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Volume 25, Issue 1
  • ISSN: 1568-0096
  • E-ISSN: 1873-5576

Abstract

Background

Emerging evidence identified sex as a variable regulating immune system functions and modulating response to immunotherapy in cancer patients.

Objective

This retrospective study analysed sex-related differences in immunotherapy outcomes in a real-world population of non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs).

Methods

We retrospectively investigated clinical data of 99 patients with advanced NSCLC and treated with single-agent nivolumab and pembrolizumab at Medical Oncology Unit, Careggi University Hospital, Florence (Italy), between April 2014 to August 2019. Main clinical characteristics and clinical outcomes were analysed.

Results

Our study showed that the efficacy of ICI treatment differed according to gender. A trend for better median progression-free survival (mPFS) was reported in males (mPFS 5.0 months, 95% Confidence Interval [CI] 4.0-11.0) than females (mPFS 4.5 months, 95% CI 2.0-9.0) (p=0.133), while no significant difference for overall survival (OS) between the two sex groups was observed (p=0.622). In the nivolumab cohort, we showed a statistically significant difference for a longer PFS in men compared to women (log-rank p=0.054), HR for PFS in females males was 1.81 (95% CI 0.97-3.37, p=0.062). Disease control rate (DCR) was achieved in 55.7% and 45.7% of men and women, respectively, while disease progression was registered in 44.3% of males and 54.3% of females (p=0.386).

Conclusion

Gender is a variable that should be taken into account in the choice of immunotherapy. Future prospective randomized trials testing tailored sex-based immunotherapy strategies are required to validate our findings before integrating into clinical practice.

© 2025 Bentham Science Publishers
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2024-06-21
2024-12-03

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References

  1. SungH. FerlayJ. SiegelR.L. LaversanneM. SoerjomataramI. JemalA. BrayF. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin.202171320924910.3322/caac.2166033538338
     [Google Scholar]
  2. FidlerM.M. BrayF. SoerjomataramI. The global cancer burden and human development: A review.Scand. J. Public Health2018461273610.1177/140349481771540028669281
     [Google Scholar]
  3. MalvezziM. CarioliG. BertuccioP. BoffettaP. LeviF. La VecchiaC. NegriE. European cancer mortality predictions for the year 2017, with focus on lung cancer.Ann. Oncol.20172851117112310.1093/annonc/mdx03328327906
     [Google Scholar]
  4. MalhotraJ. MalvezziM. NegriE. La VecchiaC. BoffettaP. Risk factors for lung cancer worldwide.Eur. Respir. J.201648388990210.1183/13993003.00359‑201627174888
     [Google Scholar]
  5. CorralesL. RosellR. CardonaA.F. MartínC. Zatarain-BarrónZ.L. ArrietaO. Lung cancer in never smokers: The role of different risk factors other than tobacco smoking.Crit. Rev. Oncol. Hematol.202014810289510289510.1016/j.critrevonc.2020.10289532062313
     [Google Scholar]
  6. DreslerC.M. FratelliC. BabbJ. EverleyL. EvansA.A. ClapperM.L. Gender differences in genetic susceptibility for lung cancer.Lung Cancer200030315316010.1016/S0169‑5002(00)00163‑X11137199
     [Google Scholar]
  7. MacRostyC.R. RiveraM.P. Lung cancer in women: A modern epidemic.Clin. Chest Med.2020411536510.1016/j.ccm.2019.10.00532008629
     [Google Scholar]
  8. StapelfeldC. DammannC. MaserE. Sex-specificity in lung cancer risk.Int. J. Cancer202014692376238210.1002/ijc.3271631583690
     [Google Scholar]
  9. GasperinoJ. RomW.N. Gender and lung cancer.Clin. Lung Cancer20045635335910.3816/CLC.2004.n.01315217534
     [Google Scholar]
  10. DoningtonJ.S. ColsonY.L. Sex and gender differences in non-small cell lung cancer.Semin. Thorac. Cardiovasc. Surg.201123213714510.1053/j.semtcvs.2011.07.00122041044
     [Google Scholar]
  11. BouchardyC. FiorettaG. De PerrotM. ObradovicM. SpiliopoulosA. Determinants of long term survival after surgery for cancer of the lung: A population-based study.Cancer199986112229223710.1002/(SICI)1097‑0142(19991201)86:11<2229::AID‑CNCR9>3.0.CO;2‑K10590362
     [Google Scholar]
  12. HirschF.R. ScagliottiG.V. MulshineJ.L. KwonR. CurranW.J.Jr WuY.L. Paz-AresL. Lung cancer: Current therapies and new targeted treatments.Lancet20173891006629931110.1016/S0140‑6736(16)30958‑827574741
     [Google Scholar]
  13. KimS.Y. HalmosB. Choosing the best first-line therapy: NSCLC with no actionable oncogenic driver.Lung Cancer Manag.202093LMT3610.2217/lmt‑2020‑000332774467
     [Google Scholar]
  14. DoroshowD.B. SanmamedM.F. HastingsK. PolitiK. RimmD.L. ChenL. MeleroI. SchalperK.A. HerbstR.S. Immunotherapy in non-small cell lung cancer: Facts and hopes.Clin. Cancer Res.201925154592460210.1158/1078‑0432.CCR‑18‑153830824587
     [Google Scholar]
  15. BrahmerJ. ReckampK.L. BaasP. CrinòL. EberhardtW.E. PoddubskayaE. AntoniaS. PluzanskiA. VokesE.E. HolgadoE. WaterhouseD. ReadyN. GainorJ. Arén FronteraO. HavelL. SteinsM. GarassinoM.C. AertsJ.G. DomineM. Paz-AresL. ReckM. BaudeletC. HarbisonC.T. LestiniB. SpigelD.R. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.N. Engl. J. Med.2015373212313510.1056/NEJMoa150462726028407
     [Google Scholar]
  16. BorghaeiH. Paz-AresL. HornL. SpigelD.R. SteinsM. ReadyN.E. ChowL.Q. VokesE.E. FelipE. HolgadoE. BarlesiF. KohlhäuflM. ArrietaO. BurgioM.A. FayetteJ. LenaH. PoddubskayaE. GerberD.E. GettingerS.N. RudinC.M. RizviN. CrinòL. BlumenscheinG.R.Jr AntoniaS.J. DorangeC. HarbisonC.T. Graf FinckensteinF. BrahmerJ.R. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.N. Engl. J. Med.2015373171627163910.1056/NEJMoa150764326412456
     [Google Scholar]
  17. HerbstR.S. BaasP. KimD.W. FelipE. Pérez-GraciaJ.L. HanJ.Y. MolinaJ. KimJ.H. ArvisC.D. AhnM.J. MajemM. FidlerM.J. de CastroG.Jr GarridoM. LubinieckiG.M. ShentuY. ImE. Dolled-FilhartM. GaronE.B. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): A randomised controlled trial.Lancet2016387100271540155010.1016/S0140‑6736(15)01281‑726712084
     [Google Scholar]
  18. MokT.S.K. WuY.L. KudabaI. KowalskiD.M. ChoB.C. TurnaH.Z. CastroG.Jr SrimuninnimitV. LaktionovK.K. BondarenkoI. KubotaK. LubinieckiG.M. ZhangJ. KushD. LopesG. KEYNOTE-042 Investigators Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial.Lancet2019393101831819183010.1016/S0140‑6736(18)32409‑730955977
     [Google Scholar]
  19. KleinS.L. FlanaganK.L. Sex differences in immune responses.Nat. Rev. Immunol.2016161062663810.1038/nri.2016.9027546235
     [Google Scholar]
  20. LibertC. DejagerL. PinheiroI. The X chromosome in immune functions: When a chromosome makes the difference.Nat. Rev. Immunol.201010859460410.1038/nri281520651746
     [Google Scholar]
  21. WuY. JuQ. JiaK. YuJ. ShiH. WuH. JiangM. Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and CTLA-4 inhibitors).Int. J. Cancer20181431455110.1002/ijc.3130129424425
     [Google Scholar]
  22. ConfortiF. PalaL. BagnardiV. De PasT. MartinettiM. VialeG. GelberR.D. GoldhirschA. Cancer immunotherapy efficacy and patients’ sex: A systematic review and meta-analysis.Lancet Oncol.201819673774610.1016/S1470‑2045(18)30261‑429778737
     [Google Scholar]
  23. ClocchiattiA. CoraE. ZhangY. DottoG.P. Sexual dimorphism in cancer.Nat. Rev. Cancer201616533033910.1038/nrc.2016.3027079803
     [Google Scholar]
  24. PolanczykM.J. HopkeC. VandenbarkA.A. OffnerH. Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway.J. Neurosci. Res.200684237037810.1002/jnr.2088116676326
     [Google Scholar]
  25. LinP-Y. SunL. ThibodeauxS.R. LudwigS.M. VadlamudiR.K. HurezV.J. BaharR. KiousM.J. LiviC.B. WallS.R. ChenL. ZhangB. ShinT. CurielT.J. B7-H1-dependent sex-related differences in tumor immunity and immunotherapy responses.J. Immunol.201018552747275310.4049/jimmunol.100049620686128
     [Google Scholar]
  26. DineshR.K. HahnB.H. SinghR.P. PD-1, gender, and autoimmunity.Autoimmun. Rev.20109858358710.1016/j.autrev.2010.04.00320433954
     [Google Scholar]
  27. LitchfieldK. ReadingJ.L. PuttickC. ThakkarK. AbboshC. BenthamR. WatkinsT.B.K. RosenthalR. BiswasD. RowanA. LimE. Al BakirM. TuratiV. Guerra-AssunçãoJ.A. CondeL. FurnessA.J.S. SainiS.K. HadrupS.R. HerreroJ. LeeS.H. Van LooP. EnverT. LarkinJ. HellmannM.D. TurajlicS. QuezadaS.A. McGranahanN. SwantonC. Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition.Cell20211843596614.e1410.1016/j.cell.2021.01.00233508232
     [Google Scholar]
  28. BagchiS. YuanR. EnglemanE.G. Immune checkpoint inhibitors for the treatment of cancer: Clinical impact and mechanisms of response and resistance.Annu. Rev. Pathol.20211622324910.1146/annurev‑pathol‑042020‑04274133197221
     [Google Scholar]
  29. Abdel-RahmanO. Correlation between PD-L1 expression and outcome of NSCLC patients treated with anti-PD-1/PD-L1 agents: A meta-analysis.Crit. Rev. Oncol. Hematol.2016101758510.1016/j.critrevonc.2016.03.00726969107
     [Google Scholar]
  30. GibneyG.T. WeinerL.M. AtkinsM.B. Predictive biomarkers for checkpoint inhibitor-based immunotherapy.Lancet Oncol.20161712e542e55110.1016/S1470‑2045(16)30406‑527924752
     [Google Scholar]
  31. ChenD.S. MellmanI. Elements of cancer immunity and the cancer-immune set point.Nature2017541763732133010.1038/nature2134928102259
     [Google Scholar]
  32. BotticelliA. OnestiC.E. ZizzariI. CerbelliB. SciattellaP. OcchipintiM. RobertoM. Di PietroF. BonifacinoA. GhidiniM. ViciP. PizzutiL. NapoletanoC. StrigariL. D’AmatiG. MazzucaF. NutiM. MarchettiP. The sexist behaviour of immune checkpoint inhibitors in cancer therapy?Oncotarget2017859993369934610.18632/oncotarget.2224229245905
     [Google Scholar]
  33. ConfortiF. PalaL. PaganE. CortiC. BagnardiV. QueiroloP. CataniaC. De PasT. GiacconeG. Sex-based differences in response to anti-PD-1 or PD-L1 treatment in patients with non-small-cell lung cancer expressing high PD-L1 levels. A systematic review and meta-analysis of randomized clinical trials.ESMO Open20216510025110.1016/j.esmoop.2021.10025134455288
     [Google Scholar]
  34. ConfortiF. PalaL. BagnardiV. VialeG. De PasT. PaganE. PennacchioliE. CocorocchioE. FerrucciP.F. De MarinisF. GelberR.D. GoldhirschA. Sex-based heterogeneity in response to lung cancer immunotherapy: A systematic review and meta-analysis.J. Natl. Cancer Inst.2019111877278110.1093/jnci/djz09431106827
     [Google Scholar]
  35. KimA.M. TingenC.M. WoodruffT.K. Sex bias in trials and treatment must end.Nature2010465729968868910.1038/465688a20535184
     [Google Scholar]
  36. PetrelliF. MalteseM. TomaselloG. ContiB. BorgonovoK. CabidduM. GhilardiM. GhidiniM. PassalacquaR. BarniS. BrighentiM. Clinical and molecular predictors of pd-l1 expression in non-small-cell lung cancer: Systematic review and meta-analysis.Clin. Lung Cancer201819431532210.1016/j.cllc.2018.02.00629530732
     [Google Scholar]
  37. PolanczykM.J. HopkeC. VandenbarkA.A. OffnerH. Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1).Int. Immunol.200719333734310.1093/intimm/dxl15117267414
     [Google Scholar]
  38. ConfortiF. PalaL. PaganE. BagnardiV. De PasT. QueiroloP. PennacchioliE. CataniaC. CocorocchioE. FerrucciP.F. SaponaraM. OrsoliniG. ZagamiP. NicolóE. De MarinisF. TortoraG. BriaE. MinucciS. JoffeH. VeronesiP. WargoJ. RosenthalR. SwantonC. MantovaniA. GelberR.D. VialeG. GoldhirschA. GiacconeG. Sex-based dimorphism of anticancer immune response and molecular mechanisms of immune evasion.Clin. Cancer Res.202127154311432410.1158/1078‑0432.CCR‑21‑013634016641
     [Google Scholar]
  39. XiaoD. PanH. LiF. WuK. ZhangX. HeJ. Analysis of ultra-deep targeted sequencing reveals mutation burden is associated with gender and clinical outcome in lung adenocarcinoma.Oncotarget2016716228572286410.18632/oncotarget.821327009843
     [Google Scholar]
  40. RizviN.A. HellmannM.D. SnyderA. KvistborgP. MakarovV. HavelJ.J. LeeW. YuanJ. WongP. HoT.S. MillerM.L. RekhtmanN. MoreiraA.L. IbrahimF. BruggemanC. GasmiB. ZappasodiR. MaedaY. SanderC. GaronE.B. MerghoubT. WolchokJ.D. SchumacherT.N. ChanT.A. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.Science2015348623012412810.1126/science.aaa134825765070
     [Google Scholar]
  41. Abdel-RahmanO. Smoking and EGFR status may predict outcomes of advanced NSCLC treated with PD-(L)1 inhibitors beyond first line: A meta-analysis.Clin. Respir. J.20181251809181910.1111/crj.1274229115057
     [Google Scholar]
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Gender Matters. Sex-related Differences in Immunotherapy Outcome in Patients with Non-small Cell Lung Cancer
Curr. Cancer Drug Targets< 25, 64 (2025); https://doi.org/10.2174/1568009622666220831142452
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  • Article Type:     Research Article
Keyword(s): gender; gender-medicine; immune-checkpoint inhibitors; immunotherapy; Non-small cell lung cancer; sex differences

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