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Biomarker activation appears associated with improved survival among obese colorectal cancer patients


Shuji OginoShuji Ogino, MD, PhD 

Among obese patients, activation of the protein biomarker CTNNB1 was associated with better colorectal cancer-specific survival and overall survival, whereas post-diagnosis physical activity was associated with better colorectal cancer-specific survival among patients negative for CTNNB1, according to a study led by Dana-Farber Cancer Institute researchers that was published in the April 27 issue of the Journal of the American Medical Association.

Activation of the WNT signaling pathway (a network of proteins known for their roles in cancer) and cadherin-associated protein beta-1 (CTNNB1; [beta-catenin]) plays a critical role in colorectal carcinogenesis.

Accumulating evidence indicates a role of WNT-CTNNB1 signaling in obesity and metabolic diseases, according to background information in the article.

Considering the dual roles of CTNNB1 in carcinogenesis and energy metabolism, the authors hypothesized that activation of WNT-CTNNB1 signaling might confer proliferative ability to cancer cells.

"In addition, epidemiological evidence suggests causal effects of obesity or excess energy balance on colon cancer incidence and mortality. Notably, physical activity (exercise) has emerged as a modifiable lifestyle factor that may improve cancer survival," the authors write.

The study's first author is Teppei Morikawa, MD, PhD, and the senior author is Shuji Ogino, MD, PhD, both from Dana-Farber.

The researchers conducted a study to examine whether CTNNB1 activation in colorectal cancer modified prognostic associations of body mass index (BMI) and level of postdiagnosis physical activity.

The study included data from two U.S. prospective cohort studies (Nurses' Health Study and the Health Professionals Follow-up Study) to evaluate CTNNB1 among 955 patients with stage I, II, III, or IV colon and rectal cancer from 1980 through 2004.

A model was used to compute the risk of death, adjusting for clinical and tumor features.

During follow-up through June 2009, there were 440 deaths, which included 266 colorectal cancer-specific deaths.

Analysis indicated there was a significant modifying effect of BMI.

In obese patients (BMI 30 or greater), positive status for nuclear CTNNB1 was associated with significantly better colorectal cancer-specific survival (five-year survival: 0.85 for patients with positive nuclear CTNNB1 status versus 0.78 for those with negative status) and overall survival (five-year survival, 0.77 for patients with positive nuclear CTNNB1 status vs. 0.74 for those with negative status).

In contrast, among non-obese patients, positive status for nuclear CTNNB1 was not significantly associated with cancer-specific survival or overall survival.

The authors also found that for patients with negative status for nuclear CTNNB1, high level of post-diagnosis physical activity was associated with significantly better colorectal cancer-specific survival (5-year survival, 0.97 vs. 0.89).

However, for patients with positive status for CTNNB1, physical activity was not associated with colorectal cancer-specific survival or with overall survival.

"These results provide evidence for a possible interactive effect of tumor CTNNB1 signaling and patients' energy balance status in determining tumor cell behavior,” the authors write.

“Our data support the hypothesis that progression of a tumor with an inactive WNT-CTNNB1 signaling pathway might be influenced by energy intake and expenditure, whereas a tumor with an active WNT-CTNNB1 signaling pathway might progress independent of energy balance status,” they added. “Although our data need to be confirmed by independent data sets, tumor CTNNB1 status may serve as a predictive biomarker for response to a prescription for physical activity (exercise) in clinical practice. Because physical activity is a modifiable lifestyle factor, our data may have considerable clinical implications,"

In addition to Ogino and Moirkawa, the paper's other authors are Aya Kuchiba, PhD; Mai Yamauchi, PhD; Jeffrey A. Meyerhardt, MD, MPH; Kaori Shima, DDS, PhD; Katsuhiko Nosho, MD, PhD; and Charles Fuchs, MD, MPH, Dana-Farber; Andrew Chan, MD, MPH, Massachusetts General Hospital; and Edward Giovannucci, MD, ScD, Harvard Medical School.

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