Identifying a New EGFR Germline Mutation in Lung Adenocarcinoma: A Case Report and Review of the Literature

Published in Clinical Lung Cancer, on April 16, 2024

Authors: Parth Sharma, Himil Mahadevia, Sreekanth Donepudi, Lara Kujtan, Beth Gustafson, Ben Ponwilawan, Ammar Al-Obaidi, Janakiraman Subramanian, Dhruv Bansal

Introduction:

Lung cancer remains a leading cause of cancer-related deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. While tobacco smoking is a primary risk factor, recent studies have highlighted the role of genetic susceptibility and familial predisposition. This case report and literature review shed light on a novel EGFR germline mutation, T725M, associated with lung adenocarcinoma, emphasizing the importance of genomic profiling and inherited risk assessment.

Design and Methods:

The authors describe a case of an 84-year-old Caucasian male, a former smoker, diagnosed with stage IB right lung adenocarcinoma. After initial surgical resection and disease recurrence, comprehensive next-generation sequencing (NGS) revealed a somatic EGFR p.L858R mutation and a germline EGFR p.T725M mutation, along with a concomitant germline ATM p.V1268fs mutation. The patient was treated with osimertinib, a third-generation EGFR tyrosine kinase inhibitor, resulting in a partial response.

Key Highlights:

• The EGFR T790M mutation has been identified as the most common germline variant in lung cancer, with emerging evidence for other EGFR germline mutations.
• The reported EGFR p.T725M germline mutation is the first known case in the US population and only the second globally, underscoring its rarity.
• The prevalence of pathogenic or likely pathogenic germline variants in lung cancer patients ranges from 4.3-14.9%, indicating a significant inherited risk.
• Germline mutations may be weakly oncogenic, and the presence of a concomitant somatic mutation may act as a “second hit” and accelerate carcinogenesis.
• The implementation of universal germline testing could increase the detection of clinically actionable germline variants compared to the current guideline-based approach.

What We Learned:

• This report highlights the importance of comprehensive genomic profiling in lung cancer patients, as it can uncover rare and actionable germline mutations.
• The identification of germline lung cancer mutations holds the potential to identify new therapeutic targets and aid in the development of screening and surveillance guidelines for patients with hereditary lung cancer.
• The advent of precision medicine and targeted therapies underscores the need for germline testing to personalize treatment strategies and provide genetic counseling for patients and their families.

Key Takeaway Messages:

• Lung cancer has a significant inherited risk component, and germline mutations in various genes, including EGFR, play a crucial role.
• The discovery of novel germline mutations, such as EGFR p.T725M, expands our understanding of inherited lung cancer susceptibility and highlights the importance of comprehensive genomic profiling.
• Implementing universal germline testing in lung cancer patients could improve the detection of clinically actionable variants and pave the way for personalized treatment approaches and preventive strategies.
• Further research is needed to establish the true prevalence of inherited lung cancer germline alterations and develop appropriate screening and surveillance guidelines for at-risk individuals.

Summary by Amalya Sargsyan, MD

A Novel EGFR Germline Mutation in Lung Adenocarcinoma: Case Report and Literature Review

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