Major Findings in High-Risk Patients
In both the ET-alone and chemotherapy-ET trials, higher recurrence score, nodal status, tumor size, higher baseline Ki-67, and higher post-ET Ki-67 were associated with poorer iDFS and dDFS in a univariate analysis. The negative prognostic impact of involved axillary nodes was particularly apparent for younger patients.
In a multivariate analysis of patients in the chemotherapy trial, only higher recurrence score, nodal status, and tumor size were significantly associated with poorer iDFS and dDFS.
In both trials, long-term outcomes were not significantly different between Ki-67 responders who received only ET and Ki-67 non-responders who were assigned to chemotherapy plus ET. The 5-year iDFS rates were 93% and 90%, respectively, and the 5-year dDFS rates were 96% and 93%, respectively.
For patients with up to 3 positive lymph nodes and recurrence scores of 12-25, the 5-year dDFS rates were excellent. In patients age 50 and younger, the 5-year dDFS was 97% in Ki-67 responders who received only ET and 92% in Ki-67 non-responders who received chemotherapy plus ET. In patients older than 50 years, the 5-year dDFS rates were 95% and 94%, respectively.
The prognostic importance of Ki-67 response was observed in both younger and older subsets, although the percentage of Ki-67 responders in the older group was nearly double that in the younger group (81.6% and 42.5%, respectively).
Among chemotherapy-treated patients with more than 4 involved axillary nodes, dDFS was highly correlated with recurrence score. The 5-year dDFS was 94% in patients with recurrence scores of 0-11, 76% in those with recurrence scores of 12-25, and 69% in patients with recurrence scores greater than 25.
In patients who received chemotherapy for having recurrence scores greater than 25, a Ki-67 response to ET was associated with good 5-year dDFS — 88%, compared with 81% for Ki-67 non-responders. The prognostic value Ki-67 response persisted in multivariate analysis (hazard ratio for dDFS, 0.42; P =.02).
Monday Morning Recommendations
The themes that permeate the analysis of the WSG ADAPT HR+/HER2- trial resonate deeply with oncologists and their patients. Those themes are: personalizing treatment for patients with early breast cancer, defining meaningful surrogate endpoints to guide therapeutic recommendations, and using adaptive techniques to escalate treatment intensity only in patients who require it.
For the investigators, the major take-home points from the WSG-ADAPT HR+/HER2- trial were clear:
- ET response by Ki-67 provides important prognostic information in many patients with luminal early breast cancer.
- Patients with low tumor burden, high recurrence scores, and Ki-67 response have good outcomes and can be spared the risks of chemotherapy.
- Patients with 4 or more involved axillary nodes and genomic low-risk tumors had excellent outcomes with chemotherapy plus ET.
For oncologists in clinical practice, the “Monday morning lessons” are not as clear, as suggested by Lisa Carey, MD, of the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, who was the discussant for the ASCO session.
From a methodological perspective, Dr Carey warned that cross-trial conclusions from a combined analysis of separate treatment trials should be regarded as hypothesis-generating, not guideline-changing. Across- and within-cohort comparisons in trials with adaptive designs may not be generalizable in practice.
Undeniably, patients in the WSG-ADAPT HR+/HER2- trial represent highly selected populations. Histologic grade and baseline Ki-67 were among the eligibility criteria for the study. Histologic grade determinations and Ki-67 measurements were performed by central pathology review, minimizing the inter-observer variation that can be seen in routine clinical practice.3,4
As Dr Carey noted, Ki-67 response is an emerging factor of potential prognostic value. The POETIC trial showed that on-treatment Ki-67 had a strong prognostic impact in postmenopausal women with HR+ breast cancer who received brief ET.5
The ALTERNATE trial also tested brief exposure to ET, and the long-term prognostic impact of Ki-67 response is not yet known.6
In the WSG-ADAPT HR+/HER2- trial, patients with up to 3 positive lymph nodes and intermediate genomic risk were assigned to ET alone or chemotherapy plus ET entirely by Ki-67 response to brief ET.
Among the Ki-67 responders, the 5-year iDFS of 93% is similar to the outcome for patients in the TAILORx7 and RxPONDER trials8 treated with either ET alone or chemotherapy plus ET.
Participants in TAILORx and RxPONDER were selected by clinical-pathologic and genomic criteria alone and not by Ki-67 response to ET. Therefore, the magnitude of the additive value of Ki-67 response in patients with up to 3 positive lymph nodes is uncertain.
Overall, the first results from the prospective, high-risk cohort of the WSG-ADAPT HR+/HER2- trial do not influence what oncologists recommend on Monday morning.
However, the trial adds to the literature suggesting the value of on-treatment response assessment. It advances the goals of precision oncology and illustrates the power of adaptive trial designs in refining prognosis, objectifying treatment selection, and improving outcomes for patients with early breast cancer.
Disclosures: The WSG-ADAPT HR+/HER2- trial was supported by Genomic Health (Exact Sciences), Celgene, Amgen, and AOK. Dr Gluz, his fellow investigators, and Dr Carey declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original references for a full list of disclosures.
Read more of Cancer Therapy Advisor’s coverage of the 2021 ASCO Annual Meeting by visiting the conference page.
- Harbeck N, Gluz O, Kuemmel S, et al. Endocrine therapy alone in patients with intermediate or high-risk luminal early breast cancer (0-3 lymph nodes), Recurrence Score <26 and Ki67 response after preoperative endocrine therapy: First efficacy results from the ADAPT HR+/HER2- trial (n=4,690). Presented at: 2020 Virtual San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract GS4-04.
- Gluz O, Nitz U, Christgen M, et al. Prognostic impact of recurrence score, endocrine response and clinical-pathological factors in high-risk luminal breast cancer: Results from the WSG-ADAPT HR+/HER2- chemotherapy trial. J Clin Oncol. 2021:39(suppl 15; abstr 504). doi:10.1200/JCO.2021.39.15_suppl.504
- Chung YR, Jang MH, Park SY, et al. Interobserver variability of Ki-67 measurement in breast dancer. J Pathol Transl Med. 2016 Mar; 50(2): 129-137. doi:10.4132/jptm.2015.12.24
- Longacre TA, Ennis M, Quenneville LA, et al. Interobserver agreement and reproducibility in classification of invasive breast carcinoma: an NCI breast cancer family registry study. Mod Pathol. 2006;19(2):195-207. doi:10.1038/modpathol.3800496
- Smith I, Robertson J, Kilburn L, et al. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020;21(11):1443-1454. doi:10.1016/S1470-2045(20)30458-7
- Ma C, Suma, V, Leitch AM, et al. Neoadjuvant chemotherapy (NCT) response in postmenopausal women with clinical stage II or III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) resistant to endocrine therapy (ET) in the ALTERNATE trial (Alliance A011106). Presented at: 2020 Virtual San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract GS4-05.
- Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121. doi:10.1056/NEJMoa1804710.
- Kalinsky K, Barlow, WE, Meric-Bernstam, F, et al. First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy (ET) +/- chemotherapy (CT) in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25: SWOG S1007 (RxPonder). Presented at: 2020 Virtual San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract GS3-00.