Park, Ben

Abstract Background: A significant number of patients with breast cancer may develop chest wall recurrence, which can be difficult to treat, and is associated with a poor prognosis. Given the inflammatory nature of chest wall disease, and the association of chest wall disease with lymphovascular invasion, we hypothesized that immunotherapy may be beneficial in this setting. Furthermore, combining immunotherapy and chemotherapy may have a synergistic effect; indeed, the combination of the anti-programmed cell death 1 (PD-1) antibody, pembrolizumab, with chemotherapy has been approved for metastatic triple negative breast cancer (TNBC). Consequently, in this study, we are evaluating the combination of pembrolizumab/carboplatin vs. carboplatin alone for chest wall recurrence. Trial design: This is a phase II study of patients with chest wall disease from breast cancer. Patients are randomized in a 2:1 manner to pembrolizumab/carboplatin x 6 cycles (Arm A) with the option to continue pembrolizumab +/- carboplatin after 6 cycles (Arm Ax) vs. carboplatin alone (Arm B) with the option to cross-over to pembrolizumab +/- carboplatin on progression (Arm Bx). Carboplatin is dosed at AUC 5 IV every 3 weeks, and pembrolizumab at 200 mg IV every 3 weeks. Trastuzumab may be continued with study treatment in patients with HER2 positive disease. Imaging scans (CT chest, abdomen, and pelvis, and bone scan) occur at baseline and every 3 cycles. Chest wall biopsies and peripheral blood is collected at baseline and after completing 2 cycles of treatment for correlative studies. Eligibility criteria: Patients must have chest wall disease from breast cancer. Distant metastases are allowed. TNBC, hormone receptor positive/HER2 negative disease (after 2 prior hormone therapies), and HER2 positive disease (progressed on standard HER2 directed treatment) are eligible. Any number of prior lines of chemotherapy are acceptable, including a prior platinum chemotherapy in the absence of disease progression on the platinum. Specific Aims: Primary aim is to determine disease control rate in the chest wall and other distant sites at 18 weeks of treatment with RECIST 1.1. Secondary aims including determining toxicity, progression-free survival, response based on irRECIST, and response based on tumor PD-L1 expression. Exploratory aims include studying changes in: 1) immune composition of tumor and peripheral blood, 2) peripheral blood cell-free DNA and circulating tumor cells, 3) soluble PD-L1 expression, and 4) association of MYC with PD-1 and immune markers, based on preclinical data demonstrating that MYC upregulates these markers. Statistical Methods: 84 patients (Arm A: 56, Arm B: 28) are being enrolled at 7 sites in the Translational Breast Cancer Research Consortium. The study is powered to identify a 20% difference in disease control rates between Arms A and B (HR 0.52, α= 0.10, ß=0.20). A futility analysis will occur for Arm B after 18 patients are enrolled to allow for early closure if lack of efficacy. Accrual: Present accrual is 57 patients (Arm A: 39, Arm B: 18). (NCT03095352). This trial is partly funded by grants from Merck and University of California San Francisco. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu Citation Format: Neelima Vidula, Rita Nanda, Kathy Miller, Leisha Emens, Vandana Abramson, Ben Park, Minetta C. Liu, Andrei Goga, Hope Rugo. Randomized phase II trial of pembrolizumab/carboplatin vs. carboplatin alone for breast cancer with chest wall recurrence: TBCRC044 [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 OT1-18-08.

Abstract Patients with metastatic breast cancer (MBC) typically have short survival times and their successful treatment represents one of most challenging aspects of patient care. This poor prognostic behavior is in part due to molecular features including increased tumor cell clonal heterogeneity, multiple drug resistance mechanisms, and alterations of the tumor microenvironment. The AURORA US Metastasis Project was established with the goal to identify molecular features specifically associated with metastasis. We therefore collected and molecularly characterized specimens from 55 metastatic breast cancer (BC) patients representing 51 primary cancers and 102 metastases. The 153 unique tumors were assayed using RNAseq, tumor/germline DNA exomes and low pass whole genome sequencing, and global DNA methylation microarrays. We found intrinsic molecular subtype differences between primary tumors and their matched metastases to be rare in triple negative breast cancer (TNBC)/Basal-like subtype tumors. Conversely, tumor subtype changes were relatively frequent in estrogen receptor positive (ER+) cancers where ~30% of Luminal A cases switched to Luminal B or HER2-enriched (HER2E) subtypes. Clonal evolution studies identified changes in expression subtype coincident with DNA clonality shifts, especially involving HER2 amplification and/or the HER2E expression subtype. We further found evidence for ER-mediated downregulation of genes involved in cell-cell adhesion in metastases. Microenvironment differences varied according to tumor subtype where ER+/Luminal metastases had lower fibroblast and endothelial cell content, while TNBC/Basal-like metastases showed a dramatic decrease in B cells and T cells. In 17% of metastatic tumors, we identified DNA hypermethylation and/or focal DNA deletions near HLA-A that were associated with its’ significantly reduced expression, and with lower immune cell infiltrates. We also identified low immune cell features in brain and liver metastases when compared to other metastatic sites, even within the same patient. These findings have direct implications for the treatment of metastatic breast cancer patients with immune- and HER2-targeting therapies and suggest potential novel therapeutic avenues for the improvement of outcomes for some patients with MBC.

Abstract Background: Chest wall recurrence can occur as a complication of breast cancer. This type of breast cancer is difficult to treat with short-lived responses to therapy, and associated with the development of distant metastases. Better therapies are needed in this setting. Immune checkpoint inhibition is being explored in breast cancer, with an immunotherapy agent currently approved for triple-negative breast cancer (TNBC). We hypothesize that pembrolizumab, an anti-programmed cell death 1 (PD-1) antibody, may be effective in treating chest wall recurrence of breast cancer given the inflammatory nature of this disease and high expression of PD-1 seen in tumors with lymphovascular invasion that may predispose patients to chest wall recurrence. Platinum chemotherapy may augment anti-tumor immunity, with the combination of pembrolizumab and carboplatin shown to be effective in advanced lung cancer. This study is evaluating the efficacy of pembrolizumab and carboplatin for breast cancer patients with chest wall disease. Methods: In this phase II study, 84 patients are being randomized 2:1 to treatment with pembrolizumab in combination with carboplatin (Arm A) versus carboplatin alone (Arm B) with an option to cross over to pembrolizumab alone (Arm Bx) on progression. Pembrolizumab is dosed at 200 mg IV every 3 weeks, and carboplatin is dosed at AUC 5 IV every 3 weeks. Patients may have TNBC, hormone receptor positive (HR)+/HER2- breast cancer that has progressed on 2 prior lines of hormone therapy, or refractory HER2+ breast cancer (may continue herceptin). Patients may have distant metastases, but must have surgically unresectable disease. Prior chest wall radiation is allowed. The primary endpoint is to determine the disease control rate (chest wall and distant sites) at 18 weeks of treatment. Patients undergo chest wall assessments with photography of skin lesions with every cycle of treatment, and imaging (CT chest, abdomen, and pelvis, and bone scan) every 2 cycles to evaluate for progression. The study is powered to determine a 20% difference in disease control rates between arms A and B (hazard ratio of 0.52, α= 0.10, β= 0.20). Secondary endpoints include response stratified by tumor programmed death ligand 1 (PD-L1) expression, progression free survival, response by irRECIST, and toxicity. The study incorporates many translational studies using chest wall biopsy tissue collected at baseline and after 2 cycles of treatment, as well as correlative blood tests, including assessing changes in tumor and blood PD-L1 expression, circulating cell-free DNA, circulating tumor cells, soluble PD-L1 expression, and changes in the expression of MYC, an oncogene that may upregulate the expression of PD-1. Patients are currently being enrolled at 7 sites in the TBCRC. As of July 2019, 30 patients are enrolled. This study is supported by Merck and the TBCRC. (NCT03095352). Citation Format: Neelima Vidula, Rita Nanda, Kathy Miller, Vandana Abramson, Paula Pohlmann, Adam Brufsky, Ben Park, Minetta Liu, Andrei Goga, Hope S. Rugo. Pembrolizumab in combination with carboplatin versus carboplatin alone in breast cancer patients with chest wall disease: Translational Breast Cancer Research Consortium (TBCRC) 44 trial [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 OT2-04-05.