Correspondence to: Matti A. Rookus, PhD, Department of Epidemiology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands (e-mail: m.rookus{at}nki.nl).
Dr. Foulkes indicates correctly that the effect of parity on breast and ovarian cancer risk among BRCA1 and BRCA2 mutation carriers may be different from that in the general population. However, whether this difference really exists remains to be seen. Among the general population, women have a transient increased risk of breast cancer after pregnancy and a decreased risk only after 1015 years (1). Because most women who decide to be tested for BRCA mutations are relatively young, studies among carriers may measure transient effects. Luckily, adjustments for confounders can be made in analyses without advanced knowledge of the detailed relationships between confounder and disease.
If, for the time being, it is assumed that parity reduces the overall risk of breast cancer, then the preference of parous women to choose prophylactic surgery will result in confounding by parity, if it is not controlled for. This bias will result in an overestimation of the effect of the surgery because the surgery group will have a baseline risk that is lower than that of the nonsurgery group.
Another issue is whether parity-associated genetic testing evokes a testing bias, i.e., a distortion of the effect from selective testing. Unlike the association between parity and prophylactic surgery, selective testing does not introduce a systematic difference between the comparison groups. If parity is a confounder and is properly adjusted for, then the estimated effect is not biased and is directly applicable to the untested group of carriers, irrespective of any confounder-associated selection from testing. If parity is an effect modifier, then it is most informative to present the estimated efficacy for each of the groups separately. These estimates for parous and nulliparous women, respectively, then apply to tested and untested carriers. Only a less informative summary estimate should be weighted for the difference between the tested and untested groups.
It is important to realize that a risk factor of a disease is not necessarily an effect modifier in an efficacy study. The classification of a factor as an effect modifier is directly related to the scale of measurement. If parous and nulliparous women experience the same relative risk reduction from a prophylactic surgery, efficacy will differ on an absolute scale. Although the relative effect is most often presented in prophylactic studies, the absolute effect will generally be more appealing to physicians and their patients.
REFERENCE
1 Lambe M, Hsieh C, Trichopoulos D, Ekbom A, Pavia M, Adami HO. Transient increase in risk of breast cancer after giving birth. N Engl J Med 1994;331:59.
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