It's Time to Move Beyond the Genome in Breast Cancer

Jane de Lartigue, PhD
Published: Friday, Dec 02, 2016
Matthew J. Ellis, MB BChir, PhD, FRCP

Matthew J. Ellis, MB BChir,
PhD, FRCP

Matthew J. Ellis, MB BChir, PhD, FRCP, is a renowned clinician scientist with expertise in the genomics and molecular profiling of breast cancer. His accomplishments include helping to develop a Genome Atlas and Therapeutic Road Map for estrogen receptor– positive breast cancer and groundbreaking research into activating HER2 mutations.

Ellis is director of the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston. He also serves as co-leader for The Cancer Genome Atlas (TCGA) Breast Project and as one of the principal investigators for the Clinical Proteomic Tumor Analysis Consortium, which seeks to translate TCGA discoveries into protein-based biomarkers with clinical utility.

OncLive: How has our understanding of breast cancer evolved with the availability of high-throughput genome screening?

Ellis: We have certainly made progress in understanding the genomic structure of breast cancer, with an emphasis on the fact that every breast cancer has a unique genome, that there are somatic changes of every conceivable type, that there’s a huge difference between tumors in the degree of genomic change, and that breast cancers are multiclonal diseases whereby not every tumor cell harbors every mutation detected by sequencing.

This has generated a lot of analytical complexity and challenges for informaticians. Where we have partially failed is to link these somatic mutations in robust ways to clinical outcomes or to drug efficacy. Of course, this failure is related to the complexity of the breast cancer genomes. So in terms of clinical impact, you’d have to say that sequencing technology has had a very modest effect so far, although there’s one or two developments on the horizon, so that maybe if you were to interview me in a year or two I might be more positive.

What have we learned about the central drivers of breast cancer and how is this informing therapeutic development?

Obviously, we identified some of the key drivers a long time ago. When I say drivers, generally I mean druggable drivers, because they would be the highest-impact findings. By performing these genomic screens, we were looking for other examples of HER2 amplification–like hits. With the advent of next-generation sequencing, we were looking at point mutations rather than just amplicons, in druggable kinases, for example.

Upon initial examination of the data on recurrently mutated genes, activating point mutations were conspicuously absent at high frequency, except for PIK3CA. But we still don’t have a prudent PIK3CA mutation drug match. So thus far, PIK3CA mutations themselves haven’t generated a successful clinical algorithm. Interestingly, though, there is a successful algorithm on the horizon around HER2 mutations.

These occur in non-HER2 amplified, primarily estrogen receptor–positive breast cancer, where point mutations in HER2 have been shown to be activating and in preclinical data shown to be druggable with neratinib.

At ASCO we reported that if we screened more than 600 patients to find 14 patients with mutations that were known activating in vitro, we could get a reasonable clinical response rate to single-agent neratinib.1 So a new treatment for breast cancer is born.

But, of course, you could say that you screened more than 600 patients and you found only 14 whom you could treat, but the point is that small percentages in breast cancer still involve, relatively speaking, absolute patient numbers that are important. For example, our latest data suggest that about 3% of patients with metastatic breast cancer have detectable HER2 mutations in the circulation. The number of patients living with metastatic breast cancer in the United States is about 200,000. Thus, 3% is about 6000 patients, which is more than enough to conduct randomized trials to establish a standard of care for patients with HER2-mutant disease.


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