Expert Addresses Controversies in Management of HR+ Early-Stage Breast Cancer

Rachel C. Jankowitz, MD

Adjuvant endocrine therapy has become the standard treatment for patients with hormone receptor (HR)—positive, HER2-negative breast cancer. However, while therapeutic developments and longer follow-up data have led to a shift to more individualized treatment, a lack of consensus persists.

“Part of the problem centers around the fact that there are so many choices and individual patient factors that you consider when making these decisions in the clinic,” explained Rachel C. Jankowitz, MD.

With the availability of new and effective agents, options for endocrine therapy have expanded, and many have been integrated into the early-stage setting. However, many questions remain regarding timing of ovarian suppression and the optimal use of available agents.

OncLive: Could you provide an overview of your presentation on adjuvant hormonal therapy in earlystage breast cancer?

In a recent presentation at the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Jankowitz, assistant professor of medicine at the University of Pittsburgh School of Medicine and the University of Pittsburgh Medical Center Hillman Cancer Center, discussed the range of risk associated with HR-positive, HER2-negative breast cancer, important factors physicians should consider when choosing the appropriate therapy, and the importance of communicating with patients about associated adverse events (AEs).Jankowitz: The beginning part of my presentation was an overview of duration of tamoxifen therapy and how we arrived at 10 years of tamoxifen being superior to 5 years in this patient population.

I then discussed the duration of aromatase inhibitors and what we’ve learned, now that trials looking at 10 years of aromatase inhibitor use versus 5 years have started to mature. The final part of my presentation was about ovarian function suppression for premenopausal women with breast cancer.

The overarching theme of my presentation is that there’s a range of risk when it comes to HR-positive/HER2-negative breast cancer, where certain patients are on the lower end of that scale and other patients are on the higher end. We have a number of ways to assess that risk. Generally, we look at factors such as the stage of their disease, but we have also come to look more at quantitative expression of HR status, grade, Ki-67, and gene expression profiles when we’re making decisions about adjuvant endocrine therapy.

Could you explain how 10 years of tamoxifen use proved to be superior to 5 years? What else do we know now about aromatase inhibitors?

The other important thing that we need to consider when talking to our patients about these therapies is tolerance, quality of life, and AEs. Often, more aggressive hormonal therapies are accompanied by AEs. We’re always weighing these incremental gains against how well patients are tolerating these therapies and how high breast cancer risk was to begin with.The ATLAS and aTTom trials are 2 very large studies that looked at approximately 17,000 women with early-stage breast cancer who were randomized to receive either 10 years or 5 years of tamoxifen. It took a long time to see this, but at about 10 years of follow-up you started to see an improvement in disease-free survival [DFS] with 10 years of tamoxifen use compared with 5 years.

What are the controversies in the management of HR-positive early-stage disease? How do you assess risk for these patients?

That benefit was apparent regardless of stage, age, and menopausal status—so really, all subsets benefited. Does that mean that every patient needs 10 years of tamoxifen? Not necessarily. Women with stage I cancer who also have low gene expression profiles, for instance, may not do 10 years of tamoxifen, but yes, there is a benefit to receiving it beyond 5 years.In the beginning of my presentation, I highlighted some of the current consensus guidelines from the St. Gallen International Breast Cancer Expert Panel and ASCO, and they don’t always match; they’re not always updated. That, in and of itself, is sometimes confusing to patients and providers.

Also, in terms of how long to give an aromatase inhibitor, there is controversy at face value because 1 large trial showed a DFS advantage with 10 years of aromatase inhibitor use versus 5 years, while another trial did not. However, if you really break down the data and look at the way that they define that endpoint, the data are actually quite similar between the 2 trials; [the problem] was [with the] language they used to define DFS.

How did the SOFT and TEXT trials inform this management? Are we awaiting longer follow-up?

Just clarifying that for providers is important because in reality, the 2 trials are very similar with the results that they showed— that 10 years of aromatase inhibitor use over 5 provides a slight advantage in what is more accurately described as breast cancer—free interval, not necessarily DFS in the traditional sense.The SOFT and TEXT trials now have 8-year follow-up data and are showing an advantage to ovarian suppression for premenopausal women with early-stage breast cancer. Those trials also took a long time to mature, and to be honest, I’m not sure whether there’s going to be another incremental report of those trials.

But again, you can look at subsets of patients who participated on those trials as well and can see that the advantage is more apparent in the women with higher-risk disease—the patients who were appropriate for chemotherapy in general. In the higher-risk patients who participated on those trials, the rate of chemotherapy use was quite high, at nearly 60%. Therefore, therein lies another controversy when you look at the results of SOFT and TEXT versus ABCSG-12, for instance.

That [ABCSG-12] did not show an advantage to ovarian function suppression, but the patient populations were incredibly different in the 2 trials. It was a much lower-risk group in the ABCSG-12 trial. Additionally, the duration of ovarian function suppression was different between the 2 studies, so that is another important area of potential risk reduction for women with higher risk, especially in those with node-positive, earlystage breast cancer and in patients who are aged less than 35 years or who remain premenopausal after chemotherapy. Those patients are going to get a larger incremental advantage from ovarian function suppression.

What ongoing clinical trials are you excited about in this space?

Individual patient factors, when you make these decisions, is important because the rate of nonadherence with that therapy was pretty high on that trial; it was approximately 24% or 25%. These decisions really do impact quality of life, but there are definitely patients where we should be considering that. With the most recent guidelines—both ASCO and St. Gallen— there was overwhelming consensus that at least for some of our patients with early-stage breast cancer, we should be considering ovarian function suppression in addition to either tamoxifen or an aromatase inhibitor.The most exciting trials that we have ongoing at this time are the adjuvant trials incorporating CDK4/6 inhibitors into the management of our high-risk patients with early-stage disease. We’ve seen a doubling of DFS in the metastatic setting with these drugs, so it would be surprising to me if they didn’t also yield a benefit in the adjuvant setting.

Those trials should mature fairly quickly. The PALLAS study is also ongoing, which is looking at adjuvant palbociclib [Ibrance]; we will hopefully get the results of those trials in the next several years and that could [lead to] a new standard of care for our patients. That could save lives of many women with higher-risk breast cancer.

I have found those drugs to be fairly well tolerated, to be honest. You can have some fatigue; abemaciclib [Verzenio] can cause diarrhea. You have to pay attention to the white blood cell count—that is not usually clinically significant in terms of infection. Perhaps those drugs will afford us the opportunity to lower risk without so many AEs.