WHI: Same Study, Same Results?

Less than 2 weeks ago, I was in the midst of reviewing the new Global Consensus Statement regarding menopausal hormone therapy aka the new hormone replacement therapy.  Specifically, statement #8 (my numbering) noted that breast cancer risk was associated w/addition of progestogen to estrogen.  I should point out that medroxyprogesterone acetate (MPA) has been the progestin of choice for years, even though it's physiologic effects are nothing like progesterone.  The authors also noted that breast cancer risk due to E+P was small and decreased w/time after cessation.

Of course, most of these statements have been based off the Women's Health Initiative whose initial findings were published over a decade ago in JAMA in 2002.  Since then, we've had time to mull over the results which initially led us from one extreme to the other, such that we're a bit more midline now.  However, academicians in the ivory tower still argue over the different results of this single large randomized controlled trial that contradict those of multiple large observational studies.

As it turns out, WHI was actually quite a bit more complicated than meets the eye.  There was that arm of WHI which caught everyone's attention in  which women were randomized to conjugated equine estrogen (CEE+MPA) vs placebo.  There was a another arm of WHI was didn't garner as much attention in which women were randomized to CEE alone because they'd already undergone a hysterectomy.  In fact, those hysterectomized women who received E alone had a lower rate of breast cancer as noted initially in 2006 in JAMA and confirmed last May in Lancet.  Which is why I've been pointing the accusatory finger at MPA for a while now.

Anyway, there was yet another arm of WHI in which women were just observed (WHI Observational Study or WHIOS if you will), whether their physicians started them on CE/E, CE/E+P/MPA or nothing at all.  So in an attempt to analyze the outcome of WHI's observational arm (WHIOS), in a study published early online just 3 days ago in the Journal of the National Cancer Institute, the authors followed for 11+yrs 25,328 postmenopausal women w/o prior hysterectomy who did not take any hormones while 16,121 others elected to take some form of E+P. Note that while the RCT version of WHI explicitly randomized women to either placebo or CEE+MPA, the women in WHIOS were observed taking whatever form of E their physician felt appropriate.   

Keeping all that in mind, perhaps it's not so surprising that the authors concluded that E+P was associated w/increased risk of breast cancer compared to placebo in this observational arm of WHI, consistent w/RCT.  Also concordant w/WHI, breast cancer risk decreased as time increased off regimen.

I suppose I could imagine some sort of bias since I would expect these same authors of the original WHI to want to find similar findings in the observational arm.  After all, if they did not and all the observational studies were aligned, then we could claim something wrong with the RCT design or the participants chosen for inclusion.  I think it's also important to point out something the editorialists noted: why were only 41,449 of the 93,176 who participated in WHIOS included in this new analysis?  As far as the editorialists are concerned, this study still doesn't settle everything and isn't the last word on E+P vs breast cancer, unlike what you might read in a quick 2 line summary in the newspaper or 10 second blurb on TV.

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