These data from 1419 pairs of breast cancer patients in 242 largely Caucasian families provided no evidence to support the hypothesis that the breast cancers of blood relatives have similar propensities to metastasize. None of the estimated correlation coefficients for metastatic risk in pairs of relatives differed significantly from zero, regardless of the outcome (occurrence of metastasis or metastasis-free survival time), the kinship coefficient of the relatives, and the covariates included in the correlation analysis. Similarly, the presence of lymph node involvement at diagnosis was uncorrelated in family members. However the ER statuses of cancers in first-degree relatives were positively correlated.
The absence of correlation in metastatic risk contrasts with observations from Swedish national data for some 2000 pairs of mother–daughter breast cancer patients [16
]. These data showed significantly elevated breast cancer death rate ratios of 1.6 to 1.8 among patients whose mothers had poor breast cancer outcome, compared to patients whose mothers had good outcome. Reasons for the differences in the US and Swedish data include different distributions of potential confounding factors between the two populations, and chance. In particular, the positive findings in the Swedish data could reflect confounding by familial correlation in SES, a strong determinant of breast cancer prognosis [19
]. Alternatively, the negative results reported here could reflect lack of statistical power in the present data.
According to the first of these two explanations, there is no strong correlation in metastatic risk among relatives, and the positive correlations in the Swedish data reflect residual confounding by SES that did not affect the educated, homogeneous clinic-based population studied here. The population of Sweden is heterogeneous with respect to SES, and although the death rate ratios were adjusted for occupational status (recorded as the highest job category held in a household as obtained from census data), this measure is crude and residual confounding by SES cannot be excluded.
The second explanation for the discrepant findings is lack of statistical power in the present study. According to this explanation, metastatic potential is correlated in close relatives independently of SES, and the current negative findings are due to insufficient sample size. To investigate this possibility, we used simulations to assess the power of this study to detect correlations of various magnitudes in the metastatic statuses of the 420 available pairs of first-degree relatives. The simulations suggest that this sample size would have 84% power to detect correlation coefficients of magnitude 0.13 and higher, and 92% power to detect those of magnitude 0.15 and higher. In a population of breast cancer patients with 33% risk of metastasis, correlation coefficients of these magnitudes would correspond at most to risks of about 43% among the daughters, sisters and mothers of metastatic patients. Thus the present negative findings indicate that, if patients with a family history of metastatic breast cancer themselves have increased metastatic risk, the increase is unlikely to be large.
The absence of detectable correlation within families noted here, if replicated, would imply that germline variants with strong effects on breast cancer metastatic potential are unlikely in humans. However common variants of moderate effect cannot be excluded, since such variants would not produce easily detectable familial correlations in metastasis occurrence. Evidence of such variants from animal experiments is provided by the development of inbred mouse strains that harbor unidentified genetic modifiers of metastatic progression in mammary tumors [21
], and by findings linking such progression to variants in the genes Sipa1 [3
] and Brd4 [22
]. Epidemiological studies suggest that variants in several candidate genes, including TP53, may be associated either with prognostic characteristics at diagnosis [22
] or subsequent recurrence or breast cancer death [26
]. However apart from associations concerning variants in the TP53 gene, none of the findings have been replicated.
Some limitations of the current study warrant consideration. First, we did not have high power to detect positive correlations of magnitude less than 10–15%. Thus we cannot rule out the small correlations that would be expected to arise from modest similarities in metastatic propensity due to genetic variants of small to moderate effect. Second, we did not have data on cancer treatment, particularly adjuvant chemotherapy, and differences in treatment efficacy within families might have obscured underlying correlations in metastatic propensity. Still, in this educated population, treatment efficacy may have been captured adequately by year of diagnosis, which was negatively associated with metastatic risk. Third, our findings concerning educated Caucasian women in families who present to high-risk cancer clinics may not apply to other racial, ethnic or socio-economic groups. However, although the homogeneity of this study population limits the generalizability of the findings, it has the advantage of minimizing possible confounding by familial correlation in SES.
In conclusion, the present data do not support the existence of strong correlation among relatives in the metastatic characteristics of their cancers. These negative findings need replication in other populations. If confirmed, they indicate that a family history of metastatic breast cancer does not influence a patient’s risk that her own breast cancer will metastasize, a conclusion with clinical relevance for both the prevention and treatment of breast cancer. For example, a woman’s choice between risk-reducing surgery and surveillance may be influenced by her perceptions not only of her risk of developing breast cancer (which is often overestimated), but of her risk of dying from breast cancer. These data suggest that the metastatic outcomes of her relatives’ breast cancers should not influence her decisions. Similarly, had the data suggested a strong inherited component to the risk of metastasis, more aggressive treatment for early stage breast cancer would be warranted for patients with a family history of fatal breast cancer than for those with a family history of nonfatal disease. The absence of such evidence mitigates against tailoring the aggressiveness of therapy to patients’ family histories of metastatic breast cancer.