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Emerging therapies & novel combinations:clipping the wings of HER2-positive metastatic breast cancer

Breast cancer is the most devastating type of tumor in females. Globally, the breast cancer burden accounts for 6.9% of cancer-related fatalities and 11.7% of newly diagnosed cancer cases each year. Breast cancer is a heterogeneous disease entity with multiple subtypes. The most common and widely recognized classification of breast cancer is from an immunohistochemical perception, based on the expression of the hormone receptors namely estrogen (ER), progesterone (PR), and human epidermal growth factor-2 (HER2). The following four subtypes of breast cancer are widely accepted:

  • Luminal A

  • Luminal B

  • HER2-positive

  • Triple-negative

These subtypes differ in etiology, risk factor profile, preferred organ site for metastases, therapeutic responses, and prognosis [1].

What is HER2-positive breast cancer?

Breast Cancer

Breast cancer that tests positive for the HER2 protein is known as HER2-positive breast cancer. The development of cancer cells is encouraged by this protein. Reduced apoptosis and increased cell proliferation, motility, adhesion, invasiveness, angiogenesis, metastasis, and epithelial cell survival distinguish HER2-positive cancer subtypes from other breast cancer subtypes. Genetic HER2 mutations are present in 20–30% of cases of invasive breast tumors. HER2-positive breast cancer typically grows more rapidly and is linked to a higher risk of developing systemic and brain metastases [1,2].

Current therapies for HER2-positive breast cancer

Patients with HER2-positive metastatic breast cancer have a bad prognosis with survival rates of 3–5 years only. Several treatment approaches are preferred which include:

First-line treatment options:

  • Trastuzumab, pertuzumab, and chemotherapy

  • HER2 blockade and endocrine therapy

Second-line treatment options

  • T-DM1 (antibody-drug conjugate)

Beyond first- and second-line treatment options:

  • Oral tyrosine kinase inhibitors: Tucatinib, Neratinib, Pyrotinib

  • DS-8201a (antibody-drug conjugate)

  • Margetuximab (anti-HER2 monoclonal antibody)

  • Combination of Lapatinib with Capecitabine or Trastuzumab [2].

Why new therapies are needed for HER2-positive breast cancer?

A major advancement in the treatment of highly aggressive HER2-positive breast cancer was made possible by the long-sought discovery of HER2, a tyrosine kinase protein that is a member of the epidermal growth factor receptor family. This discovery led to the approval of the first HER2-targeted drug, the monoclonal antibody trastuzumab, almost 25 years ago. Since then, the development of newer platforms and more focused treatments has been vigorously pursued.

HER2-positive breast cancer is a highly immunogenic and aggressive subtype with poor clinical results and high recurrence rates, due to its resistance to treatment. Innovative drugs that can stop tumor development and increase overall survival rates in patients with HER2-positive metastatic breast cancer are required to dramatically progress the treatment options [1,2].

Emerging therapies and novel combinations for HER2-positive breast cancer