Classification of Gastric Cancer Subtypes May Help Development of Different Treatment Approaches

According to researchers at Duke-NUS Graduate Medical School in Singapore, stomach or gastric cancer is a heterogeneous disease which falls into three broad subtypes with distinct biological properties and effects that respond differently to currently available therapies.

Understanding these research findings may help improve patient care. The researchers expect that the development of a genetic test designed to classify tumors and match them to the therapies that offer the best outcomes, may increase positive treatment outcomes.

The classification of gastric cancers … could guide development of therapies tailored to the molecular subtypes.

Second most common cause of cancer-related death
Based on recent data from the U.S. National Cancer Institute, in 2013, more than 13,000 men and 8,000 women will be diagnosed with stomach cancer in the United States, making it the second most common cause of cancer-related death in the world. Because most patients present with advanced disease, gastric cancer remains difficult to cure in Western countries. Worldwide, only lung cancer is more lethal than stomach cancer. Rates in almost all countries have been dropping for decades, and are much lower in the United States than in Asia. Most patients will be over 70 years old when they are diagnosed.

“One of the features that makes gastric cancer so lethal is that it arises from many genetic alterations, creating differences in how the tumors respond to therapies,” said Steve Rozen, Ph.D., director of the Centre for Computational Biology at Duke-NUS. Rozen is senior author of the study published in the September issue of the journal Gastroenterology.[1] “What our study has shown is that there are actually three distinct molecular classifications that appear to be biologically and therapeutically meaningful.”

Despite differences in the way their tumors respond to treatments, patients often receive a “one-size-fits-all” treatment approach, resulting in a five-year survival rate of about 27% in the United States. “There has been an urgent need for improved classification of gastric cancer that provides insight into the biology of the tumors that might help predict treatment response,” noted co-senior author Patrick Tan, M.D., PhD., professor in the Cancer and Stem Cell Biology Program at Duke-NUS.

Gene expression
Using a technology called microarray-based gene expression profiling, Rozen and colleagues analyzed 248 gastric tumors, then further grouped them according to the genes that were expressed in the tumors. The gene expression analysis broadly sorts the tumors into three subtypes: proliferative, metabolic and mesenchymal. These subtypes also differ in their genomic and epigenomic properties.

Tumors of the proliferative subtype have high levels of genomic instability and a mutation in the TP53 tumor suppressor gene that occurs in many types of cancers. Cancer cells of the metabolic subtype are more sensitive to the chemotherapy agent 5-fluorouracil (5-FU). Cancer cells of the mesenchymal subtype have some features of cancer stem cells, and are particularly sensitive to a class of therapies called PI3K?AKT?mTOR inhibitors.

Treatment Options
“In terms of clinical treatment, there are two promising findings from our research,” Rozen explained. “One is that 5-FU has been particularly effective against metabolic- subtype tumors, and the second is that drugs targeting the PI3K?AKT?mTOR pathway may be particularly effective against mesenchymal-subtype cancers.”

Previous, unrelated studies have shown that mTOR inhibitors such as everolimus (Afinitor?; Novartis), which belongs to the pharmaceutical class of rapalogues, have been investigated in advanced gastric cancer. One of these studies investigates everolimus in combination with chemotherapeutic agents such as leucovorin calcium, fluorouracil, and oxaliplatin. Because these agents work in different ways, the combination may offer a better option to stop the growth of tumor cells, either by directly killing the cells or by stopping them from dividing.[2] Other studies show that rapamycin (Sirolimus, Rapamune), a potent immunosuppressive agent, has shown to enhance the cytotoxic effects of 5-fluorouracil, docetaxel and cisplatin in preclinical models.

“If confirmed in future studies, the classification of gastric cancers reported here could guide development of therapies tailored to the molecular subtypes,” said lead author Zhengdeng Lei, PhD.

For more information:
[1] Lei Z, Tan IB, Das K, Deng N, Zouridis H, Pattison S, Chua C, Feng Z, et al. Identification of Molecular Subtypes of Gastric Cancer With Different Responses to PI3-Kinase Inhibitors and 5-Fluorouracil. Gastroenterology. 2013 Sep;145(3):554-65. doi: 10.1053/j.gastro.2013.05.010. Epub 2013 May 14.[Article][PubMed]
[2] NCT01231399 – Everolimus and Combination Chemotherapy in Treating Patients With Metastatic Stomach or Esophageal Cancer

Illustration: Stomach cancer falls into three broad subtypes that respond differently to currently available therapies. Illustration Courtesy: Duke Medicine.

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