The Effect of Estrogen Plus Progestin Hormone Therapy on Breast Cancer Mortality: Still Unresolved

Extract

The article by Chlebowski et al. in this issue of the Journal ( 1 ) follows upon eight articles that have described the relationship between estrogen/progestin therapy and invasive breast cancer risk/mortality in studies from the Women’s Health Initiative (WHI) ( 2–9 ). Although a previous analysis addressed relationships between estrogen plus progestin use and breast cancer incidence among participants in the WHI Observational Study (WHIOS) ( 5 ), a cohort noted to have characteristics similar to participants in the WHI Randomized Trial (WHIRT), this is the first presentation of data from the WHIOS related to mortality outcomes. A major goal of the Chlebowski et al. study was to explore discrepancies between the randomized trial, which noted increased breast cancer mortality and adverse tumor characteristics associated with estrogen plus progestin therapy, and previous observational studies, which have mainly found usage to be associated with favorable prognosis breast cancers.

Findings about increased breast cancer incidence associated with estrogen plus progestin therapy from the WHIRT were first published in 2002 after a mean follow-up of 5.2 years ( 2 ). Tumor characteristics were reported after a mean follow-up of 5.6 years; with 199 observed breast cancers in the estrogen plus progestin group ( 3 ), the invasive breast cancers were larger, more likely to be node positive, and diagnosed at substantially more advanced stages compared with the placebo group. In subsequent analyses, adverse tumor characteristics associated with the estrogen plus progestin group were primarily limited to those with prior hormone use ( 4 ) or to breast tumors diagnosed during the postintervention phase ( 8 ). After a mean follow-up of 11 years ( 9 ) and 385 breast cancers and 25 deaths due to breast cancer in the estrogen plus progestin group, considerably larger fractions of breast cancer patients were diagnosed with positive lymph nodes compared with the placebo group; in addition, breast cancer mortality was nearly doubled.