Neoadjuvant chemotherapy combined with endocrine therapy for hormone receptor-positive breast cancer: A systematic review and meta-analysis.

The role of hormone therapy as a neoadjuvant to radical prostate radiotherapy.

Background: Small prospective studies show comparable response rates (RR) and breast conservation rates (BCR) among neoadjuvant endocrine therapy (NET) and neoadjuvant chemotherapy (NCT) in post-menopausal hormone receptor (HR) positive breast cancer patients. Recently we reported statistically significant differences in utilization, trends, RR, BCR and overall survival (OS) outcomes in HR positive post-menopausal women from NCDB (2004-2014) at ASCO 2017 meeting. The absolute difference in OS calculated at 5 yrs for NCT vs NET was 10.9%. However, we were not able to exclude human epidermal growth factor receptor (HER-2) positive group due to the unavailability of information. Therefore, our results might have been skewed. Thus, here we report RR, BCR and OS outcomes in post-menopausal women with HR positive, HER-2 negative breast cancer using NCDB from 2010-2014 during which HER-2 status was recorded. Methods: We extracted data on HR positive, HER-2 negative breast cancer patients aged ≥ 50 without metastasisfrom the NCDB registry (2010-2014). RR and BCR between NET and NCT was assessed using univariate and multivariate analysis. OS was calculated using Kaplan Meier analysis with hazard ratio (HR) from cox regression model. We excluded patients who did not receive adjuvant endocrine therapy after NCT and patients who received adjuvant chemotherapy after NET as this could affect OS. Results: Out of 25,609 breast cancer patients reported in NCDB from 2010-2014, 19,988 women met our inclusion criteria. 5759 received NET and 14,229 received NCT. On multivariate analysis NET use was higher in academic centers [Odds ratio (OR) 1.327, 95% CI 1.222-1.440], patients with age>70 (OR 6.213, 95% CI 5.615-6.875)]. NET use was lower in black race (OR 0.774, 95% CI 0.679- 0.882), tumors with higher grade (OR 0.160, 95% CI 0.141-0.181), higher T stage (OR 0.352, 95% CI 0.314-0.395), higher N stage (OR 0.209, 95% CI 0.177-0.246) and private insurance (OR 0.65, 95% CI 0.525- 0.806), (all p<0.0001). RR was significantly higher for patients receiving NCT (88.7%) compared to NET (77.1%), with an adjusted OR (aOR) of 2.058, however the mastectomy rate was higher in NCT (68.9%) compared to NET group (48.9%) with aOR of 1.755. OS was calculated in 15,268 women. OS rate was 98.0% vs 98.9% at 1 yr for NET vs NCT and 73.6% vs 76.9% at 5 yrs for NET and NCT respectively with adjusted hazard ratio (HR) of 1.216; 95% CI (1.072-1.380). Conclusions : Our analysis demonstrates higher response rate with NCT over NET even in HER-2 negative HR positive breast cancer. However, more patients underwent mastectomy in the NCT group despite high RR. Statistically significant improvement in OS was also seen with the use of NCT however the magnitude was less pronounced compared to our previous cohort which included HER-2 positive as well as negative patients. Limitations that should be considered in this registry based study are: differences in surgical technique, patient's choice, duration and choices of adjuvant therapy. Citation Format: Basnet A, Wang D, Sivapiragasam A. Neoadjuvant chemotherapy vs neoadjuvant endocrine therapy in ER/PR positive HER-2 negative post-menopausal women with breast cancer, is one superior than other? A NCDB analysis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-15-08.

Background: Early biologic response to endocrine therapy, such as changes in Ki67 labeling index (LI), has been suggested to predict long-term outcomes in hormone sensitive breast cancer. The addition of a CDK4/6 inhibitor to endocrine therapy has been shown to augment biological response in breast cancer. Pre-operative Endocrine Prognostic Index (PEPI) scores, generated based on post-treatment Ki67 LI, have been shown to predict patient outcomes. EndoPredict® is a multigene assay that predicts the risk of distant recurrence in patients with operable estrogen receptor (ER)-positive HER2-negative breast cancer. This study was conducted to evaluate the efficacy of the neoadjuvant endocrine therapy plus palbociclib versus neoadjuvant endocrine therapy plus placebo. Patients and Methods: This is a phase III randomized, double-blind study of neoadjuvant hormonal therapy plus palbociclib versus neoadjuvant hormonal therapy plus placebo in untreated pre/peri- and post-menopausal women with operable, hormone receptor-positive (ER and/or progesterone receptor), HER2-negative breast cancer. The other major inclusion criteria included tumor size ≥ 15mm, T1c-3N0-1, Ki67 LI ≥14% by central assessment, and no previous history of radiotherapy or systemic therapy for breast cancer. Patients were randomly assigned 1:1 to receive 16 weeks of hormonal therapy plus palbociclib or hormonal therapy plus placebo. Hormonal therapy consisted of letrozole for post-menopausal patients and tamoxifen plus LH-RH agonist for pre/peri-menopausal patients. The co-primary endpoints included PEPI score and EPclin Risk Score, a score combining EndoPredict® molecular score with clinical factors. These scores were sequentially analyzed on a modified intent-to-treat basis according to the gatekeeping procedure: if statistical significance was detected on the PEPI score, the statistical significance of EPclin Risk Score would be assessed. The sample size was 100 patients in each arm, which was calculated with < 5% type I error rate (two sided) and 80% power. Results: Between 16 July 2019 – 7 July 2021, 141 eligible patients were randomized from 25 participating institutes in Japan, Korea, Taiwan, Hong Kong and Australia. One hundred twenty-six patients completed the treatment duration and surgical samples were collected to evaluate endpoints. All randomized patients were evaluable for safety assessment. Randomization was well-balanced in terms of age, menopausal status and cancer stage. The proportion of patients who had a low, moderate, or high PEPI score was 15.2%, 50.0% and 34.8% in the hormonal therapy plus palbociclib arm and 13.3%, 55.0% and 31.7% in the hormonal therapy plus placebo arm, respectively. There was no statistically significant difference in PEPI score between two arms (one-sided p-value=0.563). The proportion of patients who had a high risk EPclin Risk Score seemed lower in the palbociclib arm than in the placebo arm (62.1% vs 68.3%) although hypothesis testing was not performed on EPclin Risk Score because statistical significance was not detected on the PEPI score. No new safety signals were found in the study. Permanent discontinuation from the study in association with adverse events was reported for 7 (9.7%) patients in the hormonal therapy plus palbociclib arm and for 0 patients in the hormonal therapy plus placebo arm. Conclusions: The addition of palbociclib to neoadjuvant hormonal therapy did not improve efficacy measured by PEPI score. In palbociclib arm, the rate of patients who had a high risk EPclin Risk Score after treatment was lower than in placebo arm. Translational researches are ongoing to analyze molecular changes by treatments. The role of chemotherapy after neoadjuvant therapy is under investigation. Clinical trial identification: NCT03969121 Funding: Pfizer Inc. Citation Format: Takayuki Ueno, Louis W.C. Chow, Wonshik Han, Chiun Sheng Huang, G Bruce Mann, Satoshi Morita, Hironori Haga, Elham Fakhrejahani, Takayuki Kobayashi, Kenichi Inoue, Mariko Tokiwa, Hirofumi Suwa, Tomoyuki Aruga, Sachiko Minamiguchi, Yosuke Yamada, Yuko Tanabe, Masahiro Takada, Toshinari Yamashita, Hiroji Iwata, Chi-Feng Chung, Sachiko Takahara, Eriko Tokunaga, Shigeru Imoto, Eun Sook Lee, Yasuaki Sagara, Jee Hyun Kim, Richard H DeBoer, Hyun-Ah Kim, Hung Wen Lai, Ming-Feng Hou, Michelle White, Yoshiko Umeyama. Neoadjuvant hormonal therapy plus palbociclib versus hormonal therapy plus placebo in women with operable, hormone sensitive and HER2-negative primary breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-09-01.

CDK4/6 inhibitors as neoadjuvant treatment in breast cancer—what can we learn?

Background:Adjuvant endocrine therapy remains the standard of care for patients (pts) with early stage, HR+ BC who can safely omit chemotherapy based on RS results; however, the role of NET remains unclear. There are limited data regarding the optimal duration of treatment with NET and the ideal patient (pt) population for NET in terms of age and RS result. This question rose to critical importance amidst the COVID-19 pandemic, during which NET was utilized more broadly in attempts to delay surgery or chemotherapy while preserving optimal pt outcomes. This study re-examines the use of NET among a cohort of pts with HR+ BC randomized to NET or neoadjuvant chemotherapy (NCT) based on RS (performed on initial core biopsy specimens).Methods:Data were pooled from two independent studies performed at Emory’s Winship Cancer Institute and Massey Cancer Center at Virginia Commonwealth University (VCU) from 2010-2012. These studies evaluated rates of clinical and pathologic complete response (pCR) among pts with early stage, HR+ BC assigned to treatment groups based on RS results. Pts with RS 0-10 received NET (Group (Grp) A), RS 11-24/25 (Emory 11-24 vs VCU 11-25) were randomized to NET (Grp B) or NCT (Grp C), and those with RS 25/26-100 received NCT (Grp D). Associations between RS result, neoadjuvant therapy and pCR in the breast, lymph nodes (LN) and breast plus LN were evaluated using Fisher’s exact test. Results:109 pts were included in this analysis. The Emory cohort was younger (median age 56 years (yrs) vs 63 yrs in VCU cohort) and more diverse (37.5% African American (AA) vs 18.6% AA in VCU cohort). The pts were predominantly post-menopausal (69.6% Emory vs 83.1% VCU). Nodal status among the Emory cohort was evenly divided with 50% N0 and 50% N+, while the majority of VCU pts were N0 (76.3% N0 vs 22.0% N+). Pts were grouped based on RS result: RS <11 (18% Emory vs 20.3% VCU), RS 11-24/25 (36% Emory vs 55.9% VCU) and RS 24/25 or higher (46% Emory vs 23.7% VCU). Pts with low RS result were older (median 64 yrs vs 59 yrs among RS > 24/25) with higher percentage of low-grade tumors (47.6% grade 1 vs 5.4% grade 1 among RS >24/25). With regard to pCR, there were no significant differences among pts with low or intermediate RS results, as no pts in these groups achieved pCR in the breast or breast + LN (Table). Pts with RS result 25/26-100 (Grp D) were the only pts shown to achieve pCR in breast + LN (18.9%, p= 0.0043 across groups). Notably, while pts on the Emory study received longer courses of NET (median 10 months vs 5.5 months), there were no significant differences in pCR across RS result subgroups noted between the two institutions. Conclusion:Our results demonstrate that the use of Oncotype DX Breast Recurrence Score® or other genomic assays in the neoadjuvant setting may help guide treatment decisions when considering the use of NET versus NCT. Pt age and length of endocrine therapy as well as pt preferences should be considered when determining neoadjuvant treatment plans. There are currently ongoing studies evaluating the use of NET with CDK4/6 inhibitors that will offer further insight into optimal neoadjuvant treatment strategies in HR+ BC. Subsequent phase III evaluation of the role of genomic assays in the neoadjuvant setting is feasible and may help determine whether NET + CDK 4/6 inhibitors could replace NCT for pts with higher RS values. Table: pCR according to treatment groups (All Eligible Patients)VariableGroup A (N=21)Group B (N=23)Group C (N=22)Group D (N=37)P value (a)pCR Breast0 (0.0%)0 (0.0%)0 (0.0%)8 (21.6%)0.0016pCR Nodes0 (0.0%)1 (4.3%)3 (13.6%)2 (5.6%)0.2977pCR Breast + Nodes0 (0.0%)0 (0.0%)0 (0.0%)7 (18.9%)0.0043(a) Fisher's exact test was used for categorical variables with cell counts <5.Note: Group A= Recurrence Score <11,Group B= Recurrence Score 11-24 (Emory study) or 11-25 (VCUstudy) receiving NET,Group C= Recurrence Score 11-24 (Emory study) or 11-25 (VCUstudy) receiving NCT,and Group D= Recurrence Score >24 (Emory study) or >25 (VCUstudy).Note: 1 patient did not receive SLNB(sentinel lymph node biopsy) or ALND (axillary lymph node dissection) and is excluded from the denominator for pCR Nodes. Citation Format: Caitlin Taylor, Aimee Foreman, Christy Russell, Dipankar Bandyopdhyay, Xiaoyan Deng, Lisa Floyd, Amelia Zelnak, Ruth O'Regan, Harry Bear, Jane Meisel. Using Oncotype DX Breast Recurrence Score® (RS) assay to define the role of neoadjuvant endocrine therapy (NET) in early-stage hormone receptor positive (HR+) breast cancer (BC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-15-02.

581 Background: While neoadjuvant chemotherapy (NACT) has been established as the standard of care for medically fit patients, there has been renewed interest in utilizing neoadjuvant endocrine therapy (NET) for the treatment of women with estrogen-receptor (ER) positive, HER-2 negative breast cancer. Rates of pCR are known to be low in this population, but there is inconsistent data regarding downstaging and long-term outcomes in a non-trial setting with NET vs NACT. Methods: A prospective institutional databaseof breast cancer patients treated with neoadjuvant therapy at the British Columbia Cancer Agency from 2012-2016 was analyzed to identify all medically fit patients with ER positive, HER2 negative breast cancer. Patients were then divided into two groups: those who received NET or NACT. Baseline characteristics were compared between groups. A matched analysis (age, stage and grade) was then performed to compare rates of downstaging, pCR and scores from a validated neoadjuvant therapy outcomes calculator (CPS+EG). Results: A total of 154 patients met eligibility criteria for this study. One hundred and six patients (69%) received NACT and 48 (31%) received NET. Women offered NACT were significantly younger (51 vs 64y, p < 0.001) than those offered endocrine therapy and presented with a higher clinical stage (LR 27.93, p = 0.002). According to multiple linear regression for downstaging, clinical stage followed by NACT were the most important predictors of downstaging. When matched for age, stage and grade, downstaging was significantly higher with NACT (31/48, 65%) as compared to NET (12/48, 25%), p < 0.001. Of these, 12.5% achieved pCR with NACT as compared to 2.1% with NET, LR 4.243, p = 0.039. No significant differences in CPS+EG scores were identified when comparing NACT to NET. Conclusions: Significantly higher rates of downstaging were achieved with NACT as compared to NET when patients were matched for age, stage and grade. Rates of pCR remain low for ER-positive breast cancer patients. Although not validated with the use of NET, CPS+EG scores predicting long-term outcomes were not significantly different with NET compared to NACT.

Background: In early ER+ breast cancer, neo-adjuvant (NA) endocrine therapy (ET) may identify a subset of patients with endocrine sensitive disease with excellent outcomes without chemotherapy. In patients receiving a NA aromatase inhibitor, on- therapy, short term (day 14) Ki-67 of <10% and post NA pre-operative endocrine prognostic index (PEPI) 0 at surgery are associated with low relapse rates without chemotherapy. Ribociclib, a novel CDK4/6 inhibitor is active in ER+ metastatic breast cancer. We hypothesize that ribociclib+letrozole as NA ET for stage II-III breast cancer will increase the number of women with a PEPI 0 at surgery. Trial Design: Randomized, placebo-controlled, multi-center, phase II, investigator initiated trial of NA letrozole +/- ribociclib in postmenopausal women with ER+, HER2-, breast cancer. Subjects will be randomized 1:1:1 to letrozole 2.5 mg daily + placebo, letrozole 2.5mg daily + ribociclib 600mg daily on D1-21 of a 28 day cycle (intermittent dosing), or letrozole 2.5mg daily + ribociclib 400mg daily (continuous dosing). Treatment will be continued for 6 months followed by surgery. Research core biopsies and blood will be collected at baseline, at day 14, and at surgery. A Ki67 >10% at day 14 will result in discontinuation of the subject from the protocol as this may be an early indicator of resistance to endocrine therapy. An MRI will be done after 2 months of therapy to assess response/progression. Primary endpoint is a PEPI score of 0 at surgery. Key Eligibility Criteria: Postmenopausal (natural or surgical) women with stage II/III ER+, HER2- breast cancer. Must have a palpable breast mass of at least 2 cm. Multicentric/contralateral invasive disease not allowed. Ipsilateral/contralateral DCIS is allowed. Inflammatory breast cancer is excluded. Specific Aims: Primary objective: To determine if ribociclib+letrozole as a 24 week NA ET increases rate of PEPI score of 0 at surgery compared to letrozole. Secondary objectives: To determine if ribociclib+letrozole as a 24 week NA ET increases the proportion of tumors with complete cell cycle arrest compared to letrozole; to determine if ribociclib in combination with letrozole for 24 weeks results in improved 5 year RFS compared to letrozole; to examine differences in response rates between the two ribociclib containing arms vs letrozole. Statistical Methods: The two ribocilib containing arms (n=80) will be combined for analysis against placebo + letrozole (n=40). Assuming that addition of ribociclib will increase the rate of PEPI 0 by 20%, and setting Type I error rate at 10% and Type II error rates at 20% in the final analysis, a sample size of 80 women in the treatment arms (40 in each arm) and 40 women in the control arm are needed to show significance. Patient accrual and target accrual: Participating sites include The Univ of Kansas Med Ctr, City of Hope National Med Ctr, Massachusetts General Hospital, University of Miami Sylvester Comprehensive Cancer Ctr, University of Arkansas for Medical Sciences, and University of Wisconsin. The trial has accrued 16 patients with a target accrual of 120 patients. Accrual should be complete in 2/2017. Contact information: Qamar Khan, MD (qkhan@kumc.edu). Citation Format: Khan QJ, Prochaska LH, Mohammad J, Yuan Y, O'Dea A, Bardia A, Wisinski K, Hard M, Baccaray S, Makhoul I, Wagner J, Laura S, Ma C, Sharma P. Femara plus ribociclib or placebo as neo-adjuvant endocrine therapy for women with ER+, HER2-negative early breast cancer - The Feline trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-02-06.

183PD - Neoadjuvant endocrine therapy with palbociclib in patients with high-risk breast cancer

Neoadjuvant therapy in breast cancer has evolved from a modality able to facilitate surgery into a sophisticated treatment approach, where patterns of response influence the extent of surgery (i.e. breast and axilla) and inform treatment decisions in the adjuvant setting. This is particularly true for patients diagnosed with HER2-positive or triple-negative breast cancer (TNBC). In the subset of estrogen receptor-positive (ER+) disease, the neoadjuvant treatment model has proven to be a successful clinical research tool. Studies investigating pharmacodynamic markers (i.e., Ki67) demonstrated the differences in the relative effectiveness of tamoxifen versus aromatase inhibitor and, more recently, neoadjuvant studies with endocrine therapy plus CDK4/6 inhibitors demonstrated the efficacy of CDK4/6 inhibitors in potentiating the effects of endocrine therapy through a profound suppression of Ki67. However, in clinical practice neoadjuvant endocrine therapy remains underutilized. Routinely, ER+ candidates for neoadjuvant therapy are treated with chemotherapy with minimal attention to disease biology. By contrast, disease biology plays a major role in the adjuvant setting, and the “old notion” of disease burden predicting chemotherapy benefit is fading away. The disconnect between the choices of systemic therapy in the neoadjuvant versus adjuvant setting in ER+ breast cancer has multiple roots: 1) Physicians and patients may expect higher response rates to neoadjuvant chemotherapy; 2) genomic biomarkers to guide chemotherapy treatment decisions were developed using material from surgical specimens; 3) there are limited data with neoadjuvant endocrine therapy in premenopausal women; and 4) the objectives with neoadjuvant endocrine therapy are not always clear. While additional clinical studies are warranted, the available clinical data suggest neoadjuvant endocrine therapy is an appropriate treatment approach for patients with ER+ disease. When selecting patients by ER+ status only, response rates to neoadjuvant endocrine therapy are similar or higher than chemotherapy. Clinical studies have successfully used diagnostic biopsies for genomic profiling, and if anything, the quality of FFPE material should be superior due to pre-analytical variables (e.g., reduced ischemic time). Additionally, neoadjuvant endocrine therapy for ER+ breast cancer and favorable disease biology fulfills the promise of a tailored treatment approach and avoids unnecessary use of cytotoxic therapy. When selecting neoadjuvant endocrine therapy for patients, it is important to understand some key points regarding this treatment approach. The maximum treatment response is not expected before four to six months of therapy, and the interpretation of pathologic response should not be confounded by data from HER2+ and TNBC. Residual disease after neoadjuvant endocrine therapy is not a predictor of survival outcomes. And, lastly, if the patient was not deemed as an ideal candidate for neoadjuvant chemotherapy at baseline, the extent of residual disease should not be used a predictor of chemotherapy benefit. There are, however, caveats and extensive disease at the time of surgery (e.g., four or more positive nodes) might justify a course of adjuvant chemotherapy. In summary, neoadjuvant endocrine therapy should not be a treatment of exception for elderly patients when trying to avoid the toxicities of chemotherapy. Neoadjuvant endocrine therapy is an effective treatment modality with proven clinical utility for postmenopausal patients with ER+ breast cancer. Citation Format: O Metzger. Neoadjuvant therapy for hormone receptor-positive breast cancer: challenges and advances [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES5-1.

Background: Although neoadjuvant endocrine therapy has been used to improve breast conservation rate, its prognostic relevance is unknown. The search for a valid prognostic factor equivalent to pCR in neoadjuvant chemotherapy is a current challenge in neoadjuvant endocrine therapy. In this study, we investigated the efficacy of short term neoadjuvant endocrine therapy utilizing the waiting period for surgery and the prognostic factor including Preoperative Endocrine Prognostic Index (PEPI) score. Patients and Methods: A total of 269 postmenopausal women with hormone receptor-positive, HER2-negative breast cancer was treated with endocrine therapy with non-steroidal aromatase inhibitor during the waiting period for surgery between October 2012 and November 2021. Of the entire 269 patients, 92 and 177 patients had anastrozole and letrozole, respectively. The primary endpoint was change in tumor size by ultrasound and Ki67 before and after short-term endocrine therapy. The secondary endpoint was prognosis of patients divided by PEPI score which was calculated using tumor size, lymph node metastasis, Ki67, and ER Allred score. This study was approved by the institutional review board of Teikyo University. Results: Median age was 68 years old (range, 41-89). ER and PgR was positive in 266 (98%) and 232 (86%) of the entire 269 patients, respectively. Median tumor size was 1.65 cm (range, 0.4-7.5). Seventeen (6.3%) pts were clinically node-positive. Patients with histological grade I tumor were 190 (70.6%). The median duration of endocrine therapy was 39 days (range, 2-88). Average pretreatment Ki67 expression was 10% (range, 0-90). Tumor diameter was significantly decreased to 1.43cm (range,0.45-5.83) after short-term endocrine therapy (p=0.01). The Ki67 expression was significantly decreased to 3.0% (range, 0-85) after endocrine therapy (p< 0.01) and only five patients (1.9%) showed marked increase in Ki-67 expression. PEPI score 0, 1-3 and ≥ 4 was found in 83 (30.9%),147 (54.7%) and 39 patients (14.5%), respectively. After the median observation period of 928 days, patients with PEPI score ≥ 4 showed worse disease-free survival (Figure) compared with patients with PEPI score 0 and 1-3 (p=0.06). In terms of mortality, patients with PEPI score ≥ 4 had worse overall survival than patients with PEPI score 0 and 1-3 (p=0.07). Conclusions: These results suggested that neoadjuvant endocrine therapy during the waiting period for surgery might be effective in reducing the size and Ki67 expression level and PEPI score might be useful in predicting the prognosis of postmenopausal hormone receptor positive breast cancer patients. Citation Format: Yuka Maeda, Saki Naruse, Yuka Isono, Ayana Sato, Miki Yamada, Akiko Matsumoto, Tatsuhiko Ikeda, Hiromitsu Jinno. The efficacy of neoadjuvant endocrine therapy during the waiting period for surgery in postmenopausal hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-03-19.

Background: Endocrine therapy provides significant improvement in the long-term outcomes of patients with hormone receptor-positive (HR+) breast cancer (BC). However, metastatic recurrences of endocrine resistant disease develop in about 20-25% of patients and remain a major cause of BC mortality. Up-regulation of the HER2 growth factor receptor represents a common escape strategy used by cancer cells to survive and continue to proliferate in an ER-independent manner. Neoadjuvant endocrine therapy (NET) offers a unique opportunity to identify responsiveness of HR+ BCs and detect tumors that display up-regulation of HER2, an early endocrine resistance mechanism. Methods: A single arm, interventional, exploratory clinical trial evaluating four weeks of NET in early stage HR+/HER2-negative BC patients was conducted at our institution (NCT03219476). The primary objective was to assess changes in HER protein expression (HER1-4) from diagnostic core biopsies to surgically resected tumors treated with NET. Secondary objectives included assessment of other molecular markers, tumor proliferation and volumetric responses. Optimized protocols for immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were used to assess HER2 status in the pre- and post-treatment tumor specimens. Chi-square and t-tests were performed. Linear regression multivariate analysis was performed to evaluate association of covariates with the primary outcome with 80% power at a significance level of 0.05. Here we present the changes in HER2 protein expression with NET in this study. Up-regulation was defined as an increase of ≥ 1 in IHC scores (ordinal 0,1,2,3) or gene amplification by FISH. Results: Thirty-seven patients with cT1-T3, cN0 HR+/HER2-negative BC were enrolled. Median age at diagnosis was 64 yrs (42-81) and median BMI was 28.3 (19.3-55.1). Most patients were post-menopausal (83.8%). Median tumor size clinically was 1.3 cm (0.5-7.7). Most tumors were low (42.1%) or intermediate (47.4%) grade and invasive ductal histology was seen in 70%. Median tumor size at surgery was 1.2 cm (0.09-4). One patient had a complete pathologic response (pCR) at surgery. Seven patients had pN1 disease at surgery (six with 1 lymph node involved, one with pN1mi). There was no significant change in ER-positivity between pre and post-treatment specimens. However, a trend towards decrease in PR-positivity was seen in post-treatment tumors consistent with functional ER pathway disruption (p=0.08). On HER2 protein assessment by IHC, most patients had IHC 0 (37.8%) or IHC 1+ (54%) at diagnosis. Significant up-regulation in HER2 protein was seen in 46% (17/37) of patients (p=0.0004), whereas down-regulation was detected in only 5% (2/37) and no change in the remaining 49% (18/37). Three patients converted to HER2-positive status (IHC 3+ or FISH amplified) at surgery and received adjuvant trastuzumab-based treatment. No significant associations were identified between any clinicopathologic covariates and change in HER2 protein expression. Conclusions: HER2 was up regulated in 46% of tumors after short-term NET in patients diagnosed with early stage HR+/HER2-negative BC. Short-term NET is a promising strategy to identify HR+ tumors that up-regulate HER2 as an early escape pathway and endocrine resistance mechanism. Patients with such HER2 up-regulated tumors after NET may benefit from HER2-directed therapies upon disease recurrence or as adjuvant combination therapy. These findings need to be further explored in larger randomized clinical trials. Citation Format: Lubna N Chaudhary, Julie M Jorns, Yee Chung Cheng, Sailaja Kamaraju, Mary Beth Gonyo, Amanda Kong, Caitlin Patten, Tina Yen, Chandler Cortina, Ebony Carson, Nedra Johnson, Carmen Bergom, Anjishnu Banerjee, Yu Wang, Christopher R Chitambar, Hallgeir Rui. Neoadjuvant endocrine therapy helps identify HER2 up-regulation in patients with hormone receptor-positive HER2-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD7-07.

Introduction: Neoadjuvant endocrine therapy (NET) is often used in HR+, HER2-negative primary BC to decrease tumor extent prior to surgery. In neoadjuvant chemotherapy treatment of HER2-positive and triple negative BC, the residual cancer burden (RCB) is prognostic and utilized for treatment decisions of adjuvant therapy. However, in HR+, HER2-negative BC, RCB is not a surrogate for sensitivity to NET and long term outcomes. Moreover, despite the approval of a CDK4/6 inhibitor for high risk early-stage HR+ BC, there are currently no biomarkers predictive of sensitivity to this class of drug in this setting. This study aimed to investigate the potential utility of baseline ctDNA and dynamic changes during NET as a biomarker to help guide systemic treatment decisions. Methods: The phase II PELOPS trial (NCT02764541) enrolled pts with clinical stage I-III HR+, HER2-negative BC and randomized to NET plus palbociclib or NET alone for 24 weeks prior to surgery; plasma samples were collected at baseline (BL) and prior to surgery (PS). Cell-free DNA was analyzed using Guardant Reveal powered by Infinity, a tissue-free, epigenomic assay that utilizes comprehensive methylome and DNA sequencing data for ctDNA detection. Categorical group comparison was performed using Fisher’s exact test, and Mann-Whitney test were used to evaluate ctDNA dynamics. Results: A total of 104 plasma samples from 54 pts were analyzed with successful sequencing achieved in 95.0% (95/100) of samples. At BL and PS, the detection rates were 20/50 (40%) and 6/45 (13.3%), respectively. Overall, ctDNA was detected in 27.4% (26/95) of samples. Higher tumor fraction at BL (measured as methylation score) was associated with pathological stage at surgery (median 0.049% for stage III disease vs. 0% for stage I/II, p = 0.0006) and higher RCB scores following NET (median 0.049% for RCBIII vs. 0% for RCBI-II, p = 0.049). Using binary detection methods, BL ctDNA was detected in 0% (0/3) pts with RCBI, whereas BL ctDNA was detected in 20.8% (5/24) of pts with RCBII, and 61.1% (11/18) of pts with RCBIII (RCBI-II vs. RCBIII p = 0.005). Comparison of ctDNA between matched BL and PS samples showed that most pts (63.4%, 26/41) with undetectable ctDNA at BL remained with undetectable ctDNA post NET (PS). Six (14.6%, 6/41) pts, all with lobular BC and RCBIII, had persistent ctDNA at both timepoints. Within this subset of pts, 67% (4/6) developed metastatic disease recurrence within 5 years of surgery. Interestignly, there were no pts (0%, 0/41) that became ctDNA positive at PS, and 22% (9/41) pts experienced ctDNA clearance from BL to PS. Somatic variants were identified in 27% (7/26) of ctDNA detected samples. There were alterations in five oncogenes at BL (PIK3CA, MAP3K1, TERT, RHOA, AKT1), and two alterations were acquired after NET (ATM, ESR1 D538G). Conclusions: Ultra-sensitive tissue-free ctDNA testing can detect ctDNA in a substantial proportion of pts with primary HR+ BC. The presence of ctDNA at BL in this population was associated with larger pathologic tumor size and higher RCB scores following NET. Furthermore, persistence of ctDNA after NET was associated with high rates of recurrence. This study is the first investigation into the dynamics of ctDNA during NET using the Guardant Infinity platform, and our findings suggest that ctDNA has the potential to provide valuable insights into tumor burden, sensitivity to ET, and the emergence of endocrine resistance mutations. These results are limited by the sample size but warrant further investigation of the role of ctDNA as a tool to predict sensitivity to ET and long term outcomes. Such a tool could be valuable in tailoring treatment approaches, particularly given the ongoing development of novel ETs and the addition of CDK4/6i in the adjuvant setting. Citation Format: Albert Grinshpun, Derek Dustin, Mingyang Cai, Melissa Hughes, Molly DiLullo, McKenna Moore, Erica L Mayer, Eric P Winer, Nancy U Lin, Sara M Tolaney, Otto Metzger, Rinath Jeselsohn. Ultra-sensitive detection of circulating tumor DNA (ctDNA) in patients (pts) undergoing neoadjuvant endocrine therapy for hormone receptor-positive (HR+) early breast cancer (BC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS9-08.

Session Title: Multidisciplinary approaches to optimize surgical therapy in hormone receptor positive breast cancer Talk Title: Surgical considerations after preoperative therapy in hormone receptor positive breast cancer Abstract: Preoperative therapy increases rates of breast conservation and decreases the need for axillary lymph node dissection (ALND) in select patients. In hormone receptor positive (HR+) HER2 negative breast cancer patients the choice between neoadjuvant chemotherapy (NAC) and neoadjuvant endocrine therapy (NET) to achieve breast conservation can be challenging and the low rates of axillary pCR with either approach have been associated with higher rates of ALND. For HR+ HER2- patients receiving NAC, available literature supports performing sentinel lymph node biopsy (SLNB) after receipt of therapy with the decision to perform axillary lymph node dissection dictated by the status of the sentinel lymph nodes. For patients receiving NET, there is little data to guide surgical management of the axilla. In a recent review of the NCDB, we assessed axillary management by initial treatment strategy (NET, NAC, or upfront surgery) among a large population of Stage II-III HR+ HER2- breast cancer patients and found that SLNB use after NET in both clinically node negative and clinically node positive patients was similar to SLNB use with upfront surgery. However, among those with pN1 disease, patients who received NET were less likely to undergo ALND. While failure to achieve a nodal pCR after NAC is associated with inferior DFS and OS outcomes; whether or not the same is true after NET remains uncertain. Further, the impact of residual nodal disease after NET on LRR remains an area of ongoing investigation. Understanding the differences in and implications of residual nodal disease after neoadjuvant therapy (NAC vs NET) in HR+ HER2- breast cancer provides the opportunity to develop subtype specific strategies for optimal surgical management of the axilla. Citation Format: TA King. Surgical considerations after preoperative therapy for hormone receptor positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES5-3.

BackgroundNational medical/surgical organizations have recommended the use of neoadjuvant endocrine therapy (NET) to bridge surgery delay of weeks to months for patients with hormone receptor positive (HR+) breast cancer during the ongoing coronavirus disease 2019 (COVID-19) pandemic. The effects of NET of varying durations on pathologic response are unclear. Using the National Cancer Database (NCDB), we evaluated objective response to short (< 9 weeks), moderate (9–27 weeks), and long (> 27 weeks) duration of NET.Patients and MethodsThe study cohort included female patients diagnosed with nonmetastatic invasive HR+ breast cancer, stratifying by those who received NET versus no NET between 2004 and 2016. Pathologic response was grouped into four categories (complete, downstaged, stable, upstaged) by comparing clinical and pathologic staging data. Objective response to NET included complete, downstaged, and stable pathologic response. Clinical characteristics were compared using χ2 and analysis of variance (ANOVA) tests. Multivariable logistic regression was used to determine factors associated with NET use and objective response according to NET duration.ResultsA minority (1.2%) received NET in our cohort. Factors associated with NET use included older age, non-Black patients, more advanced clinical stage, higher comorbidity score, government insurance, and lobular histology. Objective response rate (ORR) was 56.7%, 52.1%, and 49.0% after short, moderate, and long NET duration, respectively.ConclusionShort NET duration did not result in an inferior ORR. Future study to evaluate the interaction between surgery delay and NET use on clinical outcome will provide insights into the safety of NET to bridge potential surgery delay in patients with HR+ breast cancer.Supplementary InformationThe online version contains supplementary material available at 10.1245/s10434-021-10287-5.

Neoadjuvant chemotherapy (NAC) is the standard treatment for locally advanced breast cancer. NAC is also recognized as the initial treatment of choice for patients who are candidates for adjuvant chemotherapy. A pathologic complete response (pCR) is a predictor of outcome associated with improved disease-free and overall survival. The identification of accurate predictors of a pCR to NAC is important to spare patients unnecessary toxicity. Hormone receptors, histologic grade, HER2, and ki-67 labeling index were evaluated as predictors of a pCR. An early response to NAC might be correlated with a high probability of a pCR. Jinno et al. reviewed indications for and predictors of NAC. The histological effects differ among the subtypes of breast cancer when the same NAC regimen is administered. In clinical studies of patients with HER2positive breast cancer, NAC with trastuzumab resulted in high pCR rates. The induction of personalized medicine and new molecular targeted therapies are expected to result in higher pCR rates in NAC. Dr Kinoshita summarized the current consensus on the adoption and benefits of NAC, especially for operable breast cancer patients. Hormone receptor (HR)-positive, HER2-negative breast cancer is regarded as a subtype with a good prognosis and which is sensitive to hormone therapy. Endocrine therapy may be sufficient for some HR-positive, HER2-negative breast cancer patients. Neoadjuvant endocrine therapy (NAE) is a new treatment option for such patients. Takei et al. reviewed NAE for premenopausal breast cancer patients using a luteinizing hormone-releasing hormone (LH-RH) analogue plus tamoxifen and for postmenopausal breast cancer patients using tamoxifen or aromatase inhibitors. The prognosis of HR-positive breast cancer patients receiving NAE has not been evaluated thoroughly. No comparative study of pre and postoperative endocrine therapy is available. Dr Iwata has introduced a new clinical study, N-SAS BC06, which is a randomized phase III trial conducted in Japan. Postmenopausal women with ER-positive, HER2-negative T1c-T2 N0 M0 breast cancer were classified into complete response (CR), partial response (PR), or stable disease (SD) groups and the progressive disease (PD) group, and patients in the CR, PR, or SD groups were randomized to a chemotherapy followed by endocrine therapy group or to an endocrine therapy group. The primary endpoint is disease-free survival. Immunohistochemical (IHC) biomarkers such as ER, PgR, and HER2 are very important predictors of the sensitivity to endocrine therapy or chemotherapy. Recently, there has been a focus on IHC evaluation of Ki-67 as a predictor of breast cancer outcome. Kumaki et al. reviewed our present understanding of the IHC evaluation of biomarkers for breast cancer under NAC.