Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy

Abstract

PURPOSE The randomized Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women With High-Risk Endometrial Cancer (PORTEC-3) trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk endometrial cancer (EC). Because The Cancer Genome Atlas defined an EC molecular classification with strong prognostic value, we investigated prognosis and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants. METHODS Paraffin-embedded tissues of 423 consenting patients were collected. Immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for POLE exonuclease domain were done to classify tumors as p53 abnormal (p53abn), POLE-ultramutated ( POLEmut), MMR-deficient (MMRd), or no specific molecular profile (NSMP). The primary end point was recurrence-free survival (RFS). Kaplan-Meier method, log-rank test, and Cox model were used for analysis. RESULTS Molecular analysis was successful in 410 high-risk EC (97%), identifying the 4 subgroups: p53abn EC (n = 93; 23%), POLEmut (n = 51; 12%), MMRd (n = 137; 33%), and NSMP (n = 129; 32%). Five-year RFS was 48% for patients with p53abn EC, 98% for POLEmut EC, 72% for MMRd EC, and 74% for NSMP EC ( P < .001). The 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% ( P = .019); 100% versus 97% for patients with POLEmut EC ( P = .637); 68% versus 76% ( P = .428) for MMRd EC; and 80% versus 68% ( P = .243) for NSMP EC. CONCLUSION Molecular classification has strong prognostic value in high-risk EC, with significantly improved RFS with adjuvant CTRT for p53abn tumors, regardless of histologic type. Patients with POLEmut EC had an excellent RFS in both trial arms. EC molecular classification should be incorporated in the risk stratification of these patients as well as in future trials to target specific subgroups of patients.

HER2 Status in High-Risk Endometrial Cancers (PORTEC-3): Relationship with Histotype, Molecular Classification, and Clinical Outcomes

“…The study was approved by the Dutch Cancer and medical ethics committees at participating. Patient, tumor, and treatment characteristics were not significantly different between PORTEC-3 trial patients included in and excluded from the molecular analyses, as reported previously [ 9 ].…”

“…These findings encourage further exploration of combined chemotherapy with anti-HER2 therapeutics in HER2-positive EC. Of interest, recently published survival analysis of p53abn EC (of all histotypes) in PORTEC-3 showed a significant benefit in 5-year RFS when chemotherapy was added to adjuvant radiotherapy (5-year RFS of 58.6% with CTRT vs. 36.2% with RT; HR: 0.52, 95% CI: 0.30–0.91), while this was not found for other molecular subgroups [ 9 ]. It is possible that the underlying aberrant p53 status in HER2-positive EC (partially) explains the promising results of combined adjuvant chemotherapy–trastuzumab in contrast to single-agent trastuzumab treatment.…”

“…For the purpose of previous publications, targeted next-generation sequencing (NGS) using AmpliSeq Cancer Hotspot Panel v5 was performed on PORTEC-3 tumor samples. Detailed description of DNA isolation and sequencing was described previously [ 9 ]. In cases with a failed DISH assay, the final HER2 status was determined by visual examination of copy number plots generated for every individual sample for the presence of unequivocal ERBB2 amplification.…”

“…Furthermore, the molecular classification provides a strong biological basis for future subclass-specific clinical trials. Defining therapeutic targets within the p53abn EC subgroup should be prioritized given its poor prognosis despite adjuvant CTRT [ 9 ].…”

Adjuvant therapy for endometrial cancer in the era of molecular classification: radiotherapy, chemoradiation and novel targets for therapy

“…Prognostic Relevance of Molecular Sub-groups in High-risk Endometrial Cancer Results of PORTEC-3 related translational research on outcomes and differences between the trial arms by molecular sub-group were presented at international meetings and have been recently published. 45 Even in these high-risk cancers the molecular groups were found across all histological sub-types, stages, and grades. Moreover, clear differences in prognosis between the molecular sub-groups were observed, as was found also in an international molecular analysis of grade 3 endometrial cancers.…”