Receptor-positive HER2-negative Breast Research Articles

Populations of Triple Negative and Hormone Receptor Positive HER2 Negative Breast Tumors Share Immune Gene Profiles

Populations of Triple Negative and Hormone Receptor Positive HER2 Negative Breast Tumors Share Immune Gene Profiles

Populations of triple negative and hormone receptor positive HER2 negative breast tumors share immune gene profiles.

In breast cancer, triple negative (TN) breast cancer has most responses to immune checkpoint inhibitor (ICI) therapy. Lymphocyte infiltrate does not impact prognosis in Hormone receptor positive HER2 negative (HR + HER2-) breast tumors and few HR + HER2- tumors respond to ICI. We contrasted immune-associated gene expression between 119 TN and 475 HR + HER2- breast tumors from The Cancer Genome Atlas (TCGA) and confirmed our findings in 299 TN and 1369 HR + HER2- breast tumors in the METABRIC database. TN and HR+ HER2- tumors grouped into immune-high or -low tumors, both subtypes were represented in the immune-high group. The largest difference between the immune-high TN and HR + HER2- tumors was TN tumors had more abundant Th1 and Th2 CD4+ T cells while HR + HER2- tumors had more abundant fibroblasts (log2FC > 0.3; p < 10×10-10). This suggests an immune-high signature is not dictated by breast cancer subtype, but fibroblast subsets associated with worse outcome were higher in the immune-high HR + HER2- tumors.

Abstract PO2-15-01: EZH2 protein expression in early hormone receptor positive HER2 negative breast cancer with high recurrence score

Abstract Background: The 21 gene recurrence score assay (RS) is both prognostic and predictive of chemotherapy benefit in hormone receptor positive (HR+) HER2 negative (HER2-) breast cancer (BC). While patients (pts) with RS&amp;gt;26 benefit from chemoendocrine therapy, they remain with poorer outcomes than pts with lower RS. Overexpression of the enhancer of zeste homolog 2 oncoprotein (EZH2) is linked to poor prognosis in multiple cancers, and is associated with resistance to endocrine therapy in HR+/HER2- BC. We evaluated association between EZH2 expression and distant metastases in a single institution cohort of pts with HR+/HER2- BC and RS&amp;gt;26. Methods: Pts with ER+/HER2- BC and RS&amp;gt;26 who underwent surgery at our institution between 2011 and 2017 were identified from pathology database. All pts with available tumor specimens were included in analysis. Immunohistochemistry was performed to evaluate EZH2 protein expression within invasive tumor cells and quantified as follows: nuclear staining intensity was scored as 3 (strong), 2 (moderate), 1 (weak), and 0 (no stain). Percentage of positive nuclei at each intensity was multiplied, and all values were added to arrive at a final EZH2 score multiplied by 100, ranging from 0 (no nuclei staining) to 300 (strong nuclear staining in 100% of cells). The investigator scoring EZH2 staining was blinded as to pts clinical outcomes. EZH2 score was both evaluated as a continuous variable and dichotomized at a score of 140. Associations between EZH2 score and age at diagnosis, progesterone receptor (PR) status, tumor size, grade, node involvement, RS, and metastatic recurrence were determined by Kruskal-Wallis or Wilcoxon rank-sum tests for categorical variables and Spearman correlation coefficients for continuous variables. Results: 45 pts were included. Median (IQR) age was 60 (55, 69). 32 (71.1%) pts received chemotherapy. 37 (82.2%) pts received endocrine therapy. Tumor size was ≤2 cm in 26 pts (57.8%), and &amp;gt;2 cm but ≤5 cm in 19 pts (42.2%). 7 pts (15.6%) had involved axillary nodes. Median RS was 31 (28, 37). Median EZH2 score was 120 (90, 170). With median follow-up of 7.6 (5.7, 9.2) years, 4 pts (8.9%) developed distant metastatic disease. EZH2 score was significantly associated with development of metastatic disease, both when EZH2 was expressed as a continuous variable (p=0.040) and when dichotomized at 140 (p=0.015). EZH2 score was positively associated with RS (r = 0.37; p=0.013) and negatively associated with age at diagnosis (r = -0.44; p=0.002), but was not associated with clinicopathologic features such as tumor size, grade, node involvement, and PR status. Younger age was also associated with development of metastatic disease (p=0.023), whereas tumor size, grade, node involvement, PR status, RS, and receipt of chemotherapy were not. Conclusion: In this single institution cohort of pts with early HR+/HER2- BC and high RS, EZH2 protein expression and younger age were associated with development of distant metastases. This preliminary data suggests that determination of EZH2 expression levels may assist in risk stratification of pts with high RS. This should be investigated in a larger data set. Citation Format: Shuwen Lin, Yungtai Lo, Della Makower, Jinyu Lu, Susan Fineberg. EZH2 protein expression in early hormone receptor positive HER2 negative breast cancer with high recurrence score [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 PO2-15-01.

Abstract PO5-20-04: A Phase II Study of Ribociclib and Endocrine Treatment of Physician’s Choice for Locoregional Recurrent, Resected Hormone Receptor Positive HER2 Negative Breast Cancer (RaPhLRR Study)

Abstract Background Hormone receptor positive (HR+) breast cancer (BC) is the most common subtype of BC (70-80%). This subset tends to have good prognosis, therefore most patients with localized disease have excellent long-term survival, approaching 100% 5-year relative survival. However, 10% of patients experience loco-regional recurrence (LRR) within 5 year of final surgical management of the primary disease-well within the typical treatment window of adjuvant endocrine therapy. Few studies exists to guide the systemic treatment of patients who have suffered LRR of HR+ HER2 - BC. The randomized controlled CALOR trial demonstrated no benefit to systemic cytotoxic chemotherapy for this subgroup of patients and persistent high rate of subsequent recurrences (50% within 10 years on LRR event). There is no standard of care for managing this patient population. The combination of ribociclib and endocrine therapy (ET) (fulvestrant and aromatase inhibitors) is FDA approved for management of unresectable recurrences and metastatic HR+HER- BC (MONALEESA trials). CDK4/6 inhibitors have been investigated in early BC setting too, several trials showing positive results (monarchE, NATALEE). Data is needed to investigate their use in patients with LRR. Trial design This is a multicenter, single arm phase II study to evaluate efficacy and safety of ribociclib and ET in patients with LRR of HR+HER2- BC. Treatment includes ribociclib for 36 months, 600 mg daily for 21 days, 28-day cycle plus physician’s choice ET for 60 months (fulvestrant or AIs). Ribociclib dose was chosen based on approved dose in metastatic BC. Eligibility Criteria Patients ≥ 18 of age, with LRR of BC (ipsilateral breast, axilla, regional lymph nodes, chest wall), histologically confirmed estrogen receptor positive and/or progesterone receptor positive, HER 2 negative. Patients must have adequate local treatment for LRR (surgery and/or radiation) with negative microscopic margins, no evidence of distant metastatic disease. Prior treatment with neo-adjuvant and adjuvant chemotherapy and ET is allowed, no prior CDK 4/6 inhibitor in the last 12 months. Pre and post-menopausal women are allowed. Patient must enroll within 6 months of the last local therapy. Specific aims Primary objective: to estimate subsequent recurrence-free survival (RFS) at 3 years for ribociclib when administered with ET in patients with HR + HER2- BC with adequately resected local recurrence. Secondary objectives: to estimate distant metastasis-free survival and overall survival, to evaluate safety and tolerability, to identify predictors of LRR. Correlative analysis will explore prognostic and predictive biomarkers of treatment with ribociclib and ET and potential molecular mechanisms of resistance to treatment. Statistical Methods From previous published data (J Clin Oncol. 2018 Apr 10;36(11):1073-1079), we assume that patients receiving standard of-care management following recurrence would have a recurrence free survival (RFS) rate of 80% at 3 years and that treatment with ribociclib + ET will increase it by 7%. We wish to have at least 80% power at that significance level of 0.0487 to correctly detect that improvement in RFS rate at 3 years from 80 to 87%. Because only an improvement in RFS rate is of clinical interest, we have a directional hypothesis, and have used a 1-sided alpha. Using a one-sample survival study design, with assumed accrual duration of 3-years and additional follow-up time of 3 years, the minimum sample size requirement is N=180 patients. Target accrual The minimum sample size requirement is N=180 patients. A bigger sample size of N=200 patients will achieve a power of at least 84%. Current accrual is 6/200. This study will be open at up to 35 sites. Contact information The study is being administered through the HCRN, it can be identified as BRE20-468, NCT05467891, ocdanciu@uic.edu Citation Format: Oana Danciu, Nancy Chan, Kari Wisinski, Trish Millard, Kathleen Kemmer, Sneha Phadke, Zhengjia Chen, Ana Cuesta Fernandez, Melanie Clark, Alison Conlin, Coral Omene, Sima Ehsani, Stephanie Dublis, Vijayakrishna K. Gadi. A Phase II Study of Ribociclib and Endocrine Treatment of Physician’s Choice for Locoregional Recurrent, Resected Hormone Receptor Positive HER2 Negative Breast Cancer (RaPhLRR Study) [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 PO5-20-04.

Detection of circulating tumor DNA following neoadjuvant chemotherapy and surgery to anticipate early relapse in ER positive and HER2 negative breast cancer: Analysis from the PENELOPE-B trial.

502 Background: The PENELOPE-B phase III trial investigated the addition of one year of palbociclib to endocrine therapy (ET), in patients with hormone receptor positive HER2 negative breast cancer with residual invasive disease after neoadjuvant chemotherapy. Prior research has demonstrated that detection of circulating tumor DNA (ctDNA) in the adjuvant setting is associated with a high risk of disease relapse. We assessed the potential of ctDNA analysis to predict future clinical relapse for patients enrolled in the PENELOPE-B trial. Methods: Patients who were endocrine naïve at the time of study entry were selected for ctDNA analysis. Plasma samples were collected at baseline (after completion of neoadjuvant chemotherapy and surgery), prior to cycle 7 (approximately 6 months into ET +- palbociclib), end of treatment (EOT), and progressive disease. A tumor sample was subjected to exome sequencing, and up to 50 tumor somatic mutations were tracked in plasma using error-corrected sequencing combined with a proprietary algorithm for ctDNA detection (RaDaR assay). Detection of ctDNA was associated with invasive disease-free survival (iDFS) and distant metastasis-free survival using Cox proportional hazard models. Results: Of 1250 patients enrolled in PENELOPE-B, 129 were endocrine naïve at trial entry, and 78 had a baseline ctDNA sample analyzed. The ctDNA analysis group was representative of the overall endocrine naïve group, with median follow-up of 42.9 months. Seven patients had baseline ctDNA detected, with detection strongly associated with iDFS (HR 8.8, 95% CI 3.3-23.4, p &lt; 0.0001). Detection of ctDNA at cycle 7 (4 patients) was also strongly associated with iDFS (HR 25.5, 95% CI 6.5-99.6, p &lt; 0.0001). Of the 7 patients with baseline ctDNA detection, 2 had undetectable ctDNA at cycle 7 and remained progression free at 30 months, although one later relapsed; the 3 patients with detectable ctDNA at cycle 7 all relapsed within 25 months. Of the 12 patients with a distant relapse within 24 months, only 4 had ctDNA detected at baseline and 3 first at cycle 7/EOT. Of the 8 patients with distant relapse after 24 months, 2 had ctDNA detected at baseline and none first at cycle 7/EOT. Conclusions: Detection of ctDNA following neoadjuvant chemotherapy, and surgery, is associated with a very high risk of early relapse suggesting limited efficacy of adjuvant ET. Clinical imaging and studies of experimental therapy are warranted in this patient population. Testing ctDNA after recent neoadjuvant chemotherapy in luminal-A like breast cancer has relatively low ‘sensitivity’ for predicting future relapse, in particular for later relapses, in part suggesting that response to neoadjuvant chemotherapy may reduce ctDNA detection. Clinical trial information: NCT01864746 .

Abstract P5-09-05: A phase II, single-arm study of histone deacetylases inhibitor Tucidinostat and Exemestane as neoadjuvant therapy in patients with hormone receptor positive HER2 negative breast cancer (NeoTEE trial)

Abstract Background: Tucidinostat (formerly known as chidamide) plus exemestane is approved for postmenopausal patients with advanced, hormone receptor-positive breast cancer. We evaluated the efficacy and safety of tucidinostat plus exemestane as the neoadjuvant strategy in hormone receptor-positive early breast cancer patients. Methods: NeoTEE is an open-label, single-center, phase II study. Patients with HR-positive, HER2-negative and stage II/III breast cancer were enrolled at the First Affiliated Hospital of Sun Yat-sen University. Eligible patients received 25 mg oral exemestane once daily for 2 weeks followed by 30 mg oral tucidinostat twice weekly in combination with 25mg oral exemestane once daily for 24 weeks. GnRHa was used for premenopausal patients. Endpoints assessed here included objective response rate (ORR), complete cell cycle arrest (CCCA, Ki-67≤2.7%) at surgery, disease control rate (DCR), pathological complete remission (pCR) and safety. Results: Between July 2020 and July 2022, 26 patients were enrolled, of whom 24 were evaluable for response per RECIST 1.1 criteria. Partial response (PR) was observed in 18 patients, with an ORR of 75% (18/24). The DCR was 100%. Of the 14 patients with surgery, one patient achieved pCR and 8 patients were exempt from postoperative adjuvant chemotherapy. CCCA at surgery was 64.3% (9/14). The follow-up remains ongoing and updated results will be presented thereafter. Most adverse events (AEs) were grade 1 or 2. Grade 3 AEs occurred in 8 of 26 patients, the most common were neutropenia 19.2%, leukopenia 7.7%, anemia 3.8%, ALT increased 3.8%, pneumonitis 3.8%. Only 1 patient experienced grade 4 neutropenia. Grade 3/4 neutropenia recovered after dose reduction or discontinuation of tucidinostat. No patient received G-CSF. Conclusions: Tucidinostat combined with exemestane was well tolerated and demonstrated meaningful responses in neoadjuvant setting for women with early HR+/HER2- breast cancer. Further investigation is warranted. Clinical trial information: NCT04465097. Citation Format: zhen shan, nan shao, xiaoling zhang, huijuan shi, yanling zheng, jia luo, tiantian zhen, ruping chen, Ying Lin. A phase II, single-arm study of histone deacetylases inhibitor Tucidinostat and Exemestane as neoadjuvant therapy in patients with hormone receptor positive HER2 negative breast cancer (NeoTEE 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 P5-09-05.

Liver metastasis in estrogen receptor-positive HER 2-negative breast cancer. Ribociclib as prognosis-changing therapy

The life expectancy of patients with metastatic luminal HER 2-negative breast cancer has stagnated at the level of 40 months for many years. The introduction of CDK4/6 inhibitors into practice has changed the standards of therapy, providing not only a significant increase in the time without progression while maintaining a high quality of life, but also significantly increasing overall survival. The presence of liver metastases determines an extremely unfavorable prognosis, with GH+HER 2-mBC reducing life expectancy to a median of 21 months. Endocrine therapy combined with ribociclib significantly increased overall survival rates on average per year, reaching medians of 36.1 and 46.5 months, depending on the line of treatment. This publication is devoted to liver metastases in breast cancer, in particular in the luminal HER 2-negative subtype. Epidemiological aspects are considered, the possibilities of modern systemic therapy are evaluated. A clinical case of successful therapy with ribociclib in a young patient with liver damage is presented.

Abstract 6151: Tumor microenvironment heterogeneity identifies potential biomarkers of response in ER-positive breast cancers treated with palbociclib

Abstract Despite the breast cancer microenvironment being recognized as a critical participant in tumor progression and therapeutic response, current technologies for tumor cell-to-cell interaction analyses are limited to qualitative and descriptive histological methods. Here, we utilized multiplex immunofluorescence (MxIF), RNA sequencing (RNA-seq), and microarray gene expression to quantitatively assess, using the BostonGene automated pipeline, the immune microenvironment composition of clinical stage 2 or 3 primary estrogen receptor-positive (ER+) HER2-negative (HER-) breast tumors (n = 29) from patients treated with neoadjuvant palbociclib in combination with anastrozole. Microenvironment characteristics of pretreatment tumor biopsies were associated with molecular subtype, cytokine signatures, and Ki67 response. MxIF analysis (21 markers, 2-13 ROIs per slide) of the tumor immune composition revealed that while the cellular composition was similar for each tumor region of the same patient, significant cellular heterogeneity was observed in tumor biopsies from different patients. The spatial heterogeneity was found in the distribution of both immune infiltrate cells and stromal components. T cells, CD68+ and CD163+ macrophages, and B cells were the predominant cell populations in the stromal component. Further MxIF analysis showed an increase in Ki67+ tumor cells in nonresponders (NR) versus responders (R). The number of immune cells was similar between Luminal A and B breast cancer molecular subtypes. A lower number of Ki67+ tumor cells was found in Luminal A compared to Luminal B tumors, as expected. MxIF analysis of cell-to-cell interactions revealed that distinct groups of cellular neighborhoods were significantly increased in NR compared with R: the immune inflammation cluster with a high density of CD4 T cells, Tregs, and CD8 T cells in the stromal component (p = 0.03); CD163+ macrophage-enriched cluster (p &amp;lt; 0.001); and tertiary lymphoid structures cluster (p &amp;lt; 0.001). Transcriptomic analysis showed that while CXCL1, CCL17, CCL13, CXCL9, and CCL5 expression correlated with the high density of CD4 and CD8 T cells in the stromal component cluster, VEGFA, IL1B, CXCL16, CCL3, and CCL7 were increased in the CD163+ and CD68+ macrophage-enriched clusters, indicating that differential cytokine expression is associated with the tumor architecture.Comprehensively characterizing, via MxIF, the immune microenvironment of ER+ HER2- breast cancer provided resolution of cellular architecture and elucidated spatial relationships among the immune and stromal cells of the tumor. Quantitatively assessing breast tumor cell-to-cell interactions has the potential to identify imaging markers of response, ultimately leading to the development of effective therapy options. Citation Format: Maria Bruttan, Souzan Sanati, Anna Belozerova, Ilia Galkin, Akshaya Ramachandran, Pavel Ovcharov, Grigory Perelman, Viktor Svekolkin, Ekaterina Postovalova, Alexander Bagaev, Krystle Nomie, Shana Thomas, Jeremy Hoog, Ravshan Ataullakhanov, James Hsieh, Cynthia Ma. Tumor microenvironment heterogeneity identifies potential biomarkers of response in ER-positive breast cancers treated with palbociclib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6151.

Comparison of predicted benefit using RS clin versus observed benefit in a U.S. registry of stage I ER-positive HER2-negative high oncotype DX RS breast cancer.

544 Background: The 21-gene recurrence score assesses the risk of distant breast cancer recurrence and predicts the benefit of adjuvant chemotherapy in ER positive early-stage breast cancer. However, clinicopathologic risk factors continue to impact absolute benefit of adjuvant chemotherapy. Absolute benefit of adjuvant chemotherapy in low clinicopathologic risk Stage I ER positive breast cancer with high Oncotype RS is an important clinical component of shared decision making. The RSClin clinical tool, which integrates the 21-gene recurrence score (RS) and clinicopathologic features, was found to be more prognostic than RS result alone. We assessed RS Clin predicted benefit and compared to absolute benefit in low clinicopathologic risk Stage I ER positive breast cancer with high Oncotype RS as observed in the NCDB. Methods: Using the National Cancer Data Base (NCDB), we identified female patients age 18-75, ER positive and Her 2 negative, 21 gene signature high risk &gt; 25 with negatives surgical margins, &lt;2cm, lymph node negative breast cancers, who had received endocrine therapy with either Tam or AI diagnosed during 2010 - 2017. Clinicopathologic factors and RS were entered into the RSClin calculator, and a predicted benefit of chemotherapy was calculated for each patient. Using NCDB data, Cox proportional hazards regression models were used to project absolute survival benefit at 10 years from diagnosis for those who did vs those who did not receive chemotherapy. NCDB-derived absolute benefit of chemotherapy was compared to estimated absolute benefit as predicted by the RSClin tool. Results: 18,226 patients were identified. Stages T1a = 670(4%), T1b = 4,289(23%), and T1c = 13,267(73%). Median age 59 years (21-75). Race white 84% (15,365), black 10% (1840), and other 1021(6%). AI use 80% (14,711) was greater than Tam use 20% (3515). Chemotherapy was administered in 75% (13,827) of patients. Most patients had high or intermediate grade disease, G3 45% (8225), G2 46% (8328), and G1 9% (1672). Median duration of follow up was 57 months (2-160). Probability of death T1b at 10yrs with chemotherapy was 8.5%, and without chemotherapy was 15.1% with an absolute benefit of 6.6%. Predicted benefit in T1b using RS Clin at 10yrs was 10.8%. Probability of death for T1c at 10yrs with chemotherapy was 15.1%, and without chemotherapy was 23.5% with an absolute benefit of 8.4%. Predicted benefit in T1c using RS Clin at 10yrs was 14%. Conclusions: Patients with stage IB and IC hormone receptor positive HER2 negative breast cancers with high RS had a lower absolute benefit than predicted by RS Clin. The RSClin tool overestimated benefit of therapy in both IB and IC stages requiring caution when using this tool in patients with the lowest clinicopathologic risks.

Treatment sequence for hormone receptor-positive HER2-negative advanced breast cancer: Results of a retrospective analysis of Russian patients diagnosed with aBC in 2014-2021.

e13032 Background: CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) have dramatically changed therapeutic landscape of hormone receptor-positive HER2-negative advanced breast cancer (HR+ HER2- aBC). There are three iCDK4/6 in Russia, which are available and included into the clinical guidelines as a preferred first line treatment option beginning since 2018. The aim of this study was to assess evolution of treatment approaches to HR+ HER2- aBC and identify demographic and disease characteristics in correlation with available groups of therapy (chemotherapy, endocrine therapy ±mTOR inhibitors/ CDK4/6i). Methods: Аdult patients diagnosed with de novo or recurrent HR+ HER2- aBC in 2014-2021 identified in outpatient departments of Moscow state oncology hospitals were included into our non-interventional, descriptive, retrospective cohort study. Primary objective of this real-world study was to describe the rate of CDK4/6i usage in the first line setting. As a secondary objective, we describe patient and disease characteristics in iCDK4/6 group, as well as in the endocrine monotherapy and chemotherapy groups. Results: From the cohort of 1000 patients (full-set analysis population) 874 cases were selected, who received treatment since 2018. 45.9% (95% CI 42.6, 49.2) patients were treated with CDK4/6i in combination with endocrine therapy in the first-line setting. From them in the subgroups of patients with or without visceral metastases 50.5% (95% CI 45.5, 55.5) and 42.1% (95% CI 37.7, 46.5) were treated with CDK4/6i in the first line setting, respectively. Among 874 cases 78.0% (95% CI 75.3, 80.7) patients received endocrine therapy ± targeted therapy; in the subgroups of patients with or without visceral metastases 69.5% (95% CI 64.9, 74.1) and 84.9% (95% CI 81.7, 88.1) were treated with endocrine therapy ± targeted therapy in the first line setting, respectively. Conclusions: Endocrine therapy is a predominant therapeutic option in the first line setting for HR+ HER2- aBC. Clinical trial information: NCT04852081. [Table: see text]

Abstract OT2-09-01: Phase I/II study of stereotactic radiation and abemaciclib in the management of hormone receptor positive HER2 negative breast cancer brain metastases

Abstract Background: Breast cancer patients with brain metastases have a high unmet clinical need and improved management strategies are needed. There has been interest in studying CDK 4/6 inhibitors in the management of breast cancer brain metastases. A phase II study has shown abemaciclib to have activity in the management of hormone receptor (HR)+/HER2- brain metastases. Pre-clinical data suggests a potential synergy with CDK inhibitors and radiation therapy. Stereotactic radiosurgery (SRS) is a cornerstone in the management of limited brain metastases. We hypothesize treatment with abemaciclib and SRS will be safe and improve intracranial progression free survival (PFS) compared to abemaciclib alone. Trial Design: The study is designed as a prospective, single-arm, nonrandomized, open-label, phase I/II trial of abemaciclib and endocrine therapy with SRS among patients with HR+/HER2- metastatic breast cancer brain metastases. Treatment will be initiated with one week of abemaciclib followed by stereotactic radiation to sites of brain metastases or post-operative cavities with continued abemaciclib. Safety will be monitored initially by a 3+3 design. If unexpected neurologic toxicities are noted, the dose of radiation therapy will be reduced. This will be followed by a phase II study to evaluate intracranial PFS. Eligibility: Eligible patients include those that are HR+/HER2-, ≥18, ECOG ≤2 with ≤15 breast cancer brain metastases with measurable disease per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Specific Aims: The primary objective of the phase I study is to evaluate the safety and feasibility of abemaciclib and SRS to sites of brain metastases in the management of HR+/HER2- metastatic breast cancer with brain metastases. The primary objective of the phase II portion is to determine PFS intracranially. Secondary objectives include evaluation of extracranial PFS, local and distant intracranial control, and overall survival. Statistical Methods: Safety and feasibility will be monitored in the phase I study using a 3 + 3 design followed by a phase II study to assess intracranial PFS. The phase II study is designed as a single-arm, two-stage trial using the Restricted-Kwak-and-Jung’s method. In the first stage, a total of 21 patients will be enrolled. If pre-specified endpoints are met, an additional 10 patients will be enrolled in the second stage. Patient Accrual: A total of up to 31 patients will be enrolled inclusive of patients in the phase I portion treated at the recommended phase II dose. Clinical trial information: NCT04923542. Citation Format: Kamran A. Ahmed, Youngchul Kim, Michelle DeJesus, Sasha J. Beyer, Nicole O. Williams, Joshua Palmer, Kristina D. Woodhouse, Rashmi K. Murthy, Jing Li, Avan J. Armaghani, John A. Arrington, Ricardo L. Costa, Brian J. Czerniecki, Arnold B. Etame, Peter A. Forsyth, Hung T. Khong, Daniel E. Oliver, Marilin Rosa, Solmaz Sahebjam, Hatem H. Soliman, Aixa E. Soyano, Michael A. Vogelbaum, Michael Yu, Hyo S. Han. Phase I/II study of stereotactic radiation and abemaciclib in the management of hormone receptor positive HER2 negative breast cancer brain metastases [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-09-01.

Abstract GS3-10: Study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in combination with fulvestrant in patients with advanced hormone receptor positive HER2 negative breast cancer (HR+BC)

Abstract Background: CDK7 inhibition is a promising therapeutic strategy in cancer; acting as a regulator of the cell cycle, transcription and endocrine receptor signalling [1]. Patients with HR+BC post CDK4/6 inhibitor treatment have a poor prognosis; median progression free survival (mPFS) of ~ 8 weeks for fulvestrant post CDK4/6i in HR+BC [2,3]. Pre-clinical HR+BC models indicate the potential for synergy when the CDK7 inhibitor samuraciclib is combined with the Selective Estrogen Receptor Degrader fulvestrant [4]Materials and Methods: This single arm cohort assessed the tolerability and efficacy of samuraciclib in combination with standard dose fulvestrant in patients with advanced HR+BC; all patients had previously received an aromatase inhibitor and a CDK4/6i for advanced disease.Results: 31 patients with HR+BC received the combination of standard dose with fulvestrant and samuraciclib. 6 patients received samuraciclib dose of 240mg once daily (QD) and 25 patients a dose of 360mg QD. The combination treatment was generally well tolerated, with adverse drug reactions (AE) of note being G1-2 nausea, vomiting and diarrhoea; the majority of patients staying on treatment until disease progression.RECIST evaluation indicates evidence of reduction in tumor disease burden, including a partial response in one patient who has been on treatment for ~ 1 year.Graphic illustrations of data, including ‘waterfall’ and ‘swimmer’ plots, will be presented along with stratification data based on demographic factors such as hepatic involvement and cfDNA analysis (ESR1m, PI3Km).Conclusions: Samuraciclib has demonstrated an acceptable safety profile with evidence of anti-tumour activity in combination with fulvestrant for patients with advanced HR+BC who have progressed on their prior CDK4/6i.

Abstract P4-06-03: Clinical-risk assessment of ER positive, Her2 negative breast cancer patients: Correlation between the average modified magee score and mammaprint

Abstract Background: MammaPrint (MP) is an FDA approved early breast cancer prognostic genomic assay that examines the expression levels of 70 genes and classifies clinically high-risk patients with early-stage breast cancer into low or high risk of distant metastasis. Current ASCO guidelines do not support using MP testing in clinically low-risk patients. Historically, assessing a patient’s clinical risk for breast cancer recurrence has relied on a subjective evaluation of histologic factors, immunohistochemical features, and clinical characteristics. Genomic assay testing provides more objective prognostic and predictive information than those more traditional methods; however, several studies have shown that statistical models using standard histologic variables can give valuable prognostic information, and might be used as an alternative approach to genomic assays for clinical risk-assessment and risk-stratification, particularly in lower risk breast cancer patients, potentially resulting in significant cost savings for health care systems. One of these statistical models, the average Modified Magee equation, has been shown to be prognostic for a low risk of recurrence in ER positive Her2 negative breast cancer patients who have an average Modified Magee score (aMMs) of ≤ 12. The aMMs has been shown to correlate well with the Oncotype DX recurrence score; however, there is limited data on the correlation between the aMMs and MP. In this study, we evaluated the concordance between the aMMs and the MP index (MPI). Methods: 222 consecutive patients with a new diagnosis of hormone receptor positive Her-2 negative breast cancer at the University of Rochester between April 2020 and December 2020 were sent for MP testing. The aMMs was determined for each patient based on the estrogen receptor status, progesterone receptor status, HER-2 status, Ki-67 proliferation index, Nottingham score, and tumor size. Based on the previous literature, patients were risk-stratified by the aMMs into three groups: 1) low risk (aMMs ≤ 12; n = 75); 2) low - intermediate risk (aMMs &amp;gt;12 and ≤ 18; n = 96); and, 3) high risk (aMMs &amp;gt;18, n = 51). Based on the previous literature, patients were risk-stratified by the MPI into two groups: 1) low risk (MPI 0 to +1); and, 2) high risk (MPI -1 to 0). The correlation between the aMMs and the MPI was evaluated using the Pearson correlation coefficient. Results: The aMMs showed a negative correlation (r= -0.55) with the MPI, consistent with a lower risk aMMs more likely being associated with a lower risk MPI. 92% of patients with an aMMs ≤ 12 (very low risk) were classified as low risk by MP. 72% of patients with an aMMs &amp;gt; 12 and ≤ 18 (low - intermediate risk) were classified as low risk by MP. 47% of patients with an aMMs &amp;gt; 18 (high risk) were classified as high risk by MP (Table 1). All patients with an aMMs ≥ 24.7 (n=8) were classified as high risk by MP. Conclusion: Our study suggests that hormone receptor positive, Her-2 negative breast cancer patients with a lower risk aMMs are likely to have a lower MPI, suggesting that these patients have a decreased risk for breast cancer recurrence. As the aMMs approaches higher risk, the concordance with the MPI decreases; however 100% of patients with an aMMs ≥ 24.7 were classified as high risk by MP. The aMMs can be helpful in clinical risk-assessment prior to making a decision about sending a patient specimen out for MP testing. Additional studies are warranted. Table 1.Risk of recurrence using the average Modified Magee score (aMMs) and the MammaPrint (MP) IndexaMMs Risk-stratification categoryMP Low risk n (%)MP High risk n (%)Very low (aMMs ≤ 12)69 (92%)6 (8%)Low - Intermediate (aMMs &amp;gt; 12 and ≤ 18)69 (72%)27 (28%)High (aMMs &amp;gt;18)27 (53%)24 (47%) Citation Format: Hani Katerji, Huina Zhang, David Hicks, Bradley M Turner. Clinical-risk assessment of ER positive, Her2 negative breast cancer patients: Correlation between the average modified magee score and mammaprint [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-06-03.

Abstract PD14-09: APOBEC signature, clinical characteristics, and outcome in hormone receptor-positive (HR+) HER2-negative (HER2-) breast cancer (BC) patients (pts) in real-world data (RWD)

Abstract Background: APOBEC mutagenesis underlies somatic evolution and accounts for tumor heterogeneity in several cancers, including BC. In our clinical experience, HR+HER2- BC with an APOBEC signature do poorly on standard of care (SOC) first line endocrine therapy (ET) + CDK4/6 inhibitor (CDK4/6i) and need additional treatment options. Here we evaluated the characteristics of a real-world cohort for time-to-treatment discontinuation (TTD) and overall survival (OS) on SOC and immune checkpoint inhibitors (ICI).Methods: Hybrid capture-based comprehensive genomic profiling (CGP) results from 29,833 formalin-fixed paraffin-embedded tissue biopsies of all BC subtypes were analyzed. For outcomes (TTD and OS), this study used a de-identified nationwide (US-based) BC clinico-genomic database (CGDB, ~800 sites of care, 1/2011 - 12/2020). HR+HER2- metastatic BC pts who received first line ET + CDK4/6i were included (CGDB cohort).TTD was defined as the difference between the first and last drug episode within a given line of treatment (LOT). LOT were derived based on FH algorithms. OS was defined as the time from LOT start to the date of death or data cutoff. Log-rank test and Cox model were used to evaluate the difference in outcomes. To reduce the impact of confounding variables (Age at Dx, Stage at Dx, Tumor Type, Metastases sites, TMB group (≥10 vs &amp;lt;10), SOC treatment group, PIK3CA), inverse probability of treatment weighting (IPTW) was used. Eligible pts from Mayo Clinic and Duke University were HR+HER2- mBC with sequencing data from FMI between 9/2013-7/2020. Clinical data were manually extracted from Mayo and Duke EHR. Results: Of all 29,833 BC samples in the CGP cohort, 7.9% were APOBEC+ with high rate in invasive lobular carcinoma (ILC) 16.7% vs. 4.9% in invasive ductal carcinoma (IDC) and metastatic lesions 9.7% vs. 4.3% from breast. APOBEC+ samples had a higher median TMB 12.5 vs. 2.5 mut/Mb. In CGDB, 857 HR+HER2- BC met inclusion criteria; 69 (8%) pts were APOBEC+ and 788 (9.2%) were APOBEC-. APOBEC+ pts had significantly shorter TTD on SOC ET+CDK4/6i than APOBEC- pts, 7.8 (95% CI 4.3-14.6) vs. 12.4 (95% CI 11.2-14.1) months (p=0.0036). APOBEC+ pts also had noticeably shorter OS compared to APOBEC- pts, 32.4 (95%CI 19.8-47.4) vs. 40.5 (95%CI 36.9-45.7) months (p=0.06).Cox regression results indicate that the relative risk of shorter TTD for the APOBEC+ vs the APOBEC- was 1.6 (95%CI 1.03-2.39). Also, APOBEC+ pts had almost twice the risk that APOBEC- pts had of death (HR=1.96, 95%CI 1.2-3.3). In CGDB, there were 10 APOBEC+ pts who received ICI, 9/10 had evaluable TTD data, 4/9 were still on treatment as of Dec 2020. 5/9 received ICI monotherapy, 4 pts received ICI + chemotherapy. TTD ranged from 0.3 to 11.3 mo, 1 pt’s TTD was &amp;gt; 6 mo. In Mayo and Duke cohort, there were 6 pts, 5/6 received ICI + chemotherapy. The TTD was 0.9-40.5 months with longest 2 pts receiving 5-FU plus ICI (11 and 40.5 months). To better understand the ICI treatment landscape, TTD in HR+HER2- hTMB MSS APOBEC- CGDB cohort (N=6) was analyzed: 5/6 had evaluable treatment data, 4/5 finished ICI treatment, 1 pt’s TTD was &amp;gt; 3 mo, 0/5 had TTD &amp;gt; 6 mo. Conclusions: APOBEC+ occurs in ~7% of BC and is more common in ILC and metastatic lesions. APOBEC+ HR+HER2- pts had shorter TTD and OS on SOC ET+CDK4/6i relative to APOBEC- pts. However, TTD on ICI tended to be longer in APOBEC+ pts, but our data is limited, and more research is needed. CGDB APOBEC+ vs. APOBEC- with SOC 1st lineAPOBEC+ (N=69)APOBEC- (N=788)p adjusted (FDR)*Age at Dx, Median (IQR)59.0 (53.0, 65.0)56.0 (47.0, 65.0)0.102Stage at Dx0.067- 0-III52 (75.4%)505 (64.1%)- IV11 (15.9%)245 (31.1%)- Not documented6 (8.7%)38 (4.8%)Metastasis free interval, yrs, Median (IQR)5.2 (3.0, 10.5)5.1 (2.8, 9.3)0.734Tumor Grade0.104- Grade 12 (2.9%)49 (6.2%)- Grade 234 (49.3%)259 (32.9%)- Grade 311 (15.9%)163 (20.7%)- Not documented22 (31.9%)317 (40.2%)Tumor Type0*- IDC7 (10.1%)251 (31.9%)- ILC30 (43.5%)138 (17.5%)- Other /Not documented32 (46.4%)399 (50.6%)Metastases sites0.734- Bone-only17 (24.6%)169 (21.5%)- CNS11 (15.9%)104 (13.2%)- Visceral41 (59.4%)514 (65.3%)TMB, Median (IQR)11.3 (8.8, 18.8)2.5 (1.3, 3.8)0*MSI0.946- MSI-H0 (0.0%)4 (0.5%)- MSI-I0 (0.0%)1 (0.1%)- MSS68 (98.6%)728 (97.2%)- Not documented1 (1.4%)16 (2.1%)BRCA5 (7.2%)45 (5.7%)0.734PIK3CA46 (66.7%)341 (43.3%)0.001*Treatments0.005*- AI + CDK4/6i31 (44.9%)510 (64.7%)- Fulvestrant + CDK4/6i38 (55.1%)278 (35.3%) Citation Format: Saranya Chumsri, Kira Raskina, Sarah Sammons, Laura Alder, Natalie Danziger, Alexa B Schrock, Kim McGregor, Ethan Sokol. APOBEC signature, clinical characteristics, and outcome in hormone receptor-positive (HR+) HER2-negative (HER2-) breast cancer (BC) patients (pts) in real-world data (RWD) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD14-09.

Abstract P5-16-11: Ipatasertib (ipat) in combination with palbociclib (palbo) and fulvestrant (fulv) in patients (pts) with hormone receptor-positive (HR+) HER2-negative advanced breast cancer (aBC)

Abstract Background: Ipat is a potent oral AKT inhibitor that has been studied in multiple clinical trials, primarily in breast and prostate cancers. Combining fulv and AKT inhibition demonstrated efficacy in pts with HR+ aBC regardless of PI3K/AKT pathway alterations [Jones, Lancet Oncol 2020]. IPATunity150 (NCT04060862) was designed as a phase III trial with an open-label phase Ib portion adding ipat to palbo plus fulv in biomarker-unselected HR+ HER2-negative aBC. The biological rationale was to prevent or delay resistance to CDK4/6 inhibition plus endocrine therapy (ET). AKT1 alterations and PTEN loss have been implicated in resistance to CDK4/6 inhibitors [Wander, Cancer Discov 2020; Costa, Cancer Discov 2020]. We report results from the open-label phase Ib portion. Patients and Methods: The primary objective was to assess safety and pharmacokinetics (PK) of ipat in combination with palbo and fulv; several efficacy parameters were also analyzed. Pts with measurable disease who had not previously received a CDK4/6 inhibitor and had experienced relapse during adjuvant ET were treated with ipat at a dose of 300 mg/d, d1-21 q28d, plus standard-of-care doses of palbo (125 mg/d, d1-21 q28d) plus fulv (500 mg q28d with a loading dose in cycle 1). The selected ipat dose was lower than the 400 mg typically used in other studies because of the anticipated drug-drug interaction (DDI) when combining ipat (a sensitive CYP3A4 substrate and mild-to-moderate CYP3A inhibitor) with palbo (a weak time-dependent CYP3A4 inhibitor and CYP3A substrate). Results: Of the 20 pts treated, 20% were Asian, 65% had primary endocrine resistance (relapse ≤2 years after starting adjuvant ET), 80% had received prior (neo)adjuvant chemotherapy, and 60% had liver and/or lung metastases. At the data cutoff (19 Mar 2021; median follow-up 6.1 months), median treatment duration was 5.1, 5.9, and 5.3 months for ipat, palbo, and fulv, respectively. Treatment was ongoing in 13 pts. Grade 3/4 adverse events (AEs) occurred in 80% of pts (no grade 5). The most common AEs were diarrhea (80% any grade, 10% grade 3, no grade 4) and neutropenia (75% any grade, 45% grade 3, 20% grade 4). Other notable grade ≥3 AEs were grade 3 liver function test elevations in 10%. There were no cases of febrile neutropenia and only 1 case of pneumonitis (grade 1). AEs led to at least one dose reduction of ipat in 6 pts (30%; diarrhea n=3 [with vomiting in 1 pt], neutropenia n=3 [with fatigue in 1 pt]) and of palbo in 9 pts (45%; all for neutropenia). One pt (5%) discontinued ipat and palbo permanently due to ongoing neutropenia after protocol-defined dose reductions. As expected, a DDI led to increased ipat exposure (AUC0-24,ss ~60% and Cmax ~40%) when ipat and palbo were combined. Based on population PK analysis, palbo AUC0-24,ss was ~30% higher than reported from the PALOMA 1 and 2 trials, which was expected and consistent with previously reported physiologically based PK modeling of palbo exposure when administered with moderate CYP3A inhibitors [Yu, J Clin Pharmacol 2017]. All 20 pts had at least one post-baseline tumor assessment. Best overall response rate was 45% (95% CI: 23-68%), including confirmed responses in 7 pts (35%; 5% complete response, 30% partial response) at the clinical cutoff date. Median duration of response was 9.6 months (95% CI: 7.1-not estimable). An additional 10 pts (50%) had stable disease. Progression-free survival results were immature (events in 7 pts). There was no obvious association between efficacy and mutations in PIK3CA/AKT1 as tested in ctDNA. Conclusion: The triplet combination of ipat, fulv, and palbo had an acceptable safety profile generally consistent with that of the individual study drugs; ipat exposure was increased through a predicted DDI. Updated results will be presented. Citation Format: Mafalda Oliveira, Aditya Bardia, Sung-Bae Kim, Naoki Niikura, Cristina Hernando, Gustavo Werutsky, Yoland Antill, Pedro Liedke, Catherine Oakman, Eriko Tokunaga, Seth Wander, Vanessa Krause, Toshinari Yamashita, Frauke Schimmoller, Jacob Rotmensch, Heidi Savage, Rucha Sane, Nicholas Turner. Ipatasertib (ipat) in combination with palbociclib (palbo) and fulvestrant (fulv) in patients (pts) with hormone receptor-positive (HR+) HER2-negative advanced breast cancer (aBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-11.

Abstract P1-18-14: Alpelisib monotherapy for PI3K-altered, pre-treated advanced breast cancer: A phase II study

Abstract Background: The PI3Kα subunit specific inhibitor alpelisib in combination with fulvestrant is approved in advanced breast cancer harbouring PIK3CA mutations, but predictive biomarkers are lacking. We performed a phase II single arm study of alpelisib monotherapy in previously treated advanced hormone receptor-positive HER2-negative (HR+HER2-) and triple negative breast cancer (TNBC) cohorts. Methods: Eligible patients with genomic aberrations in the PI3K pathway determined via tumour sequencing or ctDNA were given alpelisib 350mg oral daily as monotherapy. The primary endpoint was RECIST objective response rate (ORR) by central review. Secondary endpoints were clinical benefit rate (CBR), defined as complete or partial response or stable disease for ≥24 weeks, and progression free survival (PFS). Positron emission tomography (FDG-PET) was performed at baseline and 8 weeks. Efficacy was analysed according to baseline tumour alterations and serial ctDNA assays. Analyses were conducted separately for the HR+HER2- and TNBC cohorts. Stated p values are nominal without multiplicity adjustment. Results: 43 patients were recruited in total (33 in ER+HER2-, 10 in TNBC). Median follow-up was 44.6 months. In the TNBC cohort ORR and CBR were 0%, hence the cohort was stopped early. Data will be presented here for the HR+HER2- cohort. Of 33 ER+HER2- patients recruited, 28 (85%) were evaluable and 26 (79%) were evaluable for ORR after central review. PI3K pathway aberrations at study entry were mutations in PIK3CA (26/28; 93%) and PTEN (2/28; 7%). The median age was 60 (41 - 77yrs) and 27/28 of patients were female. 85.7% of cases had visceral disease, and 57% had &amp;gt;3 metastatic sites. 100% of patients had received prior endocrine therapy and 78.6% prior chemotherapy, with a median of 3 prior lines (range 1 - 9). All patients were endocrine refractory. The ORR was 38% and CBR 43%. Median PFS was 4.6 months (95% CI, 3.7 - 7.3) and median OS 16.0 months (95% CI, 8.5 - 34.4). In patients with PET scans at baseline and 8 weeks, 67% (17/25) achieved a partial metabolic response but this was not associated with clinical benefit. In patients with partial response by RECIST, serial ctDNA levels at week 8 declined from baseline (p = 0.008) compared to patients with stable or progressive disease (p = 0.17), with similar results seen for patients with clinical benefit. Decline in ctDNA at week 8 was also associated with improved PFS (HR 0.24 [95% CI 0.08-0.67], p = 0.0065; 5.6 v 3.6 months). Multiple PIK3CA mutations were detected in plasma in 31% (8/26) of patients but had no impact on ORR/CBR. 39% (11/28) of patients had mutations in ESR1 detected in plasma at baseline, and this was associated with clinical benefit (p = 0.019) and improved PFS (HR=0.22 [95% CI 0.078-0.60], P=0.0032, 8.21 v 4.53 months). ctDNA assays detected 11 cases with ESR1 mutations compared to tumour sequencing which detected 5 cases only. No other baseline alterations were significantly associated with outcomes, although no patients (0/4) with PTEN alterations achieved clinical benefit. End of treatment ctDNA analysis identified multiple new alterations including MAP3K1 in 39% (11/28), TP53 in 32% (9/28) and PTEN in 25% (7/28). Adverse events included 20.9% grade ≥3 hyperglycaemia and 25.6% ≥grade 3 rash consistent with reported data. Permanent discontinuation of alpelisib for toxicity occurred in 15.2% (5/33) of patients. Conclusions: Alpelisib monotherapy in pre-treated ER+HER2- disease showed evidence of clinical efficacy. Decline in the levels of PIK3CA mutations detected with ctDNA on therapy are significantly associated with clinical benefit, as are the presence of ESR1 mutations at baseline. ctDNA improves the yield of ESR1 mutation detection and warrants further study as a biomarker of alpelisib monotherapy benefit in endocrine-refractory populations. Citation Format: Peter Savas, Louisa Lisa Lo, Stephen James Luen, Elizabeth Fay Blackley, Courtney Templeton van Geelen, Yi-An Ko, Kate Moodie, Jason William Callahan, Chen-Fang Weng, Andjelija Zivanovic Bujak, Miriam Manning Yeung, Sarah Ftouni, Prudence Anne Francis, Sarah-Jane Dawson, Sherene Loi. Alpelisib monotherapy for PI3K-altered, pre-treated advanced breast cancer: A phase II study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-14.

Abstract OT1-18-01: A randomized controlled phase III study of bevacizumab and paclitaxel in combination with atezolizumab as a treatment for patients with locally advanced or metastatic hormone receptor-positive HER2 negative breast cancer: JCOG1919E/AMBITION study

Abstract Background: Hormone receptor (HR)-positive HER2-negative breast cancers have a lower tumor mutation burden than other types of cancer and triple-negative breast cancer, resulting in relatively low immunogenicity. It is also known that estrogen suppressively regulates immunity through regulatory T cells in the tumor microenvironment. Therefore, the development of immunotherapy in HR-positive and HER2-negative breast cancer is a challenging issues. Anti-VEGF therapy has been shown to improve antigen presentation, local migration of cytotoxic T lymphocytes, and suppressive tumor microenvironment in preclinical and clinical studies of various cancers. Anti-VEGF therapy can be hypothesized to modulate immunotherapy. Methods: JCOG1919E (AMBITION) is a randomized, multicenter, open-label, phase III trial to evaluate efficacy and safety of bevacizumab and paclitaxel in combination with atezolizumab (BEV+PTX+ATZ) comparing to bevacizumab and paclitaxel (BEV+PTX) in patients with HR-positive HER2 negative locally advanced or metastatic breast cancer. The key eligibility criteria are as follows: 1) ECOG PS 0-2, 2) ER and/or PgR positive and HER2-negative breast cancer, 3) endocrine resistance or life-threatening disease, 4) measurable disease, 5) centrally confirmed programmed death-ligand 1 (PD-L1) status on tumor-infiltrating immune cells, 6) no prior chemotherapy for locally advanced or metastatic breast cancer, 7) adequate organ function. Patients will be randomized (staratified by recurrence/de novo, liver metastasis, or PD-L1 status) in a 1:1 ratio, to BEV+PTX arm or BEV+PTX+ATZ arm. Patients in arm A receive PTX (90 mg/m2/day, days 1, 8 and 15, iv) and BEV (10 mg/kg/day, days 1 and 15, iv) on a 28-day cycle. Patients in arm B receive PTX and BEV plus ATZ (840 mg/body/day, days 1 and 15, iv). Treatment in both arms is continued until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) assessed by investigators. The secondary endpoints include overall survival, PFS assessed by blinded independent central review, response rate, adverse events, PFS (PD-L1 positive), and OS (PD-L1 positive). We assumed a median PFS of 16 months in BEV+PTX+ATZ arm and 11 months in BEV+PTX arm. The planned sample size was calculated as a total of 280 patients (140 patients per arm) with a one-sided alpha of 2.5%, power of 80%, an accrual period of 2.5 years, and a follow-up period of 2 years. Translational research also will be conducted accompanying with this trial. Patient accrual was started in January 29, 2021 and 37 patients were enrolled by June 18, 2021. Safety of patients in this study is being monitored by IDMC. For further information on this trial, visit ClinicalTrials.gov (NCT04732598). Citation Format: Fumikata Hara, Makiko Ono, Shigehisa Kitano, Shigehira Saji, Akihiko Shimomura, Takashi Yamanaka, Takayuki Kadoya, Mitsuya Ito, Hiroko Bando, Hiroyuki Yasojima, Keita Sasaki, Tomoko Kataoka, Tadahiko Shien, Kan Yonemori, Hiroji Iwata. A randomized controlled phase III study of bevacizumab and paclitaxel in combination with atezolizumab as a treatment for patients with locally advanced or metastatic hormone receptor-positive HER2 negative breast cancer: JCOG1919E/AMBITION study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-18-01.

265P Study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in combination with fulvestrant in patients with advanced hormone receptor positive HER2 negative breast cancer (HR+BC)

CDK7 inhibition is a promising therapeutic strategy in cancer; acting as a regulator of transcription, the cell cycle and endocrine receptor signalling. Patients with HR+BC post CDK4/6 inhibitor treatment have a poor prognosis; median progression free survival (mPFS) of ∼ 8 weeks for fulvestrant post CDK4/6i in HR+BC [1,2]. Pre-clinical HR+BC models indicate the potential for synergy when the CDK7 inhibitor samuraciclib is combined with fulvestrant [3]. This single arm cohort assessed the tolerability and efficacy of samuraciclib in combination with fulvestrant in patients with advanced HR+BC; all patients had previously received an aromatase inhibitor and a CDK4/6 inhibitor for advanced disease. 31 patients with HR+BC received the combination of standard dose with fulvestrant and samuraciclib. 6 patients received samuraciclib dose of 240mg once daily (OD) and 25 patients a dose of 360mg (OD). The combination treatment was generally well tolerated, with adverse drug reactions (AE) of note being G1-2 nausea, vomiting and diarrhoea; the majority of patients staying on treatment until disease progression. RECIST evaluation indicates evidence of reduction in tumor disease burden, including a partial response in one patient who has been on treatment for ∼ 1 year. Graphic illustrations of data, including ‘waterfall’ and ‘swimmer’ plots, will be presented. Samuraciclib has demonstrated an acceptable safety profile with evidence of anti-tumour activity in combination with fulvestrant for patients with advanced HR+BC who have progressed on their prior CDK4/6i.

Abstract PS6-20: The 21-gene recurrence score in early non-ductal breast cancer: A national cancer database analysis

Abstract Background: The Oncotype DX 21-gene expression assay (ODX) is prognostic for recurrence and predictive of chemotherapy benefit in early estrogen receptor-positive (ER+) HER2-negative (HER2-) breast cancer (BCA). Invasive ductal carcinoma (IDC) comprises approximately 80% of BCA. Invasive lobular carcinoma (ILC) is a subtype of BCA with distinct pathologic features, and often has low to intermediate ODX Recurrence Score (RS). We evaluated differences in clinicopathologic characteristics, RS and chemotherapy benefit between IDC, ILC, and carcinomas of mixed histologies (ductal + lobular (DLC), ductal + other (DOC), and lobular + other (LOC)) in the National Cancer Database (NCDB). Methods: Female patients (pts) diagnosed between 1/1/2010 and 1/1/2014 with ER+ HER2- BCA, measuring up to 5 cm, with 0-3 involved axillary lymph nodes (LN), treated with definitive surgery as first treatment, and with numeric ODX recurrence score (RS) available were identified from the 2005-2016 NCDB database. Associations between categorical variables were examined using the chi-square test. The Cox proportional hazards model was used to examine the difference in overall survival between histology subtypes while controlling for age, race/ethnicity, RS, tumor size, grade, LN involvement and treatment. Results: 77,472 pts met inclusion criteria, 62,395 (83.8%) node negative (N0) and 12,077 (16.2%) node positive (N+). 57,615 pts (77.4%) had IDC; 8693 (11.7%) ILC; 5393 (7.2%) DLC; 2457 (3.3%) DOC; and 312 (0.4%) LOC. DOC and LOC were more common in Black than White pts (p&amp;lt;0.0001). IDC was associated with smaller tumor size and high grade disease. ILC was associated with larger tumor size, and was least likely to be high grade (p&amp;lt;0.0001). IDC was most likely to have high RS &amp;gt;26. Presence of lobular histology (ILC, DLC and LOC) was associated with lower incidence of RS &amp;gt;26. ILC was least likely to have both low RS (0-10) and high RS (p&amp;lt;0.0001). Pts with IDC were more likely to receive adjuvant chemotherapy (27.4%) than pts with other BCA types (ILC 19.3%; DLC 21.9%; DOC 20.5%; LOC 19.2%, p&amp;lt;0.0001). Overall survival (OS) for IDC, ILC and DOC were similar. DLC was associated with improved OS compared with IDC (HR 0.82, p=0.02). Receipt of adjuvant chemotherapy was associated with improved OS in IDC (HR=0.76, p&amp;lt;0.0001) but not in ILC (HR=0.99, p=0.93), DLC (HR=1.04, p=0.86), DOC (HR=0.87, p=0.71), or LOC (HR=2.91, p=0.10). Conclusion: Lobular and mixed BCA histologies have distinct clinicopathologic features compared with IDC, and are less likely to have high RS. OS is similar for early IDC and ILC. Chemotherapy benefit was not seen in ILC or mixed BCA histologies. Citation Format: Della Makower, Jiyue Qin, Juan Lin, Xiaonan Xue, Joseph A Sparano. The 21-gene recurrence score in early non-ductal breast cancer: A national cancer database analysis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-20.

A randomized study comparing docetaxel/cyclophosphamide (TC), 5-fluorouracil/epirubicin/cyclophosphamide (FEC) followed by TC, and TC followed by FEC for patients with hormone receptor-positive HER2-negative primary breast cancer

PurposeOur primary objective was to determine the benefit/risk of anthracycline-free regimens by comparing docetaxel + cyclophosphamide (TC) alone, fluorouracil + epirubicin + cyclophosphamide (FEC) followed by TC, or TC followed by FEC as a primary treatment for patients with HR-positive, HER2-negative BC.MethodsWe randomized patients with stage I–III HR-positive HER2-negative, operable BC to receive either six cycles of TC (TC6), three cycles of FEC followed by three cycles of TC (FEC-TC), or three cycles of TC followed by three cycles of FEC (TC-FEC). The primary endpoint was the pathological response. Secondary endpoints included clinical response, type of surgical procedure, recurrence, death, and adverse events (by NCI-Common Terminology Criteria for Adverse Events v.3.0). We conducted all statistical analyses using SAS Version 9.2.ResultsWe enrolled 195 patients and analyzed data from 193 as the intention-to-treat population. Pathological complete response rates were numerically higher in the TC6 group than in the other groups (p = 0.321). The breast conservation rate was significantly higher in the TC6 group (73%) than in the other groups (FEC-TC 51%, TC-FEC 45%, p = 0.007). Adverse events with grade > 3 were not common in the treatment groups (p = 0.569). The overall and distant disease-free survivals were similar among the groups with median follow-up of 5.80 years.ConclusionsDespite similar long-term efficacy and safety profile, the higher breast conservation rate in the TC6 group suggests that preoperative chemotherapy without an anthracycline may benefit patients with HR-positive HER2-negative BC.Trial registrationUMIN000003283 https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000003873.