Endometrial Cancer Molecular Classification Could Guide Adjuvant Therapy Decisions

Author: By Shreeya Nanda, Senior medwireNews Reporter

medwireNews: Molecular classifiers have prognostic value and the potential to direct adjuvant treatment in women with high-risk endometrial cancer, shows an analysis of the PORTEC-3 trial.

The phase III study previously showed a significant survival benefit with the addition of chemotherapy to adjuvant pelvic external beam radiotherapy (EBRT), but at the cost of increased toxicity, explain the researchers, noting that the benefit was greatest in certain subgroups.

They highlight the “substantial interobserver variability in assessment of pathologic factors that define high-risk” disease, and suggest that “molecular classification might help determine appropriate adjuvant treatment.”

As reported in the Journal of Clinical Oncology, of the 410 trial participants whose tissue samples were tested successfully, 22.7% were classed as p53-abnormal (p53abn), 12.4% as POLE-ultramutated (POLEmut), 33.4% as mismatch repair-deficient (MMRd), and 31.5% had no specific molecular profile (NSMP).

Patients in the p53abn group had the worst prognosis and those in the POLEmut group had the best prognosis, with 5-year recurrence-free survival (RFS) rates of 48% versus 98% and 5-year overall survival (OS) rates of 54% versus 98%.

The MMRd and NSMP groups had intermediate outcomes; the 5-year RFS rates were 71.7% and 74.4%, respectively, and the corresponding OS rates were 81.3% and 88.5%.

These findings were confirmed in multivariable analysis, which showed a significant 2.52-fold increased risk of recurrence and 2.30-fold increased risk of death for the p53abn classifier relative to the MMRd group. By contrast, the POLEmut classifier was associated with a significant 92% and 88% reduction in the risk of recurrence and death, respectively.

Of note, patients with p53abn endometrial cancer appeared to derive a significant benefit from the addition of chemotherapy to EBRT, at 5-year RFS and OS rates of 58.6% and 64.9%, respectively, versus 36.2% and 41.8% for EBRT alone (hazard ratios [HRs]=0.52 and 0.55, respectively).

The outcomes of participants with POLEmut disease were “excellent” regardless of the treatment modality, say Tjalling Bosse, from Leiden University Medical Center in the Netherlands, and collaborators. Just one patient, in the EBRT alone group, had disease recurrence and died during the course of the study, giving 5-year RFS and OS rates of 100% with chemoradiotherapy and 96.6% with EBRT alone.

Women with MMRd disease derived no significant benefit from the addition of chemotherapy to EBRT and indeed, the RFS and OS rates were lower in the chemoradiotherapy group, albeit without reaching statistical significance.

And the NSMP group showed a trend towards better outcomes with chemoradiotherapy, but again the between-group differences were not statistically significant.

The researchers therefore summarise: “Patients with p53abn [endometrial cancer] may be considered for adjuvant treatment including chemotherapy, whereas adjuvant treatment de-escalation should be considered for those with POLEmut [endometrial cancer]; additional studies are needed especially for MMRd and NSMP [endometrial cancer].”

They conclude that “[t]his study shows that incorporation of the molecular classification into risk stratification systems is essential and future clinical trials should address specific molecular subgroups of [endometrial cancer].”

Reference

León-Castillo A, de Boer SM, Powell ME, et al. Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on prognosis and benefit from adjuvant therapy. J Clin Oncol; Advance online publication 4 August 2020. doi: 10.1200/JCO.20.00549