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The clinical progress of targeted therapy of metastatic breast cancer

Popularity 7Viewed 1845 times 2015-1-27 06:21 |Personal category:science digests|System category:Life| targeted therapy, breast cancer, FDA

Recently ‘breast cancer’ has arisen as a hot topic around. The popular singer Yao Beina, and the famous actress Chen Xiaoxu, who played the role of Daiyu in the famous drama ‘the Dream of the Red Mansion’, are both victims of the terrible disease. Cancer actually is a leading cause of death worldwide, and according to WHO, there are 521,000 deaths caused by breast cancer in the year 2012. Breast cancer is among the notorious top 5 killers, besides there are lung cancer, liver cancer, gastric cancer, and colorectal cancer.

 

About 20-25% of human breast cancers are distinguished by amplification of the human epidermal growth factor recerptor-2 (HER2) gene, and are associated with more aggressive tumor growth and worse clinical outcome in patients.

 

In September 1998, the United States Food and Drug Administration (FDA) approved trastuzumab as the first targeted therapy for HER-2 positive metastatic breast cancer (MBC), and it has since improved the overall prognosis for patients with HER2-positive MBC. Trastuzumab is a recombinant humanized monoclonal antibody that selectively targets the extra-cellular domain of the HER2 receptor. The mechanisms through which trastuzumab is believed to kill tumor cells include inhibition of constitutive HER2 signaling and disruption of HER2/HER3 interactions in HER2-overexpressing cells, resulting in inhibition of cellular proliferation, leading to antibody-dependent cell mediated cytotoxicity.

 

Although trastuzumab has had a major impact in the treatment of patients withHER2-positive MBC, a subset of patients do not respond to treatment, and most patients who are initially responsive to treatment ultimately experience disease progression. A wave of further research thus has been set off to develop alternative and additional approaches to target HER2. These included the development of small molecule kinase inhibitors and other monoclonal antibodies that bind to different sites on HER2 than trastuzumab. Despite the advances in HER2 targeted therapy, the tumor in these patients will eventually progress, underscoring the need for them.

 

In the meantime, since the introduction of classic cytotoxic agents, clinical outcomes have been significantly improved for most cancers. However, off-target collateral damage of healthy tissues is a well-recognized side effect of cytotoxics. The concept of antibody-drug conjugates thus evolved as a means either to improve the tumor selectivity of cytotoxic drugs or to confer higher potency to monoclonal antibodies that display preferential binding to tumor cells but lack sufficient cytotoxicity. In February 2013, ado-trastuzumab emtansine (T-DM1) received regulatory approval from FDA for treatment of refractory HER2-positive MBC. T-DM1 is an antibody-drug conjugate composed of trastuzumab connected to emtansine which is shown to have anti-tumor activities. The available clinical data demonstrate its improved efficacy and safety compared with traditional chemotherapy. Although this therapy is highly promising, de novo and acquired resistance to T-DM1 occurs. Understanding the mechanism of resistance is crucial to circumventing it, and there’s still an unknown long way to go.


Therefore, it’s essential for people to prevent the tumor rather than to treat it. Healthy lifestyle should be encouraged and followed. As the saying goes, early to bed, early to rise, makes a man healthy, wealthy and wise.

 

References:

1. Peddi et al, Therapeutic Advances in Medical Oncology, 2014.

2. Lambert et al, Journal of Medicinal Chemistry, 2014.

3. Jeyakumar et al, Clinical Medicine Insights: Oncology, 2012.

(Opinions of the writer in this blog don't represent those of China Daily.)


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