Gene Signature Predicts Metastases in Hepatocellular Carcinoma

A team of researchers, including several from NCI, found a unique gene signature in the normal immune cells populating the liver tumor’s microenvironment that could predict potential for metastasis, according to a study in the August Cancer Cell.

The study included 115 hepatocellular carcinoma (HCC) patients treated at the Zhongshan Hospital in Shanghai, China. Fifty-two patients had tumors that metastasized, and 63 had tumors that did not. In addition, samples from 22 patients with chronic liver disease and 8 patients with normal liver tissues were used as the controls. The researchers used a set of 17 genes, some which encode messages for cytokines, to analyze the gene expression signatures of immune cells in the nearby vicinity of the tumor. Earlier, they had analyzed gene expression within the liver tumors, but the profile from that study could only predict metastasis in 78 percent of the cases.

The latest study identified a unique 17-gene signature in the liver’s normal immune cells that could predict if a liver tumor would metastasize in 92 percent of the samples. This unique signature is associated with anti-inflammatory and suppressed-immune responses. These combined activities are associated with a poor prognosis of cancer.

The study’s lead author, Dr. Xin Wei Wang of the Liver Carcinogenesis Unit at NCI’s CCR said, “This is the first example where we can stratify HCC patients to identify those who would benefit from certain postsurgical treatments to prevent metastases and recurrence.” 

Two new studies suggest that women treated for breast cancer should have their cardiac health monitored if they receive long-term therapy with trastuzumab (Herceptin) or radiation on their left sides. The findings, published early online August 14 in the Journal of Clinical Oncology, are particularly relevant to women who may be at risk for heart problems prior to treatment for cancer.

In the trastuzumab study, researchers at the University of Texas M.D. Anderson Cancer Center reported that the long-term use of the drug appears to be safe, but that some patients will develop cardiac toxicity. Forty-nine of 173 women with metastatic HER2-positive breast cancer in the study (28 percent) experienced a cardiac event after taking trastuzumab for at least 1 year.

The toxicity was reversible in the majority of patients, and some patients who experienced a cardiac event were considered for additional treatment with trastuzumab after recovering cardiac function. Trastuzumab is the standard treatment for metastatic HER2-positive breast cancer and, for this population, the overall risk of cardiac toxicity from long-term treatment involving trastuzumab is acceptable, the researchers concluded.

The second study, led by Dr. Eleanor Harris of the Moffitt Cancer Center, examined the long-term effects on cardiac health after irradiation of the breast using contemporary techniques. The researchers found that irradiation of the left breast was not associated with an increased mortality from cardiac disease for up to 20 years after treatment, but it was associated with a higher rate of coronary artery disease and myocardial infarction compared with treatment of the right breast.

The results of this and another study suggest that other known risk factors for cardiac disease may interact with the coronary artery that has been damaged by irradiation and further increase the risk of developing ischemic heart disease after treatment. Women treated for left-sided breast cancer should be monitored over the long term for hypertension and other risk factors, and treated accordingly, the researchers said.

While most Americans know that mammograms, Pap tests, and colonoscopies are screening exams for cancer, the majority of Americans do not know the appropriate ages at which initiation of these tests is recommended, according to the latest brief from the Health Information National Trends Survey (HINTS). HINTS, which was developed by NCI, is a nationally representative telephone survey of the general population that was designed to evaluate how the public accesses and uses information about cancer, and how this information can be delivered most effectively.

HINTS data collected in 2005 showed that 57 percent of American women were unaware that they should begin to receive mammograms to screen for breast cancer at age 40. Seventy-nine percent of women were unaware that they do not need to have a Pap test yearly to screen for cervical cancer - current general guidelines advise women to get Pap tests at least once every 3 years. Forty percent of all HINTS respondents could not name a test available to screen for colorectal cancer. However, 54 percent did know that screening for colorectal cancer is recommended for men and women age 50 or older, according to general recommendations.

“We must significantly increase our efforts to inform all Americans of what cancer screening tests are available so that we can catch cancer in its earliest stages when it is most treatable,” said NCI Acting Director Dr. John E. Niederhuber in response to these results. “We need to get into communities with a renewed education effort.”

How Some Tumors Evade Attack by Immune Cells

Researchers have identified a potential mechanism by which some tumors in mice evade attack by antitumor immune cells. Tumors produce a molecule called adenosine that normally serves as a “stop signal” to prevent inflammatory cells from attacking healthy tissue after an infection. The researchers found that when tumors produce adenosine, antitumor T-cell activity is suppressed, and an attack is averted.

“Tumors have hijacked a mechanism that evolved to protect normal tissues from collateral damage that occurs when the body mounts a defense against infection,” said lead investigator Dr. Misha Sitkovsky of Northeastern University. Inflammation caused by the host’s response to infection triggers the release of adenosine from surrounding cells, which binds to so-called A2A adenosine receptors on immune cells and slows the production of damaging inflammatory molecules.

In the study, the researchers genetically and pharmacologically inactivated A2A adenosine receptors in mice, using various substances, including caffeine, to render antitumor T cells less susceptible to inhibition by tumor-produced adenosine. Most of these mice displayed better antitu­mor immune responses and delayed tumor growth than mice with intact A2A adenosine receptors, according to findings reported early online this week in the Proceedings of the National Academy of Sciences.

“Antitumor T cells that lacked A2A adenosine receptors overcame this type of tumor defense mechanism and inhibited tumor growth in a majority of mice,” said co-investigator Dr. Scott Abrams of NCI’s CCR. The genetic inactivation strategy was not effective in about 40 percent of the mice, however. One reason may be the existence of other adenosine receptors in these mice; identifying these molecules will be a focus of future research.

Genetic variants of HPV16 and HPV18 are linked to a woman’s race and the persistence of HPV infection, according to a study in the August 2 Journal of the National Cancer Institute (JNCI).

Researchers from the University of Washington in Seattle analyzed HPV16 and HPV18 nucleotide sequence variations in 1,025 HPV16- and HPV18-positive women. Variants were compared with prototype sequences of HPV16 and HPV18, and were classified as European, Asian, North American, Asian American, African 1, and African 2.

The researchers found that HPV16 and HPV18 African variants were predominant in African American women, while HPV16 and HPV18 European variants were predominant in white women. These variants also are linked to the persistence of HPV infection among different racial groups. HPV16- and HPV18-positive white women with European variants had a greater likelihood of remaining positive for viral DNA than white women with African variants. In contrast, HPV16- and HPV18-positive African American women with European variants had a smaller likelihood of remaining positive for viral DNA than African American women with African variants.

“Given that women with persistent, compared with transient, HPV16 or HPV18 infections are at increased risk of cervical cancer, future studies should be conducted to examine possible mechanisms involving variant-specific immune evasion and their potential clinical therapeutic implications,” the authors noted.

In a JNCI editorial, Drs. Robert D. Burk and Rob DeSalle stated that because of the unknown link between variants and race, “the ‘tangle’ is trying to figure out what these factors might be and how the relationships among virus variation, host variation, and persistence lead to cancer.”