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

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

JOURNAL=Frontiers in Oncology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1339302

DOI=10.3389/fonc.2024.1339302

ISSN=2234-943X

ABSTRACT=<sec><title>Purpose</title><p>Despite 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 <italic>ERBB2</italic>(HER2)-amplified PDAC with anti-HER2 therapy has been reported with mixed results. Most pancreatic adenocarcinomas have <italic>KRAS</italic> 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 <italic>ERBB2</italic>-amplified pancreatic cancer patients treated with anti-HER2 therapy and provide data on the frequency of <italic>ERBB2</italic> amplifications and <italic>KRAS</italic> alterations identified by clinical circulating cell-free DNA testing.</p></sec><sec><title>Methods</title><p>De-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.</p></sec><sec><title>Results</title><p>Of 1,791 patients with pancreatic adenocarcinoma, 36 (2.0%) had an <italic>ERBB2</italic> amplification, 26 (72.2%) of whom had a <italic>KRAS</italic> 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 <italic>KRAS</italic> alteration detected until progression.</p></sec><sec><title>Conclusion</title><p>Our case series illustrates that certain patients with <italic>ERBB2</italic>-amplified pancreatic adenocarcinoma may respond to anti-HER2 therapy and gain several months of prolonged survival. Our data suggests <italic>KRAS</italic> 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 <italic>KRAS</italic> in resistance to anti-HER2 therapy.</p></sec>