Investigator
Radiotherapiegroep
Clinical Behavior and Molecular Landscape of Stage I p53-Abnormal Low-Grade Endometrioid Endometrial Carcinomas
Abstract Purpose: The clinical significance of the p53-abnormal (p53abn) molecular subtype in stage I low-grade endometrioid endometrial carcinoma (EEC) is debated. We aimed to review pathologic and molecular characteristics, and outcomes of stage I low-grade p53abn EEC in a large international cohort. Experimental Design: Previously diagnosed stage I p53abn EC (POLE–wild-type, mismatch repair–proficient) low-grade EEC from Canadian retrospective cohorts and PORTEC-1&2 trials were included. Pathology review was performed by six expert gynecologic pathologists blinded to p53 status. IHC profiling, next-generation sequencing, and shallow whole-genome sequencing was performed. Kaplan–Meier method was used for survival analysis. Results: We identified 55 stage I p53abn low-grade EEC among 3,387 cases (2.5%). On pathology review, 17 cases (31%) were not diagnosed as low-grade EEC by any pathologists, whereas 26 cases (47%) were diagnosed as low-grade EEC by at least three pathologists. The IHC and molecular profile of the latter cases were consistent with low-grade EEC morphology (ER/PR positivity, patchy p16 expression, PIK3CA and PTEN mutations) but they also showed features of p53abn EC (TP53 mutations, many copy-number alterations). These cases had a clinically relevant risk of disease recurrence (5-year recurrence-free survival 77%), with pelvic and/or distant recurrences observed in 12% of the patients. Conclusions: A subset of p53abn EC is morphologically low-grade EEC and exhibit genomic instability. Even for stage I disease, p53abn low-grade EEC are at substantial risk of disease recurrence. These findings highlight the clinical relevance of universal p53-testing, even in low-grade EEC, to identify women at increased risk of recurrence.
Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer
PURPOSE The molecular classification of endometrial cancer (EC) has proven to have prognostic value and is predictive of response to adjuvant chemotherapy. Here, we investigate its predictive value for response to external beam radiotherapy (EBRT) and vaginal brachytherapy (VBT) in early-stage endometrioid EC (EEC). METHODS Data of the randomized PORTEC-1 trial (n = 714) comparing pelvic EBRT with no adjuvant therapy in early-stage intermediate-risk EC and the PORTEC-2 trial (n = 427) comparing VBT with EBRT in early-stage high-intermediate-risk EC were used. Locoregional (including vaginal and pelvic) recurrence-free survival was compared between treatment groups across the four molecular classes using Kaplan-Meier's methodology and log-rank tests. RESULTS A total of 880 molecularly classified ECs, 484 from PORTEC-1 and 396 from PORTEC-2, were included. The majority were FIGO-2009 stage I EEC (97.2%). The median follow-up was 11.3 years. No locoregional recurrences were observed in EC with a pathogenic mutation of DNA polymerase-ε ( POLEmut EC). In mismatch repair–deficient (MMRd) EC, locoregional recurrence-free survival was similar after EBRT (94.2%), VBT (94.2%), and no adjuvant therapy (90.3%; P = .74). In EC with a p53 abnormality (p53abn EC), EBRT (96.9%) had a substantial benefit over VBT (64.3%) and no adjuvant therapy (72.2%; P = .048). In EC with no specific molecular profile (NSMP EC), both EBRT (98.3%) and VBT (96.2%) yielded better locoregional control than no adjuvant therapy (87.7%; P < .0001). CONCLUSION The molecular classification of EC predicts response to radiotherapy in stage I EEC and may guide adjuvant treatment decisions. Omitting radiotherapy seems to be safe in POLEmut EC. The benefit of radiotherapy seems to be limited in MMRd EC. EBRT yields a significantly better locoregional recurrence-free survival than VBT or no adjuvant therapy in p53abn EC. VBT is the treatment of choice for NSMP EC as it is as effective as EBRT and significantly better than no adjuvant therapy for locoregional tumor control.
Cost-utility-analysis of molecular-integrated-profile for women with (high)intermediate risk endometrial cancer - PORTEC-4a an international, randomised, phase 3 trial.
The international PORTEC-4a trial demonstrated that individualised adjuvant treatment for women with (high)intermediate risk endometrial cancer (HIR-EC), guided by a molecular-integrated-risk-profile, achieves similar high local tumour control, while nearly half of patients were spared adjuvant treatment. Although determination of the molecular-integrated-profile increases diagnostics costs due to additional immunohistochemistry and DNA-sequencing, these costs may be offset by savings on other care and improved patient outcomes. Women with early-stage HIR-EC eligible for the PORTEC-4a trial, were randomised (2:1) to either adjuvant treatment according to their molecular-integrated-profile or standard vaginal brachytherapy (VBT). EC-related costs were evaluated from a healthcare perspective over a three-year follow-up period. Costs were related to quality-adjusted-life-years (QALYs) using the EORTC-QLU-C10D instrument. T-test compared mean QALYs and costs, with multiple imputation for missing data. All 564 patients were included in the cost-utility-analysis; 367 in molecular-profile arm and 197 in standard arm. QALYs were comparable (p = 0.58). Total healthcare costs were somewhat, but not significantly, lower in molecular-profile arm compared to standard arm (€11,898 vs €13,047, p = 0.11). Costs spent up until recurrence were significantly lower in molecular-profile arm (€9,995 vs €11,926, p < 0.01), while there was no significant difference in treatment for recurrence (€1,903 vs €1,121, p = 0.17). At a willingness-to-pay threshold of €20,000/QALY, the strategy as proposed by PORTEC-4a was 89% likely to be cost-effective. Individualised adjuvant treatment based on a molecular-integrated-profile was more cost-effective than standard VBT for patients with HIR-EC. These results further support the implementation of the molecular-integrated-profile in routine clinical practice.
