KRAS Mutations Impact Clinical Outcome in Metastatic Non-Small Cell Lung Cancer

Abstract

There is an urgent need to identify new predictive biomarkers for treatment response to both platinum doublet chemotherapy (PT) and immune checkpoint blockade (ICB). Here, we evaluated whether treatment outcome could be affected by KRAS mutational status in patients with metastatic (Stage IV) non-small cell lung cancer (NSCLC). All consecutive patients molecularly assessed and diagnosed between 2016–2018 with Stage IV NSCLC in the region of West Sweden were included in this multi-center retrospective study. The primary study outcome was overall survival (OS). Out of 580 Stage IV NSCLC patients, 35.5% harbored an activating mutation in the KRAS gene (KRASMUT). Compared to KRAS wild-type (KRASWT), KRASMUT was a negative factor for OS (p = 0.014). On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.478, 95% CI 1.207–1.709, p < 0.001). When treated with first-line platinum doublet (n = 195), KRASMUT was a negative factor for survival (p = 0.018), with median OS of 9 months vs. KRASWT at 11 months. On multivariate analysis, KRASMUT persisted as a negative factor for OS (HR 1.564, 95% CI 1.124–2.177, p = 0.008). KRASMUT patients with high PD-L1 expression (PD-L1high) had better OS than PD-L1highKRASWT patients (p = 0.036). In response to first-line ICB, KRASMUT patients had a significantly (p = 0.006) better outcome than KRASWT patients, with a median OS of 23 vs. 6 months. On multivariable Cox analysis, KRASMUT status was an independent prognostic factor for better OS (HR 0.349, 95% CI 0.148–0.822, p = 0.016). kRAS mutations are associated with better response to treatment with immune checkpoint blockade and worse response to platinum doublet chemotherapy as well as shorter general OS in Stage IV NSCLC.

Percolate: an exponential family JIVE model to design DNA-based predictors of drug response

“…We observe that TP53 mutation status is associated with resistance to three drugs, concordant with earlier observations showing that TP53 mutant are more resistant to chemotherapy [14]. Resistance to Gemcitabine and Vincristine is also associated with KRAS and PI3KCA mutations, known for their proliferative potential [18,10]. Interestingly, mutations in MYC and MAPK8IP2 are associated with sensitivity to these three drugs.…”

Systematic analysis of cancer‐specific synthetic lethal interactions provides insight into personalized anticancer therapy

“…Interestingly, among these genes, the highest number of genetic interactions were found for KRAS (Fig. 3E), which had important roles in the occurrence and development of diverse cancers [37,38]. These findings confirmed a crucial role and great potential application of KRAS in synthetic lethality.…”

Equalizing prognostic disparities in stage III KRAS-mutant NSCLC: addition of durvalumab to combined chemoradiotherapy improves survival

“…KRAS mutation is the most prevalent oncogenic driver in NSCLC (35%) but the prognostic and predictive role of KRAS mutations is under debate. While we and others have shown KRAS mutations to negatively influence the prognosis of NSCLC, 12-15 some studies found no difference in OS. 16-18 In addition, some have reported shorter OS for KRAS MUT compared to wild type (KRAS WT ) patients following first-line platinum-based chemotherapy.…”

“…The predictive role of KRAS mutation in relation to outcome in NSCLC is a controversial topic, particularly for stage III NSCLC where the literature is relatively sparse in contrast to earlier stages and metastatic stage IV disease. In the latter, treated with chemotherapy, some studies describe KRAS mutation as a negative prognostic factor for OS and PFS [13][14][15] while others demonstrate an equal survival benefit for KRAS MUT and KRAS WT patients [16][17][18] . After the introduction of ICB in the stage IV treatment paradigm new assessment of the impact of KRAS have been performed but do not consistently point in the same direction, and the predictive value of KRAS related to ICB treatment remains debatable.…”