National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
April 3, 2012 • Volume 9 / Number 7

Cancer Research Highlights

Drawbacks of Adding MRI to Mammography Plus Ultrasound May Outweigh Benefits

Adding ultrasound or magnetic resonance imaging (MRI) to annual screening mammograms for women with an increased risk of breast cancer and dense breast tissue detects more new breast cancers than mammography alone but also results in more false-positive findings, according to results of a multicenter clinical trial. Findings from the ACRIN 6666 trial, which was co-sponsored by NCI’s Cancer Imaging Program and the Avon Foundation for Women, will be published April 4 in JAMA.

More than 2,800 women with dense breasts and at least one other risk factor for breast cancer, such as a personal history of breast cancer, consented to undergo three annual screens with mammography plus ultrasound. After three rounds of screening, 703 women underwent an MRI. Complete data were available for 612 of these women.

Researchers found that adding ultrasound to mammography increased breast cancer detection by an average of 3.7 cases per 1,000 women screened after the second and third rounds of annual screening. The majority of cancers detected only by ultrasound were node-negative invasive cancers. Until now, it had been unclear whether continuing annual ultrasound screening would detect more cancers.

Although the risk of false-positive results with annual screening ultrasound was lower in the second and third screens than in the first screen, the addition of ultrasound led to an increased rate of biopsies, with about 5 percent of women in the second and third screening rounds having a biopsy—only 7.4 percent of which revealed cancer.

Adding a single MRI further increased cancer detection to a rate of 14.7 cases per 1,000 women screened. Of the women screened with MRI, 7 percent had a biopsy only because of the MRI, of whom 19 percent were found to have cancer. The number of screens needed to detect one cancer was 127 for mammography, 234 for supplemental ultrasound, and 68 for supplemental MRI.

Although MRI was better at detecting cancer than mammography plus ultrasound, women found it less tolerable. The authors also noted that the rate of cancers found between screenings because of a palpable lump or other breast change was low and that all of these cancers were node negative at diagnosis. Thus, they said, “it is unclear that the added cost and reduced tolerability of screening MRI are justified in women at intermediate risk for breast cancer in lieu of supplemental screening with ultrasound.”

“Despite its higher sensitivity, the addition of screening MRI rather than ultrasound to mammography in broader populations of women at intermediate risk with dense breasts may not be appropriate, particularly when the current high false-positive rates, cost, and reduced tolerability of MRI are considered,” the authors concluded.

See also: “Mammography Plus Breast Ultrasound Yields Mixed Results

Ultrasound-Guided Breast-Conserving Surgery May Reduce Need for Further Surgeries

Using ultrasound to guide the surgical removal of tumors from women with palpable breast cancer is significantly better than the standard approach in ensuring that all cancerous tissue is removed while minimizing the removal of healthy tissue, a new study shows. The results, from a Dutch randomized, controlled clinical trial, were presented March 23 at the Eighth European Breast Cancer Conference, in Vienna, Austria.

If confirmed in other trials, the ultrasound-guided approach could become standard practice.

Breast-conserving surgery for palpable breast cancer is generally performed with guidance from [the] surgeon’s palpation only,” lead investigator Dr. Nicole Krekel of VU University Medical Center in Amsterdam said in a news release. Unfortunately, she noted, the standard approach “is associated with a high rate of margins that contain cancer cells, as well as the excision of excessively large volumes of tissue.” If a pathologist finds that tumor cells are still present at the site of surgery, additional surgery is usually needed to eliminate cancerous tissue and reduce the risk of local recurrence.

Dr. Krekel and her colleagues randomly assigned 124 patients with palpable early-stage breast cancer to either ultrasound-guided surgery or palpation-guided surgery. They found that only 3.3 percent of the margins in the ultrasound-guided surgery group contained cancer cells, compared with 16.4 percent in the palpation-guided surgery group. They also found that less healthy tissue was removed in the ultrasound-guided surgery group.

Using ultrasound enables surgeons to see all around the tumor during surgery and to position the incision on the breast optimally, Dr. Krekel explained.

“If we get the same results in the United States, and these results can be incorporated into community practice, it will spare many women unnecessary re-excision surgery,” said Dr. Jo Anne Zujewski, head of Breast Cancer Therapeutics in NCI’s Division of Cancer Treatment and Diagnosis.

See also: “Additional Surgery after Breast-Conserving Surgery Varies Widely

Also in the Journals: Methylation Levels in HPV DNA May Indicate Risk for Cervical Precancer

A new study suggests that human papillomavirus (HPV) DNA methylation levels could be used as a biomarker to predict which cervical HPV infections are most likely to progress to cervical precancer.

Using samples from some women in the Costa Rica HPV Vaccine Trial, Dr. Lisa Mirabello of NCI’s Division of Cancer Epidemiology and Genetics and her colleagues measured methylation levels at several sites of the genome of HPV 16, the HPV type that causes the majority of cervical cancers and precancers. Women with high methylation levels were at greater risk for persistent infection and cervical precancer than women who cleared the virus within 2 years.

The authors of the study, published March 23 in the Journal of the National Cancer Institute, are conducting follow-up studies to confirm their findings.

Anal HPV Infections and Precancerous Lesions Are Common in Men Who Have Sex with Men

A large percentage of men who have sex with men (MSM) have anal human papillomavirus (HPV) infections and anal precancerous lesions, according to a meta-analysis of data from more than 50 studies. The rate is even higher among those infected with the human immunodeficiency virus (HIV). The findings were published online March 23 in Lancet Oncology.

MSM are known to be at elevated risk for developing HPV-associated anal cancer, but because of a lack of data it has been unclear whether anal cancer screening would be beneficial in this subgroup. Dorothy A. Machalek of the University of New South Wales in Sydney, Australia, and her colleagues examined 53 studies published before November 2011 to determine the frequency of HPV infections, anal lesions, and anal cancers in HIV-negative and HIV-positive MSM.

The researchers estimated that nearly three-quarters of HIV-positive MSM are infected with high-risk HPV types, which can cause cancer. In contrast, 37 percent of HIV-negative MSM were infected with the same high-risk types.

Moderate and severe anal lesions were detected in 29.1 percent of HIV-positive and 21.5 percent of HIV-negative MSM. The overall incidence of anal cancer in these two groups was 46 per 100,000 HIV-positive MSM and 5 per 100,000 HIV-negative MSM.

Using these data, the researchers estimated that, each year, high-grade lesions progress to anal cancer in 1 of 600 HIV-positive MSM and in 1 of 4,000 HIV-negative MSM. These progression rates are much lower than those seen for high-grade cervical lesions, which progress to cervical cancer in 1 of 80 women with those lesions every year, suggesting that anal cancer screening in MSM may need to be approached differently than cervical cancer screening.

However, in an accompanying editorial, Dr. Nicolas Wentzensen of NCI’s Division of Cancer Epidemiology and Genetics pointed out that progression rates for cervical cancer and anal cancer may not be directly comparable. The researchers “were not able to differentiate between moderate and severe dysplasia,” said Dr. Wentzensen. “The progression models in the cervix are based only on severe dysplasia. If we also included moderate dysplasia in the cervix, we might find similarly lower progression rates.”

The researchers and editorialist agree that more research is needed before anal cancer screening is recommended as part of standard clinical care for MSM. “There needs to be a lot of standardization and better appreciation for how [screening] methods perform and how the treatment triggered by those findings affects men,” said Dr. Wentzensen. “That is very important data to obtain before implementing widespread screening.”

Olaparib Delays Progression of Ovarian Cancer after Initial Treatment

Long-term therapy with the targeted drug olaparib significantly improved progression-free survival among women with the most common type of ovarian cancer in a randomized, placebo-controlled phase II clinical trial. The interim findings were published online March 27 in the New England Journal of Medicine.

The trial included 265 women with relapsed, high-grade serous ovarian cancer who had responded to previous treatment with platinum-based chemotherapy. Patients were randomly assigned to receive either olaparib, a drug that blocks a DNA-repair protein called PARP, or a placebo.

Women who received olaparib experienced a median progression-free survival of 8.4 months, compared with 4.8 months for those who received the placebo. Patients in the olaparib group had a lower risk of disease progression after researchers took into account factors including BRCA gene mutation status, age, ancestry, and previous time to progression. Side effects were more common among women who received olaparib, but most of these were mild to moderate; few patients stopped therapy because of side effects.

The improvement in progression-free survival did not lead to improved overall survival. In an interim analysis, overall survival was virtually identical between the olaparib and placebo groups, at 29.7 months and 29.9 months, respectively.

Ovarian cancer usually responds to platinum-based combination chemotherapy, and if the disease returns, it may respond again to another platinum-based chemotherapy regimen. However, responses to subsequent courses of chemotherapy tend to be short-lived, explained the authors, who were led by Dr. Jonathan Ledermann of the University College London Cancer Institute.

This trial is one of several recent studies investigating whether maintenance therapy can help improve control of ovarian cancer. Researchers have found that maintenance therapy with either extended chemotherapy or the targeted agent bevacizumab may help delay cancer recurrence. Olaparib was recently found to induce tumor responses in women with recurrent, high-grade serous ovarian cancer or ovarian cancer associated with a BRCA1 or BRCA2 mutation. 

The results from the current study show that “maintenance treatment with olaparib [is] associated with a significant improvement in progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer,” the authors wrote. Furthermore, the authors noted that 21 percent of patients were still receiving the drug at the time of writing, which “indicates that the disease is controlled for a prolonged period in some patients,” they concluded.

“This is an important gain for ovarian cancer patients,” commented Dr. Elise Kohn of NCI’s Center for Cancer Research. “The doubling in time to progression with olaparib is an exciting observation and should be the stimulus for further olaparib-based studies.”

See also: “Drug that Inhibits DNA-Repair Enzyme Shrinks Some Breast and Ovarian Tumors

Transplant Recipients at Higher Risk of Aggressive Form of Lymphoma

Recipients of solid organ transplants are about 14 times more likely than the general population to develop diffuse large B-cell lymphoma (DLBCL), an aggressive type of non-Hodgkin lymphoma (NHL). This finding and additional data from a comprehensive study of risk factors for this NHL subtype in transplant recipients were presented at the 2012 American Association for Cancer Research annual meeting.

Transplant recipients are known to be at increased risk for cancer, due in part to the immunosuppressive therapies they receive to prevent organ rejection. “NHL is one of the most common cancers diagnosed among transplant recipients, and there are many distinct histological types that are likely to have different causes,” explained the study’s senior investigator Dr. Lindsay Morton of NCI’s Division of Cancer Epidemiology and Genetics (DCEG). “Previous studies have looked at NHL, but have lacked the large number of patients or the detailed information needed to determine risk factors for NHL subtypes across all solid organ transplants.”

Dr. Todd Gibson of DCEG led the analysis using data from the Transplant Cancer Match Study, which links the Scientific Registry of Transplant Recipients with 14 population-based cancer registries. He and his colleagues identified 948 cases of DLBCL from among more than 175,000 transplant recipients. The risk of DLBCL was greater for younger transplant recipients, those who received a lung or pancreas transplant, and those who tested negative for the Epstein-Barr virus at the time of their transplant.

“Organ transplants are necessary and often life-saving treatments,” said Dr. Gibson. “But our work shows that these patients are at greatly increased risk for this particular subtype of lymphoma. We hope that our work can play a role in identifying the subgroup of people within the transplant population that is at greatest risk and can help inform efforts for surveillance and possibly prevention.”

Additional analyses are examining other risk factors for DLBCL in transplant recipients, including immunosuppressive medication use.

Some Melanoma Cells May Use the Body's Immune Response to Escape Destruction

Researchers have found evidence that some melanomas may use a protein induced by T cells—a type of immune cell that can attack cancer cells—to evade the immune system. The retrospective study involving tumor samples from 150 patients suggests that this protein, called B7-H1, suppresses T cells, ultimately preventing the immune system from destroying the cancer cells.

Treatments that block the B7-H1 pathway may, therefore, benefit patients with melanomas that express this protein, wrote Dr. Janis Taube of the Johns Hopkins Medical Institutions and her colleagues in a study published March 28 in Science Translational Medicine.

Almost 40 percent of the tumor samples expressed B7-H1, and expression of B7-H1 was strongly associated with the presence of tumor-infiltrating lymphocytes. Previous studies had shown that the immune-system protein interferon-gamma (IFN-gamma) induces B7-H1 expression in melanoma, and the Hopkins researchers found IFN-gamma in the B7-H1-positive tumors where the tumor cells came into contact with tumor-infiltrating lymphocytes.

The researchers then examined outcomes in patients with metastatic melanoma and found that overall survival was longer in patients with B7-H1-positive tumors than in those with B7-H1-negative tumors. This may be because B7-H1 expression indicates the presence of an active antitumor response that initially fends off cancer before it is turned off by the melanoma cells.

Monoclonal antibodies that target B7-H1, which may help restore the immune system’s recognition of melanoma cells, are being tested in clinical trials.