Refining Risk Assessment for Adjuvant CDK4/6 Inhibitors beyond Trial Inclusion Criteria: Integrating Recurrence Score...

In HR+/HER2- high-risk early breast cancer (eBC), the NATALEE and monarchE trials demonstrated improved survival after the addition of CDK4/6 inhibitors to endocrine treatment (ET). However, the absolute benefit varies according to prognostic factors. We analyzed the outcome of subgroups based on monarchE and NATALEE inclusion criteria in the WSG-ADAPT-HR+/HER2- trial investigating Ki67 response to ET in treatment decision.

In WSG-ADAPT-HR+/HER2- (NCT01779206), HR+/HER2- eBC patients with cT2-4 or cN+ or G3 or baseline Ki67 ≥15% received 3-week induction ET. pN0-1 patients with RS 0-11 or RS 12-25 with ET-response (central Ki67_postET ≤10%) received ET alone (ET subtrial); patients with RS 12-25 and no ET-response received chemotherapy (CTx) in CTx subtrial. Patients with c/pN2-3 or G3 with Ki67 >40% were randomized directly to CTx subtrial evaluating (neo)adjuvant paclitaxel vs. nab-paclitaxel, followed by epirubicin + cyclophosphamide and ET. For this retrospective analysis, the intermediate-risk group (meeting NATALEE but not monarchE criteria for "high risk") included patients with N0 and T3-4 or T2 with G3, or RS >25 or baseline Ki67 ≥20%, and those with N1, T1-2, G1-2, and RS ≤25. The high-risk group (meeting monarchE criteria for "high risk") included remaining patients with node-positive eBC, and the low-risk group included remaining N0 patients.

In the CTx (n = 2,230) and ET subtrials (n = 2,135), 609 and 481 patients were at intermediate risk, and 963 and 303 were at high risk, respectively. Risk classifications were prognostic in ET and CTx subtrials (median follow-up: 60 months). Low-risk patients in the ET subtrial (n = 1,351) had 5-year invasive disease-free survival (iDFS) and distant DFS (dDFS) of 94.7% and 96.4%, respectively, vs. 90.1% and 93.6% for intermediate-risk patients, and vs. 88.3% and 88.9% for high-risk patients. In the CTx-subtrial, 5-year iDFS and dDFS rates were 93.9% and 94.9% in the low-risk group (n = 658), versus 84.7% and 87.0% in the intermediate-risk group, and 77.7% and 79.6% in the high-risk group. Survival outcomes were similar between pN0 and pN1 intermediate-risk patients in the ET and CTx subtrials.

Among 4365 WSG-ADAPT-HR+/HER2- patients, N0-1 cases receiving ET after ET-response and meeting NATALEE but not monarchE criteria had only slightly inferior outcomes vs. the low-risk group. Assuming a hazard ratio of 0.7 for a ribociclib effect in NATALEE, an absolute benefit of approximately 2% fewer dDFS events after 5 years could be expected in this group based on the WSG-ADAPT-HR+/HER2- experience. ET-response evaluation can refine prognosis to better inform shared decision-making in this intermediate-risk group.