Preoperative Endocrine Prognostic Index Score Research Articles

Abstract PO1-02-04: The efficacy of endocrine therapy during the waiting period for surgery for 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. Methods: A total of 480 patients with StageⅠ-Ⅲ hormone receptor-positive, HER2-negative breast cancer was treated with endocrine therapy during the waiting period for surgery between October 2012 and December 2021. Premenopausal and postmenopausal patients received tamoxifen (TAM) and non-steroidal aromatase inhibitor (AI), respectively. The primary endpoint was change in tumor size by ultrasound and Ki67 expression 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 expression, and ER Allred score. This study was approved by the institutional review board of Teikyo University. Results: Median age and tumor size of the entire 480 patients was 55 years (range, 31 - 89), 1.65 cm (range, 0.4 – 7.5), respectively. The median duration of endocrine therapy was 39 days (range, 1-90). 19 (0.3 %) pts were clinically node-positive. Of the entire 480 patients, 211 and 269 patients had TAM and AI, respectively. After short term endocrine therapy, the tumor size was significantly reduced from 1.83cm to 1.62cm in AI group (p=0.02), although TAM did not decrease the tumor size (p=0.89). The Ki67 expression was significantly decreased from 16.4% to 11.3% in TAM group (p=0.002), and from 15.9% to 6.98% in AI group (p < 0.001). There were significant differences in the distribution of PEPI scores between TAM and AI group (p < 0.05) (Table). At the median follow-up of 1012 days, patients with PEPI score ≥ 4 showed worse disease-free survival compared with patients with PEPI score < 4 in TAM group (Figure1). Overall survival is not available because there were no deaths in TAM group. At the median observation period of 833 days, patients with PEPI score ≥ 4 showed worse disease-free survival compared with patients with PEPI score < 4 in AI group (Figure2). 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 Ki67 expression level and PEPI score might be useful in predicting the prognosis of hormone receptor positive breast cancer patients. Table. Distribution of PEPI score Figure 1. Disease-free survival in patients treated with tamoxifen Figure 2. Disease-free survival in patients treated with non-steroidal aromatase inhibitor Citation Format: Yuka Maeda, Saki Naruse, Yuka Isono, Ayana Sato, Akiko Matsumoto, Tatsuhiko Ikeda, Hiromitsu Jinno. The efficacy of endocrine therapy during the waiting period for surgery for hormone receptor-positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-02-04.

Abstract PO1-18-10: ANNE: A phase II single-arm clinical trial to assess the feasibility and efficacy of neoadjuvant anastrozole in patients with luminal breast cancer and low proliferative index in TNM stages II and III

Abstract Background: Neoadjuvant endocrine therapy (NET) is recommended for the treatment of invasive breast cancer (BC), particularly luminal subtypes, in locally advanced stages. Previous randomized studies have demonstrated the benefits of aromatase inhibitors (AIs) in this context. However, in clinical practice, NET is typically reserved for elderly or frail patients who may not tolerate neoadjuvant chemotherapy. Ideally, after identifying suitable candidates for NET, patients undergo tumor re-biopsy after 2 to 4 weeks of treatment, and only those with Ki67 ≤ 10% proceed with NET. Limitations of this strategy include the standardization of re-biopsy and the reliability of Ki67 immunohistochemical analysis, as treatment decisions are based on these results. Objective: To evaluate the feasibility and efficacy of NET in postmenopausal patients with stage II and III luminal BC and to identify predictive biomarkers of therapeutic response. The efficacy will be measured by the rate of patients with Ki67 ≤ 10% after 4 weeks and Preoperative Endocrine Prognostic Index (PEPI) score 0 on the surgical specimen. The feasibility of the study will be assessed by the acceptance rate of participating in the study (recruitment rate ≥ 50%) and the inclusion rate of >2 patients per month. Methods: This non-randomized phase II clinical trial includes postmenopausal women with invasive breast carcinoma, Scarf-Bloom-Richardson histological grades 1 or 2, Estrogen Receptor positive (Allred ≥ 6), progesterone receptor positive (any value), HER2 negative, Ki-67 antigen < 50% on immunohistochemistry, stages TNM II-III, with palpable tumor ≥ 2 cm, and ECOG 0-2. All eligible patients will receive anastrozole (1 mg/day) continuously until the day before the surgical procedure or exclusion from the study (in case of disease progression during endocrine therapy). After 2 to 4 weeks, a re-biopsy of the breast tumor will be performed. If Ki67 > 10%, endocrine therapy will be suspended, and the patient will be excluded from the study and redirected to neoadjuvant chemotherapy (routine care) or immediate surgery (as per attending clinical oncologist and surgeon). If Ki67 ≤ 10%, the patient will continue to receive NET. Extended NET will be administered for up to 10 months, with monthly physical examinations (using calipers) and bimonthly breast ultrasound. The presence of stable disease on ultrasound at 4, 6, and 8 months indicates scheduling surgery within 2 months thereafter, and disease progression at any time indicates surgery within one month. Patients will complete the EORTC QLQ-C30 and its supplemental module BR45 questionnaires every 2 months. Toxicity will be assessed using CTCAE version 4.0, and patients will respond to 11 specific items extracted from the Brazilian version of PRO-CTCAE. The radiological response will be evaluated by RECIST 1.1. Blood samples for molecular analyses will be collected at baseline and during re-biopsy. MicroRNA profiles will be evaluated using Nanostring, and extracellular vesicles will be examined using ATR-FTIR to identify predictive markers of therapeutic response (Ki67 < 10%) in re-biopsy. All cases will be evaluated using PAM50 at the initial biopsy and at surgery to determine the molecular phenotype (luminal A, B, or other) and molecular response (ROR score difference). Pathologic therapeutic response will be assessed using the PEPI score in all operated cases. The sample size was calculated to be 59 patients. The study was initiated in July 2022, and since then, a total of 26 patients have been enrolled. This study is registered with The Brazilian Registry of Clinical Trials (ReBEC): RBR-5pygzhj. Citation Format: Carlos Paiva, Izabella Oliveira, Vitor Guimarães, Alinne Faria, Domício Lacerda, Anapaula Uema, Nilton Onari, Bianca Paiva, Augusto Antoniazzi, Karina Oikawa, Maria Fernanda Machado, Matheus Godinho, Cristiano Souza, Chrissie Amirati, Gustavo Teixeira, Idam de Oliveira Jr, Márcia Marques, Yara Maia. ANNE: A phase II single-arm clinical trial to assess the feasibility and efficacy of neoadjuvant anastrozole in patients with luminal breast cancer and low proliferative index in TNM stages II and III [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-18-10.

Tucidinostat Plus Exemestane as a Neoadjuvant in Early-Stage, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer.

To assess the efficacy and safety of tucidinostat plus exemestane as a neoadjuvant strategy in early-stage breast cancer. This prospective, open-label, single-arm phase II trial enrolled patients with stage II-III breast cancer with hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative. Eligible patients received tucidinostat plus exemestane, and then breast-conserving surgery (BCS) or modified radical mastectomy. Among 20 enrolled patients, 3 of them achieved preoperative endocrine prognostic index (PEPI) score of 0. Additionally, complete cell cycle arrest was observed in 7, radiologic objective response rate in 10, and disease control rate in 20 patients, pathological complete response in 1 patient, and 5 patients performed BCS. Ki67 suppression from baseline to surgery was observed in 17 of patients, with the Ki67 change ratio of -73.5%. Treatment-emergent adverse event included neutropenia, leukopenia, thrombocytopenia, lymphopenia, hypoalbuminemia, aspartate aminotransferase elevation, glutamyl transpeptidase elevation, anemia, and alanine aminotransferase elevation. Despite the rate of PEPI score 0 was not high, tucidinostat plus exemestane as a neoadjuvant therapy might be well tolerated and showed promising clinical responses in patients with early hormone receptor-positive, HER2-negative breast cancer. To clarify the safety and efficacy of this strategy, further investigation is warranted. ChiCTR2100046678.

A prospective study on tumour response assessment methods after neoadjuvant endocrine therapy in early oestrogen receptor-positive breast cancer

BackgroundNeoadjuvant endocrine therapy (NET) in oestrogen receptor-positive (ER+) /HER2-negative (HER2-) breast cancer allows real-time evaluation of drug efficacy as well as investigation of the biological and molecular changes that occur after estrogenic deprivation. Clinical and pathological evaluation after NET may be used to obtain prognostic and predictive information of tumour response to decide adjuvant treatment. In this setting, clinical scales developed to evaluate response after neoadjuvant chemotherapy are not useful and there are not validated biomarkers to assess response to NET beyond Ki67 levels and preoperative endocrine prognostic index score (mPEPI).MethodsIn this prospective study, we extensively analysed radiological (by ultrasound scan (USS) and magnetic resonance imaging (MRI)) and pathological tumour response of 104 postmenopausal patients with ER+ /HER2- resectable breast cancer, treated with NET for a mean of 7 months prior to surgery. We defined a new score, tumour cellularity size (TCS), calculated as the product of the residual tumour cellularity in the surgical specimen and the tumour pathological size.ResultsOur results show that radiological evaluation of response to NET by both USS and MRI underestimates pathological tumour size (path-TS). Tumour size [mean (range); mm] was: path-TS 20 (0–80); radiological-TS by USS 9 (0–31); by MRI: 12 (0–60). Nevertheless, they support the use of MRI over USS to clinically assess radiological tumour response (rad-TR) due to the statistically significant association of rad-TR by MRI, but not USS, with Ki67 decrease (p = 0.002 and p = 0.3, respectively) and mPEPI score (p = 0.002 and p = 0.6, respectively). In addition, we propose that TCS could become a new tool to standardize response assessment to NET given its simplicity, reproducibility and its good correlation with existing biomarkers (such as ΔKi67, p = 0.001) and potential added value.ConclusionOur findings shed light on the dynamics of tumour response to NET, challenge the paradigm of the ability of NET to decrease surgical volume and point to the utility of the TCS to quantify the scattered tumour response usually produced by endocrine therapy. In the future, these results should be validated in independent cohorts with associated survival data.

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< 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.

Abstract P5-09-01: Neoadjuvant hormonal therapy plus palbociclib versus hormonal therapy plus placebo in women with operable, hormone sensitive and HER2-negative primary breast cancer

Abstract 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.

Real-world data on neoadjuvant endocrine therapy in ER-positive/HER2-negative breast cancer.

Neoadjuvant endocrine therapy (NET) has been shown to be effective in ER-positive/HER2-negative breast cancer in clinical trials. However, adoption in clinical practice is still limited. Real-world data may provide useful insights into effectiveness, toxicities and quality of care, potentially rendering clinical trial results to the real-world setting. Our purpose was to report real-world data of a cohort of postmenopausal patients submitted to NET. This prospective cohort study evaluated 146 postmenopausal female patients with ER-positive/HER2-negative breast cancer treated with NET at three tertiary hospitals between 2016 and 2018. Clinicopathological information were collected prospectively. Preoperative Endocrine Prognostic Index (PEPI) score was calculated for tumors submitted to at least 16weeks of NET. Median age was 67years old, and 87.8% had stage I-II disease. Most tumors had histological grade II (76.1%). Median pretreatment Ki67 expression was 10%. Aromatase inhibitor was used in 99.5% of patients, and median treatment duration was 21.0weeks. No tumor progressed during NET. Breast-conserving surgery was performed in the majority of patients (63.0%), as well as sentinel lymph-node biopsy (76.7%). Pathological complete response rate was 1.0%. 43 patients (29.5%) had PEPI score 0, and 26% had PEPI scores 4-5. Posttreatment Ki67 median expression was 3.0%, and only five tumors (3.4%) showed marked increase in Ki67 expression during treatment. Seven patients (4.8%) had HER2-positive residual disease, and were treated with adjuvant chemotherapy plus trastuzumab. Our real-world data shows that NET is effective and safe in postmenopausal patients with ER-positive/HER2-negative breast cancer. Postmenopausal status and low-risk luminal tumor features (luminal A-like) should be used as selection criteria to ensure the best results with NET.

Letrozole + ribociclib versus letrozole + placebo as neoadjuvant therapy for ER+ breast cancer (FELINE trial).

505 Background: Ribociclib (R) + letrozole (L) is superior to L in metastatic breast cancer (BC). Preoperative endocrine prognostic index (PEPI) score 0 after neoadjuvant endocrine therapy (NET) is associated with low risk of relapse without chemotherapy in ER+ BC. On-therapy change in Ki-67 predicts adjuvant recurrence. FELINE is a biomarker-based multicenter randomized trial comparing changes in Ki-67 and PEPI between L+ Placebo (P) & L+R. Methods: Postmenopausal women with >2 cm or node+ ER+ HER2- BC were randomized 1:1:1 between L+P, L+R 400 mg continuous dose (Rc) and L+R 600 mg, 3 weeks on/1 week off - intermittent dose (Ri). Treatment was continued for six 28-day cycles. Core biopsies, blood samples were obtained at baseline, Day 14 cycle 1 (D14C1), and surgery. Clinical measurement, mammogram and US were obtained at baseline, surgery; MRI at baseline, week 8. Primary endpoint was rate of PEPI score 0 between L+P and L+R (i+c combined). Other endpoints were change in centrally performed Ki-67, complete cell cycle arrest (CCCA): Ki-67 <2.7%, clinical/imaging response, and difference in response & toxicity between the two R (Rc and Ri) arms. Results: From 2/2016 to 8/2018, 120 women were enrolled at 9 US centers. Thirty-eight were randomized to L+P and 82 to L+R groups (41 in Ri and Rc). Treatment groups were balanced at baseline. PEPI score of 0 was equal (25%) in L+P & L+R groups. CCCA at D14C1 was observed in 52% vs. 92% in L+P, L+R respectively (p < 0.0001). CCCA at surgery was observed in 63.3% vs. 71.4% in L+P, L+R respectively (p = NS). A significant increase in Ki-67 was observed between D14C1 and surgery in 66% vs. 33% in L+R, L+P respectively (p = 0.006). There was no difference in clinical, mammographic, US or MRI response between L+P and L+R. CCCA at D14C1 and surgery was similar in Ri & Rc arms. Grade >3 AEs were observed in 4 (10%) patients in L+P, 23 (56%) in L+Ri, 19 (46%) in L+Rc arms. Conclusions: Addition of R to L as NET did not result in more women with a PEPI score of 0. At D14C1 twice as many women on L+R had CCCA compared to L+P (92% vs 52%). However, significantly more women on L+R had increased proliferation between D14C1 and surgery , resulting in similar CCCA at surgery. Correlative studies are being performed to determine mechanisms of on-therapy acquired resistance to ribociclib. Continuous and intermittent doses of R have similar efficacy, toxicity. Clinical trial information: NCT02712723 . [Table: see text]

Taking a Second Look at Neoadjuvant Endocrine Therapy for the Treatment of Early Stage Estrogen Receptor Positive Breast Cancer During the COVID-19 Outbreak.

Taking a Second Look at Neoadjuvant Endocrine Therapy for the Treatment of Early Stage Estrogen Receptor Positive Breast Cancer During the COVID-19 Outbreak.

ESR1 Mutations Are Not a Common Mechanism of Endocrine Resistance in Patients With Estrogen Receptor-Positive Breast Cancer Treated With Neoadjuvant Aromatase Inhibitor Therapy.

Introduction: Mutations in the ESR1 gene (ESR1m) are important mechanisms of resistance to endocrine therapy in estrogen receptor–positive (ER+) metastatic breast cancer and have been studied as a potential therapeutic target, as well as a predictive and prognostic biomarker. Nonetheless, the role of ESR1m as a possible mechanism of primary endocrine resistance, as well as whether it also occurs in tumors that are resistant to ET administered in early-stage disease as (neo)adjuvant, has not been adequately studied. In this study, we evaluated the prevalence of ESR1m in tumor samples from patients with ER+ breast cancer resistant to neoadjuvant aromatase inhibitor therapy.Methods: We followed a prospective cohort of patients with ER+ HER2– stages II and III breast cancer treated with neoadjuvant endocrine therapy (NET). Tumor samples from patients with a pattern of primary endocrine resistance [defined as a Preoperative Endocrine Prognostic Index (PEPI) score of ≥4] were identified and analyzed for the presence of ESR1m.Results: One hundred twenty-seven patients were included in the cohort, of which 100 (79%) had completed NET and underwent surgery. Among these patients, the PEPI score ranged from 0 to 3 in 70% (70/100), whereas 30% (30/100) had a PEPI score of 4 or more. Twenty-three of these patients were included in the analysis. ESR1 mutations were not identified in any of the 23 patients with early-stage ER+ breast cancer resistant to NET.Discussion: Growing evidence supports the notion that there are different mechanisms for primary and secondary endocrine resistance. Our study suggests that ESR1 mutations do not evolve rapidly and do not represent a common mechanism of primary endocrine resistance in the neoadjuvant setting. Therefore, ESR1m should be considered a mechanism of acquired endocrine resistance in the context of advanced disease. Further research should be conducted to identify factors associated with intrinsic resistance to ET.

Abstract P2-11-08: ESR1 mutations are not a mechanism of primary resistance to aromatase inhibitors in ER-positive breast cancer treated with neoadjuvant endocrine therapy

Abstract Introduction: Mutations in the ESR1 gene (ESR1m) are important mechanisms of resistance to endocrine therapy (ET) in estrogen receptor-positive (ER+) advanced breast cancer and have been recognized as a prognostic and predictive biomarker as well as a potential therapeutic target. ESR1m prevalence has been described as 9-45% in cohorts of ET-resistant metastatic tumors in a variety of publications. We recently reported a prevalence of 25% in a cohort of ER+ breast cancer patients with visceral metastasis. However, the role of ESR1m as a mechanism of resistance to ET used in early-stage disease is not well studied. Neoadjuvant endocrine therapy (NET) is being increasingly explored, not only to allow less extensive surgery but also as a scientific tool, exploring biomarkers to predict outcomes. The preoperative endocrine prognostic index (PEPI) combining Ki67 score, ER Allred score, tumor size, and nodal status after NET is a surrogate of endocrine sensitivity and can identify a subgroup of patients with primary resistance to ET. In this study, we evaluated the prevalence of ESR1m in tumor samples from patients with ER+ breast cancer that were primarily resistant to neoadjuvant aromatase inhibitor (AI) therapy. Methods: We followed a prospective cohort of postmenopausal patients with ER+ HER2- stages II-III breast cancer treated with neoadjuvant endocrine therapy (NET). Patients were treated with anastrozole for a recommended period of at least three months. Tumor samples from patients with a pattern of primary endocrine-resistant tumors (defined as a PEPI Score higher than 3) were selected and analyzed for the presence of ESR1m. ESR1m were evaluated in formalin-fixed paraffin-embedded (FFPE) breast cancer tissue using real-time quantitative polymerase chain reaction (RT-qPCR). Mutations in codons 380, 537, and 538 of the ESR1 gene were analyzed. Results: 127 patients were included in the cohort, of which 100 (79%) had completed NET and had surgery. Among these patients, the PEPI Score ranged from 0 to 3 in 70% (70/100), and 30% (30/100) had a PEPI Score of 4 or more and were selected. 23 patients were included in the analysis (6 did not consent or were lost to follow-up, and one was HER2-positive). Patients characteristics are summarized in Table 1. The median duration of NET was 22 weeks. All samples of tumor tissue from the surgical specimens after NET were evaluable. Quantification of DNA extraction and reference gene cycle threshold values confirmed that the material was adequate for the analysis. We compared these findings with a study from our group using the same methodology in patients with advanced disease where ESR1 mutations were detected in 25% (n=32) of patients with visceral metastasis of ER+ breast cancer resistant to endocrine therapy. ESR1 mutations were not identified in any of the 23 patients with early-stage ER+ breast cancer resistant to NET (p 0.01, Fisher´s exact test) Discussion: Growing evidence supports the notion that there are different mechanisms of primary and secondary endocrine resistance. Our study suggests that ESR1 mutations do not evolve rapidly and do not represent a common mechanism of primary endocrine resistance in the neoadjuvant setting. Therefore, ESR1m should be considered a mechanism of acquired endocrine resistance in the context of advanced disease. Further research should be conducted to identify factors associated with intrinsic resistance to ET. Citation Format: Tomas Reinert, Susana Ramalho, Vivian CA Vasconcelos, Leonardo R Silva, Ana Elisa R Silva, Camila A Andrade, Maria Beatriz PL Kraft, Guilherme P Coelho, Jovana Mandelli, Monique Binotto, Cesar Cabello, Geisilene RP Silva, Jose Bines, Carlos H Barrios, Matthew J Ellis, Marcia S Graudenz. ESR1 mutations are not a mechanism of primary resistance to aromatase inhibitors in ER-positive breast cancer treated with neoadjuvant endocrine therapy [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 P2-11-08.

Abstract OT2-04-02: CheckMate 7A8: A phase 2 trial of nivolumab + abemaciclib or palbociclib + anastrozole in postmenopausal women with ER+, HER2−primary breast cancer

Background: Programmed death-1 (PD-1) pathway inhibition has demonstrated clinical activity in breast cancer (BC), with modest response rate in advanced, heavily pretreated, hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) BC. Cyclin-dependent kinase 4/6 (CDK 4/6) inhibition coupled with estrogen receptor (ER) signaling blockade is an efficient treatment approach for patients with metastatic HR+/HER2− BC, evaluated in the primary setting. Preclinical data suggest potential synergistic activity of CDK 4/6 inhibition coupled with PD-1 blockade through modulation of the tumor microenvironment by the former modality. In a syngeneic mouse tumor model, improved efficacy and complete tumor regression were observed with abemaciclib priming the immune response in phased administration of abemaciclib + anti-programmed death ligand 1 (PD-L1) therapy. Preliminary clinical data demonstrated activity of pembrolizumab + abemaciclib in a phase 1b study of pretreated patients with metastatic HR+, HER2− BC. Trial Design: CheckMate 7A8 is a randomized, noncomparative, multicenter, phase 2 study evaluating nivolumab + either abemaciclib or palbociclib + anastrozole in postmenopausal patients with ER+, HER2− primary BC. After determining safe doses for the nivolumab combination regimens in the safety run-in phase, patients will be randomized in a 4:4:3:4:4:3 ratio to 1 of 6 treatment arms (Table) stratified by PD-L1 expression (+ or −), node status (+ or −), and tumor size (> 3 cm or ≤ 3 cm). Following treatment, all patients will undergo surgery and safety follow-up. Eligible patients are postmenopausal women with newly diagnosed, untreated, histologically confirmed ER+, HER2− BC with primary tumor ≥ 2 cm; with measurable disease based on RECIST v1.1; suitable for neoadjuvant endocrine monotherapy and surgery; have an ECOG PS of 0 or 1; have tumor tissue available at baseline; and are willing to undergo on-treatment research biopsy and tissue collection at surgery. Women of childbearing potential or who are breastfeeding, have a history of ipsilateral invasive BC regardless of treatment or DCIS treated with radiotherapy, metastatic disease, inflammatory/inoperable, multicentric, or bilateral invasive BC, or those suitable for neoadjuvant chemotherapy are excluded. Primary study endpoints are: i) number of patients with occurrence of dose-limiting toxicity (safety run-in phase), and ii) residual cancer burden (RCB) 0-I rate by central assessment at time of definitive surgery (randomized phase). Secondary endpoints include safety and tolerability, pathologic complete response, and objective response rate. Key exploratory endpoints include biomarkers indicative of pharmacodynamic changes in the tumor microenvironment, biomarkers predicting treatment sensitivity, changes in Ki67 levels, ER status and preoperative endocrine prognostic index score, and efficacy by PD-L1 status. Sample size was calculated assuming a 22% target RCB rate; 40 treated patients will provide 81% power at 10% 2-sided type I error to reject the null hypothesis that the true RCB rate is 8%, below which is not clinically meaningful. For primary and secondary endpoints, estimates of response rates and corresponding 95% confidence intervals will be generated for each arm using the Clopper-Pearson method. No patients have yet been recruited. For information, please contact Xiaochun.Liu@bms.com. Citation Format: Sara Tolaney, Guy Jerusalem, Roberto Salgado, Xiaochun Liu, Tian Chen, Hongxia Zhang, Mustimbo Roberts, Dimitrios Zardavas, Aleix Prat. CheckMate 7A8: A phase 2 trial of nivolumab + abemaciclib or palbociclib + anastrozole in postmenopausal women with ER+, HER2−primary 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 OT2-04-02.

Abstract P5-13-02: Neoadjuvant aromatase inhibitor therapy plus the mTOR inhibitor everolimus in postmenopausal women with hormone receptor positive/HER2 negative breast cancer and an oncotype Dx recurrence score (≤25)

Abstract Background: Breast cancer (BC) patients (pts) with Oncotype Dx recurrence scores (RS) ≤ 25 represent a large fraction of BC cases. The TAILORx study demonstrated that these pts did not receive significant benefit from adjuvant chemotherapy. Despite their low to moderate risk and sensitivity to endocrine therapy, a number of BC pts may benefit from neoadjuvant therapy. The goal of this study is to assess tumor response, utilizing the preoperative endocrine prognostic index (PEPI), to a combination of the mTOR inhibitor everolimus and an aromatase inhibitor (AI) in this pt population. Methods: This is a phase II study evaluating the efficacy and safety of neoadjuvant AI and everolimus in postmenopausal pts with hormone receptor positive (HR+)/HER2 negative clinical stage II-III BC with low risk RS (≤ 25). Patient enrollment initiated in November 2014 at the Yale Cancer Center/Smilow Cancer Hospital and Care Centers. Key inclusion criteria are ECOG 0-2, adequate organ function, a fasting cholesterol ≤ 300 mg/dl and triglycerides ≤ 2.5 x IULN. Eligible pts received daily AI therapy (anastrozole 1 mg, letrozole 2.5 mg, or exemestane 25 mg) and everolimus 10 mg daily for up to a total of 26 weeks. The primary objective of the study was to determine the percent of postmenopausal pts with clinical stage II-III HR+/HER2- BC and a RS ≤ 25 who achieve a PEPI score of 0 following neoadjuvant AI and everolimus. The secondary objectives are to assess the tolerability and side effect profile, and to identify biologic markers predictive of a PEPI 0. Simon’s optimal two-stage design was utilized with a planned sample size of 27 eligible pts. First, 15 pts will be enrolled, if 5 or more of 15 eligible patients achieve a PEPI 0, the plan is to enroll another 12 pts. If 10 or more of the 27 eligible patients achieve a PEPI 0, we will conclude that the regimen warrants further study. This design has a power of 80% and a one-sided significance level of 0.1. Results: Of the 17 pts initially enrolled, 15 were evaluable for response; 4 of 15 (26%) had a PEPI scores of 0 which did not meet the primary endpoint; 4 (26%) had a path CR and 6 (40%) had PR. Grade 3 toxicities determined to be possibly/probably study related included anemia, anorexia, hypertension, maculopapular rash and hyperglycemia. One pt developed grade 3 atrial flutter and grade 4 QT prolongation which required a dose delay. One pt required hospitalization for pneumonia. Gene expression analysis by RNA seq was performed on 9 baseline (6 pts with CR/PR vs 3 non-responders); 13 post treatment (8 pts with CR/PR vs 5 non-responders) samples with 8 matched pairs (5 pts with CR/PR vs 3 non-responders). Baseline samples from pts who had CR/PR have significantly lower expression of MYC targets and oxidative phosphorylation genes, and significantly higher expression of genes associated with epithelial mesenchymal transition and interferon signaling, in comparison to non-responders. The expression of CYP19A1 gene, that codes aromatase, is significantly increased after therapy in samples from pts with CR/PR (logFC=1.33), but not in other pts. Expression of mTORC1 signaling pathway genes is increased after therapy only in samples from pts with CR/PR. Conclusion: Although this trial did not meet the set primary endpoint, 26% of pts achieved a PEPI 0. The combination of an AI and everolimus was overall well tolerated. Our study suggested that baseline expression levels of key pathways were associated with response to neoadjuvant AI plus everolimus. Citation Format: Maysa M Abu-Khalaf, Kimberly Aderhold, Michal Marczyk, Gina Chung, Erin Hofstatter, Tara Sanft, Andrea Silber, Michael DiGiovanna, Daniel Zelterman, Lajos Puzstai, Christos Hatzis. Neoadjuvant aromatase inhibitor therapy plus the mTOR inhibitor everolimus in postmenopausal women with hormone receptor positive/HER2 negative breast cancer and an oncotype Dx recurrence score (≤25) [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 P5-13-02.

Predictive factors of 5-year relapse-free survival in HR+/HER2- breast cancer patients treated with neoadjuvant endocrine therapy: pooled analysis of two phase 2 trials

BackgroundFew data are available on survival and predictive factors in early breast cancer (BC) patients treated with neoadjuvant endocrine therapy (NET).MethodsThis is a pooled analysis of two multicentre, randomised non-comparative phase 2 clinical trials evaluating neoadjuvant anastrozole and fulvestrant efficacy for postmenopausal HR+/HER2- breast cancer patients: HORGEN (NCT00871858) and CARMINA02 (NCT00629616) studies.ResultsIn total, 236 patients were included in CARMINA02 and HORGEN trials. Modified intention-to-treat analysis was available for 217 patients. Median follow-up was 65.2 months. Relapse-free survival (RFS) and overall survival (OS) at 5 years were 83.7% (95% CI: 77.9–88) and 92.7% (95% CI: 88.2–95.6), respectively, with no difference between treatment arms. On univariate analysis, tumour staging (T2 vs T3–4; p = 0.0001), Ki-67 at surgery (≤10% vs >10%; p = 0.0093), pathological tumour size (pT1–2 vs pT3–4; p = 0.0012) and node status (pN negative vs positive; p = 0.007), adjuvant chemotherapy (p = 0.0167) and PEPI score (PEPI group I + II vs III; p = 0.0004) were associated with RFS. No events were observed in patients with pathological response according to the Sataloff classification. Multivariate analysis showed that preoperative endocrine prognostic index (PEPI) group III was associated with significantly worse RFS (p = 0.0069, hazard ratio = 3.33 (95% CI: 1.39–7.98)).ConclusionsPostmenopausal HR+/HER2- breast cancer patients receiving NET generally have a favourable outcome. The PEPI score identifies a subset of patients of poorer prognosis who are candidates for further additional treatment.

The Immune Checkpoint Kick Start: Optimization of Neoadjuvant Combination Therapy Using Game Theory.

In an upcoming clinical trial at the Moffitt Cancer Center for women with stage 2/3 estrogen receptor-positive breast cancer, treatment with an aromatase inhibitor and a PD-L1 checkpoint inhibitor combination will be investigated to lower a preoperative endocrine prognostic index (PEPI) that correlates with relapse-free survival. PEPI is fundamentally a static index, measured at the end of neoadjuvant therapy before surgery. We have developed a mathematical model of the essential components of the PEPI score to identify successful combination therapy regimens that minimize tumor burden and metastatic potential, on the basis of time-dependent trade-offs in the system. We considered two molecular traits, CCR7 and PD-L1, which correlate with treatment response and increased metastatic risk. We used a matrix game model with the four phenotypic strategies to examine the frequency-dependent interactions of cancer cells. This game was embedded in an ecological model of tumor population-growth dynamics. The resulting model predicts evolutionary and ecological dynamics that track with changes in the PEPI score. We considered various treatment regimens on the basis of combinations of the two therapies with drug holidays. By considering the trade off between tumor burden and metastatic potential, the optimal therapy plan was a 1-month kick start of the immune checkpoint inhibitor followed by 5 months of continuous combination therapy. Relative to a protocol giving both therapeutics together from the start, this delayed regimen resulted in transient suboptimal tumor regression while maintaining a phenotypic constitution that is more amenable to fast tumor regression for the final 5 months of therapy. The mathematical model provides a useful abstraction of clinical intuition, enabling hypothesis generation and testing of clinical assumptions.

Open label, phase II trial of neoadjuvant TAK-228 plus tamoxifen in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor type 2 (HER2)-negative breast cancer-ANETT.

584 Background: Neoadjuvant endocrine therapy is standard care for women with hormone receptor-positive breast cancer. However, both primary and acquired endocrine resistance is not uncommon, thereby limiting efficacy. [1] The PI3K-Akt-mTOR pathway is a major mediator of endocrine resistance. [2,3] Therefore, we determined the efficacy and safety of the mTORC1/2 inhibitor TAK-228 in combination with tamoxifen in neoadjuvant setting. Methods: In this single-arm, open-label phase II trial, newly diagnosed patients with stage I−III ER-positive, HER2-negative breast cancer received TAK-228 (30 mg weekly) and tamoxifen (20 mg daily) for 16 weeks until 2-4 weeks prior to surgery. The primary endpoint was the change in Ki67 after 6 weeks. Secondary endpoints included pathological complete response rate (pCR), preoperative endocrine prognostic index (PEPI) score, and safety. Results: Of the 28 patients enrolled in the study, 3 were excluded due to non-compliance. Mean patient age was 51.7 years. Most patients had stage I or II disease (12 [43%] each); 4 (14%) had stage III disease. Mean Ki67 was significantly lowered from baseline to Week 6 (17.2% vs. 15.2%, p = 0.0023). Interestingly, mean Ki67 increased to 20.1% from baseline to the time of surgery. This may have been due to a rebound effect, as TAK-228 was discontinued 2-4 weeks prior to surgery. Tumor size also significantly decreased from baseline to surgery, with a median decrease of 0.75 centimeters (p < 0.0001). PEPI score was intermediate risk (score 1−3) in 6 patients and high risk group (score ≥4) in 15 patients. No patients achieved a PEPI score of 0 and no pCR was achieved. Overall, the combination was well tolerated, the most common side effects were nausea (72%), vomiting (72%), fatigue (72%), mucositis (45%), and headache (45%). The any Grade 3 AE rate was 7.7%. Conclusions: The TAK-228 and tamoxifen combination was found to be an effective neoadjuvant strategy with a favorable safety profile in newly diagnosed patients with hormone receptor-positive breast cancer. Further molecular analysis (PI3K-Akt-mTOR pathway) are pending and will be presented. Clinical trial information: NCT02988986.

5-years RFS and prognostic factors study in HR-positive HER2-negative breast cancer patients treated with neoadjuvant endocrine therapy : Pooled analysis of two phase II trials

Background Few data are available on survival of breast cancer (BC) patients (pts) treated with neoadjuvant endocrine therapy (NET). Understanding how tumor response to NET is related to relapse risk would help clinicians make decisions about additional treatments for these pts. Methods The primary objective was to assess 5-years relapse-free survival (RFS) in previously published two sister phase II studies evaluating anastrozole and fulvestrant as NET in post-menopausal HR-positive/HER2-negative BC pts (CARMINA02 NCT00629616 ; HORGEN NCT00871858 ). Prognostic factors of RFS were explored by pooling the two databases : age ( 70), tumor and node staging, histological type and grade, clinical response, pathological response according to the Sataloff classification, baseline and surgical ER Allred score and Ki-67 expression, treatment arm, preoperative endocrine prognostic index (PEPI) score, adjuvant chemotherapy. The factor study (Horgen vs. Carmina02) was also introduced in the model as covariate. Univariate and multivariate Cox regression analysis (covariates from univariate model with P-value Results Intention-to-treat analysis is available for 217 of 236 pts included in the two trials. Post-menopausal pts with T2–T4, N0–N1, M0, HR-positive/HER2-negative BC were randomized to receive anastrozole (PO, 1 mg daily) or fulvestrant (IM, 500 mg on D1, D15 and D29 and then every 4 weeks) for 4 to 6 months before surgery. Mean age at diagnosis was 71.2 years. Baseline tumor characteristics were : 73.7 % T2, mean tumor size 44.3 mm, 66.4 % N0, 19.4 % SBR grade 1, 98.6 % ER Allred score 6-8, mean Ki67 score 17.5 % with Ki67 > 20 % in 29.5 % of cases. A clinical response (complete or partial) was observed in 50.2 % of pts and pathological response rate defined as TA or TB and NA or NB was 15.7 %. Mean Ki67 at surgery was 8.8 % (11.4 % of cases > 20 %). Among the pts, 12.4 % were classified in PEPI risk group I (risk score 0), 35.5 % in group II (score 1–3) and 30.4 % in group III (score > 4) (PEPI not available for 21.7 % of pts) ; 21.7 % of pts received adjuvant chemotherapy. Median follow-up is 65.2 months. RFS and overall survival at 5 years are 83.7 % [95 % CI : 77.9–88 %] and 92.7 [95 % CI : 88.2–95.6 %] respectively. On univariate analysis, tumor staging (T3–4 versus T2, P = 0.0001) and PEPI score (I + II versus III, P = 0.0004) are associated with RFS. So far, no relapses/death have been observed in pts with pathological response (n = 34, 15.7 %). Multivariate analysis (T, baseline Ki67, ER Allred score at surgery, PEPI and study) shows that PEPI group III is associated with significantly worse RFS (P = 0.0014, HR : 3.9 [95 % CI : 1.7–9.0]). Conclusion Post-menopausal HR-positive/HER2-negative BC pts receiving NET have a very favorable outcome. Within this population eligible for NET, the PEPI score identifies a subset of pts of poorer prognosis who are candidate for further additional treatment like chemo/or targeted therapies. The PEPI may be a tool routinely used for individualization of adjuvant treatment in NET setting. According to recent published studies, further analysis will be performed with Ki67 > 10 % and PEPI risk (group I versus groups II–III).

Abstract P4-12-04: Cost-effectiveness analysis of locally advanced estrogen receptor-positive, HER-2 negative breast cancer care using a tailored treatment approach in Brazil

Abstract Introduction: Breast cancer is the most common cancer in women worldwide, and 70% of breast cancer deaths occur in women from low-income and middle-income countries. In Brazil there were 14388 deaths due to this disease in 2013 and an estimate of over 58000 new cases in 2016. Neoadjuvant endocrine therapy (NET) is an attractive alternative to Neoadjuvant chemotherapy (NAC) for Hormone Receptor-positive tumors and could be a resources-saving strategy of treatment. Methods: We built a decision analysis model of breast cancer treatment to compare a NET schema, with response based on the evaluation of Ki-67, against the surgery followed by adjuvant chemotherapy (AC) and radiation therapy (RT) standard-of-care as two competing approaches to breast cancer management. Our objective is to determine whether tailoring chemotherapy treatment based on response to neoadjuvant endocrine therapy is a cost-effective approach. The NET schema is based on the ACOSOG Z1031B trial, in which post-menopausal women with estrogen receptor-positive, HER-2 negative disease would receive 4 weeks of NET followed by a core-needle biopsy for Ki-67 evaluation. If Ki-67 were lower than 10%, patients would continue in NET for 16-18 weeks followed by surgery and RT according to international guidelines. The indication of AC in these patients would be based on the preoperative endocrine prognostic index (PEPI). Patients with a PEPI score equal to zero would be spared from AC. If Ki-67>10%, patients would be triaged to NAC or surgery. The cost-effectiveness analysis was conducted using a Markov model from the provider's perspective, in this case the Brazilian Health ministry. Healthcare costs, in the form of charges from the hospitals to the health ministry, were obtained from cost tables available at the federal government's webpage. In the Markov model, possible health states were disease-free, local relapse, metastatic disease and death.Transition probabilities and mortality rates were extracted from randomized studies. Our assumptions were that both treatment strategies have similar clinical outcomes and that Ki-67 is a reliable method to triage patients to NAC or surgery. We performed one-way sensitivity analysis to assess the impact of the failure of the Ki-67 test on cost-effectiveness. Results: Our model shows that the NET schema dominates the standard-of-care strategy. Costs were R$ 47799.89 per patient for the NET strategy and R$79809.24 for the standard-of-care strategy. There was an incremental cost saving of R$32009.36 per patient for the NET strategy compared to the standard-of-care strategy. Cost-effectiveness of the NET strategy was R$2612.63 and R$4369.11 for the standard-of-care. Considering the willingness-to-pay of R$ 85494.00, defined by the World Health Organization as three times the gross domestic product per capita, the standard-of-care strategy would only be more cost-effective in the scenario of a Ki-67 test that misclassifies patients more than 9.1% of the time. Conclusion: The use of response to neoadjuvant endocrine treatment based on Ki-67 analysis as a way to tailor locally advanced breast cancer treatment is a cost-saving strategy in the presence of robust biomarkers. Citation Format: Goncalves R, Reinert T, Ellis MJ, Sarian LO, Filassi JR. Cost-effectiveness analysis of locally advanced estrogen receptor-positive, HER-2 negative breast cancer care using a tailored treatment approach in Brazil [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 P4-12-04.

Abstract P4-01-03: Predictive value of FDG-PET/CT after neoadjuvant endocrine treatment in breast cancer

Abstract Background: Neaodjuvant endocrine therapy (NET) has demonstrated efficacy in terms of clinical response and outcome in hormone-receptor positive (HR+) post-menopausal patients (pts) with breast cancer (BC) not eligible for primary breast conservative surgery (BCS). However, the monitoring of tumor response to NET is challenging and clinical response is the current gold standard. The aim of the present study was to investigate the contribution of the early metabolic response (eMR) at one month in FDG-PET/CT in a NET setting for post-menopausal pts with HR+, HER2- BC compared to morphological and pathological responses. We also aimed to evaluate the prognostic value of eMR. Methods: This was a prospective and ancillary study of CARMINA 02, UCBG0609 (Cancer in press), a phase II clinical trial evaluating the efficacy of 4 to 6 months neoadjuvant anastrozole or fulvestrant. FDG-PET/CT exams were performed at baseline (M0), after 1 month of treatment (M1: eMR) and pre-Op (late metabolic response: lMR) in 11 pts (74.2 years ± 3.6) from 2007 to 2010. Pts were classified “metabolic responders” (mR) if SUVmax values decrease was ≥ 40% at M1 and “non-metabolic responders” (mNR) if otherwise; lMR was also assessed in mR and mNR groups defined at M1. We compared eMR to morphological response (clinical, breast US and MRI) at M1 and pre-op, to the pathological response according to Sataloff classification and to Ki67 score variation during treatment. Early metabolic response was also correlated with the PEPI (Preoperative Endocrine Prognostic Index) score and survival (overall survival, OS and relapse free survival, RFS). Results: Main results are summarized in Table I. There was a significant difference between mR and mNR pts at M1 (eMR) and pre-op (lMR). One patient with a complete metabolic response at pre-op had the best pathological response (Sataloff TB). Also, mR pts had a better clinical response: 2 partial response (PR) in mR vs 1 in mNR group and 2 mNR patients were classified PD (progressive disease). There was a trend toward better survival for mR pts in OS and RFS (Kaplan-Meier p=0.18 and 0.06, respectively) and all the pejorative events occurred in the mNR group: 3 deaths and 3 metastatic progressions. Besides, no difference in eMR was observed regarding the histological subtype (ductal or lobular; p>0.05) nor the treatment group (p>0.05). Table I: Metabolic, morphological and pathological response at M1, Pre-Op and on the surgical specimen. MR : 5ptsmNR : 6ptsP valueM1SUVmax2.6±1.13.9±1.40.00017 Clinical size42.5mm±11.951.7mm±7.50.19 US size22.6mm±6.334.2mm±2.40.02 MRI size21.2mm±4.239.7mm±4.79.16 E-5 Ki 673.6%±1.98.2%±80.19Pre-OpSUVmax2±1.33.3±1.40.018 Clinical size31mm±12.448.3mm±10.80.035 US size18.5mm±7.331.3mm±9.50.07 MRI size17.9mm±7.134.8mm±7.70.003Surgical SpecimenSataloff (TA+TB vs TC+TD)20% vs 80%0 vs 100%1 PEPI score (I+II vs III)80% vs 20%33 vs 67%0.048 Ki 678.6%±9.812.3%±7.90.41 Conclusions: These preliminary results showed the value of the early metabolic response in FDG- PET/CT in a NET setting compared to the morphological or the pathological responses alone. Early metabolic responders patients had better OS, RFS and PEPI scores. Citation Format: Boughdad S, Champion L, Becette V, Cherel P, Fourme E, Edeline V, Lemonnier J, Lerebours F, Alberini JL. Predictive value of FDG-PET/CT after neoadjuvant endocrine treatment in breast cancer [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 P4-01-03.

Abstract OT3-02-06: Femara plus ribociclib or placebo as neo-adjuvant endocrine therapy for women with ER+, HER2-negative early breast cancer - The Feline trial

Abstract 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.