key: cord-0944419-t84gbf5r
authors: Murphy, Brenna M.; Hoskin, Tanya L.; Degnim, Amy C.; Boughey, Judy C.; Hieken, Tina J.
title: Surgical Management of Axilla Following Neoadjuvant Endocrine Therapy
date: 2021-07-17
journal: Ann Surg Oncol
DOI: 10.1245/s10434-021-10385-4
sha: d7a7580bfc89cd004c582a852f02fd60350699ad
doc_id: 944419
cord_uid: t84gbf5r

BACKGROUND: Randomized clinical trials support deescalation of axillary surgery in breast cancer patients with low-volume axillary disease treated with a surgery-first approach. However, few data exist to guide axillary surgery following neoadjuvant endocrine therapy (NET). Therefore, we evaluated the extent and outcomes of axillary surgery in a contemporary cohort of NET patients, a treatment approach that has become particularly relevant during the coronavirus disease-19 (COVID-19) pandemic. PATIENTS AND METHODS: We identified invasive breast cancer patients treated with NET between October 2008 and November 2019. Patients presenting with stage IV disease or recurrent disease were excluded. Statistical analyses were performed using chi-square, Fisher’s exact, and Wilcoxon rank-sum tests. RESULTS: 194 invasive breast cancers in 186 patients (median age 66 years) were evaluated; 81 patients had breast-conserving surgery (BCS), while 113 underwent mastectomy. Eighty-four patients (43.3%) were biopsy-proven cN+ with 4/84 (4.8%) ypN0 following NET. Among cN+ patients, 14 (16.7%) had sentinel lymph node biopsy (SLNB) only, 27 (32.1%) had SLNB + axillary lymph node dissection (ALND), and 43 (51.2%) had ALND. Among 110 cN0 patients, 99 had axillary surgery with 28/99 (28.3%) ypN+: SLNB in 83 (75.5%), SLNB+ALND in 14 (12.7%), and ALND in 2 (1.8%). Among all ypN+ patients, 23/108 (21.3%) had SLNB alone: 18/43 (41.9%) of BCS and 5/65 (7.7%) mastectomy patients (p < 0.001). After median follow-up of 35 months, no regional recurrences were observed. CONCLUSIONS: Among biopsy-proven cN+ NET patients, we observed deescalation of axillary surgery in selected patients, despite a low nodal pathologic complete response (pCR) rate, without nodal recurrences. These data suggest that patients with low-volume axillary disease treated with NET may be managed similarly to patients treated with a surgery-first approach. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1245/s10434-021-10385-4.

patients treated with sentinel lymph node (SLN) surgery versus axillary lymph node dissection (ALND) with lowvolume disease in one or two SLNs and managed with breast-conserving surgery followed by whole-breast irradiation. 11, 12 Patients in the Z0011 trial were treated with a surgery-first approach, not neoadjuvant therapy, although the majority were prescribed adjuvant endocrine therapy. This approach is supported by similar data from other clinical trials that enrolled patients with early-stage ER? breast cancer and low axillary disease burden whose first course of treatment was operation. [13] [14] [15] In an effort to decrease long-term toxicities, especially for patients with favorable disease, there has been a concerted effort to deescalate axillary surgery over the past decade in the context of multidisciplinary care. 16 In parallel, efforts to base decisions for chemotherapy in breast cancer patients on biologic tumor features have led to a decrease in administration of cytotoxic chemotherapy for ER? breast cancer patients, including those with nodepositive disease. 17 Another approach has been to test the efficacy of endocrine therapy (versus chemotherapy) by administering endocrine therapy prior to surgery, NET. This has been pursued increasingly on and off clinical trials. 6, 9, 10 During the current COVID-19 pandemic, NET has been used as the initial approach to treat ER? breast cancer when surgical access is restricted due to resource reallocation. As healthcare institutions ramp up operations, surgical demand may again exceed capacity as both newly diagnosed patients and those whose surgery was canceled or deferred present for surgical treatment. In March and April 2020, multiple national organizations rapidly created guidelines to help manage this workflow. An overall consensus emerged suggesting that it was safe for patients with early ER? operable breast cancer to be treated with NET for 6-12 months prior to definitive operation. [18] [19] [20] Thus, in this past year, we are seeing a rapid uptick in the number of newly diagnosed ER? breast cancer patients treated with NET.

Prior studies of NET addressing surgical management have focused most on efficacy of this approach in downstaging disease in the breast to permit breast conservation; however, few data exist on axillary lymph node status and treatment following NET. For patients with low-volume axillary disease, in whom a surgery-first approach is employed, axillary dissection may be avoided if operation identifies two or fewer positive SLNs. Thus, it is important that initiating treatment with NET does not result in more extensive axillary surgery. The aim of this study is to evaluate the impact of NET on axillary surgical treatment, pathologic nodal stage, and cancer outcomes.

With institutional review board (IRB) approval, we identified all patients with ER? breast cancer treated with NET for a minimum of 30 days prior to surgery between October 2008 and November 2019 from our prospective breast surgery registry. Patients presenting with stage IV disease or recurrence, or treated with radiation or any axillary surgery prior to NET were excluded. All patients with invasive breast cancer undergo axillary ultrasound; if abnormal lymph nodes (LNs) are identified, percutaneous biopsy of the most abnormal node is performed. Data were verified by review of the electronic medical record and imaging studies. Data collected included patient characteristics and demographics, clinical and imaging data, duration and agents for NET, details of surgical treatment of the breast and axilla, pre-and posttreatment pathology, adjuvant therapies, and follow-up information regarding disease status, including any local, regional, or distant recurrence. Pathologic nodal positivity was defined as metastasis size [ 0.2 mm; patients with either ypN0 or ypN0i? disease were classified as node negative.

Descriptive statistics for the cohort overall and by clinical nodal (cN) status as reported as median (range) for continuous variables and frequency (percentage) for categorical variables. Comparisons between groups were performed using chi-square or Fisher's exact tests for nominal variables and Wilcoxon rank-sum tests for ordinal or continuous variables. Staging shift between clinical (pre-NET) and pathologic (post-NET) stage was compared using McNemar's test for paired proportions, and tumor size estimate from pre-NET imaging was compared with invasive tumor size at surgery using Wilcoxon signed-rank test. Recurrence-free survival (RFS) was defined as time from diagnosis to last follow-up or to an event of either disease recurrence or death. RFS was estimated using the Kaplan-Meier method and is reported with 95% confidence interval (CI), with comparisons between groups performed using log-rank tests. p values \ 0.05 were considered statistically significant. Analysis was performed using SAS (version 9.4, SAS Institute, Inc., Cary, NC).

We identified 194 breast cancers (8 bilateral) in 186 patients who were treated with NET followed by surgical resection. Median (range) patient age was 66 (29- Among 110 cN0 patients, 11 (10.0%) were ypNX (no axillary surgery), 71 (64.5%) were ypN0 at operation, and 28 (25.5%) were ypN?. All ypN0 patients underwent SLN only, while the 28 with positive nodes at surgery were treated with SLN surgery alone in 11 (39.3%), with SLN surgery and ALND in 15 (53.6%), and with ALND in 2 (7.1%). Among the 11 ypN? patients who had SLNB only, 10/11 (90.9%) had one or two positive SLNs (8 with one positive SLN, 2 with two positive SLNs) and 1/11 had three positive SLNs; 9/11 (81.8%) had no extranodal extension, 4/11 (36.4%) had ypN1mi disease, and none had more than two abnormal LNs identified on pretreatment axillary ultrasound.

Of the 84 cN? patients, 4 (4.8%) were ypN0 at operation while the remainder were node positive (Fig. 1a) . Among the ypN? patients, 12 (15.0%) were treated with SLN surgery alone, 27 (33.8%) with SLNB and ALND, and 41 (51.3%) with ALND. There were 12 cN? ypN? patients treated with SLN surgery alone. The majority (9/ 12, 75.0%) had one or two positive SLNs, with a minimum of two SLNs examined in all cases and more than two SLNs examined in 9/12 (75.0%). The four biopsy-proven cN? patients with nodal pCR received NET with aromatase inhibitors (anastrozole in two, letrozole in two) for a median of 222 days (individual durations of 151, 202, 241, and 268 days). Three had cN1 disease, whereas one patient had cN2 disease. On axillary ultrasound at presentation, one patient had one abnormal axillary node, two had two abnormal axillary nodes, and the remaining patient had more than two sonographically abnormal nodes. Three of the four patients had concomitant T category downstaging.

Among 108 ypN? patients (combining the cN0 and cN? cohorts), SLNB alone was performed more frequently for patients treated with BCS than mastectomy (41.9% versus 7.7%, p \ 0.001). Trends over time stratified by cN status and breast operation are illustrated in Fig. 1b . A significant change in use of SLNB alone was seen for cN0 BCS patients comparing the first half of the time period (2008-2013) with the latter half (2014-2020), with an increase from 72.7% (8/11) to 96.6% (28/29), respectively (p = 0.04).

Adjuvant radiation was administered to 69/81 (85.2%) of BCS patients and 59/113 (52.2%) of mastectomy patients. Endocrine therapy was continued in the adjuvant setting in 180/194 patients (92.8%), while 47/194 (24.2%) received adjuvant chemotherapy.

With median follow-up of 35 months, no regional nodal recurrences were observed across the entire patient cohort. Fourteen patients did have a breast cancer recurrence, including four patients with both local and distant recurrence, eight patients with distant recurrence only, and two patients with local recurrence only. A total of 23 patients died during follow-up, of whom 8 died due to breast cancer and 15 due to other causes. For the entire group, RFS was (Fig. 2a) . Assessed by axillary surgery type, the best RFS outcomes were for patients in the SLN surgery-only group, who had 5-year RFS of 91% (95% CI: 84-99%) (Fig. 2b) .

We report that, among breast cancer patients treated with NET, selective deescalation of axillary surgery can be done safely in a manner that parallels the current approach to patients with similar breast cancers who are treated first with surgery. Among clinically node-negative patients, although 25.5% were ypN? at operation, only 14.5% were treated with axillary dissection. Among 84 biopsy-proven cN? patients, NET resulted in nodal pCR in only 4 patients (4.8%), yet 14 (16.7%) were managed without axillary dissection. With this risk-adapted approach to treatment, using clinical judgment and extrapolating from studies addressing management of low-volume axillary disease in breast cancer patients with similar tumor biology whose first course of treatment was surgery, we observed no nodal recurrences after median follow-up of 35 months.

This report, which assesses pathologic response to NET in 84 patients with biopsy-proven nodal disease at presentation, is, to the best of our knowledge, the largest such series to date including postmenopausal women. One clinical trial (NCT01622361) randomized premenopausal women with ER? histologically proven node-positive breast cancer to neoadjuvant chemotherapy (NAC) versus NET. 21 Among 87 women treated with 24 weeks of NET consisting of ovarian function suppression with goserelin ? tamoxifen, nodal pCR was noted in 4 patients (4.9%), paralleling the findings of our study. Details of ypN stage and axillary operation were not provided in that publication. Three smaller series have reported on pathologic 23 After a minimum of 12 weeks (median 18 weeks) of NET, despite a clinical nodal response rate of 77%, only one patient (2.6%) had nodal pCR. The third study evaluating axillary response to NET evaluated 38 patients with biopsy-proven nodal disease at presentation from among 127 cancers treated with NET. 24 This study included patients treated on clinical trials testing enzalutamide and taselisib with preoperative endocrine therapy and reported nodal pCR in 4 of 38 cN? patients (10.5%). The median duration of NET was 6.4 months for the four patients with nodal pCR versus 3.7 months for the cN? patients without nodal pCR, but this difference did not reach statistical significance (p = 0.10). The sum of these findings is in line with our nodal pCR rate of 4.8% after a median duration of NET of 25 weeks. While most studies of NET have focused on downstaging the breast tumor to permit BCS or, more recently, to assess response to NET in an effort to determine whether chemotherapy might be avoided, some recent larger-scale reports also have examined the effect of NET on axillary nodal disease and treatment. However, these studies were based on clinical assessment of the regional nodes without cytologic or histologic confirmation of axillary disease. Axillary ultrasound and FNA or core-needle biopsy (CNB) of suspicious nodes is well established as the most accurate approach to axillary staging at presentation, while physical examination noting palpable ipsilateral axillary adenopathy has accuracy of approximately 60%. 15, 25 Weiss and colleagues evaluated axillary treatment in stage II and III patients treated with NET, neoadjuvant chemotherapy, or a surgery-first approach from the National Cancer Database (NCDB) during 2012-2015. 26 They reported nodal pCR in 76 of 571 cN? patients (13.1%) treated with NET. Unfortunately, the NCDB does not provide information on cytologic or histologic nodal staging prior to treatment, thus this study likely overestimates the frequency of axillary nodal pCR following NET. Similarly, Stafford et al. studied patients from the NCDB during 2010-2016 with ER?/HER2-breast cancers treated with NET for [ 30 days and reported a slightly higher axillary nodal pCR rate of 14.48% among 4580 patients staged as cN?. 27 They observed a higher likelihood of nodal pCR among patients with invasive ductal carcinoma, cN1 disease (75.9% of the study population), and grade II tumors. In that study, the duration of NET was unknown and patients with metastatic disease were included. Again, as the NCDB does not provide information on how clinical nodal status was determined, it is not surprising that nodal pCR rates from these two studies evaluating similar patient populations The change in use of SLNB alone for cN0 BCS patients from the first (2008-2013) to latter time period (2014-2020) was statistically significant: an increase from 72.7% (8/11) to 96.6% (28/29), respectively (p = 0.04) from the same observational database are higher than reported herein and the three NET studies discussed above in which clinical node positivity was determined by percutaneous biopsy at time of diagnosis. Further, we provide data on regional disease control, which is lacking from these two larger studies. A third study, also evaluating NCDB data, found no difference in overall survival in NET patients versus a matched upfront-surgery patient cohort stratified by ypN stage. 28 The authors suggested that those data supported a similar surgical approach to axillary operation for NET patients as for patients whose first course of treatment is operation.

In the current study, the breast pCR rate across all patients was 3.6%, but among the 87 cancers not suitable for BCS at presentation (44.8%), 19 (21.8%) were ultimately treated with BCS following NET. Similarly, while we found no difference in tumor size estimates at presentation (considering the largest linear diameter across both clinical and imaging examinations) versus pathologic tumor size at operation, we did see a shift from [ cT1 disease at presentation to ypT1 disease in 23% of patients. Prior studies of NET report widely varying conversion rates from unsuitable to suitable for BCS, ranging up to 80%. 5, 22, 24 This metric is determined by a number of variables, including study patient inclusion criteria such as T category at diagnosis, tumor location within the breast, presence of multifocal or multicentric disease, ratio of tumor to breast size, and the inherently subjective assessment of acceptable cosmesis. Duration of NET also influences breast tumor downstaging rates. This is illustrated in a study of NET with exemestane in which the BCS rate increased by * 10% when the duration of preoperative treatment increased from 3-6 months in responding patients, 29 and another testing letrozole, in which the median duration of treatment needed to downstage tumors sufficiently to permit BCS was 7.5 months. 30 A similar approach to extending therapy in responders might be explored as a future strategy for downstaging axillary nodal disease.

Historically, NET was reserved for patients unsuitable for surgical treatment of their hormone-receptorpositive breast cancer. More recently, greater attention has been focused on NET as a strategy to downstage the breast tumor to permit breast-conserving surgery and to define the optimal approach to systemic therapy, particularly in postmenopausal women. Clinical trials, as well as retrospective series, have demonstrated the safety of this approach as well as the utility of NET in facilitating breastconserving surgery in patients with larger tumors. 5, 22 Currently, trials such as Alliance A011106 ALTERNATE are expanding upon prior efforts to test a biomarker-driven strategy using NET to identify breast cancer patients unlikely to benefit from chemotherapy. 6, 9 While prior studies have shown low, albeit slowly increasing, uptake of NET for patients with ER? breast cancer, interest in this approach has been greatly accelerated by the COVID-19 pandemic and the rapid creation and adoption of guidelines for use of NET when surgery must be postponed. 4, 18, 27 Limitations of this study include its retrospective design without uniform selection criteria for NET, although patients were prospectively accrued. Additionally, longerterm follow-up will be important to further characterize oncologic outcomes given that ER? breast cancers generally recur later than other biologic subtypes. Strengths of this work include that patients were all triaged with axillary ultrasound with FNA of suspicious nodes, providing an accurate cN stage that is absent from most other studies evaluating NET, as well as the granular data we provide on imaging, pathology, and clinical course among this contemporary patient cohort. Anticipating a considerable uptick in the number of NET patients this year than previously because of the pandemic, our study shows the safety of this approach, as well as potential benefits in terms of improving suitability and feasibility of BCS and deescalating axillary surgery without the toxicities of chemotherapy in appropriately selected patients. We propose that, just as breast pCR is not required for deescalating breast surgery, axillary nodal pCR is not necessarily required to deescalate axillary surgery following NET in appropriately selected patients with ER? breast cancer. Data from the ACOSOG Z0011 and IBCSG 23-01 trials showing a low risk of locoregional recurrence suggest that these patients are adequately managed without axillary dissection or axillary-directed radiation therapy, whereas the AMAROS trial suggests axillary radiation can be substituted for axillary dissection for patients with one or two positive sentinel nodes. 11, 13, 14 Thus, we suggest that NET patients might be managed appropriately by adopting an approach similar to the one we currently take for patients with similar biology tumors treated with a surgery-first approach. For patients with one or two positive sentinel nodes at operation, whether staged as cN1 disease based on axillary ultrasound findings at diagnosis or not revealed until operation following NET, we propose a selective approach to completion axillary dissection based on multidisciplinary input and consideration of patient and tumor features. Future efforts that focus on refining patient selection for NET, augmenting the response to endocrine therapy, and further tailoring multidisciplinary treatment of ER? breast cancer patients are warranted both to improve oncologic outcomes and to minimize the morbidities of treatment.

DISCLOSURES None.

Clinicopathological characteristics and breast cancer-specific survival of patients with single hormone receptor-positive breast cancer

Feasibility of sentinel node biopsy for breast cancer after neoadjuvant endocrine therapy: a pilot study

Neoadjuvant hormonal therapy for endocrine sensitive breast cancer: a systematic review

Trends in neoadjuvant endocrine therapy use and impact on rates of breast conservation in hormone receptor-positive breast cancer: a National Cancer Data Base study

Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptorrich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype-ACOSOG Z1031

Abstract PD2-10: validation of a predictive model for potential response to neoadjuvant endocrine therapy (NET) in postmenopausal women with clinical stage II or III estrogen receptor positive (ER?) and HER2 negative (HER2-) breast cancer (BC): an ALTERNATE trial analysis (Alliance A011106)

Neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer

A Phase II Trial of Neoadjuvant MK-2206, an AKT inhibitor, with anastrozole in clinical stage II or III PIK3CA-mutant ER-positive and HER2-negative breast cancer

ALTERNATE: Neoadjuvant endocrine treatment (NET) approaches for clinical stage II or III estrogen receptor-positive HER2-negative breast cancer (ER? HER2-BC) in postmenopausal (PM) women: alliance A011106

Current status of neoadjuvant endocrine therapy in early stage breast cancer

Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis: the ACOSOG Z0011 (Alliance) randomized clinical trial

Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial

Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial

Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial

Preoperative axillary imaging with percutaneous lymph node biopsy is valuable in the contemporary management of patients with breast cancer. Surgery

Impact of radiation on locoregional control in women with node-positive breast cancer treated with neoadjuvant chemotherapy and axillary lymph node dissection: results from ACOSOG Z1071 clinical trial

Recent trends in chemotherapy use and oncologists' treatment recommendations for early-stage breast cancer

Management of cancer surgery cases during the COVID-19 pandemic: considerations

Resource for Management Options of Breast Cancer During COVID-19

ASBrS Resource Guide to Endocrine Therapy in the COVID-19 Pandemic

Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in premenopausal patients with oestrogen receptor-positive and HER2-negative, lymph node-positive breast cancer

Invasive lobular carcinoma: response to neoadjuvant letrozole therapy

Gauging the efficacy of neoadjuvant endocrine therapy in breast cancer patients with known axillary disease

How effective is neoadjuvant endocrine therapy (NET) in downstaging the axilla and achieving breast-conserving surgery?

The promise of axillary imaging in individualized surgical management of breast cancer patients: another step forward

Patterns of axillary management in stages 2 and 3 hormone receptor-positive breast cancer by initial treatment approach

Axillary response in patients undergoing neoadjuvant endocrine treatment for nodepositive breast cancer: systematic literature review and NCDB analysis

Prognostic significance of residual nodal disease after neoadjuvant endocrine therapy for hormone receptor-positive breast cancer

Efficacy of six month neoadjuvant endocrine therapy in postmenopausal, hormone receptor-positive breast cancer patients-a phase II trial

Optimum duration of neoadjuvant letrozole to permit breast conserving surgery

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