National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
November 30, 2010 • Volume 7 / Number 23

Cancer Research Highlights

Prostate Cancer Hormone Treatments May Raise Risk of Colorectal Cancer

A large, retrospective population study suggests that prostate cancer treatments that lower male sex hormones may increase the risk of colorectal cancer. Men treated with gonadotropin-releasing hormone (GnRH) agonists or surgical removal of their testicles (orchiectomy) to lower their testosterone and PSA levels experienced an increased risk of colorectal cancer of about 20 to 40 percent. The findings were reported online November 10 in the Journal of the National Cancer Institute.

More than half of nearly 108,000 prostate cancer patients identified in the linked SEER-Medicare database received androgen deprivation therapy between 1993 and 2002. Approximately 90 percent of those men had been treated with GnRH agonists, and the rest had had orchiectomy. They were followed for about 5 years after their prostate cancer diagnosis.

After adjusting for possible confounders such as obesity, diabetes, and radiotherapy, the researchers found a dose-response effect for GnRH agonists in which colorectal cancer risk increased with longer duration of treatment. Compared with prostate cancer patients who received no hormone treatments, those who had GnRH agonist therapy for 13 to 25 months had a 19 percent increase in colorectal cancer risk, those who had GnRH agonist therapy for longer than 25 months had a 31 percent increase in risk, and those who had orchiectomy had a 37 percent increase in risk.

Lead author Dr. Silke Gillessen of Kantonsspital St. Gallen in Switzerland and her colleagues noted that an inverse association between androgen levels and colorectal cancer risk is biologically plausible. “Androgen receptors are present in both normal and malignant human colonic tissues, and in various animal studies, administration of androgens protects against colon carcinogenesis, whereas androgen ablation promotes it,” they wrote. The authors went on to say that their evidence “may have broader implications beyond the field of prostate cancer” because nearly half a million men in the United States develop androgen deficiency each year.

Strategy to Screen for Lynch Syndrome May Save Lives and Be Cost Effective

An expanded screening strategy that involves genetic testing for an inherited disorder that predisposes people to several cancers, including colorectal and endometrial cancer, would save lives and be cost effective, according to a new study. The disorder, called Lynch syndrome, is caused by mutations in four genes, the products of which are involved in DNA mismatch repair. Defective DNA mismatch repair increases the risk not only of different cancer types, but also of multiple cancers at a single time and often in younger people.

Published online November 18 in Cancer Prevention Research, the study used a computer simulation model called Archimedes to assess the impact of 20 different screening strategies for Lynch syndrome on cancer incidence and mortality in a large group that is representative of the U.S. population. The strategies differed in the age of initiating risk assessment and risk thresholds for implementing genetic testing.

A strategy that involves assessing risk with the PREMM1,2 risk model for people ages 25, 30, or 35, followed by genetic tests on those whose risk of having a mutation in a DNA mismatch repair gene exceeds 5 percent, could potentially reduce the incidence of colorectal and endometrial cancer by as much as 12.4 percent and 8.8 percent, respectively, the researchers found. The average cost for this strategy per quality-adjusted life year, a measure of health care cost effectiveness, was $26,000, which is in line with that of common screening modalities such as mammography, said study co-author Dr. Stephen Gruber of the University of Michigan during a press briefing on the study.

The study, said senior author Dr. Randall Burt of the Huntsman Cancer Institute in Utah, demonstrates “what is the most medically effective way [to screen for Lynch syndrome] and the most cost-effective way.” Appropriate screening of people with Lynch syndrome, Dr. Burt added, reduces their risk of dying from colorectal cancer to that seen in the general population.

According to some estimates, approximately 1 in 375 people in the United States have Lynch syndrome, explained Heather Hampel of the Ohio State University Comprehensive Cancer Center, during the briefing. Current screening has focused on patients already diagnosed with cancers that can be caused by Lynch syndrome, said Hampel, who was not involved in the study. If the hallmark genetic mutations are identified in patients, then family members are screened for the mutations. But even this approach has been challenging to implement, Hampel stressed.

It’s important to note that the findings are based solely on a computer simulation model, said Dr. Martin Brown of NCI’s Division of Cancer Control and Population Sciences. And from a cost-effectiveness perspective, he noted, only Medicare costs were accounted for in the model, not additional out-of-pocket cost and time spent undergoing tests and associated procedures.

Anemia Drug May Interfere with Trastuzumab’s Anticancer Effects

Recombinant human erythropoietin (rHuEPO), which some cancer patients take to combat anemia and fatigue, may interfere with the anticancer effects of trastuzumab (Herceptin), researchers led by Dr. Zhen Fan of the University of Texas M. D. Anderson Cancer Center reported November 16 in Cancer Cell. Doctors use trastuzumab to treat breast cancers that overexpress the protein HER2.

In experiments using breast cancer cell lines, the researchers found that 4 out of 10 lines expressed both HER2 and the receptor for erythropoietin (EpoR), the natural form of rHuEPO. They also found EpoR in 13 out of 15 samples from patients with HER2-positive breast cancer. When three breast cancer cell lines expressing both EpoR and HER2 were cultured with trastuzumab, cell survival and proliferation decreased. However, when the cells were cultured with both rHuEPO and trastuzumab, the percentage of cancer cells that survived treatment in all three cell lines increased substantially. Similarly, trastuzumab-induced inhibition of cell migration and invasion was decreased in the presence of rHuEPO.

When the researchers implanted tumors expressing both EpoR and HER2 in mice and treated them with trastuzumab, the tumors shrank or stopped growing. When the researchers added rHuEPO to treatment, the tumors continued to grow, albeit at a slower rate than without any treatment.

The authors found that rHuEPO activates cell signaling pathways that interact with and reactivate the pathway that trastuzumab blocks. In addition, rHuEPO appears to inactivate a tumor suppressor gene called PTEN that also mediates the effects of trastuzumab on cancer cells.

To examine whether this interference translates to the clinic, the researchers looked at medical records for 37 women with HER2-overexpressing metastatic breast cancer who had received both trastuzumab and rHuEPO during treatment and 74 who received trastuzumab but not rHuEPO. They found that 40 percent of women who received only trastuzumab were alive without progression of their disease 1 year after treatment, compared with 19 percent of women who received both trastuzumab and rHuEPO.

The authors cautioned that this analysis was retrospective and included only a small number of patients. The women who received rHuEPO may have been sicker than patients who did not require a boost to their blood-cell counts, which could influence the survival data. To confirm their observations, “prospective clinical trials are warranted,” wrote the authors. “If confirmed, our findings would have a strong impact on clinical care for patients with HER2-overexpressing breast cancer,” they concluded.

Possible Causes of Resistance to Melanoma Drug Reported

Just months after researchers demonstrated the promise of a new melanoma drug called PLX4032 in early-stage trials, two studies have examined the reasons the drug eventually stops working in some patients. Resistance to single-agent targeted therapies for cancer is considered to be nearly inevitable over time. The new studies, published November 24 in Nature, describe molecular changes that may cause resistance to PLX4032 and suggest strategies for overcoming this resistance.

PLX4032 blocks overactive cell signaling through the MAPK pathway that is caused by a mutation known as V600E in the BRAF gene. One common mechanism of resistance is secondary mutations that prevent binding of a drug. However, both of the Nature studies found that resistance to the drug can occur in the absence of secondary mutations in the BRAF gene.

In one study, Dr. Levi Garraway of the Dana-Farber Cancer Institute and his colleagues described a strategy for identifying clinically relevant mechanisms of resistance and ways to overcome this resistance. Using this strategy, the researchers identified mutations in the gene encoding a protein called COT that lead to the activation of the MAPK pathway. The expression of COT was associated with resistance to PLX4032 in melanoma cells and in tissue from patients who relapsed following treatment with PLX4032 or a MEK inhibitor. (MEK is a component of the MAPK pathway.)

Some patients who have relapsed on PLX4032 have already been enrolled in a phase II trial of a MEK inhibitor based on the assumption that the MAPK pathway had been reactivated, noted the authors of the second study, which was led by Dr. Roger Lo of the University of California, Los Angeles. His team found that 5 of 12 patients with melanoma had acquired resistance to PLX4032 through the activation of the MAPK pathway. This appeared to occur due to mutations in a cancer-causing gene called N-RAS or increased levels of the growth factor receptor PDGFR-beta.

Combination therapies targeting multiple pathways may be able to overcome resistance, according to the authors of both studies. This was also the conclusion of a third study, published November 23 in Science Signaling. The researchers, led by Dr. Jeffrey Settleman of Massachusetts General Hospital Cancer Center and Harvard Medical School, found that extra copies of the BRAF gene (amplification) were a cause of resistance to both MEK and BRAF inhibitors. Further experiments suggested that combined MEK and BRAF inhibition could potentially overcome, or possibly prevent, this mechanism of resistance.

Radiation Treatment for Head and Neck Cancer May Produce Hearing Loss

Treatment for head and neck cancer that includes radiation therapy often induces hearing loss, and the damage can be substantial and permanent, Brazilian researchers have reported. Their findings were published in the November 2010 Archives of Otolaryngology—Head and Neck Surgery.

In the case-control study, which included 282 participants, case patients had head and neck cancer and had been treated with radiation therapy, either alone or in combination with chemotherapy, and the auditory system was included in the field of radiation. The control group included healthy individuals and patients with cancer who had not received therapy that affects hearing. The median age for both groups was approximately 61.

Over a median follow-up of 7 years, approximately 72 percent of case patients suffered hearing loss (as measured by standard audiologic assessment methods) compared with approximately 49 percent of the control group, reported Christiane Schultz from the Audiology Department at the A.C. Camargo Hospital in São Paulo, Brazil, and her colleagues.

The most common type of hearing loss in both groups was related to inner ear damage (sensorineural), but case patients were statistically significantly more likely than control subjects to experience severe hearing loss. Case patients were also far more likely to report (via a standardized questionnaire) that hearing loss represented a severe handicap (19.1 percent versus 2.8 percent).

Attention to this side effect is critical, the researchers wrote, because loss of hearing can promote social isolation and depression. “Concern for the quality of life of patients undergoing cancer treatment is necessarily growing,” they continued, “and determination of hearing loss should form part of such investigations to enable better rehabilitation.”