Expert Addresses Optimal Use of Endocrine Therapy in HR+ Breast Cancer

Rena D. Callahan, MD

Results of a meta-analysis revealed that the use of endocrine therapy for 5 years significantly reduced recurrence rates in women with early-stage, estrogen receptor (ER)-positive breast cancer with additive benefits that extend beyond 5 years. However, the apparent benefit, notes Rena D. Callahan, MD, must be weighed against adverse events (AEs).

The meta-analysis included findings across 88 trials of 62,923 women who were free of disease after 5 years of endocrine therapy and were followed up during a 5- to 20-year period. After the 5-year mark, breast cancer recurrences continued. The trial concluded that no group held a lower risk of recurrence for distant metastases, even in patients with low-grade T1 N0 disease.¹

“Clinical trials demonstrate a significant dropout rate,” said Callahan. “Compliance rates 5 years after randomization is only about 65%, and in real life, it is probably a lot less than that. I can tell you from my own clinical practice, it's very difficult to even get patients to the 5-year mark.”

However, the optimal duration of additional endocrine therapy has been questioned in patients with hormone-receptor (HR)-positive breast cancer. Results from the phase III ABCSG-16 trial, which were presented at the 2017 San Antonio Breast Cancer Symposium, showed that an additional 2 years of adjuvant endocrine therapy had no difference in overall survival (OS) compared with an additional 5 years—and the shorter duration reduces risk of bone fracture.

The 10-year follow-up of the 3484 women with HR-positive early-stage disease who enrolled in the trial—all of whom received 5 years of prior adjuvant endocrine therapy—showed comparable disease-free survival (DFS) rates of 71.1% and 70.3% in the 2-year arm and 5-year arms, respectively (HR, 0.997; 95% CI, 0.86-1.15; P = .982).² Rates of bone fracture were 4.7% in the 2-year arm as opposed to 6.3% in the 5-year arm.

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In an interview during the 2018 OncLive^® State of the Science Summit^TM on Breast Cancer, Callahan, an assistant clinical professor of medicine at the University of California, Los Angeles Jonsson Comprehensive Cancer Center, discussed controversies in the management of early-stage HR-positive breast cancer and neoadjuvant trial designs for these patients.Callahan: It was my pleasure to discuss the optimal duration of endocrine therapy, because this is a hot topic that affects a lot of our patients. Most of our patients have early-stage and ER-positive disease, so this is very relevant to them. Over the past several years, we’ve been toying with the idea of whether or not we can get more of a good thing. Physicians know that more aggressive cancers, such as triple-negative breast cancer or ER-negative, HER2-positive breast cancer, tend to recur early. A patient with those tumor types who reaches 5 years can feel confident that they will not have disease recurrence. It is very different for ER-positive disease.

How does 2 years of additional endocrine therapy compare with 5 years?

A study published in the New England Journal of Medicine by Dr Hongchao Pan showed that there was no group thought to be lower risk. This included patients with a node-negative T2 or under lesion; none of these patients had an expected recurrence rate of distant metastases less than 10% in years 5 to 20. Many patients hear about devastating stage IV recurrences and are looking for ways to mitigate that risk. The problem is that endocrine therapy comes with a lot of AEs.A few different studies have looked at 5 years of an extended aromatase inhibitor [beyond the initial 5 years] versus a shorter duration. At the 2017 San Antonio Breast Cancer Symposium, Dr Michael Gnant presented the ABCSG-16 study. The study showed no difference in DFS whether [a patient] took an aromatase inhibitor for an additional 5 years or 2 years. There was no overall survival benefit, so at this point it doesn't seem worth it to continue because of increased toxicity— specifically bone-related fractures and no benefit in survival.

That doesn’t necessarily mean that there isn't a patient who would benefit from 5 years over 2 years. That study [enrolled] mostly node-negative patients with smaller tumors; these are pathologic factors that are associated with a lower overall risk of recurrence.

If the additional 5 years is recommended down the line, would patients need additional counseling to encourage compliance rates?

A higher-risk group of patients who have higher-grade, stage III disease, and multiple positive lymph nodes are patients who are more likely to respond to endocrine therapy and might benefit from the additional 5 years of therapy. This may be especially true in patients with tumors that are strongly ER- and progesterone receptor—positive. Right now, we don't have the data to make that recommendation. It's a nuanced conversation that needs to happen between the patient and her doctor. Absolutely. Part of the counseling is having them truly understand what the risk is. It's very important to talk about that residual risk; a lot of patients don't appreciate that. It's also important to talk about perceived risks of extended therapy with tamoxifen, for example. There was an increase in uterine cancer deaths and deaths from pulmonary embolism, though it was minuscule in comparison with the improvements in mortality.

Are there any neoadjuvant trials designed for ER-positive disease?

Is there anything else you would like to emphasize?

[You have to] discuss the data in a way that is easy to understand and helpful. [We also have] to better treat the AEs of therapy; this involves blood pressure management, cholesterol management, and treatment of osteoporosis. Ideally, [their bones] won't fracture, and [they won’t have to] come in for more frequent office visits. Sometimes patients drop off after year 5, but if you're going to continue them on a therapy, that relationship and those visits need to continue. Right now, it's more of a concept. I don't think we can take home any “earth-shattering” data that will immediately change practice. We know that ER-positive breast cancers are less likely to show a pathologic response to preoperative chemotherapy. We're looking at the wrong outcome; pathologic complete response does not mean the same thing prognostically for an ER-positive tumor as it would for a HER2-positive or triple-negative tumor. We need to look at other variables. This idea of changing Ki-67 with treatment is interesting because you can often see those changes very early, even at the 2-week time point. If we're able to correlate that to extended DFS, it proves that concept and gives us ideas on how to design adjuvant studies. In general, we're getting an influx [of information], and it's very hard to keep up with all of the genomic tests out there. There’s EndoPredict and Oncotype DX, which we have more familiarity with, and MammaPrint. They are costly and I don't think we fully know how to use them. They can be applied to neoadjuvant studies of endocrine agents. We don't yet know if they're better than the preoperative endocrine prognostic index, which is something that we can easily find at very little cost. It'll be exciting and interesting to see studies that are designed with those tools, but right now they should be used in the research arena.

References

1. Pan H, Gray R, Braybrooke J, et al. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017;377:1836-1846. doi: 10.1056/NEJMoa1701830.
2. Gnant M, Steger G, Greil R, et al. A prospective randomized multi-center phase-III trial of additional 2 versus additional 5 years of anastrozole after initial 5 years of adjuvant endocrine therapy — results from 3,484 postmenopausal women in the ABCSG-16 trial. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Abstract GS3-01.