Expert Encourages Adjuvant Endocrine Therapy in Premenopausal Breast Cancer

Reshma Mahtani, DO

Findings of a combined analysis of the TEXT and SOFT studies demonstrated a benefit with the addition of ovarian function suppression in premenopausal women with hormone receptor (HR)-positive breast cancer, but the information, says Reshma L. Mahtani, DO, highlights the importance of longer follow-up.

At a median follow-up of 8 years, the combined analysis confirmed the superiority in disease-free survival, though not overall survival (OS), of adjuvant exemestane plus ovarian function suppression versus tamoxifen with ovarian function suppression.

Though the benefit of ovarian function suppression has been established, its use in combination with tamoxifen or an aromatase inhibitor (AI) results in considerable adverse events (AEs).

“Sometimes you have to step back so you don’t miss seeing the ‘forest for the trees,’” says Mahtani. “We’re trying to extend the time patients have on hormonal therapy, but not at the cost of significant toxicity and quality of life [QoL].”

OncLive: Can you provide an overview of your presentation?

Can you elaborate on the data backing the TEXT and SOFT trials?

How do patients generally tolerate ovarian function suppression?

What was the third trial you presented at this meeting?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Mahtani, assistant professor of clinical medicine, Sylvester Comprehensive Cancer Center, University of Miami Health System, discussed the use of adjuvant endocrine therapy in premenopausal breast cancers, specifically the use of ovarian function suppression and GnRH agonists, and the expansion of CDK 4/6 inhibitors in practice.Mahtani: My presentation centered around the use of adjuvant endocrine therapy in premenopausal patients; it’s a decision we have to make in clinic quite often. I presented the 8-year follow-up data from the SOFT trial as well as the updated data from the combined analysis of TEXT and SOFT. These presentations were given at the 2017 San Antonio Breast Cancer Symposium, and the information highlights the importance of longer follow-up in patients with HR-positive breast cancer. When the data were initially presented at 5.6 years, there was no difference with the addition of ovarian function suppression to tamoxifen in the overall group. However, the 8-year follow-up data show a benefit with the addition of ovarian function suppression in the overall population.The trial results demonstrate that there is benefit from the addition of ovarian function suppression. We also see the emergence of a survival signal. An improvement in OS is evident in the patients who had received prior chemotherapy. We understand that there is an improvement with the addition of ovarian function suppression, but we also know that the absolute benefits are higher in patients who have higher-risk disease, such as those who are very young and those who require chemotherapy. This underscores the need for individualized patient care.For most premenopausal patients, ovarian function suppression is associated with more AEs. A woman who receives an AI as opposed to tamoxifen experiences issues with joint discomfort, osteoporosis, and libido. When we use ovarian function suppression with either tamoxifen or an AI, we tend to see worsening AEs. We need to make sure that we’re exposing patients to those additional AEs only if there is going to be a benefit.The third trial I presented was a pooled analysis of 5 studies that looked at the use of GnRH agonists to help prevent premature ovarian insufficiency and to improve pregnancy rates. The analysis showed a decrease in premature ovarian insufficiency and higher rates of pregnancy with the use of GnRH agonists during chemotherapy.

Can you speak to the potential of CDK 4/6 inhibitors in this space?

This is an important issue because young patients may have fertility concerns. Maintaining menstrual cycles and keeping the ability to conceive is an important point for many of these women. Now we have pretty good data that show that we should consider GnRH agonists in young patients who have an interest in conceiving. The use of these agents did not negatively impact other endpoints we looked at, such as disease-free survival and OS.CDK 4/6 inhibitors have been a breakthrough therapy for patients with HR-positive metastatic breast cancer. For many years, hormonal therapy was the only option for patients before they needed chemotherapy. Now, we have the good fortune of not only 1 but 3 highly efficacious CDK 4/6 inhibitors, and their toxicities are well managed. We are now starting to look at these agents in different settings, including the adjuvant setting, to see if there is an improvement in outcomes in earlystage breast cancer.

Are there any concerns about the widespread adoption of these agents?

Their efficacies span across all age ranges. There was an analysis of studies that looked at how age played into CDK 4/6 efficacy. In my practice, I don’t use age alone as a reason not to give a patient a CDK 4/6 inhibitor. In general, patients experience a little bit more toxicity. However, the selected toxicities or AEs we know are very much associated with these drugs are not hugely different [from those of other therapies]. Most of these patients do very well on CDK 4/6 inhibitors, despite being older.Among the things that we struggle with, especially when we look at targeted therapies in metastatic breast cancer, is understanding who to give these treatments to. Patients with metastatic HR-positive breast cancer are going to need chemotherapy at some point. We want patients to have good QoL while they are on endocrine therapy; that’s the time they’re supposed to have the fewest AEs from their treatments.

Is OS a viable endpoint in HR-positive breast cancer?

We are constantly balancing that fine line of improvements in efficacy with toxicity concerns, especially as we consider adding a variety of agents to endocrine therapy—such as PI3K inhibitors, CDK 4/6 inhibitors, and mTOR inhibitors. Some of the pan-PI3K inhibitors showed an improvement in progression-free survival (PFS), but at the cost of considerable toxicity.OS has become the “Holy grail” of endpoints. Unfortunately, for patients with HR-positive breast cancer who receive multiple lines of therapy, it’s very difficult to establish OS benefits because you have to take subsequent lines of therapy into account.

PFS is a very important endpoint. One thing we lose sight of are the psychological benefits in patients on CDK 4/6 inhibitors for 10 months or longer than they would have been on hormonal therapy alone. These patients are dealing with the diagnosis of an incurable illness and being able to tell them that their therapy is working for 10 months longer is meaningful.

Pagani O, Regan MM, Fleming GF, et al. Randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor positive (HR+) early breast cancer (BC): update of the combined TEXT and SOFT trials. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Abstract GS4-02.