The following studies were presented at the meeting held earlier this month in San Diego, CA.

• Data from prior epidemiologic and laboratory studies have suggested that alcohol consumption increases the risk of breast cancer, but the precise mechanisms have not been clarified.  Two new studies presented at the AACR meeting have provided new information on patient characteristics, the most common type of breast cancer associated with alcohol ingestion, and an association between breast cancer risk and two genes involved in alcohol metabolism (ADH1B and ADH1C).  The first study focused on whether or not the hormone receptor status of the tumor influenced the relationship between alcohol consumption and breast cancer risk.  Researchers analyzed data from 184,418 postmenopausal women followed for an average of seven years.  Those who had less than 1 drink a day had a 7% increased risk of breast cancer compared to those who did not drink at all.  Those who drank 1-2 drinks per day had a 32% increased risk, and women who had 3 or more drinks daily had up to a 51% increased risk.  Overall, 5,461 cases of invasive breast cancer were identified and tumor type information was available on 2,391 cases.  Seventy percent (1,641 cases) of the tumors were ER+/PR+ type.  Researchers found that ER+/PR+ cancers showed the strongest association with alcohol.  They feel that alcohol affects estrogen metabolism, which increases the risk of hormone-sensitive breast cancer.  The risk was similar regardless of the type of alcohol that women drank.

The second study found that the 2 alcohol metabolizing genes were associated with a two-fold increase in breast cancer risk.  These results need to be replicated by other studies.

• Researchers at Brooke Army Medical Center in San Antonio presented data from a trial evaluating an experimental vaccine designed to trigger an immune response against HER2-positive breast cancer.  The vaccine was given to 163 women whose breast cancer expressed HER2 in both low and high levels.  At 30 months follow-up the vaccine was shown to decrease the risk of death for all patients by 50%, and in those patients with low-expressing HER2-positive tumors, no deaths were reported.  Cancer recurred in 10.7% of vaccinated low-expressors compared with 18.2% of the control group.  Due to the small size of the study, the survival results were not statistically significant.  The group has planned a phase III trial of the vaccine in more than 700 patients with low HER2 expression only, a group for which immune-targeting therapy is currently unavailable. 
  
  
• Investigators from M. D. Anderson Cancer Center presented results of a study providing the first systemic evidence that easily accessible tissue, the oral epithelium, can be used to monitor molecular events in less accessible tissue such as the lung.

Examining the oral epithelium after a simple brushing of the buccal mucosa allows one to gauge cancer-inducing molecular alterations in the lungs that could spare patients and those at risk of lung cancer from more invasive, uncomfortable procedures such as bronchoscopy and lung biopsy.

The team looked at two genes known to help prevent the development of cancer – p16 and FHIT.  There is significant damage to the 2 genes long before cancer develops.  They looked for specific damage to these genes in both lung samples and mouth samples from 125 long-time smokers.  The p16 gene was “shut down” by methylation in the lungs of 23% of volunteers, while FHIT was affected in 17%.  In the mouth tissue samples, p16 was silenced in 19% of the smokers and FHIT in 15% of them.  In 95% of those whose genes were affected, they were affected in both the mouth and the lung.  The researchers hope it will be possible to someday swab the mouth of smokers to predict who has the higher probability of developing lung cancer.

Gene Variants Linked to Lung Cancer Identified

Three separate teams of scientists have pinpointed an area on chromosome 15 that has 3 nicotine receptor genes that appear to increase the risk for lung cancer.  This finding offers yet more evidence that lung cancer is tied to genetics and not just smoking.  Whether these gene variants represent a direct risk for lung cancer and increased susceptibility to smoking is not clear, according to 2 studies (1 from Iceland and 1 from France) published in the April 3 edition of Nature and 1 (from M. D. Anderson Cancer Center in Houston) published in the April 2 online edition of Nature Genetics.

The gene variants have an impact on one’s affinity for smoking so that people are more likely to become dependent (“get hooked”) on tobacco and find it very hard to quit smoking.  They also influence the quantity of smoking so that people smoke even more cigarettes, which increases their risk of developing lung cancer and peripheral arterial disease.

These gene variants are associated with an increased risk of lung cancer as well.  Although the association between nicotine addiction, increased smoking, and lung cancer seem to be a likely explanation here, this may not be the case.  One group of investigators in France found that, in 11,000 people (4,500 with lung cancer) studied, how much someone smoked or the number of years that they had been smoking had no effect on the risk of lung cancer.  The gene variants were found among people who had never smoked and the Iceland group found the gene variants in about 40% of the population.  The various investigators who studied nearly 35,000 people, found no association between a gene variant and other tobacco-related diseases.  They conclude that these gene variants appear to be specific for lung cancer but not other diseases strongly associated with tobacco use.

It is striking how similar the results are with respect to lung cancer risk in these 3 studies from three separate research groups.  They all found that smokers who inherited 1 variant (from 1 parent) have a 30% increased risk for lung cancer and those smokers who have 2 variants (1 from each parent) have a 70-80% increased risk for lung cancer.  They believe that there is an independent risk factor for lung cancer in this chromosome region.  It should be noted that smokers who do not have the gene variants are still more than 10 times more likely to develop lung cancer than non-smokers.

US Food and Drug Administration (FDA) Actions:

On March 20, 2008 the FDA approved Cephalon, Inc.’s bendamustine hydrochloride (Treanda^®), an intravenously administered alkylating agent, for the first-line treatment of patients with chronic lymphocytic leukemia (CLL).  The approval was based on the results of a safety and efficacy trial of bendamustine compared to chlorambucil as first-line treatment in 301 patients with Binet stage B or C (Rai stages I-IV) CLL requiring treatment.  Need-to-treat criteria included hematopoietic insufficiency, B-symptoms, rapidly progressive disease, or risk of complications from bulky lymphadenopathy.  Overall response rate was 59% for bendamustine vs 26% for chlorambucil (p<0.0001) with 8% vs <1% CR favoring bendamustine.  The median PFS was 18 months vs 6 months favoring bendamustine (HR 0.27, p<0.0001).  Survival data are not yet mature.  Toxicity: Bendamustine had a higher incidence of adverse reactions (89% vs 79%) with the most common being Npenia, fever, Tpenia, anemia, leucopenia, N+V.  Npenic fever more common with bendamustine and RBC transfusions in 20% of bendamustine patients (6% chlorambucil patients).  The number of deaths was similar in both treatment arms.

Jim Jones, MD