Molecular Testing in Breast Cancer to Answer More Questions in 2017

Jenny C. Chang, MD

The challenge of giving patients more or less treatment for their breast cancer, regardless of their subtype, is a question researchers are actively investigating with the use of molecular testing, according to Jenny C. Chang, MD.

This can be accomplished with sub-categorizing the existing subtypes available, she explains, including HER2-positive, hormone receptor (HR)—positive, and triple-negative patients, and determining whether dual blockade regimens would be beneficial or a case of overtreatment.

Another challenge that practitioners are looking to solve is determining which of these patients can avoid toxic chemotherapy regimens, adds Chang.

OncLive: Could you provide an overview of your presentation?

In an interview, Chang, the Emily Herrmann Chair in Cancer Research, director, Cancer Center, professor of Cancer, Institute for Academic Medicine, Houston Methodist Hospital, spoke about the significance of molecular testing in breast cancer and how it will lead to an improvement in treatment approaches in 2017 and beyond. Chang discussed these issues during the 2017 OncLive^® State of the Science Summit on Metastatic Breast Cancer.Chang: Breast cancer management is obviously complex and has become increasingly difficult because of the increasing number of tests that we can order, which provide aid in our management of breast cancer. Basically, we still have 3 major subtypes: HR-positive, HER2-positive, and triple-negative breast cancer (TNBC). In each of these subtypes, we can sub-categorize.

For example, in HER2, other molecular tests in this disease may help us understand who would or would not benefit from targeted therapy, especially dual blockade and pathways like activated PI3K PTEN, which in some studies, has been associated with resistance to HER2 targeted therapies. Some results blocking this pathway show a modest benefit.

In TNBC, it is a huge conundrum because there are at least 6 different subtypes, so the question is, “How do we divide this up?” I've taken a practical approach in trying to figure out which of the TNBCs are responsive to chemotherapy and which of the subsets are nonresponsive to chemotherapy. Are there specific targets we can use?

Finally, what about the estrogen receptor (ER)—positive, or HR-positive breast cancers—are there new molecular markers? Are there ways in which we can detect these mutations, especially in the ESR1 mutations that are quiet during treatment with aromatase inhibitors in ER-positive breast cancers? If you have these mutations in ESR1, does it predict response to particular therapies, such as ER down-regulators like fulvestrant (Faslodex), rather than aromatase inhibitors?

Let’s reflect on the updated ASCO guidelines on tests such as Oncotype DX and MammaPrint. How would you say this helps physicians make better treatment decisions going forward, and do you think those guidelines need to be adjusted again in the near future?

We will get a better understanding, rather than test everybody that comes through with full genomic sequencing and circulating tumor cells (CTCs). I am asking whether we can be a little more thoughtful about the tests we order, especially in this era of limiting healthcare costs.These tests focus on patients for whom [we have trouble] determining whether or not they will benefit from chemotherapy. These tests have been around—I shudder to think—for more than a decade now, but they are still very valuable in determining whether or not a woman may be spared chemotherapy.

What do you hope community oncologists take away from your talk and can apply to clinical practice?

In traditional guidelines, we would consider chemotherapy after a certain tumor size—whether the nodes are involved—but these things do not address the biology of the tumor. These tests, like MammaPrint, which is a 70-gene test, and Oncotype DX, which is a 21-gene test, have been around for a very long time and have been validated in multiple studies. I believe all oncologists use these tests to guide or aid their decision making.It is an evolving field. Genomic testing is exciting; it is new, and there are new ways in which we can look at things. We can give a painless blood test and find out CTCs, cell-free DNA, and mutations that are circulating. Studies still need to be done to validate if these mutations, and blocking these mutations, actually translates into clinical benefit. Those studies are being done, but are not yet available.

Also, in the context of a clinical trial, I would be judicious in who I would choose if there are available targets. Overall, it is definitely an exciting time; we know so much more about the biology of cancer. We are moving away from anatomical descriptors to what is actually driving the cancers.

Finally, we are in the realm of immunotherapy—which has taken the oncology world by storm—and determining other predictors for response to immunotherapy. However, other than tumor-infiltrating lymphocytes, we are not in an era where we can even measure subsets of T cells.

Do you see blood-based tests becoming the standard approach?

All of these things are coming down the pike, and I do think that, over the next decade or so, breast cancer will be managed more like a chronic disease.Yes, I do, but the validations do need to get done. With liquid biopsies and blood-based tests, especially now that you can sequence a single cell, you can actually look at the plasma and see the tumor DNA—the cancer DNA that’s being shed into the plasma and exosomes in the blood.

Are there ongoing studies related to this that will be important going forward?

What role do you envision for immunotherapy in the future?

All of these fantastic tools that we now have just adds to a more complete understanding of breast cancer and who needs therapy, who does not need therapy, and what therapy to give. It’s all just very exciting.There are a few studies that have been presented regarding what kind of therapies will provide benefit if you have this ER mutation. It’s going to be different depending on the subset of cancer. Molecular testing will aid in these different subsets in different ways.Most of the effort has been in TNBC, and rightly so, because it has the most aberrant tumor with the highest mutational landscape. Approximately 15% of TNBCs respond to immune checkpoints. So, how do we make this better? Can we select who will benefit from immune checkpoints? Is it going to be as simple as immunohistochemistry testing for PD-1/PD-L1? I don't think so. Is it just going to be the mutational landscape, or are there new tests? Those studies are being done.