Ovarian cancer. Biomarkers, surgical outcome and survival

Abstract: Ovarian cancer is the eighth most common female cancer worldwide and the most lethal of the gynaecologic malignancies. Around 700 women are diagnosed in Sweden per year. Due to vague symptoms most of the patients are diagnosed with late-stage epithelial ovarian cancer (EOC) and prognosis is poor, with a five-year survival of 49%. However, for early-stage EOC the prognosis is excellent. Biomarkers for screening and early diagnosis have been sought for decades. To date, CA125 and HE4 are the only biomarkers in clinical use. Both lack sensitivity and specificity for early-stage EOC. The standard treatment for EOC is primary surgery with adjuvant chemotherapy. Centralisation of ovarian cancer care to high-volume hospitals with subspecialist surgeons and improved chemotherapy regimens have improved outcome and survival. Ovarian cancer surgery was centralised in Sweden in 2012.The aims of my thesis were to assess new biomarkers for their potential to improve the diagnostic performance of CA125 and HE4 in women with ovarian tumours (studies I and II), to evaluate ovarian cancer surgery after centralisation (study III) and to assess the incidence and survival in EOC in Sweden since the 1960s (study IV). Study I: CA125, HE4, B7-H4 and cleaved and intact suPAR were analysed in preoperative plasma samples from 350 women with ovarian tumours. Plasma levels of CA125, HE4 and suPAR(II-III) were found to increase from benign tumours to borderline, EOC type I and EOC type II while B7-H4 was only elevated in EOC II. Logistic regression models were fitted and a model combining CA125, HE4, suPAR(II-III) and age performed better (AUC=0.933) than the established ROMA algorithm (CA125, HE4 and menopause status) for discrimination of benign tumours from EOC in premenopausal women. The ROMA performed best in postmenopausal women (AUC=0.914). Furthermore, we correlated preoperative biomarker levels with survival after EOC diagnosis. High HE4, CA125 and suPAR(I) were prognostic for poor survival. At 12 months suPAR(I) was the only independent biomarker prognostic for poor short-term survival. In women above 75 years, high suPAR(I) indicated very poor prognosis in the first year after diagnosis (HR=8.9, p=0.01).Study II: 177 inflammation- and cancer-associated biomarkers were analysed in preoperative plasma samples from 180 women with ovarian tumour, using the proximity extension assay. HE4 was the best performing single biomarker for discrimination between benign tumours and EOC. Three-biomarker combinations of HE4, CA125 and one additional biomarker were compared to a reference model of HE4 and CA125. No biomarker significantly improved the diagnostic performance of HE4 and CA125. Study III: We analysed data from the GynOp Registry 2013-15. Out of 1108 cases of ovarian cancer surgery with curative intent, 30% were performed in regional hospitals with fewer than 20 cases per year. Four tertiary centres performed more than 25 surgeries per year. Compared with regional hospitals, tertiary centres perform more extensive surgery without an increased frequency of major complications. Large differences exist in patient selection for primary surgery and complete resection rates between the tertiary centres. Study IV: We identified all women with a diagnosis of epithelial ovarian, fallopian tube, and peritoneal cancers or undesignated abdominal/pelvic cancer from 1960 to 2014 in the Swedish Cancer Registry. Analyses of age-standardised incidence and relative survival (RS) were carried out and time trend graphs were modelled according to age, tumour site, and morphology. Since 1980 the age-standardised incidence of EOC has declined in Sweden. The age-standardised RS in EOC up to five years from diagnosis improved from 1960 to 2014. The 10-year RS has remained unchanged since 1960. In conclusion, CA125 plus HE4 continues to stand out as the best biomarker combination for assessment of cancer risk in a woman with ovarian tumours. CA125, HE4 and suPAR(I) are potential prognostic markers. Adding biomarkers to the preoperative assessment, especially in elderly women, could aid in the treatment decision on extensive primary surgery or neoadjuvant treatment. After centralisation of ovarian cancer surgery in Sweden, many women still have surgery at low-volume regional hospitals. The treatment for advanced EOC seems to differ considerably between the tertiary centres. Further centralisation as well as increased collaboration and exchange of knowledge between tertiary centres are needed to ensure equal access to care, regardless of region of living. Improved surgical and oncological treatment has prolonged life after EOC diagnosis. However, long-term survival remains poor. Most patients will die of their cancer. In order to cure EOC we need to find the patients at early stages. Better diagnostic tools are urgently needed.