Neoadjuvant Hormonal Therapy Research Articles

Transcriptomic signature defines two subtypes of locally advanced PCa with distinct neoadjuvant therapy benefits.

Patients with locally advanced prostate cancer (LAPCa) received docetaxel-based neoadjuvant chemo-hormonal therapy (NCHT) had better clinical outcomes after surgery compared to neoadjuvant hormonal therapy (NHT) groups, but not all patients experienced favorable clinical outcomes with NCHT, raising the necessity for potential biomarker assessment. The transcriptomic profiling offers a unique opportunity to interrogate the accurate response to NCHT and NHT treatment and to identify the predictive biomarkers for neoadjuvant therapy. The whole transcriptomic profiling was performed on baseline biopsies and surgical tissue specimens from 64 patients with LAPCa at Renji Hospital between 2014 and 2018. Biochemical progression-free survival (bPFS)-based gene-by-treatment interaction effects were used to identify predictive biomarkers for guiding treatment selection. Comparing the transcriptome profiling of pre- and post-treatment LAPCa specimens, NHT and NCHT shared 1917 up- and 670 down-regulated DEGs at least 2-fold. Pathway enrichment analysis showed up-regulated pathways in response to NHT and NCHT were both enriched in cytokine receptor interaction pathways, and down-regulated pathways in response to NCHT were enriched in cell cycle pathways. By comprehensive transcriptome profiling of 64 baseline specimens, ten predictive markers were identified. We integrated them into the signature to evaluate the relative benefits of neoadjuvant therapy, which categorizes patients into two subgroups with relative bPFS benefits from either NHCT or NHT. In the high-score (≥ -95.798) group (n = 37), NCHT treatment led to significantly longer bPFS (P< 0.0001), with a clear and early separation of the Kaplan-Meier curves. In the low-score (< -95.798) group (n = 27), NHT also led to significantly longer bPFS (P=0.0025). In this study, we proposed the first predictive transcriptomic signature might potentially guide the effective selection of neoadjuvant therapy in LAPCa and might provide precise guidance toward future personalized adjuvant therapy. The study was approved by the Ethics Committee of Renji Hospital affiliated to Shanghai Jiao Tong University (Ky2019-087).

64P Baseline characteristics associated with Ki67 drop after neoadjuvant endocrine therapy in patients with HR+/HER2- early breast cancer: A systematic review

64P Baseline characteristics associated with Ki67 drop after neoadjuvant endocrine therapy in patients with HR+/HER2- early breast cancer: A systematic review

132P Neoadjuvant zanidatamab for stage I node-negative HER2- positive breast cancer (BC)

Outcome of patients (pts) w/ stage I node neg HER2+ treated w/ wkly paclitaxel x 12 doses and trastuzumab x 1yr is excellent (10yr RFS 96%). Therefore, trials to de-escalate chemo and use targeted therapy alone are underway. Zanidatamab is a novel, humanized, bispecific, immunoglobulin G isotype 1-like, monoclonal antibody directed against the juxtamembrane extracellular domain (ECD4) and the dimerization domain (ECD2) of HER2. This results in HER2 clustering that modulates signaling and leads to immune activation. Zanidatamab demonstrated antitumor activity in heavily pre-treated HER2+ metastatic BC with acceptable safety profile. We hypothesized that zanidatamab would be a safe and effective regimen for women w/ node neg stage I HER2+ BC. Pts w/ 1-3cm, clinically node neg HER2+ BC were enrolled in this investigator-initiated clinical trial. Pts had HER2+ BC: HER2 3+ by IHC or IHC 2+ and ISH +. Pts received 2-wkly zani x6 prior to surgery. Pts with ER+ tumors also received neoadjuvant endocrine therapy: postmenopausal pts received letrozole 2.5mg daily, and premenopausal pts received tamoxifen 20mg daily or GNRH and letrozole 2.5mg on treating physician preference. The primary objective was to evaluate efficacy as determined by pathologic complete response (pCR). Secondary objectives included pathologic response by residual cancer burden (RCB), radiological response, and safety profile of zanidatamab. Eleven pts w/ HER2+ BC were enrolled. Median age was 61yrs old (range 30-72). Median tumor size was 2.2cm (range 1-3cm). Four pts were pre-menopausal. Six pts had tumors >2cm tumors. Three received tamoxifen and 3 letrozole. All pts completed 6 cycles of zanidatamab and had Sx. Four (36%) had pCR, 3 RCB1 (28%) and 4 RCB2 (36%). This met the success criterion of Simon’s design (>=3/17 pts with pCR) of targeting a 25% pCR rate against a 5% null rate. Treatment was tolerated well. There were no grade 3 or 4 toxicities. One pt had minor infusion-related reaction and grade 2 acne, and 1 grade 2 diarrhea. Neoadjuvant zanidatamab for 3 months showed significant efficacy, (pCR/RCB-1 64%) w/ acceptable safety profile in pts w/ stage I node neg HER2+ BC. The trial is ongoing and has been modified to increase treatment duration to 5mths (10 cycles).

141P Concurrent neoadjuvant endocrine therapy with chemotherapy in HR+HER2- breast cancer: A systematic review and meta-analysis

141P Concurrent neoadjuvant endocrine therapy with chemotherapy in HR+HER2- breast cancer: A systematic review and meta-analysis

An increase in tumor-infiltrating lymphocytes after treatment is significantly associated with a poor response to neoadjuvant endocrine therapy for estrogen receptor-positive/HER2-negative breast cancers

BackgroundThe reason for the poor prognosis of estrogen receptor (ER) + /human epidermal growth factor receptor 2 (HER2)− breast cancer patients with high levels of tumor-infiltrating lymphocytes (TILs) is poorly understood. The association between TILs and response to neoadjuvant endocrine therapy (NET) was examined.MethodsWe recruited 170 patients with ER + /HER2− breast cancer who were treated with preoperative endocrine monotherapy. TILs were evaluated before and after NET, and their changes were noted. Furthermore, T cell subtypes were examined using CD8 and FOXP3 immunohistochemical analyses. Neutrophil and lymphocyte counts in the peripheral blood were analyzed with reference to TIL levels or changes. Responders were defined as Ki67 expression levels ≤ 2.7% after treatment.ResultsPost-treatment (p = 0.016), but not pre-treatment (p = 0.464), TIL levels were significantly associated with the response to NET. TIL levels increased significantly after treatment among non-responders (p = 0.001). FOXP3 + T cell counts increased significantly after treatment in patients with increased TILs (p = 0.035), but not in those without increased TILs (p = 0.281). Neutrophil counts decreased significantly after treatment in patients without increased TILs (p = 0.026), but not in patients with increased TILs (p = 0.312).ConclusionAn increase in TILs after NET was significantly associated with a poor response to NET. Given that FOXP3 + T-cell counts increased, and neutrophil counts did not decrease in patients with increased TILs after NET, the induction of an immunosuppressive microenvironment was speculated to play a role in the inferior efficacy. These data might partially indicate the involvement of the immune response in the efficacy of endocrine therapy.

The impact of PIK3CA mutations and PTEN expression on the effect of neoadjuvant therapy for postmenopausal luminal breast cancer patients

BackgroundThere is pressing needs to find the biomarker in the selection of neoadjuvant therapy in postmenopausal luminal breast cancer patients. We examined the hypothesis that PIK3CA mutations and low phosphatase and tensin homolog (PTEN) expression affect the response to neoadjuvant therapy and prognosis in postmenopausal luminal breast cancer patients.MethodsPostmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, up to stage II, who underwent neoadjuvant chemotherapy (NAC; n = 60) or neoadjuvant endocrine therapy (NAE; n = 55) were selected. PIK3CA exon 9 and exon 20 mutations were screened by high resolution melting analysis and confirmed by Sanger sequence. PTEN expression was evaluated by immunohistochemistry. The relationships among PIK3CA mutations, PTEN expression, clinicopathological features, the pathological effect of neoadjuvant therapy, recurrence-free survival (RFS) and overall survival were analyzed.ResultsAmong 115 patients, PIK3CA mutations and low PTEN expression before treatment were detected in 35 patients (30.4%) and in 28 patients (24.3%), respectively. In the NAC group, tumor with PIK3CA mutations showed significantly poorer response than tumor with PIK3CA wild-type (p = 0.03). On the other hand, in the NAE group, there was no significant difference in pathological therapeutic effect between tumor with PIK3CA mutations and tumor with PIK3CA wild-type (p = 0.54). In the NAC group, the log-rank test showed no difference in RFS between patients with PIK3CA mutations and PIK3CA wild-type (p = 0.43), but patients with low PTEN expression showed significantly worse RFS compared to patients with high PTEN expression (5 year RFS 0.64 vs. 0.87, p = 0.01). In the Cox proportional hazards model for RFS, PTEN expression, progesterone receptor, and pathological therapeutic effect were predictive factors for time to recurrence (All p < 0.05).ConclusionsPIK3CA mutations are associated with resistance to NAC but do not affect the response to NAE. Low PTEN expression does not affect response to either NAC or NAE but correlates with shorter RFS in patients who received NAC. These biomarkers will be further evaluated for clinical use to treat postmenopausal luminal breast cancer patients.

Completeness of recording of neoadjuvant chemotherapy and endocrine therapy on the pathology form

Completeness of recording of neoadjuvant chemotherapy and endocrine therapy on the pathology form

Effect of Neoadjuvant Hormonal Therapy on the Postoperative Course for Patients Undergoing Robot-Assisted Radical Prostatectomy.

Neoadjuvant hormonal therapy (NHT) preceding robot-assisted radical prostatectomy (RARP) may be beneficial in high-risk cases to facilitate surgical resection. Yet, its improvement in local tumor control is not obvious. Its benefit regarding overall cancer survival is also not evident, and it may worsen sexual and hormonal functions. This study explores the effect of NHT on the perioperative course after RARP. In this study, 500 patients from a tertiary referral center who underwent RARP by a specialized surgeon were retrospectively included. Patients were divided into two groups: the NHT (n = 55, 11%) group, which included patients who received NHT (median: 1 month prior to RARP), and the standard non-NHT (NNHT) group (n = 445, 89%). Demographic and perioperative data were analyzed. Postoperative results, complications, and readmission rates were compared between the groups. NHT patients were heterogeneous from the rest regarding cancer parameters such as PSA (25 vs. 7.8 ng/mL) and tumor risk stratification, and they were more comorbid (p = 0.006 for the ASA score). They also received fewer nerve-sparing procedures (14.5% vs. 80.4%), while the operation time was similar. Positive surgical margins (PSM) (21.8% vs. 5.4%) and positive lymph nodes (PLN) (56.4% vs. 12.7%) were significantly higher in the NHT group compared to the non-NHT (NNHT) group. Hospital stay was equal, whereas catheter days were 3 days longer in the NHT group. NHT patients also suffered more minor vesicourethral-anastomosis-related complications. Major complications (p = 0.825) and readmissions (p = 0.070) did not differ between groups. Patients receiving NHT before RARP did not experience more major complications or readmissions within 90 days after surgery. Patients with unfavorable, high-risk tumors may benefit from NHT since it facilitates surgical resection. Randomized controlled trials are necessary to measure the advantages and disadvantages of NHT.

Management of the axilla in postmenopausal patients with cN0 hormone receptor-positive/HER2-negative breast cancer treated with neoadjuvant endocrine therapy and its prognostic impact.

To evaluate the differences in nodal positivity if the sentinel lymph node biopsy (SLNB) is performed before or after neoadjuvant endocrine therapy (NET) in breast cancer patients, and its impact on prognosis. A retrospective cohort study was performed in a single center including 91 postmenopausal cases with clinically node-negative and hormone receptor-positive/HER2-negative (HR + /HER2-) breast cancer, treated with NET and SLNB. SLNB was done pre-NET until 2014, and post-NET thereafter. Axillary lymph node dissection (ALND) was indicated only in SLNB macrometastasis, although in selected elderly patients, it was omitted. Kaplan-Meier survival curves were estimated in relation to the status of the axilla, and the differences assessed using the log-rank test. Between December 2006 and March 2022, SLNB was performed pre-NET in 14 cases and post-NET in 77. Both groups were similar in baseline tumor and patient characteristics. SLNB positivity was similar regardless of whether SLNB was performed before (5/14, 35.7%) or after NET (27/77, 37%), with 2/14 SLN macrometastases in the pre-NET cohort and 17/77 in the post-NET cohort. Only three patients (18.7%) with SLN macrometastasis had > 3 positive nodes following ALND. The 5-year overall survival and distant disease-free survival were 92.4% and 94.8%, respectively, with no significant differences according to SLNB status (p 0.5 and 0.8, respectively). SLN positivity did not differ according to its timing (before or after NET). Therefore, NET has no effect on lymph node clearance. Furthermore, the prognosis is good regardless of the axillary involvement. Therefore, factors other than axillary involvement may affect the prognosis in these patients.

Efficacy and safety of concomitant chemo-endocrine therapy in neoadjuvant treatment of hormone-positive HER2-negative breast cancer: a systemic review and meta-analysis

ABSTRACT Background The rate of pathological complete response (pCR) with both chemotherapy alone (CT) and endocrine therapy (ET) in the neoadjuvant (Na) treatment of hormone receptor (HR)-positive/HER2-negative breast cancer (BC) is unsatisfactory. Limited data on neoadjuvant concomitant chemotherapy and endocrine therapy (NaCET) are available. Research design and methods In this meta-analysis analyzed the efficacy and safety of randomized controlled trials (RCT) comparing the use of NaCET in HR-positive/HER2-negative BC. A comprehensive search was performed on PubMed, Cochrane Library and EMBASE databases, and congress paper lists for studies published/presented until 1 December 2022. Results Five RCTs involving a total of 630 patients were included. A pooled analysis of the five studies demonstrated that the pCR ratio was numerically higher in the NaCET arm than in the NaCT arm, but the difference was not statistically significant (6.5% vs. 3.8%; OR:1.72, 95% CI 0.82–3.62). Nonetheless, the NaCET arm exhibited a significantly higher objective response rate (ORR) (82% vs. 72.7%; OR:1.77, 95% CI 1.20–2.62). There was no difference between the arms in terms of grade 3–5 adverse events. Conclusions In HR-positive/HER2-negative BC, NaCET significantly increases ORR without an increase in serious adverse events. Although the pCR rate increased numerically, it was not statistically significant.

Neoadjuvant Endocrine Therapy: A Potential Way to Make Cold Hormone Receptor-Rich Breast Cancer Hot.

Turning the "cold" tumor immune microenvironment into "hot" is a critical issue in cancer treatment today. Hormone receptor-rich breast cancer (HR+ BC) was previously considered immunologically quiescent. This study aims to explore the immunomodulatory effects of endocrine therapy on HR+ BCs. The infiltrations and alterations of the tumor immune microenvironment in HR+ BCs before, after 10-14 days, and after three months of neoadjuvant endocrine therapy were computationally analyzed according to MCP-counter, CIBERSORT, xCell algorithms, and gene-set enrichment analysis (GSEA). The primary microarray data were obtained from three HR+ BC gene expression datasets (GSE20181, GSE55374, and GSE59515). Single-sample GSEA of hallmark and immune response gene sets was performed to evaluate the correlation between suspected treatment response and activated immune pathways in tumors. Both immune and stromal cells were specifically recruited into the HR+ BCs who responded to the neoadjuvant endocrine therapy by letrozole. Besides the enhanced infiltrations of immunosurveillance-related cells such as CD8+ T cells, dendritic cells, and the activation of immune response-related signals, the immunosuppressive M2-like macrophages, as well as the expression of immune checkpoint genes like PDCD1, SIRPA, and some HLA genes, were also stimulated in responders. We identified four pretreatment indicators (the intrinsic luminal subtype, the estrogen response early/late pathway, and the epithelial-mesenchymal transition pathway) as potential predictors of both clinical response and the activation of the tumor immune microenvironment post letrozole. Neoadjuvant endocrine therapy showed a promising way to convert the immunologically "cold" HR+ BCs into "hot" tumors. This study provides new insights into the application of immunotherapy for HR+ BCs, especially those who respond to endocrine therapy.

P113 MRI Patterns in the evaluation of pathological response after Neoadjuvant Endocrine therapy in ER+/HER2- Breast Cancer and Implications on Surgical Planning

P113 MRI Patterns in the evaluation of pathological response after Neoadjuvant Endocrine therapy in ER+/HER2- Breast Cancer and Implications on Surgical Planning

Comparing outcomes between neoadjuvant hormonal therapy followed by prostatectomy versus upfront prostatectomy in high-risk prostate cancer: The road ahead.

Comparing outcomes between neoadjuvant hormonal therapy followed by prostatectomy versus upfront prostatectomy in high-risk prostate cancer: The road ahead.

Phase III study of long-term prognosis of estrogen receptor-positive early breast cancer treated with neoadjuvant endocrine therapy with/without adjuvant chemotherapy

PurposeNeoadjuvant endocrine therapy (NET) is a treatment option for estrogen receptor-positive (ER+) postmenopausal early breast cancer (EBC). This phase III trial evaluated the prognosis of EBC patients treated with/without chemotherapy (CT) following NET.MethodsER+/HER2−, T1c-2, and clinically node-negative EBC patients were enrolled in 2008–2013 and treated with endocrine therapy (ET) in weeks 24–28. All patients, excluding those with progressive disease (PD) during NET or ≥ 4 positive lymph nodes after surgery, were randomized to ET for 4.5–5 years with/without CT. The primary endpoint was disease-free survival (DFS). Secondary endpoints included distant DFS (DDFS), overall survival (OS), and DFS/DDFS/OS according to clinical response to NET.ResultsOf 904 patients, 669 were randomized to CT+ET (n = 333) or ET alone (n = 336). The median follow-up was 7.8 years. DFS (CT+ET, 47 events; ET alone, 70 events) and DDFS did not reach the planned numbers of events. Eight-year DFS/DDFS rates were 86%/93% and 83%/92%, respectively. DFS was significantly better in CT+ET than ET alone in subgroups aged < 60 years (P = 0.016), T2 (P = 0.013), or Ki67 > 20% (P = 0.026). Progesterone receptor and histological grade were predictive markers for clinical responses to NET.ConclusionNET may be used as standard treatment for patients with ER+EBC. Although it is difficult to decide whether to administer adjuvant CT based solely on the effect of NET, the response to NET may help to inform this decision.Trial registrationThis study was registered at the UMIN Clinical Trials Registry under UMIN000001090 (registered 20 March 2008).

Using Oncotype DX breast recurrence score® assay to define the role of neoadjuvant endocrine therapy in early-stage hormone receptor-positive breast cancer

PurposeThe role of neoadjuvant endocrine therapy in the treatment of patients with early-stage, hormone receptor-positive (HR +) breast cancer is not well defined. Tools to better determine which patients may benefit from neoadjuvant endocrine therapy versus chemotherapy or upfront surgery remain an unmet need.MethodsWe assessed the rate of clinical and pathologic complete response (cCR, pCR) among a pooled cohort of patients with early-stage HR + breast cancer who had been randomized to neoadjuvant endocrine therapy or neoadjuvant chemotherapy in two earlier studies to understand better how outcomes varied by Oncotype DX Breast Recurrence Score® assay.ResultsWe observed that patients with intermediate RS results had no statistically significant differences in pathologic outcomes at the time of surgery based on whether they received neoadjuvant endocrine therapy or neoadjuvant chemotherapy, suggesting that a subgroup of women with a RS 0–25 may omit chemotherapy without compromising outcomes.ConclusionThese data suggest that Recurrence Score® (RS) results may serve as a useful tool in treatment decision-making in the neoadjuvant setting.

Abstract P1-07-01: Ki-67 index after neoadjuvant endocrine therapy as a prognostic biomarker in patients with HR+/HER2- early breast cancer: a systematic review and meta-analysis

Abstract Background: Neoadjuvant treatment allows to better distinguish responders from non-responders, and to tailor post-neoadjuvant treatment according to tumor response in patients with HER2+ and triple-negative early breast cancer. For HR+/HER2- tumors, the pathologic complete response is less likely to occur, and residual disease is predictive of inferior recurrence-free or overall survival. Therefore, Ki-67 index, a prognostic biomarker in early breast cancer, is often used in clinical trials as an endpoint for evaluating response to neoadjuvant endocrine therapy (NET). In this systematic review and meta-analysis, we aim to assess if Ki-67 level after NET is associated with disease recurrence and/or survival. Methods: We conducted a systematic literature search of PubMed, Embase, CENTRAL, and conference proceedings (ASCO and ESMO annual meetings, ESMO Breast, and SABCS) up to June 28, 2022, to identify clinical trials or observational studies reporting Ki-67 index after NET in patients with HR+/HER2- early breast cancer treated with NET (PROSPERO number CRD42021282338). We excluded studies in which all patients received neoadjuvant chemotherapy, or from which separate data from patients receiving only NET was not retrieved. Here we report data from studies screened for the availability of the primary endpoint - recurrence-free survival (RFS), and the secondary endpoint - overall survival (OS), comparing patients with low Ki-67 versus high Ki-67 index after NET, as defined per each study. We performed a sensitivity analysis of the studies measuring the post-NET Ki-67 index in a pre-planned core biopsy. We used the Higgins I2 index to evaluate the heterogeneity between included studies, which did not reach statistical significance. Therefore, we used a fixed effects model to combine RFS and OS hazard ratios (HR) with 95% confidence intervals (CI). Results: We included 11 studies reporting data from 4,231 patients: nine clinical trials (n=3,926), one pooled analysis of two clinical trials (n=217), and one retrospective cohort study (n=88). Nine studies included only post-menopausal women (n=4,069), one included both post- and premenopausal women (n=88), and one included only premenopausal women (n=74). NET was aromatase inhibitor (AI) in four studies (n=3,359), tamoxifen or AI in four (n=465), tamoxifen in two (n=190), and one study with AI or fulvestrant (n=217). There were no studies with targeted agents combined with NET. No study restricted the use of adjuvant chemotherapy in high-risk patients. Three studies evaluated post-NET Ki-67 in a pre-planned core biopsy after a window of treatment of two to four weeks (n=3,348), while the other eight evaluated KI67 in the surgery specimen (n=883). The timing of post-NET evaluation ranged from 2 to 24 weeks. The median follow-up for RFS ranged between 37 and 95 months, and between 62 to 84 months for OS. We found a statistically significant association of adverse RFS (HR 2.43, 95% CI 1.99-2.98) and OS (2.66, 95% CI 1.65-4.28) with higher Ki-67 after NET. The sensitivity analysis of the three studies evaluating post-NET Ki-67 in a pre-planned core biopsy showed the same association with RFS (HR 2.41, 95% CI 1.77-3.30). These three studies did not report OS data. Conclusion: Our data reinforce the role of Ki-67 index after NET as a valuable biomarker of response or resistance to endocrine therapy in women with HR+/HER2- early breast cancer. Despite the use of adjuvant chemotherapy in most of the high-risk patients included in this analysis, the reduction of Ki-67 after NET is strongly associated with survival outcomes (RFS/OS), even after a short course of two to four weeks NET. Ki-67 index post-NET might be a useful tool to help tailoring the use of adjuvant chemotherapy in HR+/HER2-negative breast cancer patients, particularly in low-resource settings where the access to genomic assays is limited. Citation Format: Diogo Martins-Branco, Chiara Molinelli, Guilherme Nader Marta, Lieveke Ameye, Marianne Paesmans, Roberto Salgado, Philippe Aftimos, Evandro de Azambuja. Ki-67 index after neoadjuvant endocrine therapy as a prognostic biomarker in patients with HR+/HER2- early breast cancer: a systematic review and meta-analysis [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 P1-07-01.

Abstract PD9-03: Breast Cancer Microenvironment Change After Neoadjuvant Endocrine Treatment Breast Cancer Microenvironment Change After Neoadjuvant Endocrine Treatment

Abstract Background: Estrogen receptor positive (ER+)/HER-2 negative breast cancer (BC) is considered to be an immunologically cold tumor compared to triple negative breast cancer. Therefore, the tumor microenvironment (TME) of ER+/HER-2 negative BC is understudied. The receptor activator of nuclear factor-kB ligand (RANKL)-RANK pathway was first identified, as mediator of T and dendritic cells interaction, but it is mostly known for its role as key regulator of bone remodeling and pathophysiology of bone metastases. RANK is a member of the tumor necrosis factor receptor (TNFR) superfamily that is activated upon RANKL binding, promoting cell proliferation, survival and differentiation. The RANKL-RANK pathway also emerged as a major mediator of hormone-driven breast carcinogenesis. The aim of this study is to investigate the TME and the immune response during neoadjuvant endocrine therapy (NET) and to correlate this with the treatment response in a real life setting. Methods: Expressions of immune checkpoint receptors and immune cells were examined immunohistochemically in pre- and post- NET on a cohort of 44 ER+/HER-2 negative BC patients. They were treated with tamoxifen (N=8), an aromatase inhibitor (N=36) or a combination of an aromatase inhibitor with a PI3K inhibitor (N= 7) for a median duration of 6 months (range 1-32) months. Monoclonal antibodies for PDL-1, PD-1, TIM-3, LAG-3, CTLA-4, CD4, CD68, FOXP3, RANK and RANKL were used. All staining were done according to validated protocols and scoring was done by a pathologist specialized in breast cancer. Positivity was defined as staining &amp;gt; 1% on TILs. Response to NET was evaluated according to tumor size change on imaging and Ki-67 change. Results: The median age was 62.5 (44–90.3) years. Diameter of tumor size decreased with a mean of 7.818 mm (p &amp;lt; 0.0001) during NET and the value of Ki-67 value decreased significantly after NET (value, p&amp;lt; 0.0004). An increase in PD-L1 expression after NET showed a trend towards significant (p= 0.088) and RANK expression on TILs significantly decreased with a median of 30% (range= -70 to 85) (p= 0.0007) after NET. A good response to NET defined as a decrease in tumor size and/or decrease of Ki-67 was found to be associated with a longer duration of NET, a change of CD4+ T-cells, a change of RANK expression on TILs and a higher number of CD68+ tumor-associated macrophages before the start of NET and also RANK expression on TILs before the start of NET. Conclusion: The immune micro-environment plays an important role in ER+/HER-2 negative BC. NET influences the composition and/or functional state of the infiltrating immune cells. Furthermore, changes in the immune micro-environment are also associated with treatment response. Breast Cancer Microenvironment Change After Neoadjuvant Endocrine Treatment Comparison of continuous and categorical parameters before and after NET. Comparison of the continuous parameters was done using Wilcoxon signed rank test. Comparison of the categorical parameters was done using a Chi-square test. sTIL: stromal tumour infiltrating lymphocytes and NET: neoadjuvant endocrine therapy. Bold values denote statistical significance at the p &amp;lt; 0.05 level. Citation Format: Gizem Oner, Glenn Broeckx, Christophe Van Berckelaer, Sevilay Altintas, Zafer Canturk, Wiebren Tjalma, Karen Zwaenepoel, Zwi Berneman, Marc Peeters, Patrick Pauwels, Peter A van Dam. Breast Cancer Microenvironment Change After Neoadjuvant Endocrine Treatment Breast Cancer Microenvironment Change After Neoadjuvant Endocrine Treatment [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 PD9-03.

Abstract P5-09-04: Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in pre-menopausal patients with hormone-responsive and HER2-negative, lymph node-negative breast cancer

Abstract Background: Neoadjuvant endocrine therapy (NET) has demonstrated efficacy in post-menopausal patients with hormone-responsive and her2-negative breast cancer. This trial was designed to compare the efficacy of neoadjuvant chemotherapy (NCT) with NET in pre-menopausal patients with hormone-responsive, her2-negative and lymph node-negative breast cancer. Materials and Methods: In this prospective, randomised study, pre-menopausal patients with hormone-responsive, her2-negative and lymph node-negative breast cancer were recruited. Enrolled patients were randomly assigned (1:1) to receive either NCT or NET with goserelin and tamoxifen, followed by goserelin and anastrozole. The primary purpose was to evaluate the non-inferiority of NET compared to NCT using clinical response, assessed by ultrasound. Results: A total of 68 patients were assigned to receive NCT (n = 31) or NET (n = 37). The clinical response rate was 16.1% for NCT and 35.1% for NET (estimated difference19%, 95%CI:-1.1%-39.1%, non-inferior p = 0.002). Rates of breast-conserving surgery were similar between NCT and NET (90.3% vs 83.8%, p=0.494). Conclusions: The clinical response rate of NET is non-inferior to NCT in pre-menopausal patients with hormone-responsive, HER2-negative, lymph node-negative breast cancer. Summary of ultrasound clinical response The breast surgery and MP grading system Citation Format: chongshan gu, yingjian he, jinfeng li, tianfeng wang, zhaoqing Fan, tao ouyang. Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in pre-menopausal patients with hormone-responsive and HER2-negative, lymph node-negative 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 P5-09-04.

Abstract P5-09-02: Impact of neoadjuvant endocrine therapy on tumor transcriptome in patients with early-stage breast cancer from the FLEX trial

Abstract BACKGROUND: Neoadjuvant Endocrine Therapy (NET) is seldom used in breast cancer management except in patients with several comorbidities or in elderly patients in which chemotherapy is not an option. Clinical response with NET is not typically achieved until after several months of treatment. In the NET setting, reduction of Ki67 (&amp;lt; 10%) after 2-4 weeks has been used as a predictor of positive response, but studies such as ALTERNATE have questioned this association. It remains uncertain whether a single gene or protein can adequately predict outcomes or inform how NET alters a variety of cancer genes and global tumor biology. This study evaluated the effect of short-term NET on the tumor genomics of patients with early-stage breast cancer (EBC) by comparing whole transcriptome gene expression changes in matched pre- and post-NET tumor samples. METHODS: In this single-institution FLEX substudy performed at Johns Hopkins, patients (n=30) with matched pre- and post-treatment specimens who received at least two weeks of NET between 2019 – 2021 were included. Premenopausal and male patients with breast cancer received Tamoxifen (n=10) and postmenopausal women received either Letrozole (n=10) or Exemestane (n=10). Limma R package was used for quantile normalization and differential gene expression analysis. Significant differentially expressed genes (DEGs) had a false discovery rate of &amp;lt; 0.05 and &amp;gt;2-fold change. Pathway enrichment analysis was performed using Reactome. For patients with available clinical information, changes in immunohistochemistry (IHC) between pre- and post-NET were quantified using absolute values, and the median percent change was reported, with significance assessed using the Wilcoxon test. The observational FLEX trial (NCT03053193) enrolls patients with EBC who have MammaPrint (MP) with or without BluePrint testing and consent to clinically annotated full transcriptome data collection. MammaPrint classifies tumors as having a Low Risk (LR) or High Risk (HR) of distant recurrence. BluePrint is a molecular subtyping assay, and together with MammaPrint, tumors are classified as Luminal A-Type (MP LR), Luminal B-Type (MP HR), HER2-Type, or Basal-Type. RESULTS: Transcriptional profiles between pre- and post-NET samples were distinct with short-term NET inducing 774 DEGs. The majority of significant DEGs (n=748) such as MGAT1, IQGAP3, and PRC1, which are associated with tumor aggressiveness and metastasis, were downregulated in post-NET samples. Upregulated genes in post-NET tumors, such as FOS, JUN, and EGR1, are involved in estrogen signaling and NF-κB pathways and are associated with better outcomes. Among the 30 patients, 7 (6 Luminal B and 1 Basal) remained MP HR and 16 remained MP LR (Luminal A) pre- and post-NET, 1 changed from LR (Luminal A) pre-NET to HR (Luminal B) post-NET, and 6 changed from HR (Luminal B) pre-NET to LR post-NET (Luminal A). The median percent change by IHC in matched pre- and post-NET tissue was 2.5% for estrogen receptor (ER) (range: 0-50%; p=0.750), 22% for progesterone receptor (PR) (range: 0-81%; p=0.097), and 9% for Ki67 (range: 0-43%; p=0.026). CONCLUSIONS: In this study, significant gene expression changes were discovered within a shorter timeframe than when clinical responses are usually observed in the NET setting. This could indicate biological complexity and diverse response pathways, which may be more informative when combined with a single IHC biomarker (ER/PR/Ki67). Results from this study should be confirmed using a larger cohort. Future studies will determine the significance of these DEGs and their impact on outcomes, and will further define gene expression changes by endocrine therapy type (tamoxifen versus aromatase inhibitors). ACKNOWLEDGMENTS: We would like to thank Lynn and Robert Downing for their generous support of our study. Citation Format: Mehran Habibi, Danijela Jelovac, Rima Couzi, Cesar Augusto Santa-Maria, Catherine Klein, Marissa White, Nivali Naik, Jennifer Wei, Yen Huynh, Architha Ellappalayam, Lisa E. Blumencranz, Erin B. Yoder, Patricia Dauer, Bas van der Baan, William Audeh. Impact of neoadjuvant endocrine therapy on tumor transcriptome in patients with early-stage breast cancer from the FLEX trial [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 P5-09-02.

Abstract P2-03-19: The efficacy of neoadjuvant endocrine therapy during the waiting period for surgery in postmenopausal hormone receptor positive breast cancer

Abstract 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&amp;lt; 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.