Expert Highlights Incorporation of Neoadjuvant Endocrine Therapy Into ER+ Breast Cancer

Hung T. Khong, MD

Neoadjuvant endocrine therapy is well utilized in Europe but underutilized in the United States, says Hung T. Khong, MD. Many factors are at play, but they can be boiled down to physicians’ familiarity with chemotherapy in the treatment of patients with estrogen receptor (ER)-positive breast cancer.

“Now, we know that many patients may not need chemotherapy, so we’re trying to promote the use of upfront endocrine therapy,” says Khong, a medical oncologist at Moffitt Cancer Center.

The results of numerous clinical trials demonstrate neoadjuvant endocrine therapy’s effectiveness in practice. A phase II study of 239 postmenopausal women with ER-positive and/or progesterone receptor—positive breast cancer were randomized to chemotherapy with doxorubicin and paclitaxel every 3 weeks for 4 cycles, or to 25 mg exemestane daily or 1 mg anastrozole daily for 3 months.

Both the endocrine therapy and chemotherapy arms showed a 64% clinical objective response; however, there was an absolute difference of 9% with breast-conserving surgery in the endocrine versus chemotherapy group at 33% and 24%, respectively (P = .058).

OncLive: What is the benefit of neoadjuvant endocrine therapy?

Are patients hesitant about undergoing neoadjuvant chemotherapy?

Does the optimal duration vary across endocrine therapies?

Can targeted agents enhance the efficacy of neoadjuvant endocrine therapy?

Should patients receive 2 or 5 years of additional adjuvant endocrine therapy?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Breast Cancer, Khong expanded on the benefits of neoadjuvant endocrine therapy and addressed the use of adjuvant endocrine therapy in ER-positive breast cancer.Khong: Neoadjuvant endocrine therapy is usually used to downstage tumors so that surgery can be optimally performed. In patients who [would otherwise] require a mastectomy, downstaging the tumor can enable a lumpectomy, conserving the breast. The use of neoadjuvant endocrine therapy can also convert an unresectable tumor to a resectable tumor. In addition, it can confer long-term survival benefit. The adverse events (AEs) are very minimal compared with those seen in chemotherapy. The benefit is very similar to, and in some cases better than, chemotherapy. It’s important to note that the benefit of neoadjuvant endocrine therapy is not inferior to chemotherapy.Patients want a quick means of treatment, so that they can proceed to surgery sooner rather than later. They don’t like the mental image of having a tumor in their breast. Neoadjuvant endocrine therapy is usually done for 4 to 6 months; I prefer 6 months minimum. A lot of patients don’t understand why they would wait 6 months before proceeding to surgery. They also can’t fathom that such a little pill with so few AEs can benefit them. It’s just a misconception that patients have.For postmenopausal women, we recommend 6 months [of therapy] regardless. We’ll usually use an aromatase inhibitor (AI), which are shown to be superior to tamoxifen for premenopausal women. Therefore, I usually consider chemotherapy for premenopausal women because we don’t have a lot of data aside from patients who enter studies of endocrine therapy, tamoxifen, or another combination.Absolutely. Several ongoing studies are using CDK 4/6 inhibitors that have been shown to be beneficial to patients in the metastatic setting. Right now, we’re trying to use them more in the early-stage setting. There was a study that combined CDK 4/6 inhibitors with AI. We don’t have a lot of data, but the data that we do have show more benefit.The study that compared 2 years with 5 years of additional adjuvant endocrine therapy with the AI anastrozole showed no difference between 2 and 5 years of additional therapy. The problem is that a study like this is usually focused on low-stage disease—patients with stage I and possibly stage II disease.

Are there any updates from the 2017 San Antonio Breast Cancer Symposium you would like to emphasize?

Where should clinical trials focus their attention with regard to ER-positive breast cancer?

Therefore, we cannot rule out the benefit in higher-stage patients with stage III disease, for example. We have to be careful about recommending 2 years of additional therapy to all patients. You need to look at the stage and the number of nodes a patient has. For high-stage disease, I would recommend 5 years instead of 2 years of therapy.A lot of people came away from [that meeting] with the notion that 2 years is the equivalent to 5 years of therapy and consequently recommend 2 years to patients. As I mentioned, that may be the wrong thinking because of the patient population in the study. You should be transparent with your patients about the data presented and make a decision together.In ER-positive disease, a lot of studies focus on targeted therapy. Immunotherapy is generally reserved for a more aggressive disease, such as triple-negative breast cancer or HER2—positive disease. There is a problem with that way of thinking. People believe that the more aggressive diseases are the only diseases that need more aggressive treatments. ER-positive disease is considered less aggressive because it has a lower recurrence rate in the short term. However, it has a high risk of recurrence in the long term and can reach as high as 40% to 50% recurrence in certain early stages. We should think about using immunotherapy in patients with long-term ER-positive disease.

Is overall survival (OS) a viable endpoint in hormone receptor (HR)-positive breast cancer?

Right now, I’m doing a treatment with AI plus immunotherapy in the neoadjuvant setting. ER-positive breast cancer is a slow-growing disease, so people think it doesn’t respond well to immunotherapy. We don’t have data that support that claim. We just need to know what combination to use and how to use it more efficiently.Absolutely. That is something that we want to focus on because it’s the ultimate outcome. Most of the studies that we have seen so far show progression-free survival, but some studies show OS, as well.

Patients with HR-positive breast cancer live for a long time, so you would have to follow patients for a long time to see the benefit. If you follow patients for 5 to 10 years, you might not see the survival benefit.

Semiglazov VF, Semiglazov VV, Dashyan GA, et al. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer. 2007;110(2):244-254.