Deciphering and Targeting Oncogenic Mutations and Pathways in Breast Cancer

Abstract

: Advances in DNA and RNA sequencing revealed substantially greater genomic complexity in breast cancer than simple models of a few driver mutations would suggest. Only very few, recurrent mutations or copy-number variations in cancer-causing genes have been identified. The two most common alterations in breast cancer are TP53 (affecting the majority of triple-negative breast cancers) and PIK3CA (affecting almost half of estrogen receptor-positive cancers) mutations, followed by a long tail of individually rare mutations affecting <1%-20% of cases. Each cancer harbors from a few dozen to a few hundred potentially high-functional impact somatic variants, along with a much larger number of potentially high-functional impact germline variants. It is likely that it is the combined effect of all genomic variations that drives the clinical behavior of a given cancer. Furthermore, entirely new classes of oncogenic events are being discovered in the noncoding areas of the genome and in noncoding RNA species driven by errors in RNA editing. In light of this complexity, it is not unexpected that, with the exception of HER2 amplification, no robust molecular predictors of benefit from targeted therapies have been identified. In this review, we summarize the current genomic portrait of breast cancer, focusing on genetic aberrations that are actively being targeted with investigational drugs.

Implications for practice: Next-generation sequencing is now widely available in the clinic, but interpretation of the results is challenging, and its impact on treatment selection is often limited. This work provides an overview of frequently encountered molecular abnormalities in breast cancer and discusses their potential therapeutic implications. This review emphasizes the importance of administering investigational targeted therapies, or off-label use of approved targeted drugs, in the context of a formal clinical trial or registry programs to facilitate learning about the clinical utility of tumor target profiling.

Keywords: Biomarkers of response to therapy; Breast cancer molecular subtypes; Drug resistance; Mutation-genomic landscape; Oncogenic signaling pathways; Potential therapeutic targets; Tumor heterogeneity.

Figure 1.

Major cancer susceptibility loci identified in breast cancer. Each breast cancer susceptibility locus is mapped on their chromosomal location. The risk conferred by each specific allele is indicated by color. Chromosomes are not drawn to scale.

Figure 2.

Mutation spectrum in breast cancer subtypes. (A): Percentage of somatic mutations types in breast cancer overall and molecular subtypes according to COSMIC database. The ER-positive/luminal group includes luminal A and B subtypes. (B): Frequencies of the most commonly mutated cancer-related genes across breast cancer subtypes, according to the Cancer Genome Atlas [9]. Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factor receptor 2.

Figure 3.

Biological and clinical consequences of tumor heterogeneity. (A): Tumor dissemination may occur at earlier stages of cancer progression, resulting in substantial divergences between primary and metastatic lesions. Alternatively, cell subpopulations in the primary tumor evolve by acquiring multiple genetic aberrations and aggressive phenotypes, ultimately leading to a late-stage metastatic dissemination. (B): Distinct subclones may harbor constitutive alterations that confer different drug sensitivity. Cancer therapy may trigger clonal evolution and increase intratumoral heterogeneity, allowing for the selection of cells with advantageous genetic aberrations. Further evolution of the resistant clone in response to therapy may lead to relapse after initial treatment response.