Ki67 response complements baseline risk assessment in early breast cancer
Evaluating recurrence score and Ki67 better defined subsequent treatment for women with hormone receptor-positive, HER2-negative early breast cancer, according to study results presented at the virtual San Antonio Breast Cancer Symposium.
Ki67 of 10% or less after a short course of endocrine therapy can indicate sensitivity to endocrine therapy and identify patients for whom chemotherapy can be omitted, results of one analysis of the ADAPT trial showed.
In another part of the trial, neoadjuvant nab-paclitaxel appeared safe and effective as part of a dose-dense chemotherapy regimen for those deemed high risk by Oncotype DX Breast Recurrence Score test (Genomic Health) and lack of Ki67 response. Further, compared with paclitaxel, nab-paclitaxel (Abraxane, Celgene) led to significant improvements in pathologic complete response rate.
“The Oncotype DX Breast Recurrence Score test has been shown to be predictive for pathologic complete response by retrospective analysis, but prospective data are lacking,” Sherko Kuemmel, MD, PhD, researcher at Kliniken Essen-Mitte in Germany, said during a presentation. “Ki67 as a dynamic marker is prognostic for outcome, but data on the predictive role of Ki67 response and of endocrine sensitivity for pathologic complete response after neoadjuvant chemotherapy are limited.”
ADAPT HR+/HER2- is a prospective phase 2/phase 3 umbrella trial that included 5,635 women aged 18 years and older who were candidates for adjuvant chemotherapy by conventional prognostic criteria. Women underwent a short 3-week course of endocrine therapy prior to surgery and, based on their response, were assigned to endocrine therapy alone (n = 2,356) or chemotherapy followed by adjuvant endocrine therapy (n = 2,335).
Chemotherapy subtrial
Kuemmel and colleagues evaluated the role of recurrence score and Ki67 decrease in the selection of women with high-risk disease for neoadjuvant dose-dense chemotherapy regimens. Oncotype DX testing was performed at baseline and Ki67 was centrally measured at baseline and in surgical specimens.
Researchers defined high risk as CN2-3 disease; grade 3 disease and post-endocrine Ki67 greater than 40%; or CN0-1 disease with a recurrence score of greater than 25, or a recurrence score of 12 to 25 with post-endocrine therapy Ki67 of greater than 10%.
Women with a recurrence score of 12 to 25 who had a post-endocrine therapy Ki67 of less than or equal to 10% were deemed sensitive to endocrine therapy and received that treatment in another portion of the trial, presented separately during the symposium.
In the chemotherapy portion of the trial, researchers assigned 864 women to four cycles of 175 mg/m² paclitaxel every 2 weeks (n = 427; median age, 52 years; 48.2% premenopausal) or eight cycles of 125 mg/m² nab-paclitaxel weekly (n = 437; median age, 51 years; 50.1% premenopausal), each followed by four cycles of 90 mg/m² epirubicin and 600 mg/m² cyclophosphamide every 2 weeks.
Pathologic complete response, including ductal carcinoma in situ, served as the primary endpoint of the neoadjuvant portion of the trial. Secondary endpoints included pathologic complete response by risk score group, endocrine sensitivity and clinical risk.
Results showed a significantly higher pathologic complete response rate among patients who received nab-paclitaxel vs. paclitaxel (20.8% vs. 12.9%; P = .002). Further, women with a recurrence score of more than 25 had a pathologic complete response rate more than double that of women with a score of 25 or less (16.1% vs. 7.2%; P = .006).
This trend persisted for premenopausal (17.2% vs. 4.8%; P =.003) women, but lost significance in the postmenopausal setting (15.2% vs. 12.2%).
“For both women who were pre- and postmenopausal, the pathologic complete response rate was low when the recurrence score was 25 or less, although the majority of women in this group had no response to endocrine therapy,” Kuemmel said.
When looking at outcomes by recurrence score and response to endocrine therapy, researchers found that the probability of achieving pathologic complete response was low for those with a recurrence score of 25 or less and no response to endocrine therapy (7.2%) and for those with a recurrence score of greater than 25 and a response to endocrine therapy (5.6%).
In a multivariable analysis that included women with central pathology values, researchers found that small tumor size (OR = 0.62; 95% CI, 0.43-0.89) and high recurrence score (OR = 2.47; 95% CI, 1.27-4.81) were significant predictors of pathologic complete response.
Results of the safety analysis showed 234 serious adverse events occurred, including 106 in the paclitaxel group and 128 in the nab-paclitaxel group.
“No new safety signals from serious adverse events were reported, therefore, dose-dense nab-paclitaxel is feasible,” Kuemmel said.
“The ADAPT trial is the first large prospective study confirming a recurrence score higher than 25 as a predictive factor for pathologic complete response compared with patients treated with neoadjuvant chemotherapy,” Kuemmel said. “Ki67 as an additional dynamic marker further separates the high-risk group and identifies patients who may not benefit from intensive chemotherapy. Optimal therapy for these patients is further investigated in the ongoing ADAPT trial.”
Endocrine therapy alone
Nadia Harbeck, MD, PhD, head of the breast center and chair for conservative oncology in the department of OB&GYN at University of Munich in Germany, presented data of 2,290 patients in the intent-to-treat population of the ADAPT trial assigned endocrine therapy alone, which included patients with up to three involved lymph nodes and a recurrence score of 0 to 11 (n = 868; median age, 57 years; 34.6% premenopausal), or those with a recurrence score of 12 to 25 and an endocrine response, defined as post-endocrine therapy Ki67 of 10% or less (n = 1,422; median age, 58 years; 26.3% premenopausal).
“In luminal early breast cancer, optimal patient selection for omission of adjuvant chemotherapy, particularly in pN1 disease, is still unclear,” Harbeck said. “Omission of chemotherapy seems to be safe based on data from TAILORx for [patients with pN0 disease and a recurrence score of 25 or less], at least in postmenopausal patients, but the benefit from chemotherapy cannot be excluded for some of the premenopausal patients.”
Invasive DFS at 5 years served as the primary endpoint. Secondary endpoints included distant DFS, OS and translational research.
Median follow-up was 60 months.
Results showed a 5-year invasive DFS rate of 92.6% (95% CI, 90.8-94) for women with luminal early-stage breast cancer who had up to three involved lymph nodes, a recurrence score of 12 and 25 and a post-endocrine Ki67 of 10% or less, which was noninferior to the 93.9% (95% CI, 91.8-95.4) rate observed among those with a recurrence score of 11 or less. The groups also had similarly high rates of 5-year OS (97.3% vs. 98%) and distant DFS (95.6% vs. 96.3%).
These results showed dynamic endocrine therapy response complements recurrence score as an important selection criterion for omission of chemotherapy in hormone receptor-positive, HER2-negative early breast cancer, according to the researchers.
“Dynamic Ki67 response testing is feasible in routine practice and complements baseline risk assessment to refine patient selection for therapy de-escalation and escalation,” Harbeck said.
References:
Harbeck N, et al. Abstract GS4-04. Presented at: San Antonio Breast Cancer Symposium (virtual meeting); Dec. 8-11, 2020.
Kuemmel S, et al. Abstract GS4-03. Presented at: San Antonio Breast Cancer Symposium (virtual meeting); Dec. 8-11, 2020.
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Harbeck N, et al. Abstract GS4-04. Presented at: San Antonio Breast Cancer Symposium (virtual meeting); Dec. 8-11, 2020.