In the first ecological study of its kind in the world, a Wake Forest University Baptist Medical Center researcher has uncovered the unique finding that groundwater and airborne manganese in North Carolina correlates with cancer mortality at the county level.

The study, titled, “Environmental Manganese and Cancer Mortality Rates by County in North Carolina: An Ecological Study,” was published online last month by Biological Trace Element Research. Lead researcher John Spangler, M.D., professor of family and community medicine at Wake Forest Baptist, found that groundwater manganese appears to be positively associated with total cancer, colon cancer and lung cancer death rates, while airborne manganese concentrations appear to be inversely associated with total cancer, breast cancer and lung cancer death rates.

“People need manganese in trace amounts, but if you get too much of it, manganese can be dangerous,” Spangler said. “It’s my hope that the impact of this study will be to spark additional interest and research. This really just raises the concern that something may be going on and argues for further research into these issues.”

To determine whether environmental manganese is related to cancer at the county level in North Carolina, Spangler conducted an ecological study using data from the North Carolina State Center for Health Statistics, North Carolina Geological Survey, U.S. Geological Survey, and U.S. Census.

He found that airborne manganese was associated at the county level with an 14 percent decrease in total cancer deaths, a 43 percent decrease in breast cancer deaths and a 22 percent decrease in lung cancer deaths. Additionally, Spangler found there was up to a 28 percent increase in county-level colon cancer deaths and a 26 percent increase in lung cancer deaths at the county level related to elevation of manganese in groundwater as opposed to air.

“That’s pretty astounding. These are the first data we know of to document a potential relationship between environmental manganese and population-level cancer death rates,” Spangler said. “The positive association between groundwater manganese and specific cancer mortality rates might be a function of the high concentrations measures, while the inverse relationship between air manganese and death rates might point toward adequate (e.g. healthy) county-level manganese exposures.”

Spangler points out that because manganese now replaces lead in gasoline globally, the amount of manganese in the environment is increasing and may worsen the groundwater concentration numbers in the future. The effects of these ecological findings should be confirmed at the individual level or in animal models, he said.

Source:
Bonnie Davis

Wake Forest University Baptist Medical Center

LITTLE FALLS, N.J., July 14 — Findings from a cohort study suggest that hormone therapy increases a woman’s risk of ovarian cancer, regardless of the duration of use, dose, formulation, or route of administration, researchers said.

Current hormone users had a 38% increased risk of ovarian cancer compared with never-users, Lina Steinrud Mørch, MSc, of the Gynecological Clinic, of Rigshospitalet at Copenhagen University, and colleagues reported in the July 15 issue of the Journal of the American Medical Association.

They said the findings suggest that risk of ovarian cancer “is one of several factors to take into account when assessing the risks and benefits of hormone use,” the researchers said.

• Explain that in this observational study, hormone therapy was associated with current users’ risk of ovarian cancer despite factors such as duration of use and route of administration.
• Note that the study found an increased risk of ovarian cancer even with a short duration of use, which contrasts with some prior studies.
• Explain that because this is an observational study, the findings cannot establish causality.

Hormone therapy has been previously associated with an increased risk of ovarian cancer. However, specific data on risk and duration, formulation, and routes of administration have not been well understood.

Using data from the Danish Sex Hormone Register Study (DAHORS), the researchers identified all Danish women ages 50 through 79 who used hormone therapy for the decade 1995 through 2005.

They linked those data with prescription data from the National Register of Medicinal Product Statistics. The National Cancer Register and Pathology Register provided ovarian cancer incidence data.

Over an average of eight years of follow-up, the researchers found 3,068 incident ovarian cancers, 2,681 of which were epithelial tumors.

Compared with women who never used hormone therapy, current users had an increased risk of all ovarian cancers (RR 1.38, 95% CI 1.26 to 1.51) and epithelial ovarian cancer (RR 1.44, 95% CI 1.30 to 1.58).

Previous users had a 15% increased risk of cancer compared with those who’d never used hormone therapy (95% CI 1.01 to 1.30).

The researchers found that risk declined with the number of years since last use:

• 0 to 2 years, 1.22 (95% CI 1.02 to 1.46)
• More than 2 to 4 years, 0.98 (95% CI 0.75 to 1.28)
• More than 4 to 6 years, 0.72 (95% CI 0.50 to 1.05)
• More than 6 years, 0.63 (95% CI 0.41 to 0.96)

For current users, the risk of ovarian cancer did not differ significantly with duration of use. However, they said that the finding of an increased risk of ovarian cancer even with a short duration of use “contrasts with some prior studies that were not able to detect increased risk with hormone therapy of less than five years.”

Nor did risk differ according to different hormone therapies. There was an increased risk for both estrogen (1.31, 95% CI 1.11 to 1.54) and estrogen-progestin therapies (1.50, 95% CI 1.34 to 1.68), with no significant difference between the two.

There was no significant difference in risk for method of administration either. Compared with never-users, transdermal administration carried increased risk of ovarian cancer (RR 1.13, 95% CI 0.74 to 1.71) as did oral therapy (RR 1.34, 95% CI 1.12 to 1.60) and vaginal administration (RR 1.23, 95% CI 1.00 to 1.52).

The researchers also found that both cyclic and continuous therapy increased risk of ovarian cancer (RR 1.50, 95% CI 1.31 to 1.72 and RR 2.05, 95% CI 1.44 to 2.93, respectively).

The incidence rates in current and never-users of hormones were 0.52 and 0.40 per 1,000 years, respectively, an absolute risk increase of 0.12 per 1,000 years — approximately one extra ovarian cancer for about 8,300 women taking hormone therapy each year.

Wyeth Pharmaceuticals, maker of a conjugated estrogen (Premarin) and a conjugated estrogens and medroxyprogesterone product (Prempro), contacted reporters before the study came off embargo, in order to make the case that estradiol dominates the European market for hormone replacement therapy.

Corrado Altomare, MD, senior director of global medical affairs for Wyeth, who was not involved in the study, told MedPage Today that estradiol was not a conjugated estrogen, as are the dominant forms of hormone replacement therapy in the U.S., including Wyeth’s products.

“Estradiols here in the U.S. are known as bioidenticals, so there may be some implied safety,” Dr. Altomare said. “But [this study shows] the reality is you have the same risks that you have with any other estrogens.”

“If I were counseling patients and they asked if there was a safer form of estrogen,” he added, “I’d have to say, honestly, no.”

But Dr. Altomare is not an unbiased observer. Wyeth suffered significant losses when the use of hormone therapy dropped dramatically when findings from the Women’s Health Initiative revealed that hormone therapy increased the risk of cardiovascular disease, stroke, and breast cancer. Wyeth supplied the hormones for use in the WHI. (See Hormone Therapy Linked to Stroke Regardless of Timing)

Mørch said that she and her colleagues “would expect the same results if the estrogen component had been conjugated estrogen.”

The researchers noted that their study was limited in that they could not control for age at menopause, and there was a lack of information on hormone exposure prior to study entry.

The study was supported by a grant from the Danish Cancer Society.

Mørch reported no conflicts of interest, but a co-author reported receiving grants from Schering AG, Schering Denmark, and Novo Nordisk. Dr. Altomare is an employee of Wyeth.

Primary source: Journal of the American Medical Association

Source reference:
Mørch LS, et al “Hormone therapy and ovarian cancer” JAMA 2009; 302(3): 298-305.

Related Article(s):

• Hormone Therapy Linked to Stroke Regardless of Timing

TORONTO, July 14 — In what one expert called a “fantastic breakthrough,” researchers have described a network of genetic changes involved in the development and progression of glioblastoma.

Analysis of glioblastoma in several patient populations yielded persistent patterns of genetic alteration involving so-called “territories” on 10 chromosomes, according to Markus Bredel, MD, PhD, of Northwestern University Feinberg School of Medicine in Chicago and colleagues.

“Landscape” genes associated with the persistently altered territories were linked with overall survival and a scoring model using seven of them was able to predict the length of survival after diagnosis, the researchers reported in the July 15 issue of the Journal of the American Medical Association.

Glioblastoma is uniformly fatal and attempts to intervene with therapies targeting single genes — such as the epidermal growth factor receptor (EGFR) gene — have not been successful.

• Explain that glioblastoma is a uniformly fatal brain tumor, in which many genetic changes are usually seen.
• Note that this study found that a network of gene changes plays a role in the way glioblastoma develops and progresses.

In a set of 189 glioblastoma samples, the researchers found that alterations in so-called “dosage” of the genes — dubbed POLD2, CYCS, MYC, AKR1C3, YME1L1, ANXA7, and PDCD4 — were significantly linked (at P=0.02) to duration of overall survival.

Gene dosage, Dr. Bredel and colleagues said, reflects the average number of copies of a gene in tumor tissue. Lower or higher dosages would alter the expression of the gene, compared with the wild-type.

The model assigned 119 of the 189 tumors to a high-risk group, in which at least five genes had altered dosages. Another 39 were assigned to a low-risk group, with no more than two altered. The remaining 31 were regarded as moderate risk.

The researchers found a significant difference in overall survival for the three groups, with a hazard ratio of 1.63 comparing the high-risk with the low-risk group and a hazard ratio of 1.87 comparing moderate-risk with low-risk patients. The hazard ratios were significant at P=0.02 and P=0.01, respectively.

A similar pattern was seen in several other sets of tumor samples, the researchers said.

The complexity of the model “helps explain the lack of therapeutic efficacy of strategies targeting single gene products,” they said.

The study “implies that if we can attack the most important ‘landscape’ genes, then we should have a more guided approach to destroying the cancer,” said Antonio Chiocca, MD, PhD, of The Ohio State University Medical Center in Columbus.

“The military analogy is to go after the command and control leadership centers of the opposing army instead of trying to target every single soldier and military installation,” said Dr. Chiocca, who was not involved in the research.

“This is a fantastic breakthrough,” he said.

Indeed, “the potential clinical implications of these findings are significant,” said Boris Pasche, MD, PhD, of the University of Alabama at Birmingham and Richard Myers, PhD, of the HudsonAlpha Institute for Biotechnology in Huntsville, Ala.

Writing in an accompanying editorial, they said the results “highlight a pattern of codependent genetic interactions” that will need to be taken into account when developing therapies.

They also provide “a novel prognostic tool that may guide future therapeutic interventions,” they said.

In a companion paper, the authors used their novel insights to provide an explanation for the observation that a large number of glioblastomas have only one copy of chromosome 10 as well as increased activity of EGFR on chromosome seven.

The loss of one copy of chromosome 10 is the most common chromosomal alteration in glioblastoma, while gain or amplification of EGFR is the most common defect in growth factor signaling.

The two are significantly associated, Dr. Bredel and colleagues said, but the mechanism involved has not been clear.

A possible mechanism — suggested by the seven landscape genes — is loss of one copy of ANXA7, which is found on chromosome 10, the researchers said.

Indeed, if a tumor has only one copy of ANXA7, both its mRNA transcript expression and protein expression are significantly reduced compared with wild-type glioblastomas, at P=1×10^-15 and P=0.004, respectively.

Such a loss of function, the researchers found, results in up to a 7.44-fold increase in the abundance of the EGFR protein.

In the 189-tumor sample, deletion of the ANXA7 gene was associated with poor patient survival, with a hazard ratio of 0.686 (and a 95% confidence interval from 0.476 to 0.989), compared with tumors with wild-type ANXA7.

The study was supported by the State of Illinois Excellence in Academic Medicine Program. The authors did not report any financial conflicts. The editorial had support from the NIH. Dr. Pasche reported that he has filed patents related to a gene involved in colorectal cancer.

This article was developed in collaboration with ABC News.

Primary source: Journal of the American Medical Association

Source reference:

Bredel M, et al “A network model of a cooperative genetic landscape in brain tumors” JAMA 2009; 302(3): 261-75.