ALTERNATE Reveals Surgical Patterns After Neoadjuvant Breast Cancer Care

The administration of neoadjuvant endocrine therapy to postmenopausal women with clinical stage II/III estrogen receptor (ER)–positive, HER2-negative breast cancer permitted 43.8% to become eligible for breast-conserving surgery (BCS), according to findings from the phase 3 ALTERNATE trial (NCT01953588) at the 2025 San Antonio Breast Cancer Symposium (SABCS).¹

Findings from the ALTERNATE study provide further information on a clinical space with little available data, said lead investigator A. Marilyn Leitch, MD. Unlike neoadjuvant chemotherapy, which provides a high pathological complete response (pCR) rate, neoadjuvant endocrine therapy yielded a 1% pCR rate in findings from the Z1031 study (NCT00265759), requiring a unique management strategy in this setting.² Data from the ALTERNATE study presented at SABCS provided an overview of the types of procedures commonly selected by surgeons in these tough clinical scenarios, although long-term data on recurrence rates were not yet available.

"For surgeons in the ALTERNATE trial, neoadjuvant endocrine therapy created new challenges in the decision-making regarding the node management," Leitch, from the Harold C. Simmons Comprehensive Cancer Center, said during a presentation of the results. "Based on the procedures that were performed in patients with positive sentinel lymph nodes [SLNs], it appears surgeons were applying the Z0011 criteria for those patients having BCS but were less likely to omit axillary lymph node dissection for those undergoing mastectomy."

ALTERNATE Study Design and Patient Characteristics

In the study, 1473 M0 patients with cT2 to T4c tumors and any nodal status were randomly assigned to 3 arms, each examining a different neoadjuvant and adjuvant endocrine therapy. In arm 1, patients received anastrozole (Arimidex). In arm 2, patients received fulvestrant (Faslodex), and in arm 3, patients received a combination of both therapies. Neoadjuvant therapy was given for 24 weeks. Those with a Ki67 of more than 10% at week 4 or 12 of neoadjuvant care were switched to neoadjuvant chemotherapy.

After receiving neoadjuvant therapy, patients underwent surgical resection. Those with a modified Preoperative Endocrine Prognostic Index (mPEPI) of 0 went on to receive adjuvant therapy for 1.5 to 4.5 years with the same agent received in the neoadjuvant setting. Those with an mPEPI of other than 0 received adjuvant chemotherapy followed by endocrine therapy of physician's choice. After these factors, there were 933 patients available for the analysis who received strictly endocrine therapy.

Of the 933 patients, most were between ages 60 and 69.9 (43.3%), with 27% being over the age of 70. The most common clinical stage was T2 (73.6%), followed by T3 (22.6%) and T4 (3.8%). Most patients had stage N0 disease (60.9%), with 36.2% having N1 and 2.9% having N2 or N3. The most common histology was ductal (64.8%) and the most common histologic grade was 2 (60.5%). Nine and a half percent of patients had PR-negative and ER-positive status, and 90.5% were positive for both markers. Lymph node biopsies were positive for 33.2% of patients, indeterminate for 0.9%, negative for 7.0%, and not performed for 58.9%.

Surgeons assessed patients and provided their surgical plans before neoadjuvant therapy was administered. Of the 933 patients, 74.0% were identified as candidates for BCS, and 25.1% were not considered as candidates for BCS. There were 6 patients (0.6%) who were deemed inoperable.

Surgical Procedure Data

The actual procedures that were performed included BCS for 69.7% of patients and a mastectomy for 30.3%. For those deemed candidates for BCS before neoadjuvant therapy (n = 690), 78.7% underwent this type of surgery (n = 543) whereas 21.3% received a mastectomy (n = 147). For those considered candidates for mastectomy prior to neoadjuvant therapy (n = 234), 43.6% went on to receive BCS (n = 102), and 56.4% received mastectomy (n = 132).

Axilla surgery of the SLN was completed for 64.7% of patients, 20.0% received both SLN and axillary lymph node dissection (ALND), 14.4% received ALND alone, and 0.9% had no axilla surgery. When SLN was selected, 1 (16.6%), 2 (20.6%), 3 (17.0%), and 4 or more (29.5%) nodes were identified, with 1% having no nodes identified. For ALND, 1 to 5 (3.4%), 6 to 10 (7.8%), 11 to 20 (14.6%), and 21 or more (8.5%) nodes were identified.

There were differences in the management of positive nodes associated with the type of surgical procedure, Leitch noted (P = .0002). For those undergoing BCS, 61.8% underwent SLN alone compared with 40.4% for those in the mastectomy group. SLN plus ALND was completed for 59.6% of those in the mastectomy group compared with 38.2% in the BCS group.

For those in the BCS group, if pre-neoadjuvant therapy needle biopsy was negative or not performed (n = 136), 70.6% received SLN alone, with 6.6% and 22.8% of these patients receiving ALND alone and SLN plus ALND, respectively. For those in the BCS group with a positive biopsy (n = 196), nodal procedures were evenly balanced. In the mastectomy group, if pretreatment biopsy was positive (n = 113), only 17.7% received SLN alone, with the remainder receiving ALND (43.4%) or SLN plus ALND (38.9%). If nodes were negative in this group (n = 91), procedures included SLN alone (42.9%), SLN plus ALND (47.2%), and ALND alone (9.9%).

"The knowledge that the patient was node positive from needle biopsy pretreatment influenced the management of the nodal basin at the time of definitive surgery," said Leitch. "Axillary dissection was much less likely to be performed for a positive sentinel node if the patient was clinically node negative prior to neoadjuvant therapy. This was particularly true in patients who had BCS."

Positive SLN biopsies were detected for 382 patients, with the remainder having 0 positive nodes (n = 408). Of the full population receiving SLN biopsy (n = 790), 1 positive node was present for 24.3%, 2 for 14.3%, and 3 or more for 9.7%. When 1 node was positive, ALND was omitted for 60.9% of patients; when 2 were positive, it was omitted for 48.7%; and when 3 or more were present, ALND was omitted for 49.4% of patients.

"Axillary dissection was more likely to be omitted when there was only 1 positive sentinel node compared with 2 or more, yet still those patients with even more nodes did have omission of axillary dissection," said Leitch.

Outcomes were further examined for those with a positive SLN biopsy who went on to receive ALND. For those with 1 node, no others were seen in more than half of cases (57.3%); however, in 21.3% of cases, 3 or more additional nodes were found. For those with 2 positive nodes, ALND found 3 or more additional nodes for 51.7% of patients, and for those with 3 or more at SLN biopsy, ALND uncovered 3 or more additional positive nodes for 48.7% of patients.

"Long-term follow-up is required to assess local-regional recurrence for those who only had SLNB after having node-positive disease at diagnosis," she concluded.

References

1. Leitch AM, Dockter T, Suman VJ, et al. Surgical outcomes in the ALTERNATE trial (Alliance A011106) -a randomized phase 3 neoadjuvant endocrine therapy (NET) trial in postmenopausal women with clinical stage II/III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC). Presented at: 2025 San Antonio Breast Cancer Conference; December 9-12, 2025; San Antonio, TX. Abstract RF1-02.
2. Hunt KK, Suman VJ, Wingate HF, et al. Local-regional recurrence after neoadjuvant endocrine therapy: data from ACOSOG Z1031 (Alliance), a randomized phase 2 neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-positive clinical stage 2 or 3 breast cancer. Ann Surg Oncol. 2023;30(4):2111-2118. doi:10.1245/s10434-022-12972-5