Journal of the National Cancer Institute Advance Access originally published online on December 11, 2007
JNCI Journal of the National Cancer Institute 2007 99(24):1830-1832; doi:10.1093/jnci/djm284
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© Oxford University Press 2007.
NEWS |
Lung Cancer May Be Different for Men and Women, But Researchers Ponder What To Do?
Researchers have known for many years that lung cancer manifests itself differently in men and women. Several studies have determined that women with the same level of disease live longer than men, and many underlying biological differences have been posited to explain this difference.
Now several new studies indicate that estrogen is a key player. In light of the evidence, a National Cancer Institute–funded clinical trial is under way that will prospectively look at the role of estrogen levels and carcinogen metabolism in the outcomes of lung cancer patients. Also, the U.S. Food and Drug Administration recently approved the first lung cancer clinical trial specifically designed to test whether women with higher estrogen levels metabolize an experimental chemotherapy agent differently than women with lower estrogen levels. It could represent a first step toward personalized therapeutic regimens for women with lung cancer.
Since the early 1980s, the number of women developing lung cancer has rapidly increased. Lung cancer now represents the leading cause of cancer deaths among women in the United States, surpassing all other types of the disease. In 2006, lung cancer killed 72,000 women, and almost 82,000 new cases were diagnosed. The numbers are in lock step with the reported rise in smoking among U.S. women and are mirrored in statistics for other pulmonary diseases such as chronic obstructive pulmonary disease.
The trials now under way are the result of evidence of an association between estrogen level and outcomes in lung cancer patients. The first results came from an analysis of 1,334 patients enrolled in advanced-stage non–small-cell lung cancer clinical trials through the Southwest Oncology Group (SWOG), a national clinical research cooperative. Principal investigator Kathy Albain, M.D., of Loyola University Chicago's Cardinal Bernardin Cancer Center, reported that women older than 60 years have a statistically significant survival advantage over men and younger women. The researchers arrived at the age 60 cutoff by conducting a statistical analysis exploring differences in outcomes by age; they found no differences in patient and disease characteristics by sex. Albain hypothesized that lower estrogen level best accounts for the survival advantage in older women.
Subsequent analysis using a similar dataset from Eastern Cooperative Oncology Group presented in September at the World Congress on Lung Cancer in Seoul, South Korea, confirms Albain's data by also demonstrating that women older than 60 years have a survival benefit. Older women survived a mean of 11.6 months, versus 7.4 months for older men, 9 months for younger women, and 8.3 months for younger men. The results come from a study of 1,590 patients presented by Heather Wakelee, M.D., a medical oncologist at Stanford Cancer Center in Palo Alto, Calif. Other known prognostic factors did not account for the difference.
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Albain's group didn't have serum samples on all of the patients to directly test estrogen levels. So as a follow-up, the research team examined the control arm of two phase III trials testing the efficacy of an experimental chemotherapy drug, paclitaxel poliglumex, on advanced lung cancer patients. Control patients in these studies had given serum samples and been treated with the standard therapy. The results, presented at the 2007 American Society of Clinical Oncology meeting and not yet published, showed that estrogen level is associated with patient outcome. Patients older than 60 years with low estrogen levels (<30 pg/mL, the standard cutoff for being considered postmenopausal) lived longer than women older than 60 years with higher estrogen levels. Younger women with low estrogen also lived longer than those with high estrogen. Also, some of the men in the study showed higher than expected estrogen levels, and those men didn't do as well either.
However, research on estrogen is likely to benefit both sexes, Wakelee said. "We do know that estrogen receptors are present on lung cancer cells in men and women. So even though the estrogen levels are generally higher in women—and that's why we're seeing this effect with the younger women doing poorly—blocking the estrogen pathway is probably going to be, in the end, helpful for both men and women."
Indeed, new research published in the Nov. 1 issue of Cancer Research suggests that lung cancer cells that produce their own estrogen may be linked to a poorer prognosis. Lee Goodglick, Ph.D., Richard Pietras, M.D., and their colleagues at the Jonsson Comprehensive Cancer Center at University of California, Los Angeles, examined the level of aromatase—a key enzyme that converts the estrogen precursors androgen and testosterone to active estrogen in patient tissue samples—and correlated those levels with patient outcome. (The group had already established that lung cancer cells produce active aromatase.) In 422 patients treated at UCLA, 79% of women older than 65 years with both low aromatase levels and stage I or II disease survived 5 years after surgery versus 49% in women with high aromatase levels at the same stage. The researchers saw no association between aromatase level and survival in patients with more advanced disease.
"The prediction, based on these early data, would be that in women over 65, aromatase inhibitors, which are used now primarily in breast cancer, would have a good effect on these women with higher aromatase levels," Goodglick said.
Indeed, a clinical trial is under way examining whether aromatases, in combination with chemotherapy, will have an added benefit to lung cancer patients. Pietras is collaborating with Jill Siegfried, Ph.D., codirector of the lung and esophageal cancer program at the University of Pittsburgh Cancer Institute, in a randomized clinical trial that will combine erlotinib with the aromatase inhibitor fulvestrant. The study will enroll about 120 patients at UCLA with non–small-cell lung cancer who have recurrent or progressive disease after two or more prior chemotherapy regimens. Siegfried said that her laboratory will look for many biomarkers, including aromatase level, presence of estrogen receptors, and other genetic markers of disease, such as epidermal growth factor receptor (the target of erlotinib) and K-ras.
"It's going to be tricky to figure all this out," Siegfried said. "Should [patients] have their chemotherapy and then be maintained on [aromatase inhibitors] as a chemoprevention to prevent recurrence, or should it be part of the initial chemotherapy to boost chemo response? We really don't know. This is untested waters."
Early Estrogen Influence
Estrogen may have a role in initiation of lung cancer as well. Some research has indicated that estrogen may interact with the carcinogenic components of tobacco smoke to influence cancer risk, but the results have been inconsistent. To examine this idea more fully, Albain is leading an NCI-funded SWOG prospective trial that will monitor cancer progression and survival for up to 5 years. The group is recruiting 720 stage I, II, and III lung cancer patients from NCI-funded oncology groups, including men and women, smokers and nonsmokers. The study includes a detailed questionnaire on exposures and lifestyle, as well as a serum and tissue bank. The research team will look at how estrogen and other biological markers work in metabolizing the components of cigarette smoke and will then correlate those markers with outcomes. The smoker's arm of the trial is already full, but because there are many fewer cases among nonsmokers, Albain expects that recruiting for that arm will not be complete for some time.
"We're looking at a broad scope of metabolizing enzymes so we can explore the lung cancer phenomenon among nonsmoking women in particular," Albain said. Also, "we'll be able, in this group, to look at the whole estrogen level and survival story in the earlier stage disease than in the stage IV patients."
What Now?
Understanding biological differences such as those between lung cancers in men and women may help physicians understand epidemiologic trends, but so far that information has not been convincing enough to change clinical practice.
Female lung cancer patients who have higher estrogen levels seem to be at a particular disadvantage. But findings from another analysis of the SWOG-run trials may change that. In those stage III trials, the company CTI was testing its chemotherapy drug paclitaxel poliglumex, a form of the standard chemotherapy drug paclitaxel linked to a protein carrier. The drug was designed to activate preferentially in actively dividing cancer cells, thus sparing normal tissue. In the trials, the drug showed no apparent advantage over standard chemotherapy drugs—until the investigators analyzed the outcome data for younger women. When they combined the data for the 198 women in the two trials, they discovered that paclitaxel poliglumex treatment was associated with longer survival in younger women, according to James Bianco, M.D., a hematologist–oncologist and CEO of CTI. A subsequent analysis by Siegfried and her colleague Pamela Hershberger, Ph.D., demonstrated that in lung cancer cells grown in the lab, estrogen increased expression of cathepsin B, an enzyme that helps activate paclitaxel poliglumex, releasing the active chemotherapy agent. This finding provided a possible explanation for why younger women with higher estrogen levels may benefit from the drug. This result led the FDA to approve in September a special protocol assessment, a modification to an approved clinical trial that allows a sponsor to alter an agreed upon study design to address a scientific issue that becomes apparent after the trial begins. That approval will allow CTI to run a phase III confirmatory trial that recruits only advanced lung cancer patients who are premenopausal or who are taking estrogen replacement therapy. This trial, called PGT307, will study paclitaxel poliglumex with carboplatin versus paclitaxel with carboplatin. The company is recruiting 450 patients from 70 centers throughout the United States, with additional accrual in Europe, according to Bianco.
"This will be the first such trial [in any disease] to ever look at exploiting a pharmacogenetic difference between the sexes and take a negative risk factor and make it a positive," Bianco said.
"The preliminary data I have seen on [paclitaxel poliglumex] is pretty interesting and suggestive," said John Minna, M.D., director of the Hamon Center for Therapeutic Oncology Research at University of Texas Southwestern Medical Center.
But with so much still to learn about estrogen's role in lung cancer, until the data are in, the jury is still out.
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