Genomics Are Key to Unlocking Breast Cancer Biology

Paul Kelly Marcom, MD

The evolution of genomic testing has allowed physicians to more accurately select patients with breast cancer for targeted therapies based on identifiable molecular abnormalities, explained Paul Kelly Marcom, MD, adding that the use of these assays still holds further potential.

"Genetic and genomic analyses are beginning to point the way with how we specify or select patients for the use of targeted therapies," said Marcom, a professor of medicine at Duke University School of Medicine and member of Duke Cancer Institute.

For example, in an analysis of the phase III SOLAR-1 trial, circulating tumor DNA was utilized to select patients with hormone receptor—positive, HER2-negative breast cancer who harbor PIK3CA mutations. It was also used to confirm the benefit in progression-free survival (PFS) with alpelisib (Piqray) plus fulvestrant (Faslodex) versus fulvestrant alone.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Marcom discussed the role of genomic testing in breast cancer.

OncLive: How is genomic testing utilized in breast cancer treatment?

Marcom: For a number of years, as next-generation sequencing (NGS) became available, there was skepticism regarding whether [genomic testing] was going to be helpful in guiding treatment options for patients. Now, every week, I sit in on our molecular tumor board to sequence more patients.

Yesterday, we looked at three cases that had actionable findings from that sequencing data that helped guide the next treatment—2 of which were enrolled in clinical trials. Once you see that week after week, it begins to bring home the fact that the biology is being unlocked. The genetics and genomics are the keys for unlocking the biology. That is what guides you to use the drugs in a rational way, rather than treat everyone and hope you figure out what is working.

We have a long way to go. It is hard to put quantitative estimates on the likelihood of benefitting based on the given genetic findings. That's still very much in its infancy but we will eventually get there.

Are there preferred assays that are being used in practice?

What is exciting is how broad the space is and the number of startups and companies that have gotten involved. They are all looking to maximize the service they are providing, which tends to make them very collegial, collaborative, and provide data to us clinical investigators— particularly at academic institutions—and then we go back and begin to mine that data.

Look for patterns of response, look for things that predict outcomes, and look across tumor types. On our molecular tumor board, I'm sitting in the same room as my lung cancer colleagues who I have not seen in quite some time. We get to learn off of one another's experiences, including those instances in which it's different by disease site and those in which there seems to be some commonality of the activity we're seeing.

What are your thoughts on the use of liquid biopsies in breast cancer?

There is a little less comfort with the idea of a liquid biopsy, even with assay metrics such as allele frequency. If you have some sense of the percent similarity of the sample at one end and you see a little frequency for a given mutation, you feel more comfortable in saying that you understand it.

I personally don't have as much comfort about cell-free DNA. That said, in breast cancer, data from the SOLAR-1 trial highlight that there is signal there [with the use of cell-free DNA]. You can get this positive predictor out of finding a mutation—if you find it. You have to be careful about excluding a mutation, but that begins to build our confidence. That degree of understanding and trust in [liquid biopsy] technology is 5 years behind NGS out of solid tumors, but it will get there.

You suggested that all patients should undergo upfront NGS. Is there any value in repeat sequencing?

That's a tricky thing. In the absence of financial constraints, there wouldn't be any question that we would be doing [repeat sequencing]. I've had many sequential cell-free DNA assays on patients in whom I've seen the evolution of their tumor from that result. It's hard for me to believe that's not where we're going.

I remember a point in time when [the cost of testing] 2 genes was $4000 and now it's 84 genes for $250. The price is going to collapse with all these other monitoring technologies or guiding therapy. We have to be careful not to break the bank in doing this, but it is going to benefit patients in guiding therapy and avoiding unnecessary toxicities that the costs are going to be worth it.

How do you see genomic testing evolving in this space?

[I anticipate] the ability to see that evolution of the tumor over time. It's so powerful. I hope that is going to open the door for combinatorial strategies with new targeted therapies in a way that we can accelerate response to the tumor as it's evolving and maximize the therapeutic opportunities for patients with advanced disease.

We always start with therapeutics in the metastatic space and bring it into earlier-stage disease. Those assays are going to be developed so they can be used for finding minimal residual disease and use those targeted therapies earlier.

How common are sequencing tumor boards across the United States?

Most academic centers have set up some manner of a molecular tumor board. It's complex data and you need people who are invested in looking at it on a frequent basis who are beginning to learn how to understand it.

We also need better software tools. We need to leverage our electronic health record systems with the power that they have and the data that they hold. Nobody has cracked that problem yet, but many people are trying. We need [new software] to be cost effective. We can't pay thousands of people to manually extract all this data. We need to figure out how to have [new software] seamlessly interwoven into our practices so we can marry it with the molecular data as well as marry it with the outcomes data.

Juric D, Ciruelos EM, Rubovszky G et al. Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): Phase 3 SOLAR-1 trial results. Presented at: 2018 San Antonio Breast Cancer Symposium; December 5-8; San Antonio, Tx. Abstract GS3-08.