Molecular 8-ball.

Top Line: Maybe molecular classification can help clarify results of PORTEC 3.

The Study: PORTEC3 compared adjuvant radiation alone to adjuvant chemoradiation for women with high-risk endometrial cancer, defined as stage I + grade 3 + deep invasion or LVI, any stage II-III, or any stage I-III serous or clear cell histology. Initial analysis showed that adding chemo improved failure-free survival with a strong benefit among women with stage III disease or age >70, and a later analysis showed an improvement in overall survival driven by those with stage III disease and serous histology. In this secondary analysis, 97% of PORTEC3 tumors were classified into four molecular subgroups: p53-abnormal (p53abn, 23%), POLE-ultramutated (POLEmut, 12%), mismatch repair-deficient (MMRd, 33%), and no specific molecular profile (NSMP, 32%). Compared to the overall population, there was a disproportionately high number of serous tumors in the p53abn group, grade 3 endometrioid tumors in the POLEmut group, and grade 1-2 endometrioid tumors in the NSMP group. MMRd was predominately endometrioid of all grades. P53abn patients had the worst clinical outcomes with less than half (48%) free from recurrence and just over half (54%) alive at 5 years. On the other hand, there was only one recurrence and death in the POLEmut group for a 5-year RFS and OS rate of 98%. Outcomes for MMRd and NSMP fell in the middle: RFS 70-75% and OS 80-90%. So, how did each group fare with the addition of chemo? As expected, there was no chemo benefit for POLEmut and neither with MMRd or NSMP. On the other hand, p53abn saw a 23% absolute improvement in 5-year RFS and OS with the addition of chemo.. 

TBL: Molecular classification of high-risk endometrial cancer is prognostic of clinical outcomes and predictive of the benefit of chemotherapy. | Leon-Castillo, J Clin Oncol 2020

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