Genomic Risk Scoring Reduces Unnecessary Chemotherapy for Breast Cancer

William Audeh, MD, MS, chief medical officer for Agendia, discusses the results of the MINDACT study, including how genomic risk scoring in women with breast cancer could successfully prevent unnecessary chemotherapy treatment, as well as the importance of understanding tumor biology before choosing a treatment option.

Read the full transcript:

My name is Dr William Audeh. I am a medical oncologist specialized in breast cancer. I am the chief medical officer for Agendia. I've been in this role for five years.

Prior to that time, I practiced medical oncology for nearly 30 years at the Cedars-Sinai Cancer Center in Los Angeles, where for a time, I was the director of the cancer center, clinical chair of our hematology-oncology division, and also was an associate clinical professor at UCLA.

Throughout those years, I was very much involved in clinical research, in translational research, patient care. Because I came to medicine already with a master's degree in genetics, I have always focused my medical attention in oncology on the genetics of cancer. That is why I specialized in the genomics of breast cancer.

What existing data led you and your co-investigators to conduct this research?

The research that was published in Lancet Oncology just recently, the long-term follow-up from the MINDACT Trial was a trial that I was not personally involved with, but the company for whom I work, Agendia, provided the genomic test that was used in this trial.

I can certainly tell you, however, that the issue that led to the development of this trial, which began in 2007 was the concern that women with early-stage breast cancer were potentially being over-treated with chemotherapy. This was an effort to use a genomic method of analyzing breast cancer to identify women who could perhaps safely avoid chemotherapy based upon their genomic profile.

Please briefly describe your study and its findings. Were any of the outcomes particularly surprising?

I'm happy to describe the trial and the findings because they were not only surprising in some regards but also truly practice-changing in others, and they have created additional questions that we are actively pursuing to answer.

The trial, which is referred to as the MINDACT Trial, was a trial of nearly 7000 women across over 112 centers throughout Europe. This was a trial conducted by cooperative groups in Europe, enrolling women with newly diagnosed early-stage breast cancer, primarily hormone receptor-positive breast cancer.

The question was, can we take women who have clinical features that would make me as a medical oncologist want to give them chemotherapy to make certain that cancer didn't recur? Things like larger tumors or higher grade, more aggressive-looking tumors, or cancers that had already reached the lymph nodes.

These are all features which increase the likelihood of cancer spreading beyond the breast. For those women, for many years, certainly throughout my career, we gave them all chemotherapy, in addition to anti-estrogen therapy, to try to protect them from any recurrence.

The design of the trial was to take women with those high-risk clinical features and analyze their tumors genomically with the 70-gene assay known as MammaPrint. These are 70 genes whose levels of expression can predict whether or not a cancer is likely to spread or not.

The theory was, if we can identify those women whose cancers are not likely to spread because of their genomic profile, we can save them from needing chemotherapy. That was the purpose of the trial. The goal was to analyze how these women did after 5 years, and the most recent publication, in Lancet Oncology, extended the length of follow-up to over 8 years.

What we were looking for was a group of women who were randomly assigned to receive the standard treatment which would have been chemotherapy, followed by anti-estrogen therapy, and compare them to a group of women that was assigned to not get chemotherapy because they were genomically low risk by the MammaPrint.

When we compared the outcomes of these women, how many had recurrences of their cancer and how many did not, we found at the end of 5 years that there was absolutely no difference in the likelihood of cancer recurring, whether or not they received chemotherapy, if they were found to be low risk by the MammaPrint assay.

This was a triumph of genomic information adding to clinical information and guiding us in perhaps a more rational and informed manner as to who really does need chemotherapy and who does not.

The additional findings that appeared in the latest publication, extended the follow-up to over 8 years. The findings were quite consistent. We still have showed that the women who were genomically low risk by the MammaPrint test did not benefit from chemotherapy in any significant way.

I'll also point out that in that high-risk group, one of the most surprising findings was that women who had cancer that has spread to the lymph nodes under their arm still did not need chemotherapy if they were generally low risk by MammaPrint. It was a surprising finding.

It was the first finding of its kind in such a prospective and randomized trial to show that even with women who had positive nodes—this was one, two, or three nodes under the arm—even women with that kind of breast cancer, if they were genomically low risk, they did extremely well with anti-estrogen therapy alone and did not benefit from the addition of chemotherapy.

By the end of the trial, we had established that 46%, or nearly half of the women who would have gotten chemotherapy if we had followed the clinical features, were able to safely avoid chemotherapy.

What are the possible real-world applications of these findings in clinical practice?

The initial findings were reported in 2016 and had already affected clinical practice in the sense that rather than relying just on clinical features, as I said, such as the size of the tumor or whether the cancer had spread to the lymph nodes, it's now considered standard of care to add in and integrate the genomic information.

This is a test done on a sample of the cancer itself before any treatment is given. This kind of information is available almost immediately after the diagnosis is made. It helps to plan how to approach the patient, whether they should go directly to surgery, whether they might need to get treatment prior to surgery. It has helped to plan treatment.

The outcome, which is what was hoped for, is that many women who would have previously been exposed to chemotherapy and its toxicities can now safely avoid chemotherapy because of the findings of this large trial.

Do you and your co-investigators intend to expand on this research?

One of the surprising findings which I didn't mention earlier is that, although in the overall group, if you're MammaPrint low risk or genomically low risk when the tumor was analyzed, you did not benefit from chemotherapy, it was observed that for women who were 50 years or younger, there was a small chemotherapy benefit even when they were genomically low risk.

That is in comparison to women over the age of 50 with exactly the same clinical features, exactly the same genomic low risk, who had no benefit at all from chemotherapy. We asked, why would age affect whether or not a woman benefits from chemotherapy?

The most likely explanation is actually just that. That it's the woman's age. That chemotherapy is thought to work by directly killing cancer cells and that is why it has been used for many years and is still used for women who really need it.

But for women who are genomically low risk, the reason that chemotherapy might still help some of those who are young is because the chemotherapy might not be acting directly on the cancer but it's having a secondary effect, which is to turn off the hormone production from a woman's ovaries.

Women who are 50 years and younger, most are pre-menopausal and are still having monthly cycles. For a cancer that’s estrogen-positive, the most essential part of the treatment is to diminish or remove the estrogen. We think that the only reason that we saw a small benefit for chemotherapy in those younger women is that the chemotherapy was secondarily tuning the ovaries down and giving additional anti-estrogen effect.

Our research is focused on these younger women and seeking to determine whether there is anything different about the nature of breast cancer in younger women, or whether the reason we see differences in how they respond is more about their age and menopausal status.

Even then, if we can avoid chemotherapy and perhaps be more effective in diminishing estrogen, we can get the same excellent outcomes, but without the harm and toxicity the unnecessary chemotherapy would produce.

Is there anything else pertaining to your research and findings you would like to add?

Absolutely. The goal for all of us clinicians, everyone involved in the care of women with breast cancer, is to cure them because the majority of women diagnosed, at least in this country, are diagnosed at a curable stage.

The goal is to cure them, which is well within our reach, but to do it with as little toxicity and harm as possible to those women so that they can achieve the best quality of life as well as duration of life with cure. What I think this research has truly done is to allow a large group of women to avoid unnecessary chemotherapy.

My goal and my role with Agendia as chief medical officer is to continue to support research that continues to personalize and improve the treatment for women with early-stage breast cancer so that we can achieve more cures with less toxicity and more accurately personalize the treatment we do give them.

That is the power of genomics. Ultimately, the power of genomics that we are putting in the hands of clinicians and women with breast cancer will lead to much better outcomes and better quality of life.