National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
February 8, 2011 • Volume 8 / Number 3

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Cancer Research Highlights

Starting Hormone Therapy at Menopause Increases Breast Cancer Risk

Women who start taking menopausal hormone therapy around the time of menopause have a higher risk of breast cancer than women who begin taking hormones a few years later. The finding, from the Million Women Study (MWS)—a large observational study in the United Kingdom—adds to a growing body of evidence that the use of combined hormone therapy (estrogen plus progestin) to treat menopausal symptoms increases the risk of breast cancer and deaths from the disease. The results appeared in the Journal of the National Cancer Institute on January 28.

The pattern of increased breast cancer risk “was seen across different types of hormonal therapy, among women [in the MWS] who used hormonal therapy for either short or long durations, and also in lean and in overweight and obese women,” Dr. Valerie Beral of Oxford University and her colleagues wrote. Their findings support results from the Women’s Health Initiative (WHI), a randomized clinical trial that, in 2002, first reported evidence linking combined hormone use to breast cancer.

“The new findings underscore the idea that there’s really no safe window of time for women to take combined hormone therapy,” said Dr. Leslie Ford of NCI’s Division of Cancer Prevention and the Institute’s WHI liaison. After the initial WHI results were announced, she noted, some people had argued that hormones may be safer when started at the time of menopause. “The new findings refute that argument,” she added.

WHI and MWS investigators have both reported that breast cancer incidence rates declined rapidly once women stopped taking combined hormone therapy. “It is important for women to know that if they stop using hormones, the risk of breast cancer very quickly returns to where it was before hormone therapy began,” Dr. Ford said.

There has been a discrepancy between the WHI and MSW results to date as to whether estrogen-only therapy raises breast cancer risk in postmenopausal women. WHI reports have found little risk associated with this treatment, whereas the MWS investigators have observed a statistically significant increased risk.

Additional follow-up from the WHI estrogen-only intervention trial should help clarify this issue in the coming years, noted Drs. Rowan T. Chlebowski of Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and Garnet L. Anderson of the Fred Hutchinson Cancer Research Center in an accompanying editorial.

Vaccine Reduces HPV Infections in Young Men

An international randomized clinical trial has shown that the vaccine Gardasil, which arms the immune system against four strains of the human papillomavirus (HPV), can reduce the incidence of anogenital HPV infections in young men 16 to 26 years of age at the time of vaccination. The results were published in the New England Journal of Medicine on February 3.

Gardasil was first approved by the FDA in 2006 for females 9 to 26 years of age to prevent cervical, vulvar, and vaginal cancers, as well as genital warts. Two of the four strains targeted by the vaccine—HPV-6 and HPV-11—cause most cases of genital warts, and the other two strains—HPV-16 and HPV-18—cause about 70 percent of all cervical cancers. In addition, HPV-16 and HPV-18 have been linked to cancers of the anus, penis, and oropharynx. In 2009, the FDA extended approval of the vaccine for the prevention of genital warts in young men based on the results of the current trial.

The trial, designed by Merck Pharmaceuticals, enrolled 4,065 young men from 18 countries; 2,032 of the participants were randomly assigned to receive the three-dose vaccine over a 6-month period, and 2,033 received a series of placebo injections over the same period of time. Dr. Anna R. Giuliano of the H. Lee Moffitt Cancer Center and Research Institute and her colleagues measured HPV infection status at the time participants joined the study and again periodically for up to 3 years after enrollment. The men also underwent regular physical examinations to identify genital skin lesions associated with HPV.

The researchers performed analyses in two overlapping groups of men. The intention-to-treat cohort included men who all received at least one dose of vaccine or placebo, regardless of HPV status at enrollment. The per-protocol cohort included only men who received all three doses and tested negative for all four HPV types targeted by the vaccine throughout the vaccination phase of the study, and thus excluded men who developed infections before the vaccination was complete. Gardasil is designed to prevent HPV infections and does not appear to increase the rate of clearance of established infections; thus, the estimates of effectiveness will be higher in the per-protocol cohort than in the intention-to-treat cohort.
                  
In the intention-to-treat cohort, the vaccine prevented 65.5 percent of skin lesions, mostly genital warts, associated with two of the four targeted HPV types; in the per-protocol population containing men with no evidence of previous exposure to the viruses, the vaccine prevented 83.8 percent of lesions.

The rate of persistent HPV infection with any of the four types anywhere in the body that lasted at least 6 months was reduced by 47.8 percent in the intention-to-treat cohort and by 85.6 percent in the per-protocol cohort. For HPV types 16 and 18—the two that can eventually cause cancer in a small proportion of infected individuals—persistent infection was reduced by 79 percent and 96 percent, respectively, in the per-protocol cohort, though these data are based on very small numbers of people. Much longer follow up and additional studies will be needed to determine whether the vaccine prevents the development of HPV-related cancers in men, explained the authors.

On December 22, 2010, the FDA approved Gardasil for both men and women ages 9 through 26 to prevent anal cancer and associated precancerous lesions. This approval was based on results in the subset of men in the current trial who have sex with other men. Dr. Giuliano and her colleagues found a 78 percent reduction in anal intraepithelial neoplasia grades 1, 2, and 3 related to HPV-16 and HPV-18 infection. Approximately 90 percent of anal cancers have been linked to HPV infection.

Adoptive Cell Transfer Targets New Cancer Antigen for Immunotherapy

Results from a phase II trial suggest that an immunotherapy strategy called adoptive cell transfer (ACT) may be effective for patients with metastatic cancers, including melanoma and a tumor of the soft tissues of joints known as synovial cell sarcoma. The study, published January 31 in the Journal of Clinical Oncology, is part of an effort by researchers from NCI’s Center for Cancer Research to engineer a patient’s own white blood cells to recognize and attack his or her specific cancer.

For the treatment, Dr. Steven Rosenberg and his colleagues genetically modified the receptors on the patient’s own T cells to bind to an antigen called NY-ESO-1, which is expressed in 80 percent of synovial cell sarcomas and 15 to 30 percent of metastatic melanoma, breast, prostate, lung, and ovarian cancers. The antigen is not commonly present in normal tissues except in the testis.

From each patient who had tumors that heavily expressed the NY-ESO-1 antigen, T cells were removed. The extracted T cells were then genetically altered using a retrovirus that delivered the genetic code for building NY-ESO-1 receptors into the cells. The modified T cells were then grown in the laboratory and infused back into the patients. To prepare for the infusion of their altered T cells, the patients received chemotherapy to eliminate any other immune cells in their blood.

All 17 patients enrolled in the trial had progressive metastatic disease. The six patients with synovial cell sarcoma had been treated with multiple chemotherapies, and the 11 melanoma patients had been previously treated with interleukin-2. After ACT, five of the melanoma patients had measurable responses, and two of them had complete responses (disappearance of all signs of cancer) that were sustained at 20 and 22 months, respectively. Among the three remaining melanoma responders, one had a partial response (shrinkage of tumor size) that persisted 9 months after initial treatment. Four of the synovial cell sarcoma patients had objective partial responses, with one patient’s response lasting 18 months.

Patients in the trial experienced no toxic effects beyond those that are common with stem-cell transplantation and interleukin-2 treatment, which include neutropenia and thrombocytopenia, and the toxicities were less severe than in other trials in which ACT was used against different tumor antigens, the authors wrote.

The study “represents the first successful immunotherapy for patients with synovial cell sarcoma,” they concluded, noting that the small number of patients in the trial limits the interpretation of their results. However, the strategy against NY-ESO-1 should be explored further, they continued, because the antigen is expressed by common cancers and, thus, the treatment may be extended to many tumor types.

Mouse Studies Point to Prognostic Test for Prostate Cancer

Some mice, like some men, develop prostate cancer that never spreads beyond the prostate, and researchers have used these mice to learn why only some tumors metastasize and become fatal. By studying genetically engineered mice, the researchers identified four genes that drive the progression of prostate tumors. The corresponding genes in humans also appear to influence the spread of prostate cancer and could become prognostic markers for identifying potentially lethal tumors in patients, the researchers reported online in Nature on February 2.

New tests are needed to distinguish lethal prostate tumors from those that would never cause harm in a man’s lifetime. But, given the enormous intratumoral heterogeneity of human prostate cancers, Dr. Ronald DePinho of the Belfer Institute for Applied Cancer Science at Dana-Farber Cancer Institute and his colleagues decided to look for prognostic markers in genetically engineered mice, which are more amenable to genetic analysis. Using unbiased approaches, the investigators discovered that a mouse gene called Smad4 constrains the spread of tumor cells.

Additional experiments and lines of evidence, including functional studies and cross-species comparisons of genes, implicated four genes, including Smad4, in the progression of prostate cancer in mice. The researchers concluded that the process is governed largely by the inactivation of the genes Smad4 and Pten and activation of two other genes, cyclinD1 and Spp1.

They next assessed the prognostic value of the corresponding genes in human prostate cancer, using the protein products of the genes as markers. When added to standard clinical parameters such as the Gleason score, the researchers found these markers improved predictions of death from metastatic prostate cancer among men who participated in the Physicians’ Health Study and in a second study.

“We used the mouse models to filter out the intractable genomic complexity that presents itself in early-stage human cancers,” said Dr. DePinho. “And this allowed us to identify a collection of markers that are functionally relevant to the biology of invasion.” A company has licensed the four markers for further development, he added.

Protein May Help Predict Cancer Recurrence and Metastasis

An altered form of a protein called CPE-delta N that is found in several cancer types may be used to predict cancer recurrence and metastasis with high sensitivity, reported an international team of researchers online February 1 in the Journal of Clinical Investigation.

The researchers, led by Drs. Terence Lee of the University of Hong Kong and Saravana Murthy of the National Institute of Child Health and Human Development, found that highly metastatic liver cancer cell lines had elevated levels of messenger RNA (mRNA) for CPE-delta N compared with liver cancer cells that were unlikely to spread. When the scientists blocked CPE-delta N expression in the metastatic cells using small interfering RNA (siRNA) technology, both cell growth and invasiveness were inhibited. Similar results were obtained with breast, colon, and head and neck cancer cell lines.

The researchers also found that CPE-delta N-expressing liver tumors implanted in mice grew as much as 16-times larger than control tumors containing siRNA that blocked CPE-delta N, and that the tumors without the siRNA block spread in the liver and to the lungs.

The researchers then evaluated whether CPE-delta N could be used as a biomarker to predict recurrence (including metastasis) in patients with hepatocellular carcinoma, a type of liver cancer. Using data from 99 patients, the researchers found that 75.8 percent of those whose disease did not return had CPE-delta N mRNA levels in their liver tumors that were no more than twice the level found in normal tissues. In contrast, 92.3 percent of patients whose tumors recurred had liver tumors with CPE-delta N mRNA levels greater than twice the level found in normal tissues. These findings translate to a sensitivity—the likelihood of the biomarker correctly predicting whether disease will recur—of 92.3 percent

A confirmatory study in 80 additional patients showed similar results. Importantly, explained the authors, CPE-delta N was able to predict risk of recurrence independent of tumor stage, a parameter that is commonly used to help predict risk of recurrence in the clinic.

The researchers then tested the predictive power of CPE-delta N in 14 patients with pheochromocytoma or paraganglioma, rare neuroendocrine tumors. They found that highly elevated copy numbers of CPE-delta N mRNA predicted recurrence with 100 percent accuracy in those patients.

“What’s unique about this paper is the fact that the marker works in two unrelated cancers,” said Dr. Stephen Hewitt, staff scientist in NCI’s Center for Cancer Research and a co-author on the paper. “Many biomarkers do not generalize into multiple tumor types.” If confirmed, CPE-delta N could be used to guide clinical care for some patients, such as sparing a patient whose tumor has already spread unnecessary surgery, he explained.

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