ABSTRACT
BACKGROUND: The purpose of this study was to investigate whether combining pembrolizumab with palliative radiation therapy (RT) improves outcomes in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). PATIENTS AND METHODS: Eligible patients had HR+/human epidermal growth factor receptor 2-negative MBC; were candidates for RT to ≥ 1 bone, soft tissue, or lymph node lesion; and had ≥ 1 lesion outside the RT field. Patients received 200 mg pembrolizumab intravenously 2 to 7 days prior to RT and on day 1 of repeating 21-day cycles. RT was delivered to a previously unirradiated area in 5 treatments each of 4 Gy. The primary endpoint was objective response rate. The study used a 2-stage design: 8 women were enrolled into the first stage, and if at least 1 of 8 patients experienced an objective response, 19 more would be enrolled. Secondary endpoints included progression-free survival, overall survival, and safety. Exploratory endpoints included association of overall response rate with programmed death-ligand 1 status and tumor-infiltrating lymphocytes. RESULTS: Eight patients were enrolled in stage 1. The median age was 59 years, and the median prior lines of chemotherapy for metastatic disease was 2. There were no objective responses, and the study was closed to further accrual. The median progression-free survival was 1.4 months (95% confidence interval, 0.4-2.1 months), and the median overall survival was 2.9 months (95% confidence interval, 0.9-3.6 months). All-cause adverse events occurred in 87.5% of patients, including just 1 grade 3 event (elevation of aspartate aminotransferase). CONCLUSIONS: RT combined with pembrolizumab did not produce an objective response in patients with heavily pre-treated HR+ MBC. Future studies should consider alternative radiation dosing and fractionation in patients with less heavily pre-treated HR+ MBC.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents, Immunological/administration & dosage , Breast Neoplasms/therapy , Carcinoma, Ductal, Breast/therapy , Chemoradiotherapy/methods , Palliative Care/methods , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents, Immunological/adverse effects , Biomarkers, Tumor/analysis , Biomarkers, Tumor/metabolism , Breast/pathology , Breast Neoplasms/immunology , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/immunology , Carcinoma, Ductal, Breast/mortality , Carcinoma, Ductal, Breast/pathology , Chemoradiotherapy/adverse effects , Drug Administration Schedule , Female , Humans , Infusions, Intravenous , Middle Aged , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Progression-Free Survival , Receptor, ErbB-2/analysis , Receptors, Estrogen/analysis , Receptors, Estrogen/metabolism , Receptors, Progesterone/analysis , Receptors, Progesterone/metabolism , Response Evaluation Criteria in Solid TumorsABSTRACT
PURPOSE: Hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer is associated with low levels of stromal tumor-infiltrating lymphocytes (sTIL) and PD-L1, and demonstrates poor responses to checkpoint inhibitor therapy. Evaluating the effect of standard chemotherapy on the immune microenvironment may suggest new opportunities for immunotherapy-based approaches to treating HR+/HER2- breast tumors. EXPERIMENTAL DESIGN: HR+/HER2- breast tumors were analyzed before and after neoadjuvant chemotherapy. sTIL were assessed histologically; CD8+ cells, CD68+ cells, and PD-L1 staining were assessed immunohistochemically; whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed. RESULTS: Ninety-six patients were analyzed from two cohorts (n = 55, Dana-Farber cohort; n = 41, MD Anderson cohort). sTIL, CD8, and PD-L1 on tumor cells were higher in tumors with basal PAM50 intrinsic subtype. Higher levels of tissue-based lymphocyte (sTIL, CD8, PD-L1) and macrophage (CD68) markers, as well as gene expression markers of lymphocyte or macrophage phenotypes (NanoString or CIBERSORT), correlated with favorable response to neoadjuvant chemotherapy, but not with improved distant metastasis-free survival in these cohorts or a large gene expression dataset (N = 302). In paired pre-/postchemotherapy samples, sTIL and CD8+ cells were significantly decreased after treatment, whereas expression analyses (NanoString) demonstrated significant increase of multiple myeloid signatures. Single gene expression implicated increased expression of immunosuppressive (M2-like) macrophage-specific genes after chemotherapy. CONCLUSIONS: The immune microenvironment of HR+/HER2- tumors differs according to tumor biology. This cohort of paired pre-/postchemotherapy samples suggests a critical role for immunosuppressive macrophage expansion in residual disease. The role of macrophages in chemoresistance should be explored, and further evaluation of macrophage-targeting therapy is warranted.
Subject(s)
Breast Neoplasms/immunology , Estrogen Receptor alpha/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Neoadjuvant Therapy/methods , Receptor, ErbB-2/metabolism , Receptors, Progesterone/metabolism , Tumor Microenvironment/immunology , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B7-H1 Antigen/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , CD8-Positive T-Lymphocytes/immunology , Female , Humans , Middle Aged , PrognosisABSTRACT
BACKGROUND: Coronary computed tomographic angiography (CCTA) is an accurate test for the identification of coronary artery disease (CAD), yet the impact of CCTA results on subsequent medical therapy and risk factors has not been widely reported. METHODS AND RESULTS: We identified consecutive patients aged >18 years without prior CAD who underwent CCTA from 2004 to 2011 and had complete data on medications before and after CCTA. CCTA results were categorized as no CAD, <50% stenosis, and ≥50% stenosis. Based on the number of involved segments, extent of disease was categorized as nonextensive (≤4 segments) or extensive CAD (>4 segments). Electronic medical records and patient interviews were reviewed blinded to CCTA findings to assess initiation of aspirin and intensification of lipid-lowering therapies. Survival analysis was performed to evaluate intensification of lipid therapy as a predictor of cardiovascular death or nonfatal myocardial infarction. Among 2839 patients with mean follow-up of 3.6 years, the odds of physician intensification of lipid-lowering therapy significantly increased for those with nonobstructive CAD (odds ratio, 3.6; 95% confidence interval, 2.9-4.9; P<0.001) and obstructive CAD (odds ratio, 5.6; 95% confidence interval, 4.3-7.3; P<0.001). Low-density lipoprotein cholesterol levels declined significantly in association with intensification of lipid-lowering therapy after CCTA in all patient subgroups. In a hypothesis-generating analysis, among patients with nonobstructive but extensive CAD, statin use after CCTA was associated with a reduction in cardiovascular death or myocardial infarction (hazards ratio, 0.18; 95% confidence interval, 0.05-0.66; P=0.01). CONCLUSIONS: Abnormal CCTA findings are associated with downstream intensification in statin and aspirin therapy. In particular, CCTA may lead to increased use of prognostically beneficial therapies in patients identified as having extensive, nonobstructive CAD.