The concentration of histamine in breast cancer was sufficient to inhibit lymphocyte function and could be locally immunosuppressive.
BACKGROUND: Previously, we demonstrated the clinical validity of cMethDNA, a circulating methylated tumor DNA (ctDNA) assay, in serum samples from TBCRC 005 (J Clin Oncol, 2017; 35:751-758) to predict progression free- and overall-survival, and to monitor therapeutic response in patients with stage IV breast cancer. Here, Johns Hopkins (JH) and Cepheid partnered to develop an automated GeneXpert (GX) cartridge-based system to provide quantitative measures of DNA methylation within 5 hours.METHODS: With a goal of discriminating stage IV breast cancer from healthy and benign breast disease with high sensitivity and specificity, we evaluated breast cancer-specific DNA methylation markers (selected through comprehensive methylome analysis) in STRECK tube plasma of 46 patients with metastatic breast cancer enrolled in Individualized Molecular Analyses Guide Efforts in Breast Cancer (IMAGE II trial), 17 benign breast disease and 9 healthy normal controls (J0888 repository). Blood from IMAGE II participants was collected upon disease progression. A newly designed GX Breast Cancer Monitoring Assay for research use only (RUO*) first converted unmethylated CpG sites in ctDNA from 1 ml plasma with bisulfite. The sample was then split into two methylation detection cartridges, which quantitated DNA methylation of 9 markers along with an ACTB reference. Cumulative methylation (CM) of the 9-gene panel was calculated using a novel algorithm. Performance was assessed based on Receiver Operating Characteristic (ROC) curves and Mann-Whitney analyses.RESULTS: The GX Breast Cancer Monitoring Assay (RUO)* showed that the 9-gene panel was significantly more methylated in cancer compared to normal/benign plasma samples (median for cancer: 428.0 CM units versus for benign: 0.0 CM units; P< 0.0001), and revealed a sensitivity of 85% and specificity of 92%, using a cumulative methylation threshold of 35.5 units based on ROC area under the curve (AUC) = 0.909 (95% CI 0.836 – 0.982, P<0.0001). We will present comparisons of the GX results to cMethDNA, the gold standard assay, which reported 85-90% sensitivity at 90% specificity.CONCLUSIONS: We identified a panel of methylated DNA markers that discriminates stage IV breast from benign breast disease and healthy normal subjects using ctDNA. Our automated cartridge-based assay prototype demonstrates high sensitivity and specificity for detecting invasive breast cancer. Its ability to assess changes in DNA methylation will be tested next with clinical trial samples collected longitudinally during treatment. This assay has potential clinical utility in monitoring therapeutic response and predicting disease recurrence.* For Research Use Only. Not for use in diagnostic procedures. Not reviewed by any regulatory body. Citation Format: Mary Jo Fackler, Suzana Tulac, Neesha Venkatesan, Adam J. Aslam, Leslie M. Cope, Jennifer Lehman, Rita Denbow, Jeffrey Reynolds, Morgan Buckley, Bradley M. Downs, Kala Visvanathan, Christopher B. Umbricht, Antonio C. Wolff, Vered Stearns, Edwin W. Lai, Saraswati Sukumar. An automated DNA methylation assay for monitoring treatment response in patients with metastatic breast cancer [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 PS4-03.
76 Background: Preoperative chemoradiotherapy using a platinum plus either a taxane or 5FU results in a pathological complete response rate (pCR) of approximately 25% to 30% in patients with operable esophageal cancer. A predictive biomarker to personalize chemotherapy in an effort to increase pCR would be a significant advance. Checkpoint with forkhead and ring finger domains (CHFR) is an E3 ligase which plays a role in response to mitotic stress. In our retrospective data, hypermethylation and silencing of CHFR, correlates with improved response and prolonged survival following therapy with taxanes. The primary endpoint of this study is to determine if there is a higher pCR rate when CHFR methylation status (MS) is used to decide if patients receive a taxane or 5FU. Methods: All patients presenting to Johns Hopkins with operable T2-T4/N0-N3 esophageal cancer are eligibile. A methylation-specific PCR which demonstrates CHFR MS has been developed by our lab. Methylated (M) patients receive weekly cisplatin (30mg/m2)/paclitaxel (50mg/m2) and unmethylated (U) patients receive previously described regimens of folfox or cisplatin/5FU. All patients receive concurrent radiation. Results: From July 2011 to September 2013, 35 patients have been assessed, 18 U (51%), 14 M (40%) and 3 unknown (9%). Twenty-four patients (22 males and 2 females) have been treated on study (age 48 – 74 years old, median 63.8) with 14 tumors U (58%) and 10 tumors M (42%) respectively. To date, 2/13 U patients (15%) have had a pCR and 3/8 M patients (38%) have had a pCR (p=0.32). Toxicities of each regimen are consistent with previous reports. Conclusions: Trimodality therapy is standard of care for operable esophageal cancer in the United States. Different chemotherapies have been combined with radiation prior to surgery to improve pCR rates but no biomarkers to personalize chemotherapy exist at present. Epigenetic biomarkers such as CHFR MS potentially may be used to decide which patients are more sensitive to taxane based regimens. Accrual to this study is ongoing. Clinical trial information: NCT01372202.
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