Although chemotherapy is the standard neoadjuvant treatment in postmenopausal women with large breast tumors, an endocrine approach may be more suitable and may, in fact, help further optimize systemic treatment as well.

"Estrogen receptor (ER)-positive disease is highly heterogeneous, and this heterogeneity can be studied and treatment personalized by taking advantage of the neoadjuvant setting," said Matthew J. Ellis, PhD, MB, BChir, of Washington University, St. Louis.

Dr. Ellis, who has been studying the characteristics of ER-rich tumors for years, is leading the multicenter phase II American College of Surgeons Oncology Group (ACOSOG) Z1031 study, which is evaluating the benefit of an endocrine neoadjuvant approach in postmenopausal patients with ER-rich tumors. Preliminary analyses, reported at the 2010 ASCO Annual Meeting by Dr. Ellis, showed clinical response rates to exceed 60%, and the breast-conservation rate to be 51% for patients slated for mastectomy at presentation.¹

'Dramatic Effect'

"For the 150 or so women in this study who were clearly headed for mastectomy this is really a dramatic effect, achieved with very low toxicity, and arguably more efficacious than the results we quote from traditional chemotherapy studies to justify the use of neoadjuvant treatment," Dr. Ellis said.

The breast-conservation rate was 83% for women considered marginal for breast-conserving surgery at baseline, and successful breast conservation was seen even in patients deemed inoperable

The study evaluated an ER-rich population (Allred score* of 6-8) with stage II/III breast cancer and median tumor size of 4.0 cm. The 374 women were randomly assigned to 16 weeks of daily exemestane, 25 mg; letrozole (Femara), 2.5 mg; or anastrozole, 1 mg. In the intent-to-treat analysis, clinical response rates were 60.5% for exemestane, 70.9% for letrozole, and 66.7% for anastrozole; per-protocol response rates were 69%, 79.3%, and 77%, respectively. Differences between the agents were not considered clinically significant, based on equivalent surgical outcomes, Dr. Ellis said.

These response rates are clearly higher than those achieved in other neoadjuvant studies, which may be due to better patient selection.

"One thing we learned from the previous P024 trial of letrozole² is that clinical response is clearly related to ER level. We therefore set an Allred score of 6 to 8 as criteria for eligibility, so Z1031 was a strongly ER-rich group. We think this explains why our surgical outcome is so impressive, although the interesting thing is that we still saw wide variation in response," he said. "ER level alone is an insufficient predictive biomarker."

Using Ki67 to Differentiate

It appears that Ki67, the proliferation index, may be another piece to the puzzle. In another study presented at ASCO's Annual Meeting (the GEICAM/2006-03 trial), Spanish investigators concluded that chemotherapy is more effective than endocrine therapy in women with localized luminal breast cancer-particularly those with "luminal B" disease, as indicated by high Ki67 levels. This conclusion was based on clinical response rates of 66% with chemotherapy (epirubicin/cyclophosphamide/docetaxel) vs 48% with endocrine therapy (exemestane plus goserelin [Zoladex] for premenopausal women).³ Rates of breast-conserving surgery were 51% with chemotherapy and 65% with hormonal therapy. Grade 3/4 toxicity was significantly more common with chemotherapy-47% vs 9%-reported Emilio Alba, MD, of the Hospital Universitario Virgen de la Victoria, Málaga, Spain.

Dr. Ellis, who was familiar with the GEICAM/2006-03 study, pointed out, however, that its eligibility criteria differed from ACOSOG Z1031 because of the inclusion of premenopausal women. Regardless, he added, the findings were not contradictory. "If you drill down on the GEICAM data and just look at the postmenopausal subset (54% of patients) you see that those with a low baseline Ki67 have similar outcome for chemotherapy vs endocrine therapy," he noted.
In fact, he added, Ki67 may prove to aid in personalizing neoadjuvant treatment, a hypothesis that is being tested in a follow-up of ACOSOG Z1031 (Cohort B). Patients will receive 2 weeks of endocrine therapy, and then have tumors biopsied to measure Ki67. Those with a Ki67 level of 10% or less will continue on preoperative endocrine therapy, whereas those with a Ki67 greater than 10% will switch immediately to neoadjuvant chemotherapy or undergo surgery, as this is considered a marker of early treatment resistance (Fig. 1).

"We presented data at San Antonio last year4 showing that if you successfully suppress Ki67 at 2 weeks, you enrich for endocrine therapy responders, but if the proliferation index is still high despite the use of a potent aromatase inhibitor, you identify nonresponders," he said.

He added that his group has found that patients with a node-negative, small, persistently ER-positive tumors with a fully suppressed Ki67 after neoadjuvant endocrine therapy have extremely low rates of recurrence and resemble patients with a complete pathologic response to chemotherapy.5 This subset of the Cohort B study, therefore, will not receive adjuvant chemotherapy.

Using this approach, he predicted that treatment decisions could be straightforward for about half the ER-positive clinical stage II/III population with a group of about 25% who definitely do not need chemotherapy and 25% who definitely do. "By assessing the patient's responsiveness to endocrine therapy using a simple algorithm based on pathologic stage, ER, and Ki67, sensible decisions regarding the need for further systemic therapy can be made," he said. ■

References

1. Ellis MJ, Buzdar A, Unzeitig GW, et al: ACOSOG Z1031: A randomized phase II trial comparing exemestane, letrozole, and anastrozole in postmenopausal women with clinical stage II/III estrogen receptor-positive breast cancer. 2010 ASCO Annual Meeting. Abstract LBA513. Presented June 7, 2010.

2. Eiermann W, Paepke S, Appfelstaedt J, et al: Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol 12:1527-1532, 2001.

3. Alba E, Calvo L, Albanell J, et al: Chemotherapy versus hormone therapy as neoadjuvant treatment in luminal breast cancer: A multicenter, randomized phase II study (GEICAM/2006-03). 2010 ASCO Annual Meeting. Abstract 500. Presented June 6, 2010.

4. Ellis MJ, Luo J, Tao Y, et al: Tumor Ki67 proliferation index within 4 weeks of initiating neoadjuvant endocrine therapy for early identification of non-responders. 2009 Annual CTRC-AACR San Antonio Breast Cancer Symposium. Abstract 78. Presented December 12, 2009.

5. Ellis MJ, Tao Y, Luo J, et al: Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J Natl Cancer Inst 100:1380-1388, 2008.