At the General Motors Cancer Research Foundation 2005 Annual Scientific Conference at NIH last week, keynote speaker Dr. Larry Norton of Memorial Sloan-Kettering Cancer Center framed breast cancer as a puzzle and told participants that "we're beginning to assemble the pieces of that puzzle in molecular terms into a picture that can guide clinicians." Conference sessions illustrated his metaphor.
One puzzle piece has to do with the different ways in which cancer cells operate. Sessions on how BRCA2 suppresses cell growth and how CHK2 mutations impede DNA repair illustrated the contributions of genetics and cell biology.
A second puzzle piece looks at how mammary epithelial cells interact in a particular biological microenvironment. The extracellular matrix can destabilize the genome, cause local tissue changes, and alter gene expression, cell growth and death, and drug resistance.
The third puzzle piece involves tumor behavior. Oncogenes provide only part of the answer, with a number of other regulatory molecules now under study. Tissue-specific cancer stem cells, for example, may drive a central aspect of tumor growth.
Puzzle piece four is cancer at the patient and population levels. While crucial, the genomic mechanisms of breast cancer do not capture the profound influences of the environment, nor do they reflect the experience over the life spans of women facing cancer.
Effective treatments provide the final piece of the puzzle model of clinical oncology. Herceptin (trastuzumab) shows how years of work at the molecular and genetic levels built a successful targeted therapy for a specific population. Gene expression profiling and similar approaches also allow phased treatment strategies to track progress and improve prognosis.
The Food and Drug Administration (FDA) has approved new labeling for gefitinib (Iressa) that will restrict use to lung cancer patients who are currently taking the tablets or who have previously benefited from the treatment in the judgments of their doctors.
New patients with non-small-cell lung cancer (NSCLC) will not receive the drug unless they are participants in clinical trials that were approved by an Institutional Review Board prior to June 17, 2005, the day the FDA and the drug's manufacturer, AstraZeneca PLC, announced the label change.
The FDA's decision was based on a review of data from two trials in which gefitinib did not help lung cancer patients live longer. The agency noted that patients with NSCLC have other treatment options. Even before the announcement, many doctors were prescribing erlotinib (Tarceva) for patients with NSCLC.
Gefitinib was approved for use in NSCLC in May 2003 through the agency's early approval mechanism. The approval was based on the drug's ability to shrink tumors in about 10 percent of patients and was contingent on follow-up studies.
One of the follow-up trials, which included nearly 1,700 patients who had failed one or two previous treatment regimens, found no significant survival benefit in the overall study population. Nor did patients with high levels of epidermal growth factor receptor (EGFR), the protein targeted by gefitinib, benefit significantly.
As of September 15, 2005, patients will receive gefitinib through a single mail-order pharmacy. Approximately 4,000 patients are currently taking gefitinib in the United States. The FDA is not considering withdrawing gefitinib from the market at this time.
High levels of consumption of red and processed meat are associated with an increased risk of colorectal cancer, while high levels of fish consumption are associated with a decreased risk of the disease, according to a new European study published in the June 15 Journal of the National Cancer Institute.
Drs. Elio Riboli and Teresa Norat of the International Agency for Research on Cancer in Lyon, France, and their colleagues used data from the European Prospective Investigation into Cancer and Nutrition (EPIC), a cohort of 478,000 Western Europeans enrolled between 1992 and 1998.
At a mean follow-up of 4.8 years, 1,329 cases of colorectal cancer were diagnosed. Within the EPIC population, the risk of developing colorectal cancer over a 10-year period was 1.71 percent for subjects in the highest category of red and processed meat consumption (more than 160 grams daily) compared with 1.28 percent for those in the lowest category (less than 20 grams daily).
Among subjects in the highest category of fish consumption (more than 80 grams daily), the risk of developing colorectal cancer over a 10-year period was 1.28 percent compared with 1.86 percent among those in the lowest category (less than 20 grams daily). The researchers found no association between poultry consumption and colorectal cancer risk.
Although the findings confirm previous studies, "the results reported here are from one of the largest cohorts of men and women that has been developed specifically to examine the relationship between diet and cancer," the researchers note.
Radiotherapy used to treat childhood cancers may contribute to survivors developing subsequent thyroid cancer, say researchers from NCI's Division of Cancer Epidemiology and Genetics (DCEG) in the June 11 Lancet. Chemotherapy given for the original cancer had no impact on later thyroid cancer risk, nor did it modify the risk found from radiotherapy.
The Childhood Cancer Survivor Study is a cohort of more than 14,000 individuals who were diagnosed with cancer between 1970 and 1986 and survived at least 5 years following diagnosis.
By correlating the dose of cumulative radiation received with the occurrence of secondary thyroid cancer, the researchers found evidence for decline in risk at high doses that earlier studies could not. The risk varies with the radiation that the researchers calculated was absorbed by the patient's thyroid gland at the time of original treatment. From 1 Gy up to 20 Gy, the risk increases, peaking between 20 and 29 Gy. Above 30 Gy and up to 50 Gy the risk decreases, "consistent with a cell-killing effect at high doses," said the authors. The study results do not have implications for clinical treatment decisions with regard to childhood cancers because other serious late effects of radiotherapy and chemotherapy do show increasing risk with increasing doses.
"Childhood cancer survivors with a history of radiation exposure to the chest, neck, or head should be considered at risk for thyroid cancer and these patients should have yearly thyroid and neck examinations," the authors said.
This nested case-control study, led by Dr. Alice J. Sigurdson from the Radiation Epidemiology Branch of DCEG, identified 72 children who were under 21 years of age when they were diagnosed with a childhood cancer, had survived more than 5 years, and later developed thyroid cancer. For each patient, a set of four controls with healthy, intact thyroid glands were matched by gender, approximate age of first cancer diagnosis, and follow-up interval.
In an editorial, Dr. Judith Kingston of the Royal London Hospital said the study clearly showed "that the thyroid gland in younger children is more susceptible to the oncogenic effects of radiation than in older children."
A report in the June 15 Journal of the National Cancer Institute provides the first hints of how to identify brain tumor patients who will respond to the drug erlotinib (Tarceva), originally developed for lung cancer.
In lung cancer, researchers are finding that patients who respond to the drug have a specific molecular signature. The current study examined similar signatures in glioblastomas.
Drs. Daphne A. Haas-Kogan and David Stokoe of the University of California, San Francisco, and colleagues studied tissue samples from 41 participants in a phase I trial of erlotinib for glioblastoma. They wanted to know if levels of the protein biomarker, epidermal growth factor receptor (EGFR), could predict which patients would respond. Erlotinib is a small molecule that targets that specific protein.
Eight of the 41 glioma patients responded to erlotinib treatment. The researchers report that response was predicted by high levels of EGFR and low levels of a related enzyme, PKB/Akt. None of the 22 patients whose tumors had high levels of phosphorylated PKB/Akt responded to erlotinib, whereas 8 of the 18 patients with low levels of phosphorylated PKB/Akt did respond. The researchers plan to use these results in the design of a phase II trial.
"Future trials of EGFR inhibitors should build on our current findings and, with prospective molecular profiling, should establish the most appropriate agent(s) for each individual patient. Clearly, in clinical trials testing signaling inhibitors, selection of patients with appropriate molecular characteristics will not only help to assess the true efficacy of specific novel agents but will also maximize benefits to individual patients," the authors wrote.