: 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.
