By: Charles Bankhead
Ki67 values before, after preop endocrine therapy associated with recurrence risk
Preoperative endocrine therapy with an aromatase inhibitor (AI) did not reduce the risk of breast cancer recurrence, but helped identify risk groups to guide adjuvant therapy decisions, a biomarker-supported clinical trial suggested.
Preoperative letrozole or anastrozole led to a 5-year recurrence-free survival (RFS) of 91.0% versus 90.4% for patients who did not receive an AI prior to surgery. Most patients who had low levels of the proliferation marker Ki67 at baseline (Ki67B) or after 2 weeks of AI treatment (Ki672w) did well with adjuvant endocrine therapy alone. However, those with high Ki67 values after neoadjuvant therapy with an AI had worse 5-year recurrence rates, reported Ian Smith, MD, of the Royal Marsden Hospital and Institute of Cancer Research in London, and colleagues.
“[The POETIC trial] has provided evidence for the clinical validity of on-treatment aromatase inhibitor Ki672w in addition to Ki67B to predict those with high residual risk of recurrence in spite of standard-of-care therapy,” they wrote in Lancet Oncology. “At the initiation of POETIC, we believed that the evidence was insufficient to withhold or direct therapy on the basis of the Ki672w. Our results provide an early indication of endocrine sensitivity or resistance, including for the large number of patients who are not routinely considered for adjuvant chemotherapy.”
The study provided support for a clinical strategy that will improve clinical trials and, ultimately, treatment for early-stage, hormone receptor (HR)-positive breast cancer, according to the authors of an accompanying editorial.
“If we want to improve precision medicine in early-stage, hormone receptor-positive disease, primary surgery should not be the first option for most patients, similar to those with triple-negative and HER2-positive breast cancer,” said Montserrat Muñoz, MD, and Aleix Prat, MD, of the University of Barcelona in Spain. “The invaluable information provided by on-treatment tumor specimens is to identify the individual patient’s long-term prognosis and treatment benefit should be used to design novel trials. The era in which thousands of patients are randomly assigned to various adjuvant treatment strategies without preselecting patients by means of prognostic or predictive tools should be over.”
Preclinical studies showed that cancer surgery has a growth-stimulating effect that could promote metastasis in HR-positive breast cancer, and perioperative endocrine therapy could inhibit the stimulatory effect. The findings were subsequently confirmed in human breast cancer. The findings provided the basis for the POETIC trial, which tested two hypotheses: short-term preoperative endocrine therapy with an AI might improve clinical outcomes and that measurement of Ki67 levels before and after endocrine therapy could identify a good-prognosis subgroup of patients for whom adjuvant endocrine therapy would be sufficient.
Investigators at 130 centers in England and Scotland randomized 4,480 postmenopausal women with early-stage breast cancer 2:1 to a 2-week course of preoperative endocrine therapy with letrozole or anastrozole or no pre- or perioperative endocrine therapy. Ki67 levels were assessed before and after the short course of endocrine therapy. The primary endpoint was time to breast cancer recurrence.
During a median follow-up of 62.9 months, 434 patients had a breast cancer recurrence, 280 (9%) in the patients who received preoperative endocrine therapy and 10% in the control group. The difference translated into a nonsignificant hazard ratio of 0.92 in favor of endocrine therapy (95% CI 0.75-1.12).
Subgroup analysis included an assessment of Ki67B and Ki672w values by HER2 status among patients randomized to preoperative AI therapy. In the HER2-negative subgroup, which accounted for about 90% of the study population, the 5-year recurrence risk for patients with low Ki67 values at both measurements (low-low) was 4.3%. The rate increased to 8.3% for patients with high Ki67B and low Ki672w (high-low) and to 21.5% for those with high Ki67 values at both time points (high-high). Among patients with HER2-positive breast cancer, 5-year recurrence rates were 10.1% for the low-low subgroup, 7.7% in the high-low subgroup, and 15.7% in the high-high subgroup.
“We believe that we have identified a subgroup with a low baseline Ki67 who have a sufficiently good prognosis that the majority will do well on standard endocrine therapy alone (except perhaps for a minority as dictated by other clinical-pathological factors) and who do not require a repeat 2-week biopsy,” the authors concluded.
“Second, giving POAI [preoperative AI] to the subgroup with high baseline Ki67 can differentiate two groups of patients according to their 2-week Ki67 value: those who convert to a low Ki67 might not need anything beyond adjuvant endocrine therapy (taking consideration of other clinical-pathological factors), whereas those with a high Ki67 that has remained high, should be considered for further adjuvant treatments and trials.”
Barbara Jacoby is an award winning blogger that has contributed her writings to multiple online publications that have touched readers worldwide.