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A new study involving data from more than 20,000 individuals has uncovered several DNA sequences linked to impaired pulmonary function. The research, an analysis that combined the results of several smaller studies, provides insight into the mechanisms involved in reaching full lung capacity. The findings may ultimately lead to better understanding of lung function and diseases like asthma and chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the United States.

“We have known for a while that genetic factors put some people at risk for lower lung function — a factor in COPD and a risk for early mortality. But, we did not know which specific genetic regions were involved,” said Stephanie London, M.D., Dr.P.H., senior investigator at the National Institute of Environmental Health Sciences (NIEHS), part of National Institutes of Health (NIH), and a senior author on the paper. “These findings point to specific gene regions.”

Impaired lung function is a hallmark of COPD and other lung diseases. But it is also linked to mortality from a wide range of other diseases, including cardiovascular disease and cancer. So knowing some of the genes involved is a first step toward understanding the relationship between lung function and mortality, as well as developing new interventions to manage lung diseases.

“Leveraging our investment in collecting these samples has led to new findings and will help focus future research efforts,” said James P. Kiley, Ph.D., director of the Division of Lung Diseases at the National Heart, Lung, and Blood Institute (NHLBI).

To conduct the analysis that is published online in the Dec. 13, 2009 issue of Nature Genetics, the researchers used data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. CHARGE is an ongoing study — a group of groups — that combines genome-wide association study (GWAS) results from several population-based studies. Pooling data from many studies gives much greater power to find the specific genes involved than looking at any one study alone.

The GWAS approach involves measuring hundreds of thousands of genetic variants, in thousands of individuals, in hopes of finding novel genetic variations associated with specific diseases or conditions.

This meta-analysis provided data from more than 20,000 participants. The individual studies included three US-based population studies supported by the NHLBI — the Artherosclerosis Risk in Communities, the Cardiovascular Health Study, and the Framingham Heart Study — and the Rotterdam Study in the Netherlands.

The researchers focused on finding genetic commonalities in DNA that lead to some people having lower lung function than others of the same age, gender, race, size and smoking history.

One way researchers determine airflow obstruction is by using a machine called a spirometer to measure how much air a person breathes in and out, as well as how fast it is blown out, or expired. Spirometry is an important tool used to diagnose asthma, pulmonary fibrosis, cystic fibrosis, COPD, as well as the impact of environmental exposure on lung health. In disease, the ratio between forced expiratory volume (FEV1) and forced vital capacity (FVC) — an indicator of airflow obstruction — is abnormally low.

“This is a beautiful example of how modern genomic approaches can unearth valuable new insights from previous research,” said NIEHS Director Linda Birnbaum, Ph.D. “It sets us on a course for learning much more about how lung diseases develop and how environmental triggers like smoking and air pollution work in combination with genes.”

For more information about lung diseases, visit http://www.nhlbi.nih.gov/health/public/lung/index.htm.

With a growing array of choices for breast cancer treatment, researchers are now trying to pinpoint the best combination of therapies or the best order in which to give cancer drugs to patients.

In some cases, combination therapies will improve survival and sometimes the order in which therapies are given does not matter, said experts presenting new data at a Friday press briefing at the San Antonio Breast Cancer Symposium.

“The most dramatic finding [presented at the briefing] is that continuing Herceptin therapy after tumor progression improves survival,” said moderator Dr. Edith Perez, director of the Breast Cancer Program at the Mayo Clinic in Jacksonville, Fla. “It is the first time this has been shown.”

In that study, Dr. Kimberly Blackwell, director of the Clinical Trials Program in Breast Cancer at Duke University Medical Center, reported that combining the drug lapatinib (Tykerb) with trastuzumab (Herceptin) was better than single-drug therapy in women who have HER2-positive breast cancer that has spread.

Cancers that are HER2-positive test positive for a protein called human epidermal growth factor receptor 2, which fuels cancer cell growth.

Tykerb inhibits HER2 and the receptor, while Herceptin binds to the HER2 protein — a kind of double-punch, the researcher explained.

Blackwell reported on 296 women with breast cancer that had spread. Half got the drug Tykerb, 1,500 milligrams a day; the other half got 1,000 milligrams of Tykerb a day plus the Herceptin at a dose geared to their body weight.

The women’s tumors had already progressed while on a number of other treatments, so they were running out of options.

The findings? “There was significant improvement in overall survival in favor of the combination of lapatinib and trastuzumab compared to the single agent lapatinib,” Blackwell said. There was a 26 percent reduction in the risk of death if both agents were used.

Put in more human terms, that means that “15 more out of 100 women are alive at a year because of combination therapy.”

In another report, Dr. Daniel Rea, senior lecturer in medical oncology at the University of Birmingham in the UK, compared two approaches for postmenopausal women with early stage hormone-sensitive breast cancer. In the trial, 9,775 postmenopausal women with hormone-positive (the most common type) early breast cancer were assigned to get the drug exemestane (Aromasin) at 25 milligrams a day or tamoxifen at 20 milligrams a day. That was in 2001, and in 2004 the researchers assigned all the women who were getting tamoxifen to switch to Aromasin after 2.5 or three years.

Another 2,500 patients were enrolled and assigned to get either Aromasin or tamoxifen followed by Aromasin.

“The outcome is identical,” Rea said. At five years, there was 85 percent disease-free survival in both groups.

“Both of these strategies appear to be reasonable approaches for those with early cancer,” he said.

Perez said the additional option to choose between the drugs may be of special interest to patients because of the cost savings. Aromasin typically costs more than tamoxifen, she said. Tamoxifen is now available as a generic drug.

Blackwell received honorariums from GlaxoSmithKline (which makes Tykerb) and Genentech (which makes Herceptin) to conduct the study; Rea reports research funding from Novartis and Pfizer.

Adding chemotherapy to standard cancer-suppressing tamoxifen can boost survival in postmenopausal women with the most common type of breast cancer, known as estrogen receptor-positive, and it’s best given before the tamoxifen regimen starts, according to a new study.

“Chemotherapy with Adriamycin adds to your survival benefit over and above what tamoxifen would do if you are postmenopausal and have positive lymph nodes and estrogen receptor-positive cancer [the most common type],” explained Dr. Kathy Albain, the lead researcher and professor of medicine at Loyola University Chicago Stritch School of Medicine.

And in another study, Albain found that screening breast tumors with an available multi-gene test spots patients who may not need this form of chemotherapy, despite fitting the standard profile.

Both studies are published online Dec. 10, the first in the journal The Lancet and the second in The Lancet Oncology. Albain is also due to present her findings Thursday at the annual San Antonio Breast Cancer Symposium in San Antonio, Texas.

In estrogen receptor-positive cancer, tumor cells carry many receptors on their surfaces to which estrogen can attach, fueling tumor growth. Tamoxifen works by blocking the receptors.

Experts have long debated whether women with estrogen receptor-positive cancers — whose growth is fueled by circulating estrogen — would get more benefit from having a chemotherapy regimen on top of tamoxifen.

Albain led a research team from multiple centers that followed nearly 1,500 breast cancer patients for up to 13 years, with a median (half longer, half less) of nearly nine years. All were past menopause and had hormone receptor-positive cancer that had spread to at least one lymph node in the armpit area.

Albain’s team assigned 381 women to tamoxifen alone, 587 to chemotherapy alone and 590 to both, with some receiving tamoxifen and chemo together and some in a sequential manner.

Tamoxifen was taken daily for five years. The chemo regimen used is called CAF, for “cyclophosphamide, Adriamycin and 5-fluorouracil.”

In all, after accounting for study dropouts, 1,460 women received treatment.

The combined treatments of chemo plus tamoxifen increased the women’s disease-free survival by 24 percent, Albain found. When her team looked at which delivery protocol worked best — simultaneous tamoxifen and chemotherapy or chemo followed by tamoxifen — the sequential approach was found to be better, giving slightly better disease-free survival.

Ten-year disease-free survival estimates were 57 percent for the combination group and 48 percent for the tamoxifen-only group, the researchers found.

However, women receiving chemo were more likely to have drops in white blood cells, important for fighting infections, the team noted. And they were also more prone to blood clots, congestive heart failure and other complications.

In a second study, Albain’s team analyzed whether a gene test, called Oncotype DX, could predict which women would benefit from chemotherapy. Genomic Health, which makes the test, helped fund the study, along with the U.S. National Cancer Institute.

The test, which Albain said is already widely used, is done on the tumor itself. “This puts 21 genes together and comes up with a score,” she said. The score — low, intermediate, high — predicts the risk of recurrence over 10 years if a woman used tamoxifen alone.

When the researchers performed the test on 367 specimens, they found a low score identified those women who may not need the chemo, despite the fact that they have cancer that spread to lymph nodes.

“This is a positive study, there’s no question,” said Dr. Joanne Mortimer, vice chair of medical oncology for the City of Hope Cancer Center in Duarte, Calif., of the first study. “This study tells us [that] if you have positive lymph nodes [and are postmenopausal with estrogen receptor-positive cancer], you should have both chemo and tamoxifen, because the survival was better.”

But, she added, “when you give everyone [who has the estrogen receptor-positive, node-positive breast cancer] chemotherapy, probably there are some who don’t need it.”

According to Mortimer, that’s why the gene test looks promising — it may spare some women from having to have chemo while ensuring that those who will benefit from the treatment get it.