Studies Show Complex Effect of Obesity in Cancer

Better survival with obesity in one study, worse in another

Different types and stages of cancer appeared to respond differently to the influence of obesity, results of two studies showed.

Overweight and obese patients with metastatic renal cell carcinoma (RCC) lived significantly longer than their normal-weight counterparts, according to analyses of two large cohorts of patients with metastatic RCC. Body mass index (BMI) had a difference possibly related to fatty acid synthase (FASN) gene expression. FASN expression had an inverse correlation with body mass index, and low expression was associated with significantly better survival.

On the other hand, a separate analysis indicated that patients with early-stage colorectal cancer had worse survival if they were obese and had metabolic syndrome.

Both studies were reported online in the Journal of Clinical Oncology.

"In two large and distinct clinical data sets, we demonstrate that BMI affects mRCC clinical outcomes, even after adjustment for known prognostic factors," Toni Choueiri, MD, of Dana-Farber Cancer Institute in Boston, and co-authors concluded. "[We] showed that FASN pathway activation is associated with BMI and survival. This suggests an integral role for fatty acid metabolism in the prognosis of patients with mRCC and lays the groundwork for future therapeutic interventions that target the FASN pathway."

Evaluating metabolic dysregulation further stratified the hazards associated with obesity in the study of patients with colorectal cancer.

"Metabolic dysregulation helps identify a subgroup of obese patients who are at high risk," Elizabeth M. Cespedes Feliciano, ScD, of Kaiser Permanente in Oakland, Calif., said in an email. "Each additional metabolic risk factor present at diagnosis increased the risk of death, independent of body mass index. Whether optimizing clinical management of metabolic syndrome in newly diagnosed colorectal cancer patients leads to improved survival will be an important area for future research."

"For now, considering metabolic dysfunction identifies a group of obese patients who are at high risk and should be monitored closely," said Cespedes Feliciano, who was not involved in either study. "Further, not just body mass index and body weight, but also body composition and muscularity should be considered when guiding patients and assessing their risk level."

The result of the RCC study should not be interpreted as making a case that "obesity is a good thing if you have certain types of cancer," said Jennifer Ligibel, MD, a member of the American Society of Clinical Oncology Working Group on Obesity. "There really is no data to support that at all."

Many patients with advanced cancers develop cachexia, which was not specifically addressed in the RCC study but could have been a factor in the findings, added Ligibel, who also is from Dana-Farber but did not participate in the study. The analysis also did not examine the relationship between FASN expression and cachexia.

The data from the study of patients with colorectal cancer are consistent with other studies, Ligibel continued.

"We know obesity is a risk factor for many, many kinds of cancer, and it's increasingly being found to be a prognostic factor in early-stage disease for several types of malignancy," she said.

Better Survival in Obese Patients

Some evidence has suggested that RCC in obese patients has a more indolent clinical course. Continuing investigation of the issue, Choueiri and colleagues examined the relationship between BMI and treatment outcomes in 1,975 patients in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and in an external validation cohort of 4,657 patients.

Investigators also conducted gene expression profiling of The Cancer Genome Atlas (n=61), focusing on the fatty acid metabolism pathway, and performed immunohistochemistry staining for FASN. They defined a high BMI as ≥25.

In the IMDC cohort, patients with a high BMI had a median overall survival of 25.6 months compared with 17.1 months for patients with a BMI <25 (HR 0.84, 95% CI 0.73 to 0.95). Similar results emerged from the validation cohort, as patients with a high BMI had a median overall survival of 23.4 months versus 14.5 months for the low-BMI subgroup (HR 0.83, 95% CI 0.74 to 0.93).

Gene-expression profiling results showed that FASN expression had a significant inverse correlation with BMI (P=0.034). Additionally, low FASN expression was associated with median overall survival of 36.8 months compared with 15.0 months for low FASN expression (P=0.002).

FASN immunohistochemistry proved to be positive more often in IMDC poor- and intermediate-risk groups (48% and 34%, respectively) as compared with the favorable-risk group (17%, P=0.015 for trend).

Obesity and Metabolic Syndrome

Obesity is an established risk factor for colorectal cancer, but data regarding its effect on survival remain inconsistent, Cespedes Feliciano and co-authors noted in their background information. The inconsistent survival data reflect incomplete understanding of the underlying mechanisms of obesity's relationship to cancer survival.

Obesity and metabolic dysfunction may act synergistically to influence cancer survival, they continued. Obesity and associated insulin resistance create a chronic inflammatory environment that may contribute to increased tumor aggression and worse prognosis. Better insulin sensitivity may help reduce levels of pro-inflammatory molecules.

No previous study had examined the effect of metabolic syndrome in combination with obesity on cancer survival. To address the issue, the authors analyzed data for 2,446 patients with early-stage colorectal cancer (stages I-III). They hypothesized that metabolic syndrome and obesity would identify patients with poor survival, independent of other prognostic factors, such as disease stage and treatment.

Diagnosis of metabolic syndrome was based on presence of at least three of the following: fasting glucose >100 mg/dL or diagnosed diabetes; systolic blood pressure ≥130 mm Hg, diastolic pressure ≥85 mm Hg, or treatment with antihypertensives; HDL cholesterol <40 mg/dL in men or <50 mg/dL in women; triglycerides ≥150 mg/dL or treatment with lipid-modifying agents; and highest quartile sex-specific quartile of visceral fat determined by computed tomography (a surrogate for waist circumference). They defined obesity as BMI of at least 30.

During a median follow-up of 6 years, 601 patients died, including 325 who died of colorectal cancer. As compared with the reference status of nonobese and absence of metabolic syndrome (n=1,225), obese patients with metabolic syndrome had a survival hazard ratio of 1.45 (95% CI 1.12 to 1.82). Presence of both obesity and metabolic syndrome increased the hazard ratio for colorectal cancer death to 1.49 versus patients without either characteristic (95% CI 1.09 to 2.02). The presence of metabolic syndrome or obesity without the other did not significantly increase either survival hazard.

The authors also found that the hazard for death increased with the number of metabolic syndrome components, independent of obesity.

The use of CT imaging to define visceral adiposity distinguished the study from previous investigations, the authors noted. BMI values do not differentiate between fat and lean mass, which can exert different influences on metabolic dysregulation and cancer survival.

Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner

last updated 09.09.2016

Primary Source: Journal of Clinical OncologyAlbiges L, et al "Body mass index and metastatic renal cell carcinoma: Clinical and biological correlations" J Clin Oncol 2016; DOI: 10.1200/JCO.2016.66.7311.

Secondary Source: Journal of Clinical OncologyCespedes Feliciano EM, et al "Metabolic dysfunction, obesity, and survival among patients with early-stage colorectal cancer" J Clin Oncol 2016; DOI: 10.1200/JCO.2016.67.4473.

This article was first published on MedPage Today and reprinted with permission from UBM Medica. Free registration is required.

Disclosures:

Charles Bankhead, Staff Writer, F Perry Wilson, MD, MSCE; Assistant Professor, Section of Nephrology, Yale School of Medicine, Reviewer, and Dorothy Caputo, MA, BSN, RN, Nurse Planner, have disclosed that they have no relevant financial relationships or conflicts of interest with commercial interests related directly or indirectly to this educational activity.The staff of Projects In Knowledge®, Inc. and the staff of MedPage Today have no relevant financial relationships or conflicts of interest with commercial interests related directly or indirectly to this educational activity.

Choueiri disclosed relationships with the National Comprehensive Cancer Network, UpToDate, Pfizer, Bayer HealthCare, Novartis, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Genentech, Eisai, Prometheus, Foundation Medicine, Exelixis, TRACON Pharmaceuticals, AstraZeneca, and Peloton Therapeutics. Several co-authors disclosed relationships with multiple commercial interests.

Cespedes-Feliciano disclosed no relevant relationships with industry. One or more co-authors disclosed relationships with SynDevRx, Pfizer, and Valeant Pharmaceuticals.