National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
August 7, 2012 • Volume 9 / Number 16

Cancer Research Highlights

Trial Suggests New Treatment Option for Some Women with Metastatic Breast Cancer

Results from a phase III clinical trial suggest that, for some women with metastatic breast cancer, combining two drugs that work in different ways to disrupt estrogen's ability to fuel cancer growth may delay disease progression and death. The results were published August 2 in the New England Journal of Medicine.

Several breast cancer specialists cautioned, however, that the trial results are not enough to change clinical practice and need to be confirmed.

In the trial, women with metastatic breast cancer treated with the aromatase inhibitor anastrozole (Arimidex) and the antiestrogen fulvestrant (Faslodex) had better progression-free and overall survival than women who were treated with anastrozole alone. Both drugs are already approved to treat metastatic breast cancer.

About 700 women took part in the NCI-funded trial, which was led by SWOG, formerly the Southwest Oncology Group. All of the women in the trial were postmenopausal, had hormone receptor-positive metastatic breast cancer, and had not been previously treated for metastatic cancer. Women in the combination group were given the standard dose of fulvestrant (500 mg) the first time they received it, followed by a lower dose (250 mg) for the remaining treatments. About 40 percent of the women in the anastrozole-only arm began to receive low-dose fulvestrant after their disease began to progress.

Median progression-free survival—the trial's primary endpoint—was 15.0 months in women who received both drugs and 13.5 months in women who received only anastrozole. Overall survival was 47.7 months in the combination therapy arm and 41.3 months in the anastrozole-only arm.

In general, toxic effects were relatively mild and did not differ greatly between the two groups. Nevertheless, 42 patients who received anastrozole alone, and 51 who received both drugs, experienced severe toxic effects, including musculoskeletal pain, flu-like symptoms, and difficulty breathing.

But the results are convincing, said lead investigator Dr. Rita Mehta of the University of California, Irvine, in an interview. "Fulvestrant and anastrozole should be standard for women who would qualify for the study," she said.

But Dr. Jung-Min Lee, of NCI's Medical Oncology Branch, stressed that overall survival was a secondary endpoint of the study and said that several questions need to be answered before the combination therapy is used in clinical practice. "We first have to define the population who might benefit most from the combination therapy," Dr. Lee said. "And we need more data to confirm the overall survival benefit."

The results also conflict with those from a similar international trial, called FACT, which found no difference in overall survival between women who received anastrozole and fulvestrant and women who received anastrozole alone. The trials had several major differences that likely explain the discrepant findings, Dr. Mehta said.

The FACT trial was smaller, she explained, included more women who had received prior tamoxifen (70 percent versus 40 percent), enrolled patients who had completed chemotherapy for earlier-stage disease within the previous 12 months, and was restricted to patients who had suffered a relapse. These differences in the study populations likely "enriched [the trial] for patients with relatively endocrine-resistant disease," she said.

This research was supported by grants from the National Institutes of Health (CA32102, CA38926, CA35431, CA35281, CA20319, CA04919, CA67575, CA58861, CA37981, CA46368, CA86780, CA46282, CA63848, CA12644, CA27057, CA95860, CA35119, CA46441, CA11083, CA45450, CA35178, CA13612, CA58882, CA45377, CA45807, CA58723, C14028, CA128567, CA22433, CA52654, CA45560, CA35261, CA073590, CA45808, CA35192, CA42777, CA16385, CA35176, CA63845, CA35128, CA35090, CA63844, CA76447, CA58416, CA63850, CA76462, CA35262, CA77202, and CCSRI155469).

U.S. Prostate Cancer Incidence Falls after Change in Screening Recommendations

Soon after an independent task force recommended against routine screening of men aged 75 and older for prostate cancer with the prostate-specific antigen (PSA) test, the incidence of early-stage prostate tumors in that population declined, a new analysis shows. The findings suggest that the revised recommendations led to a reduction in prostate cancer screening rates in older men.

The U.S. Preventive Services Task Force (USPSTF) conducted a systematic review of the medical literature and issued the recommendations in August 2008.

"There's a lot of skepticism that these types of recommendations will have an impact on practice patterns, but at least in this case it looks like there has been some [impact]," said study author Dr. David Howard of Emory University in an interview posted online.

For his analysis, published July 23 in Archives of Internal Medicine, Dr. Howard used data from more than 254,000 men with prostate cancer from NCI's Surveillance, Epidemiology, and End Results registry.

He hypothesized that if screening rates in men aged 75 and older fell, the incidence of early-stage prostate tumors, which are detected primarily by PSA-based screening, would also fall relative to the incidence of late-stage tumors and of early-stage tumors in younger men. "And that's exactly what I found," he said in the online interview.

Between 2007 and 2009, the incidence rate for early- and late-stage prostate tumors fell 25.4 percent and 14.3 percent, respectively, among men aged 75 and older. By contrast, the incidence rate for early-stage tumors dropped 15.2 percent among men aged 65 to 74, and 11 percent among men aged 30 to 64, over the same period.

Dr. Howard's conclusions differ from those of an earlier report that found that self-reported PSA screening rates in men aged 75 and older did not change between 2005 and 2010. Several factors may explain the discrepancy. For instance, "patients do not [always] accurately report receipt of PSA testing," he explained via e-mail, noting that physicians who stopped screening older men may not have discussed this decision with their patients.

Over time, a clearer picture should emerge of physicians' responses to revised screening recommendations. "Dr. Howard's data are interesting and relevant," commented Dr. Scott Eggener of the University of Chicago, senior author of the earlier study. "As with all self-reported or population-based data, it's important to replicate using multiple sources."

In a study that is still under review for publication, Dr. Howard also examined PSA testing rates directly using Medicare claims, which he noted are more reliable than patient self reports. He expects the findings from that study to be published soon.

Further reading: "U.S. Preventive Services Task Force Advises against PSA Screening"

Single HPV Test Predicts the Risk of Cervical Cancer for 18 Years

In a group of more than 20,000 women, the human papillomavirus (HPV) DNA test more accurately predicted the risk of developing cervical cancer over an 18-year follow-up period than the Pap test. Although both tests could identify women who were most likely to develop high-grade precancerous cervical lesions or squamous cervical cancers within 2 years of testing, only the HPV test result predicted the risk for women up to 18 years later.

Dr. Philip Castle of the American Society for Clinical Pathology and his colleagues reported their findings July 30 in the Journal of Clinical Oncology.

The authors, including researchers from NCI's Division of Cancer Epidemiology and Genetics (DCEG), used data from a study initiated by NCI and Kaiser Permanente of women who, in 1989 and 1990, underwent routine Pap testing in Portland, OR. Samples collected at the start of this study were used for Pap and HPV testing.  

Recently reported research from this group also showed that HPV testing could predict risk for 18 years, but those results were based on HPV tests that are used only in research settings. These new results are based on the type of HPV tests that are used in current clinical practice.

The researchers found that the HPV test more accurately stratified women by their risk of developing cervical cancer than the Pap test. Over the 18-year follow-up period, 199 women were diagnosed with cervical intraepithelial neoplasias grade 3 or cervical cancer (CIN 3+); more of these cases developed in those with a positive HPV test (112 women) than in women who had an abnormal Pap test (65 women). Conversely, fewer cases of CIN 3+ developed over the follow-up period in women with a negative HPV test at the start of the study than in women with a normal Pap test taken at the same time (87 women versus 134 women).

Current screening guidelines recommend that most women aged 30 to 65 be tested for high-risk HPV types in conjunction with a Pap test every 5 years.

DCEG's Dr. Sholom Wacholder, senior author on the study, said that data from the study showed that, for women aged 30 or older, the 3- and 5-year risks for precancer or cancer after a negative HPV test and negative Pap test were very low, consistent with the guidelines.

Risk of Developing Precancer or Cancer 
after Negative HPV and Pap Tests in Women Older than 30

  CIN 2+ CIN 3+
3-year risk0.23 percent0.08 percent
5-year risk0.36 percent0.16 percent

Recent reports have suggested that some doctors worry that if they offer HPV and Pap co-testing every 5 years in accordance with the new guidelines, women might go several more years between screenings.

"HPV testing is a powerful predictor of cervical cancer risk.  This work provides evidence to support extended screening intervals after negative HPV and Pap tests," said Dr. Wacholder. "The very low risk over 10 years in women with a single negative HPV test provides a reassuringly large margin of safety."

This research was supported in part by NCI's Intramural Research Program.

Discovery of Fused Genes in Brain Cancer Points to Possible Treatments

Researchers have found that a small percentage of glioblastoma brain tumors, one of the most lethal forms of cancer, harbors mutations in which portions of two genes are spliced together. The researchers also showed that although the aberrant proteins produced by these fusion genes can transform normal cells into cancer cells, the actions of these fusion genes can be blocked by two experimental drugs being tested for other cancers.

Their findings, published July 26 in Science, raise the possibility that a small subset of people with glioblastoma could be treated with drugs that specifically target the fusion proteins produced by the newly identified fusion genes.

A team led by Drs. Antonio Iavarone, Raul Rabadan, and Anna Lasorella of Columbia University Medical Center found that about 3 percent of the glioblastoma tumors they examined contain FGFR-TACC fusion genes. The fusion activates a tyrosine kinase enzyme whose altered activity has been found to promote tumor growth and survival in several cancer types.

The FGFR-TACC fusion proteins "have a potent pro-tumorigenic effect," Dr. Iavarone said. "That means that when we introduce this fusion [protein] into the brain, we can transform the normal brain cells into cancer cells," he explained. When the researchers put FGFR-TACC into brain cells of healthy mice, 7 of 8 mice died of malignant brain tumors that resembled human glioblastoma.

Additional experiments showed that the FGFR-TACC fusion protein disrupts the process that apportions chromosomes between two daughter cells during cell division. This results in a condition known as aneuploidy, in which cells have an abnormal number of chromosomes. Aneuploidy is a hallmark of cancer, Dr. Iavarone noted.

Finally, the researchers showed that compounds that block the kinase activity of the fusion protein can correct aneuploidy and stop the growth of glioma cells containing FGFR-TACC. These compounds also slowed tumor growth and prolonged survival of mice with malignant brain tumors caused by FGFR-TACC. Two of the compounds, AZD4547 and BGJ398, are being tested in early-stage clinical trials for other cancers, including lung cancer.

Based on these results, "we believe that there is a strong rationale to do a clinical trial where we would target tumors that harbor these gene fusions with these drugs," Dr. Iavarone said. He and his colleagues in the United States and Europe have formed a cooperative research group and begun talks with the drug manufacturers in hopes of moving forward with such a trial.

Further reading: "Common Cancers May Involve Fused Genes"

This research was supported by grants from the National Institutes of Health (R01CA101644, R01CA131126, R01CA085628, R01CA127643, U54 CA121852-05,1R01LM010140-01, R01NS061776).