TY - JOUR
T1 - Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer
T2 - Impact on prognosis and benefit from adjuvant therapy
AU - Leon-Castillo, Alicia
AU - De Boer, Stephanie M.
AU - Powell, Melanie E.
AU - Mileshkin, Linda R.
AU - Mackay, Helen J.
AU - Leary, Alexandra
AU - Nijman, Hans W.
AU - Singh, Naveena
AU - Pollock, Pamela M.
AU - Bessette, Paul
AU - Fyles, Anthony
AU - Haie-Meder, Christine
AU - Smit, Vincent T.H.B.M.
AU - Edmondson, Richard J.
AU - Putter, Hein
AU - Kitchener, Henry C.
AU - Crosbie, Emma J.
AU - De Bruyn, Marco
AU - Nout, Remi A.
AU - Horeweg, Nanda
AU - Creutzberg, Carien L.
AU - Bosse, Tjalling
N1 - Publisher Copyright:
© 2020 by American Society of Clinical Oncology.
PY - 2020/10/10
Y1 - 2020/10/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85091611055&partnerID=8YFLogxK
U2 - 10.1200/JCO.20.00549
DO - 10.1200/JCO.20.00549
M3 - Article
C2 - 32749941
AN - SCOPUS:85091611055
SN - 0732-183X
VL - 38
SP - 3388
EP - 3397
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 29
ER -