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. 2022 Oct 20;14(20):5145.
doi: 10.3390/cancers14205145.

Sex-Related Differences in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibition

Ken Kudura  1 , Lucas Basler  2 , Lukas Nussbaumer  3 , Robert Foerster  4
Affiliations

Sex-Related Differences in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibition

Ken Kudura et al. Cancers (Basel). .

Abstract

Objectives: We aimed to investigate sex-related differences in patients with advanced melanoma treated with ICI by linking the assessment of inflammatory response in peripheral blood, onset of immune-related adverse events IRAEs during therapy and treatment response in short- and long-term. Methods: For the purpose of this single-center retrospective study metastatic melanoma patients treated with ICI were included. Baseline patient characteristics, blood sample tests and the onset of immune-related adverse events IRAEs were documented based on clinical records. The short-term treatment response was assessed with 18F-2-Fluor-2-desoxy-D-glucose Positron Emission Tomography/Computed Tomography FDG-PET/CT scans performed six months after initiation of ICI. The overall survival OS and progression-free survival PFS were used as endpoints to assess the long-term response to immunotherapy. Results: In total, 103 patients with advanced melanoma (mean age 68 ± 13.83 years) were included, 29 women (mean age 60.41 ± 14.57 years) and 74 men (mean age 65.66 ± 13.34 years). The primary tumor was located on a lower extremity in one out of three women and on the head/neck in one out of three men (p < 0.001). While the superficial spreading (41%) and nodular (36%) melanoma subtypes represented together 77% of the cases in male population, women showed a more heterogenous distribution of melanoma subtypes with the superficial spreading (35%), nodular (23%), acral lentiginous (19%) and mucosal (12%) melanoma subtypes being most frequent in female population (p < 0.001). Most differences between women and men with regards to inflammatory parameters were observed six months after initiation of ICI with a higher median NLR (p = 0.038), lower counts of lymphocytes (p = 0.004) and thrombocytes (p = 0.089) in addition to lower counts of erythrocytes (p < 0.001) and monocytes (p < 0.001) in women towards men. IRAEs were more frequent in women towards men (p = 0.013). Women were more likely to display endocrinological IRAEs, such as thyroiditis being the most frequent adverse event in women. Interestingly IRAEs of the gastrointestinal tract were the most frequent ones in men. Finally, men with advanced melanoma showed a significantly better response to immunotherapy in short- (p = 0.015) and long-term (OS p = 0.015 and PFS p < 0.001) than women. In fact, every fourth man died during the course of the disease, while every second woman did not survive. (p = 0.001). Conclusion: Men with advanced melanoma showed a significantly better response to immunotherapy in short- and long-term than women. Higher immune activation in peripheral blood before and after initiation ICI might be linked to favorable treatment response during and after ICI in favor of men and decoupled from the onset of IRAEs. Given the significantly higher immunotoxicity and worse outcome experienced by women compared to men the use of ICI should be chosen carefully in women with advanced melanoma.

Keywords: CTLA-4; PD-1; Positron Emission Tomography Computed Tomography; gender medicine; immunotherapy; melanoma; sex differences.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Baseline characteristics of all included female and male patients with advanced melanoma before initiation of immune checkpoint inhibition.
Figure 2
Figure 2
Blood parameters of all included female and male patients with advanced melanoma treated with ICI at baseline, and three and six months after treatment start.
Figure 3
Figure 3
Immune-related adverse events in male and female patients with advanced melanoma treated with ICI.
Figure 4
Figure 4
Immune-related adverse events in all included patients with advanced melanoma treated with single versus double ICI.
Figure 5
Figure 5
Total tumor load (volume in ml) and total metabolic tumor load (metabolic tumor volume MTV and total lesion glycolysis TLG) at baseline, and three and six months after initiation of ICI in female and male patients with advanced melanoma.
Figure 6
Figure 6
Clinical benefit in all included female and male patients with metastatic melanoma treated with ICI. Clinical benefit being defined as no disease progression displayed on FDG-PET/CT scan six months after initiation of ICI.
Figure 7
Figure 7
Overall survival OS and progression free survival PFS of female and male patients with advanced melanoma treated with ICI.
Figure 8
Figure 8
Kaplan–Meier survival curve stratified by overall survival OS (in days) in men (orange) and women (blue) with advanced melanoma treated with immunotherapy. The female curve ends earlier than the male curve due to a shorter follow-up time (mean 620 days vs. 880 days for men), as displayed in Figure 7.
Figure 9
Figure 9
Kaplan–Meier survival curve stratified by progression free survival PFS (in days) in men (orange) and women (blue) with advanced melanoma treated with immunotherapy. The female curve ends earlier than the male curve due to a shorter follow-up time (mean 620 days vs. 880 days for men), as displayed in Figure 7.
Figure 10
Figure 10
Overall survival OS and progression free survival PFS of female and male patients with advanced melanoma treated with single vs. double ICI.
See this image and copyright information in PMC

References

    1. Kudura K., Dimitriou F., Mihic-Probst D., Muehlematter U., Kutzker T., Basler L., Förster R., Dummer R., Mangana J., Husmann L., et al. Malignancy Rate of Indeterminate Findings on FDG-PET/CT in Cutaneous Melanoma Patients. Diagnostics. 2021;11:883. doi: 10.3390/diagnostics11050883. - DOI - PMC - PubMed
    1. Buja A., Rugge M., Damiani G., Zorzi M., De Toni C., Vecchiato A., Del Fiore P., Spina R., Baldo V., Brazzale A.R., et al. Sex Differences in Cutaneous Melanoma: Incidence, Clinicopathological Profile, Survival, and Costs. J. Women’s Health. 2022;31:1012–1019. doi: 10.1089/jwh.2021.0223. - DOI - PMC - PubMed
    1. Kudura K., Dimitriou F., Basler L., Förster R., Mihic-Probst D., Kutzker T., Dummer R., Mangana J., Burger I.A., Kreissl M.C. Prediction of Early Response to Immune Checkpoint Inhibition Using FDG-PET/CT in Melanoma Patients. Cancers. 2021;15:3830. doi: 10.3390/cancers13153830. - DOI - PMC - PubMed
    1. Raimondi S., Suppa M., Gandini S. Melanoma Epidemiology and Sun Exposure. Acta Derm. Venereol. 2020;100:adv00136. doi: 10.2340/00015555-3491. - DOI - PMC - PubMed
    1. Olsen C.M., Thompson J., Pandeya N., Whiteman D.C. Evaluation of Sex-Specific Incidence of Melanoma. JAMA Dermatol. 2020;156:553–560. doi: 10.1001/jamadermatol.2020.0470. - DOI - PMC - PubMed

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