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AACR Annual Meeting Coverage

APC 5-Year Results: Adenoma Recurrence Reduced, Cardiac Risks Clearer

The 5-year results of the Adenoma Prevention with Celecoxib (APC) trial indicate that 2 years after daily use of celecoxib (Celebrex) has ended, there continues to be a modest reduction in the recurrence of colorectal polyps.

Initially presented at the 2006 AACR annual meeting, the trial's results showed that compared with placebo, adenoma recurrence and advanced adenoma recurrence were significantly reduced in participants who took celecoxib daily for 3 years. Participants, all of whom had previously had lesions removed, had significantly fewer total adenomas and advanced adenomas at 3 years.

Speaking yesterday at the 2008 AACR annual meeting in San Diego, CA, the trial's lead investigator, Dr. Monica Bertagnolli, reported that although the effect diminished after the drug was discontinued, a treatment benefit was still present at 5 years. Celecoxib use, however, was associated with an increased risk of serious side effects, including heart attacks and strokes. The safety analysis suggests that these serious adverse events were greatest in participants with pre-existing cardiovascular risk factors.

Overall, compared with participants in the placebo arm, advanced adenoma risk was reduced by 41 percent among patients taking the 400 mg/day dose and 26 percent among patients taking the 800 mg/day dose.

Cardiovascular events were far more likely among participants who had at least two pre-existing cardiovascular risk factors (e.g., high blood pressure, diabetes, age of more than 65 years) at study entry: 5.9 percent of participants in the placebo arm, compared with 8.2 percent in the 400 mg/day arm and 11.2 percent in the 800 mg/day arm, reported a cardiovascular adverse event. By contrast, for APC participants who had no cardiovascular risk factors at study entry, the rates of cardiovascular adverse events were 0.9 percent, 3.9 percent, and 1.9 percent, respectively.

The results, said Dr. Bertagnolli, of Brigham and Women's Hospital demonstrate that COX-2 inhibitors "are risky for some patients." But, she continued: "Our study also shows that for patients without major cardiovascular risk factors, celecoxib at low doses protects against high-risk lesions that can lead to colon cancer."

These results come on the heels of a more extensive, NCI-funded cross-study safety analysis of six placebo-controlled studies involving celecoxib. These data were presented in late March at the annual meeting of the American College of Cardiology. That analysis showed a threefold increased risk of cardiovascular events in patients given the highest celecoxib dose, but also showed that risk was significantly higher among study participants with underlying cardiovascular risk factors.

Finding and Studying Pancreatic Cancer Stem Cells

A refined strategy for isolating cancer stem cells in pancreatic tumors and preliminary evidence that these rare cells may influence patient survival were presented at the 2008 AACR annual meeting. The results are from a series of studies at the Johns Hopkins Kimmel Cancer Center aimed at understanding the potential role of pancreatic cancer stem cells in this deadly disease.

The cancer stem cell hypothesis holds that many cancers are initiated and driven by these elusive cells, which are capable of perpetuating themselves while giving rise to tumors.

In 2003, lead investigator Dr. William Matsui and his colleagues identified cancer stem cells in patients with multiple myeloma, a cancer of the bone marrow. Building on this work, the researchers have now developed a strategy for isolating potential pancreatic cancer stem cells that integrates markers from different studies.

The strategy combines the surface proteins CD44 and CD24 (used last year by a University of Michigan team to identify pancreatic cancer stem cells) with the enzyme aldehyde dehydrogenase, which was a marker in the Hopkins multiple myeloma studies.

Using all three markers together yielded a stem cell population that was 2 to 10 times more concentrated than using either type of marker alone, Dr. Zeshaan Rasheed from Johns Hopkins reported at AACR.

In further studies, the researchers found that patients whose tumors lack the cancer stem cell markers live a few months longer than other patients. This difference may be meaningful in a disease in which most patients die within a year of diagnosis.

"We're starting to get some inkling that these cells are clinically relevant in this disease," noted Dr. Matsui. His team has been investigating whether cancer stem cells contribute to metastasis, and a publication describing all of the studies is planned.

Synthetic Vitamin D Shows Anti-cancer Effect and No Toxicity in Mice and Rats

Researchers at Rutgers University have developed a form of active vitamin D called Gemini 0097 that dramatically reduced the growth of both ER-positive and ER-negative breast cancer cells and showed no toxicity in rats and mice. Dr. Nanjoo Suh presented the results of her team's study at AACR yesterday.

The active form of vitamin D is a hormone synthesized by the skin, liver, and kidneys from dietary precursors. Epidemiological studies have shown that people deficient in active vitamin D have a higher risk of colorectal, breast, prostate, and other cancers.

Clinical studies using vitamin D supplements to prevent cancer have produced mixed results, in part because of the fact that high doses of vitamin D in its active form can cause an imbalance in other electrolytes, including toxic levels of calcium in the blood. For this reason, researchers have been testing analogs of vitamin D, chemically modified forms of the vitamin that have a slightly different molecular structure.

The Rutgers team tested 60 new analogs of active vitamin D against a placebo in rats that had been exposed to mammary carcinogens. One of the analogs, Gemini 0097, was superior for preventing tumor development, cutting ER-positive breast cancer growth by 60 percent. In a mouse model of ER-negative breast cancer, Gemini 0097 reduced tumor development by 50 percent. Blood calcium levels remained normal in mice and rats that received the analog treatment.

"Our analog has a side-chain that makes the molecule much bulkier than naturally occurring vitamin D, such that the binding of the molecule to its receptor is only 40 percent, but somehow the activity is better," explained Dr. Suh. She speculated that this superior activity may be caused by alternative recruitment of co-factors to the vitamin D receptor. Dr. Suh noted that more data from animal studies are needed before Gemini 0097 is tested in humans.

Reduction in Breast Cancer Incidence Differs by Race

Recent studies have reported that after rising for two decades, the breast cancer incidence rate in the United States dropped sharply between 2002 and 2003 and continued to decline in 2004. However, new research presented April 15 at the 2008 AACR annual meeting shows that this decline was not equally distributed across racial groups.

Investigators from the University of Chicago used data from 17 cancer registries of the Surveillance, Epidemiology, and End Results program to calculate changes in incidence for invasive and in situ female breast cancer between 2000 and 2004 by race and tumor stage in women aged 50 to 69.

The incidence rate of in situ cancer remained stable in most groups of women. However, the investigators found that while rates of invasive breast cancer decreased significantly for Caucasian women by the end of 2003, the incidence rates did not change significantly for African American, American Indian/Alaskan Native, or Asian American/Pacific Islander women.

"This racial disparity is consistent with the hypothesis that discontinuation of hormone replacement therapy (HRT) may have caused the dramatic reduction," stated the authors in their abstract presented at AACR.

"We suspect that the widespread discontinuation of menopausal hormone use had a greater effect on Caucasians," said Dr. Dezheng Huo in a press release from the University of Chicago.

African Americans are less likely to develop breast cancers that are receptive to estrogen, Dr. Huo explained, so they were harmed less by taking hormones and benefited less by discontinuing them.

In addition, African Americans had "a similar magnitude of reduction in hormone therapy," said Dr. Huo, "yet it did not lead to any benefit, suggesting that genetic variations in estrogen and progesterone metabolism play a role."