Those with a higher body mass index who are given atezolizumab to treat cancer have an improved rate of survival

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Above average or high BMI – often linked to cancers, diabetes, cardiovascular and other diseases – may in some cases improve the chance of survival among certain cancers, new research from Flinders University indicates.

Focusing on clinical trials of atezolizumab, a common immunotherapy treatment for non-small-cell lung cancer (NSCLC), the Australian cancer researchers found improved responsiveness to the drug in those with a high body mass index (BMI).

The surprising result – published today in JAMA Oncology – contrast with regular warnings about the health risks of patients who are overweight and obese.

“This is an interesting outcome and it raises the potential to investigate further with other cancers and other anti-cancer drugs,” says lead investigator Dr Ganessan Kichenadasse, a medical oncology researcher at the Flinders Centre for Innovation in Cancer.

“We need to do further studies into the possible link between BMI and related inflammation, which might help to understand the mechanisms behind paradoxical response to this form of cancer treatment.”

“Previous studies have explored a concept called as ‘obesity paradox’ where obesity is associated with increased risks for developing certain cancers and, counter-intuitively, may protect and give greater survival benefits in certain individuals.

“Our study provides new evidence to support the hypothesis that high BMI and obesity may be associated with response to immunotherapy,” says Dr Kichenadasse.

The Flinders researchers found NSCLC patients with high BMI (BMI ? 25 kg/m2) in four clinical trials had a significant reduction in mortality with atezolizumab, apparently benefiting from immune checkpoint inhibitor (ICI) therapy.

The Flinders researchers found NSCLC patients with high BMI (BMI ? 25 kg/m2) in four clinical trials had a significant reduction in mortality with atezolizumab, apparently benefiting from immune checkpoint inhibitor (ICI) therapy.

Treatment options for this form of lung cancer are rapidly evolving and includes ICIs, molecular targeted drugs and chemotherapies.

“While our study only looked at baseline and during treatment, we believe it warrants more studies into the potentially protective role of high BMI in other cancer treatments.”

The WHO estimates at least 2.8 million people die each year as a result of being overweight or obese. Overweight and obesity leads to adverse metabolic effects on blood pressure, cholesterol, triglycerides and insulin resistance.

Risks of coronary heart disease, ischemic stroke and type 2 diabetes mellitus increase steadily with increasing body mass index (BMI), a measure of weight relative to height.

Of the 1434 participants studied in the Australian research, 49% were normal weight, 34% were overweight and 7% were obese.

Funding: The research was part funded by Cancer Council of South Australia.


Although the interaction between malnutrition and chronic inflammation has been widely investigated, whether this association is causative or correlative is still debated [1]. Historically, body mass index (BMI) has been considered the major surrogate of nutritional status and its correlation with clinical outcomes in advanced cancer patients has already been investigated without conclusive results [25].

It is now becoming clear that the nutritional assessment, which should include BMI, could be seen in a “new light” in the era of immune checkpoint inhibitors (ICIs). A large retrospective study has recently found an association between BMI and improved progression free survival (PFS) and overall survival (OS) in melanoma patients treated with either targeted therapy or immunotherapy [6].

Another study has reported that overweight sarcopenic melanoma patients treated with anti-PD1 (Programmed cell death protein 1) inhibitors experienced early acute limiting toxicity [7].

Additionally, another retrospective analysis by Richtig et al. revealed that overweight (BMI ≥ 25) melanoma patients (76 total) treated with ipilimumab had significantly higher response rate (p = 0.024) and a trend for longer OS (p = 0.056), when compared to non-overweight patients [8].

Lastly, Wang and colleagues have recently reported an improvement in terms of PFS (p = 0.003) and OS (p = 0.049) in a cohort of obese advanced cancer patients (BMI ≥ 30) treated with ICIs [9].

To further dissect this question, we conducted a large, multicentre, retrospective transverse study to evaluate clinical outcomes of patients with advanced solid tumors treated with ICIs according to baseline BMI.

Discussion

In this study we demonstrated that patients with a BMI ≥ 25 experienced a better clinical outcome compared to those with a BMI < 25. Recently, the association between BMI and OS of metastatic renal cell carcinoma patients, has been reported regardless of the use of anti-PD-1/PD-L1 therapy [420]. However, in our study we found a strong correlation between overweight and improved clinical outcomes with anti-PD-1/PD-L1.

Some authors have already speculated about the negative impact of body composition alteration on immune cells activity [21].

Interestingly, it has been increasingly recognized that white adipose tissue, which is the most related to the fattening process [22], is also involved in the induction and/or coordination of host defenses, being a source of cytokines and chemokines [23]. In fact, adipose tissue modulates the Th1/Th2 balance, decreases the activation of Treg through adiponectin, increases pro-inflammatory macrophages, activates T-cells with the binding between LIGHT-HVEM (herpesvirus entry mediator) and increases the inflammatory status through CD40 pathway [2426].

Moreover, a recent preclinical study revealed that white adipose tissue might also play a role in immune homeostasis [27].

In this study, white adipose tissue of mice was reported to accumulate pathogen-specific memory T-cells after a microbial infection, including tissue-resident cells expressing a distinct metabolic profile.

Intriguingly, these data support the hypothesis that adipose tissue can act as a reservoir of tissue-specific memory T-cells, which can undergo a rapid response to reactivation against exogenous stimuli. This evidence raises an interesting question, can these adipose tissue-specific T-cells be promptly reactivated against cancer-specific antigens as they do against microbial antigens?

In a recent meta-analysis of patients with immune-mediated inflammatory diseases treated with anti-TNF (tumor necrosis factor), the authors reported a trend towards a lower response rate to treatment among overweight patients [28].

This is likely to reflect the reduced responsivity of T-cells of obese individuals, which has also been confirmed in preclinical models showing a significant increase in dysfunctional exhausted T-cells in obese mice [9]. Nevertheless, such inflamed and immune-exhausted status may be more likely susceptible to the immune checkpoint blockade.

In support of this, in preclinical models, T-cell dysfunction in obese mice was proven to be partly mediated by the PD-1 axis and driven by leptin, strengthening the already known correlation between JAK/STAT pathway and immune checkpoint inhibition [929].

Importantly, in our study we also found a significantly higher incidence of irAEs of any grade among overweight/obese patients. In light of the emerging association between the development of irAEs and improved clinical outcomes with ICIs across different tumor types, our findings are not unexpected [3035]. In our cohort, the development of irAEs of any grade was independently associated with improved clinical outcomes along with a BMI ≥25 in multivariate analyses.

The analysis performed by separating overweight and obese patients, demonstrated that a linear relationship between BMI and positive outcomes cannot be assumed. Even though we found no statistically significant differences in TTF, PFS and OS between overweight and obese patients, when separately comparing obese patients to non-overweight patients (Table ​(Table6),6), we observed the loss of significance regarding TTF and PFS, while not regarding OS.

This result is of particular interest, considering the possibility of a negative impact on survival of obese patients due to cardiovascular and metabolic complications of obesity itself. Noteworthy, the HRs are concordantly lower for overweight (non-obese) patients in each survival analysis, compared to obese patients, thus supporting the hypothesis that the prognostic weight of obesity, could have partially influenced the final results.

On the other hand, despite the small sample size (4.1% of the entire population), underweight patients had significantly shorter TTF, PFS and OS, when compared to normal weight patients, confirming that malnutrition (and cachexia) is an independent negative prognostic factor. Nonetheless, when we compared obese and overweight patients (Table ​(Table7)7) with normal weight patients we observed significantly improved clinical outcomes favouring the overweight group, which suggests that overweightness has a direct impact on the efficacy of ICIs.

In our study we also carried a gender-based analysis. Previously, it has been reported that female patients tend to have lower benefit from ICI compared to males [3637]. However, whether the gender plays a key role in determining the clinical outcome to immunotherapy is still in need of further investigation.

In our study, we found that overweight female patients derived a greater clinical benefit form immunotherapy as compared to the male counterpart (Table ​(Table5).5). However, it should be highlighted that overweightness was associated with improved outcomes in both males and females in the multivariate analysis. This led us to speculate that in our population the predictive role of BMI was to be stronger than the predictive role of gender.

Certainly, the relationship between sex, adipose tissue and immunity is complex and ambiguous. Sex-hormones, in particular estrogens, could affect adipose tissue functions [38], but in some respects their influence on the immune systems does not seem unidirectional [39].

Furthermore, the median age of female patients in our study was 67, indicating a prevalence of postmenopausal patients. In this specific population the adipose tissue becomes a major source of circulating estrogens [40].

Another way to explain how BMI might affect sex hormones levels and the immune response, is through diet regimens which underpin the weight gain. Indeed, gut microbiota may be influenced by the different “modifying pressures” of various diet types.

Interestingly, males and females have recently been reported to have gender-specific differences in their immune system and gut microbiota composition. Whether these differences in gut microbiota composition might impact the efficacy or the safety profile of immunotherapy is subject of intense research and is expected to provide us further insight in the optimal management of our patients [4143].

Our study is certainly flawed by several caveats, including the retrospective design with the risk of selection and data collection biases, the heterogeneity of the analyzed population, the lack of a centralized imaging review for response assessment and the lack of data about patient comorbidities. In addition, the lack of control group of patients who did not received ICIs further limit the power of our analysis.

On the other hand, a unique strength of our study is that we evaluated the predictive role of baseline assessment of BMI in a “real life” population of individuals candidate to receive ICIs.


Source:
Flinders University
Media Contacts:
Ganessan Kichenadasse – Flinders University

Original Research: Closed access
“Association between body mass index (BMI) and overall survival with immune checkpoint inhibitor therapy for advanced non-small cell lung cancer: analysis of atezolizumab clinical trials”. Ganessan Kichenadasse, FRACP; John O. Miners, PhD; Arduino A. Mangoni, PhD; Andrew Rowland, PhD; Ashley M. Hopkins, PhD; Michael J. Sorich, PhD.
JAMA Oncology doi:10.1001/jamaoncol.2019.5241.

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