Expert Shows Promise of Neoadjuvant Endocrine Therapy in ER-Positive Breast Cancer

“Neoadjuvant endocrine therapy trials are feasible with relatively low toxicity,” Kelly K. Hunt, MD, FACS, FSSO, said during the 38th Annual Miami Breast Cancer Conference®.

Neoadjuvant endocrine therapy trials are feasible with relatively low toxicity for older women with estrogen receptor (ER)–positive breast cancer, according to a presentation at the 38th Annual Miami Breast Cancer Conference®.1

At the conference, Kelly K. Hunt, MD, FACS, FSSO, Department of Breast Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, discussed the role of neoadjuvant endocrine therapy in ER-positive breast cancer.

“So typically, the traditional approach for breast cancer management has been surgery first followed by chemotherapy; however, the neoadjuvant approach has been popularized in order to provide systemic therapy for a short period of time before surgery, where you can then assess response and perhaps improve local regional therapy treatments,” Kelly explained.

Neoadjuvant Therapy in Breast Cancer

In breast cancer treatment, neoadjuvant therapy has not shown any survival difference from adjuvant approaches; however, it does decrease the rate of mastectomies and the incidence of nodal metastasis, while improving pathologic complete responses (pCR) and long-term outcomes.

In hormone receptor (HR)–positive breast cancer specifically, improved outcomes from neoadjuvant chemotherapy is dependent on age. Therefore, neoadjuvant endocrine therapy has been used as an alternative to surgery for these older adults, in particular individuals aged 70 or older with comorbidities.

“There have been increased local failure rates, but similar survival outcomes in observational studies. It’s considered as the best option for patients with a very low life expectancy,” Hunt said, adding that they now know aromatase inhibitors (AIs) are more effective in postmenopausal patients.

Aromatase Inhibitors

In the ACOSOG Z1031 study (NCT00265759), researchers compared 3 AIs–exemestane (Aromasin), letrozole (Femara), and anastrozole (Arimidex)–for 16 weeks prior to surgery.2

“There were no large neoadjuvant endocrine therapy studies that had been conducted in the United States. We also didn’t really understand, at that time, what would be the appropriate end points to look at success,” Hunt explained.

In the trial, postmenopausal women with ER-positive disease, at a clinical stage of 2 or 3, were randomized to receive 1 of the 3 AIs for 16 weeks. They then had surgery and continued AI therapy and had radiation chemotherapy at the discretion of treating physicians.

In the intent-to-treat population, patients treated with exemestane, letrozole, and anastrozole demonstrated response rates of 62.9% (95% CI, 53.9%-71.4%), 74.8% (95% CI, 66.3%-82.1%), and 69.1% (95% CI, 60.1%-77.1%), respectively. While response rates were similar across all 3 arms, the investigators did find an increase in the number of women who could undergo breast-conserving surgery. For example, 83.1% of women who presented as a candidate for breast-conserving surgery (n = 189), 50.9% of women who presented as a candidate for mastectomy only (n = 159), and 75.0% of women who appeared to be inoperable by standard mastectomy (n = 4) were candidates for breast-conserving surgery after AI therapy.

When the investigators evaluated biomarkers in the cohort, like Ki67, once again all 3 AIs appeared equally as effective, leading them to question: “What about response to neoadjuvant therapy in terms of tailoring therapy? Does the lack of Ki67 suppression identify patients more suited for chemotherapy? And another question, is there an alternative to pCR in hormone receptor–positive breast cancer?” Hunt said.

Preoperative Endocrine Prognostic Index

The preoperative endocrine prognostic index (PEPI) predicts survival following neoadjuvant endocrine therapy using AIs, incorporating tumor size, node status, Ki67 level, and Allred scores.3

“This has been shown that if you achieve PEPI 0 status, that patients have improved recurrence-free survival and breast cancer–specific survival,” Hunt explained.

However, investigators have also found that Ki67 at 2 to 4 weeks identified patients who were less likely to have a PEPI score of 0. For example, Hunt noted, data from the POL and IMPACT trials showed that 2- to 4-week Ki67 correlated with surgical specimen that was obtained 3 to 4 months later. “The cutoff of about 10% appears to be a good cutoff. Twenty percent of patients will have a Ki67 of greater than 10% at 2 to 4 weeks.”

Also in the ACOSOG Z1031 study, investigators found that in the patients who achieved PEPI 0 status, there was improved recurrence-free survival in the overall population (P = .00268) and in those who did not receive chemotherapy (P = .0221).2

As a result, Hunt questioned: “How can we increase PEPI 0? Can we identify alternative endocrine therapies? Are there pathways that are responsible for endocrine therapy resistance? Or are there combination therapy strategies that we can use?

Tumor Volume

Hunt noted that one thing that is known is that tumor volume decreases with longer durations of therapy. Therefore, there is an increase in breast conservation rates with treatments lasting longer than 3 months. “So typically, we’ve used 3 to 4 months of neoadjuvant endocrine therapy and then patients are taken to surgery. But we know from several studies now that longer duration of therapy will increase breast conservation rates,” she said.

For example, in a 2013 study, investigators showed that pCR rates improved from 4 (2%) to 8 (8%) and 12 months (17%).4

Hunt also noted that physicians use genomic tools for patient selection as well, in particular immunohistochemistry for the approximated subtype. Oncotype Dx 21 and the Mammaprint/BluePrint assay have also proven effective in various studies.

“Neoadjuvant endocrine therapy trials are feasible with relatively low toxicity,” Hunt said. “We know that conversion from mastectomy to breast conservation can occur and for 50% of patients, this is a clinically meaningful end point and does underscore the value of NET for women who have these ER-rich tumors who desire breast conservation.”

“Ki67 at 2 to 4 weeks and PEPI score are measures of resistance to AI therapy and they can be used going forward,” she added. “And biomarker and somatic mutation–based stratification are necessary for rational trial design of combination therapies that may be important in the future.”


1. Hunt KK. Neoadjuvant Endocrine Therapy: Optimal Strategies and Impact on Surgical Outcomes. Presented at: 38th Annual Miami Breast Cancer Conference®; March 4-7, 2021; virtual.

2. Ellis MJ, Babiera G, 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. J Clin Onc. 2010;28(suppl 18):LBA513. doi:10.1200/jco.2010.28.18_suppl.lba513

3. 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. doi: 10.1093/jnci/djn309.

4. Allevi G, Strina C, Andreis D, et al. Increased pathological complete response rate after a long-term neoadjuvant letrozole treatment in postmenopausal oestrogen and/or progesterone receptor-positive breast cancer. Br J Cancer. 2013;108(8):1587-1592. doi:10.1038/bjc.2013.151