Genetic approach provides new insight into trastuzumab resistance in breast cancer

Oct 15, 2007

A new study provides important insight into the mechanisms involved in resistance to treatment of breast cancer patients with trastuzumab (Herceptin). The research, published by Cell Press in the October issue of the journal Cancer Cell, identifies markers that may help to identify patients who are unlikely to respond to trastuzumab treatment and provides a potential strategy for treating these patients.

Trastuzumab is an antibody used as a therapy for patients whose breast cancers produce excess amounts of the protein HER2. However, almost half of these breast cancer patients are nonresponsive to trastuzumab therapy or become resistant during treatment. To better understand the antitumor activity of trastuzumab, Dr. Rene Bernards from The Netherlands Cancer Institute and his colleagues used a large-scale genome-wide RNA interference screen to search for genes involved in trastuzumab resistance in breast cancer.

The researchers identified only the tumor suppressor PTEN as a modulator of trastuzumab sensitivity in a breast cancer cell line. Earlier findings had associated PTEN with resistance to trastuzumab-based therapy, and loss of PTEN is known to result in hyperactivation of the PI3K pathway. Abnormal activation of this cell survival signaling pathway has been identified in many primary breast cancers. Hyperactivation of the PI3K pathway also can be caused by activating mutations of the PIK3CA gene.

“This finding, along with the high frequency of PIK3CA activating mutations in breast cancer, led us to investigate whether PI3K pathway activity, as assessed by cancer-associated activating mutations (of PIK3CA) or altered levels of PTEN, was able to predict trastuzumab resistance in the clinic,” explains Dr. Bernards. This combined analysis identified twice as many patients at increased risk for disease progression as would analyzing PTEN alone and proved to be statistically significant as a biomarker for prognosis after trastuzumab therapy, indicating that assessment of PTEN expression together with PIK3CA mutation is required for optimal prediction of disease progression after trastuzumab therapy for breast cancer.

“Importantly, this study also illustrates the power of in vitro RNAi screens combined with confirmation on patient samples to identify biomarkers useful for predicting treatment response in the clinic,” says Dr. Bernards. “It is too early to use these biomarkers; further validation studies are required before they can be used in the clinic. Nevertheless, it is likely that these findings will lead to a better understanding of resistance mechanisms and how to circumvent them as well as more reliable identification of the most effective treatment for individual patients.”

Source: Cell Press

Explore further: New tool to probe cancer's molecular make-up

add to favorites email to friend print save as pdf

Related Stories

China Telecom profit rises as mobile data grows

21 minutes ago

China Telecom Ltd., one of the country's three main state-owned carriers, said Wednesday its profit rose 11.8 percent in the first half of the year as its Internet and mobile data businesses grew.

Biotech firm's GM mosquitoes to fight dengue in Brazil

1 hour ago

It's a dry winter day in southeast Brazil, but a steamy tropical summer reigns inside the labs at Oxitec, where workers are making an unusual product: genetically modified mosquitoes to fight dengue fever.

Snapchat valued at $10 bln

1 hour ago

US media on Tuesday reported that Snapchat was valued at $10 billion based on funding pumped into the startup by a powerhouse Silicon Valley venture capital firm.

Japan lab unable to replicate 'stem cell' findings

1 hour ago

Researchers in Japan have been unable to replicate experiments that were hailed earlier this year as a "game-changer" in the quest to grow transplant tissue, amid claims evidence was faked, a report said ...

Recommended for you

Better classification to improve treatments for breast cancer

5 hours ago

Breast cancer can be classified into ten different subtypes, and scientists have developed a tool to identify which is which. The research, published in the journal Genome Biology, could improve treatments and targeting of tre ...

Risk of diabetes up in hodgkin's lymphoma survivors

7 hours ago

(HealthDay)—Para-aortic radiation correlates with increased diabetes mellitus (DM) risk for Hodgkin's lymphoma (HL) survivors, according to a study published online Aug. 25 in the Journal of Clinical On ...

User comments : 0