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5 results on '"Mohammad Amin Nezami"'

1. ERBB2 (HER2) amplifications and co-occurring KRAS alterations in the circulating cell-free DNA of pancreatic ductal adenocarcinoma patients and response to HER2 inhibition

Author

Afsaneh Barzi, Caroline M. Weipert, Carin R. Espenschied, Victoria M. Raymond, Andrea Wang-Gillam, Mohammad Amin Nezami, Eva J. Gordon, Daruka Mahadevan, and Kabir Mody

Subjects
pancreatic cancer, HER2 amplification, ERBB2, ctDNA, liquid biopsy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

PurposeDespite accumulating data regarding the genomic landscape of pancreatic ductal adenocarcinoma (PDAC), olaparib is the only biomarker-driven FDA-approved targeted therapy with a PDAC-specific approval. Treating ERBB2(HER2)-amplified PDAC with anti-HER2 therapy has been reported with mixed results. Most pancreatic adenocarcinomas have KRAS alterations, which have been shown to be a marker of resistance to HER2-targeted therapies in other malignancies, though the impact of these alterations in pancreatic cancer is unknown. We describe two cases of ERBB2-amplified pancreatic cancer patients treated with anti-HER2 therapy and provide data on the frequency of ERBB2 amplifications and KRAS alterations identified by clinical circulating cell-free DNA testing.MethodsDe-identified molecular test results for all patients with pancreatic cancer who received clinical cell-free circulating DNA analysis (Guardant360) between 06/2014 and 01/2018 were analyzed. Cell-free circulating DNA analysis included next-generation sequencing of up to 73 genes, including select small insertion/deletions, copy number amplifications, and fusions.ResultsOf 1,791 patients with pancreatic adenocarcinoma, 36 (2.0%) had an ERBB2 amplification, 26 (72.2%) of whom had a KRAS alteration. Treatment data were available for seven patients. Two were treated with anti-HER2 therapy after their cell-free circulating DNA result, with both benefiting from therapy, including one with a durable response to trastuzumab and no KRAS alteration detected until progression.ConclusionOur case series illustrates that certain patients with ERBB2-amplified pancreatic adenocarcinoma may respond to anti-HER2 therapy and gain several months of prolonged survival. Our data suggests KRAS mutations as a possible mechanism of primary and acquired resistance to anti-HER2 therapy in pancreatic cancer. Additional studies are needed to clarify the role of KRAS in resistance to anti-HER2 therapy.

Published
2024
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2. Supplemental Table 1 from Routine Plasma-Based Genotyping to Comprehensively Detect Germline, Somatic, and Reversion BRCA Mutations among Patients with Advanced Solid Tumors

Author

Massimo Cristofanilli, Aditya Bardia, Richard B. Lanman, Stephen R. Fairclough, Victoria M. Raymond, Benjamin L. Maughan, Neeraj Agarwal, Benjamin B. Bridges, Barbara A. Parker, Adam M. Brufsky, Alice C. Fan, Benedito A. Carneiro, Sandip P. Patel, Mohammad Amin Nezami, Michael B. Lilly, Tracy Nance, Aaron Hardin, Jennifer Yen, Oliver Sartor, Thereasa A. Rich, and Neelima Vidula

Abstract

Supplemental Table 1

Published
2023

3. Data from Routine Plasma-Based Genotyping to Comprehensively Detect Germline, Somatic, and Reversion BRCA Mutations among Patients with Advanced Solid Tumors

Author

Massimo Cristofanilli, Aditya Bardia, Richard B. Lanman, Stephen R. Fairclough, Victoria M. Raymond, Benjamin L. Maughan, Neeraj Agarwal, Benjamin B. Bridges, Barbara A. Parker, Adam M. Brufsky, Alice C. Fan, Benedito A. Carneiro, Sandip P. Patel, Mohammad Amin Nezami, Michael B. Lilly, Tracy Nance, Aaron Hardin, Jennifer Yen, Oliver Sartor, Thereasa A. Rich, and Neelima Vidula

Abstract

Purpose:PARP inhibitors (PARPi) are efficacious in multiple cancers harboring germline (and possibly somatic) BRCA1/2 mutations. Acquired reversions can restore BRCA1/2 function, causing resistance to PARPi and/or platinum-based chemotherapy. The optimal method of identifying patients with germline, somatic, and/or reversion mutations in BRCA1/2 has not been established. Next-generation sequencing (NGS) of cell-free DNA (cfDNA) provides a platform to identify these three types of BRCA1/2 mutations.Experimental Design:Patients with advanced breast, ovarian, prostate, or pancreatic cancer were tested using a clinically validated 73-gene cfDNA assay that evaluates single-nucleotide variants and insertion–deletion mutations (indels) in BRCA1/2, and distinguishes somatic/reversion from germline mutations with high accuracy.Results:Among 828 patients, one or more deleterious BRCA1/2 mutations were detected in 60 (7.2%) patients, including germline (n = 42) and somatic (n = 18) mutations. Common coexisting mutations included TP53 (61.6%), MYC (30%), PIK3CA (26.6%), BRAF (15%), and ESR1 (11.5%). Polyclonal reversion mutations (median, 5) were detected in 9 of 42 (21.4%) germline BRCA1/2-mutant patients, the majority (77.7%) of whom had prior PARPi exposure (median duration, 10 months). Serial cfDNA demonstrated emergence of reversion BRCA mutations under therapeutic pressure from initial PARPi exposure, which contributed to subsequent resistance to PARPi and platinum therapy.Conclusions:cfDNA NGS identified high rates of therapeutically relevant mutations without foreknowledge of germline or tissue-based testing results, including deleterious somatic BRCA1/2 mutations missed by germline testing and reversion mutations that can have important treatment implications. Further research is needed to confirm clinical utility of these findings to guide precision medicine approaches for patients with advanced malignancies.

Published
2023

4. Routine Plasma-Based Genotyping to Comprehensively Detect Germline, Somatic, and Reversion

Author

Neelima, Vidula, Thereasa A, Rich, Oliver, Sartor, Jennifer, Yen, Aaron, Hardin, Tracy, Nance, Michael B, Lilly, Mohammad Amin, Nezami, Sandip P, Patel, Benedito A, Carneiro, Alice C, Fan, Adam M, Brufsky, Barbara A, Parker, Benjamin B, Bridges, Neeraj, Agarwal, Benjamin L, Maughan, Victoria M, Raymond, Stephen R, Fairclough, Richard B, Lanman, Aditya, Bardia, and Massimo, Cristofanilli

Subjects
BRCA2 Protein, Gene Expression Regulation, Neoplastic, Germ Cells, BRCA1 Protein, Diagnostic Tests, Routine, Neoplasms, Mutation, Biomarkers, Tumor, High-Throughput Nucleotide Sequencing, Humans, Prognosis, Cell-Free Nucleic Acids
Abstract

PARP inhibitors (PARPi) are efficacious in multiple cancers harboring germline (and possibly somatic)Patients with advanced breast, ovarian, prostate, or pancreatic cancer were tested using a clinically validated 73-gene cfDNA assay that evaluates single-nucleotide variants and insertion-deletion mutations (indels) inAmong 828 patients, one or more deleteriouscfDNA NGS identified high rates of therapeutically relevant mutations without foreknowledge of germline or tissue-based testing results, including deleterious somatic

Published
2019

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