Tolaney Discusses Developments Across Breast Cancer Subtypes

Sara M. Tolaney, MD, MPH

CDK4/6 inhibitors have drastically changed practice in the treatment of patients with HR-positive breast cancer; however, their rise has left physicians with a new challenge: deciding which patients derive the most benefit from which treatment approach, said Sara M. Tolaney, MD, MPH.

“The key that we need is either a molecular biomarker that will help predict who will derive benefit from CDK4/6 inhibition, or we need some sort of clinical parameter that will help decide that,” explained Tolaney.

Additionally, there have been a number of advances for the HER2-positive breast cancer population, but unanswered questions remain. The PERSEPHONE trial, for example, explored whether patients could receive a shorter duration of trastuzumab therapy at 6 months versus the standard 1 year of therapy. Though the 6-month course showed noninferiority, Tolaney said the data are difficult to interpret.

OncLive: Please provide an overview of your presentation at the conference.

With all of these new therapies, how do you determine which agent is best for which patient population?

In an interview with OncLive^® at the 17th Annual International Congress on the Future of Breast Cancer^® East, Tolaney, professor of Medicine, Harvard Medical School, medical oncologist, Dana-Farber Cancer Institute, discussed developments in the treatment paradigms for patients with HR-positive or HER2-positive breast cancer.Tolaney: Over the last few decades, we've seen a lot of changes in the management of metastatic HR-positive disease. This is particularly the case over the last decade, when we saw the introduction of mTOR inhibitors. More recently, over the last 3 years, we had approval of 3 different CDK4/6 inhibitors. I touched upon data looking at CDK4/6 inhibitors in both the upfront setting and then in the second-line setting with fulvestrant. I also discussed the use of CDK4/6 inhibition as monotherapy with data looking at abemaciclib alone, with efficacy in the refractory setting.This is where we are struggling. We don't know how to decide which patients need a CDK4/6 inhibitor or which patients could get away with endocrine therapy alone. We also don't know what to do after progression on a CDK4/6 inhibitor.

When you look at all the biomarker work that has been done—and this is rich across a number of large phase III trials—most of them have yet to determine a molecular biomarker that predicts benefit. There's one interesting finding from the PALOMA-3 study, where investigators saw that patients who had low levels of cyclin E seemed to derive greater benefit from the addition of palbociclib (Ibrance) to fulvestrant. However, overall, it seems like the only biomarker we really have is estrogen receptor (ER) positivity.

What are the unmet needs in ER-positive disease?

There are some clinical parameters that look intriguing. For example, there was a pooled analysis of the MONARCH 2 and 3 studies. These were the trials that explored the addition of abemaciclib to endocrine therapy. Interestingly, they found that high-risk patients—patients who had liver metastases or who had short treatment-free intervals—derived significant benefit from the addition of abemaciclib. This helps us better understand that patients who have visceral or high-risk disease are getting a lot of benefit from these agents. This has changed how we practice because these are patients we used to just give chemotherapy to.One is that we don't know what to do with someone who progresses on a CDK4/6 inhibitor. There is a lot of work that's been done to try to understand the resistance mechanisms. Thus far, the data seem to be that there are multiple ways you could become resistant. You could become resistant to the endocrine therapy or the CDK4/6 inhibitor. The way you become resistant to the CDK4/6 inhibitor might be through multiple different mechanisms like cyclin E amplification or FGFR amplification. It's going to be complicated and more work certainly needs to be done there.

Moving on to HER2-positive disease, there were some interesting data presented at the 2018 ASCO Annual Meeting from the PERSEPHONE trial. Could you reflect on this?

We also don't know if you should continue CDK4/6 inhibition beyond progression. Sequencing is going to be a big question. Do you give the CDK4/6 inhibitor in the frontline or second-line setting? Will this impact long-term outcomes? We don't know what to do with the patients who develop ESR1 mutations on aromatase inhibition. There are certainly lots of unmet needs here.There has been a lot of interest in trying to determine how long we need to give trastuzumab (Herceptin). The original pivotal trial said 12 months of therapy, but this was not determined by any rational data. It was just picked as 1 year. Then they looked at trials for 2 years, and there was no additional benefit to continuing trastuzumab beyond 1 year. Now we have seen a series of trials looking at the opposite question: can we shorten the duration of trastuzumab?

PERSEPHONE tried to see if we could give 6 months instead of 1 year of therapy. While it's intriguing that the shorter duration may be similar in terms of outcomes, the problem was this was done in a very different era. It was done at a time where a lot of patients were getting sequential therapy, whereas now we know concurrent treatment with chemotherapy yields better outcomes. It was also done in an era with different chemotherapy backbones. For these reasons, it's hard to interpret these data.

Is chemotherapy becoming less relevant in HER2-positive disease?

Now, we take high-risk patients and we usually give them pertuzumab (Perjeta) and trastuzumab. Low-risk, stage I patients typically get abbreviated chemotherapy with paclitaxel and then trastuzumab. We don't know if low-risk patients could get less trastuzumab. Could you give this combination with just 6 months of trastuzumab? This is a question everyone would love to know. It's probably fine to do for a low-risk patient, but we need to prove it in a current era with concurrent chemotherapy. Our practice has changed so much since then.It is true that as we improve with our biological therapies, we can potentially reduce the amount of chemotherapy we give. We're trying to head in this direction. A lot of us wonder if we can do well with a lot of biological therapy and a little less chemotherapy. For example, if we gave patients preoperative taxane with trastuzumab or pertuzumab, and they achieve complete remission, could we just get away with biologics out back? We need more data to get here. Ado-trastuzumab emtansine (TDM-1; Kadcyla) could potentially replace at least part of the chemotherapy. There are some pending trials that could answer this question for us.

Earl HM, Hiller L, Vallier A-L, et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. J Clin Oncol. 2017;36 (suppl; abstr 506).