272 t n e c r e P e v i t a l u m u C -1.05 100 90 80 70 60 50 40 30 20 10 0 -0.75 -0.45 -0.15 0.15 0.45 0.75 1.05 Intra-pair difference for the PCB score (case-control) Fig. 1 Cumulative distribution of case–control differences for the PCB score (N = 112 age-matched case control pairs). Each point represents one case–control pair. The points on the right side of the y- axis (center axis) are positive values that represent pairs where the woman who developed breast cancer had a higher PCB score postpartum than her matched control. In a majority of pairs (62 %), the woman who subsequently developed breast cancer had a higher PCB score. The differential for the PCB score was also greater for pairs where the case had a higher score than her matched control (compare points on the right of the y-axis to points on the left of the y- axis) concentration PCBs or sums of PCBs in functional groupings previously proposed by Wolff et al. [24]. No prior studies reported on the independent contribution of the three lower concentration congeners that predicted breast cancer in this study. It is notable that prior studies did not measure exposure in young women, during windows of susceptibility during early life, when the breast might be more susceptible to endocrine disruption, including in utero, puberty, preg- nancy, or the postpartum [1–3]. Our ability to directly measure exposure during the early postpartum is a partic- ular strength of this study. A recent meta-analysis of pregnancy-associated breast cancer outcomes found that women diagnosed with breast cancer in pregnancy, and particularly women diagnosed postpartum, had poorer survival [4], providing further evidence supporting the hypothesis that pregnancy and the postpartum period are vulnerable periods for the breast. As PCBs are highly persistent, it is likely that post- partum levels also reﬂect pregnancy levels, as suggested by one longitudinal study that reported high correspondence between early postpartum levels and levels across all three trimesters of pregnancy [15]. As women were young at the time of blood collection, it is also possible that the early postpartum levels of PCBs reﬂect exposure even prior to 123 Breast Cancer Res Treat (2012) 136:267–275 pregnancy, possibly during puberty, as well. This might explain the strength of the association observed for PCB 203, a higher chlorinated compound, as compounds with this structure tend to have longer half-lives [14]. Other strengths of this study include prospective assessment of exposure an average of 17 years before diagnosis, simultaneous consideration of individual PCB congener effects, and the opportunity to observe a popu- lation during active exposure because blood samples were obtained before PCBs were restricted. Our focus on breast cancer at a young age is an addi- tional strength. Molecular studies strongly suggest that pre- menopausal breast cancer may not share the same features or risk factors as breast cancer diagnosed in middle age and older [27, 28]. Our ﬁndings could lead to better under- standing about etiology, prevention, and treatment of early breast cancer, if the mechanisms for the associations we observed can be validated and investigated by experimental toxicology and molecular studies. Our choice to estimate the net effect of exposure to observed PCB mixtures found in our study participants is an additional strength. While our approach will likely be improved upon as the methods for analyzing mixed expo- sures advances; here, we applied an empirical approach to describe more than individual congener associations. It is of interest that the protective associations for PCBs 187 and 167 did not overcome the stronger, deleterious asso- ciation observed for PCB 203. There are several specula- tive explanations for this ﬁnding, the ﬁrst being that PCB 203 is a particularly strong risk factor, as evidenced by its point estimate. Alternatively, as the higher chlorinated PCBs are eliminated more slowly, it is possible that post- partum levels of PCB 203 more accurately reﬂect exposure even earlier in life, including accumulations in utero, childhood and during puberty, periods of susceptibility for the breast in addition to pregnancy and postpartum. Limitations of our study include the possibility of unmeasured confounding by other exposures. In particular, we were unable to measure dioxin exposure or activity, raising the possibility that this or other unmeasured con- founders could have masked or accounted for the associ- ations we report here. However, as we observed dose response, unmeasured confounding would have to follow the same pattern, making this alternative explanation of our ﬁndings less likely. It is also possible that host factors that inﬂuence the metabolism or selective excretion of various PCB congeners underlie the associations we observed. We used early postpartum samples to save valuable timed serum samples during pregnancy for other studies in the cohort. However, prior studies conducted in serum samples of the same age found good correspondence of these per- sistent organochlorines across all trimesters and the early postpartum [15], suggesting that postpartum PCB levels