The sexist behaviour of immune checkpoint inhibitors in cancer therapy?

Botticelli, Andrea; Onesti, Concetta Elisa; Zizzari, Ilaria Grazia; Cerbelli, Bruna; Sciattella, Paolo; Occhipinti, Mario; Roberto, Michela; Pietro, Francesca Di; Bonifacino, Adriana; Ghidini, Michele; Vici, Patrizia; Pizzuti, Laura; Napoletano, Chiara; Strigari, Lidia; d’Amati, Giulia; Mazzuca, Federica; Nuti, Marianna; Marchetti, Paolo

doi:10.18632/oncotarget.22242

Cited by 95 publications

(90 citation statements)

References 65 publications

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“…Recent studies demonstrated that males derive more benefit in ICI vs. chemotherapy than females. [39][40][41] Here, we report that the ICI predictive biomarker TMB has a better separation effect in female than in male patients. These two findings actually do not contradict each other.…”

Section: Discussionmentioning

confidence: 75%

“…Recently, it has been shown through systematic meta-analysis that male patients derive more benefit in ICI versus standard chemotherapy when compared to female patients. [39][40][41] Overall, for both men and women, immunotherapy was more effective than the control, whether this was a placebo or another type of cancer drug. 39 Here we hypothesize that the biomarker for predicting immunotherapy response could also be separated based on the patients' sex.…”

Section: Introductionmentioning

confidence: 99%

“…The inherent sex differences in immune response could be relevant to the natural course of chronic inflammatory conditions such as cancer. Recently, it has been shown through systematic meta‐analysis that male patients derive more benefit in ICI versus standard chemotherapy when compared to female patients . Overall, for both men and women, immunotherapy was more effective than the control, whether this was a placebo or another type of cancer drug …”

Section: Introductionmentioning

confidence: 99%

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The predictive power of tumor mutational burden in lung cancer immunotherapy response is influenced by patients’ sex

Wang

Zhang

et al. 2019

Intl Journal of Cancer

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Immunotherapy, represented by immune checkpoint inhibitors (ICI), is transforming the treatment of cancer. However, only a fraction of patients show response to ICI, and there is an unmet need for biomarkers that will identify patients more likely to respond to ICI. Here we report that the ICI response prediction biomarker tumor mutational burden (TMB) shows significant sex differences. TMB's predictive power is significantly better for female than for male lung cancer patients. Receiver operating characteristic curve analysis was performed and the area under the curve (AUC) was reported to evaluate the predictive power of TMB in lung cancer ICI response. Hazard ratios (HR) of TMB‐high vs. TMB‐low patients were compared between male and female patients. Both AUC and HR differences between female and male are significant in all available independent lung cancer datasets. However, the AUC of programmed death ligand 1 (PD‐L1) expression does not show a difference between female and male, suggesting TMB, but not PD‐L1 expression has a better predictive power for female than for male lung cancer patients. Our study suggests significant sex differences in the performance of TMB in ICI response prediction. Future development of ICI biomarker should consider sex differences and special efforts should be paid to improve the performance of ICI predictive biomarkers for male lung cancer patients.

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The predictive power of tumor mutational burden in lung cancer immunotherapy response is influenced by patients’ sex

Wang

Zhang

et al. 2019

Intl Journal of Cancer

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“…Women mount more vigorous antibody‐ and cell‐mediated immune responses than men following either infection or vaccination . Also, women have a higher incidence of autoimmune diseases, and the onset of these conditions are common during the reproductive years, suggesting that the pathogenesis of irAEs could be influenced by sex hormones . Studies in patients with endometriosis have reported a higher rate of autoimmune conditions in these patients, strengthening the link between autoimmunity and sex hormones .…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in Tolerability to Anti-Programmed Cell Death Protein 1 Therapy in Patients with Metastatic Melanoma and Non-Small Cell Lung Cancer: Are We All Equal?

et al. 2019

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Background Immune‐related adverse events (irAEs) have emerged as a serious clinical issue in the use of immune checkpoint inhibitors (ICIs). Risk factors for irAEs remain controversial. Therefore, we studied sex differences in irAEs in patients treated with anti‐programmed cell death protein 1 (PD‐1) therapy. Materials and Methods All patients with metastatic melanoma and non‐small cell lung cancer (NSCLC) treated with anti‐PD‐1 therapy at Mayo Clinic Rochester and Florida from 2015 to 2018 were reviewed. Kaplan‐Meier method and log‐rank test was used for time‐to‐event analysis. Results In 245 patients with metastatic melanoma, premenopausal women were more likely to experience irAEs (all grades) compared with postmenopausal women and men (67% vs. 60% vs. 46%), primarily because of an increase in endocrinopathies (33% vs. 12% vs. 10%, respectively). In patients with NSCLC (231 patients), women (all ages) were also more likely to develop irAEs of all grades (48% vs. 31%). Women with NSCLC were more likely to develop pneumonitis (11% vs. 4%) and endocrinopathies (14% vs. 5%). No differences in grade ≥3 toxicities were seen across sexes in both cohorts, but women were more likely to receive systemic steroids for the treatment of irAEs compared with men. Better progression‐free‐survival was observed in women with NSCLC and irAEs (10 months vs. 3.3 months) compared with women without irAEs. Conclusion Women with metastatic melanoma and NSCLC are more likely to experience irAEs compared with men. We also observed differences between sexes in the frequency of certain irAEs. Larger studies are needed to investigate the mechanisms underlying these associations. Implications for Practice The results of this study suggest that women may be at a higher risk for immune‐related adverse events (irAEs) compared with men when treated with anti‐programmed cell death protein 1 therapy. In addition, women were more likely to develop certain irAEs, including endocrinopathies and pneumonitis. Close follow‐up of women undergoing treatment with immune checkpoint inhibitors will allow clinicians to diagnose these treatment‐related complications early, potentially reducing their associated morbidity and mortality. In addition, a possible association between irAEs and response to therapy was observed.

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“…Five different meta‐analysis have been reported to investigate the efficacy of immune checkpoint inhibitors according to the sex of cancer patients . In the previous meta‐analysis conducted by Botticelli and colleagues, there was no significant improvement of overall survival in male cancer patients treated with anti‐PD‐1 or anti‐CTLA‐4 antibodies. No available data of OS data and PFS data was found in the stratified analysis of cancer type like NSCLC according to the sex.…”

Section: Discussionmentioning

confidence: 99%

Effect of sex on the efficacy of patients receiving immune checkpoint inhibitors in advanced non‐small cell lung cancer

et al. 2019

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Immune checkpoint inhibitors (ICIs) have shown promising efficacy in the treatment of non‐small cell lung cancer (NSCLC). Sex‐associated dimorphism in immune system response is acknowledged, but the effect of patients’ sex on efficacy of ICIs as treatment in NSCLC still remains controversial. The present study was conducted to investigate the difference in efficacy of NSCLC patients receiving immune checkpoint inhibitors according to the sex. A total of 9583 patients involved 6567 men and 3016 women with advanced lung cancer from 15 randomized controlled trials were included in this study. An overall survival (OS) benefit of immune checkpoint inhibitors was illustrated in both male (HR 0.76, 95% CI 0.71‐0.82) and female (HR 0.73, 95% CI 0.58‐0.91) patients, and a progression‐free survival (PFS) benefit was also found in both men (HR 0.67, 95% CI 0.58‐0.77) and women (HR 0.73, 95% CI 0.56‐0.95) in NSCLC. Both PD‐1/PD‐L1 inhibitors alone and PD‐1/PD‐L1 plus chemotherapy significantly improved the OS and PFS in male patients. Whereas in females, PD‐1 inhibitors or monotherapy significantly benefited the OS but not the PFS, PD‐L1 inhibitors or combination therapy significantly prolonged the PFS but not the OS. No survival benefit was found in both male and female patients from the CTLA‐4 inhibitors. The current study indicated that the magnitude of survival benefit is sex‐dependent and male patients seemed to obtain more consistent and favorable outcomes from ICIs than women patients in NSCLC.

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The sexist behaviour of immune checkpoint inhibitors in cancer therapy?

Cited by 95 publications

References 65 publications

The predictive power of tumor mutational burden in lung cancer immunotherapy response is influenced by patients’ sex

The predictive power of tumor mutational burden in lung cancer immunotherapy response is influenced by patients’ sex

Sex Differences in Tolerability to Anti-Programmed Cell Death Protein 1 Therapy in Patients with Metastatic Melanoma and Non-Small Cell Lung Cancer: Are We All Equal?

Effect of sex on the efficacy of patients receiving immune checkpoint inhibitors in advanced non‐small cell lung cancer

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