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Department of Surgery, NorthShore University HealthSystem, Evanston, IllDepartment of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, Ill
Department of Medicine, NorthShore University HealthSystem, Evanston, IllDepartment of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, Ill
Department of Pathology, NorthShore University HealthSystem, Evanston, IllDepartment of Pathology, Pritzker School of Medicine, University of Chicago, Chicago, Ill
Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, IllDepartment of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, Ill
To determine the frequency of pathogenic mutations in high-penetrance genes (HPGs) in patients with non–small cell lung cancer (NSCLC) and identify whether such mutations are associated with clinicopathologic outcomes.
Methods
Patients with NSCLC who had consented to participate in a linked clinical database and biorepository underwent germline DNA sequencing using a next-generation sequencing panel that included cancer-associated HPGs and cancer risk–associated single nucleotide polymorphisms (SNPs). These data were linked to the clinical database to assess for associations between germline variants and clinical phenotype using Fisher's exact test and multivariable logistic and Cox regression.
Results
We analyzed 151 patients, among whom 33% carried any pathogenic HPG mutation and 23% had a genetic risk score (GRS) >1.5. Among the patients without any pathogenic mutation, 31% were at cancer stage II or higher, compared with 55% of those with 2 types of HPG mutations (P = .0293); 40% of patients with both types of HPG mutations had cancer recurrence, compared with 21% of patients without both types (P = .0644). In multivariable analysis, the presence of 2 types of HPG mutations was associated with higher cancer stage (odds ratio [OR], 3.32; P = .0228), increased recurrence of primary tumor (OR, 2.93; P = .0527), shorter time to recurrence (hazard ratio [HR], 3.03; P = .0119), and decreased cancer-specific (HR, 3.53; P = .0039) and overall survival (HR, 2.44; P = .0114).
Conclusions
The presence of mutations in HPGs is associated with higher cancer stage, increased risk of recurrence, and worse cancer-specific and overall survival in patients with NSCLC. Further large studies are needed to better delineate the role of HPGs in cancer recurrence and the potential benefit of adjuvant treatment in patients harboring such mutations.
Carrier status for pathogenic germline mutations in high-penetrance genes in a non–small cell lung cancer population was associated with more advanced stage and worse clinical outcomes.
Knowledge regarding the impact of germline mutations in non–small cell lung cancer is limited. This study suggests that germline pathogenic mutations in high-penetrance genes are associated with a more aggressive cancer phenotype. Future work combining germline genetic risk stratification along with somatic tumor changes may further improve our ability to treat patients with lung cancer.
Advancements in our understanding of the somatic mutations in non–small cell lung cancer (NSCLC) has led to the development of targeted molecular therapy and immunotherapy, with practice-changing results.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non–small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
The role of the patient's underlying genetic makeup also may have a significant impact on cancer development and outcomes, but this historically has received less attention than somatic driver mutations. The heritability of lung cancer was estimated at 18% in twin studies.
Many questions regarding tumor biology cannot be answered based on somatic mutations alone: Why do some heavy smokers develop lung cancer while others do not? Why do some patients present with widely metastatic disease and others with a small primary tumor and a single metastasis? Why do cancers that are seemingly similar biologically have radically different outcomes in different patients?
Across a variety of cancers, pathogenic germline mutations in high-penetrance genes (HPGs) have been implicated in both an increased risk of developing cancer and the development of more aggressive cancers. Our group has published work showing how a targeted inherited cancer panel including HPGs and using single nucleotide polymorphisms (SNPs) to generate a polygenic genetic risk score (GRS) not only can help identify patients at increased risk of developing prostate cancer, but also is associated with worse clinical outcomes.
Although research on germline mutations among lung cancer patients is in its early stages, recent evidence suggests that a considerably high proportion of lung cancer patients have germline pathogenic mutations in HPGs.
Genes that have been associated with lung cancer include ATM, BRCA1, DIS3, ERCC2, FANCG, MRE11A, PALB2, PIK3C2G, and XRCC2 in lung adenocarcinoma, and BRCA2, BRIP1, DIS3, FANCA, FANCC, MAP3K15, and PARP3 and lung squamous cell carcinoma.
In this study, we used a prospectively collected linked clinical database and biorepository along with next-generation sequencing (NGS) of DNA to analyze the prevalence of pathogenic mutations in HPGs and overall GRS in patients with NSCLC. We also assessed for any association between pathogenic mutations and clinicopathologic outcomes, including cancer stage, histologic grade, cancer recurrence, and overall survival (OS) and cancer-specific survival. It was our hypothesis that an increased prevalence of pathogenic HPG mutations and elevated GRS would be associated with worse clinical outcomes.
Methods
Study Population
The study cohort comprised patients with either primary lung adenocarcinoma or squamous cell carcinoma, diagnosed between March 1, 2013, and November 1, 2017, who had consented to participate in a prospectively collected linked clinical database and biorepository and had either a blood or tissue sample from which DNA could be extracted. Patients had to be age ≥18 years at the time of diagnosis. This study was approved by the NorthShore University HealthSystem Institutional Review Board (IRB EH18-162, March 20, 2018).
Data Collection
Clinicopathologic data, including age, sex, age at diagnosis, smoking history, clinical and pathologic stage, vital status, recurrence, and type of therapy, were obtained from a prospectively collected clinical database along with the electronic medical record and the institutional cancer registry.
Genetic Analysis
Germline DNA was sequenced using a targeted NGS panel targeting 355 HPGs and 23 SNPs associated with lung cancer risk (Online Data Supplement). HPGs are genes in which rare disruptive or protein-truncating variants confer a high risk of disease. The probes for capturing exon regions in these genes were manufactured by Roche NimbleGen. The SeqCap EZ Library SR User's Guide (Roche) was followed for library preparation and capture of targeted sequences. Paired-end sequencing of 2 × 150 bp was performed on an Illumina NextSeq500 sequencer. The median coverage for the samples was at 300×.
Candidate HPGs evaluated in this study include those involved in DNA repair and/or cancer-related genes. Selection of DNA repair genes was based on the catalog of 178 human DNA repair genes, including genes involved in base excision repair, nucleotide excision repair, mismatch repair, homologous recombination, and nonhomologous end joining.
Cancer-related genes were selected based on our review of published articles on susceptibility genes in all major types of cancer, including lung cancer.
Cancer-related genes have a very broad range of functions, including those ubiquitously expressed, and participate in such fundamental processes as cell cycle regulation.
Bioinformatics Analysis
Paired-end reads were aligned to the GRCh37 version of the human genome using Burrows–Wheeler Aligner v0.7 to generate BAM files.
After sorting the BAM files using samtools, polymerase chain reaction duplicates were marked using Picard, and realignment around putative gaps was performed using the Genome Analysis Toolkit v3.2-2. Variant calling was performed with the Genome Analysis Toolkit Haplotype caller. ANNOVAR (http://annovar.openbioinformatics.org/en/latest) and snpEff were used for annotating variants and for retrieving information on variants in the population-based studies, such as the 1000 Genomes Project (www.1000genomes.org), NHLBI-ESP 6500 exomes, ExAC (http://exac.broadinstitute.org/), and gnomAD (http://gnomad.broadinstitute.org/), and clinical databases, such as the Human Gene Mutation Database
Specifically, pathogenic and likely pathogenic mutations are defined as (1) all protein-truncating mutations unless their allele frequency is ≥5% in any racial group in population databases or is reported as benign or likely benign in ClinVar, and (2) nonsynonymous changes if their allele frequency is <5% and reported as pathogenic and likely pathogenic mutations in ClinVar.
GRS
GRS, a population-standardized polygenic risk score (PMID: 31037745), was calculated based on 23 lung cancer risk–associated SNPs identified from previous genome-wide associated studies as
where gi is the genotype of SNP i in an individual (0, 1, or 2 risk alleles), ORi is the odds ratio (OR) of SNP i estimated from external studies, and fi is the risk allele frequency of SNP i based on gnomAD (non-Finnish European population). The GRS value can be interpreted as relative risk to the general population.
Statistical Analysis
The genomic data were linked to the corresponding clinical database. Because consent for the biorepository and clinical database was granted prior to the revised common rule outlining broad consent, the genetic data and the clinical data were kept separate and were linked only by an “honest broker,” which kept the investigators blinded to the link between genetic data and any protected health information.
With the blinded, linked data, we assessed for associations between germline mutations and clinical phenotype, including pathologic stage, tumor grade, and disease recurrence, using Fisher's exact test. Recurrence rate was defined as any recurrence of the primary tumor. Time to recurrence was measured from the last day of definitive treatment to the documented first recurrence. OS and cancer-specific survival were measured from the date of diagnosis. No adjustments for multiple comparisons were made because of the small sample size with too few mutations and clinical events for adequate power. Univariate analyses of time to recurrence, OS, and cancer-specific survival were performed using the Kaplan–Meier method and log-rank test. Estimated 5-year survival rates were reported. Multivariable logistic regression and Cox regression were used to assess factors associated with clinical outcomes. OR was reported for logistic regression, and hazard ratio (HR) was reported for Cox regression. All statistical analyses were performed using SAS 9.4 (SAS Institute) with 2-tailed tests and a significance level of P < .05.
Results
Demographics
We analyzed 151 patients with NSCLC for whom both genetic material and clinicopathologic data were available. Demographic and clinicopathologic data for the entire cohort are presented in Table 1. The majority of patients were at pathologic stage I (n = 96; 64%) with only 7 patients (4.6%) at pathologic stage IV. Twenty-seven patients (18%) were never smokers, and only 13 (9%) were current smokers. Thirty-eight patients (26%) had a family history of lung cancer, and 92 patients (65%) had a family history of other cancers. Most cancers were adenocarcinomas (n = 109; 72%). Thirty-five patients (35%) had documented recurrence of their primary cancer.
Table 1Patient characteristics
Characteristic
Value
Total patients
151
Age, y, mean ± SD
69 ± 9
Female sex, n (%)
91 (60.3)
Race, n (%)
Caucasian
135 (89.4)
African American
4 (2.6)
Asian
8 (5.3)
Other
4 (2.6)
Smoking status, n (%)
Never smoker
27 (17.9)
Former smoker
111 (73.5)
Current smoker
13 (8.6)
Pack-y smoked, median (IQR) (missing, n = 38)
30 (21-50)
Previous history of lung cancer, n (%)
7 (4.6)
Family history of lung cancer, n (%) (missing, n = 4)
38 (25.9)
Family history of other cancer, n (%) (missing, n = 9)
92 (64.8)
Topology, n (%) (missing, n = 3)
Upper lobe
83 (56.1)
Middle lobe
10 (6.8)
Lower lobe
55 (37.2)
Histology, n (%)
Adenocarcinoma
109 (72.2)
Squamous cell carcinoma
42 (27.8)
Laterality, n (%)
Left
61 (40.4)
Right
90 (59.6)
Surgery type, n (%)
None
7 (4.6)
Wedge
20 (13.2)
Segmentectomy
12 (7.9)
Lobectomy
112 (74.2)
Complications, n (%) (missing, n = 10)
46 (32.6)
Lymph node dissection, n (%) (missing, n = 4)
141 (95.9)
Lymph nodes examined, n, median (IQR)
13 (8-18)
Lymph nodes positive, n, median (range) (missing, n = 9)
0 (0-7)
Surgical resection, n (%) (missing, n = 23)
R0
127 (99.2)
R1
1 (0.8)
R2
0
AJCC pathologic staging, n (%)
pT stage
pT0
5 (3.3)
pT1
81 (53.6)
pT2
46 (30.5)
pT3-T4
19 (12.6)
pN stage
pN0
119 (78.8)
pN1
15 (9.9)
pN2
16 (10.6)
pN3
1 (0.7)
pM stage
pM0
147 (97.4)
pM1
4 (2.6)
Pathologic stage group, n (%)
I
96 (63.6)
II
31 (20.5)
III
17 (11.3)
IV
7 (4.6)
Lymphovascular invasion, n (%) (missing, n = 19)
23 (17.4)
Tumor grade, n (%) (missing, n = 16)
Well differentiated
44 (32.6)
Moderately/moderately to poorly differentiated
50 (37.0)
Poorly differentiated
41 (30.4)
Chemotherapy, n (%)
49 (32.5)
SD, Standard deviation; IQR, interquartile range; AJCC, American Joint Committee on Cancer.
We identified 50 patients (33%) who were carriers of any pathogenic mutation of HPGs, with 34 patients (23%) carrying a pathogenic mutation in a cancer-related gene, 38 (25%) harboring a pathogenic mutation in a DNA repair gene (25%), and 22 (15%) harboring a pathogenic mutation in a gene involved in both DNA repair and cancer-related functions (Table 2). The most common mutations were a GBA, MUTYH, or POLQ mutation in 4 patients (3%) and either a CHEK2 or GJB2 mutation in 3 patients (2%). The mean GRS was 1.2; 34 patients (23%) had a GRS >1.5 and 16 (11%) had a GRS >2.0.
Table 2Frequency of cancer-related and DNA repair genes
Both carrier status of a pathogenic HPG mutation and elevated GRS were associated with a higher pathologic stage, with the strength of the association varying based on the degree of genetic mutation (Figure 1, A). Among the patients with no pathogenic HPG mutation, 31% (31 of 101) presented at stage II or higher and 11% (11 of 101) were at stage III or higher. Among patients with a pathogenic mutation in either a cancer-related gene or a DNA repair gene but not both, 43% (12 of 28) were at stage II or higher and 21% (6 of 28) were at stage III or higher, a rate not statistically different from those without any mutations (P = .3069). For patients who were carriers for both a cancer-related gene and a DNA repair gene pathogenic mutation, there was a significant clinical and statistical difference compared to patients without any mutation, with 55% (12 of 22) presenting at stage II or higher and 32% (7 of 22) presenting at stage III or higher (P = .0293). When combined with an elevated GRS, the presence of any pathogenic HPG mutation showed the largest difference compared to those without any mutation (P = .0147). Although only 11 patients had both an HPG mutation and a GRS >1.5, 8 of them (73%) were at stage II or higher and 4 (36%) were at stage III or higher. GRS alone was not associated with later stage at presentation. There was not significant association between HPGs or GRS and histologic grade.
Figure 1Pathologic stage (A) and recurrence of primary tumor (B) stratified by high-penetrance gene (HPG) mutation and genetic risk score (GRS). HPG, High-penetrance gene; GRS, genetic risk score.
We also looked at recurrence of the primary tumor and found a higher overall rate of recurrence in patients with a pathogenic HPG mutation compared with patients without an HPG mutation, with the degree of statistical significance varying according to the type of HPG mutation. Recurrence data were available for the entire cohort. Nine patients where never disease-free and were excluded from the analysis. The clinical association was strongest in patients with pathogenic mutations in both a DNA repair gene and a cancer-related gene, as 8 out of the 20 patients (40%) harboring such mutations experienced recurrence, compared with only 20 of 97 patients (21%) without any pathogenic mutation, although the statistical association fell just below the preset threshold of significance (P = .0644) (Figure 1, B). Patients who were carriers of a pathogenic HPG mutation in either a cancer-related gene or a DNA repair gene had only a slightly higher rate of primary tumor recurrence compared with patients who were not carriers of any pathogenic HPG mutation (28% [7 of 25] vs 21%; P = .4279). Unlike stage at presentation, the combination of a pathogenic HPG mutation and elevated GRS did not have a meaningful clinical or statistical difference with respect to overall recurrence (P = .6783).
In addition to overall recurrence rate, we measured time to recurrence, OS, and cancer-specific survival (Figure 2). Among patients without any pathogenic HPG mutation, 80% were free of recurrence at 5 years, compared with only 69% of patients harboring a pathogenic mutation in either a cancer-related gene or a DNA repair gene but not both and only 55% of patients harboring pathogenic mutations in both a cancer-related gene and a DNA repair gene (P = .0330 both vs none) (Figure 2, A). The 5-year OS rate for patients without any pathogenic mutation was 75%, compared with 68% for patients with only one type of mutation and 51% for those harboring mutations in both a cancer-related gene and a DNA repair gene (P = .0063 both vs none) (Figure 2, B). The 5-year cancer-specific survival rate for patients without any pathogenic mutation was 86%, compared with 77% for patients with only one type of mutation and 65% for patients with mutations in both a cancer-related gene and a DNA repair gene (P = .0020 both vs none) (Figure 2, C).
Figure 2Kaplan-Meier curves of time to recurrence (A), overall survival (B), and cancer-specific survival (C) stratified by type of high-penetrance gene (HPG) mutation. Shaded areas represent Hall–Wellner 95% confidence bands. HPG, High-penetrance gene.
Multivariable logistic and Cox regression analysis was performed on all clinical and genetic variables to assess for association with increased tumor grade, increased pathologic stage at presentation, recurrence of primary tumor, OS, and cancer-specific survival (Tables 3 and 4). None of the genetic variables were associated with increased tumor grade, although patients with squamous cell cancer were much more likely to have moderate to poor tumor grade (HR, 5.53; P = .0032). Harboring a mutation in both a DNA repair gene and a cancer-related gene was most strongly associated with presentation at higher stage (OR, 3.32; P = .0228), shorter time to recurrence (HR, 3.03; P = .0119), worse OS (HR, 2.44; P = .0114), and worse cancer-specific survival (HR, 5.53; P = .0039) compared with a lack of pathogenic mutation. We also found evidence of an association with any recurrence of the primary tumor (OR, 2.93; P = .053), although with a weaker statistical significance than the other clinical outcomes. Patients harboring only a mutation in either a DNA repair gene or a cancer-related gene did not show any statistically significant differences compared with those without any pathogenic mutation. GRS was not associated with any measured pathologic or clinical outcomes.
Table 3Multivariable logistic regression analysis
Variables
Moderate to poor tumor grade
Pathologic stage II-IV
Recurrence of primary tumor
OR (95% CI)
P value
OR (95% CI)
P value
OR (95% CI)
P value
Female vs male
1.06 (0.43-2.59)
.8980
0.57 (0.27-1.20)
.1385
0.81 (0.35-1.89)
.6248
Current or former smoker, yes vs no
1.26 (0.48-3.33)
.6407
1.05 (0.37-3.03)
.9259
1.93 (0.53-7.07)
.3230
Histology, squamous cell vs adenocarcinoma
62.59 (3.99-982.72)
.0032
1.44 (0.61-3.40)
.4080
1.07 (0.43-2.70)
.8845
Lymphovascular invasion, yes vs no
1.73 (0.55-5.46)
.3508
5.93 (2.14-16.46)
.0006
1.78 (0.60-5.35)
.3016
Pathogenic HPG mutation
Cancer-related or DNA repair vs none
1.21 (0.41-3.54)
.7304
1.80 (0.68-4.76)
.2361
1.06 (0.34-3.33)
.9198
Cancer-related and DNA repair genes vs none
0.87 (0.22-3.48)
.8386
3.32 (1.18-9.31)
.0228
2.93 (0.99-8.68)
.0527
Significant P values are in bold type. OR, Odds ratio; CI, confidence interval; HPG, high-penetrance gene.
In this study of 151 patients with NSCLC, we found that more than 30% of the patients harbored a pathogenic mutation in an HPG, and nearly 25% had a GRS >1.5. We also identified an association between the presence of HPG pathogenic mutations and a more aggressive clinical phenotype. Patients who were carriers for pathogenic HPG mutations were more likely to present at a higher pathologic stage, had an increased likelihood of cancer recurrence and shorter time to recurrence, and had decreased OS and cancer-specific survival, with the strongest clinical and statistical associations seen in patients harboring pathogenic mutations across both cancer-related genes and DNA repair genes. Although GRS by itself was not associated with a more aggressive cancer phenotype, those patients who had both an HPG mutation and an elevated GRS were much more likely to present at a more advanced pathologic stage (Figure 3 and Video 1).
Figure 3Graphical abstract summarizing the background, methods, major findings, and implications of this study. HPG, High-penetrance gene; GRS, genetic risk score.
There are relatively few published studies on germline HPG mutations and NSCLC, and many of them had either small patient samples or used relatively small gene panels. One exception is a large study from China that looked at 1764 patients using a 381-gene NGS panel and found pathogenic or likely pathogenic mutations in 3.8% of the patients and in 25 different genes, the majority of which are involved in DNA repair pathways.
Although neither of these studies looked at outcomes, the second study did look at family history. Patients with pathogenic or likely pathogenic mutations were more likely than patients without such mutations to have a first-degree relative who also had lung cancer. Compared with the general population, patients with lung cancer were nearly 18 times more likely to have a pathogenic or likely pathogenic mutation.
These findings suggest that these mutations are associated with an increased risk of developing lung cancer. The most common mutations were in BRCA2, CHECK2, and ATM. In our study, we found a significantly higher proportion of patients—33%—who harbored an HPG mutation. Whether this is due to differences in the panels is unclear, although the larger study used a 381-gene panel, so that is unlikely to be the sole reason. Our population was mostly Caucasian, compared with an East Asian population in the Chinese studies, and further validation across more varied and larger populations will be necessary. CHECK2 was also among the higher-frequency mutations in our study, but still represented only 2% of the total patients and 6% of patients with an HPG mutation.
Even fewer studies have examined the clinical impact of germline mutations in lung cancer. Reckamp and colleagues
published a study in 2021 that looked a subset of mutations, specifically TP53/EGFR, BRCA2, Fanconi anemia (FA) genes, and non-FA DNA repair genes, in 187 patients with NSCLC. They found a similar proportion of patients with pathologic variants as we found in our study (26.7% vs 33%) and an earlier age of cancer onset depending on the gene mutation. The greatest impact was in patients with a BRCA2 mutation, in whom cancer was diagnosed a median of 12.2 years earlier than in patients without this mutation. TP53, EGFR, and FA genes all showed associations with earlier age of onset, whereas non-FA DNA repair genes were not associated with age of onset. A separate study of 12 different cancers and >4000 patients found that pathogenic germline mutations were associated with early age of onset across multiple cancers.
In that study, lung cancer patients with a BRCA1 or BRCA2 mutation presented at a median age of 63 years, compared with 66 years for patients who did not carry a pathogenic mutation.
An analysis of 119 patients with NSCLC looked the relationship between repair gene (ERCC1, XP, and XRCC1) and glutathione S-transferase gene (GSTP1, GSTT1, and GSTM1) SNPs and clinical outcomes, including response to response to platinum-based chemotherapy, treatment toxicity, and OS.
In that study, SNPs within ERCC1 were associated with improved treatment response and better OS (9.8 months vs 14.1 months), whereas the combination of ERCC1 and XRCC1 polymorphisms was identified as a prognostic factor for improved OS in a Cox multivariable analysis.
The clinical implications of our findings are unclear. As highlighted, this is a burgeoning field, and although the data presented here are intriguing, this study is merely a starting point for further research into the complex interplay between patients' genetic risk and cancer outcomes. The outcomes on which we focused—stage at presentation, cancer recurrence, and OS and cancer-specific survival—are complex and lie at the intersection of numerous competing factors, including underlying patient genetics, epigenetic and environmental factors, tumor-specific factors, and social determinants of health. In the study reported by Lu and colleagues,
germline mutations in BRCA1 and BRCA2 were associated with a greater frequency of somatic mutations across multiple cancers. This is especially relevant in light of several recently reported studies using serum biomarkers and tumor molecular profiling to identify patients at increased risk of cancer recurrence. Seder and colleagues
used a panel of 47 biomarkers to accurately identify patients with early-stage cancer <4 cm who were at risk of recurrence with a negative predictive value of 83% and overall accuracy of 78%. A now commercially available product (DetermaRx; Oncocyte) uses a 14-gene panel (of tumor somatic mutations) and has been shown to very accurately predict recurrence and to guide adjuvant chemotherapy use in patients with stage I-IIA NSCLC.
Molecular risk stratification is independent of EGFR mutation status in identifying early-stage non–squamous non–small cell lung cancer patients at risk for recurrence and likely to benefit from adjuvant chemotherapy.
In future studies, we hope to study the interaction between somatic predictors of recurrence with a patient's underlying genetic risk. This may allow us to better stratify which patients are at risk for recurrence and poor outcomes and which patients may respond best to the ever-increasing number of available therapies, and could serve as the next level of advancement in treating patients with lung cancer.
Study Limitations
Our study has several limitations. First, our population was relatively small, consisting of only 151 patients, the majority of whom were stage I, which may preclude generalization to the broader lung cancer population. Second, the overall frequency of pathogenic mutations and clinical events was small, and thus our results may be underpowered to show a statistically significant impact, especially in patients with only a single class of gene mutation. The mutation frequency in specific genes was even lower, leaving us unable to draw any specific conclusions with respect to specific mutations and clinicopathologic outcomes. Third, the targeted NGS panel was developed based on studies published before 2017, and as such, several newly reported lung cancer risk-associated SNPs were not analyzed, including the recent genome-wide associated study of Gabriel and colleagues.
Our study is one of the first in a North American population to apply a large gene panel to patients with NSCLC. Unlike previous studies that correlated results with specific mutations, our study has demonstrated that genome-wide identification of pathogenic HPG mutations is associated with worse outcomes, most significantly in patients with mutations in multiple oncogenic pathways. Further studies, including larger studies and studies considering somatic variables, will help further define the role of genetic testing in the treatment of NSCLC (Video Abstract).
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non–small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
Molecular risk stratification is independent of EGFR mutation status in identifying early-stage non–squamous non–small cell lung cancer patients at risk for recurrence and likely to benefit from adjuvant chemotherapy.
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