Abstract
Bevacizumab, combined with platinum-based chemotherapy, has been widely used in the treatment of advanced-stage lung adenocarcinoma (LADC). Although KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation is the most common genetic alteration in human LADC and its role in promoting angiogenesis has been well established, its prognostic and predictive role in the above setting remains unclear. The association between KRAS exon 2 mutational status and clinicopathological variables including progression-free survival and overall survival (PFS and OS, respectively) was retrospectively analyzed in 501 Caucasian stage IIIB-IV LADC patients receiving first-line platinum-based chemotherapy (CHT) with or without bevacizumab (BEV). EGFR (epidermal growth factor receptor)-mutant cases were excluded. Of 247 BEV/CHT and 254 CHT patients, 95 (38.5%) and 75 (29.5%) had mutations in KRAS, respectively. KRAS mutation was associated with smoking (p = 0.008) and female gender (p = 0.002) in the BEV/CHT group. We found no difference in OS between patients with KRAS-mutant versus KRAS wild-type tumors in the CHT-alone group (p = 0.6771). Notably, patients with KRAS-mutant tumors demonstrated significantly shorter PFS (p = 0.0255) and OS (p = 0.0186) in response to BEV/CHT compared to KRAS wild-type patients. KRAS mutation was an independent predictor of shorter PFS (hazard ratio, 0.597; p = 0.011) and OS (hazard ratio, 0.645; p = 0.012) in the BEV/CHT group. G12D KRAS-mutant patients receiving BEV/CHT showed significantly shorter PFS (3.7 months versus 8.27 months in the G12/13x group; p = 0.0032) and OS (7.2 months versus 16.1 months in the G12/13x group; p = 0.0144). In this single-center, retrospective study, KRAS-mutant LADC patients receiving BEV/CHT treatment exhibited inferior PFS and OS compared to those with KRAS wild-type advanced LADC. G12D mutations may define a subset of KRAS-mutant LADC patients unsuitable for antiangiogenic therapy with BEV.
Highlights
The KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) protein, encoded by the KRAS proto-oncogene, is a small GTPase that plays a key role in regulating various cell functions [1]
Incidence of KRAS Mutations in lung adenocarcinoma (LADC) Patients Treated with Bevacizumab and Chemotherapy
One hundred and seventy patients of the full cohort of 501 cases were identified as KRAS-mutant (33.9%) and 331 (66.1%) as KRAS WT
Summary
The KRAS (V-Ki-ras Kirsten rat sarcoma viral oncogene homolog) protein, encoded by the KRAS proto-oncogene, is a small GTPase (guanosine triphosphatase) that plays a key role in regulating various cell functions [1]. Alterations of the KRAS gene are typically missense mutations that can lead to the oncogenic conversion of KRAS resulting in the constitutive activation of its effector pathways and cancer development and progression [2]. KRAS is frequently mutated in pancreatic and colorectal cancer (CRC), and in lung adenocarcinoma (LADC). With an incidence of up to 30%, KRAS mutation is the most common driver mutation in LADC. The most prevalent G12C and G12V KRAS mutation subtypes are associated with smoking, while the G12D subtype has been observed in those who have never smoked [3,4]. Several other rare mutations of KRAS codon 12, 13, and 61 have been reported [3]
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