This article is more than 5 years old. Information may no longer be current.
Obesity may extend survival for men with metastatic melanoma
Click Here to Manage Email Alerts
Obesity appeared associated with improved survival among men with metastatic melanoma who underwent treatment with targeted therapy or immunotherapy, according to results of a pooled analysis.
“These results have implications for the design of future clinical trials for patients with metastatic melanoma, and the magnitude of the benefit found supports further investigation of the underlying mechanism of these associations,” Jennifer L. McQuade, MD, instructor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, and colleagues wrote.
Researchers pooled data from 1,918 patients who received targeted therapy, immunotherapy or chemotherapy between Aug. 8, 2006, and Jan. 15, 2016.
Of these, 839 patients participated in randomized controlled trials of targeted treatment with dabrafenib (Tafinlar, Novartis) plus trametinib (Mekinist, Novartis; n = 599) or vemurafenib (Zelboraf, Genentech) plus cobimetinib (Cotellic, Genentech; n = 240).
Another 538 patients received treatment with immunotherapy. These included 207 patients who participated in a randomized controlled trial of ipilimumab (Yervoy, Bristol-Myers Squibb) plus dacarbazine, and 331 patients from a retrospective cohort who received pembrolizumab (Keytruda, Merck) nivolumab (Opdivo, Bristol-Myers Squibb) or atezolizumab (tecentriq, Genentech).
Another 541 patients received chemotherapy.
For this study, the researchers classified all patients into one of three WHO BMI categories: normal (n = 694; 36%), overweight (n = 711; 37%) or obese (n = 513; 27%).
Results of the pooled analysis showed obese patients achieved improved PFS (adjusted HR = 0.77; 95% CI, 0.66-0.9) and OS (adjusted HR = 0.74; 95% CI, 0.58-0.95) compared with those who had normal BMI.
However, the survival benefit observed with obesity appeared limited to those treated with targeted therapy and immunotherapy.
In addition, the association between BMI and OS varied by sex.
In the subgroup of patients treated with targeted therapy or immunotherapy, obesity appeared associated with a near doubling of OS (HR = 0.53; 95% CI, 0.4-0.7) among men but did not appear associated with improved OS among women.
HemOnc Today spoke with McQuade about the study, the potential explanation for the “obesity paradox” observed in this analysis, and the possible reasons behind the survival differences between men and women.
Question: How did this study come about?
Answer: In clinic, our patients want to know if there is something they can do in terms of diet or lifestyle to improve their outcomes. The relationship between obesity and cancer has been studied in many other malignancies but has not been well studied in melanoma. We previously found that, in early-stage melanoma, obesity appeared associated with worse melanoma-specific survival and OS. This relationship had not been studied in metastatic melanoma, and there was a strong biological rationale to examine obesity in this disease. In other cancers in which obesity has been shown to increase cancer progression, one of the key mechanisms was through PI3 kinase pathway activation. In our lab and others, this pathway has been shown to mediate resistance to both targeted therapy and immunotherapy.
Q: How did you conduct the study?
A: We conducted a retrospective review of data from more than 1,900 patients from six independent cohorts, including many of the clinical trials that led to the FDA approval of these agents. We classified patients according to BMI, following WHO definitions, as underweight, normal, overweight or obese. We excluded patients without BMI data and those who were underweight.
Q: What did you expect you would find?
A: We thought obesity would be associated with worse outcomes among patients with metastatic melanoma treated with either targeted or immune therapy.
Q: What did the results show?
A: Completely contrary to our hypothesis, we found that obesity appeared associated with significantly improved OS and PFS in metastatic melanoma. Interestingly, this varied by treatment — obesity appeared associated with improved outcomes with both immunotherapy and targeted therapy but not chemotherapy. The effects were quite large and remained significant after adjustment for conventional prognostic factors, including age, sex, stage, lactate dehydrogenase and performance status. We then wanted to know if this could be secondary to medications that obese patients are more likely to take for metabolic syndrome that may have anticancer activity. As expected, patients with obesity appeared more likely to take metformin, aspirin, statins, and beta-blockers, but the BMI effect was independent of these medications. We next examined treatment tolerance as a potential mechanism, such as whether patients with obesity are better able to tolerate treatment. However, we did not see any difference in the rate of adverse events between those with normal BMI and obese patients. More telling, we saw the BMI association among patients treated with immunotherapy and targeted therapy — which do not typically cause weight loss — and not with chemotherapy, which does cause weight loss. We additionally separately looked at men and women, as we have known for a long time that females have a survival advantage in melanoma, and we observed a sex difference in BMI distribution. We found BMI does not really matter among women; women do well regardless of BMI. Men with obesity had similar survival outcomes as women. Men with normal BMI had much worse outcomes. Thus, it appears that obesity overcomes the survival disadvantage associated with male sex in melanoma.
Q: What are the potential clinical implications of your findings?
A: In the context of other data, this research suggests that the association between obesity and outcomes in cancer varies based on the specific cancer type, stage, treatment and sex. We need to understand this complexity to be able to make appropriate recommendations for our patients. Ultimately, we need to understand the biological basis for this ‘obesity paradox’ so we can design rational interventions to improve outcomes.
Q: Is there anything else that you would like to mention?
A: The next research steps will involve understanding the biology. We are examining potential differences by BMI in both tumor biology and host immune response. However, the sex differences point toward a potential hormonal mediator. Todd Ridky, MD, PhD, and colleagues at University of Pennsylvania, demonstrated that melanoma expresses a G-protein-coupled ER that drives differentiation and immunogenicity, and that G-protein-coupled ER activation synergizes beautifully with anti-PD-1 in preclinical trials. – by Jennifer Southall
Reference:
McQuade JL, et al. Lancet Oncol. 2018;doi:10.1016/S1470-2045(18)30078-0.
For more information:
Jennifer L. McQuade, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: jmcquade@mdanderson.org.
Disclosure: McQuade reports no relevant financial disclosures.