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JNCI May 12 issue tip sheet

Journal of the National Cancer Institute

Numerous Methods Available for Dose Escalation in Phase I Trials

Numerous methods are available for dose escalation in phase I clinical trials, but most trialists continue to use traditional designs, according to a review by Lillian L. Siu, M.D., of the University of Toronto, and colleagues.

The authors describe traditional rule-based designs, as well as newer methods, including model-based designs that aim to more rapidly predict toxic doses. They also discuss trial methods for the assessment of molecularly targeted drugs that rely on biological endpoints rather than toxicity endpoints. Advantages and disadvantages of each of these designs are elucidated, as well.

By searching the literature for phase I trials published in 2007 or 2008, the authors found that the vast majority of phase I studies still use traditional rule-based designs.

"Deriving the optimal (ie, efficient and safe) dose escalation methods for anticancer therapies continues to be a chal¬lenge. However, there are many new designs proposed in recent literature. The use and evaluation of these new methods should be encouraged so that further improvements can be made to expedite the drug development process," the authors conclude.

Contact: Lillian L. Sui;; 416-946-2911

Lymphovascular Invasion Is Not an Independent Risk Factor for Breast Cancer Recurrence

Lymphovascular invasion was associated with poorer outcomes in patients already classified as having high risk breast cancer, but not in patients classified as having low-risk disease.

Prior studies have suggested that lymphovascular invasion by tumor cells was associated with poorer outcome. It has not been clear, however, whether lymphovascular invasion was sufficient reason to upstage a patient from a low-risk category to a high-risk category in the absence of other high-risk disease features.

In the current study, Bent Ejlertsen, M.D., Ph.D., of the Copenhagen University Hospital in Denmark, and colleagues examined the association between lymphovascular invasion and patient outcomes in more than 15,000 women diagnosed with breast cancer between 1996 and 2002 and included in the Danish Breast Cancer Cooperative Group registry.

Lymphovascular invasion was associated with a greater than two-fold increased risk of disease recurrence and nearly a 2.5-fold increased risk of death in women who were classified by other methods as having high risk of disease. It was not associated with a difference in outcomes for patients classified by other methods as having low-risk disease.

"Based on a cohort of more than 15,000 breast cancer patients, our results do not support that lymphovascular invasion has suf¬ficient independent prognostic influence to move patients from a low-risk group to a high-risk group," the authors conclude.

In an accompanying editorial, Nancy E. Davidson, M.D., of the University of Pittsburgh Medical School, and colleagues note that the newly reported data are in conflict with previous reports supporting the association between lymphovascular invasion and poorer patient outcomes. "...[T]he study gave the unexpected and somewhat disappointing result that lymphovascular invasion was associated with adverse outcome in patients who are at high risk for recurrence by other recognized prognostic factors, but not in those who are low risk by the same criteria," the editorialists write. "It is therefore apparently not useful as a means to subdivide the low risk group, the group in which many clinicians and patients would like assistance."

Contact: Article: Bent Ejlertsen, Editorial: Courtney McCrimmon,, 412-715-8894

Immunohistochemistry Tests Distinguish Breast Cancer Subtypes

A panel of four immunohistochemistry tests can distinguish luminal A and B breast cancer subtypes.

No simple immunohistochemical test has been available to distinguish luminal A from B, which are the most common of five breast cancer subtypes defined by gene expression profiling. Luminal B is characterized by more proliferating cells and worse patient prognoses.

In the current study, Torsten O. Nielsen, M.D., Ph.D., of the University of British Columbia in Vancouver, and colleagues subtyped 357 breast tumors by gene expression profiling and tested them for Ki67 expression by immunohistochemistry to determine a cut point that distinguished between luminal A and B tumors. They then examined 2,847 independent breast tumors with four immunohistochemical tests, including estrogen and progesterone receptor expression, Ki67 expression, and HER2 status.

The researchers found that Ki67 was expressed in 13 percent or less of the cells in luminal A tumors. Using that cut point for Ki67 expression, the four immunohistochemistry tests could distinguish between luminal A and luminal B subtypes in the independent series of breast cancers.

"Although we consider breast cancer molecular subtyping by gene expression profiling to be the gold standard, we nevertheless believe that there is an immediate need for well-defined and validated immunopanels for worldwide clinical diagnostic use," the authors conclude.

Contact: Lisa Carver,, 604-708-5283

Formaldehyde Exposure Associated with Risk of Blood and Lymph System Malignancies

Individuals exposed to relatively higher amounts of formaldehyde had a higher rate of death due to blood and lymph system malignancies than those exposed to lower levels of formaldehyde in a large cohort study.

In the National Cancer Institute's formaldehyde cohort, which was previously followed through 1994, formaldehyde exposure was associated with an increased risk of leukemia. In the current study, Laura Beane Freeman, Ph.D., of the NCI in Rockville, Md., and colleagues, extended the follow-up through 2004. The cohort includes 25,619 individuals exposed to formaldehyde at work.

With a median follow-up of 42 years, the investigators observed a positive association between all lymphohematopoietic malignancies and peak formaldehyde exposure, with a 1.37-fold higher risk among those with the highest peak exposures compared with those with the lowest level of peak exposures. There was no statistically significant association with cumulative exposure or average intensity of exposure. An excess risk was seen for several sub-types of these malignancies, most notably myeloid leukemia, with a 1.78-fold higher risk. Myeloid leukemia is the type most often associated with chemical exposures. The level of increased risk was highest earlier in the follow-up period and then declined steadily over time such that the cumulative excess risk no longer reached statistical significance.

"In the current follow-up, the overall risk of myeloid leukemia has declined from our previous report, but remains somewhat elevated. While that time trend may suggest that the previous excess risk estimates were due to chance, the pattern is consistent with a possible causal association, with the largest risks occurring closer in time to relevant exposure," the authors write. "It is our opinion that the overall pattern of risks seen in this extended follow-up of formaldehyde workers, while not definitive, warrants continued concern."

Contact: NCI Press Officers,, 301-496-6641

Disruption of PPAR-d Gene Protects Mice Against Colon Tumors

Mice deficient for the peroxisome proliferator-activated receptor-d (PPAR-d) gene developed statistically significantly fewer colon tumors in response to azoxymethane exposure than did mice carrying intact PPAR-d genes.

PPAR-d is overexpressed in human colon tumors and experimentally-induced rodent tumors, but its role in colon cancer development was unclear.

In the current study, Imad Shureiqi, M.D., of the University of Texas MD Anderson Cancer Center in Houston, and colleagues targeted disruption of PPAR-d to the intestine in mice and then tested the rate of large intestine (colon) tumor formation in response to azoxymethane exposure.

Mice with colons lacking PPAR-d developed 98.5 percent fewer tumors compared with wild-type mice. Additionally, vascular endothelial growth factor expression was suppressed in the mice lacking PPAR-d.

"These findings indicate that PPAR-d has a crucial role in promoting colonic tumorigenesis," the authors write. "Our current demonstration of the substan¬tial involvement of PPAR-d in colonic tumorigenesis should stimulate future efforts to test PPAR-d inhibitors for the treatment and prevention of colon cancer and should serve to caution against clinical testing of PPAR-d agonists without a com¬plete preclinical evaluation of their possible capacity to promote tumorigenesis."

Contact: Robin Davidson,, 713-794-1731


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