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Introduction/BackgroundThe role of molecular classification in patients with low/intermediate risk endometrial cancer (EC) is uncertain. Higher precision in diagnostics will inform the unsettled debate on optimal adjuvant treatment.MethodologyWe retrospectively included patients referred to The Norwegian Radium Hospital, Oslo, Norway (2006–2017). Patients with low/intermediate risk EC were molecularly classified as pathogenic polymerase epsilon (POLE)-mutated, mismatch repair deficient (MMRd), p53 abnormal, or no specific molecular profile (NSMP). The main outcome was time to recurrence (TTR) and cancer-specific survival (CSS) within the molecular subgroups. We also studied patterns of recurrence in molecular groups.ResultsOf 626 patients, 610 could be molecularly classified and only 24 received adjuvant treatment. Molecular subgroup distribution was: 57 patients (9%) with POLE-mutated tumors, 202 (33%) with MMRd tumors, 34 (6%) with p53 abnormal tumors, and 317 (52%) with NSMP tumors. After a median follow-up time of 8.9 years (95% confidence interval (CI): 6.2–12.6 years), there was a statistically significant difference in TTR (p<0.001) and CSS (p<0.001) by molecular groups. Patients with p53 abnormal tumors had poor prognosis with a 5-year cumulative incidence for recurrence of 32.4% (95% CI: 17.6–48.0) and cancer-specific death (CSD) of 29.4% (95% CI: 15.4–44.9). The majority of these recurrences were para-aortic/distant metastases. Patients with POLE mutations had excellent prognosis with a 5-year cumulative incidence for recurrence of 3.5% (95% CI: 0.7–10.7%) and CSD of 0%. In the NSMP group, L1CAM expression was associated with shorter CSS (HR 12.52, 95% CI: 3.53–44.42, p<0.0001) but not TTR (HR 2.7, 95% CI: 0.95–7.7, p=0.053).ConclusionLarge differences in prognosis and localization of recurrence by molecular groups demand a higher precision in diagnostics, also in patients with low and intermediate risk EC. Tailored adjuvant treatment strategies need to consider systemic treatment for patients with p53 abnormal tumors and de-escalation of treatment in patients with POLE mutated tumors.DisclosuresKL: Receipt of grants/research supports: GSK, research funding paid toInstitution; Receipt of honoraria or consultation fees: Advisory board fees: Astra Zeneca, Nycode, GSK, EisaGK: Stockholder: Novo NordicAbstract 259 Figure 1

Introduction/BackgroundThere is scarce real-world evidence on patients with advanced endometrial cancer (EC) treated with platinum-based chemotherapy in the literature. This study described the oncological outcome in groups by molecular classification.MethodologyThis retrospective cohort study included patients referred to The Norwegian Radium Hospital, Oslo University Hospital (OUH), Norway who were diagnosed or operated for EC at OUH between January 2006 and December 2017. Patients with Stage III/IV EC treated with platinum-based chemotherapy after hysterectomy and with sufficient tumor tissue available at the biobank were molecularly classified as pathogenic polymerase epsilon (POLE)-mutated, mismatch repair deficient (MMRd), p53 abnormal, or no specific molecular profile (NSMP).ResultsOf 264 patients, 263 were molecularly classified, 10 (4%) as POLE-mutated, 67 (26%) as MMRd, 117 (44%) as p53 abnormal and 69 (26%) as NSMP. One patient could not be molecularly characterized. Median age was 68 (61–74) years with a median follow up time of 5.3 (2.2–10.3) years. Patients with MMRd tumors had significantly longer time to recurrence (HR 0.43, 95% CI: 0.27–0.67, p=0.0001) and longer cancer-specific survival (HR 0.36, 95%CI: 0.22–0.58, p<0.0001) than patients with mismatch repair proficient (MMRp) tumors. Compared to patients with NSMP tumors, patients with p53 abnormal tumors had shorter cancer-specific survival (HR 1.78, 95% CI: 1.19–2.65) while patients with MMRd tumors had longer cancer-specific survival (HR 0.50, 95% CI: 0.29–0.87). Patients with POLE tumors had the longest cancer-specific survival (HR 0.32, 95% 0.08–1.32).ConclusionResults show that molecular classification is prognostic in patients with advanced-stage endometrial cancer. Based on the recently reported clinical trials of a checkpoint inhibitor added to platinum-based chemotherapy in advanced and recurrent EC, patients with MMRd, and maybe also p53 abnormal tumors, have a better clinical outcome when treated with this combination treatmentDisclosuresThis supported collaborative study was funded by GSK (SCS: 219026)KL: Receipt of grants/research supports: GSK, research funding paid toInstitution; Receipt of honoraria or consultation fees: Advisory board fees: Astra Zeneca, Nycode, GSK, EisaBM, DS: Stockholder: GSK, Other: Employee GSKHE: Other: Employee GSKGK: Stockholder: Novo Nordic

Machine learning (ML) is expected to improve biomarker assessment. Using convolution neural networks, we developed a fully-automated method for assessing PTEN protein status in immunohistochemically-stained slides using a radical prostatectomy (RP) cohort (n = 253). It was validated according to a predefined protocol in an independent RP cohort (n = 259), alone and by measuring its prognostic value in combination with DNA ploidy status determined by ML-based image cytometry. In the primary analysis, automatically assessed dichotomized PTEN status was associated with time to biochemical recurrence (TTBCR) (hazard ratio (HR) = 3.32, 95% CI 2.05 to 5.38). Patients with both non-diploid tumors and PTEN-low had an HR of 4.63 (95% CI 2.50 to 8.57), while patients with one of these characteristics had an HR of 1.94 (95% CI 1.15 to 3.30), compared to patients with diploid tumors and PTEN-high, in univariable analysis of TTBCR in the validation cohort. Automatic PTEN scoring was strongly predictive of the PTEN status assessed by human experts (area under the curve 0.987 (95% CI 0.968 to 0.994)). This suggests that PTEN status can be accurately assessed using ML, and that the combined marker of automatically assessed PTEN and DNA ploidy status may provide an objective supplement to the existing risk stratification factors in prostate cancer.

Homocysteine has been related to increased risk of CVD. Matrix degradation and inflammation may be involved in this link between hyperhomocysteinaemia and CVD. Recent studies suggest that cystatin C can modulate matrix degradation and inflammation. The present study measured cystatin C at protein (plasma) and mRNA levels (peripheral blood mononuclear cells (PBMC)) in hyperhomocysteinaemic individuals (n 37, female seven and male thirty, aged 20–70 years) before and after B-vitamin supplementation for 3 months in a randomised, placebo-controlled double-blind trial. In a cross-sectional study, seventeen of the hyperhomocysteinaemic subjects were age- and sex-matched to healthy controls (n 17). Our main findings were: (i) as compared with controls, hyperhomocysteinaemic subjects tended to have higher plasma concentrations of cystatin C and lower mRNA levels of cystatin C in PBMC; (ii) compared with placebo, treatment of hyperhomocysteinaemic individuals with B-vitamins significantly increased plasma levels of cystatin C and mRNA levels of cystatin C in PBMC; (iii) while plasma levels of cystatin C were positively correlated with plasma levels of TNF receptor-1, mRNA levels of cystatin C in PBMC were inversely correlated with this TNF parameter. Taken together, our findings suggest that disturbed cystatin C levels may be a characteristic of hyperhomocysteinaemic individuals, potentially related to low-grade systemic inflammation in hyperhomocysteinaemic subjects, and that B-vitamins may modulate cystatin C levels in these individuals.

Homocysteine has been related to increased risk of CVD. Matrix degradation and inflammation may be involved in this link between hyperhomocysteinemia and CVD. Recent studies suggest that cystatin C can modulate matrix degradation and inflammation. The present study measured cystatin C at protein (plasma) and mRNA levels (peripheral blood mononuclear cells (PBMC)) in hyperhomocysteinemic individuals (n 37, female seven and male thirty, aged 20-70 years) before and after B-vitamin supplementation for 3 months in a randomized, placebo-controlled double-blind trial. In a cross-sectional study, seventeen of the hyperhomocysteinemic subjects were age- and sex-matched to healthy controls (n 17). Our main findings were: (i) as compared with controls, hyperhomocysteinemic subjects tended to have higher plasma concentrations of cystatin C and lower mRNA levels of cystatin C in PBMC; (ii) compared with placebo, treatment of hyperhomocysteinemic individuals with B-vitamins significantly increased plasma levels of cystatin C and mRNA levels of cystatin C in PBMC; (iii) while plasma levels of cystatin C were positively correlated with plasma levels of TNF receptor-1, mRNA levels of cystatin C in PBMC were inversely correlated with this TNF parameter. Taken together, our findings suggest that disturbed cystatin C levels may be a characteristic of hyperhomocysteinemic individuals, potentially related to low-grade systemic inflammation in hyperhomocysteinemic subjects, and that B-vitamins may modulate cystatin C levels in these individuals. [PUBLICATION ABSTRACT]