Neoadjuvant Endocrine Therapy Vastly Underutilized by U.S. Clinicians

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Many of us are comfortable using neoadjuvant chemotherapy in our patients, but neoadjuvant endocrine therapy is often the treatment that offers the greatest benefit in patients with strongly hormone receptor–positive disease.

—Judy C. Boughey, MB, BChir
Neoadjuvant endocrine therapy is an exciting treatment since dramatic improvements in surgical outcomes can be achieved at low cost to the patient, and it also provides important prognostic information.

—Matthew Ellis, MD, PhD

Neoadjuvant endocrine therapy in the management of breast cancer is woefully underutilized by U.S. clinicians, according to advocates of this approach who made their case at the 2016 Miami Breast Cancer Conference.1 In postmenopausal women with estrogen receptor–rich tumors, neoadjuvant endocrine therapy is often a better choice than neoadjuvant chemotherapy, for a number of reasons, said Judy C. Boughey, MB, BChir, Professor and Research Chair in the Department of Surgery at the Mayo Clinic, Rochester.

“Many of us are comfortable using neoadjuvant chemotherapy in our patients, but neoadjuvant endocrine therapy is often the treatment that offers the greatest benefit in patients with strongly hormone receptor–positive disease. It has relatively low toxicity, can significantly downstage the extent of disease, and increase breast-conservation rates,” Dr. Boughey declared.

Dr. Boughey was joined by Matthew Ellis, MD, PhD, Director of the Lester and Sue Smith Breast Cancer and Professor of Medicine and Cellular and Molecular Biology at Baylor College of Medicine, Houston; Dr. Ellis discussed the Ki67 proliferation-based preoperative endocrine prognostic index and shared additional comments with The ASCO Post.

Received by Only 3.2% of Eligible Patients

Despite these observations, in the 2012 National Cancer Data Base, only 3.2% of patients with estrogen receptor–positive, large tumors had the benefit of this treatment approach, Dr. Boughey and her colleagues reported at the 2016 Society of Surgical Oncology Annual Cancer Symposium.2 They analyzed the treatment of 79,909 patients with breast cancer from 2004 to 2012; patients were at least 50 years old and had hormone receptor–positive tumors that were clinical stage T2–4.

Matthew Ellis, MD, PhD

Matthew Ellis, MD, PhD

Of this group of almost 80,000 women, only 2,038 (2.9%) underwent neoadjuvant endocrine therapy. The number increased over time, but only to 3.2% in 2012. The rate increased to 11% for T4 tumors. In all clinical stages, the use of neoadjuvant endocrine therapy improved the feasibility of breast-conserving surgery over primary surgery. One-fourth of patients with T3 and T4 tumors treated with neoadjuvant endocrine therapy were able to have breast-conserving surgery. This study was performed by the American College of Surgeons Clinical Research Program Education Committee, whose mission is to decrease the time from clinical trial resulting to incorporation in clinical practice.

Although neoadjuvant endocrine therapy is well accepted in Europe and the United Kingdom, it is rarely used in the United States. “We have a ways to move forward with this,” said Dr. Boughey.

Judy C. Boughey, MB, BChir

Judy C. Boughey, MB, BChir

Dr. Ellis attributes this practice to the old concept established 20 years ago when chemotherapy was offered to everybody with high-stage disease. “There is also a bias against academic investigations focused on inexpensive drugs that are not commercially promoted. Neoadjuvant endocrine therapy is nonetheness an exciting treatment since dramatic improvements in surgical outcomes can be achieved at low cost to the patient, and it also provides important prognostic information that can be potentially used to guide subsequent adjuvant treatment decisions,” Dr. Ellis said. 

“In the United States, we are routinely giving neoadjuvant chemotherapy, but based on our PEPI model, one-third of patients did not even need chemotherapy since endocrine therapy alone was sufficient to control their disease long term,” Dr. Ellis added. “For these patients, neoadjuvant endocrine therapy was unequivocally the best approach to avoid mastectomy.”

Another Perspective

Discussion moderator Patrick Borgen, MD, Chief of the Department of Surgery at Maimonides Medical Center, Brooklyn, New York, offered his perspective. “Those of us who trained in the 90s, when all women got chemo for 1-cm node-negative breast cancer, grew up with the core belief that chemo is our best treatment. We have learned that is not true. There is a subset that gets all its benefit from endocrine therapy.”

“Older patients with estrogen receptor–positive, HER2-negative T2 and T3 disease are still getting neoadjuvant chemotherapy, but our studies suggest at least one-third of these patients don’t actually need chemotherapy at all, adjuvant endocrine therapy is sufficient. In the United States we are still offering neoadjuvant chemotherapy or immediate surgery to older patients with stage II/III estrogen receptor–positive, HER2-negative disease. Long-term studies of neoadjuvant endocrine therapy suggests a third of these patients could avoid chemotherapy all together, and 50% of them could avoid mastectomy,” Dr. Ellis added. 

Supportive Data

The pivotal study that established the benefit of neoadjuvant endocrine therapy was the prospective phase II ACOSOG (American College of Surgeons Oncology Group) Z1031 trial, which compared letrozole, anastrozole, and exemestane in postmenopausal women with strongly estrogen receptor–positive (Allred score between 6 and 8), clinical stage II and III breast cancer.3 Candidates for breast-conserving surgery were not included, but those considered borderline were included.

Update on Neoadjuvant Endocrine Therapy

Neoadjuvant endocrine therapy is appropriate for many patients with breast cancer but is vastly underused. In the National Cancer Data Base, only 3.2% of eligible patients received this therapy. Neoadjuvant endocrine therapy effectively downstages tumors and enhances the feasibility of breast-conserving surgery. Patients can be assessed mid-way through endocrine treatment for Ki67 or preoperative endocrine prognostic index score to determine response and can be switched to chemotherapy if warranted.

After 16 to 18 weeks of treatment with one of the aromatase inhibitors, patients were reassessed for surgery. Initially, 163 patients were recommended for mastectomy; after neoadjuvant endocrine therapy, 79 patients required mastectomy. Only 49% of the patients originally thought to require mastectomy ultimately had to undergo one.

“So 51% of patients who were recommended for mastectomy when they presented were ultimately able to keep their breasts,” Dr. Boughey noted. “These are striking data, and I think we have not incorporated them enough into our practice.”

For the 189 patients considered borderline-eligible for breast-conserving surgery, 157 ultimately completed breast-conserving surgery, for an 83% breast-conservation surgery rate in this subset.

Response Indicators

A cohort in ACOSOG Z1031 was evaluated mid-way through neoadjuvant therapy for changes in Ki67, a measure of proliferation. A fall in Ki67 was predictive of favorable tumor response and improved prognosis; these patients were continued on endocrine therapy. Patients with high Ki67 (> 10%) were deemed endocrine-resistant and were switched to neoadjuvant chemotherapy or immediate surgery.

Ki67 is a component of the preoperative endocrine prognostic index, developed by Dr. Ellis and his team. The preoperative endocrine prognostic index score assesses the risk of relapse based on pathologic tumor size, lymph node status, Ki67 level, and estrogen receptor status after neoadjuvant treatment. A preoperative endocrine prognostic index score of 0 is the most favorable and is achieved when the tumor size is T1/2, nodes are negative, Ki67 is < 2.7%, and the Allred score is between 3 and 8. Preoperative endocrine prognostic index 0 is prognostic for excellent disease-free survival.4,5

Preoperative endocrine prognostic index score and Ki67 levels mid-treatment are more prognostic than baseline Ki67 and can be used to tailor treatment, for example, to determine the need for chemotherapy after surgery. “We can take advantage of this setting by identifying extreme endocrine responders for whom chemotherapy is not necessary,” Dr. Ellis told The ASCO Post. 

Future Studies May Boost Its Use

The randomized phase III ALTERNATE trial is comparing three neoadjuvant endocrine regimens—anastrozole, fulvestrant (Faslodex), and the combination of both agents—with 400 patients per arm. The objective is to compare their efficacy in achieving modified preoperative endocrine prognostic index score 0 (≤ 5 cm, node-negative, Ki67 ≤ 2.7%) and showing a 95% 5-year disease-free survival rate among patients achieving this score.

Tumors will be biopsied 4 weeks after patients start endocrine therapy. If Ki67 is < 10%, the tumor’s proliferation is considered “shut down,” and the patient remains on endocrine therapy for a total of 24 weeks before surgery. If the Ki67 level is higher, patients are transitioned to neoadjuvant chemotherapy or sent directly to ­surgery.

For patients completing neoadjuvant endocrine therapy, the modified preoperative endocrine prognostic index score is calculated at the time of surgery; those with a score of 0 will receive adjuvant endocrine therapy, whereas those with a score > 0 will be recommended for adjuvant chemotherapy, which can be followed by endocrine therapy.

Still Need to Convince Physicians

An attendee who remained unconvinced questioned Dr. Ellis: “In the absence of randomized trials, and when the most important criteria are to cure the patient, how do we know at the moment that neoadjuvant endocrine therapy first is better than neoadjuvant chemotherapy that will be followed by postsurgery endocrine therapy?”

Dr. Ellis responded: “It’s the same reason that we give neoadjuvant chemotherapy—to improve surgical outcomes. And you give patients a chance to show who is a true responder and who has resistant disease.”

“A number of large-scale comparative studies were initiated but accrued poorly because people thought they knew the answer,” he continued. “But there are a small number of randomized controlled trials in postmenopausal women with estrogen receptor–rich breast cancer showing that surgical outcomes are more impressive with neoadjuvant endocrine than chemotherapy. They are cross-study comparisons, but the data seem pretty clear.”

Dr. Ellis also recommended neoadjuvant endocrine therapy for patients expected to have a low pathologic complete response to chemotherapy—those with estrogen receptor–rich, HER2-negative, low- to intermediate-grade tumors. The option of giving chemotherapy is always on the table for those with high Ki67 levels, which is the value of monitoring, he added. ■

Disclosure: Dr. Boughey received grant/research support from Myriad Genetics. Dr. Ellis has been a consultant for Pfizer, Celgene, Novartis, and AstraZeneca as well as owns stock in Prosigna. Dr. Borgen is on the speakers bureau for Genomic Health and Genentech Technologies.


1. Boughey JC: Impact of neoadjuvant endocrine therapy on breast conservation candidacy. 2016 Miami Breast Cancer Conference. General Session. Presented March 11, 2016. (download brochure to view presentations)

2. Chiba A: Neoadjuvant endocrine use in the U.S. for hormone receptor positive breast cancer: Results from the National Cancer Data Base. 2016 Society of Surgical Oncology Annual Cancer Symposium. Abstract 19. Presented March 3, 2016.

3. Ellis MJ, Suman VJ, Hoog J, et al: Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: Clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype—ACOSOG Z1031. J Clin Oncol 29:2342-2349, 2011.

4. 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.

5. Olson JA Jr, Budd GT, Carey LA, et al: Improved surgical outcomes for breast cancer patients receiving neoadjuvant aromatase inhibitor therapy: Results from a multicenter phase II trial. J Am Coll Surg 208:906-914, 2009.