This quantitative overview estimates that each birth reduces the risk of ER+PR+ breast cancer by 11% and that women who were in the oldest age at first birth category were, on average, at 27% higher risk of ER+PR+ cancer than those who were in the youngest age at first birth category after adjustment for parity. Furthermore, we found that neither parity nor age at first birth was associated with reduced risk of ER-PR- cancer. Breastfeeding and late age at menarche decreased the risk of both subtypes of breast cancer. The protective effect of late age at menarche was statistically significantly greater for ER+PR+ than ER-PR- cancer.
The most recent qualitative review of risk factors by ER/PR status was published by Althuis et al
. in 2004 [6
]. They reported that parity and age at first birth were associated with ER+
but not ER-
breast cancer and that breastfeeding protected against both receptor-positive and -negative breast cancer. These results are consistent with the findings from our meta-analysis. However, Althuis et al
. also concluded that late age at menarche was more consistently associated with reduced risk of ER+
breast cancer, whereas we found that late age at menarche protected against both ER+
breast cancer. The difference between our conclusion and that of Althuis et al
. may be due partly to the quantitative nature of a meta-analysis, in which we weight the results of the studies by the precision of their estimates, and partly due to our incorporation of data from three more studies [8
]. Two of these studies found that late age at menarche protected against both ER+
], whereas the other found no association with either subtype.
All the studies we summarised have been published, except for one study that is currently in press [8
]. If studies that detected a difference in association by ER/PR status were more likely to be published, our results for parity and age at first birth could be biased. However, we found no evidence for publication bias for either parity or age at first birth results. If survival among cases depends on the two reproductive factors and differs between receptor-positive and receptor-negative tumors, this could result in bias among case-control studies. However, cohort studies also observed that the protective effect of parity [9
] and early first birth [9
] was restricted to ER+
cancer. We therefore think it is unlikely that survival bias explains why parity and age at first birth are associated with ER+
tumors, but not ER-
We also considered whether the different association by receptor status could be caused by residual confounding by age given that the ratio of ER+
subtypes increases with age [20
]. We therefore examined the effect of parity using stratified analyses by age (5 years) from our own data [7
]. We found that the protective effect from parity was still confined to ER+
cancer (results not shown). We therefore think it is unlikely that the difference in association by receptor status is due to residual confounding by age.
The main source of hormone receptor information for studies that we reviewed was medical records. Although we assume that the majority of laboratories have used immunoassays since 1995, we could not exclude the possibility that the assays and cutoffs for determining ER and PR status differed across studies. However, we believe that any such inconsistencies would be unlikely to cause the observed associations and, if anything, that they would bias the RR estimates toward the null value.
Some data suggest that compared with Caucasian women, African-American women are more likely to develop ER-
]. We were unable to address whether race modifies these associations, because only one study provided results by race [7
]. However, in this study, we found that the associations for parity or breastfeeding were similar in Caucasian and African-American women.
The differences between the comparison and reference categories for age at first birth varied substantially across the studies, ranging from 1 [9
] to 11 years [7
] with a 4-year average. One would expect that the effects would be greater for the studies with the greater difference or gap, but this was not the case. Because we did not know the underlying distribution of age at first birth in each specific category from each study, we were unable to pursue this further.
The protective effects of a greater number of births and an early age at first birth against ER+
but not ER-
breast cancer suggest that their effects influence risk predominantly through hormonal mechanisms that involve estrogen and progesterone. The effects of these hormones on breast tissue depend upon the amount of both hormones and their specific receptors [22
]. A greater number of births and an early first birth may protect against receptor-positive breast cancer through several mechanisms: (a) by reducing estrogen and progesterone in plasma [26
], (b) by increasing levels of sex hormone-binding globulin [26
], or (c) by causing further differentiation of the breast epithelium, which may reduce the susceptibility to estrogen and progesterone [29
Contrary to expectations, breastfeeding and late age at menarche protected against both ER+
subtypes, although menarche had greater protective effects against ER+
than did ER-
cancer. This seems to be inconsistent with the hypothesis that these factors act through estrogen and progesterone mediated by their respective receptors [22
]. However, evidence shows that when ER+
progenitor cells are exposed to estrogen, they produce paracrine signals that cause neighbouring populations of ER-
cells to proliferate [30
]. Thus, our findings do not preclude a hormonal mechanism for breastfeeding and late age at menarche but suggest that the mechanism differs from that involved in parity and age at first birth.