Letters to the editor.

Abstract

The original article by Malvezzi et al. provided data showing a reduction in European breast cancer mortality over the last three decades in women of all ages and concluded this was attributable to treatment improvements and earlier diagnosis, the latter including an impact of screening [1.Malvezzi M. Carioli G. Bertuccio P. et al.European cancer mortality predictions for the year 2019 with focus on breast cancer.Ann Oncol. 2019; Abstract Full Text Full Text PDF Scopus (136) Google Scholar]. In addition, decreased use of hormone replacement therapy (HRT) was also cited as likely to be a contributory factor. There has been a sustained, worldwide fall in HRT prescribing initiated by publication of the Women’s Health Initiative (WHI) placebo-controlled randomised trial of combined HRT in the early 2000s [2.Chlebowski R.T. Hendrix S.L. Lander R.D. et al.Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women.JAMA. 2003; 289: 3243-3253Crossref PubMed Scopus (1677) Google Scholar]. Whilst a short-lived decrease in hormone-sensitive cancers diagnosed in the first few years post WHI publication was observed in some countries, breast cancer diagnosis rates overall have been rising for decades across Europe and continue to do so [3.https://gateway.euro.who.int/en/indicators/hfa_375-2350-incidence-of-female-breast-cancer-per-100-000/ (30 March 2019, date last accessed).Google Scholar]. This reflects the multifactorial nature of this condition, being influenced for example by population ageing, screening availability and uptake, reproductive behaviours and exposure to other modifiable lifestyle factors in addition to HRT. Moreover, the fall in breast cancer mortality from its peak rates in the late 1980s, pre-dates the reduction in HRT prescribing by over a decade. Assuming a fall in the incidence of HRT-associated hormone-sensitive breast cancer diagnosis inevitably results in an improved breast cancer survival may be too simplistic to conclude given estimation of breast cancer prognosis and mortality data in women taking HRT up to the time of their diagnosis fails to support a detrimental impact. Application of the Nottingham Prognostic Index (NPI) to breast cancers diagnosed in women allocated to receive HRT or placebo in both randomised arms of the WHI trial places them all in the same moderate prognostic group 1 (i.e. NPI range of 3.41–4.4 (combined oestrogen/progestogen HRT arm, HRT 3.65 versus placebo 3.51; unopposed oestrogen HRT arm, HRT 3.85 versus placebo 3.62) (J. Marsden, personal communication). The long-term follow-up data from WHI showed no increase in all cause or breast cancer mortality with a duration of use between 5 and 7 years [4.Manson J.E. Aragaki A.K. Rossouw J.E. et al.Menopausal hormone therapy and long-term all-cause and cause-specific mortality: the Women's Health Initiative Randomized Trials.JAMA. 2017; 318: 927-938Crossref PubMed Scopus (0) Google Scholar]. The Finnish registry data, which followed up 489 105 women from HRT initiation between 1994 and 2009, showed breast cancer mortality was significantly reduced in all HRT users, regardless of duration of exposure [≤5 years, standardised mortality ratio (SMR) 0.56, 95% confidence interval (CI) 0.52–0.60; >5 to 10 years SMR 0.46, 95% CI 0.41–0.51; >10 years SMR 0.62, 95% CI 0.56–0.68). A significantly larger risk reduction was detected in the 50–59 compared with 60–69 or 70–79 years age groups (SMR 0.33, 95% CI 0.29–0.37, SMR 0.64, 95% CI 0.59–0.70 and SMR 0.78, 95% CI 0.69–0.87, respectively). Mortality reductions in unopposed oestrogen users tended to be larger across all age groups compared with combined HRT [5.Mikkola T.S. Savolainen-Peltonen H. Tuomikoski P. et al.Reduced risk of breast cancer mortality in women using postmenopausal hormone therapy: a Finnish nationwide comparative study.Menopause. 2016; 23: 1199-1203Crossref PubMed Scopus (31) Google Scholar]. We feel this article provides reassuring findings showing reduction in breast cancer mortality over the last three decades. However, the reduction in HRT use since the publication of the WHI findings is less likely to explain the improvement in survival reported by Malvezzi et al. [1.Malvezzi M. Carioli G. Bertuccio P. et al.European cancer mortality predictions for the year 2019 with focus on breast cancer.Ann Oncol. 2019; Abstract Full Text Full Text PDF Scopus (136) Google Scholar].