PSA Velocity Distinguishes More Lethal Prostate Cancer

Screening for prostate specific antigen (PSA) can detect early stage prostate cancer, but evidence is mixed about whether this knowledge improves health outcomes, according to the U.S. Preventive Services Task Force. However, new findings in the November 1 Journal of the National Cancer Institute (JNCI) indicate that the change in PSA over time (PSA velocity) is a better marker for more aggressive prostate cancers (see related article); thus, the authors concluded that PSA screening should begin earlier to capture a more dynamic view of prostate carcinogenesis.

Dr. H. Ballantine Carter and colleagues of Johns Hopkins University and the National Institute on Aging (NIA) showed that men whose PSA rises less than 0.35 ng/mL per year have only an 8 percent chance of prostate cancer death 25 years after their velocity was determined. This risk is nearly five times lower than men whose PSA velocity rises more quickly than 0.35 ng/mL per year, 46 percent of whom will succumb to their disease in that same time frame.

The researchers were able to look back at data from a large, ongoing prospective cohort study begun by NIA in 1958 and test blood samples for PSA in 980 men - 124 of whom were eventually diagnosed with prostate cancer. In a related editorial, Dr. Timothy R. Church of the University of Minnesota said the study encourages optimism about the value of PSA velocity, though it had "weaknesses…and the implication of the results is not straightforward."

And while the study did not examine whether men with high PSA velocity might have benefited from early treatment, the authors concluded that "as much as 10 to 15 years before diagnosis, it would appear that PSA velocity is an indicator of disease that is destined to progress and threaten life."

Tobacco Use Decline Has Stalled, CDC Report Shows

The overall prevalence of smoking among U.S. adults was the same as in the previous year, in contrast to a steady decline seen over the last 8 years. This news, based on data from the Centers for Disease Control and Prevention's (CDC) annual National Health Interview Survey (NHIS), was reported in the October 27 Morbidity and Mortality Weekly Report.

The NHIS questionnaire was administered to a nationally representative sample of 31,428 people aged 18 years or older. The survey found that, in 2005, an estimated 20.9 percent of U.S. adults - 45 million people - were current cigarette smokers (people who had smoked at least 100 cigarettes during their lifetimes, and were now smoking every day or on some days); 80.8 percent smoked every day, and 19.2 percent smoked some days. As in past years, there were striking differences between population groups. For example, smoking prevalence among highly educated Americans (those with graduate degrees) fell to 7.1 percent, while prevalence among those with a GED was 43.2 percent. Prevalence was also higher among people living below the poverty level than among those at or above the poverty level (29.9 percent vs. 20.6 percent).

The authors cite smaller annual increases in the price of cigarettes, increased tobacco industry expenditures on price discounts, and a significant drop in state tobacco control program funding as possible contributors to their findings. "The huge differences in smoking rates associated with income, education, and other factors are of great concern to tobacco control researchers and practitioners," said Dr. Cathy Backinger, acting chief of NCI's Tobacco Control Research Branch in the Division of Cancer Control and Population Sciences (DCCPS).

More information about tobacco use and cancer can be found at http://www.cancer.gov/cancertopics/smoking.

New Therapeutic Target Identified in Retinal Tumors

A new study published in the November 2 Nature has shown that overexpression of a protein in the p53 cell-signaling pathway called MDMX allows retinoblastoma cells to survive and proliferate. While previous studies have implicated mutations in the tumor-suppressor gene RB1 as necessary for the formation of retinoblastoma, researchers had thought that these tumors developed independently of mutations in the p53 pathway.

The investigators from St. Jude Children's Research Hospital in Memphis first determined that MDMX was overexpressed in retinoblastoma tissue samples and that the p53 pathway downstream of MDMX was fully functional in several retinoblastoma cell lines. They next induced MDMX expression in a mouse model of retinoblastoma. Expression of the protein promoted both proliferation and survival in cells that were genetically susceptible to malignant transformation.

When the investigators introduced MDMX into cultured human retinas, cell death was suppressed even if RB1 was inhibited at the same time. When a mutant form of MDMX that cannot bind to p53 was introduced in place of normal MDMX, cells underwent apoptosis (cell death).

The investigators next tested a small-molecule inhibitor called nutlin-3 on retinoblastoma in vitro and in vivo. Nutlin-3 was able to inhibit MDMX from binding to p53 in vivo, and a subconjunctival injection of nutlin-3 plus the chemotherapy drug topotican synergistically killed retinoblastoma cells in a mouse model, with no systemic or eye complications.

The authors encourage further clinical examination of this drug combination: "On the basis of our preclinical studies, we propose that subconjunctival administration of these two drugs could achieve the same synergistic effect in individuals with retinoblastoma without causing the side effects associated with prolonged systemic exposure to broad-spectrum chemotherapeutic drugs."

Epirubicin Improves Standard Breast Cancer Chemotherapy

The addition of several treatment cycles with the anthracycline drug epirubicin (Ellence) to the standard adjuvant chemotherapy regimen for early breast cancer significantly increased relapse-free and overall survival rates compared with patients using the standard therapy alone, according to an analysis of two studies in the November 2 New England Journal of Medicine.

The National Epirubicin Adjuvant Trial (NEAT) and the BR9601 trial included 2,391 women who received either the combination of four cycles of epirubicin and the standard CMF regimen (cyclophosphamide, methotrexate, and fluorouracil) or CMF alone. At a median follow-up of 48 months, the relapse-free and overall survival rates were significantly higher in the epirubicin-CMF groups than in the CMF-alone groups - the 2-year relapse-free survival was 91 percent vs. 85 percent, and the 2-year overall survival was 95 percent vs. 92 percent.

"The overall incidence of adverse effects was significantly higher with epirubicin plus CMF than with CMF alone but did not significantly affect the delivered-dose intensity or the quality of life," reported the researchers, led by Dr. Christopher J. Poole of the Cancer Research U.K. Clinical Trials Unit in the United Kingdom.

In an accompanying editorial, Dr. Mark N. Levine and Timothy Whelan noted as background that the 2000 NIH Consensus Conference recommended anthracycline-containing regimens for the adjuvant treatment of breast cancer. Although the analysis of the two studies showed modest benefit from adding epirubicin to the standard CMF regimen, the editorial cautioned that the considerable toxic effects and costs require that physicians "tailor the aggressiveness of the chemotherapy to the risk of recurrence" in each patient.