Expert Raises QoL Concerns With Adjuvant Hormonal Therapy in ER+ Breast Cancer

Michelle E. Melisko, MD

As research of early-stage estrogen receptor (ER)-positive breast cancer continues, experts are relying more on extended adjuvant hormonal therapy with aromatase inhibitors, but are concerned about patient quality of life (QoL) with such treatment.

“My passion is to really try to figure out how to make the side effects of these therapies more tolerable and how to help women be able to actually have reasonably good and normal QoL while they're taking these therapies, so that we can increase compliance,” said Michelle E. Melisko, MD.

OncLive: Can you give an overview of your presentation?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Breast Cancer, Melisko, a clinical professor of medicine at the University of California, San Francisco (UCSF), discussed a variety of pivotal trials with adjuvant hormonal therapy and other developments in the treatment of patients with ER-positive breast cancer.Melisko: I spoke about the value of extending adjuvant hormonal therapy beyond 5 years and reviewed the data from clinical trials looking at extending tamoxifen beyond 5 years, tamoxifen followed by aromatase inhibitors, and the most recent data looking at aromatase inhibitors for 5 years versus 10 years.

It's been a very confusing time over the past year, because there have been several large clinical trials that reported out within 6 months of each other that seem to have disparate results. One was a positive trial suggesting that we should continue hormonal therapy, mainly an aromatase inhibitor, beyond 5 years. The second suggested that we shouldn't. But when we take a deeper dive into data, we realize that the results of these trials are very similar, and it simply has to do with the differences in the outcomes or results—one was statistically significant in favor of extending [therapy] and the other was not.

It has to do with the definitions of the endpoints, the patient population, and what they defined as being a statistically significant outcome. I spoke about that and hopefully it resolved some controversies and help oncologists understand a practical approach that I take to discussing this with patients in making it a very individualized decision. I also spoke a little bit about neoadjuvant endocrine therapy in advance of surgery.

How has treatment changed over the past couple of years?

We can give some form of treatment before surgery to improve the chances of a patient having breast-conserving surgery, and we are also able to risk stratify to help us understand which patients are going to have good outcomes after surgery and which won’t. In some tumor types, primarily strongly ER-positive cancers, the rates of the cancer going away completely—what we call pathologic complete response (pCR)—is very low in strongly ER-positive cancers. Using chemotherapy might not be the optimal approach, so I spoke about some of the data comparing neoadjuvant endocrine therapy with neoadjuvant chemotherapy to help the community of oncologists understand what we at an academic center do to guide our treatment recommendations for women who have these large, but potentially more biologically indolent, cancers.At the 2017 ASCO Annual Meeting, there was a presentation about the MA17R study. This was a follow-up of a very well-known trial where patients who originally received 5 years of tamoxifen were randomized to receive either placebo or an aromatase inhibitor.

More than 10 years ago, we found out that continuing with an aromatase inhibitor was beneficial. However, this trial looked at the MA17R component, the “R” being the extension of an aromatase inhibitor beyond those 5 years. There were some women in this trial who had received hormonal therapy for as long as 15 years, and they looked at the added benefit of continuing an aromatase inhibitor for 10 years compared with 5. That trial did meet a statistically significant endpoint of reducing recurrence and improving disease-free survival.

At that time, it was a practice-changing data point. I came home from that meeting telling patients who were coming in, after having taken 4.5 or 5 years of an aromatase inhibitor, to say we now have data that say that they should continue this for 10 years. Fast forward about 6 months to the NSABP B-42 trial, which had a similar design but [included] patients who perhaps had never taken an aromatase inhibitor. They started out taking tamoxifen, took an aromatase inhibitor for 5 years, and then they were randomized to continue it for another 5 years or just stop.

In that trial, there was also a reduction in recurrences, but it did not meet the statistically significant endpoint. One of the big differences that I’ll point out in my presentation is that the definition of a recurrence event is different in these 2 trials. One includes the events of other cancers and one doesn't.

Because of these subtle differences, one ended up being a positive study and one didn't. The NSABP B-42 trial did not meet its endpoint of showing that continuation of an aromatase inhibitor was statistically significant. However, when you look at them side by side, look at the hazard ratios, and you look at how much they reduce the risk of a distant recurrence, they both were very similar.

Do you believe that there is a role for chemotherapy in the neoadjuvant setting?

Also, what are the consequences for continuing the hormonal therapy—the aromatase inhibitor—for more than 5 years in terms of cardiac events, atherothrombotic events, or osteoporotic fractures? A lot of patients worry about that. When it comes down to taking a pill for another 5 years, and realizing that it may only be a 1% to 2% further reduction risk of recurrence, patients are not going to buy into it. Absolutely. We have compelling data that are very advantageous to offer treatment before going to surgery for some patients who have large tumors, node-positive tumors, or biologically high-risk cancers. There are a number of different ways that we can actually characterize the tumors as being more biologically high risk through prognostic and predictive markers.

I'm at an institution, UCSF, where we are the leaders in a multicenter, national, and soon-to-be international clinical trial called I-SPY where we look at neoadjuvant chemotherapy in combination with experimental therapies to try to improve the rates of pCR, which we know and believe is associated with better outcomes in certain biological subtypes such as triple-negative breast cancer or HER2-positive breast cancer.

What agents coming down the pipeline look promising?

The challenge we face is that, for ER-positive disease or also HER2-negative disease, achieving a pCR is a nice thing, but it happens rarely. Therefore, chemotherapy may not be the best way to get there for those ER-positive cancers, particularly those with low proliferation rates. That's why looking at neoadjuvant endocrine therapy, particularly now in combination with biological therapies such as CDK4/6 inhibitors, may be a better approach for those types of cancers.Now, it's not a matter of what's coming down the pipeline. All three CDK4/6 inhibitors are now FDA approved; palbociclib (Ibrance) has been FDA approved now for several years for ER-positive metastatic breast cancer in combination with both aromatase inhibitors and fulvestrant. Within the past year, ribociclib (Kisqali) gained FDA approval and then [recently] abemaciclib (Verzenio) gained FDA approval. These are all drugs that are, at this point, only approved in the metastatic setting for ER-positive disease.

There are multiple trials going on looking at these drugs in women with…high-risk early-stage breast cancer to see if adding them to hormonal therapy will reduce the risk of recurrence. We don’t have any data on that yet. Areas of further exploration are looking at the value of these drugs in combination with HER2-targeted therapies in patients who have ER-positive/HER2-positive metastatic disease and then also trying to define whether we will prove that these drugs have value in the early-stage setting.

What was your take-home message for the audience who sat in on your lecture?

If any of these trials—PALLAS and PENELOPE—end up being positive studies, everyone is going to want to extrapolate that data to lower-risk patients. These medications are not without [adverse] effects, such as fatigue and neutropenia. The question is, “How low do you go in terms of absolute benefit to recommend something that is very costly and can also impact QoL?”It's all about personalized medicine, and there is a lot of fanciness around next-generation sequencing, but we must remember that endocrine therapy is our oldest and most tried-and-true targeted therapy for breast cancer, and recognizing that tailoring your approach to targeting endocrine therapy for each individual patient is important.

I discussed extended adjuvant therapy with aromatase inhibitors, combining a biological agent with aromatase inhibitors or fulvestrant, but there are patients who are not going to tolerate even an aromatase inhibitor for 5 years and recognize that there are some patients that the best we can do is get them through 5 years of tamoxifen or the best we can do is get them through 5 years of an aromatase inhibitor.