Obese patients with metastatic melanoma who are treated with targeted or immune therapies live significantly longer than those with a normal body mass index (BMI), investigators report in a study of 1,918 patients in six independent clinical cohorts. This effect, referred to as the "Obesity Paradox," principally manifested itself in men, said Dr Jennifer McQuade., lead author and instructor of melanoma medical oncology at The University of Texas MD Anderson Cancer Centre.
"Obese men consistently did much better than men with a normal BMI, with nearly a doubling of overall survival," McQuade said. The researchers found no significant differences in survival between women with normal, overweight or obese BMI.
"The question is what underlying mechanism causes this advantage in obese men, and can we take advantage of it to improve outcomes in patients with melanoma?" McQuade said. "One hint may be the interaction between obesity, sex, and outcomes, which has not been detected before in any cancer."
Women with metastatic melanoma have long been known to have better outcomes compared to men, McQuade noted. In this study obesity overcame that survival disadvantage for men, leading researchers to now look at the possible impact of sex hormones in this effect.
Associations don't prove causation, the researcher's note, but point to new areas to study in greater depth. "The public health message is not that obesity is good. Obesity is a proven risk factor for many diseases," McQuade said. "Even within our metastatic melanoma population, we would not suggest that patients intentionally gain weight. We need to figure out what is driving this paradox and learn how to use this information to benefit all of our patients."
Obesity is a known risk factor for developing 13 types of cancer according to the World Health Organisation and is set to overtake smoking as the leading preventable cause of cancer. The relationship between obesity and survival in patients that already have cancer is not as consistent. Recent studies have shown a similar survival benefit for obese patients with colorectal or kidney cancer.
The team expected to find obesity to be harmful for melanoma patients, based in part on research that implicates obesity in activation of a cancer-promoting molecular pathway called IGF-1/PI3K/AKT. They analysed the association between body mass index (weight divided by height) and progression-free survival (PFS) and overall survival (OS) in six independent cohorts of patients treated with targeted therapy, immunotherapy or chemotherapy in pivotal trials that led to US Food and Drug Administration (FDA) approval of these drugs.
While advantages in PFS and OS emerged in an overall meta-analysis of the entire group, the survival benefit associated with obesity was restricted to men treated with targeted or immunotherapies, where obese men had a 47% decreased risk of death compared to men with normal BMI.
Results from 599 patients receiving combination targeted therapy of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) were: Normal BMI of 18.5-24.9 – median PFS of 9.6 months, OS of 19.8 months; and obese BMI 30 and above – median PFS 15.7 months, OS 33.0 months
A multivariable analysis that included factors such as age, sex, stage, disease burden, certain mutations and prior treatment showed that obesity still improved PFS and OS compared to normal BMI patients.
The team analysed results by sex and found significant differences only among men. Normal BMI men – PFS 7.2 months, OS 16.0 months; and obese men – PFS 12.8 months, OS 36.5 months. By contrast, women, for example, had overall median survival of at least 33 months, regardless of BMI. A validation cohort of 240 patients treated with vemurafenib (BRAF inhibitor) and cobimetinib (MEK inhibitor) yielded similar results.
For immunotherapy, in a cohort (330 patients) treated with checkpoint inhibitors blocking either the PD1 check point on T cells or its PD-L1 ligand, results again showed no differences among women, but: normal BMI men – PFS 2.7 months, OS 14.3 months; and obese men – PFS 7.6 months, OS 26.9 months A cohort of patients treated with the immune checkpoint inhibitor ipilimumab (207 patients) showed similar results. There was no effect of obesity found among two cohorts (541 patients) treated only with the chemotherapy dacarbazine.
The researchers are following up to understand biological factors that might provide an advantage to obese male patients. Obesity is associated with increased inflammation, which could improve the effectiveness of checkpoint blockade drugs that unleash an immune response against cancer.
The sex-specificity of the observed differences points to a potential hormonal mediator. Fat (adipose) tissue produces an enzyme called aromatase that converts male hormones called androgens into oestrogens, female hormones. Perhaps this happens enough in obese men to help them clear some type of hurdle toward greater survival, McQuade said. The researchers are collaborating with investigators at the University of Pennsylvania that have found that turning on a very specific type of oestrogen receptor on melanoma makes it vulnerable to immunotherapy.
The MD Anderson team also is looking at gene expression, mutations and immune profiling to identify potential differences in melanoma in obese and non-obese patients and developing preclinical models.
Background: Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy.
Methods: This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy. Patients were classified according to BMI, following the WHO definitions, as underweight, normal, overweight, or obese. Patients without BMI and underweight patients were excluded. The primary outcomes were the associations between BMI and progression-free survival or overall survival, stratified by treatment type and sex. We did multivariable analyses in the independent cohorts, and combined adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise estimate of the association between BMI and survival outcomes; heterogeneity was assessed with meta-regression analyses. Analyses were done on the predefined intention-to-treat population in the randomised controlled trials and on all patients included in the retrospective study.
Findings: The six cohorts consisted of a total of 2046 patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016. 1918 patients were included in the analysis. Two cohorts containing patients from randomised controlled trials treated with targeted therapy (dabrafenib plus trametinib [n=599] and vemurafenib plus cobimetinib [n=240]), two cohorts containing patients treated with immunotherapy (one randomised controlled trial of ipilimumab plus dacarbazine [n=207] and a retrospective cohort treated with pembrolizumab, nivolumab, or atezolizumab [n=331]), and two cohorts containing patients treated with chemotherapy (two randomised controlled trials of dacarbazine [n=320 and n=221]) were classified according to BMI as normal (694 [36%] patients), overweight (711 [37%]), or obese (513 [27%]). In the pooled analysis, obesity, compared with normal BMI, was associated with improved survival in patients with metastatic melanoma (average adjusted hazard ratio [HR] 0·77 [95% CI 0·66–0·90] for progression-free survival and 0·74 [0·58–0·95] for overall survival). The survival benefit associated with obesity was restricted to patients treated with targeted therapy (HR 0·72 [0·57–0·91] for progression-free survival and 0·60 [0·45–0·79] for overall survival) and immunotherapy (HR 0·75 [0·56–1·00] and 0·64 [0·47–0·86]). No associations were observed with chemotherapy (HR 0·87 [0·65–1·17, pinteraction=0·61] for progression-free survival and 1·03 [0·80–1·34, pinteraction=0·01] for overall survival). The association of BMI with overall survival for patients treated with targeted and immune therapies differed by sex, with inverse associations in men (HR 0·53 [0·40–0·70]), but no associations observed in women (HR 0·85 [0·61–1·18, pinteraction=0·03]).
Interpretation: Our results suggest that in patients with metastatic melanoma, obesity is associated with improved progression-free survival and overall survival compared with those outcomes in patients with normal BMI, and that this association is mainly seen in male patients treated with targeted or immune therapy. 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, Carrie R Daniel, Kenneth R Hess, Carmen Mak, Daniel Y Wang, Rajat R Rai, John J Park, Lauren E Haydu, Christine Spencer, Matthew Wongchenko, Stephen Lane, Dung-Yang Lee, Mathilde Kaper, Meredith McKean, Kathryn E Beckermann, Samuel M Rubinstein, Isabelle Rooney, Luna Musib, Nageshwar Budha, Jessie Hsu, Theodore S Nowicki, Alexandre Avila, Tomas Haas, Maneka Puligandla, Sandra Lee, Shenying Fang, Jennifer A Wargo, Jeffrey E Gershenwald, Jeffrey E Lee, Patrick Hwu, Paul B Chapman, Jeffrey A Sosman, Dirk Schadendorf, Jean-Jacques Grob, Keith T Flaherty, Dana Walker, Yibing Yan, Edward McKenna, Jeffrey J Legos, Matteo S Carlino, Antoni Ribas, John M Kirkwood, Georgina V Long, Douglas B Johnson, Alexander M Menzies, Michael A Davies
[link url="https://www.mdanderson.org/newsroom/2018/02/obesity-associated-with-longer-survival-for-men-with-metastatic-melanoma.html"]University of Texas MD Anderson Cancer Centre material[/link]
[link url="http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30078-0/fulltext?elsca1=tlxpr"]The Lancet Oncology article summary[/link]