Cystic fibrosis (CF) is the most common genetic disease in the Caucasion population. Thanks to the CFTR modulators therapy, life expectancy will significantly improve. New therapeutic challenges can be expected, including diseases associated with ageing and higher incidence of cancer, as evidenced by recent epidemiological studies. The increasing incidence of tumors includes also breast cancer. The risk of breast cancer is higher in CF patients compared to the general population. Sex hormones, especially estrogens, also affect on the pathophysiology and immunology of the CF. Previous research, has demonstrated unequivocal survival rates for female CF patients compared to their male counterparts. Is demonstrated, that chemotherapy used for breast cancer affects the CFTR channel and CFTR modulator therapy has frequent side effects on breast tissue. In this review, we focus on the effects of female sex hormones on CF disease, pathophysiological relationships between CF and breast cancer, and the impact of antitumor treatment on both, malignant disease and CF. The potential for further investigation is also discussed.

Department of Children's Infectious Diseases University Hospital Brno Jihlavska 20 Brno 62500 Czech Republic

Department of Hematology Oncology and Internal Medicine University Hospital Brno Jihlavska 20 Brno 62500 Czech Republic

Department of Pulmonary Medicine Oslo University Hospital Kirkeveien 166 Ullevål Oslo 0450 Norway

Department of Respiratory Diseases University Hospital Brno Jihlavska 20 Brno 62500 Czech Republic

Faculty of Medicine Masaryk University Brno Kamenice 5 Brno 62500 Czech Republic

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ECFSPR Report. 2019. [cited 2022 14th July]. Available from: https://www.ecfs.eu/sites/default/files/general-content-files/working-groups/ecfs-patient-registry/ECFSPR_Report_2019_v1_16Feb2022.pdf.

Cystic Fibrosis Canada. The Canadian Cystic Fibrosis Registry 2017 Annual Data Report. [cited 2022 14th July]. Available from: www.cysticfibrosis.ca/blog/2017-registry-annual-data-report/.

Archangelidi O, Cullinan P, Simmonds NJ, Mentzakis E, Peckham D, Bilton D, et al. Incidence and risk factors of cancer in individuals with cystic fibrosis in the UK; a case-control study. J Cyst Fibros. 2022;21(2):302–8. doi: 10.1016/j.jcf.2021.07.004. PubMed DOI

Alicandro G, Bisogno A, Rota M, Padoan R, Colombo C. No gender differences in growth patterns in a cohort of children with cystic fibrosis born between 1986 and 1995. Clin Nutr. 2019;38(4):1782–7. doi: 10.1016/j.clnu.2018.07.025. PubMed DOI

Schram CA, Stephenson AL, Hannam TG, Tullis E. Cystic fibrosis (CF) and ovarian reserve: a cross-sectional study examining serum anti-mullerian hormone (AMH) in young women. J Cyst Fibros. 2015;14(3):398–402. doi: 10.1016/j.jcf.2014.09.008. PubMed DOI

Lam GY, Goodwin J, Wilcox PG, Quon BS. Sex disparities in cystic fibrosis: review on the effect of female sex hormones on lung pathophysiology and outcomes. ERJ Open Res. 2021;7(1):000475–2020. doi: 10.1183/23120541.00475-2020. PubMed DOI PMC

Garcia FU, Galindo LM, Holsclaw DS. Breast abnormalities in patients with cystic fibrosis: previously unrecognized changes. Ann Diagn Pathol. 1998;2(5):281–5. doi: 10.1016/S1092-9134(98)80019-1. PubMed DOI

Neglia JP, Fitzsimmons SC, Maisonneuve P, Schöni MH, Schöni-Affolter F, Corey M, et al. The risk of Cancer among patients with cystic fibrosis. N Engl J Med. 1995;332(8):494–9. doi: 10.1056/NEJM199502233320803. PubMed DOI

Maisonneuve P, Marshall BC, Knapp EA, Lowenfels AB. Cancer risk in cystic fibrosis: a 20-Year Nationwide Study from the United States. JNCI: J Natl Cancer Inst. 2013;105(2):122–9. doi: 10.1093/jnci/djs481. PubMed DOI

Johannesson M, Askling J, Montgomery SM, Ekbom A, Bahmanyar S. Cancer risk among patients with cystic fibrosis and their first-degree relatives. Int J Cancer. 2009;125(12):2953–6. doi: 10.1002/ijc.24679. PubMed DOI

Appelt D, Fuchs T, Steinkamp G, Ellemunter H. Malignancies in patients with cystic fibrosis: a case series. J Med Case Rep. 2022;16(1):27. doi: 10.1186/s13256-021-03234-1. PubMed DOI PMC

Shi Z, Wei J, Na R, Resurreccion WK, Zheng SL, Hulick PJ, et al. Cystic fibrosis F508del carriers and cancer risk: results from the UK Biobank. Int J Cancer. 2021;148(7):1658–64. doi: 10.1002/ijc.33431. PubMed DOI

Southey MC, Batten L, Andersen CR, McCredie MR, Giles GG, Dite G, et al. CFTR delF508 carriers status, risk of breast cancer before the age of 40 and histological grading in a population-based case-control study. Int J Cancer. 1998;79:487–9. doi: 10.1002/(SICI)1097-0215(19981023)79:5<487::AID-IJC7>3.0.CO;2-X. PubMed DOI

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: CA Cancer J Clin 2021;71(3):209 – 49. PubMed

Saha T, Makar S, Swetha R, Gutti G, Singh SK. Estrogen signaling: an emanating therapeutic target for breast cancer treatment. Eur J Med Chem. 2019;177:116–43. doi: 10.1016/j.ejmech.2019.05.023. PubMed DOI

Mercogliano MF, Bruni S, Elizalde PV, Schillaci R. Tumor necrosis factor α blockade: an opportunity to tackle breast Cancer. Front Oncol. 2020;10:584. doi: 10.3389/fonc.2020.00584. PubMed DOI PMC

Chen GG, Zeng Q, Tse GMK. Estrogen and its receptors in cancer. Med Res Rev. 2008;28(6):954–74. doi: 10.1002/med.20131. PubMed DOI

Hughan KS, Daley T, Rayas MS, Kelly A, Roe A. Female reproductive health in cystic fibrosis. J Cyst Fibros. 2019;18:95–S104. doi: 10.1016/j.jcf.2019.08.024. PubMed DOI

Chotirmall SH, Greene CM, Oglesby IK, Thomas W, O’Neill SJ, Harvey BJ, et al. 17β-Estradiol inhibits IL-8 in cystic fibrosis by Up-Regulating secretory leucoprotease inhibitor. Am J Respir Crit Care Med. 2010;182(1):62–72. doi: 10.1164/rccm.201001-0053OC. PubMed DOI

Zhang JT, Jiang XH, Xie C, Cheng H, Da Dong J, Wang Y, et al. Downregulation of CFTR promotes epithelial-to-mesenchymal transition and is associated with poor prognosis of breast cancer. Biochim Biophys Acta Mole Cell Res. 2013;1833(12):2961–9. doi: 10.1016/j.bbamcr.2013.07.021. PubMed DOI

Song Y, Wang Q, Huang W, Xiao L, Shen L, Xu W. NF kappaB expression increases and CFTR and MUC1 expression decreases in the endometrium of infertile patients with hydrosalpinx: a comparative study. Reprod Biol Endocrinol. 2012;10(1):86. doi: 10.1186/1477-7827-10-86. PubMed DOI PMC

Rochwerger L, Buchwald M. Stimulation of the cystic fibrosis transmembrane regulator expression by estrogen in vivo. Endocrinology. 1993;133(2):921–30. doi: 10.1210/endo.133.2.7688293. PubMed DOI

Ajonuma LC, Tsang LL, Zhang GH, Wong CHY, Lau MC, Ho LS, et al. Estrogen-Induced abnormally high cystic fibrosis transmembrane Conductance Regulator expression results in ovarian hyperstimulation syndrome. Mol Endocrinol. 2005;19(12):3038–44. doi: 10.1210/me.2005-0114. PubMed DOI

Prulière-Escabasse V, Fanen P, Dazy AC, Lechapt-Zalcman E, Rideau D, Edelman A, et al. TGF-β1 downregulates CFTR expression and function in nasal polyps of non-CF patients. Am J Physiol Lung Cell Mol Physiol. 2005;288(1):L77–L83. doi: 10.1152/ajplung.00048.2004. PubMed DOI

Abraham EH, Vos P, Kahn J, Grubman SA, Jefferson DM, Ding I, et al. Cystic fibrosis hetero–and homozygosity is associated with inhibition of breast cancer growth. Nat Med. 1996;2(5):593–6. doi: 10.1038/nm0596-593. PubMed DOI

Vertex Pharmaceuticals Inc., Kaftrio (ivacaftor/tezacaftor/elexacaftor) full prescribing information. 2020

Jeyaratnam J, van der Meer R, Berkers G, Heijerman HGM, Beekman JM, van der Ent CK. Breast development in a 7 year old girl with CF treated with ivacaftor: an indication for personalized dosing? J Cyst Fibros. 2021;20(5):e63–6. doi: 10.1016/j.jcf.2021.06.001. PubMed DOI

Burger H, Foekens JA, Look MP, Meijer-van Gelder ME, Klijn JG, Wiemer EA, et al. RNA expression of breast cancer resistance protein, lung resistance-related protein, multidrug resistance-associated proteins 1 and 2, and multidrug resistance gene 1 in breast cancer: correlation with chemotherapeutic response. Clin Cancer Res. 2003;9(2):827–36. PubMed

Imberti R, Garavaglia ML, Verduci I, Cannavale G, Balduzzi G, Papetti S, et al. Antiestrogen- and tamoxifen-induced effects on calcium-activated chloride currents in epithelial cells carrying the ∆ F508-CFTR point mutation. Respir Res. 2018;19(1):198. doi: 10.1186/s12931-018-0901-1. PubMed DOI PMC

Nobuzane T, Tashiro S, Kudo Y. Morphologic effects of epithelial ion channels on the mouse uterus: differences between raloxifene analog (LY117018) and estradiol treatments. Am J Obstet Gynecol 2008;199(4):363.e1-363.e6. PubMed

Maitra R, Hamilton J. Altered Biogenesis of ∆F508-CFTR following treatment with Doxorubicin. Cell Physiol Biochem. 2007;20(5):465–72. doi: 10.1159/000107530. PubMed DOI

Lallemand JY, Stoven V, Annereau JP, Boucher J, Blanquet S, Barthe J, et al. Induction by antitumoral drugs of proteins that functionally complement CFTR: a novel therapy for cystic fibrosis? Lancet. 1997;350(9079):711–2. doi: 10.1016/S0140-6736(05)63510-6. PubMed DOI

Ruffles TJC, Black R, Nicholls W, Laing B, Isles A. Osteogenic sarcoma in an adolescent with cystic fibrosis: successful treatment despite significant obstacles. Front Pediatr. 2018;6:345. doi: 10.3389/fped.2018.00245. PubMed DOI PMC

Ballmann M, Junge S, Von Der Hardt H. Low-dose methotrexate for advanced pulmonary disease in patients with cystic fibrosis. Respir Med. 2003;97(5):498–500. doi: 10.1053/rmed.2002.1471. PubMed DOI

The relationship between cancer risk and cystic fibrosis: the role of CFTR in cell growth and cancer development