Germline variants and impact on lung cancer outcomes following chemotherapy: A systematic review

Abdullah Al Matrafi; Mark A. Baxter; Ewan R. Pearson; Russell D. Petty

doi:10.1016/j.critrevonc.2026.105453

Germline variants and impact on lung cancer outcomes following chemotherapy: A systematic review

Abdullah Al Matrafi
, Mark A. Baxter
, Ewan R. Pearson
, Russell D. Petty (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

Abstract

Background
Lung cancer is the primary cause of cancer deaths in the UK and globally, and the main subtypes are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Many treatment options are available, with platinum-based chemotherapy being a key component for many patients. However, variation in survival outcomes exists among individuals of European ancestry, which makes it important to identify germline genetic variants that help guide decision-making and optimise patient treatment and outcomes.

Method
A systematic literature search was conducted in PubMed and Web of Science for lung cancer studies investigating the impact of germline genetic variants on systemic anti-cancer therapy (SACT) outcomes in populations of European ancestry. The review was conducted according to the Preferred Reporting Items of Systematic Review and Meta-Analysis (PRISMA) and Synthesis without Meta-Analysis (SWiM) guidelines.

Results
A total of 20 studies were included in the review out of 4469 on NSCLC and SCLC, encompassing 3639 patients. The most thoroughly investigated area was NSCLC treated with platinum-based chemotherapy. Genetic variants associated with overall survival and/or progression-free survival included XPD Lys751Gln, XPD Asp312Asn, ERCC1 C118T, and XRCC1 Arg399Gln. For non-platinum-treated NSCLC and SCLC, there was insufficient evidence to conduct a meaningful investigation.

Conclusion
The XPD Lys751Gln, XPD Asp312Asn, ERCC1 C118T, and XRCC1 Arg399Gln variants showed potential associations with survival outcomes among patients of European ancestry with NSCLC after platinum-based chemotherapy. To support clinical implementation, large real-world pharmacogenomics studies stratified by ancestry are needed to overcome statistical power and heterogeneity limitations.

Original language	English
Article number	105453
Number of pages	15
Journal	Critical Reviews in Oncology/Hematology
Volume	226
Early online date	1 Jul 2026
DOIs	https://doi.org/10.1016/j.critrevonc.2026.105453
Publication status	E-pub ahead of print - 1 Jul 2026

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Lung cancer
NSCLC
SCLC
Pharmacogenomics
Germline
Survival
Toxicity
SACT

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10.1016/j.critrevonc.2026.105453

Cite this

@article{15b192cf96934d60bc0c41f4015806fa,

title = "Germline variants and impact on lung cancer outcomes following chemotherapy: A systematic review",

abstract = "Background Lung cancer is the primary cause of cancer deaths in the UK and globally, and the main subtypes are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Many treatment options are available, with platinum-based chemotherapy being a key component for many patients. However, variation in survival outcomes exists among individuals of European ancestry, which makes it important to identify germline genetic variants that help guide decision-making and optimise patient treatment and outcomes. Method A systematic literature search was conducted in PubMed and Web of Science for lung cancer studies investigating the impact of germline genetic variants on systemic anti-cancer therapy (SACT) outcomes in populations of European ancestry. The review was conducted according to the Preferred Reporting Items of Systematic Review and Meta-Analysis (PRISMA) and Synthesis without Meta-Analysis (SWiM) guidelines. Results A total of 20 studies were included in the review out of 4469 on NSCLC and SCLC, encompassing 3639 patients. The most thoroughly investigated area was NSCLC treated with platinum-based chemotherapy. Genetic variants associated with overall survival and/or progression-free survival included XPD Lys751Gln, XPD Asp312Asn, ERCC1 C118T, and XRCC1 Arg399Gln. For non-platinum-treated NSCLC and SCLC, there was insufficient evidence to conduct a meaningful investigation. Conclusion The XPD Lys751Gln, XPD Asp312Asn, ERCC1 C118T, and XRCC1 Arg399Gln variants showed potential associations with survival outcomes among patients of European ancestry with NSCLC after platinum-based chemotherapy. To support clinical implementation, large real-world pharmacogenomics studies stratified by ancestry are needed to overcome statistical power and heterogeneity limitations.",

keywords = "Lung cancer, NSCLC, SCLC, Pharmacogenomics, Germline, Survival, Toxicity, SACT",

author = "\{Al Matrafi\}, Abdullah and Baxter, \{Mark A.\} and Pearson, \{Ewan R.\} and Petty, \{Russell D.\}",

note = "{\textcopyright} 2026",

year = "2026",

month = jul,

day = "1",

doi = "10.1016/j.critrevonc.2026.105453",

language = "English",

volume = "226",

journal = "Critical Reviews in Oncology/Hematology",

issn = "1040-8428",

publisher = "Elsevier",

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TY - JOUR

T1 - Germline variants and impact on lung cancer outcomes following chemotherapy: A systematic review

AU - Al Matrafi, Abdullah

AU - Baxter, Mark A.

AU - Pearson, Ewan R.

AU - Petty, Russell D.

PY - 2026/7/1

Y1 - 2026/7/1

N2 - Background Lung cancer is the primary cause of cancer deaths in the UK and globally, and the main subtypes are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Many treatment options are available, with platinum-based chemotherapy being a key component for many patients. However, variation in survival outcomes exists among individuals of European ancestry, which makes it important to identify germline genetic variants that help guide decision-making and optimise patient treatment and outcomes. Method A systematic literature search was conducted in PubMed and Web of Science for lung cancer studies investigating the impact of germline genetic variants on systemic anti-cancer therapy (SACT) outcomes in populations of European ancestry. The review was conducted according to the Preferred Reporting Items of Systematic Review and Meta-Analysis (PRISMA) and Synthesis without Meta-Analysis (SWiM) guidelines. Results A total of 20 studies were included in the review out of 4469 on NSCLC and SCLC, encompassing 3639 patients. The most thoroughly investigated area was NSCLC treated with platinum-based chemotherapy. Genetic variants associated with overall survival and/or progression-free survival included XPD Lys751Gln, XPD Asp312Asn, ERCC1 C118T, and XRCC1 Arg399Gln. For non-platinum-treated NSCLC and SCLC, there was insufficient evidence to conduct a meaningful investigation. Conclusion The XPD Lys751Gln, XPD Asp312Asn, ERCC1 C118T, and XRCC1 Arg399Gln variants showed potential associations with survival outcomes among patients of European ancestry with NSCLC after platinum-based chemotherapy. To support clinical implementation, large real-world pharmacogenomics studies stratified by ancestry are needed to overcome statistical power and heterogeneity limitations.

AB - Background Lung cancer is the primary cause of cancer deaths in the UK and globally, and the main subtypes are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Many treatment options are available, with platinum-based chemotherapy being a key component for many patients. However, variation in survival outcomes exists among individuals of European ancestry, which makes it important to identify germline genetic variants that help guide decision-making and optimise patient treatment and outcomes. Method A systematic literature search was conducted in PubMed and Web of Science for lung cancer studies investigating the impact of germline genetic variants on systemic anti-cancer therapy (SACT) outcomes in populations of European ancestry. The review was conducted according to the Preferred Reporting Items of Systematic Review and Meta-Analysis (PRISMA) and Synthesis without Meta-Analysis (SWiM) guidelines. Results A total of 20 studies were included in the review out of 4469 on NSCLC and SCLC, encompassing 3639 patients. The most thoroughly investigated area was NSCLC treated with platinum-based chemotherapy. Genetic variants associated with overall survival and/or progression-free survival included XPD Lys751Gln, XPD Asp312Asn, ERCC1 C118T, and XRCC1 Arg399Gln. For non-platinum-treated NSCLC and SCLC, there was insufficient evidence to conduct a meaningful investigation. Conclusion The XPD Lys751Gln, XPD Asp312Asn, ERCC1 C118T, and XRCC1 Arg399Gln variants showed potential associations with survival outcomes among patients of European ancestry with NSCLC after platinum-based chemotherapy. To support clinical implementation, large real-world pharmacogenomics studies stratified by ancestry are needed to overcome statistical power and heterogeneity limitations.

KW - Lung cancer

KW - NSCLC

KW - SCLC

KW - Pharmacogenomics

KW - Germline

KW - Survival

KW - Toxicity

KW - SACT

U2 - 10.1016/j.critrevonc.2026.105453

DO - 10.1016/j.critrevonc.2026.105453

M3 - Article

C2 - 42342141

SN - 1040-8428

VL - 226

JO - Critical Reviews in Oncology/Hematology

JF - Critical Reviews in Oncology/Hematology

M1 - 105453

ER -

Germline variants and impact on lung cancer outcomes following chemotherapy: A systematic review

Abstract

UN SDGs

Keywords

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