Parity

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It is well established that parity reduces the risk of female breast cancer in the general population in the longer term, with the degree of protection increasing with the number of births (19). The largest dataset analyzed estimated the risk reduction to be around 7% per additional birth (20). Each full-term pregnancy is associated with a transient increase in risk, so that the protective effect of parity is most apparent in women over the age of 40 years (21). Women who have their first birth at a younger age are also at reduced risk (19).

It has been suggested that the protective effect of parity is reduced, or not evident, in women who are carriers of mutations in BRCA1 and BRCA2 (22-25), but few of the studies on which this was based compared affected and unaffected mutation carriers separately by gene. Jernstrom et al. (24) found that being parous increased the risk of breast cancer before the age of 41 years [odds ratio (OR) = 1.71; 95% confidence interval (CI) = 1.13-2.62] among pooled samples of 472 BRCA1 and BRCA2 mutation carriers, and that risk increased with each additional birth (p = 0.007). These results were not confirmed in a subsequent analysis of an expanded dataset (including 2520 carriers from 55 collaborating centers) by the group led by Narod (26), which found that the associations differed by mutation. Risk was found to increase with parity among BRCA2 carriers under the age of 50 years, who represented only 20% of the sample in the earlier study (OR = 1.17 per birth; 95% CI = 1.01-1.36), but not among older carriers. On the other hand, among BRCA1 carriers, having four or more children was associated with a

Table 1 Summary of Large Studies of Environmental Modifiers of Breast Cancer Risk Comparing Exposures of Affected Carriers to Unaffected Carriers

Authors, year (Consortium)

Methodology

Exposure(s) assessed

Jernstrom et al., 1999 (24) (Narod Consortium)

Cullinane et al., 2005 (26) (Narod Consortium)

Gronwald et al., 2006 (27) (data may be included in the Narod Consortium studies)

Conditional logistic regression analysis of matched case-control data from pooled female BRCA1 and BRCA2 mutation carriers aged <40 years Conditional logistic regression analysis of matched case-control data from female BRCA1 and BRCA2 mutation carriers of all ages, by gene and by age (divided at age 50 years)

Conditional logistic regression analysis of matched case-control data from female BRCA1 mutation carriers of all ages with mutations in BRCA1

189/189 Pooled carriers

(BRCAly, Parity (ever)

47/47 Per birth

(.BRCA2) 934/934 BRCA1 carriers

(BRCAly, Parity (ever)

326/326 >4 births vs. never

(BRCA2) Per birth

BRCA2 carriers Parity (ever) >2 births vs. never Per birth

Per birth, women aged <50 years Per birth, women aged >50 years 348/348 BRCA1 carriers

(BRCA1) Parity (per birth)

Breastfeeding (>12 months vs. never) Age at menarche (per year) Oral contraceptive use (ever)

1.37 (0.93-2.03) 1.53 (1.01-2.32) 1.15 (1.00-1.33) 1.17 (1.01-1.36) 0.97 (0.58-1.53)

1.2 (Phc = 0.02) 0.5 (Pc = 0.02) 0.9 (Pc = 0.004) 0.8 (Pc = 0.3)

Andrieu et al., 2006 Weighted Cox regression analysis of

(28) (IBCCS affected and unaffected female BRCA1 and

Consortium) BRCA2 mutation carriers of all ages, by gene and by age (divided at age 40 years)

Rebbeck et al., 2001 Unconditional logistic regression analysis

(29) (PROSE/ of affected and unaffected female BRCA1

MAGIC and BRCA2 mutation carriers of all ages

Consortium) pooled

278/170 (BRCA1 and

BRCA2 pooled)

BRCA1 carriers Parity (ever)

Age at first birth (<20 years vs.

>30 years) Induced abortion (ever) Miscarriage (ever) Breastfeeding (>12 months vs.never) BRCA2 carriers Parity (ever)

Age at first birth (<20 years vs.

>20 years) Induced abortion (ever) Miscarriage (ever)

Breastfeeding (>12 months vs. never) Pooled carriers Parity (per birth)

(Per birth, women aged <40 years) (Per birth, women aged >40 years) Pooled carriers

Age at first birth (<30 years vs.

>30 years or nulliparous) Age at menarche ( >13 years vs. <13 years)

(Continued)

Table 1 Summary of Large Studies of Environmental Modifiers of Breast Cancer Risk Comparing Exposures of Affected Carriers to Unaffected Carriers (Continued)

Authors, year (Consortium)

Methodology

iva

Exposure(s) assessed

RR (95% CI)

Friedman et al., 2006

Conditional logistic regression analysis of

1,313/1,313

BRCA1 carriers

(31) (Narod

matched case-control data from female

(.BRCA1)

Induced abortion (ever)

0.98 (0.78-1.22)

Consortium)

BRCA1 and BRCA2 mutation carriers of all

380/380

Miscarriage (ever)

1.09 (0.89-1.32)

ages, by gene

(.BRCA2)

BRCA2 carriers

Induced abortion (ever)

0.64 (0.41-1.00)

Miscarriage (ever)

0.75 (0.55-1.04)

Jernstrom et al., 2004

Conditional logistic regression analysis of

685/685

BRCA1 carriers

(32) (Narod

matched case-control data from female

(BRCA1)

Breastfeeding (>12 months vs. never)

0.55 (0.38-0.80)

Consortium)

BRCA1 and BRCA2 mutation carriers of all

280/280

(Per month)

0.98 (0.97-0.99)

ages, by gene

(.BRCA2)

BRCA2 carriers

Breastfeeding (>12 months vs. never)

0.95 (0.56-1.59)

(Per month)

0.99 (0.98-1.01)

Narod et al., 2002 (12)

Conditional logistic regression analysis of

981/981

BRCA1 carriers

(Narod Consortium)

matched case-control data from female

(BRCA1)

Oral contraceptive use (ever)

1.20 (1.02-1.40)

BRCA1 and BRCA2 mutation carriers of all

330/330

(Ever, women aged <40 years)

1.38 (1.11-1.72)

ages, by gene

(.BRCA2)

(>5 years use vs. never)

1.33 (1.11-1.60)

(Use before the age of 30 years vs.

1.29 (1.09-1.52)

never)

(Use before 1975 vs. never)

1.42 (1.17-1.75)

(Per year)

1.02 (1.00-1.03)

BRCA2 carriers

Oral contraceptive use (ever)

0.94 (0.72-1.24)

Haile et al., 2006 (17) Unconditional logistic regression analysis

(BCFR Consortium) of affected and unaffected female BRCA1

and BRCA2 mutation carriers aged <50 years, by gene

McGuire et al., 2006 (44) (BCFR Consortium)

Brunei et al., 1998 (45) (Narod Consortium)

Unconditional logistic regression analysis of affected and unaffected female BRCA1 and BRCA2 mutation carriers aged <50 years, by gene

Conditional logistic regression analysis of matched case-control data from pooled female BRCA1 and BRCA2 mutation carriers of all ages

Ghadirian et al., (46) (Narod Consortium)

2004

Colilla et al., 2006 (48) (PROSE/MAGIC Consortium)

Conditional logistic regression analysis of matched case-control data from female BRCA1 and BRCA2 mutation carriers of all ages, by gene

Cox regression analysis of affected and unaffected female BRCA1 mutation carriers of all ages

Cox regression analysis of affected female carriers (of all ages) of one of three ancient mutations in BRCA1 and BRCA2

195/302

195/302

186/186 (BRCA1 and

BRCA2 pooled) 806/806

176/140 (BRCA1)

104/0 (BRCA1 and

BRCA2 pooled)

BRCA1 carriers

Oral contraceptive use (ever) 0.77 (0.53-1.12) BRCA2 carriers

Oral contraceptive use (ever) 1.62 (0.90-2.92)

BRCA1 carriers

Alcohol use (ever) 1.06 (0.73-1.52) BRCA2 carriers

Pooled carriers

Cigarette smoking (ever) 0.54 (0.34-0.84)

BRCA1 carriers

Cigarette smoking (ever) 1-09 (0.87-1.33) BRCA2 carriers

Cigarette smoking (ever) BRCA1 carriers

Cigarette smoking (ever) 0.63 (0.47-0.87)

Pooled carriers

Physical activity as teenager 0.63 (P = 0.03) Body mass index at the age of

(Continued)

Table 1 Summary of Large Studies of Environmental Modifiers of Breast Cancer Risk Comparing Exposures of Affected Carriers to Unaffected Carriers (Continued)

Authors, year (Consortium)

Methodology

Exposure(s) assessed

Kotsopoulos et al., 2005 (50) (Narod Consortium)

Narod et al., 2006 (11) (Narod Consortium)

Andrieu et al., 2006 (53) (IBCCS Consortium)

Conditional logistic regression analysis of 797/797

matched case-control data from pooled (BRCA1)

female BRCA1 and BRCA2 mutation 276/276

carriers aged >30 years, by gene and by age (BRCA2) (divided at age 40 years)

Conditional logistic regression 1260/1260

analysis of matched case-control data from (BRCA1)

pooled female BRCA1 and BRCA2 mutation 340/340

carriers of all ages, by gene and by age (BRCA2) (divided at age 40 years)

Weighted Cox regression analysis of 602/585

affected and unaffected female BRCA1 and (BRCA1)

BRCA2 mutation carriers of all ages, by 251/163

gene, by age (divided at age 40 years), and (BRCA2) by year of birth (divided at 1950)

Weight change at ages 18-30 (loss of >10 lb vs. loss/gain within 10 lb) Pooled carriers

Pooled carriers aged <40 years Pooled carriers aged >40 years BRCA1 carriers aged <40 years BRCA2 carriers aged <40 years Mammography (ever) Pooled carriers

Pooled carriers aged <40 years Pooled carriers aged >40 years BRCA1 carriers BRCA2 carriers Chest X rays (ever) Pooled carriers

Pooled carriers aged <40 years Pooled carriers born >1950 Exposed before the age of 20 years BRCA1 carriers BRCA2 carriers

0.66 (0.46-0.93) 0.47 (0.28-0.79) 0.97 (0.52-1.65) 0.35 (0.18-0.67) 0.88 (0.35-2.23)

1.54 (1.1-2.1) 1.97 (1.3-2.9) 2.56 (1.8-3.7) 4.64 (2.2-10.9) 1.42 (1.0-2.0) 2.33 (1.1-5.0)

Kotsopoulos et al., 2005 (56) (Narod Consortium)

Weighted Cox regression analysis of 945/945

affected and unaffected female BRCA1 and (BRCA1)

BRCA2 mutation carriers of all ages, by 366/366

gene (BRCA2)

Unconditional logistic regression analysis 52/72 of affected and unaffected female BRCA1 (BRCA1)

and BRCA2 mutation carriers, by gene 44/38

BRCA1 carriers

Age at menarche (>15 vs. <11) (Trendb—per year) BRCA2 carriers

Age at menarche (>15 vs. <11) (Trend b—per year) Breast density

(Dense area >50% vs. <50%) BRCA1 carriers BRCA2 carriers

"Number of affected carriers/number of unaffected carriers (gene in which a mutation is carried in parenthesis). bP-value for trend only, as elative risk estimate was not provided. CP, p-value (95% CI not provided).

Abbreviations'. BCFR, Breast Cancer Family Registry; CI, confidence interval; IBCCS, International BRCA1/2 Carrier Cohort Study; PROSE/MAGIC; RR, estimate of relative risk associated with the exposure.

modest reduction in risk relative to being nulliparous (OR = 0.62; 95% CI = 0.41-0.94), and this effect did not appear to differ by age. The investigators also analyzed time since last birth and found some evidence that while for BRCA2 mutation carriers, there was a nonsignificant transient increase in breast cancer risk following each birth, for BRCA1 mutation carriers, there was a modest nonsignificant decrease in risk in the two years immediately following a full-term pregnancy. Gronwald et al. (27) recently published results based on an analysis of 696 Polish BRCA1 (mostly founder) mutation carriers in which they reported that the risk of breast cancer increased with each live birth (OR = 1.2 per birth; p = 0.02). It is possible, though not certain, that this Polish dataset is a subset of the larger collaboration led by Narod.

Using a different analytical approach, the IBCCS consortium has also recently published its analysis of 1187 BRCA1 and 414 BRCA2 mutation carriers in which it found that while breast cancer risk did not appear to differ between parous and nulliparous women, among parous women, an increasing number of full-term pregnancies was associated with protection from breast cancer [hazard ratio (HR) = 0.86; 95% CI = 0.78-0.94] (28). This effect appeared to be restricted to women over the age of 40 years, with some evidence that risk increased with number of pregnancies in younger parous women. These results were seen consistently in both BRCA1 and BRCA2 mutation carriers analyzed separately, although the effects appeared to be slightly stronger among BRCA2 mutation carriers. The IBCCS consortium also evaluated the risk associated with age at first birth, and found that among BRCA2 mutation carriers, women who first gave birth before the age of 20 years were found to be at approximately 50% reduced risk of breast cancer, but that the opposite was the case for BRCA1 mutation carriers, with risk appearing to be higher for those with an earlier age at first birth.

Rebbeck et al. (29) also assessed the effect of age at first live birth among a pooled sample of 448 female BRCA1 and BRCA2 mutation carriers of all ages, most of whom had BRCA1 mutations, and found that women who had their first live birth before the age of 30 years were at a reduced risk compared to nulliparous and other parous women (OR = 0.33; 95% CI = 0.16-0.66).

Although these various findings appear to be contradictory and certainly require further investigation to clarify exactly how full-term pregnancies influence breast cancer risk in carriers of mutations in BRCA1 and BRCA2, some preliminary conclusions can be drawn that may have relevance for genetic counseling of mutation carriers. The effects of parity on breast cancer risk may not be the same for BRCA1 and BRCA2 mutation carriers, and so studies that pool them may be less informative. Having many children is possibly associated with an increased risk of breast cancer among younger (aged less than 40 years) female carriers of mutations in either gene, but particularly BRCA2 mutation carriers. This is perhaps consistent with the observation that the transient increase in risk associated with a full-term pregnancy seen in the general population may occur in BRCA2 mutation carriers but not BRCA1 mutation carriers. While the protection associated with having a first birth at a young age (before the age of 20 years) among women in the general population may also be present among BRCA2 mutation carriers, it is not clear whether this is the case for BRCA1 mutation carriers.

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