Analysis of KRAS, NRAS, BRAF, PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients

Abstract

Little information is available on the clinical significance of cancer‐related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in nonmetastatic rectal cancer. We investigated mutations of these genes in a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials. Mutational analyses were performed with diagnostically validated methods including polymerase chain reaction, capillary electrophoresis single‐strand conformational analysis, Sanger sequencing and next‐generation sequencing. Associations between single or multiple gene mutations and clinicopathological characteristics and treatment outcomes were explored. Of these 269, 210 (78%) patients were assessable. Mutations of KRAS, NRAS, BRAF, PIK3CA and TP53 occurred in 43, 9, 4, 9 and 60% of patients, respectively. Concordance between paired biopsy and resection specimens was 82% for KRAS, 95% for NRAS, 99% for BRAF, 96% for PIK3CA and 63% for TP53. TP53 mutations were associated with extramural venous invasion on baseline MRI (78% vs. 65%, p = 0.04), poor pathological tumour regression (23% vs. 36%, p = 0.05) and a trend toward a worse 5‐year progression‐free survival (PFS; 60% vs. 74%, HR 1.59, p = 0.06). Patients with tumours harbouring mutation of TP53 and either KRAS or NRAS (32%) had a worse 5‐year PFS than those with TP53/KRAS/NRAS wild‐type tumours (54% vs. 72%, HR 1.75, p = 0.02). In univariate analysis, BRAF mutation predicted poor 5‐year overall survival only among patients treated without cetuximab (20% vs. 73%, HR 3.29, p = 0.03). This is one of the largest biomarker studies in a prospective, largely homogeneous, LARC population. Our findings are hypothesis generating and require validation in independent series.

Identification of biomarkers of immune checkpoint blockade efficacy in recurrent or refractory solid tumor malignancies

“…**** p-value < 0.0001; *** p-value < 0.001; ** p-value < 0.01, * p-value < 0.05. www.oncotarget.com infiltration by CD8+ T cells [32]. TP53 mutation was the most common molecular alteration in our patient population and was associated with worse survival, similar to its known association with unfavorable outcome in solid and hematologic malignancies [33][34][35][36]. Our data demonstrate that while TP53 mutations are associated with unfavorable survival, the effect of ICB therapy is not diminished by the presence of this gene mutation.…”

Characterizing MRI features of rectal cancers with different KRAS status

“…In daily practice, the biopsy is still the routine way to get tumour mutant status before treatment. Considering the spatial and temporal intra-tumour molecular heterogeneity, the results for biopsy samples are yet to be consistent [11][12][13]50]. Recently, a large prospective study [50] showed that the concordance ratio between paired biopsy and resection specimens was 82% for KRAS status.…”

“…Considering the spatial and temporal intra-tumour molecular heterogeneity, the results for biopsy samples are yet to be consistent [11][12][13]50]. Recently, a large prospective study [50] showed that the concordance ratio between paired biopsy and resection specimens was 82% for KRAS status. In the current study, although the best sensitivity (Variance) and specificity (Mean) of the texture features were both over 83% in the study, the sensitivity and specificity of GLNU, which harboured the best diagnostic significance (AUC = 0.813), were both lower than 80%.…”

Next Generation Sequencing in MPNs. Lessons from the Past and Prospects for Use as Predictors of Prognosis and Treatment Responses

“…It may be speculated that MPN patients with PPM1D mutations may be more prone to development of second cancer. Importantly, several other MPN-associated mutations such as ASXL1, SH2B3, TET2, JAK2, TP53, KRAS, NRAS, and U2AF1 are found in other cancers as well [92,[202][203][204][205]. Indeed, studies have shown that patients with MPNs have a higher risk of developing second cancer [206][207][208].…”