KRAS genetic variant as a prognostic factor for recurrence in resectable non-small cell lung cancer.
OBJECTIVE
Several angiogenic prognostic markers are under investigation because of their potential clinical utility, aiming to improve patient outcomes. We hypothesized that genetic variant in the VEGF pathway could be used as prognostic markers of survival in non-small cell lung cancer (NSCLC) patients undergoing pulmonary resection.


METHODS
We evaluated the relationship between genetic variants in the VEGF pathway and relapse-free survival (RFS, main endpoint) and overall survival (OS, secondary endpoint) among 131 patients with stage I-III NSCLC treated with surgical resection from 2009 to 2013. Clinical, pathological and surgical data were prospectively collected. Twenty-five variants in sixteen relevant genes were selected and genotyped in tumor samples by real time PCR. The Kaplan-Meier method with the log-rank test and Cox's regression models were used for RFS and OS analyses.


RESULTS
With a median follow-up of 36 (min = 2.8; max = 67.4) months, there were 31 (24%) relapses and 31 (24%) deaths. Overall, median RFS was not reached and median OS was 65 [95% confidence interval (CI) 56-75] months. The KRAS rs1137282 and PIK3C2A rs4356203 variants were significantly associated with RFS. For KRAS rs1137282, the 3-year RFS was 76% [95% CI 64-84%] in patients harboring an A/A genotype compared to 53% [95% CI 37-69%] in patients harboring an A/G or G/G genotype (p = 0.02). For PIK3C2A rs4356203, patients with an A/A or an A/G genotype had a 3-year RFS of 72% [95% CI 58-76%], whereas in patients with a G/G genotype was 49% [95% CI 28-70%] (p = 0.02). These associations remained statistically significant after adjusting for all the relevant clinical parameters in the multivariable analysis.


CONCLUSIONS
Genetic variants in VEGF pathway may be associated with recurrence in stage I-III NSCLC. Specifically, the KRAS rs1137282 could be considered as a prognostic factor for recurrence in resectable NSCLC patients. Although PIK3C2A rs4356203 was associated with RFS, further analyses are necessary to confirm these data.
Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.|Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
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I
Sullivan
Genetics Department, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret 167, 08025, Barcelona, Spain. jsalazar@santpau.cat.|CIBERER U-705, Barcelona, Spain. jsalazar@santpau.cat.
J
J
Salazar
Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
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C
Arqueros
Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
M
M
Andrés
Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
A
A
Sebio
Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
M
M
Majem
Pathology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
J
J
Szafranska
Thoracic Surgery Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
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E
Martínez
Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
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D
Páez
Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
A
A
López-Pousa
Genetics Department, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret 167, 08025, Barcelona, Spain.|CIBERER U-705, Barcelona, Spain.
M
M
Baiget
Medical Oncology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.|Universitat Autònoma de Barcelona (UAB), Barcelona, Spain.
A
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Barnadas
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000473:pathology / Q000601:surgery; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000601:surgery; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011110:Polymorphism, Genetic; D011379:Prognosis; D011446:Prospective Studies; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate
C117307:KRAS protein, human; D019869:Phosphatidylinositol 3-Kinases; C546621:PIK3C2A protein, human; D016283:Proto-Oncogene Proteins p21(ras)
Genetic variants; KRAS; Prognostic marker; Resectable non-small cell lung cancer; VEGF pathway