Secondhand Smoke Linked to Decreased Lung Cancer Survival

Lung cancer patients who had been exposed to high levels of secondhand smoke over many years did not live as long on average as patients who had been exposed to lower levels, researchers reported last week at the AACR annual meeting. The study, led by Dr. David Christiani of Harvard Medical School, might be the first to show a strong association between exposures to secondhand smoke and survival in patients with lung cancer.

The study included 393 patients diagnosed with early-stage, non-small-cell lung cancers (NSCLCs) at Massachusetts General Hospital and followed them for 5 years. At diagnosis, patients provided information on their exposures to secondhand smoke in the home, at work, and at places of leisure, such as restaurants. For the analysis, patients were divided into quartiles based on their average exposure levels.

The highest quartile had more than 48 years of exposure; those in the lowest had on average less than 28 years of exposure. Patients with the least exposure had the highest survival rates, and the overall 5-year survival rate decreased with increasing exposure: 71 percent of patients with the lowest exposure were alive after 5 years, while just 47 percent of those with the highest exposure survived 5 years.

The association between secondhand smoke and survival in lung cancer patients was strong even after taking into account age, gender, stage of cancer, and the patients' cigarette smoking habits over their respective lifetimes (of the group, 37 percent were current smokers, and 8 percent were never smokers). The most important factor appeared to be workplace exposure, perhaps because of the amount of time people spend at work and/or the higher levels of secondhand smoke they might be exposed to there.

"The take-home message is that people should try their best to limit their exposure to secondhand smoke," said Dr. Wei Zhou of the Harvard School of Public Health, who presented the results.

Study Points to Potential Method for Overcoming Trastuzumab Resistance

The inability of some women with HER2-positive breast cancer to clinically respond to treatment with trastuzumab (Herceptin) may be overcome by combining the drug with an agent that inhibits PI3K, an intracellular growth-promoting protein. Researchers from the University of Texas M.D. Anderson Cancer Center, led by Dr. Dihua Yu, a professor in the Department of Surgical Oncology, reported lasted week at the AACR annual meeting that they tested seven different PI3K inhibitors and found that two of them, when combined with trastuzumab, increased its antitumor activity in a breast cancer mouse model.

The study builds on previously published work by Dr. Yu and colleagues, in which women who failed to respond to trastuzumab had tumors with low levels of PTEN, a known tumor-suppressor gene.

Because PTEN exerts its tumor-suppressor function in part by inhibiting PI3K, the group decided to test some PI3K inhibitors in clinical development to see if they could mimic the effect that PTEN would have if it were being expressed at adequate levels. Two of these agents showed antitumor activity when combined with trastuzumab, triciribine, and RAD001 (everolimus). The latter combination, Dr. Yu said, had an additive therapeutic effect on tumor growth in a mouse model of breast cancer compared with trastuzumab alone.

"We think the combination of Herceptin and a PI3K inhibitor is affecting multiple cancer pathways," Dr. Yu said. "It will be interesting to see if other PI3K inhibiting agents now being developed also will work in HER2-positive, PTEN-negative tumors, as well as in other breast tumors that lack PTEN."

M.D. Anderson is launching a phase I/II trial to test the combination of RAD001 and trastuzumab in women with HER2-positive breast cancer who have failed to respond to trastuzumab alone as a first-line therapy.

Nicotine May Interfere with Lung Cancer Chemotherapy

A new study from investigators at the H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, published online April 6 in the Proceedings of the National Academy of Sciences has shown that nicotine has the potential to interfere with the activity of several chemotherapy drugs commonly used to treat NSCLC. This research highlights the importance of smoking cessation for lung cancer patients, but also raises the possibility that nicotine replacement products that help patients quit smoking - such as nicotine patches - may also interfere with cancer treatment.

When the investigators treated NSCLC cell lines with gemcitabine, cisplatin, or paclitaxel in the presence of nicotine, the apoptotic (cell-killing) effects of all three chemotherapy drugs were suppressed. Molecular analysis revealed that this suppression was mediated by increased levels of the proteins survivin and x-linked inhibitor of apoptosis (XIAP). These two antiapoptotic proteins interact with specific subunits of the nicotinic acetylcholine receptors, which are found on the surface of lung cancer cells. When both survivin and XIAP were targeted with small interfering RNAs, the antiapoptotic effect of nicotine was reversed and the cells were again sensitive to the chemotherapy drugs.

In light of these results, the investigators stress the need to take the effects of nicotine into account in the development of new treatments for lung cancer.

Study Suggests Significant Social Value of Cancer Mortality Reduction

The social value of a 1-percent reduction in U.S. cancer mortality would be approximately $500 billion, according to a new study by economists from the University of Chicago.

Speaking last week at the AACR annual meeting, study co-author Dr. Kevin Murphy, who was recently named a MacArthur Fellow, argued that the study results suggest that, even if it had only a one-in-five chance of reducing mortality, it would be "worthwhile" to spend an additional $100 billion on cancer research.

To conduct the study, the authors developed a complex framework that placed a value on health improvements, such as new life-extending treatments for heart disease or cancer. This framework was based, he explained, on assessments of Americans' willingness to pay for improvements in longevity. The researchers then used the framework to estimate the value of individual financial gains seen as a result of advances in public health over the past three decades and to place a social value on future gains.

They found, for example, that the gains in life expectancy seen during the last three decades of the 20th century added nearly $3.2 trillion annually in national wealth. And while a permanent 1-percent mortality reduction would have a social value of approximately $500 billion, a cure for cancer would be worth approximately $50 trillion, they concluded.

The study did not directly account for the value of improved quality of life, Dr. Murphy noted, or factors such as increased productivity.

The danger, he stressed, is that gains in longevity and health brought about by a substantial increase in cancer research (and other areas of biomedical research) could be offset by costs associated with delivering the interventions generated by this research.

"Cost containment," Dr. Murphy concluded, "is an essential component of arguing for increased research funding."

Genes May Play Role in Lung Cancers of Never Smokers

Genetic factors may help explain why some people who have never smoked develop lung cancer, researchers reported last week at the AACR annual meeting. Their evidence comes from a comparison showing that first-degree relatives (parents, siblings, and children) of lung cancer patients who never smoked were 25 percent more likely to develop any type of cancer than the relatives of a comparison group of healthy individuals. The cancers diagnosed in the relatives include colorectal, melanoma, head and neck, lung, prostate, and breast.

In one of the largest such studies to date, Dr. Margaret Spitz of the University of Texas M.D. Anderson Cancer Center and her colleagues determined the incidence of cancer in 2,465 first-degree relatives of 316 lung cancer patients who never smoked. For comparison, they determined the incidence rate of cancer in 2,442 first-degree relatives of 318 healthy individuals.

The relatives of lung cancer patients had more than a sixfold increased risk of developing lung cancer than relatives in the comparison group. The cancer group also had a 44-percent excess risk of developing cancer before age 50 than the comparison group; relatives in the cancer group were on average 10 years younger at the time of diagnosis than relatives in the comparison group who developed cancer.

"We suspect that genetic susceptibility plays a role in lung cancer in patients who have never smoked," said Dr. Olga Gorlova of M.D. Anderson, who presented the findings. "Our next step is to prove that there is a genetic component in this risk." Among the genes she plans to study are those involved in repairing damage to DNA.