Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal antibodies in colorectal cancer

Abstract

Background: KRAS mutations occur in 35-45% of metastatic colorectal cancers (mCRC) and preclude responsiveness to EGFR-targeted therapy with cetuximab or panitumumab. However, less than 20% patients displaying wild-type KRAS tumors achieve objective response. Alterations in other effectors downstream of the EGFR, such as BRAF, and deregulation of the PIK3CA/PTEN pathway have independently been found to give rise to resistance. We present a comprehensive analysis of KRAS, BRAF, PIK3CA mutations, and PTEN expression in mCRC patients treated with cetuximab or panitumumab, with the aim of clarifying the relative contribution of these molecular alterations to resistance.

Methodology/principal findings: We retrospectively analyzed objective tumor response, progression-free (PFS) and overall survival (OS) together with the mutational status of KRAS, BRAF, PIK3CA and expression of PTEN in 132 tumors from cetuximab or panitumumab treated mCRC patients. Among the 106 non-responsive patients, 74 (70%) had tumors with at least one molecular alteration in the four markers. The probability of response was 51% (22/43) among patients with no alterations, 4% (2/47) among patients with 1 alteration, and 0% (0/24) for patients with > or =2 alterations (p<0.0001). Accordingly, PFS and OS were increasingly worse for patients with tumors harboring none, 1, or > or =2 molecular alteration(s) (p<0.001).

Conclusions/significance: When expression of PTEN and mutations of KRAS, BRAF and PIK3CA are concomitantly ascertained, up to 70% of mCRC patients unlikely to respond to anti-EGFR therapies can be identified. We propose to define as 'quadruple negative', the CRCs lacking alterations in KRAS, BRAF, PTEN and PIK3CA. Comprehensive molecular dissection of the EGFR signaling pathways should be considered to select mCRC patients for cetuximab- or panitumumab-based therapies.

Figure 1. Representation of the distribution of molecular alterations in individual tumors of the 132 patients: mutations of KRAS and BRAF occurred in a mutually exclusive manner, while an overlapping pattern was observed between other alterations.

Figure 2. Distribution of the number of mutations (table) and response to EGFR-targeted therapy (pie-charts) according to the number of molecular abnormalities within individual tumor samples.

Figure 3. Progression-free survival according to the number of molecular abnormalities within individual tumor samples.

Data from the cohort of patients with a known molecular status of all four markers.

Figure 4. Overall survival according to the number of molecular abnormalities within individual tumor samples.

Data from the cohort of patients with a known molecular status of all four markers.

Figure 5. Algorithm of molecular diagnostics based on data discussed in this study for patients with mCRC candidates to cetuximab- or panitumumab-based therapies.

The area marked in grey within the dotted line box describes the hypothesis generated in this study.

Figure 6. Following evaluation of KRAS status in individual tumors, enhancement of predictability of clinical benefit may derive from assessment of the status of BRAF, PIK3CA and PTEN, as simulated here based on analyses of subgroups from the present cohort (n = 131).

We propose to define as “quadruple negative” the mCRCs lacking alterations in KRAS, BRAF, PTEN and PIK3CA.