Breast Cancer Genome to Shape Precision Medicine

José Baselga, MD, PhD

As the breast cancer genome continues to be unraveled, a host of new targetable alterations outside of HER2 and the estrogen receptor (ER) are beginning to emerge, providing the exciting potential for development of new therapies, according to José Baselga, MD, PhD, at the 2017 Lynn Sage Breast Cancer Symposium.

As more targets begin to emerge and are validated, there will be a greater need for next-generation sequencing in clinical practice, Baselga said. The need for more genetic information could change the way tissue samples are handled and increase the need for liquid biopsies, since there is a high capacity for looking at DNA alterations in the blood. Given the non-invasiveness of this approach, it could be easily incorporated into practice, he believes.

“With the deciphering of the breast cancer genome, we now have identified that there are many genes that are mutant, amplified, or absent, which provides us with opportunities to develop new therapies,” said Baselga, physician-in-chief and chief medical officer, at Memorial Sloan Kettering Cancer Center. “I think that DNA will give us the opportunity to diagnose cancers earlier and therefore shift our cure rate higher. The earlier you diagnose breast cancer the higher the cure rate. With these new genomic tools, we ought to be able to move the curve.”

In an interview withTargeted Oncologyat the symposium, Baselga discussed targeting the breast cancer genome and the shaping of precision medicine for patients with breast cancer.

Targeted Oncology:What are the most pressing challenges in this space that you would like to see addressed?

Baselga: There are many challenges. First, these assays, which are clinically useful, are not reimbursed. I think that is important and we are applying a lot of pressure to allow it to happen. They are not that expensive and they can help tremendously in the management of patients with breast cancer.

The second challenge is how to make the results of this test be easily understood by our practicing physicians. We are talking about hundreds of genes and many mutations so it is almost impossible for any single physician to understand what everything means. There is a challenge with how to communicate these data in a way that is easily understood by the patient and the physician.

The third challenge is the fact that breast cancer is not static. If you check for some genes that were mutant a year ago under selective pressure, those mutations have probably evolved. That is the real promise of the liquid biopsies They have the capacity to integrate at any given time so that the physician has a real picture on what is happening at that precise moment in the life of the tumor.

Are there any ongoing trials in this space you are excited about?

At our institution, we have about 25 clinical trials in which we are targeting the genome, specifically in different tumor types in breast cancer. We call these trials “basket trials” and we are beginning to see some interesting clinical results. We have a program in which we are monitoring DNA in plasma over time. We are beginning to make decisions based on the emergence of specific clones that we can detect.

It's a very dynamic and promising area of research. Many institutions are attempting to work out the details to try to identify these targets.

What impact do you think precision medicine will have on patient care?

I think this genome analysis of tumors and liquid biopsies will have a very significant impact on patient care. Firstly, it will help us identify those therapies that will not work and better discriminate responses.

Secondly, in about 40% of breast cancers, we will be able to identify potential targets. We will not treat them with single therapy, we will most likely need to use combinations. There are some of these genes that are mutant quite frequently. For example, in the case of ER-positive breast cancer, PI3-kinase mutations are present in 43% of cases. We just presented at ESMO the first positive, randomized neoadjuvant study with PI3-kinase alpha inhibitor [taselisib]. We will have more details of these other phase III studies in the metastatic setting by the first quarter of next year. If those studies are positive, then we will need to check PI3-kinase mutations on every patient. Ultimately, I think we are building evidence that genomic information is actionable and that will have a deep influence in the way we look at breast cancer.

Where do you believe the future of this space is heading?

Genetic alterations are only part of the story. We know that breast cancer is also heavily driven by epigenetic changes. I don't know what proportion of cases we will be able to target with genomic-driven agents, maybe between 30% to 40%, but in some cases when you do it correctly, the effect is substantial. This is similar to what is happening in HER2-positive disease with the combination of pertuzumab (Perjeta) and trastuzumab (Herceptin). We are having patients that survive more than 5-years as the median in the first-line setting and with 93% disease-free survival in the adjuvant disease.

The others are probably going to be driven by epigenetic drivers and we are beginning to untangle them. We are going to continue to see separation among the different breast tumor types. ER-positive, HER2-positve, and triple-negative will be seen on their own merit as different species. These are tumors that have tremendous DNA repair abnormalities and there is a window of opportunity there. Triple-negative breast cancer is perhaps the one that might see the most benefit with immunotherapies. There are a lot of clinical trials ongoing and we will see what those results are. I suspect that at least in early-disease, these PD-1/PD-L1 inhibitors will play a role.