Bone health in post-menopausal patients with breast cancer treated with aromatase inhibitors: factors predicting the risk for osteoporosis.

Baatjes, Karin Jeanné (2018-12)

Thesis (PhD)--Stellenbosch University, 2018.

Thesis

ENGLISH ABSTRACT: Aromatase inhibitors (AI), the gold standard for treatment of postmenopausal women with hormone-sensitive breast cancer, add an additional burden to the risk of osteoporosis in the postmenopausal population. Individual variation in AI associated bone loss is related to clinical risk factors as well as genetic variations in drug metabolism. The aim of the study is to identify postmenopausal breast cancer patients at highest risk for AI- associated bone loss by utilizing clinical, biochemical and genetic parameters. In parallel, clinically meaningful patient reports were developed from a secure online genomics database resource, enriched during the study. This prospective study was conducted at the Tygerberg Hospital Breast Clinic in affiliation with Stellenbosch University. Postmenopausal women with endocrine sensitive breast cancer, aged 50 to 80 years, were enrolled after obtaining informed consent. A baseline questionnaire documented demographic-, lifestyle- and medical history before commencing AI treatment. Clinical, biochemical and bone mineral density (BMD) measurements were obtained at baseline. Cytochrome P450 19A1 (CYP19A1) genotyping was performed using real-time polymerase chain reaction (PCR), and a screening algorithm applied to select patients for whole exome sequencing (WES). Results relevant to breast cancer diagnosis, comorbidities and treatment response were integrated into an adaptable report format for clinical application. Descriptive statistics were used to analyze the data. A total of 101 participants were recruited, with a mean age of 61±7 years. Thirty-two women fulfilled global criteria for bone protection at baseline [BMD T-score ≥-2SD (n=18); BMD T-score -1.5SD to < -2SD with risk factors (n=14)]. In women with osteoporosis, significantly lower body weight, body mass-, fat mass- and lean mass index were documented (p <0.001). Low vitamin D status was present in more than 90% of the cohort tested (n=95). After one year of AI treatment, 72 patients remained in the study, of whom 10 (14%) experienced more than 5% bone loss at the lumbar spine. Genotyping for the CYP19A1 rs10046 in 72 patients revealed that patients with two copies of the A-allele are 7,37 times more likely to have a higher percentage bone loss at the total hip compared to those without this allele (CI of 1.101- 49.336, p=0.04). At the lumbar spine, CYP19A1 rs10046 AA homozygotes were 10.79 times more likely to have a higher percentage bone loss compared to patients with the GA or GG genotypes (CI of 1.771- 65.830, p=0.01). Extended genetic testing using Sanger sequencing and WES in the 10 patients with more than 5% bone loss supported the clinical findings. None of the 34 patients without bone loss at the lumbar spine at month 12 were homozygous for the functional CYP19A1 polymorphism. At baseline, a third of women fulfilled global criteria for bone protection. This highlights bone fragility associated with body composition variables of postmenopausal women in our predominantly Mixed Ancestry study cohort. Homozygosity for CYP19A1 rs10046 provides additional information for individual risk stratification to optimize bone health maintenance. New insights gained into the mechanisms impacting bone health merit continued health outcome studies embedded in routine clinical practice.

AFRIKAANSE OPSOMMING: Aromatase inhibitore (AI), die goue standaard vir die behandeling van postmenopausale vroue met hormoon-sensitiewe borskanker, dra by tot die risiko vir osteoporose in die postmenopausale bevolking. Individuele variasie in AI geassosieёrde beenverlies is verwant aan kliniese risiko faktore asook genetiese variasie in middel metabolism. Die doel van die studie is om postmenopausale borskanker pasiënte te identifiseer wat die hoogste risiko het vir AI geassosieërde beenverlies deur gebruik te maak van kliniese, biochemiese en genetiese maatreёls. In parallel hiermee, is klinies betekenisvolle pasiёnt verslae ontwikkel vanuit die aanlyn geslote genomiese databasis bron, wat verryk is tydens die studie. Die prospektiewe studie het plaasgevind by die Tygerberg Hospitaal Borskliniek, geaffilieёr met die Universiteit van Stellenbosch. Postmenopausale vroue met endokrien-sensitiewe borskanker, tussen die ouderdomme van 50-80 jaar, is opgeneem in die studie, na verkryging van ingeligte toestemming. ‘n Basislyn vraelys het demografiese- leefstyl- en mediese geskiedenis gedokumenteer voor die aanvang van AI behandeling. Kliniese, biochemiese en been mineraal digtheid mates is geneem met basislyn. Sitochroom P450 19A1 (CYP19A1) genotipering is uitgevoer deur die gebruik van reёl-tyd polimerase ketting reaksie (PCR) en ‘n siftingsalgoritme is toegepas om pasiёnte te selekteer vir heel eksoom volgorde bepaling (WES). Alle inligting is ingelees in ‘n geslote aanlyn genomiese bron, op ‘n aangaande basis. Resultate wat relevant is tot die borskanker diagnose, ko-morbiditeite en behandelingsrepons is geintegreer in ‘n aanpasbare verslag formaat vir kliniese toepassing. Beskrywende statistiek is gebruik om die data te analiseer. ‘n Totaal van 101 deelnemers is gewerf, met ‘n gemiddelde ouderdom van 61±7 jaar. Twee-en-dertig vroue het voldoen aan die internasionale kriteria vir been beskerming, met basislyn [BMD T-telling ≥-2SD (n=18); BMD T-telling -1.5SD to < -2SD met risiko faktore (n=14)]. In vroue met osteoporose is beduidend laer liggamsgewig, liggamsmassa-, vet massa- en spier massa indeks gedokumenteer (p <0.001). Lae vitamin D status was teenwoordig in meer as 90% van die kohort wat getoets is (n=95). Na een jaar van AI behandeling, het 72 pasiёnte oorgebly in die studie, van wie 14% (n=10) meer as 5% beenverlies ervaar het by die lumbale area. Genotipering van CYP19A1 rs10046 in 72 pasiёnte het geoon dat pasiёnte met twee kopiee van die A-alleel, 7,37 meer geneig sal wees om n hoёr persentasie been verlies by die heup te hê in vergelyking met die sonder hierdie alleel (CI of 1.101- 49.336, p=0.04). By die lumbale area, was CYP19A1 rs10046 AA homosigote, 10.79 meer geneig om ‘n hoёr persentasie beenverlies te hê in vergelyking met pasiёnte wat die GA or GG genotipes het (CI of 1.771- 65.830, p=0.01). Uitgebreide genetiese toetsing met Sanger volgorde bepaling en WES in die 10 pasiente met meer as 5% beenverlies, ondersteun die kliniese bevindinge. Nie enige van die 34 pasiënte wat geen been verlies getoon het by die lumbale area teen maand 12, was homosigote vir die funksionele CYP19A1 polimorfisme nie. By basislyn het ‘n derde van vroue voldoen aan die internasionale kriteria vir beenbeskerming, wat die assosiasie van liggaamsamestelling in postmenopausale vroue van Gemengde Oorsprong, beklemtoon. Homosigote vir CYP19A1 rs10046 verskaf bykomende inligting wat in oorweging gebring kan word ten einde individuele risiko bepaling vir optimale beengesondheid te verwesenlik. Nuwe insigte in meganismes wat beengesondheid beinvloed, vereis voortgaande navorsing vasgelê binne ‘n kliniese opset.

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