Purpose Hot flashes are a common symptom and an important cause of decreased quality of life in women with breast cancer. Hot flashes involve vasodilatation and flushing, however, their complex etiology is not fully understood. We evaluated the association between germline polymorphisms in genes important to angiogenesis and subjective reporting of hot flashes. Experimental design We recruited 1,244 subjects; 520 were breast cancer cases, 715 were documented healthy controls, and nine were of unknown status. Subjects were asked to provide a blood specimen and complete a questionnaire which included whether they had recently or had ever experienced hot flashes. We evaluated candidate polymorphisms in the following genes: hypoxia inducible factor-1 alpha (HIF1α), vascular endothelial growth factor (VEGF), VEGF-receptor 2 (VEGFR-2), endothelial nitric oxide synthase (eNOS), neuropilin-1 (NRP-1), and NRP-2. Testing for an association between polymorphisms and a history of current flashes or ever having hot flashes was performed. Results 441 premenopausal and 533 postmenopausal, Caucasian women were evaluable for hot flash analysis. For premenopausal women the eNOS-786 CT and TT genotypes were significantly associated with a greater likelihood of a subject reporting current hot flashes than the CC genotype (P = 0.03). After adjusting for clinical variables, the genotype association was no longer significant (P = 0.08). For postmenopausal women, the HIF1α 1744 CT and TT genotypes were significantly associated with a greater likelihood of a subject reporting current hot flashes (P = 0.05) and this remained significant after consideration of established clinical variables (P = 0.04). Conclusion Hot flashes may be regulated by genes that control angiogenesis.
Hot flash Breast cancer Single nucleotide polymorphism Hypoxia inducible factor 1-alpha Endothelial nitric oxide synthase Angiogenesis
Supported by: ASCO Career Development Award (BPS), Catherine Peachey Fund (BPS), Indiana University GCRC CReFF Award (BPS), Breast Cancer Research Foundation (GWS), K24 and 401 from NIH, Bethesda. MD (DAF) & Indiana University Melvin, Bren Simon Cancer Center and on behalf of the Friends for Life Consortium.
Stearns V, Schneider B, Henry NL, Hayes DF, Flockhart DA (2006) Breast cancer treatment and ovarian failure: risk factors and emerging genetic determinants. Nat Rev Cancer 6:886–893. doi:10.1038/nrc1992PubMedCrossRefGoogle Scholar
Coombes RC, Hall E, Gibson LJ et al (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081–1092. doi:10.1056/NEJMoa040331PubMedCrossRefGoogle Scholar
Mouridsen H, Gershanovich M, Sun Y et al (2001) Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 19:2596–2606PubMedGoogle Scholar
Loibl S, Schwedler K, von Minckwitz G, Strohmeier R, Mehta KM, Kaufmann M (2007) Venlafaxine is superior to clonidine as treatment of hot flashes in breast cancer patients—a double-blind, randomized study. Ann Oncol 18:689–693. doi:10.1093/annonc/mdl478PubMedCrossRefGoogle Scholar
Pandya KJ, Raubertas RF, Flynn PJ et al (2000) Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a university of Rochester cancer center community clinical oncology program study. Ann Intern Med 132:788–793PubMedGoogle Scholar
Loprinzi CL, Kugler JW, Barton DL et al (2007) Phase III trial of gabapentin alone or in conjunction with an antidepressant in the management of hot flashes in women who have inadequate control with an antidepressant alone: NCCTG N03C5. J Clin Oncol 25:308–312. doi:10.1200/JCO.2006.07.5390PubMedCrossRefGoogle Scholar
Cieraad D, Conradt C, Jesinger D, Bakowski M (2006) Clinical study comparing the effects of sequential hormone replacement therapy with oestradiol/dydrogesterone and conjugated equine oestrogen/norgestrel on lipids and symptoms. Arch Gynecol Obstet 274:74–80. doi:10.1007/s00404-006-0132-4PubMedCrossRefGoogle Scholar
Krippl P, Langsenlehner U, Renner W et al (2003) A common 936 C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk. Int J Cancer 106:468–471. doi:10.1002/ijc.11238PubMedCrossRefGoogle Scholar
Schneider BP, Radovich M, Sledge GW et al (2008) Association of polymorphisms of angiogenesis genes with breast cancer. Breast Cancer Res Treat 111(1):157–163PubMedCrossRefGoogle Scholar
Summers AM, Coupes BM, Brennan MF, Ralph SA, Short CD, Brenchley PE (2005) VEGF-460 genotype plays an important role in progression to chronic kidney disease stage 5. Nephrol Dial Transplant 20:2427–2432. doi:10.1093/ndt/gfi029PubMedCrossRefGoogle Scholar
Greene RA (2000) Estrogen and cerebral blood flow: a mechanism to explain the impact of estrogen on the incidence and treatment of Alzheimer’s disease. Int J Fertil Womens Med 45:253–257PubMedGoogle Scholar