Genetic implications of bilateral breast cancer: a population based cohort study

Summary

Background

Women with breast cancer are at high risk of bilateral breast cancer. We aimed to assess the incidence of bilateral breast cancer in relation to age and time since diagnosis of first cancer.

Methods

We analysed a population-based cohort of 123757 women with a first primary breast cancer diagnosed in Sweden from 1970 to 2000 for frequency of bilateral breast cancers and deaths by means of record linkage. Second primary breast cancers were categorised as synchronous bilateral breast cancers if diagnosed within 3 months of the first primary cancer or as metachronous if diagnosed more than 3 months after diagnosis of first primary cancer.

Findings

We identified 6550 women who had developed bilateral breast cancer. Age-incidence patterns of synchronous and unilateral breast cancer were similar, although the absolute rates of synchronous bilateral cancer were 50–100 times lower than those of unilateral cancer. A woman aged 80 years or older is at least twice as likely to be diagnosed with synchronous bilateral breast cancer than is a woman younger than 40 years. In the first 20 years after diagnosis of primary breast cancer, incidence of metachronous bilateral cancer decreased from about 800 per 10⁵ person-years to 400 per 10⁵ person-years in patients diagnosed with primary breast cancer before the age of 45 years, whereas incidence remained at 500–600 per 10⁵ person-years in those age 45 years or older at diagnosis. After 30 years' follow-up, cumulative risk of metachronous bilateral breast cancer was about 15% irrespective of age at first primary breast cancer.

Interpretation

The higher than expected risk of synchronous bilateral breast cancer could be explained by non-genetic factors. By contrast, incidence of metachronous bilateral cancer fits neither a model of highly penetrant genes nor aggregation of environmental risk factors.

Introduction

An estimated 73000 women in Sweden¹ and 2·2 million in the USA² have a history of breast cancer. Bilateral breast cancer accounts for between 2% and 11% of all breast cancer,³ and every year about 0·7% of all patients with breast cancer will develop a second, bilateral breast cancer.⁴ Thus, identification of when and why women are at high risk of bilateral breast cancer might have far-reaching consequences.

Inherent instability in genes that maintain genomic integrity, and exogenous chemicals and environmental pollutants, have been implicated in the development of multifocal breast cancer, and might have a role in other multicentric diseases. Breast cancer occurs after both breasts have been affected by the same genetic and environmental factors for several decades. Accumulated exposure to environmental factors affects the association between age and development of malignant disease. However, if multiple breast cancer is determined mainly by germline mutations that affect all somatic cells equally, then bilateral disease would be expected to develop early.

The risk of bilateral breast cancer in a woman diagnosed with breast cancer is substantially higher than the risk of unilateral disease in a previously healthy individual.3, 5 The risk of bilateral breast cancer is associated with early age of onset of the first breast cancer.6, 7, 8 Of the many established risk factors for unilateral breast cancer, only family history of breast cancer has been associated consistently with risk of bilateral disease.6, 8, 9 Furthermore, only 5% of patients with bilateral breast cancer carry mutations in the high-penetrance genes BRCA1 and BRCA2.¹⁰ Radiotherapy after breast cancer has been shown to increase the risk of bilateral breast cancer 10 years after the primary tumour,¹¹ although data are conflicting.¹² A 30–50% reduction in the incidence of bilateral breast cancer has been recorded after adjuvant systemic treatment13, 14, 15, 16, 17 further hinders the interpretation of inheritance patterns.

Low statistical power, uncertain assessment of bilateral primary cancers (ie, classification of some women with metastatic breast cancer as having new primary disease), limited age ranges, and short follow-up³ have hampered the interpretation of studies of bilateral breast cancer. Therefore, we aimed to assess the incidence of bilateral breast cancer by age of onset and time since diagnosis of first breast cancer.