Extending Adjuvant Endocrine Therapy in Patients With ER-Positive Breast Cancer

In a session on Friday at the 2018 ASCO Annual Meeting, William John Gradishar, MD, FASCO, discussed the pros and cons of extending adjuvant endocrine therapy for patients with ER-positive breast cancer.

Dr Gradishar began by pointing out that it long has been known that adjuvant endocrine therapy with tamoxifen, and more recently aromatase inhibitors, can improve disease outcomes for patients with early stage ER-positive breast cancer. However, the optimal duration of treatment remains an important question.

Pointing to the NCCN Clinical Practice Guidelines for breast cancer, Dr Gradishar noted that the fundamental takeaway is the variety of options available. The challenge, he said, is to define which option is best for an individual patient. In the case of adjuvant endocrine therapy, a particular challenge is determining whether it is worth using in a particular patient given the associated side effects.

Early clinical studies in patients with ER-positive breast cancer showed an incremental improvement in outcome with tamoxifen, with a carryover effect that extends beyond the duration of therapy. However, a later trial in node-negative ER-positive patients showed inferior outcomes, in terms of disease-free survival (DFS), for patients that continued tamoxifen past 5 years. Thus, Dr Gradishar said, it became dogma that patients should not receive adjuvant therapy with tamoxifen for more than 5 years.

Later on, the aTTOM (Adjuvant Tamoxifen–To Offer More?) and ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) trials addressed the question of longer durations of tamoxifen, comparing 5 years vs 10 years of treatment. In these trials, continued therapy demonstrated improvements in risk of recurrence with longer therapy; however, this effect was not evident until past 10 years.

Across the various trials that have been done to date, the absolute benefit of extended tamoxifen therapy has been calculated to be 3-4%. Given this incremental benefit, it is important for oncologists to assess which patients are likely to benefit, or not benefit, from this approach.

The issue of tolerability is an important factor in making this decision, Dr Gradishar said. For one, poor tolerance can lead to low adherence to treatment. In particular, the youngest and oldest patients, nonwhite patients, and patients with metastatic disease have been shown to have the lowest adherence to tamoxifen treatment. Additionally, treatment adherence tends to falls off over time.

A significant cause of poor adherence is serious adverse events associated with treatment. Across clinical trials, tamoxifen-treated patients show an increased risk of cardiovascular disease, fractures, and secondary cancers. Dr Gradishar added that these trials only capture the major adverse events, and they fail to account for the day-to-day long-term side effects and quality of life impairments that can result from treatment.

Thus, Dr Gradishar concluded that oncologists should be selective in the decision to extend adjuvant therapy beyond 5 years. Recurrence risk, prior tolerance, age, comorbidities, bone health, and reproductive concerns should all be taken into account.

Dr Gradishar also noted that various tools are emerging to support decision-making in this area, which can help oncologists to look at an individual patient and selectively make a decision about the likelihood they will benefit from continued adjuvant endocrine therapy.—Kara Rosania