BRCA2 Mutation Carriers, Reproductive Factors and Breast Cancer Risk

Laufey Tryggvadottir, Elinborg J Olafsdottir, Sigfridur Gudlaugsdottir, Steinunn Thorlacius, Jon G Jonasson, Hrafn Tulinius, Jorunn E Eyfjord

Disclosures

Breast Cancer Res. 2003;5(5) 

In This Article

Materials and Methods

The design was a nested case-control study. Information on reproductive factors for all participants was obtained from the CDC cohort, where most Icelandic women 20 years or older have given answers to questions on potential risk factors for breast cancer. These data have been collected as a part of the nationwide, centralized cervical cancer screening programme that started in 1964 and later also as a part of the nationwide breast cancer screening that started in 1987. The questions have changed with time; for example, information on breast feeding has only been collected since 1979. The data-bank is described in more detail elsewhere [12,30,31].

The number of women in the cohort to date is 98,000. A large proportion of the women have responded to the questionnaire on more than one occasion. The information used in the present study was that given at the last visit before diagnosis of the BRCA2-positive cases (and the same year for the matched BRCA2-negative cases and matched controls). There was a possibility of supplementing missing or invalid items with information given at other visits, concerning events that had evidently already occurred at the last visit before diagnosis. However, analyses on data corrected in this way showed that the information for controls became considerably more complete than for the cases, although the analyses were performed blindly with respect to case-control status. This was because the average number of visits to the CDC was lower after the date of diagnosis for cases than for their matched controls, which is probably due to their lower life expectancy. Since this fact might have introduced a bias, uncorrected information given at the last visit before diagnosis was used. Variables used in the present analysis were age at menarche, age at first birth, number of births and breast feeding.

All participants in the study, two case groups and controls, belonged to the CDC cohort. Only information given before diagnosis was used for the breast cancer cases.

The group of BRCA2-positive cases was defined using information on mutation status for breast cancer patients who had participated in studies of the Icelandic Cancer Society that included collection of blood or paraffin samples (see a further description later). The number of mutation carriers with invasive breast cancer that had been identified in those studies before closure of the present study was 145. Using precoded personal identifiers, record linkage with the CDC cohort resulted in 142 BRCA2-positive cases who had ever contributed information as a part of the CDC cohort. Of these cases, 39 women were excluded because they had only given information after diagnosis of breast cancer. For three of the remaining 103 mutation carriers it was not possible to find a matching case (see later), leaving 100 mutation carriers for the analysis. They were diagnosed in the years 1967-2001.

When defining the matched group of BRCA2-negative cases, we started with all Icelandic women diagnosed in the period January 1965 to December 2001 (3290 women). Record linkage with the CDC cohort resulted in 2679 cases or 81% of all women diagnosed in the period. After exclusion of women who had only given information after diagnosis, we sought four cases from this group, individually matched to each of the BRCA2-positive cases on year of birth, on year of diagnosis and on year when giving information on reproductive factors (± 3 years). A total of 1572 women fulfilled the criteria, but as only four BRCA2-negative cases per mutation carrier were sought and since for some of the 100 mutation carriers less than four matching women were found, this resulted in a group of 361 BRCA2-negative cases that best matched the 100 mutation carriers. Of those cases 286 had been tested for mutation status, leaving 75 cases with unknown status (because they had not been participants in the later-described studies). However, it is probably justified to refer to the group as BRCA2-negative because, from the earlier-defined subgroup of (1572 + 100) Icelandic breast cancer cases, the 100 mutation carriers had already been removed. Since 7-8% of Icelandic breast cancer patients carry the BRCA2 founder mutation, around 125 positive cases were expected from this subgroup. However, 100 of those positive cases had already been removed so, among the remaining 1572 women, only 25 carriers are expected (1.6%). Therefore, only one or two mutation carriers are expected among the 75 cases with unknown status.

The control group of 1000 unaffected women was drawn from the CDC cohort with individual matching to the BRCA2-positive cases on year of birth and on year when contributing information. The controls had to have been alive when their matched mutation carrier was diagnosed.

It could be of concern that the BRCA2-positive cases might be a selected group with respect to family history, since they were participants in earlier studies of the Icelandic Cancer Society. However, the majority of the group of 100 BRCA2-positive cases (81 women) came from an ongoing investigation inviting all cases who are alive in Iceland. These cases are thus unselected with respect to family history. An additional six women belonged to an unselected group of breast cancer cases recruited in a study on p53 mutations and risk factors using paraffin-embedded samples. The 13 remaining women had participated in earlier studies on family history of breast cancer. To check whether the inclusion of these cases could have introduced a bias, a separate analysis was performed excluding those 13 women.

The unaffected controls were not tested for mutation status. The prevalence of the BRCA2 mutation 999del5 in the general population is around 0.6%[2] so only six positive women were expected to be among the 1000 controls.

Odds ratios and 95% confidence intervals were estimated applying conditional logistic regression.[32] The risk associated with age at menarche, with parity, with age at first birth and with total duration of breast feeding was estimated separately for the BRCA2-positive cases and for the BRCA2-negative cases, comparing them with controls, using conditional logistic regression. This comparison is not likely to be invalidated by the lack of information on mutation status in the controls since so few positive controls were expected. Furthermore, since it was not practical to try to estimate the effects of reproductive factors in a carrier group of six positive individuals among the 1000 controls, interaction between the reproductive factors and the BRCA2 mutation status had to be tested using a case-only approach[33] where the BRCA2-negative cases were compared with the BRCA2-positive cases. Interaction was assumed to be present for a reproductive variable if the odds ratio for that variable differed significantly from 1.0. The analyses were performed using STATA Statistical Software.[34]

Screening for the BRCA2 999del5 germline mutation was performed by PCR amplification and electrophoresis as previously described.[1] All analyses were carried out on precoded material and in full accordance with the requirements of the Icelandic Data Protection Authority and The National Bioethics Committee.

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