Expert Sheds Light on Adjuvant Treatment of HR+ Breast Cancer

Michael Savin, MD

Upwards of 70% of all breast cancers express estrogen receptors (ERs) or progesterone receptors (PRs), categorizing them as receptor-positive cancers. All patients with these hormone receptor (HR)-positive breast cancers can be considered for adjuvant treatment with endocrine therapy, said Michael A. Savin, MD.

There are several classes of drugs that are used in adjuvant endocrine therapy for receptor-positive breast cancer. There are selective ER modulators (SERMs), of which tamoxifen is the primary drug, and aromatase inhibitors, which include anastrozole, letrozole, and exemestane.

These agents work by different mechanisms. SERMs work antagonistically to block ER, and aromatase inhibitors work by blocking the small amount of estrogen produced in the adrenal gland. SERMs can be used in both pre- and postmenopausal women, but aromatase inhibitors can only be used in postmenopausal women.

Use of Tamoxifen

In a presentation at the 2018 OncLive^® State of the Science Summit™ on Breast Cancer, Savin, clinical medical director, Oregon Health and Science University Knight Cancer Institute, shared his insight on adjuvant endocrine therapy for premenopausal women with HR-positive breast cancer.Tamoxifen is the treatment of choice for patients with standard-risk premenopausal breast cancer, Savin said. This agent has been in use since the 1970s and is one of the cheapest options available, costing uninsured patients $15 to $18 per month. It remains a dominant drug in this setting.

The Early Breast Cancer Trialists’ Collaborative Group reported that 5 years of adjuvant tamoxifen versus no additional adjuvant therapy showed that at 10 years, there is a substantial reduction in the recurrence rate, independent of PR status, age, nodal status, or use of chemotherapy.¹ At 15 years, breast cancer mortality was reduced by one-third for women under the age of 45. Additionally, the contralateral breast cancer risk fell by 50% after 15 years.

The ATLAS trial addressed the question of whether there is additional benefit in extending adjuvant tamoxifen beyond 5 years.² Findings from this trial showed a clear benefit of continued tamoxifen beyond 5 years, a significant reduction of breast cancer recurrence after year 7, and significant reduction in breast cancer mortality after year 10.

“Ten years of tamoxifen compared with 5 years has a real impact on remaining disease-free survival (DFS), and staying alive,” Savin said. “Overall survival (OS) clearly improved.”

Savin said that responses in postmenopausal women treated with an aromatase inhibitor have been slightly higher than with tamoxifen. This prompted studies in premenopausal women, in which a functional postmenopausal state had been created. It is possible to treat a premenopausal woman with an aromatase inhibitor if ovarian function is suppressed.

“For women under 50 years of age in whom aromatase inhibitor therapy is contemplated, consider ovarian suppression or oophorectomy, even if [they are deemed] clinically postmenopausal,” Savin said.

The MA.17 trial evaluated tamoxifen for 5 years, followed by letrozole versus placebo for 5 years for disease-free survival (DFS) in women who were premenopausal at diagnosis.³ The true benefit is still a little unclear, Savin said, but it is still being explored.

Investigators are exploring the benefit of making premenopausal women postmenopausal to try to take advantage of these differences in response to treatment. Two of these trials are SOFT and TEXT,⁴ both of which produced nearly identical results, Savin said. Findings showed that tamoxifen alone is less effective in these patients than tamoxifen plus ovarian functional suppression. There was an even more dramatic difference when tamoxifen was switched out for an aromatase inhibitor, noted Savin.

Beyond Tamoxifen

There appears to be additional benefit with aromatase inhibitors with ovarian suppression in premenopausal women who are considered high risk, Savin said. This is based on several factors including the intrinsic aggressiveness of the cancer, the presence of nodal metastases, and tumor size.After 5 years of adjuvant tamoxifen, there are several options. In patients who become postmenopausal and are treated after 50 years of age, the treating physician can switch the patient to an aromatase inhibitor like in the MA.17 trial, or they can continue giving tamoxifen as an option if an aromatase inhibitor is not acceptable or tolerated. Tamoxifen can also be extended to 10 years if a patient remains premenopausal, or discontinuing endocrine therapy after 5 years of tamoxifen if the patient tolerated tamoxifen poorly.

“Even though there is clearly benefit to going beyond 5 years, the difference between them is relatively small,” said Savin. “For the vast majority of women, [tamoxifen] produces very minimal side effects—mild hot ashes, and that’s about it.”

Adjuvant therapy for patients with HR-positive breast cancer commonly includes chemotherapy in addition to endocrine therapy, Savin said. The question then becomes, “Does chemotherapy add an additional benefit to adjuvant endocrine therapy?” The 2 choices are surgery followed by endocrine therapy versus surgery followed by chemotherapy and then endocrine therapy.

“The data are designed to distinguish high-risk from low-risk patients, as it makes more sense for patients with higher risk of recurrence to benefit from chemotherapy,” said Savin.

Defining Breast Tumors

Moreover, updates from the 2018 ASCO Annual Meeting of the phase III TAILORx study showed that adjuvant endocrine therapy alone was found to be noninferior to adjuvant chemendocrine therapy in patients with HR-positive, HER2-negative, node-negative, early breast cancer with an intermediate risk of distance recurrence—suggesting that many women with breast cancer can avoid overtreatment with chemotherapy.High- and low-risk breast cancers have historically been defined by tumor size and grade, nodal status, proliferative rate, and HER2 status, Savin explained. Now, there are molecular profiling tools such as Oncotype DX and MammaPrint, which created multigenerational profiles on the tumor specimen. These tools can help predict whether chemotherapy further reduces recurrence risk compared with endocrine therapy alone.

Oncotype DX is a 21-gene recurrence score assay. There are 5 reference genes and 16 cancer genes that look at different aspects of the cancer that coincide with behavior. Out of this, a numerical score is developed. The scores are divided into low-, intermediate-, and high-risk groups.

“If you look at those with a high-risk recurrence score, there is a dramatic difference with the addition of chemotherapy over endocrine therapy alone,” Savin said. “This is compelling evidence that the use of these scores helps decide who is going to benefit from a chemotherapy element.”

For patients who are premenopausal, childbearing is a serious issue that needs to be discussed, Savin emphasized. This is especially true, considering that women are now more likely to have children in their 30s as opposed to their 20s, he added. Endocrine therapy can decrease the potential for women to have a successful pregnancy, especially when chemotherapy is on the table.

When considering adjuvant endocrine therapy for patients who are premenopausal, Savin advised that fertility consultation is appropriate for women who desire children in the future. However, this should be considered prior to the initiation of chemotherapy. Additionally, there is the consideration of ovarian suppression, which may protect ovarian function prior to, and during, chemotherapy.

References

1. Savin M. Adjuvant Endocrine Therapy - Premenopausal Women. In: Proceedings from the 2018 OncLive^® State of the Science Summit™ on Breast Cancer; May 23, 2018; Portland, Oregon.
2. Davies C, Pan H, Godwin J, et al; Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of estrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381(9869):805-816. doi: 10.1016/S0140-6736(12)61963-1.
3. Goss PE, Ingle JN, Pritchard NJ, et al. A randomized trial (MA.17R) of extending adjuvant letrozole for 5 years after completing an initial 5 years of aromatase inhibitor therapy alone or preceded by tamoxifen in postmenopausal women with early-stage breast cancer. J Clin Oncol. 2016;34 (suppl; abstr LBA1). doi: 10.1200/JCO.2016.34.15_suppl.LBA1.
4. Pagani O, Regan M, Walley B, et al; TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014;371(2):107-118. doi: 10.1056/NEJMoa1404037.