Response to preoperative endocrine therapy in breast cancer patients can alter surgical and chemotherapy options

Use of systemic chemotherapy before surgery has become an accepted approach in the management of breast cancer patients in the effort to improve the chance of achieving breast conservation or rendering an inoperable cancer operable. However, it took some time for many surgeons to embrace the idea of delaying surgical intervention.

Neoadjuvant chemotherapy

The National Surgical Adjuvant Breast and Bowel Protocol B-18 clinical trial compared outcomes in women receiving chemotherapy before surgery with those patients receiving adjuvant chemotherapy and demonstrated equivalent survival rates.1 This trial also showed a higher rate of breast preservation with neoadjuvant chemotherapy.

Since the results of these initial trials using the neoadjuvant approach were disseminated, the biologic underpinnings of breast cancer have become better understood. Previously, systemic chemotherapy decision making was largely based on tumor size and nodal status. The advent of molecular profiling has expanded and improved the definition of breast cancer to include biologic subtype in addition to the clinical stage at which the patient presents. When response to neoadjuvant chemotherapy is assessed by biologic subtype, the hormone receptor-positive tumors are less likely to achieve a pathologic complete response (pCR).2 Based on this finding and the responsiveness of hormone receptor positive tumors to endocrine therapy, the use of endocrine therapy in the neoadjuvant setting has evolved.

Initial neoadjuvant endocrine therapy trials

Initial studies using neoadjuvant endocrine therapy originated in Europe and the U.K. Two international randomized trials of neoadjuvant endocrine therapy demonstrated objective clinical response rates of 37 percent and 55 percent, with breast preservation rates of 44 percent to 45 percent, and showed that aromatase inhibitors were more effective than tamoxifen.3,4


In January 2006, the American College of Surgeons Oncology Group (ACOSOG) activated Z1031, a randomized phase II study designed to select the ideal agent for neoadjuvant endocrine therapy among three aromatase inhibitors (AI), with the ultimate goal of “picking the winner” to compare head-to-head in a subsequent trial with neoadjuvant chemotherapy. The trial opened in 2006 and accrual was completed in 2009. A total of 377 postmenopausal women with clinical stage II or III estrogen receptor (ER)-positive breast cancer were enrolled.

Patients were randomized to exemestane 25 mg, letrozole 2.5 mg, or anastrozole 1 mg daily for 16 to 18 weeks before surgery (cohort A). The surgical study aims included the following:

  • Rate of breast-conserving surgery at first attempt without re-excision for patients classified as potential candidates for breast conservation
  • Rate of breast-conserving surgery for patients classified as requiring mastectomy at baseline
  • Rate of successful mastectomy with primary skin closure and negative margins for patients classified as inoperable at baseline

A core needle biopsy of the tumor was performed after two to four weeks of therapy to evaluate changes in Ki67, a measure of the proliferation in the tumor. A fall in Ki67 has been shown to be predictive of better tumor response to endocrine therapy and improved long-term prognosis.5

In the second phase of Z1031 (cohort B), the needle biopsy was performed at four weeks and was used to determine therapy. If the Ki67 remained high at four weeks (greater than 10 percent, presumed endocrine resistant), the patient would discontinue endocrine therapy and switch to neoadjuvant chemotherapy or go directly to surgery. If the Ki67 was low (presumed endocrine sensitive) the patient would continue on endocrine therapy. This on-treatment biopsy result with a high Ki67 has been shown in other trials to portend resistance to endocrine therapy.

Clinical response rates with aromatase inhibitors in Z1031 were very high: 63 percent with exemestane, 69 percent with anastrozole, and 75 percent with letrozole. Disease progression was uncommon, seen in only 6 percent of patients.6 The overall breast conservation rate was 68 percent. Of the 163 patients initially deemed to require mastectomy or who were felt to be inoperable, surgical recommendations were changed in 56 percent after AI therapy. Among patients thought to require mastectomy before AI treatment, 51 percent were able to undergo breast-conserving operations. Of patients deemed marginal for breast-conserving surgery at presentation, 83 percent ultimately achieved breast preservation. Interestingly, on the final pathology of patients undergoing mastectomy, 24 percent had T1 tumors. This finding suggests that better tools are needed to assess response and measure the extent of residual disease following neoadjuvant endocrine therapy. Surgeons also may have underestimated the reduction in tumor size.

Of the 245 needle biopsies performed at the two to four-week intervals, 20 percent had Ki67 >10 percent, indicating endocrine therapy resistance.7 At the completion of neoadjuvant endocrine therapy and surgery, prognosis and endocrine sensitivity were further assessed using the preoperative endocrine prognostic index (PEPI) score, which reflects long-term outcomes and lack of benefit from adjuvant chemotherapy. The PEPI score is derived from four factors assigned a numerical score following neoadjuvant endocrine therapy, including Ki67 expression in the surgical specimen, pathologic tumor size, lymph node status, and estrogen receptor (ER) level (see Table 1). In the P024 and IMPACT [Immediate Preoperative Anastrazole, Tamoxifen, or Combined with Tamoxifen] neoadjuvant endocrine therapy trials, no relapses occurred at five years among patients with a PEPI score of 0.8 In the Z1031 trial, approximately 17 percent of patients achieved a PEPI score of 0.

Table 1. Preoperative endocrine prognostic index

biomarker status
Points related to
relapse-free survival
Points related to
breast cancer-specific survival
Pathologic tumor size



Node status



Ki67 level



ER status, Allred score



*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. 2008;100(19):1380-1388.

Surgeons’ role

Surgeons are often the first physicians to evaluate patients with newly diagnosed breast cancer and, therefore, are critically important in presenting and explaining the option of neoadjuvant treatment to patients. Neoadjuvant endocrine therapy can reduce the extent of breast surgery and provide information that may allow patients with low-risk ER-positive tumors that achieve a favorable PEPI score to avoid chemotherapy.

Despite the dramatic responses seen with neoadjuvant endocrine therapy in Z1031, the uptake of neoadjuvant endocrine therapy in the U.S. has been slow. The Z1031 study results were presented at the American Society of Clinical Oncology annual meeting in 2010 and were published in the Journal of Clinical Oncology in 2011. In subsequent years, use of neoadjuvant endocrine therapy in patients with stage II–III ER-positive breast cancer has slowly increased. However, the overall use of neoadjuvant endocrine therapy remains low, with 2.4 percent of cT2-4c ER-positive breast cancer patients age ≥50 being treated with neoadjuvant endocrine therapy.

Historically, it has been shown that it can take 17 years for the results of a clinical trial to impact clinical practice. Allowing our patients the benefit of recent advances in oncology is important to improve the clinical care of our patients. Tailoring both surgical and systemic treatment based on the response to endocrine therapy in patients with hormone receptor-positive breast cancer allows us to take another step forward in individualizing patient care.


  1. Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997;15(7):2483-2493.
  2. Colleoni M, Viale G, Zahrieh D, et al. Chemotherapy is more effective in patients with breast cancer not expressing steroid hormone receptors: A study of preoperative treatment. Clin Cancer Res. 2004;10(19):6622-6628.
  3. 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. 2001;12(11):1527-1532.
  4. Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: The Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol. 2005;23(22):5108-5116.
  5. Dowsett M, Smith IE, Ebbs SR, et al. Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst. 2007;99(2):167-170.
  6. 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. 2011;29(17):2342-2349.
  7. Ellis MJ, Suman V, McCall L, et al. Z1031B Neoadjuvant aromatase inhibitor trial: A phase 2 study of triage to chemotherapy based on 2 to 4 week Ki67 level > 10% [Abstract PD07-01:]. Cancer Res. 2012;72(24 supplement):PD07-01.
  8. 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. 2008;100(19):1380-1388.

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