Saranya Chumsri, MD, Mayo Clinic, FL, highlights outcomes from a real-world study on the use of immune checkpoint inhibitors to treat hormone receptor-positive (HR+), HER2-negative (HER2-), metastatic breast cancer with a high tumor mutational burden.

Transcript

My name is Dr. Saranya Chumsri. I'm one of the breast medical oncologists here at Mayo Clinic in Florida.

As you know, with KEYNOTE-158, which was the clinical trial that evaluated the response of patients with high tumor mutational burden to single-agent pembrolizumab, that particular trial led to the FDA approval of pembrolizumab with high TMB, or high tumor mutational burden, anyone with TMB greater than 10 mutation per megabase.

However, if you look at that particular study, there were only five patients with breast cancer in that particular study, and that was with the unknown subtype of breast cancer. As you know, with breast cancer we have ER-positive, HER2-positive, and triple-negative.

Right now, most of the data that we have with the immunotherapy is mainly in triple-negative breast cancer.

If you look at the data with the single-agent immune checkpoint, like with Avelumab in the JAVELIN trial, in ER-positive, HER2-negative breast cancer, the objective response rate is only about 2.8 percent in this group of patients.

Commonly, we think that ER-positive, HER2-negative breast cancer it's on the immunologically cold tumor, and they may not respond well to immune checkpoint blockade agent.

Then, we want to try to look specifically at this subset of patients in hormone receptor-positive, HER2-negative, but has high tumor mutational burden to see they still respond well to immune checkpoint blockade agent, like other tumors with a high tumor mutational burden like in KEYNOTE-158 trial.

This study is in collaboration with the Foundation Medicine people, which has that real-world data that link with Flatiron Health.

In collaboration with Flatiron Health and Foundation Medicine, we basically had patients in the CGDB database of about 6,389 patients. Of those, about 3,955 patients had hormone receptor-positive HER2-negative breast cancer. Then we identify about 99 of those patients receive immune checkpoint blockade agent in that real-world database.

We have the collaboration going on between Mayo Clinic and Duke looking at our patients that had high TMB and had gone to receive immune checkpoint blockade agent. What we found was that, in the CGDB database, out of the 99 patient that had the immune checkpoint, 20 of them had high tumor mutational burden.

Specifically looking at this group of patients, in the 20 patients in the CGDB that has hormone receptor-positive high tumor mutational and had immune checkpoint, how did they do? Same thing with we identified eight patients from Mayo Clinic and Duke that has similar things.

20 patients from the Flatiron real-world data, and then eight Duke and Mayo Clinic patients, we found that these patients also seem to have a good long-term outcome with the immune checkpoint blockade agent. We did find this as clinical benefit of greater than six months.

We found that 28 percent of patients in the real-world data from that CGDB database had clinical benefit of greater than six months. About half of our patients, like 50 percent of our Mayo Clinic and Duke cohort, had greater than six months' clinical benefit.

Interesting part that we found in our study is that most patient that had long durable response has really tumor mutational burden.

If you look at breast cancer, most people with high tumor mutational burden in breast cancer usually have the mutation in the range of 10, 12, 13, 14, usually less than 15 or so, barely meet the cutoff for high TMB, unlike other type of cancer, like melanoma, lung cancer, that mutation is really high.

We found that people that have long, durable response of patients that has higher mutations. 66 percent of patients that had durable response has mutation of greater than 40.

We feel that perhaps those patient might be a better...each tumor probably need a different cutoff for high TMB, but the higher the TMB correspond to a better, longer durable response.

We found that patients with breast cancer, particularly invasive lobular carcinoma, which you normally think this tumor might not be immunologically high, invasive lobular cancer actually 15 percent might have high TMB. That's another point that we want to make for treating oncologists.

If you have invasive lobular patient, then it might be worthwhile trying to send sequencing because they are more likely to have high TMB, and these patient might respond better to immune checkpoint blockade agent.

Most of the signature that we found that causing high TMB is from the APOBEC mutation rather than MSI high like in other type of cancer like colon or endometrial cancer. Those are the interesting finding points that we have for the poster.

We just got the email from San Antonio Breast Cancer Symposium that our abstract got accepted for spotlight poster. We dived into more detail about that APOBEC signature that I mentioned since it seemed to be more prevalent theme.

Up to 70 percent of tumor that has high TMB in breast cancer is from the APOBEC. Unlike colon or endometrial cancer, MSI high is rare. It's less than three percent. We further looked at those APOBEC patients with APOBEC signature, and then see how they do with the endocrine therapy.

This study that we has started from one of my patients -- we wrote the case report with Foundation Medicine -- actually had high TMB ER positive. She blow through multiple lines of therapy, but then had complete response with the immune checkpoint, last longer than two years.

We dive into that in more detail. This poster is about how they do with immune checkpoint. The other one that we got accepted for, our discussion is to look at how they do with the standard care therapy.