Study Raises Questions about Melanoma Incidence Rates

A new study by researchers from the Veterans Affairs Outcomes Group concludes that the dramatic increase in melanoma incidence seen over the past two decades is actually a consequence of increased skin biopsies and not a jump in true disease rates. Dr. H. Gilbert Welch and colleagues, relying on data from Medicare and NCI's SEER program, showed that skin biopsy rates for people 65 and older increased 2.5-fold during the 1986 to 2001 study period, while overall incidence rates increased 2.4-fold.

The article in the British Medical Journal (BMJ), published online on August 4, concludes that the extra cases diagnosed were confined to early-stage cancer while mortality remained stable, suggesting overdiagnosis - the increased incidence being largely the result of increased diagnostic scrutiny and not an increase in the true incidence of disease.

Melanoma incidence has increased 6-fold since 1950. As the BMJ paper noted, there has been some debate in the dermatology community about whether this increase is more apparent than real. Dr. Welch and his colleagues acknowledge that while they show an association between the biopsy rate and incidence, the causes of this association are not clear.

Dr. Kathy Cronin of NCI's Division of Cancer Control and Population Sciences, agrees that interpreting data on incidence and mortality trends after the introduction of screening is difficult, but believes that the conclusion that the observed patterns suggest overdiagnosis is not evident from the available data.

"Stable mortality and late-stage incidence rates, along with an increase in early-stage incidence, could be indicative of either overdiagnosis or an increasing background trend," says Dr. Cronin. "Particularly in light of increasing mortality observed before 1986, the stable mortality since 1986 does not necessarily denote overdiagnosis."

Screen for Kinase Mutations Points to Single Pathway

Researchers have identified mutations in eight genes that relay signals from a cell's surface to its interior. The mutations were found mainly in colon tumors, but the set of genes - a "signaling pathway" known as PI(3)K - may also be disrupted in other types of tumors, the researchers report in the August 11 Nature.

Dr. Victor Velculescu of the Johns Hopkins Kimmel Cancer Center was the senior author of this study and two previous ones that collectively suggest the importance of this pathway to cancer. Last year, his team reported in Science that the main gene in the pathway, PIK3CA, is commonly mutated in colorectal cancers and in some other cancers as well. Mutant forms of PIK3CA help tumor cells in the colon proliferate, the researchers reported in a follow-up study this past June in Cancer Cell.

The new study identifies three other genes in the PI(3)K pathway that are either mutated or altered in some colorectal tumors. The researchers found the mutations by screening 340 serine/threonine kinase genes for changes likely to be related to cancer. The family of genes was targeted because it makes enzymes that regulate the growth of cells and other important activities related to cancer. In addition, kinases make good drug targets, as the leukemia drug imatinib has demonstrated.

After identifying mutations in the three genes, the researchers looked at the rest of the pathway. "Overall, we found that almost 40 percent of the tumors we screened had mutations in at least one member of the pathway," says Dr. Will Parsons of Johns Hopkins, the study's first author. The next challenge, he adds, is to identify how these mutations contribute to cancer.

"This study shows that a number of genes in the pathway are important in colon cancer and possibly in other cancers," says Dr. Velculescu. "We hope that this research will lead to targets for intervening against the tumors."

Depression, Fatigue Not Linked to Cancer

"Vital exhaustion" - the energy-draining combination of depression and fatigue - does not increase the risk of cancer, according to a large prospective study from Denmark. Although people who reported the most vital exhaustion exercised less and smoked more than their more energetic peers, they were still not at increased risk for any cancer, according to a study reported in the August 8 online edition of Cancer.

"We deduce that there is neither a direct positive influence of vital exhaustion on cancer risk via an immune mechanism nor an indirect association promoted by unhealthy life style factors," wrote the authors from the Danish Cancer Society in Copenhagen.

The researchers investigated the possibility of a cancer link after discovering that vital exhaustion increased risk for heart attacks and all-cause mortality. With questionnaire results from 8,500 people already in hand through the long-running Copenhagen City Heart Study, the authors linked the results to the Danish Cancer Registry, which records every diagnosis in the country of 5.4 million people. The questionnaires completed from 1991 to 1994 and the cancer data collected in 2002 resulted in a mean follow-up time of 8.6 years.

The authors cautioned that selection bias could have been at play - that is, the most eager study participants tended to be the healthiest. Only 61 percent of the original heart study participants completed the exhaustion questionnaire.

Switching from Tamoxifen to Anastrozole Lowers Breast Cancer Recurrence

For two decades, the estrogen blocker tamoxifen has been the most effective hormone treatment for the first 5 years following surgery for early breast cancer, whether used alone or with other adjuvant chemotherapy. Results from two large prospective European trials reported in the August 6 Lancet, however, showed that women who received 5 years of adjuvant hormone therapy and were switched to analstrozole after 2 years on tamoxifen had a 40 percent decrease in disease recurrence, compared with women who received only tamoxifen for the full 5 years.

The trials were conducted in cancer centers across Germany and Austria, and combined the results from more than 3,200 postmenopausal, node-positive, estrogen-receptor-positive patients. With about 1,600 patients in each arm, after a median follow-up of 28 months, 100 events had occurred in the tamoxifen-only group, compared with just 67 events for those who switched to anastrozole. Events were defined as local or regional recurrence, distant metastasis, or death from any cause.

This finding echoes other recent studies suggesting an enhanced role for the class of drugs called aromatase inhibitors. These drugs have had comparable or superior results in other trials, while avoiding some of tamoxifen's more troublesome risks, such as blood clotting and endometrial cancer. In the Lancet study, however, the anastrozole arm had significantly more bone fractures.

Study lead author Dr. Raymond Jakesz, of the Austrian Breast and Colorectal Cancer Study Group in Vienna, and colleagues concluded that tamoxifen "is no longer the optimum therapy for postmenopausal women with endocrine-responsive early breast cancer."

Nicotine Enzyme Structure Solved

In a step toward shutting down the damage done by nicotine, researchers have decoded the structure of an enzyme key to nicotine metabolism. The results "should aid the design of inhibitors to reduce smoking and tobacco-related cancers," wrote the authors from the Scripps Research Institute in the August 7 online version of Nature Structural & Molecular Biology.

Researchers became interested in the enzyme, known as cytochrome P450 2A6, when they noticed that variations in it correspond to variations in smoking behavior. They then discovered that the enzyme plays a prime role in turning nicotine into its cancer-causing metabolites. Inhibiting the enzyme slows the entire process.

The researchers mapped the entire 3-dimensional structure of the enzyme with a technique called x-ray crystallography. The process outlines every part of a molecule to pinpoint locations where other molecules - in this case nicotine - dock, or bind.

The researchers found a site that binds a drug called methoxsalen, which inhibits the enzyme. When it binds the enzyme, methoxsalen shuts down nicotine metabolism. Future research will focus on designing safer molecules that fit into the same slot, the researchers wrote.