Hormone replacement therapy and elevated breast cancer risk: An artifact of growth acceleration?

Background Available data on accelerated proliferation and increased breast cancer risk due to hormone replacement therapy (HT) are inconsistent. Data on long-term effects of HT are limited. The interaction between several key factors was examined using a model-based approach. Methods Cohorts of 50 year old women, BCs were randomly generated for 30 years based on the age-specific incidence. A control group received a HT that increased the growth of occult BCs. In a 3rd cohort BCs were additionally induced by HT. This model illustrates the interrelationship of important parameters and allows the simulation and comparison of previously published clinical studies. Results Using plausible parameters for BC growth factor (GF) and HT-related effects it was demonstrated that HT caused accelerated growth of occult BCs with an apparent increase in incidence and shortened time to diagnosis. The Women’s Health Initiative (WHI) study was reconstructed assuming a GF of 1.43 induced by HT. The decision of millions of women to discontinue or forego HT based on the published risks of the WHI-study in 2002 could explain the marked jump of 6.7% in incidence within a few months. If additional BCs were induced by HT, then these BCs may become apparent after 10 or more years together with those appearing according to the normal incidence. At this time conclusive data on type, timing, and molecular characteristics of HT induced BCs are not yet available. Conclusion The acceleration in growth of occult BC has been underestimated. Initially HTs can cause an apparent increase in BC incidence thereby explaining the WHI-dependent decrease in 2003. A HT associated BC risk should only be detectable with a delay of ten and more years. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement no external funding was received ### Author Declarations All relevant ethical guidelines have been followed; any necessary IRB and/or ethics committee approvals have been obtained and details of the IRB/oversight body are included in the manuscript. Yes All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data used in this study is publicly available: SEER agespecific incidence, lifetable (age specific normal mortality) WHI-Study:n=8506, Logrank after 7.2 ys, age distribution * BC : breast cancer ER+/- : estrogen positive/negative GD : Growth duration of BC GF : Growth factor HR : Hazard Ratio HT : hormone replacement therapy HTD : hormone replacement therapy duration WHI-S : Women health initiative study