The Predictive and Prognostic Role of RAS-RAF-MEK-ERK Pathway Alterations in Breast Cancer: Revision of the Literature and Comparison with the Analysis of Cancer Genomic Datasets

Abstract

Although gene alterations of the RAS/RAF/MEK/ERK pathway are uncommon in breast cancer, this pathway is frequently activated in breast tumors, implying its role in tumor progression. We describe, after a revision of the literature, the frequency and types of gene alterations affecting this pathway in breast cancer by analyzing some public datasets from cBioPortal. Moreover, we consider their prognostic and predictive impact on treatment response, along with the role of transcriptomic predictors of RAS pathway activation. Our analysis shows that the driver alterations in RAS/RAF/MEK/ERK pathway-related genes are detected in 11% of primary breast cancers. The most frequently mutated genes are NF1 and KRAS, while copy number alterations mainly affect KRAS and BRAF, especially in basal-like tumors. The subgroup of patients carrying these alterations shows a worse prognosis; alterations in NF1 and RAF1 are associated with significantly reduced breast-cancer-specific survival in multivariate analysis. The literature review shows that the pathway is implicated, either by genetic or epigenetic alterations or by signaling network adaptations, in the mechanisms of sensitivity and resistance to a wide range of drugs used in the treatment of breast cancer. A thorough understanding of these alterations is critical for developing combination therapies that can delay or overcome drug resistance.

Keywords: ERK cascade; MAPK; RAS pathway; breast cancer; genomic alterations; predictive impact; prognostic impact.

Figure 1

Diagram of the RAS/RAF/MEK/ERK pathway showing the molecules considered in this study. The diagram is derived from the “RAS pathway v2.0” diagram curated by the RAS Initiative of the US National Cancer Institute, originally published by the National Cancer Institute (https://www.cancer.gov/sites/g/files/xnrzdm211/files/styles/cgov_enlarged/public/cgov_image/media_image/800/100/files/ras-pathway-enlarge.jpeg?h=4233ef75&itok=aJpyY4D- (accessed on 20 September 2022)). Solid lines with arrows represent activating signals. Dashed lines represent inhibitory signals. In bold are the pivotal molecules of the pathway: the RAS isoforms and the molecules of the ERK cascade. Shown in black but not bold are the other molecules of the extended pathway that are considered in the present study (direct activators or inhibitors of RAS and molecules involved in the feedback mechanisms of the pathway). In gray and in parentheses are some other important molecules not considered in the present study. Names separated by periods represent proteins that are believed to form physical complexes. The bracket connecting KSR1/2 to the RAF, MAP2K, and MAPK genes indicates a scaffolding function.

Figure 2

The spectrum of NF1 mutations in primary breast cancer (diagram from cBioPortal).

Figure 3

Alterations of RAS/RAF/MEK/ERK pathway genes in primary breast cancer samples of 3712 patients from three studies (METABRIC, TCGA, CPTAC) (OncoPrint from cBioPortal).

Figure 4

Frequencies of alterations (including mutations, CNAs, and structural variants) of selected genes of the RAS/RAF/MEK/ERK pathway in different breast cancer subtypes.

Figure 5

Breast-cancer-specific survival according to the presence or absence of any alteration in RAS/RAF/MEK/ERK pathway genes (log-rank test).