Long-term risk for fatal and distant metastatic disease in women with ER-positive breast cancer

Breast cancer is a major cause of mortality among women worldwide, with estrogen receptor (ER)-positive disease breast cancer being the most common type of breast cancer.

A unique feature of ER-positive breast cancer is the continuous long-term risk of distant metastatic spread and fatal disease. The mechanisms influencing long-term risk however remain largely unknown but have been suggested to involve dormant tumor cells whose growth becomes awakened by undetermined microenvironmental stimuli.

Adjuvant endocrine therapy aims to minimize the risk of metastatic disease. However, the lack of clinical trials with long-term outcome has resulted in the current clinical challenge to predict long-term risk of distant metastatic disease and endocrine therapy benefit. Therefore, in this thesis we investigated long-term risk and benefit of endocrine therapy in ER-positive breast cancer patients.

In Study I, we aimed to determine whether the clinically used markers influence long-term survival and tamoxifen therapy benefit in postmenopausal women at lower clinical risk i.e., with ER-positive/HER2-negative and lymph-node negative disease. Our findings suggested a significant difference in long-term survival by tumor size and tumor grade. Additionally, within this subgroup, we observed a significant benefit from tamoxifen therapy in patients with larger tumor size, smaller tumor grade, and PR-positive tumors.

In Study II, we aimed to determine the long-term endocrine therapy benefit in premenopausal breast cancer patients. Our findings suggest a long-term benefit comparing treated patients with untreated from all endocrine therapy used i.e., tamoxifen, goserelin, and the combination of goserelin and tamoxifen. Upon stratification by genomic risk in the tumors using gene expression analysis, our findings suggest a long-term benefit for patients with genomic low-risk from tamoxifen, whereas for patients with genomic high-risk an early benefit was seen from goserelin.

In study III, we included both premenopausal and postmenopausal patients of high and low clinical risk and aimed to determine the long-term benefit from tamoxifen therapy by the clinically used tumor characteristics. Consistent with our findings from study I, our results suggested a long-term tamoxifen therapy benefit for patients with less aggressive tumor characteristics, except for tumor size, including lymph node-negative, PR-positive and Ki-67-low tumors.

In Study IV, we aimed to determine the long-term benefit from tamoxifen therapy by luminal molecular subtype in patients with ER-positive/HER2-negative breast cancer. Majority of ERpositive breast cancers are classified into either luminal A or luminal B subtype based on gene expression analysis. Our findings suggest a long-term tamoxifen therapy benefit for patients with luminal A subtype and a short-term benefit for patients with luminal B subtype. Furthermore, our findings suggest that tumor size and menopausal status influence benefit; with a benefit for luminal A patients with larger tumor size and postmenopausal status, whereas for luminal B patients a smaller tumor size and premenopausal status was associated with benefit.

This thesis together with other studies provides novel insights into long-term risk and benefit from endocrine therapy for ER-positive breast cancer patients. The heterogenous nature of ERpositive disease and long-term risk, makes it important to further understand risk and benefit within subgroups. Importantly, our studies suggest a differential endocrine treatment benefit by tumor characteristics; some patients experience early benefit, others long-term benefit and some patients have limited or no benefit from the treatment. An improved understanding of long-term risk and endocrine therapy benefit in ER-positive patients is essential for the understanding of true treatment benefit and to enable personalized treatment to patients.

List of scientific papers

I. Dar H, Johansson A, Nordenskjold A, Iftimi A, Yau C, Perez-Tenorio G, Benz C, Nordenskjold B, Stal O, Esserman L, Fornander T, and Lindstrom LS. Assessment of 25-year Survival of Women With Estrogen Receptor-Positive/ERBB2-Negative Breast Cancer Treated With and Without Tamoxifen Therapy. A Secondary Analysis of Data From the Stockholm Tamoxifen Randomized Clinical Trial. JAMA Network Open. 2021;4(6).
https://doi.org/10.1001/jamanetworkopen.2021.14904

II. Johansson A*, Dar H*, van 't Veer L, Perez-Tenorio G, Nordenskjold A, Johansson U, Hartman J, Skoog L, Yau C, Benz C, Esserman L, Stal O, Nordenskjold B, Fornander T, and Lindstrom LS. 20-Year Benefit from Adjuvant Goserelin and Tamoxifen in Premenopausal Breast Cancer Patients in a Controlled Randomized Trial. Journal of Clinical Oncology. 2022 Jul 21;JCO2102844. *Equal contributions.
https://doi.org/10.1200/JCO.21.02844

III. Dar H, Nordenskjold A, Perez-Tenorio G, Yau C, Benz C, Esserman L, Hartman J, Rodriguez-Wallberg KA, Nordenskjold B, Stal 0, Fornander T, Johansson A, and Lindstrom LS. Two Years of Adjuvant Tamoxifen Therapy Provides a Long-Term Benefit In Breast Cancer Patients With Less Aggressive Tumor Characteristics: 20-Year Follow-up of the Stockholm Tamoxifen Randomized Trials. [Manuscript]

IV. Dar H, Danielsson 0, Nordenskjold A, Perez-Tenorio G, Yau C, Benz C, van 't Veer LJ, Esserman L, Nordenskjold B, Fornander T, Stal 0, Tobin N, Johansson A, and Lindstrom LS. Tamoxifen Therapy Benefit in Breast Cancer Patients with Luminal A and Luminal B Subtype: Long-Term Follow-up of the Patients Enrolled in Stockholm Tamoxifen Randomized Trials. [Manuscript]