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

Cancer Research Highlights

Additional Surgery after Breast-Conserving Surgery Varies Widely

A new study has found that the number of women who have one or more additional surgeries to remove suspected residual tumor tissue (re-excisions) following breast-conserving surgery (BCS) for breast cancer varies widely across surgeons and hospitals. Although researchers, led by Dr. Laurence E. McCahill from the Richard J. Lacks Cancer Center in Grand Rapids, MI, could not determine whether this variation affected rates of tumor recurrence, “the wide level of unexplained clinical variation itself represents a potential barrier to high-quality and cost-effective care,” the authors wrote in a report that appeared February 1 in JAMA.

The researchers pooled data on women with breast cancer diagnosed between 2003 and 2008 who had undergone a first BCS procedure at the University of Vermont or at one of three sites in the HMO Cancer Research Network (Group Health, Kaiser Permanente Colorado, and Marshfield Clinic). Of the 2,206 women eligible for inclusion in the study, 509, or 23 percent, had one or more breast surgeries after the initial BCS. Of these women, 190, or about 8.5 percent of those who underwent initial BCS, had a total mastectomy.

A total of 311 women, or 14 percent, had positive margins (some tumor cells left at the site of surgery, as determined by a pathologist) after their initial surgery, but only about 86 percent of those women underwent re-excision. “This finding is notable given that positive margins…have been correlated with a long-term increased risk of local recurrence,” the authors stated.

The percentage of women with positive margins who underwent re-excision differed among institutions, from 73.7 percent to 93.5 percent. The re-excision rates also varied substantially among individual surgeons, from zero percent to 70 percent. Whether these variations were influenced by pathological features of the tumors, clinical factors such as whether women received radiation therapy, or preferences of individual women could not be determined from the study.

Currently, the authors explained, there is no consensus about the appropriate size of a surgical margin around a tumor to be considered “clear.” As a result, in this study, nearly half of patients with pathologically clear margins that were less than 1 mm wide and one-fifth of patients with clear margins between 1 and 1.9 mm underwent re-excision.

“I think it’s clear that we have to do more clinical research to really understand what’s behind this variation: how much of it is clinically appropriate—including where patient preference may be driving some of that variation—and how much of it is really driven by factors that could be mediated by things like better education and better resources in the operating suites,” commented Dr. Steven Clauser, chief of the Outcomes Research Branch in NCI’s Division of Cancer Control and Population Sciences.

Comparing Prostate Cancer Treatments Shows Newer Isn't Always Better

Two studies comparing the benefits and harms of different prostate cancer treatments show that newer, more expensive approaches may not produce better outcomes. The two comparative effectiveness research studies are among the first to compare newer therapies directly with older ones. The findings were presented at the 2012 Genitourinary Cancers Symposium.

Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, Dr. Ronald Chen of the University of North Carolina at Chapel Hill and his colleagues compared data on more than 12,000 men with localized prostate cancer who had received one of three types of external-beam radiation therapy treatment: three-dimensional conformal radiation therapy, intensity modulated radiation therapy (IMRT), and proton therapy.

Compared with patients who received conformal radiation, patients who received IMRT had a 9 percent lower incidence of gastrointestinal side effects, were 20 percent less likely to have hip fractures, and were 19 percent less likely to receive additional cancer treatments. These differences suggest that IMRT offers better cancer control, Dr. Chen explained at a press conference at the symposium.

Compared with IMRT, proton therapy produced higher rates of gastrointestinal side effects and no improvement in cancer control, as measured by the need for additional cancer treatments.

“I think, based on these data, we can safely say…that there is no clear evidence that proton therapy is better than IMRT. And given the costs and potential increased toxicities [of proton therapy], we must continue to study this modality,” said Dr. Nicholas Vogelzang of the Comprehensive Cancer Centers of Nevada, who moderated the press conference.

In another study, Dr. Jay Ciezki of the Cleveland Clinic and his colleagues used SEER-Medicare data to compare the benefits and harms of external-beam radiation therapy, brachytherapy, and surgery for prostate cancer. The researchers found that external-beam radiation therapy was the most toxic, most expensive, and most commonly used of these techniques.

Brachytherapy, although it was the least toxic and the least expensive, was used in only 12 percent of the patients. The limited use of brachytherapy may be due to the fact that it was initially thought to be suitable only for a small subset of men, but “I think people have gotten to the point where they’re more comfortable offering [brachytherapy],” said Dr. Ciezki.

See also: "Comparative Effectiveness Research Stirs Excitement as Well as Debate"

Oral HPV Infections May Explain Why Some Head and Neck Cancers are More Common in Men

The prevalence of human papillomavirus (HPV) infections in the oral cavity is significantly higher among men than women in the United States, according to a new study from researchers at Ohio State University and NCI’s Division of Cancer Epidemiology and Genetics (DCEG). Oral HPV infections have been associated with oropharyngeal cancer—a subset of head and neck cancers that arise in the back of the tongue, throat, and tonsils—rates of which have risen dramatically over the last several decades.

The study is the first to comprehensively document the prevalence of oral HPV infections in men and women in the United States. Overall, approximately 7 percent of people between the ages of 14 and 69 have an oral HPV infection, reported lead investigator Dr. Maura Gillison last week at the Multidisciplinary Head and Neck Cancer Symposium. (The prevalence of oral infections, however, is much lower than that of infections in the genital tract.) About 1 percent of the population has an oral infection with HPV 16, a type that is linked to cancer. The results were also published online January 26 in JAMA.

Using data from the National Health and Nutrition Examination Survey (NHANES), the researchers studied nearly 5,600 men and women ages 14 to 69, who provided an oral rinse and mouthwash gargle samples. The most common subtype of HPV in the oral cells of study participants was HPV 16, the HPV type that is responsible for more than half of all oropharyngeal cancer cases.

Oral HPV infections were three times more common in men than in women (10.1 percent versus 3.6 percent), with older men having the highest rates, Dr. Gillison said during a press briefing. Oral infections with HPV 16 were seen in 1.6 percent of men and 0.3 percent of women. The prevalence of HPV infections was highest among people who smoke at least a pack a day and those with more than 20 lifetime sexual partners.

HPV-related head and neck cancers are far more common among men than women, Dr. Gillison said. The higher oral HPV infection rates in men, “in particular the over fivefold higher prevalence of HPV 16 among men compared to women,” likely explains the discrepancy, she said.

As for why men are more likely to be infected, the available data, she said, “suggest that men are more prone to getting [HPV] infections…or, once infected, are more likely to have the infection persist.” It could also be a combination of both factors, she continued.

“These findings are particularly relevant because, in contrast to other head and neck cancers, HPV-associated oropharyngeal cancer rates have been on the rise in recent years,” commented senior author Dr. Anil Chaturvedi of DCEG’s Infections and Immunoepidemiology Branch. “The higher prevalence of both cigarette smoking and oral HPV infection in men helps complete our understanding of why men have higher rates of oropharyngeal cancer than women.”

See also: “Rising Oropharyngeal Cancer Rates Linked to HPV Infection

Cancer Screening Rates Lag Behind National Target Levels

Screening rates for breast, cervical, and colorectal cancer remained lower in 2010 than national objectives set forth in Healthy People 2020, measures set by the Department of Health and Human Services to improve the health of Americans and gauge the impact of prevention activities. The findings appeared in the January 27 Morbidity and Mortality Weekly Report (MMWR).

        2010 U.S. Cancer Screening Rates and Target Screening Rates for 2020

Screening forPercent ScreenedHealthy People 2020 Target
Breast cancer72.481.1
Cervical cancer83.093.0
Colorectal cancer58.670.5

Based on findings from the National Health Interview Survey (NHIS), scientists from NCI’s Division of Cancer Control and Population Sciences (DCCPS) and from the Centers for Disease Control and Prevention (CDC) reported that from 2000 to 2010, “the population-based estimates in this report show a slight downward trend in the proportion of women up-to-date with screening for cervical cancer but no change over time in breast cancer screening rates,” Colorectal cancer screening rates for men and women increased substantially, the report showed, and by 2010 were generally the same for both sexes.

Rates of all three cancer screening tests were significantly lower among Asians than among whites and blacks, the report noted. Hispanics were less likely than non-Hispanics to be screened for cervical and colorectal cancer.

“Higher screening rates were positively associated with education, availability and use of health care, and length of U.S. residence,” the researchers added.  For breast cancer, “immigrant women who had been in the United States for 10 or more years were almost as likely as U.S.-born women to report having had a mammogram within the past 2 years (70.3 percent and 73.1 percent, respectively),” the article stated, “whereas only 46.6 percent of immigrants [who had been] in the United States for less than 10 years reported being screened in the past 2 years.”

“Healthy People objectives are important for monitoring progress toward reducing the burden of cancer in the United States,” said Dr. Carrie Klabunde, an epidemiologist with DCCPS and a co-author of the study. “Our study points to the particular need for finding ways to increase the use of breast, cervical, and colorectal cancer screening tests among Asians and Hispanics, as well as among adults who lack health insurance or a usual source of health care.”

HPV Testing with Self-Collected Samples May Be Valid Cervical Cancer Screening Method

Data from five large studies carried out in China demonstrate that self-HPV testing—in which a woman collects a sample of her own cervical-vaginal cells for human papillomavirus (HPV) DNA testing—is as sensitive as the standard liquid-based Pap test for cervical cancer screening. This method has the potential to make cervical cancer screening available to women in rural or low-resource areas who do not have ready access to cytology screening services. The results were published online January 23 in the Journal of the National Cancer Institute.

Pap screening is often unavailable in low-resource areas. Instead, health care providers sometimes use visual inspection with acetic acid (VIA) to look for abnormal cervical cells that can be treated before they progress to cancer. However, VIA is not very accurate, and women still need the time and means to attend appointments with a health provider.

The researchers pooled data from cervical screening studies conducted in China between 1999 and 2007 that included more than 13,000 women between the ages of 17 and 56. The participants underwent an HPV test on a self-collected cervical specimen, VIA, HPV test on a physician-collected cervical specimen, and liquid-based Pap test. Women with positive results on any screening test received a colposcopy and a biopsy of any cervical lesion. By comparing the test and biopsy results, the researchers were able to determine the sensitivity and specificity of each screening method. 

Although self-HPV testing proved less sensitive than clinician sampling, self-HPV testing was more sensitive than VIA and as sensitive as the Pap test at identifying cervical precancer or cancer. However, the self-collected samples produced more false-positive results than the Pap test or VIA, meaning that more women who did not have cervical precancer or cancer underwent a colposcopy and biopsy. The researchers showed that conducting follow-up VIA or Pap tests on women whose self-collected sample tested positive could reduce the colposcopy rate from around 16 percent to less than 5 percent but would result in some loss of sensitivity for diagnosing abnormalities.

While acknowledging that self-HPV testing “is not specific enough to be a stand-alone test,” the authors point out that it “provides sensitive results without pelvic exams, medical professionals, or health-care facilities and thus has the potential to serve as a primary cervical cancer screening method for women, regardless of their geographic location or access to health care. Limited resources can then be focused on the clinical follow-up of the smaller percentage of women who tested positive.”

The authors of an accompanying editorial contend that more research is needed before self-HPV testing can be used outside of a research setting. Both the editorialists and the authors noted that the study participants received physician instruction on sample collection, and it is unclear whether the same results would be obtained by women who did not receive this instruction. Women's willingness to participate in this type of screening and their ability to access follow-up care also need to be investigated.

Genetic Studies Uncover Clues to Childhood Brain Cancers

Two genetic studies of brain tumors in children have identified a new suspect in these deadly cancers. In each study, researchers found recurrent mutations in a protein that helps package DNA in the cell nucleus. Changes to this process may alter the activity of genes and contribute to cancer, the researchers reported.

In one study, published online January 29 in Nature, researchers sequenced the entire exome (all protein-coding DNA) of tumors from 48 children with glioblastoma multiforme (GBM), an aggressive form of brain cancer. The sequencing revealed two recurrent mutations in a gene called H3F3A, which encodes a histone protein (H3.3).

Histones assemble into structures called nucleosomes, around which long strands of DNA wrap, resulting in a tightly packaged complex called chromatin. Because histones interact so closely with DNA, structural modifications to histone proteins can also control gene activity.

Two recent studies (here and here) have found evidence that mutations in genes whose products modify histones may be involved in cancer. The Nature study, however, is the first to describe mutations in a histone gene in tumors. “Histones are, in a way, the guardians of our genetic information,” said Dr. Nada Jabado of McGill University, who led the research.

She and her colleagues also found that some GBM tumors had mutations in genes that are involved in chromatin remodeling, a process in which chromatin “opens” so that transcription factors can gain access to DNA, allowing previously silent genes to be transcribed. Defects in the chromatin remodeling pathway may be common in pediatric GBM and could be the basis for exploring much-needed new treatments for the disease, the study authors concluded.

“We now have a starting point for investigating the biological basis of this disease,” Dr. Jabado continued. “Until now, we essentially have been working in the dark.”

In a separate study, researchers with the Pediatric Cancer Genome Project also found the same mutations in H3F3A or a closely related gene, HIST1H3B, in 78 percent of tumors from 50 children with a cancer known as diffuse intrinsic pontine glioma (DIPG). The findings were reported online in Nature Genetics on January 29. 

“It’s not often that you find a mutation that affects such a high proportion of [patient samples],” said senior author Dr. Suzanne Baker of St. Jude Children’s Research Hospital. “This tells us that anything we learn about this mutation will reveal something important about the biology of this disease.”

The finding also adds weight to the idea that epigenetic processes are being undermined in some cancers, Dr. Baker added. “I expect that significant resources will now be devoted to understanding how and why alterations in the histone proteins contribute to cancer.”

Also in the Journals: CDC Advisory Committee Strengthens Recommendation for HPV Vaccination in Males

The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) has strengthened and expanded its recommendation for vaccinating boys and young men with the quadrivalent human papillomavirus (HPV) vaccine, primarily to reduce the risk of anal cancer, penile cancer, and certain types of head and neck cancers caused mainly by HPV 16. The updated recommendations were published in Morbidity and Mortality Weekly Report last October and online January 31 in the Annals of Internal Medicine.

ACIP calls for the “routine [HPV] vaccination of males aged 11 to 12 years, with catch-up vaccination recommended for males aged 13 to 21 years.” The recommendations specifically call for vaccination with Gardasil, which protects against infection with four HPV types: 6, 11, 16, and 18. Types 6 and 11 cause genital warts, and types 16 and 18 cause cancer.

ACIP also recommends HPV vaccination for “previously unvaccinated males aged 22 to 26 years who are immunocompromised, who test positive for HIV infection, or who have sex with men.”

In the previous update, in January 2010, ACIP made a permissive recommendation—a weaker advisory that suggests a vaccine may be given—for males aged 9 to 26 to be vaccinated with Gardasil for the prevention of genital warts.