Intriguing: Better Survival in Melanoma in Obese Men

Alexander M. Castellino, PhD

February 16, 2018

An analysis of nearly 2000 patients with metastatic melanoma who were treated with targeted therapies or immunotherapies has found that for patients who were classified as obese (ie, who had a body mass index [BMI] ≥30), survival was significantly longer than for patients who were of normal weight. But this finding was noted only in male patients — women did not show this effect.

"Obese men consistently did much better than men with a normal BMI, with nearly a doubling of overall survival," said lead author Jennifer McQuade, MD, who is an instructor of melanoma medical oncology at the University of Texas MD Anderson Cancer Center (MDACC), Houston. There were no significant differences in survival between women with normal BMI, those who were overweight, and those who were obese.

The finding comes from analyses of six cohorts of 1918 patients. Treatment regimens differed among cohorts and ranged from targeted approaches with BRAF/MEK inhibitors, immunotherapies, and chemotherapies. The improved, durable responses were seen in patients with stage IV metastatic melanoma who were treated with targeted therapies and immunotherapies but not with cytotoxic chemotherapy.

The study was published online February 12 in Lancet Oncology.

A similar phenomenon has been described in other cancers, note Andrew J. Hayes, MBBS, PhD, and James Larkin, MD, PhD, of the Royal Marsden National Health System Trust, London, United Kingdom, in an accompanying commentary.

Observational studies across several tumor types have shown that a moderate increase in BMI is associated with improved outcomes at the time of treatment and during follow-up periods. "However, this protective effect is almost universally reversed as BMI increases to the morbidly obese level, an effect referred to as the obesity paradox," the editorialists note.

Unlike these previous studies, in this study in patients with metastatic melanoma, "there is a linear relation between benefit and increasing BMI in male patients through to the morbidly obese levels," Hayes and Larkin note. This supports the idea that there may be an underlying biological mechanism, they add.

Study Design and Cohort Populations

In previous studies, obesity was found to be associated with increased risk for melanoma in men, and in a large cohort of patients with surgically resected melanoma, a higher BMI was associated with worse outcomes. In light of these findings, the researchers postulated that obesity would be associated with worse outcomes in patients with metastatic melanoma who were treated with contemporary therapies. But what they found was the opposite.

For their study, the researchers collated data from six clinical cohorts of patients with metastatic melanoma who underwent treatment with three classes of approved therapies — targeted therapy (BRAF/MEK inhibitors), immunotherapy, or chemotherapy (two cohorts each).

For each cohort, the researchers assessed the association between BMI and clinical outcomes (progression-free survival [PFS] and overall survival [OS]). Kaplan-Meier PFS and OS curves were generated across BMI categories and by sex.

Any model that showed an association between BMI and survival was adjusted for prognostic factors, which included age, disease status, lactate dehydrogenase status, and performance status, among others.

Of the six cohorts, two were treated with the targeted agents dabrafenib and trametinib (n = 599) or vemurafenib and cobimetinib (n = 240); two (n = 320 and n = 221) were treated with dacarbazine; one (n = 207) was treated with a combination of dacarbazine and the immunotherapy ipilimumab; and one (n = 331) was treated with an anti–programmed cell death immunotherapy (pembrolizumab, nivolumab, or atezolimumab).

Across all six cohorts, 36% of patients had normal weight (BMI, 18.5 - 24.9), 37% were overweight (BMI, 25.0 - 29.9), and 27% were obese (BMI ≥30).

Significant Effect on Survival in Men

In the cohort of patients who received dabrafenib and trametinib, median PFS for those with a normal BMI was 9.6 months, and median OS was 19.8 months. However, in patients who were obese, median PFS was 15.7 months, and median OS was 33.0 months.

The difference in survival between patients of normal weight and obese patients was shown to be statistically significant only for OS and only for men. The median OS for men of normal weight was 16.0 months, vs 36.5 months for obese men.

The difference in PFS trended to significance. Median PFS for men of normal weight was 7.4 months, vs 12.8 months for obese men. The researchers also carried out an analysis of BMI as a continuous variable. In this analysis, there was a dose-dependent inverse relation between BMI and PFS that extended through morbid obesity.

By contrast, for women with a normal BMI, the median PFS was 14.5 months, compared with a median PFS of 17.1 months for obese women. Median OS was at least 33 months both for women with a normal BMI and for obese women.

Similar trends were reported for cohorts that received vemurafenib plus cobimetinib, ipilimumab plus dacarbazine, and pembrolizumab, nivolumab, or atezolimumab.

However, the obesity effects on PFS and OS were not seen for the two cohorts that received chemotherapy (dacarbazine) alone.

Underlying Mechanism?

McQuade and colleagues note that in their study, a dose effect of BMI with modestly improved outcomes in overweight patients and a strong, consistent survival advantage in obese patients suggest an underlying biological mechanism.

The sex specificity may point to a potential hormonal mediator, the researchers suggest. "Fat (adipose) tissue produces an enzyme called aromatase that converts male hormones called androgens into estrogens, female hormones. Perhaps this happens enough in obese men to help them clear some type of hurdle toward greater survival," McQuade commented in a statement.

The researchers are collaborating with investigators at the University of Pennsylvania who have discovered that turning on a very specific type of estrogen receptor on melanoma tissue makes it vulnerable to immunotherapy.

Obesity Is Major Risk Factor

In their editorial, Hayes and Larkin note that, given the overwhelming evidence that obesity is a major risk factor for developing and dying from cancer, these results should not be extrapolated. These results apply only to male patients with one tumor type who are undergoing targeted therapy or immunotherapy, and the relation between obesity and cancer is complex.

"However, some overweight patients with melanoma who are under active treatment might be reassured that the oft cited negative association of obesity with cancer outcome does not apply to them at that point in time," they opine.

McQuade agreed. "The public health message is not that obesity is good. Obesity is a proven risk factor for many diseases," she 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," she added.

The study was supported by the MDACC Melanoma Moonshot Program, the MDACC Melanoma Specialized Programs of Research Excellence program, and the Dr Miriam and Sheldon G. Adelson Medical Research Foundation. Dr McQuade has disclosed no relevant financial relationships. Many coauthors have relationships with pharmaceutical companies, and some are employees of Dr Hayes and Dr Larkin.

Lancet Oncol. Published online February 12, 2018. Abstract, Commentary

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