Postmenopausal hormone therapy and the risk of breast cancer in Norway

Abstract

There is convincing evidence that combined estrogen-progestin therapy (EPT) increases the risk of breast cancer. However, the effect of different formulations, preparations and routes of administration is largely unknown. Estrogen only-therapy (ET) is, in general, not associated or weakly associated with breast cancer risk. We investigated the effect of hormone therapy (HT) with ET, EPT, and tibolone on risk of invasive breast cancer. Information on HT use was obtained from the Norwegian Prescription Database, and breast cancer incidence from the Cancer Registry of Norway. Poisson regression was used to estimate the incidence rate ratios (RR). We analyzed data from 686,614 Norwegian women, aged 45-79 years in January 2004, followed until December 2008, of whom 178,383 (26%) were prescribed HT. During the average 4.8 years of follow-up, 7,910 invasive breast cancers were registered. Compared with nonusers, current users of estradiol-norethisterone acetate (NETA)(EPT) had a RR of 2.74 (95% CI: 2.55-2.95). Users of the high dose estradiol-NETA formulation Kliogest V R had a RR of 3.26 (95% CI: 2.84-3.73), while users of the low dose Activelle V R had a RR of 2.76 (95% CI: 2.51-3.04). Current users of tibolone had a RR of 1.91 (95% CI: 1.61-2.28). Current users of ET with oral or transdermal estradiol had a RR of 1.40 (95% CI: 1.16-1.68), and 1.40 (95% CI: 1.00-1.95), respectively. The increased incidence rates approximates one extra invasive breast cancer case diagnosed for every 259 women using estradiol-NETA for one year, and one extra case for every 475 women using tibolone. In conclusion, use of estradiol-NETA and tibolone preparations is associated with an increased breast cancer risk.

Menopausal hormone therapy and breast cancer: what is the true size of the increased risk?

“…In particular, our relative risk estimates for current use of combined MHT are compatible with the results from epidemiological studies that have updated MHT use by questionnaire (Chen et al , 2004; Calle et al , 2009; Beral et al , 2011; Fournier et al , 2014) or record linkage (Roman et al , 2016). Relative risk increased with greater duration of current combined MHT use, to 3.27 at 15+ years of use, and these long-term risks were larger than those previously reported (Li et al , 2003; Brinton et al , 2008; Saxena et al , 2010), although there is considerable overlap in the CIs around these estimates.…”

“…In our cohort, the risk of post-menopausal breast cancer was increased with current use of MHT, as in previous studies (Colditz et al , 1995; Collaborative Group on Hormonal Factors in Breast Cancer, 1997; Stahlberg et al , 2004; Campagnoli et al , 2005; Santen et al , 2010; Bakken et al , 2011; Beral et al , 2011; Salagame et al , 2011; Anderson et al , 2012; Chlebowski and Anderson, 2012), and the increase in risk was larger with combined oestrogen plus progestogen than with oestrogen-only formulations, again as seen before (Colditz et al , 1995; Olsson et al , 2003; Stahlberg et al , 2004; Campagnoli et al , 2005; Bakken et al , 2011; Beral et al , 2011; Chlebowski and Anderson, 2012; Roman et al , 2016). In particular, our relative risk estimates for current use of combined MHT are compatible with the results from epidemiological studies that have updated MHT use by questionnaire (Chen et al , 2004; Calle et al , 2009; Beral et al , 2011; Fournier et al , 2014) or record linkage (Roman et al , 2016).…”

“…There are, however, shortfalls in the way information has been collected and analysed in most published epidemiological studies (Colditz et al , 1995; Magnusson et al , 1999; Li et al , 2000; Schairer et al , 2000; Daling et al , 2002; Newcomb et al , 2002; Beral and Million Women Study Collaborators, 2003; Li et al , 2003; Bakken et al , 2004, 2011; Chen et al , 2004, 2006; Stahlberg et al , 2004; Fournier et al , 2005; Brinton et al , 2008; Saxena et al , 2010; Beral et al , 2011; Calvocoressi et al , 2012; Ritte et al , 2012; Cordina-Duverger et al , 2013; Nyante et al , 2013; Fournier et al , 2014; Thorbjarnardottir et al , 2014; Roman et al , 2016). In prospective studies that only collect information on MHT up to the time of recruitment (e.g., cohort studies with no follow-up questionnaires) current use of MHT and duration of use may be misclassified because some never users of MHT will become users during follow-up, and some users will become ex-users; this may lead to biased assessment of breast cancer risk in relation to MHT use (Van Leeuwen and Rookus, 2003; Lee et al , 2005) but the extent has not been assessed empirically.…”

“…In prospective studies that only collect information on MHT up to the time of recruitment (e.g., cohort studies with no follow-up questionnaires) current use of MHT and duration of use may be misclassified because some never users of MHT will become users during follow-up, and some users will become ex-users; this may lead to biased assessment of breast cancer risk in relation to MHT use (Van Leeuwen and Rookus, 2003; Lee et al , 2005) but the extent has not been assessed empirically. In addition, analyses that include women who have had simple hysterectomy (i.e., without oophorectomy) before natural menopause will also lead to biased results (Collaborative Group on Hormonal Factors in Breast Cancer, 1997; Pike et al , 1998; Rockhill et al , 2000; Simpson et al , 2007) but many case–control and cohort studies include such women (Colditz et al , 1995; Magnusson et al , 1999; Li et al , 2000; Schairer et al , 2000; Daling et al , 2002; Newcomb et al , 2002; Beral and Million Women Study Collaborators, 2003; Li et al , 2003; Bakken et al , 2004, 2011; Chen et al , 2004, 2006; Stahlberg et al , 2004; Fournier et al , 2005; Brinton et al , 2008; Saxena et al , 2010; Beral et al , 2011; Calvocoressi et al , 2012; Ritte et al , 2012; Cordina-Duverger et al , 2013; Fournier et al , 2014; Thorbjarnardottir et al , 2014; Roman et al , 2016). Thus, although the epidemiological evidence clearly shows an increased risk of breast cancer with MHT use (Campagnoli et al , 2005; Greiser et al , 2005; Lee et al , 2005), there is uncertainty about the magnitude of the risk.…”

Hormonbehandling etter menopausen – ny kunnskap om langtidsrisikoen

“…Mange observasjonsstudier, og også WHI-studien, viser økt risiko for brystkreft med østrogen-gestagen-kombinasjoner, mens risikoen ikke øker ved bruk av østrogen alene. En norsk registerstudie viste at risikoen for brystkreft var omtrent doblet ved kombinasjonsbehandling (5). Ifølge denne studien vil behandling av 259 kvinner i ett år medføre ett ekstra brystkrefttilfelle.…”