Perioperative Aromatase Inhibitors: No Effect on Recurrence, but Ki67 Level Important


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Updated analysis from the United Kingdom’s POETIC trial found no evidence that perioperative aromatase inhibitor therapy slows or prevents time to recurrence of breast cancer. However, the study did show that tumor Ki67 levels after 2 weeks of perioperative aromatase inhibitor therapy are prognostic for outcomes and could guide the need for additional adjuvant treatment.1 The findings were presented at the 2017 San Antonio Breast Cancer Symposium by John F.R. Robertson, MD, of the University of Nottingham School of Medicine in Darby.

John F.R. Robertson, MD

John F.R. Robertson, MD

“Experimental evidence and the small IMPACT trial2 suggested that perioperative endocrine therapy may improve long-term disease-related outcome in patients undergoing primary surgery for estrogen receptor–positive breast cancer and that tumor Ki67 levels after 2 weeks of an aromatase inhibitor might predict outcomes better than pretreatment Ki67,” Dr. Robertson said.

The POETIC trial is a phase III randomized study testing these hypotheses and determining whether Ki67 level at 2 weeks could be a better predictor of relapse than baseline Ki67 levels. The primary endpoint was time to recurrence (to locoregional or distant recurrence or breast cancer death).

POETIC Details

In the POETIC trial, 4,480 postmenopausal patients (median age, 67) with early-stage estrogen receptor–positive breast cancer were analyzed after randomization 2:1 to either a perioperative aromatase inhibitor (letrozole at 2.5 mg/d or anastrozole at 1 mg/d), for 14 days prior to and 14 days following surgery, or no perioperative aromatase inhibitor. Further treatment was given according to local practice. Adjuvant therapy included hormone therapy for more than 98% of patients, chemotherapy for approximately 30%, and radiotherapy for 77%.

To measure the effect on Ki67 tumors, tissue samples were collected at baseline and surgery for blinded testing. The final population of patients with baseline and 2-week Ki67 measurements included 2,528 who received a perioperative aromatase inhibitor and 678 controls.

No Effect on Primary Endpoint

The use of perioperative aromatase inhibitor therapy did not result in a reduction in time to recurrence. The proportion of patients free of a recurrence at 5 years was 90.9% in the treatment arm and 90.3% in the control arm, for an absolute difference of –0.52% (hazard ratio [HR] = 0.91; P = .37). Similarly, the overall survival rate was 89.0% and 89.5%, respectively (HR = 0.98; P = .83). The primary event for each arm was distant recurrence, which was observed in 7.3% of the treatment arm and 8.2% of the control arm, Dr. Robertson reported.

“We saw no evidence of improved clinical outcomes—ie, time to recurrence—with perioperative aromatase inhibitors,” he said.

Prognostic Value of Ki67 at 2 Weeks

“However, Ki67 at baseline and Ki67 at 2 weeks provided independent significant prognostic information,” he reported. “If baseline Ki67 is low (< 10%), the prognosis is good, suggesting there is no need for 2 weeks of treatment with the aromatase inhibitor and a second Ki67 measurement. If Ki67 at baseline is high (≥ 10%), then Ki67 measurement after 2 weeks on aromatase inhibitor therapy can subdivide patients further.”

In the study patients with low Ki67 levels at 2 weeks, the rate of 5-year time to recurrence was 8.4%. “These patients do relatively well. They may have no need for additional treatment beyond the standard of care,” he said.

But those with high Ki67 at 2 weeks had a poor prognosis, with a 5-year time to recurrence rate of 19.6%. “These patients should be considered for additional chemotherapy and/or for trials of new agents,” he advised. In the perioperative treatment group, the 5-year risk was 4.9% for patients with low Ki67 levels at baseline, rising to 12.1% for those with high levels (HR = 2.6; P < .0001).

A small subset of patients had low Ki67 levels at baseline but a high level at 2 weeks; these patients had a worse event-free survival than patients whose levels remained low. Similarly, among those with high Ki67 levels at baseline that remained high at 2 weeks, the risk of recurrence was doubled, compared to those that went from high to low.

PERIOPERATIVE AROMATASE INHIBITORS

  • The use of aromatase inhibitors for 2 weeks before and 2 weeks after surgery, in early-stage breast cancer, did not reduce the time to recurrence in the large phase III POETIC trial.
  • At 5 years, more than 90% of the experimental and control arms were event-free.
  • Ki67 levels at baseline and at 2 weeks postoperatively were prognostic of outcomes and could help select which patients need additional therapy.
  • At 5 years, for patients with low Ki67 levels (< 10%) at 2 weeks, the recurrence rate was 8.4%, but this rose to 19.6% for those with high Ki67 levels (≥ 10%) at 2 weeks.

Table 1 shows recurrence rates according to Ki67 levels in the perioperative treatment arm. Approximately 30% of patients had low levels at baseline that stayed low, 50% had high baseline levels that became low, and 20% had high baseline levels that remained high.

“POETIC will provide definitive evidence on the role of 2-week perioperative aromatase inhibitor–treated Ki67, to inform future practice and trials, in terms of the potential to identify a group of patients for whom the current standard of care appears insufficient in the few years post diagnosis,” Dr. Robertson said. ■

DISCLOSURE: Dr. Robertson reported no conflicts of interest.

REFERENCES

1. Robertson JFR, Dowsett M, Bliss JM, et al: Peri-operative aromatase inhibitor treatment in determining or predicting long-term outcome in early breast cancer—The POETIC Trial (CRUK/07/015). 2017 San Antonio Breast Cancer Symposium. Abstract GS1-03. Presented December 6, 2017.

2. Dowsett M, Ebbs SR, Dixon JM, et al: Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: Influence of hormonal status and HER2 in breast cancer—A study from the IMPACT trialists. J Clin Oncol 23:2477-2492, 2005.


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