Ovarian carcinoma subtypes are different diseases: implications for clinical and translational research
David Huntsman
British Columbia Cancer Agency, Canada
Although high grade serous carcinomas usually respond to platinum/taxane based therapy, the 30% of women with other ovarian carcinoma subtypes may accrue little benefit. The implementation of subtype specific management for ovarian carcinoma has been hampered by a lack of reproducibility for sub-typing and the binning of subtypes within research studies. This has occurred in spite of strong epidemiologic data suggesting the subtypes are different diseases and the recent identification of fallopian tube in-situ carcinoma as a subtype specific precursor lesion for high grade serous cancers. In order to foster subtype specific management, the OvCaRe research team in British Columbia is i) leading a trans-Canadian validation of the simplified, 5 feature, ovarian carcinoma classification, ii) developing suites of subtype specific diagnostic and prognostic biomarkers and iii) using an integrated resource that includes primary transplantable xenografts, frozen tumours, and clinically annotated tissue arrays to develop a series of subtype specific treatments. As an example of the benefits of treating subtypes as distinct diseases in research projects, our biomarker data, derived from a tissue microarray cohort of 540 early ovarian carcinomas, suggest that the practice of binning multiple subtypes in biomarkers is the most likely explanation for the irreproducibility of much of the tissue based biomarker literature and hence the lack of any clinically used tissue based biomarkers for ovarian carcinoma. Tissue based biomarker expression varies greatly between subtypes but does not vary between stages within subtypes. For example, as high grade serous carcinomas usually present as a later stage than other subtypes, markers for early ovarian carcinoma are usually anti-correlated with serous differentiation. Subtype specific expression can also lead to misleading prognostic effects. As an example WT-1 is a marker for serous differentiation and is an unfavourable prognostic marker within the entire cohort of ovarian carcinomas (OR 1.7, 95% CI 1.2-2.3), but is a favourable prognostic marker within the high-grade serous subtype (OR 0.5, 95% CI 0.3-0.8). The development of effective subtype specific management strategies for ovarian cancer will be the first and a necessary step towards individualized therapies for women with this disease.
