Behind the Breakthroughs: Optimizing Treatment for the Best Possible Outcomes

BCRF investigator Dr. Lisa Carey discusses how researchers are trying to bring personalized therapies to all forms of breast cancer

Since 1989, breast cancer deaths have declined by 40 percent—a statistic that can be attributed in large part to advances in treatment.

“Breast cancer has been a game of singles as opposed to home runs, but there have been a lot of singles,” BCRF investigator Dr. Lisa A. Carey recently told BCRF. “Over these last few decades, we’ve seen an improvement in therapies and our ability to prevent relapses.”

For the most-treatable and early-stage forms of the disease, doctors have more tools at their disposal to personalize therapy regimens to patients—and patients’ individual breast cancers—than ever. Hormone receptor-positive breast cancers, for example, have had targeted therapies for decades. The newer Oncotype DX® test can be used to predict risk of recurrence and determine whether a patient with ER-positive breast cancer needs chemotherapy.

RELATED: ASCO Annual Meeting 2020: Early-Stage Breast Cancer Treatment Updates

While we’ve made progress for the majority, rare and aggressive forms of the disease still lack targeted treatments—let alone an arsenal of them from which doctors can pick and choose. Dr. Carey sees promise, though, in the story of HER2-positive breast cancer (representing up to 20 percent of all breast cancers), which went from having one of the worst prognoses to one of the best. 

Dr. Carey spoke with BCRF about treatment optimization, new treatments for patients with rare forms the disease, and what’s to come.

What treatment successes have we seen in less-common breast cancers that don’t require hormones to grow?

The 20 to 30 percent of breast cancers that are not hormone receptor (HR)-positive and are essentially insensitive to anti-estrogen approaches fall mostly into two categories, really.

The first is HER2-positive breast cancer [which tests positive for a protein called human epidermal growth factor receptor 2 (HER2)]. For that, we've had a remarkable run over the last 15 years of developing multiple drugs that are highly effective in preventing relapse. That group went from having one of the worst prognoses to one of the best, because of drugs like trastuzumab (Herceptin®) and pertuzumab (Perjeta®).

Triple-negative is the other group, which is essentially defined by what it doesn't have: It doesn't have hormone receptors that are expressed on the tumor, and it doesn't have HER2 overexpression. That highlights the problem we have with finding treatment. It's probably more diverse than we originally recognized on a molecular and biological basis. Since we don't have any of the conventional clinical targets, we are reliant on chemotherapy for treatment. But triple-negative has had an improvement in outcomes and prognosis because the chemo drugs we give now are better. Triple-negative, though, remains our thorniest challenge at the moment.

We are entering into the era of immunotherapy, which is already being given for metastatic breast cancer. Many of us anticipate it will also be incorporated into early-stage breast cancer treatment, as well.

For ER-positive breast cancer, doctors have the Oncotype DX® test to determine if a patient needs aggressive chemotherapy to reduce the risk of reoccurrence—or if she/he can avoid it. Now that HER2-positive breast cancer has gone from a deadly disease to one with multiple targeted therapies, are we close to having a similar test for this form of the disease?

The short answer is yes, I genuinely believe that we will have the ability to better gauge the aggressiveness of HER2-positive breast cancer and decide which tumors need less therapy (particularly less chemotherapy) and which need the whole kitchen sink in order to help prevent relapse. Right now, we can tailor therapy a bit based on geography. If the cancer is small and only in the breast and not in the local lymph nodes, then treatment can be a little less aggressive. But we want to get past that. If we keep just going by anatomy, we’re still probably not going to be able to do much treatment optimization and will end up overtreating a lot of people with drugs that take a year or more to finish.

We're not there yet, but some promising findings have already come out of studies that indicate we will have assays, and then biomarkers, to help us gauge aggressiveness. There are trials looking at certain elements of tumor, such as tumor-infiltrating lymphocytes [immune cells that kill tumors], which a pathologist can see on a microscope. If these elements reflect the entire immune system and turn out to be important in enough sets of trials, we may be able to test for them pretty quickly in a couple more years. I have to say, I think we’re going to treat HER2-positive breast cancer in a much more granular, personalized way in the coming few years.

Even though we’ve made progress, therapies that are targeted for TNBC patients are still only benefitting a small portion of people with TNBC. Why?

For one, we don’t have as good a handle on the underlying biology of TNBC. We know that in HER2 positive breast cancer, HER2 drives the cancer in a high proportion of cases, so treatment that whacks HER2 works really well. TNBC doesn't have like that big, fat, juicy target. We’re looking to tease these targets out, but they’re not as obvious.

That said, I think that just as the immune system is important for HER2-positive breast cancer, it certainly looks like it affects prognosis and response to therapy in TNBC. And there are some studies coming out that suggest if you incorporate immunotherapy upfront with chemotherapy, patients may do better. We'll know for sure whether that's the case in the next year or two, at which point we'll be using immunotherapy fairly broadly.

I suspect we will have a way to gauge the tumors most likely to respond to immunotherapy. We will still have the challenge of what we call immune-cold tumors where the immune system doesn't seem to recognize the cancer, and it doesn't matter if you activate it. Some cancers sort of throw an invisibility cloak over themselves to hide. We have to figure out ways to pull that cloak back so they can be visible.

There are also some newer chemotherapy drugs that are less toxic, and I think we'll be working more and more with those. We’re getting smarter about how to give chemotherapy. Even simple things like that can an advance for patients.

Dr. Carey’s Tips for Talking to Your Team about Getting the Right Treatment:

• Make sure all your doctors—your oncologist, radiologist, surgeon, any others—are communicating with each other.
• Ask questions about why your doctor is recommending a particular therapy and whether there are other options. If there are other options, ask why your doctor is recommending one over another.
• If you’re diagnosed with a rare and/or particularly aggressive form of breast cancer, seek a second opinion, if possible, in person or online.
• Participate in research that helps investigators understand the biology of breast cancers. If you have an opportunity to be a part of a tissue-based study or clinical trial, take advantage.
• Don’t be afraid to take your time to dot your I’s and cross your T’s by doing the above: “Breast cancer is not usually a thing that changes day by day or week by week,” Dr. Carey said.

This interview has been edited and condensed. Watch more interviews with BCRF researchers on our YouTube channel.