Role of Anti HER2 Targeted Therapy in HER2 Positive Breast Cancer

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Once the diagnosis of breast cancer has been established through various investigations, next step is staging the breast cancer and planning an appropriate treatment strategy. Her-2 Neu positivity play an important role in deciding the treatment for breast cancer.

What is HER2+ Breast Cancer

Breast cancer is the most common cancer in women worldwide and is responsible for most cancer-related death in women. Normally, breast cancer cells have specialized proteins on/in their surface, called receptors. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are most common receptors detected on breast cancer cells, which can promote the growth of these cells.

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Conversely, the drugs that inhibit these receptors are utilized to retard the growth of these cancer cells. The HER2+ BC cells have HER2 expressed on/in their cell membrane. The HER2+ BC subtype accounts for about 15% to 20% of all BC cases. The expression of the HER2 receptor on BC cells confers a high growth rate and higher tendency to spread to distant body parts.

Trastuzumab, a humanized monoclonal antibody, was the first targeted agent approved for the treatment of early-stage and advanced-stage HER2+ BC. Since its approval trastuzumab has revolutionized the treatment of HER2+ BC that is not considered as a deadly disease now.

Treatment for HER2+ Breast Cancer

The treatment of HER2+ BC depends on many factors including the overall stage assigned to the disease, hormonal receptor status, and the patient’s overall health & personal preferences.

Based on the results obtained from various clinical research studies carried out so far, the following are preferred treatment approaches for HER2+ BC according to the extent of disease spread:

Disease type Preferred Treatment
Limited Disease HER2+ BC limited to a specific site is generally treated with surgery (breast-conserving surgery or mastectomy with or without lymph node dissection) followed by radiation therapy as the first-line treatment.

Depending on the risk of recurrence, a combination of targeted therapy and chemotherapy (taxane-based therapy– docetaxel and paclitaxel) is generally recommended before or after surgery. The preferred targeted therapy usually includes a combination of trastuzumab and pertuzumab.

Advanced/ Metastatic disease HER2+ BC that has spread to nearby lymph nodes or to distant body parts is generally treated with targeted therapy with chemotherapy as the first-line treatment. The preferred chemotherapeutic agents include taxanes (docetaxel and paclitaxel). The preferred targeted therapy usually includes a combination of trastuzumab and pertuzumab.

Further, surgery and/or radiation therapy may be employed for the palliation of symptoms like pain, skin ulceration, bleeding, and obstruction of blood vessels.

 

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For patients with early-stage HER2+ BC, pre-operative (neoadjuvant) systemic therapy with a combination of taxane-based chemotherapy and targeted therapy (either trastuzumab alone or trastuzumab + pertuzumab) may be considered for patients who are most likely to derive benefit.

This will allow the patient to conserve more breast tissue and will also allow sufficient time for genetic testing and for planning breast reconstruction surgery.

For patients with early-stage HER2+ BC who have received surgical treatment should be considered for post-surgical (adjuvant) systemic treatment based on the overall risk of disease relapse.

For this purpose, a combination of taxane-based chemotherapy and targeted therapy (either trastuzumab alone or trastuzumab + pertuzumab) is considered the standard of care. The optimum duration of trastuzumab treatment (along with paclitaxel) is 1 year.

For patients with advanced-stage or metastatic HER2+ BC, a combination of taxane-based chemotherapy and targeted therapy (trastuzumab + pertuzumab) is considered the standard of care.

Treatment with an antibody-drug conjugate, T-DM1 (ado-trastuzumab emtansine), may also be considered in some patients who are not the suitable candidate for the preferred treatment. Patients with previously untreated HER2+ advanced/metastatic BC who achieve a status of no evidence of disease with initial HER2-targeted systemic therapy generally have a very good prognosis.

Patients with HER2+ and hormone receptor-positive BC should be treated with hormonal therapy first followed by HER2+ targeted therapy.

Patients who have progressed on initial trastuzumab-based treatment regimen may be treated with further treatment with chemotherapy + trastuzumab + pertuzumab (if pertuzumab was not included in initial treatment regimen), trastuzumab + lapatinib (a small-molecule intracellular tyrosine kinase inhibitor [TKI]), capecitabine + lapatinib, or TDM1-based regimen.

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Selection of second-line therapy usually based on the agents used in first-line therapy and treatment free interval between the two lines of therapies. Results from various ongoing clinical trials are awaited, which will provide further guidance on the appropriate selection of second-line treatment.

The only limitation of targeted therapy appears to be the development of resistance over time. Various mechanisms of resistance development have been proposed, for example, activation of the following 3 downstream pathways– mammalian target of rapamycin (mTOR) signal transduction pathway, phosphoinositide 3-kinase (PI3K) pathway, and cyclin-dependent kinase 4 and 6 (CDK4/6) pathway.

These pathways are now being targeted to combat the development of resistance to targeted therapy. A combination of paclitaxel, trastuzumab, and a mTOR inhibitor (everolimus) has been reported to be efficacious for the treatment of HER2+ locally advanced or metastatic BC that had recurred or progressed on first-line trastuzumab-based therapy in a Phase III clinical research study. Various combination of mTOR inhibitors (everolimus and sirolimus); PI3K inhibitors (taselisib and alpelisib); and CDK4/6 inhibitors (palbocicliba and abemaciclib) with different targeted agents are under investigation.

Following are various novel molecules that are being tested in different clinical trials for the treatment of advanced/metastatic HER2+BC: margetuximab (a new anti-HER antibody); MCLA-128, ZW25, and GBR1302 (new bispecific antibodies); SYD-0985 and DS-8201a (new antibody-drug conjugates); neratinib, afatinib, poziotinib, pyrotinib, and tucatinib (pan HER TKIs); entinostat (a histone deacetylase [HDAC] inhibitor); and MP0274 (a designed ankyrin repeat protein [DARPin]). Also, some clinical trials are exploring the benefit of HER2-targeted agents for the treatment of HER2- or low HER2-expressing BC.

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