RxPG News : Gastric Cancer

Genetic mutations identified for type of gastric cancer

Tue, 05 Jun 2007 03:59:37 PST

( from http://www.rxpgnews.com ) Researchers have identified novel genetic mutations that are linked to hereditary diffuse gastric cancer, with these mutations being due to both independent mutational events and common ancestry, according to a study in the June 6 issue of JAMA. This study is being released early to coincide with its presentation at the annual meeting of the American Society of Clinical Oncology.

According to background information in the article, gastric cancer is the second most common cause of cancer death worldwide. There are two major variants of this cancer: an intestinal type and a diffuse type. A decline in the overall incidence of gastric cancer can be attributed primarily to a decrease of the intestinal variant of gastric cancer with the diffuse type remaining stable or possibly even increasing. Hereditary diffuse gastric cancer (HDGC) is caused by mutations in the gene CDH1, and is characterized by an increased risk for diffuse gastric cancer and lobular breast cancer. The identification of CDH1 mutations offers the opportunity of cancer risk-reduction strategies for unaffected at-risk individuals, the authors write.

Pardeep Kaurah, M.Sc., of the BC Cancer Agency, Vancouver, and colleagues conducted a study to assess the frequency of mutations in the CDH1 gene and whether these mutations occurred due to independent mutational events or common ancestry. The study included 38 families diagnosed clinically with HDGC, who were analyzed for CDH1 mutations. Twenty-six families had at least two gastric cancer cases with one case of diffuse gastric cancer in a person younger than 50 years; 12 families had either a single case of diffuse gastric cancer diagnosed in a person younger than 35 years or multiple cases of diffuse gastric cancer diagnosed in persons older than 50 years.

Thirteen mutations (6 novel) were identified in 15 of the 38 families (40 percent detection rate). Two families from this study plus two additional families carrying the novel 2398delC mutation shared a common haplotype (a group of alleles of different genes on a single chromosome that are closely enough linked to be inherited usually as a unit), suggesting a founder effect (a population group with an unusual frequency of a gene due to there having been only a small number of original members, one or more of whom had that gene). All four families originate from the southeast coast of Newfoundland.

Due to concentrations of lobular breast cancer cases, two branches of this family had been diagnosed as having hereditary breast cancer and were tested for BRCA mutations. Within these four families, the cumulative risk by age 75 years in mutation carriers for clinically detected gastric cancer was 40 percent for males and 63 percent for females and the risk for breast cancer in female mutation carriers was 52 percent.

Our results confirm that between 30 percent and 40 percent of families with a positive family history of gastric cancer and more than 50 percent of families with 2 diffuse gastric cancer cases diagnosed prior to age 50 years will carry germline mutations in the CDH1 gene, the researchers write.

This extended family with the 2398delC founder mutation is a useful resource for determining risk-modifying factors in the development of diffuse gastric cancer or lobular breast cancer, such as diet or genetic polymorphisms, and for studying secondary genetic events that lead to cancer formation. The identification of this mutation could permit population-based screening of diffuse gastric cancer within specific regions of Newfoundland. Testing for the founder mutation will be particularly valuable for potential HDGC families from Newfoundland in which there is no known living relative with either diffuse gastric cancer or lobular breast cancer from whom a high-quality peripheral blood DNA sample can be obtained for full CDH1 genetic screening because testing a single mutation can be readily performed on suboptimal DNA from archival tissue samples.

Less than one third gastric cancer patients actually have adequate lymph node assessments

Mon, 25 Sep 2006 18:37:37 PST

( from http://www.rxpgnews.com ) Most patients who undergo gastric cancer staging by lymph node sampling have inadequate assessments that compromise survival, according to a new study. Published in the November 1, 2006 issue of CANCER , a peer-reviewed journal of the American Cancer Society, the study reveals that less than one third of gastric cancer patients had adequate lymph node assessments (ALNA). This had a profound effect on patient survival. Median survival in the region with the highest ALNA rate (53 percent) was 33 months compared to just 17 months in the worst rate (19 percent). A change in the staging system guidelines in 1997 was intended to improve staging of gastric cancers, but made only small improvements in the quality of lymph node assessments.

Appropriate staging of gastric cancer is necessary in order to identify the most appropriate treatments. One of the most important factors in determining the stage of disease is metastasis to the lymph nodes. Lymph node assessment is quite complex, requiring collaboration between the surgeon who resects the lymph nodes and the pathologist who must analyze them. The work of either of these physicians may be impacted by patient characteristics, such as obesity.

Prior to 1997, evidence suggested that the system of staging as put forth by the American Joint Committee on Cancer (AJCC) and Union Internationale Contre le Cancer (UICC) was both improperly and variably used by physicians. To standardize staging methods, new guidelines in 1997 changed the definition of ALNA from distance from primary tumor to the number of lymph nodes with cancer out of at least 15 resected.

With evidence from other cancers showing the importance of staging to prognosis and recent advances in the management of gastric cancers, assessment of the new ALNA staging guidelines is timely. To identify compliance with the guidelines and its impact on survival, Natalie G. Coburn, M.D., M.P.H., an Assistant Professor at Sunnybrook Health Sciences Centre in Toronto and colleagues reviewed data from 10,807 patients with gastric cancers reported in the Surveillance, Epidemiology and End Results (SEER) database.

Compliance with new guidelines remains poor. After 1997 the median number of lymph nodes resected increased from 9 to only 10. Overall, only 29 percent of patients had at least 15 lymph nodes resected, indicating poor compliance by physicians. By SEER region, however, rates varied from 19 to 53 percent. Poor ALNA use in up to 11 percent of patients resulted in the possibility of inappropriately denying them new adjuvant therapy. A few of the factors that predicted use of new ALNA guidelines included the SEER region, Asian ethnicity, advanced disease, type of resection and younger age.

In the SEER region with the highest ALNA rate, median survival was 33 months. In the SEER region with the lowest ALNA rate, median survival fell to 17 months. ALNA improved survival at every stage, with the most significant benefit to patients with early stage disease.

This study, according to the authors, shows that inadequate staging of gastric cancer compromises patient care. "Education for pathologists, surgeons and medical oncologists should improve ALNA," according to Dr. Coburn, "and by proxy, improve the care received by patients with gastric cancer, and their overall survival."

Long term benefits of Imatinib in advanced gastrointestinal stromal tumors (GIST) confirmed

Mon, 05 Jun 2006 16:36:37 PST

( from http://www.rxpgnews.com ) People with advanced gastrointestinal stromal tumors (GIST) who take Imatinib for prolonged periods continue to benefit from the drug, according to a five-year study by Oregon Health & Science University Cancer Institute researchers.

It represents the long-term analysis of a randomized clinical trial begun in 2000. More than half of study participants saw their GIST go into remission on Gleevec. Those promising early results prompted the U.S. Food and Drug Administration to approve Gleevec as a treatment for GIST on Feb. 1, 2002.

The long-term analysis, completed in 2005, continues to demonstrate promising results. Eighty-four percent of the 147 GIST study participants on Gleevec showed clinical improvement during the study period, meaning that their disease stabilized or went into remission. Two of those experienced complete remission. However, some subjects developed resistance to the drug and some experienced a relapse of their cancer.

It typically took 13 weeks before a study participant responded to the drug, and the typical positive response lasted 118 weeks (2.3 years).

"This study shows that the response to Gleevec among GIST patients is durable," Blanke said. "Molecularly targeted therapy helps extend their lives."

The long-term study of GIST is especially significant because GIST is a cancer that has been considered untreatable and incurable, with life expectancy of about a year. People in the Gleevec study survived a median of 4.8 years.

Gleevec is a signal transduction inhibitor that interferes with the enzymes that trigger the spread of tumor cells. It acts on GIST by blocking the growth signal of genetic mutations called c-kit and PDGFRA. Subjects with either of these mutations were more likely to respond to Gleevec than those without the mutations.

Most of the persons in the study for whom Gleevec did not work developed resistance to the drug. Among those who developed resistance, the median time to do so was 84 weeks (1.6 years).

Gleevec was initially developed at the OHSU Cancer Institute by Brian Druker, M.D., in collaboration with scientists at Novartis, as a treatment for patients with chronic myelogenous leukemia. In addition to GIST, it is also being studied as a potential therapy for certain types of blood and skin cancers.

New discoveries to tackle stomach cancer

Fri, 03 Mar 2006 12:54:37 PST

( from http://www.rxpgnews.com ) A research team has come up with a molecular map and other discoveries to help develop better treatment for stomach cancer, which is common in Asians, researchers said Friday.

"The inroads can give doctors the means to fight the disease more effectively," said Professor Soo Khee Chee, director of the National Cancer Centre (NCC).

The team led by the NCC included experts from the University of Hong Kong, University of Tokyo and Australia's Peter MacCullum Cancer Centre. They examined more than 300 tissue samples from cancerous tumours and analysed 20 million interactions among different genes.

They uncovered key molecular changes that cause the cells to divide uncontrollably and change into intestinal tissue, often a precursor to cancer.

"We get insights not into individual genes but their networks as a whole system, the switches, which are turned on irrevocably, leading to the cancer," Patrick Tan, principal investigator at the NCC told The Strait Times.

Stomach cancer is one of the deadliest forms of cancer that kills six out of ten patients. According to doctors, early diagnosis is critical and by the time most sufferers show symptoms such as pain, weight loss and vomiting, it is too late.

Stomach cancer formation can be supressed by by lowering Stat3 hyperactivity

Mon, 25 Jul 2005 17:29:38 PST

( from http://www.rxpgnews.com ) It started several years ago with the observation that a large group of seemingly unconnected genes were behaving differently in patients with stomach cancer. Now a multi-national research team led by the Melbourne Branch of the Ludwig Institute for Cancer Research (LICR) has joined the proverbial dots and identified a potential new target for stomach cancer therapy, according to a paper published today in the prestigious Nature Medicine journal.

The paper's first author, LICR's Dr. Brendan Jenkins, says that this single study has made several substantial contributions to the understanding of Stat3, the protein linking those 'genes behaving badly' and central to development, tissue equilibrium and the immune system. "We showed that, in mice, hyperactive Stat3 shuts down a vital controller of stomach cell growth, called TGF beta, and this allows cancer formation, and this mechanistic link is a world-first. Also, the gene differences identified in human stomach cancers are similar to those we would predict if the same thing, Stat3 hyperactivity shutting down TGF, happens in humans. So this is also the first time a connection between stomach cancer and this signaling pathway has been made."

Team leader Dr. Matthias Ernst, also from LICR, says that these basic research findings may one day impact directly on the treatment of stomach and other cancers. "We've demonstrated that by lowering Stat3 hyperactivity we can suppress stomach cancer formation, importantly without affecting Stat3's other important roles in the body. Add to that the evidence suggesting that Stat3 is also involved in breast, head and neck, and prostate cancers, and we have a compelling case for investigating the development of therapies that target Stat3."