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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

Several novel compounds are being tested for the treatment of advanced HER2-positive disease, including

  • New antibody-drug conjugate

  • Immune checkpoint inhibitors

  • CDK4/6 inhibitors

  • Alpha-specific PI3K inhibitors.

New antibody-drug conjugate

Trastuzumab duocarmazine (SYD985, HER2-targeting antibody-drug conjugate) exhibited manageable toxicity and encouraging antitumor activity in phase I (Identifier: NCT04602117), phase II (Identifier: NCT01042379), and phase III (Identifier: NCT03262935) trials. Additionally, another phase I (Identifier: NCT03284723) trial for PF-06804103, an anti-HER2 monoclonal antibody showed manageable toxicity and encouraging antitumor efficacy in metastatic HER2-positive breast cancer who had received extensive pretreatment [2].

Immune Checkpoint Inhibitors

HER2-positive breast cancers typically exhibit frequent expression of programmed cell death protein ligand 1 (PD-L1) and high levels of tumor-infiltrating lymphocytes. Immune checkpoint inhibitors and HER2-targeted therapies like pembrolizumab plus trastuzumab and T-DM1 in combination with atezolizumab are supported by preclinical research. The combination was safe, and the data suggested a tendency towards increased progression-free survival and objective response seen in patients with PDL1-positive disease. The patients who tested negative for PD-L1 had no objective responses. Many clinical trials are currently examining the combination of HER2-targeted drugs plus immune checkpoint inhibitors in a more specialized subgroup of patients in light of these results [2].

CDK4/6 Inhibitors

In preclinical research, it was determined that HER2 signaling is related to the regulation of cyclin D1-CDK complexes. The three CDK4/6 inhibitors are quickly shifting the treatment paradigm for patients with HER2-positive advanced breast cancer, which includes:

  • Palbociclib

  • Ribociclib

  • Abemaciclib

Although overall survival data are still in their infancy, they have shown a considerable improvement in progression-free survival when utilized for first or later-line therapy. The three CDK4/6 inhibitors all seem to have comparable efficacy; but, due to their varying safety profiles, some patients may benefit more from the usage of one over the others. Further studies are necessary to check the function of CDK4/6 inhibitors in HER2-positive breast cancer [2,3].

Alpha-Specific PI3K Inhibitors

About 30% of all HER2-positive and HR-positive tumors include PIK3CA somatic mutations, which are common in HER2-positive disease. Alpelisib (an alpha-specific inhibitor) and T-DM1 were combined in a phase I clinical trial for HER2-positive metastatic breast cancer after taxane-trastuzumab, and the results revealed that the combination was well tolerated and active, with an objective response rate of 43%. These findings justify further research into the function of PI3K inhibition in refractory HER2-positive metastatic cancer.

There are numerous current trials combining anti-HER2 treatment with PI3K pathway inhibition, including:

o Phase I trial IPATHER (Identifier: NCT04253561) with ipatasertib

o Phase I trial B-PRECISE-01 (Identifier: NCT03767335) with the PI3K inhibitor MEN1611

o Phase III trial EPIK-B2 (Identifier: NCT04208178) with alpelisib as maintenance therapy[2].

Many therapeutic options for patients with advanced HER2-positive breast cancer have been made possible by successful clinical research conducted over the years. Overall survival and quality of life are likely to improve due to the advances in drugs and the combination of therapies. Making major strides in the treatment of metastatic HER2-positive breast cancer will require the development of new technologies for selecting the best treatments and the research to determine the best therapeutic algorithm.


1. Alasmari, M.M. 'A Review of Margetuximab-Based Therapies in Patients with HER2-Positive Metastatic Breast Cancer'. Cancers (Basel). (2022) 15(1), 38. DOI: 10.3390/cancers15010038.

2. Martínez-Sáez, O. et al. 'Current and Future Management of HER2-Positive Metastatic Breast Cancer'. JCO Oncology Practice. (2021) 17(10), 594–604. DOI: 10.1200/OP.21.00172.

3. Shah, M. et al. 'CDK4/6 Inhibitors: Game Changers in the Management of Hormone Receptor-Positive Advanced Breast Cancer?'. Oncology (Williston Park). (2018) 32(5), 216–222.



IIT Guwahati
University of Manchester
Rhenix Lifesciences
American university of Sharjah
IIT Delhi
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