Neoadjuvant Aromatase Inhibitors Lower Mastectomy Rates

Fran Lowry

May 20, 2011

May 20, 2011 — Neoadjuvant treatment with aromatase inhibitors is able to shrink estrogen receptor (ER)-rich tumors, permitting more breast-conserving surgery in postmenopausal women with stage II to III breast cancer who would otherwise undergo total mastectomy.

Dr. Matthew Ellis

The findings are from a study conducted by the American College of Surgeons Oncology Group (ACOSOG), led by Matthew J. Ellis, MD, PhD, from Washington University School of Medicine, St. Louis, Missouri, which was published online May 9 in the Journal of Clinical Oncology.

"I have been treating patients with neoadjuvant endocrine therapy for some years, and I've participated in several previous trials and noticed how effective it was in improving surgical outcomes," Dr. Ellis told Medscape Medical News. "One of my motivations was to design a relatively straightforward study that would introduce this therapy to a wider spectrum of American breast surgeons and medical oncologists."

The ACOSOG Z1031 trial randomly assigned postmenopausal women with clinical stage II to III ER-positive (Allred score, 6 to 8) breast cancer to receive 16 weeks of neoadjuvant exemestane, letrozole, or anastrozole.

The primary end point was clinical response; secondary end points included breast-conserving surgery, Ki67 proliferation marker changes, the Preoperative Endocrine Prognostic Index (PEPI), and PAM50-based intrinsic subtype analysis.

Of the 159 women in the trial who were originally told they required mastectomy, 81 (50.9%) experienced sufficient tumor shrinkage after aromatase inhibitor treatment to undergo breast-conserving surgery instead.

Of the 189 women who were originally considered marginal, 157 (83.1%) were able to undergo breast-conserving surgery.

Four women were considered inoperable at baseline; however, after 16 weeks of aromatase inhibitor treatment, 3 were able to have breast-conserving surgery and 1 had mastectomy.

No differences were found between treatments with respect to Ki67 levels.

Additionally, PAM50 analysis identified nonluminal subtypes unresponsive to aromatase inhibitors (HER2 enriched or basal-like) in 3.3% of patients. Clinical response and surgical outcomes were similar in both luminal A and luminal B tumors; however, a PEPI score of 0 — indicating the best prognosis — was higher in the luminal A subset than in the luminal B subset of patients (27.1% vs 10.7%; P = .004).

Dr. Ellis conceded there has been a certain amount of skepticism surrounding the use of aromatase inhibitors in this setting, but explained that this is because breast surgeons, and physicians in general, tend to be conservative.

"Medical practice takes a long time to change," he said. "Don't underestimate how conservative surgeons and medical oncologists are. The traditional approach was to give chemotherapy before surgery to shrink cancers, but in this particular setting of a postmenopausal woman with an estrogen-receptor-rich breast cancer, it's actually the endocrine therapy that provides the most protection against relapse and death from disease."

"It makes total sense that you'd want to use that therapy in the neoadjuvant setting," Dr. Ellis added.

Lisa Carey, MD, professor of medicine and director of the breast clinic at the University of North Carolina in Chapel Hill, agreed.

"There's sort of an old wives' tale that you don't get good responses out of neoadjuvant endocrine therapy, but in truth there have been a number of studies," explained Dr. Carey, who was approached by Medscape Medical News for an independent comment.

This study is just the most recent one, and "it demonstrated a 60% response rate with neoadjuvant endocrine therapy clinically. . . . That is what you need to convert a larger tumor to a smaller one, which sometimes results in breast-conservation improvement."

It can also result in less tissue having to be resected if a woman is already a lumpectomy candidate, she added. Another important take-home message from this study is that the neoadjuvant setting is a good predictor of what is going to happen in the adjuvant setting.

"The preoperative setting does give you a pretty good readout on what is going to happen adjuvantly. It just does it with a lot fewer patients and without having to wait 10 years," she said.

Dr. Ellis added that the study has yielded a "rich treasure trove of biologic information" that is being mined to help researchers understand the fundamental molecular basis for responsiveness to these drugs.

Weighing in with her opinion, Alissa Huston, MD, a breast cancer specialist from the University of Rochester Medical Center, New York, said: "The study further validates previous studies demonstrating a significant response to neoadjuvant hormonal blockade therapy in strongly estrogen-responsive breast cancers."

She added that the study provides more evidence for a treatment option that might help some women avoid the adverse effects of chemotherapy, and gives more information so that physicians can individualize or tailor treatments for patients with breast cancer by incorporating biomarkers to better identify patients who are more likely to have a significant response to therapy.

This study was supported by grants from the National Cancer Institute, the Breast Cancer Research Foundation, a Komen St. Louis Affiliate Clinical Trials Grant, Pfizer, and Novartis. Dr. Ellis reports financial relationships with Pfizer, Novartis, and AstraZeneca. Dr. Carey and Dr. Huston have disclosed no relevant financial relationships.

J Clin Oncol. Published online May 9, 2011. Abstract

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