Data on Extended Adjuvant Endocrine Therapy in HR+ Breast Cancer

Mark Pegram, MD: Let’s talk about the duration of adjuvant therapy. This issue doesn’t end at year 5. It used to be that we could stop all endocrine therapy at year 5, but now we have multiple data sets. Probably the most recent example was from [Lucia] Del Mastro, which he presented at ESMO [European Society for Medical Oncology Congress] last year: Extended therapy with letrozole as adjuvant treatment of postmenopausal patients with early stage breast cancer, a randomized phase 3 trial of the Gruppo Italiano Mammella group.

This was a postmenopausal patient population treated with 2 to 3 years of tamoxifen and then extended treatment with 5 years of letrozole, which resulted in a significant and clinically meaningful improvement in both DFS [disease-free survival] and OS [overall survival] compared with the duration of 2 to 3 more years of letrozole instead of 5 years of letrozole. However, the authors rightly point out that the longer duration of aromatase inhibition [AI] is associated with more AI toxicities, such as arthralgias, hypertension, and osteoporosis. Those were significantly more frequent in the experimental arm. This raises the question, should we be doing this for all comers? Or do we need a biomarker to select for benefit from extended adjuvant endocrine therapy? Tell us about the IDEAL trial. That’s an example of a study in which the issue of biomarker selection has come up.

Lee Schwartzberg, MD, FACP: The IDEAL study was looking at adding 2 additional years after 5 years of endocrine therapy. That’s 7 vs 10 years, so 5 additional years. The reasons for doing a study like this are exactly as you point out. There are cumulative toxicities of aromatase inhibition, and that might impact survival in different ways outside breast cancer survival. Because even in the individual trials, it’s hard to see a major survival advantage for 10 years, even in the higher-risk group. There’s a disease-free survival and a distant disease-free survival advantage. We want to balance the toxicities of therapy with the benefit of therapies.

The question here was, will 3 additional years after 7 make a difference? For the whole study, the answer was no. Seven years seemed to be adequate. The benefit in IDEAL and in some of the earlier studies is modest in terms of an absolute benefit, and it tends to run in the 3%-to-4% range in terms of DFS. You’re treating 100 patients to benefit 3, and 96 or 97 aren’t benefiting from a breast cancer perspective. But 100% of the population is exposed to the other toxicities, including osteoporosis and cardiovascular toxicities. We also know that many patients can’t wait to finish those 5 years. I’m sure you have patients who have the date on their calendar circled and say, “Doctor, I don’t want to go on.”

Mark Pegram, MD: If they’re adamant about not taking an additional 2 to 5 years, then there’s probably no point in doing assays to test for that.

Lee Schwartzberg, MD, FACP: Absolutely.

Mark Pegram, MD: Some patients are absolutely done at year 5 based on toxicities. Unfortunately, that’s the reality.

Lee Schwartzberg, MD, FACP: A problem that I don’t think we’ve addressed all that well as a community is that before 5 years, anywhere from 30% to 50% of patients seem to stop their endocrine therapy. We need better numbers on that to understand what we can do in terms of supportive care to get them through those toxicities. Those tend to be acute toxicities, most likely basal motor symptoms or arthralgias associated with the AIs. That’s a real problem.

But today we’re talking about how you make that decision when you get to the 4- to 5-year mark. Do you want to continue these patients for an additional 2 to 5 years? Most of the trials have looked at 5 additional years, but with tamoxifen. There are 2 large global trials with tamoxifen looking at 10 vs 5 years, and then studies after 5 years of endocrine therapy with either AI for 5 years or a combination or tamoxifen for 5 years. We have slightly different results from each of those trials.

Mark Pegram, MD: I’ll mention for our audience that the 2 long tamoxifen trials are aTTom and ATLAS. Both were positive studies for 10 vs 5 [years]. Then MA.17 was 5 years of tamoxifen followed by an additional 5 years or not of letrozole. That was also a positive study, with similar results to the other trials that we’ve mentioned.

Transcript edited for clarity.