COMMENTARY

Endocrine Therapy in Breast Cancer: Best Bet on Duration

Harold J. Burstein, MD, PhD

Disclosures

December 19, 2016

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Hi. I am Dr Harold Burstein, associate professor of medicine at Harvard Medical School and a breast cancer specialist at Dana-Farber Cancer Institute. I'm reporting to you from the first day of the 2016 San Antonio Breast Cancer Symposium (SABCS). One of the highlights of the initial session this morning was a series of papers on the role of extended endocrine therapy in the adjuvant setting for ER-positive breast cancer, particularly whether longer durations of aromatase inhibitor (AI) treatment would be clinically beneficial.

The single most important treatment we have for preventing recurrence in the majority of women with breast cancer...is the use of adjuvant endocrine therapy.

Just to remind you, ER-positive HER2-negative breast cancer is the most common type of all breast cancers, accounting for nearly two thirds of all breast cancers around the world. The single most important treatment we have for preventing recurrence in the majority of women with breast cancer, aside from surgery and radiation, is the use of adjuvant endocrine therapy. Historically, we have recommended about 5 years of antiestrogen treatment with either tamoxifen or an AI. Recent studies presented both at this meeting and at the American Society of Clinical Oncology (ASCO) meeting in June 2016 have asked whether longer durations of an AI beyond the historic 5-year benchmark would be clinically valuable for patients.

These trials [presented at SABCS] all built on a report coming out of ASCO 2016 on the MA.17R trial.[1] It was a study for women who had received 5 years of an AI and then were randomly assigned to ongoing treatment with either nothing or an additional 5 years of an AI. That study, which was a plenary paper at ASCO 2016,[1] showed a small but measurable benefit with the longer duration of AI therapy. The interesting thing about that study is that almost all of the women had had 5 years of tamoxifen, then 5 years of an AI, and then were randomized. It was a question of whether you got 15 years versus 10 years of therapy. Most of us think of 10 years as the upper limit of what we are going to offer to patients.

We also know from some previous studies, such as MA17,[2] NSABP B-33,[3] or ABCSG6,[4] that for women who had had 5 years of tamoxifen, lengthening their treatment with the use of an AI after tamoxifen was clinically valuable. They justified longer durations of therapy. Given that most women these days receive an AI in the first 5 years after diagnosis, would longer durations of an AI in years 5-10 be clinically valuable? If so, by how much? And what would the downsides of treatment be?

The three trials [presented this morning] specifically looked at this. The largest of them was NSABP B-42.[5] The investigators enrolled women who had had 5 years of adjuvant endocrine therapy—either 5 years of an AI or 2-3 years of tamoxifen and then 2-3 years of an AI—and randomized them to ongoing letrozole or placebo. The study showed about a 3%-4% reduction in the risk for breast cancer events over the next 5 years, which bordered on statistically significant. There was both a reduction in metastatic events (1%-2% reduction) and a reduction in contralateral or second breast cancers. There were also more side effects with ongoing therapy: a slightly greater rate of fracture, though it was only about a 1% difference, perhaps because one third of the women in this trial received a bisphosphonate to help protect their bones.

Two other trials looked at very similar questions, again including women who had had AI exposure after tamoxifen and, in one instance, tamoxifen alone. These were the DATA[6] and IDEAL[7] trials, both from The Netherlands. Both of these groups showed a numerical advantage favoring a lower risk for events in the group of women who got longer durations of the AIs, but in neither study were those differences statistically significant. Where does that leave us when talking to our patients and thinking about what the optimal duration of therapy should be?

The first thing is that at least 5 years is the standard recommendation. Most postmenopausal women should consider an AI at some point during those first 5 years if not starting from the very beginning. For those who have reasonably high-risk cancers (stage II or III, meaning nodal involvement or bigger cancers), it would be valuable to think about treatment beyond 5 years with an AI, towards year 10. That would probably achieve some numerical advantage.

The riskier the cancer is at baseline...the more benefit there would be from extended AI treatment.

Of course, the riskier the cancer is at baseline—because of the size of the tumor or the extent of nodal involvement—the more benefit there would be from extended AI treatment. This also seems to be the case in women who have had tamoxifen as opposed to therapy with the AI only. The switchover seems to achieve something that perhaps longer durations of monotherapy with the AI may not be able to contribute. Women who have had bilateral mastectomy are not at risk for a second breast cancer, so their numerical advantage of longer duration gets lower; much of the benefit seen in the biggest studies (MA.17R and NSABP B-42) was in terms of secondary prevention.

The final key point is that patients are often very good at telling you whether they want to continue treatment. These drugs do carry side effects. We are all familiar with arthralgia syndrome, genitourinary symptoms that go with AI therapy, and the risk for osteoporosis. For patients who have had many side effects or do not want to be taking those medications, it is also fair to say that these data show a very modest improvement in long-term outcomes. Well-informed women could quite reasonably choose not to pursue longer durations of therapy if they were not tolerating these products well.

This is an important set of papers on the duration of adjuvant endocrine therapy with AIs. For higher-risk cases, we are now pushing that boundary towards 10 years. For lower-risk cases, 5 years is probably adequate treatment.

I'm Hal Burstein, reporting to you from the 2016 San Antonio Breast Cancer Symposium. Thank you very much.

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