Focusing Treatment on Multiple Pathways to Reduce Resistance and Improve Outcomes in Triple-Positive Breast Cancer

Breast cancer is responsible for almost 600,000 deaths every year. With approximately 2 million new cases annually, it is the most widespread cancer among women. Breast cancer does occur in men, although much less frequently, comprising 1% of cases.¹

The term triple-positive breast cancer (TPBC) arises from a system classifying breast cancer into 4 subtypes dependent on expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 proliferation index. The diagnosis of TPBC arises when the expression of ER and PR is positive and HER2 expression is enhanced.² One of the challenges when treating TPBC is the interaction between these receptors. The expression of ER, PR, and HER2 increases hormone-dependent tumor proliferation and contributes to survival signaling, resulting in fast-growing, aggressive tumors.²

TPBC arises when the expression of ER and PR is positive and HER2 expression is enhanced | Image credit: © RFBSIP | stock.adobe.com

A recent literature review discusses how these signaling pathways “communicate” and how this impacts current treatment strategies. The findings suggest that combining therapies can improve outcomes in TPBC.²

Existing therapies primarily focus on 1 receptor. This limited scope of treatment allows the interplay between these receptors to synergistically enhance intricate processes within cells, such as DNA repair and cell cycle progression, leading to metastatic tumor phenotypes and invasive characteristics.²

These interactions can lessen the effectiveness of traditional treatments such as selective estrogen receptor modulators (SERMS; ie, tamoxifen) by upregulating an ER co-activator. This underscores the need to develop strategies that precisely target more than 1 pathway and combine treatments successfully. In studies, combining traditional endocrine therapy, SERMs, and aromatase inhibitors with HER2-targeted therapy showed promise in improving median overall survival and decreasing resistance.²

Other avenues explored involve gene therapy. CRISPR/Cas9 gene editing technology lends a targeted approach to modifying genes associated with tumor growth and resistance. The gene modification interferes with processes important for tumor survival, resulting in an augmentation of tumor suppressor functions.²

Individual patient factors are a consideration when developing a precise treatment plan. In addition to hormone receptor status, the patient’s cardiovascular health, autoimmune background, age, and menopausal status will impact treatment choices. This is especially important given the adverse effects of therapies such as SERMs and their effects on bone and cardiovascular tissue.²

Immune checkpoint inhibitors are a rising area of interest in TPBC. Initially investigated in triple-negative breast cancer, they are now showing potential in TPBC. Combining atezolizumab (Tecentriq; Genentech) with HER2-targeted therapies and chemotherapy resulted in improvement in progression-free survival.²

The tumor microenvironment is a small world of its own containing hormonal signals that impact cancer cell growth. Putting the focus on these signals can inhibit tumor growth.²

Additionally, molecular markers monitor changes in expression of ER, PR, and HER2. These changes can give the care team clues regarding treatment response and can even predict resistance, enabling clinicians to alter and adjust treatment plans when necessary.²

As with any disease, effective treatment requires personalization and should involve the patient in decision-making. Ideally, the care team would include clinicians from multiple disciplines and focus on the patient's unique characteristics.²

Using new treatment advances, traditional medications, genetic profiles, immunotherapies, and individualized plans enables providers to improve outcomes for patients with TPBC. Targeting multiple pathways along with precision medicine can improve quality of life and survival, both essential outcomes for all cancer patients.²

REFERENCES

1. Key Statistics for Breast Cancer. American Cancer Society. Updated January 22, 2025. Accessed February 18, 2025. https://www.cancer.org/cancer/types/breast-cancer/about/how-common-is-breast-cancer.html

2. Yang X, Yang D, Qi X, Luo X, Zhang G. Endocrine treatment mechanisms in triple-positive breast cancer: from targeted therapies to advances in precision medicine. Front Oncol. 2025;14. doi:10.3389/fonc.2024.1467033