Rate of Pathogenic Germline Variants in Patients With Lung Cancer

Steven Sorscher, Jaclyn LoPiccolo, Brandie Heald, Elaine Chen, Sara L Bristow, Scott T Michalski, Sarah M Nielsen, Alix Lacoste, Emil Keyder, Hayan Lee, Robert L Nussbaum, Renato Martins, Edward D Esplin, Steven Sorscher, Jaclyn LoPiccolo, Brandie Heald, Elaine Chen, Sara L Bristow, Scott T Michalski, Sarah M Nielsen, Alix Lacoste, Emil Keyder, Hayan Lee, Robert L Nussbaum, Renato Martins, Edward D Esplin

Abstract

Purpose: Germline genetic testing (GGT) is now recommended for all patients diagnosed with ovarian or pancreatic cancer and for a large proportion of patients based solely on a diagnosis of colorectal or breast cancer. However, GGT is not yet recommended for all patients diagnosed with lung cancer (LC), primarily because of a lack of evidence that supports a significant frequency of identifying pathogenic germline variants (PGVs) in these patients. This study characterizes GGT results in a cohort of patients with LC.

Methods: We reviewed deidentified data for 7,788 patients with GGT (2015-2022). PGV frequencies were compared to a control cohort of unaffected individuals. GGT results were stratified by genomic ancestry, history of cancer, and PGV clinical actionability per current guidelines.

Results: Of all patients with LC, 14.9% (1,161/7,788) had PGVs. The rate was similar when restricted to patients with no cancer family history (FH) or personal history (PH) of other cancers (14.3%). PGVs were significantly enriched in BRCA2, ATM, CHEK2, BRCA1, and mismatch repair genes compared with controls. Patients of European (EUR) genomic ancestry had the highest PGV rate (18%) and variants of uncertain significance were significantly higher in patients of non-EUR genomic ancestry. Of the PGVs identified, 61.3% were in DNA damage repair (DDR) genes and 95% were clinically actionable.

Conclusion: This retrospective study shows a LC diagnosis identifies patients with a significant likelihood of having a cancer-predisposing PGV across genomic ancestries. Enrichment of PGVs in DDR genes suggests that these PGVs may contribute to LC cancer predisposition. The frequency of PGVs among patients with LC did not differ significantly according to FH or PH of other cancers.

Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Steven Sorscher

Employment: Invitae, Hologic/Biotheranostics

Honoraria: Puma Biotechnology

Speakers' Bureau: Puma Biotechnology

Travel, Accommodations, Expenses: Puma Biotechnology

Brandie Heald

Employment: InVitae

Stock and Other Ownership Interests: InVitae

Elaine Chen

Employment: InVitae

Stock and Other Ownership Interests: InVitae

Sara L. Bristow

Employment: InVitae, Natera

Stock and Other Ownership Interests: InVitae

Scott T. Michalski

Employment: InVitae

Stock and Other Ownership Interests: InVitae

Sarah M. Nielsen

Employment: InVitae

Stock and Other Ownership Interests: InVitae

Travel, Accommodations, Expenses: InVitae

Alix Lacoste

Employment: InVitae

Stock and Other Ownership Interests: InVitae, BenevolentAI

Patents, Royalties, Other Intellectual Property: Patent: Generating a candidate set of entities from a training set, Patent: Ranking biological entity pairs by evidence level, Extraction and normalization of mutant genes from unstructured text for cognitive search and analytics, Accelerated pharmaceutical repurposing by finding anticorrelations and by text mining

Emil Keyder

Employment: InVitae

Stock and Other Ownership Interests: InVitae

Travel, Accommodations, Expenses: InVitae

Robert L. Nussbaum

Employment: Invitae

Leadership: Invitae

Stock and Other Ownership Interests: Genome Medical, Invitae

Honoraria: Pfizer

Consulting or Advisory Role: Genome Medical, Maze Therapeutics, Pfizer

Patents, Royalties, Other Intellectual Property: Royalties on a patented mouse model for Parkinson disease held by the National Institutes of Health and the University of California San Francisco

Open Payments Link: https://openpaymentsdata.cms.gov/physician/603319https://openpaymentsdata.cms.gov/physician/603319/summary

Renato Martins

Honoraria: Sanofi, Takeda

Research Funding: Lilly (Inst), Eisai (Inst), Pfizer (Inst), Merck Sharp & Dohme (Inst), Genentech (Inst)

Other Relationship: Takeda

Edward D. Esplin

Employment: Invitae

Stock and Other Ownership Interests: Invitae

Consulting or Advisory Role: Taproot Health Inc, Exir Bio

Travel, Accommodations, Expenses: Velsera

No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Genetic test results among all individuals in the study cohort. (A) Overall genetic test results. See the Data Supplement (Methods) (Genetic testing) for definitions of positive, carrier, uncertain, and negative. (B) Proportion of individuals with a positive result in genes. Proportion is based on the total number of individuals who had the gene ordered by their clinician. Positive rates for all genes can be found in the Data Supplement (Table S2).
FIG 2.
FIG 2.
Genetic test results by (A) genomic ancestry and (B) personal history of other cancers. Proportion is based on the number of patients in each category, with the total number of patients in each category reported on the x-axis. Of note, 20 patients (0.02% of cohort) did not demonstrate a clearly predominant genomic ancestry and are not included in the analysis in panel (A). AFR, African; AMR, Ad Mixed American; EAS, East Asian; EUR, European; SAS, South Asian.
FIG 3.
FIG 3.
Genetic test results among patients with only a personal history of lung cancer, per clinician report. (A) Overall genetic test results. See the Data Supplement (Methods) (Genetic testing) for definitions of positive, carrier, uncertain, and negative. (B) Proportion of patients with a positive result in genes. Proportion is based on the total number of patients who had the gene ordered by their clinician. Positive rates for all genes can be found in the Data Supplement (Table S3).

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