As reported in The Lancet Oncology by Ian E. Smith, MD, and colleagues, the phase III POETIC trial found that perioperative aromatase inhibitor therapy did not reduce the risk of disease recurrence in postmenopausal women with hormone receptor (HR)-positive early breast cancer vs no perioperative aromatase inhibitor therapy. However, researchers did find that high tumor Ki67 values after 2 weeks of preoperative aromatase inhibitor therapy were associated with an increased risk of disease recurrence.
Ian E. Smith, MD
POETIC Trial Details
In the open-label multicenter trial, 4,480 postmenopausal women (modified intent-to-treat population) aged ≥ 50 years with HR-positive breast cancer were randomly assigned 2:1 between October 2008 and April 2014 to receive perioperative aromatase inhibitor therapy consisting of letrozole at 2.5 mg per day or anastrozole at 1 mg per day for 14 days before and 14 days following surgery (n = 2,976) or no perioperative aromatase inhibitor therapy (control group, n = 1,504). Letrozole use was planned for 68% of patients and anastrozole for 30%. Overall, 88% of patients in both groups had HER2-negative disease and 11% vs 10% were HER2-positive. Adjuvant treatment was given according to UK standard local practice. The primary endpoint was time to disease recurrence.
Analysis of the association between tumor Ki67 values and disease outcomes was conducted among patients with available paired Ki67 values. Ki67 was analyzed by immunohistochemistry in a core biopsy taken at baseline (Ki67B) and in either a core biopsy or the excision biopsy taken at surgery after 2 weeks of aromatase inhibitor treatment (Ki672W). Ki67 scores were classified as low if < 10% and classified as high if ≥ 10%.
Breast Cancer Recurrence Risk
As of February 2018, median follow-up was 62.9 months (interquartile range = 58.1–74.1 months). Overall, breast cancer recurrence occurred in 280 patients in the perioperative aromatase inhibitor therapy group (9%) vs 154 (10%) in the control group (hazard ratio [HR] = 0.92, 95% CI = 0.75–1.12, P = .40). The proportion of patients free from breast cancer recurrence at 5 years was 91.0% vs 90.4%.
No significant differences between the perioperative aromatase inhibitor therapy group and control group were observed for 5-year rates of relapse-free survival (87.9% vs 87.6%, HR = 0.94, P = .47), local recurrence–free survival (98.6% vs 98.5%, HR = 0.86, P = .57), distant recurrence–free survival (91.7% vs 90.9%, HR = 0.90, P = .30), or overall survival (88.9% vs 88.9%, HR = 0.94, P = .50). Second primary breast cancers occurred in 26 (< 1%) vs 24 (2%) of patients.
KEY POINTS
- Aromatase inhibitor therapy for 14 days before and after surgery did not reduce risk of recurrence.
- Patients receiving perioperative aromatase inhibitor therapy with high baseline and 2-week Ki67 were at greater risk of disease recurrence.
Analysis by Ki67 Status
A total of 2,528 patients in the perioperative aromatase inhibitor therapy group and 678 in the control group had paired Ki67 data available. Overall, a significant reduction in Ki67 was observed in the perioperative aromatase inhibitor therapy group, with little change observed between paired samples in the control group. In the perioperative aromatase inhibitor therapy group, Ki672W was markedly lower among patients with HER2-negative tumors vs HER2-positive tumors (with a similar finding, with reduced magnitude of difference, in the control group).
Among patients in the perioperative aromatase inhibitor therapy group with HER2-negative disease, 5-year recurrence risk was 4.3% for those with low Ki67B and low Ki672W (n = 704), 8.4% for those with high Ki67B and low Ki672W (n = 1,097), and 21.5% for those with high Ki67B and high Ki672W (n = 406). Few patients had low Ki67B and high Ki672W (n = 28). Likelihood of disease recurrence was significantly higher in women with high Ki67B and high Ki672W vs those with high Ki67B and low Ki672W (HR = 2.59, P < .0001).
Among patients in the perioperative aromatase inhibitor therapy group with HER2-positive disease, 5-year recurrence risk was 10.1% for patients with low Ki67B and low Ki672W (n = 32), 7.7% for those with high Ki67B and low Ki672W (n = 94), and 15.7% for those with high Ki67B and high Ki672W (n = 143). Few patients had low Ki67B and high Ki672W (n = 4). Likelihood of disease recurrence was numerically higher in women with high Ki67B and high Ki672W vs those with high Ki67B and low Ki672W (HR = 2.08, P = .093).
Adverse Events
The most commonly reported grade 3 adverse events were musculoskeletal pain in 29 (1%) vs 13 (1%) patients and hot flushes in 20 (1%) vs 6 (< 1%). No grade 4 adverse events were observed. Serious adverse events occurred in 11 patients in the perioperative aromatase inhibitor therapy group, with the most common being pulmonary embolism (n = 3) and musculoskeletal pain (n = 3). No treatment-related deaths were reported.
The investigators concluded: “Perioperative aromatase inhibitor therapy has not been shown to improve treatment outcome but can be used without detriment to help select appropriate adjuvant therapy based on tumor Ki67. Most patients with low Ki67B or low perioperative aromatase inhibitor therapy–induced Ki672W do well with adjuvant standard endocrine therapy (giving consideration to clinical-pathological factors), whereas those whose perioperative aromatase inhibitor therapy–induced Ki672W remains high might benefit from further adjuvant treatment or trials of new therapies.”
Dr. Smith, of the Institute of Cancer Research, Clinical Trials and Statistics Unit, and Royal Marsden NHS Foundation Trust, London, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Cancer Research UK. For full disclosures of the study authors, visit thelancet.com.
