Metastatic Breast Cancer Genomes Point to Distinct Features, Tumor Evolution

In Clinical Trials by Barbara Jacoby

By: Staff Reporter

From: genomeweb.com

A team from France, Switzerland, and the US has characterized genomic alterations that are specific to advanced, metastatic forms of breast cancer using exome sequence and clinical outcome data.

As they reported online today in Nature, the researchers did whole-exome sequencing on samples from more than 600 individuals with metastatic breast cancer, identifying alterations that appeared to be distinct from those found in earlier-stage breast cancers from the same subtypes. Their analyses also pointed to gene mutations or mutational signatures offering clues to drug response, disease outcomes, and tumor evolution.

“[T]he genomic landscape of metastatic breast cancer is enriched in clinically relevant genomic alterations and is more complex than that of early breast cancer,” co-senior and corresponding author Fabrice Andre, an oncologist and oncology researcher affiliated with the University of Paris-Sud, INSERM, and Gustave Roussy, and his colleagues wrote.

While past studies have found that a significant proportion of metastatic breast cancer contain mutations in genes such as ESR1, apparently reflecting tumor evolution following endocrine-based therapy, the full collection of genomic changes that occur in metastatic forms of the disease are not fully characterized.

Starting with blood and tumor samples from 629 metastatic breast cancer patients enrolled in half a dozen precision medicine trials, the researchers did exome sequencing to an average depth of 100- to 120-fold on the tumor samples, subsequently identifying somatic single-nucleotide variants, small insertions and deletions, and copy number alterations in 617 metastatic breast cancer cases with their bioinformatics pipeline.

After identifying 21 genes that were significantly mutated in at least one of the metastatic breast cancer subtypes considered, the team looked for the alterations that appeared to be over-represented in the metastatic breast cancers compared with primary tumors — particularly those that appeared to coincide with specific clinical outcomes or drug responses.

In hormone receptor-positive, HER2-negative metastatic tumors, for example, the researchers narrowed in on nine apparent driver genes, 18 amplicons, and a handful of mutational signatures that appeared to be enriched relative to early-stage breast cancers profiled for the Cancer Genome Atlas.

When it came to triple-negative breast cancers lacking estrogen receptor, progesterone receptor, or HER2, meanwhile, they found that roughly 7 percent of metastatic tumors were more prone to loss-of-function mutations affecting both copies of homologous recombination genes. Those alterations turned up in just 2 percent of early-stage triple-negative breast cancers.

The new metastatic tumor profiles made it possible to search for alterations associated with patient prognoses or response to specific treatments. For example, RB1 and NF1 mutations appeared to coincide with poor outcomes in individuals with HR-positive, HER2-negative metastatic breast cancers — cases that were also stratified by the presence of specific mutational signatures in the tumors.

The team also delved into proposed CDK4 inhibitor resistance associated with the presence of RB1 mutations using additional data for more than 1,500 patients participating in randomized trials of a CDK4 inhibitor in combination with endocrine therapy.

“The identification of genomic alterations associated with poor outcome will allow earlier and better selection of patients who require the use of treatments that are still in clinical trials,” the authors wrote. “The genetic complexity observed in advanced breast cancer suggests that such treatments should be introduced as early as possible in the disease course.”