organization Ovarian Cancer Action also provides information, support, and personal stories about ovarian cancer
Wikipedia provides information about clonal evolution in cancer, tumor heterogeneity, and phylogenetics (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
More information about the MEDICC algorithm is available