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Recent advances in the genetics of susceptibility to and treatment of breast cancer.

Introduction

Since the middle of the 1990s, with the seminal identification of mutations in the breast cancer genes BRCA1 and BRCA2, which cause early onset familial breast cancer, limited progress has been made in defining additional genetic risk factors for breast cancer until very recently. A third major genetic locus, the putative BRCA3, has not been defined to account for other familial breast cancer cases. However, rather than concentrating on traditional linkage studies in multiple affected family members, recent approaches have successfully focused on candidate gene (genes selected because of their known function) and genome-wide association studies (GWAS) to define additional genes relevant to both familial and sporadic breast cancer.

In this brief review, we will summarise the important findings from this sudden avalanche of studies. In addition, we will discuss progress in defining pharmacogenetic factors relevant to the side effects and efficacy of breast cancer treatment, and consider recent reports that have indicated an important relationship between levels of the cytochrome P450 enzyme CYP2D6 and response to tamoxifen treatment.

Genetic susceptibility to breast cancer

Major breakthroughs in understanding the inherited susceptibility to breast cancer came with the identification of mutations in BRCA1 and BRCA2. It is estimated that 3-5% of all breast cancers can be attributed to mutations in these highly penetrant genes [1,2]. BRCA1 and BRCA2 mutations are associated with early-onset disease in multiple family members, an increased risk of bilateral disease and an increased risk of ovarian cancer. There is a vast literature on the impact of testing for BRCA1 and BRCA2 mutations, the specific risks in different populations, and the role of impaired DNA damage response in breast cancer aetiology. The understanding of the functional role of BRCA1 and BRCA2 proteins has led to the development of trials of poly(ADP-ribose) polymerase (PARP) inhibitors and platinum- versus taxane-based chemotherapy in patients with BRCA1/2-related metastatic breast cancer [3].

Rare mutations in TP53 have also been associated with early-onset familial breast cancer [4]. However, the fact that mutations in these three genes only account for approximately 25% of the familial risk of breast cancer has led to studies to identify additional breast cancer susceptibility genes (Table 1) [5]. A number of genes have been selected and screened, including ATM [6], CHEK2 [7], BRIP1 [8] and PALB2 [9,10], because of their putative role as checkpoint kinases in DNA repair or in Fanconi anaemia (biallelic mutations of BRCA2 cause Fanconi anaemia). The presence of mutations in these genes, which result in absent or truncated proteins, modestly (two- to four-fold) increases the risk of breast cancer. Because of their rarity in the population, the variants in these genes contribute only a small amount to the overall risk of breast cancer. Association studies of more common genetic variants in candidate genes have been undertaken. Initially, these studies produced conflicting results, but through large collaborations between research groups including thousands of samples from well-characterised patients, a greater consensus has emerged and laid the groundwork for GWAS [11]. Robust examples from the multiple case-control association studies of common variants include a missense arginine to histidine amino acid change (D302H) in CASP8 associated with a moderate reduction in breast cancer risk [12], a common amino acid change (C557S) in BARD1 which increased breast cancer risk [13], and most recently a variant in RASSF1A associated with early-onset cancer in BRCA1 and BRCA2 mutation carriers [14].

To identify common variants underlying breast cancer susceptibility, with no prior assumptions about the genes before analysis (i.e. variants that are screened because they are found evenly spaced through the genome or because they alter an amino acid), a number of groups have taken advantage of major advances in technology. High-throughput genotyping platforms including Affymetrix arrays and Illumina BeadChip are able to analyse hundreds of thousands of genetic variants [single nucleotide polymorphisms (SNPs)] in a single sample in a single assay, thus research previously taking decades can be achieved in hours. Easton et al. [15] conducted a three-stage GWAS of >200,000 SNPs in high-risk individuals from BRCA1/2-negative families, then in samples from 400 cases of invasive breast cancer and a similar number of controls. The positive associations were confirmed by an internal validation study of 30 SNPs in 21,860 cases and 22,578 controls from 22 studies [15]. The 30 SNPs were narrowed to five novel loci, not previously considered relevant to breast cancer, each containing one or two SNPs that were very strongly associated with breast cancer in several populations of diverse ethnicity. Four loci contained plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1) with no gene candidate at the 8q24 locus. Each locus conferred a small increased risk of up to 1.25-fold in individuals carrying one copy of the variant (heterozygotes) and 1.65-fold in those with two copies (homozygotes). A subsequent case-only study has defined phenotypic correlations for these variants, such that individuals carrying a MAP3K1 variant were less likely to be lymph node positive at diagnosis [16]. Individuals with the TNCR9 variant were more likely to be diagnosed at a younger age and individuals with a variant in FGFR2 had a stronger family history of breast cancer and/or ovarian cancer [16]. A further analysis of the original GWAS cohort elicited differences between oestrogen receptor (ER)positive and -negative tumour groups with FGFR2 and the 8q24 locus more strongly associated with ER-positive disease [17]. Consistent with these findings, in an independent GWAS of >500,000 SNPs in over 1000 postmenopausal women with breast cancer, Hunter et al. [18] also demonstrated an association with variants in FGFR2. Whereas other GWAS provide evidence for chromosomal regions on 6q22.33, 2q35, 16q12 and 5p12, where the specific gene variants are still unknown, they appear also to raise breast cancer risk modestly [19-21].

The role of these loci in increasing breast cancer risk in >10,000 BRCA1 and BRCA2 mutation carriers has been further investigated [22]. Variants in FGFR2 and MAP3K1 were each associated with increased breast cancer risk in BRCA2 mutation carriers, but not in BRCA1 carriers. The TNCR9 variant was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers. Of importance, the loci interacted to multiply breast cancer risk in BRCA2 mutation carriers.

In an elegant study, Meyer et al. [23] demonstrated that the variants in FGFR2 associated with breast cancer risk were associated with increased expression of FGFR2, secondary to altered binding of transcription factors Oct-1/Runx2 and C/EBP?. Although we still do not know how FGFR2 exerts its specific tumorigenic effect, this work provides an important insight into the underlying mechanisms.

Within a short period of time, GWAS have identified a number of common genetic variants that modestly increase the risk of breast cancer, and provided new insights into disease pathogenesis and further support for the hypothesis that ER-positive and -negative cancers are biologically distinct. Further challenges exist to define the functional relevance of some of the identified variants and to elucidate the specific causative changes in the associated chromosomal loci (e.g. 8q24). Additional studies in different ethnic groups, in different breast cancer subtypes will be informative. However, many further genes are likely to be identified before the entire familial component of breast cancer is understood.

Genetic predictors of drug response in breast cancer

Pharmacogenetics can be defined as the study of genetic variants that may influence the absorption, distribution, metabolism and elimination of a drug and, as a consequence, its efficacy and toxicity [24]. This contrasts with pharmacogenomics, although the two terms are often used interchangeably, which reflects the study of gene expression, for example in tumour tissue to identify potential therapeutic targets and factors relevant to drug response. The Oncotype DX is an example of a pharmacogenomic test that predicts response to chemotherapy [25] and has received considerable attention recently, but is beyond the scope of this overview. A number of studies have demonstrated an important role for pharmacogenetics in predicting which patients are most likely to benefit from breast cancer treatment [26], but the relationship between CYP2D6 and tamoxifen treatment is the one that is closest to use in clinical practice.

Pharmacogenetics of tamoxifen response

Pharmacokinetic analysis established that tamoxifen is converted to a number of metabolites, which have greater anti-oestrogenic activity than the parent drug. Predominantly, it is converted by CYP3A4 and CYP3A5 to an intermediate, which is then converted by CYP2D6 to 4-hydroxy-N-desmethyl-tamoxifen (endoxifen) [27]. CYP2D6 is the rate-limiting step in the conversion of tamoxifen to endoxifen, and studies have demonstrated that patients with low CYP2D6 activity due to variants in the CYP2D6 gene or because of concurrent administration of a CYP2D6 inhibitor [e.g. selective serotonin reuptake inhibitors (SSRIs) such as paroxetine and fluoxetine] have lower plasma endoxifen levels [28,29]. The latter is especially pertinent as SSRIs are commonly used in the treatment of hot flushes associated with tamoxifen use and for concurrent clinical depression.

Subsequent studies have considered the effect of variants in the CYP2D6 gene on outcome in postmenopausal breast cancer patients treated with tamoxifen [30-32]. CYP2D6 is a polymorphic gene with multiple variants associated with both increased and decreased/absent activity. Approximately 7-10% of white individuals lack CYP2D6 activity, which contrasts with only 1-2% of Asians and black Africans [33]. Genotyping of the common lack of activity variant (CYP2D6*4) allele in a prospective adjuvant tamoxifen trial demonstrated that women homozygous for the *4/*4 allele had a shorter time to tumour recurrence and poorer survival [29]. Co-administration of CYP2D6 inhibitors, fluoxetine and paroxetine, were also associated with a worse outcome [31]. Two small retrospective studies failed to support these findings [34,35]. However, in a large cohort, Schroth et al. [32] have recently supported the association between poor outcome and CYP2D6 status and, in addition, they demonstrated that a variant in the CYP2C19 gene (CYP2C19*17) is associated with a better response to tamoxifen and that this could be combined with knowledge of CYP2D6 status to predict outcome. This latter finding has not yet been validated in independent cohorts and further studies are required. Two recent reports show that individuals with two copies of the CYP2D6*10 allele, which is more common in Asians and associated with reduced enzyme activity, have a poorer outcome when treated with tamoxifen compared to individuals with normal copies of the CYP2D6 gene [36,37]. It is therefore vital that the relevant alleles are considered and that appropriately powered studies are conducted across different ethnic groups to establish the value of CYP2D6 genotyping before initiating tamoxifen therapy.

We have investigated the impact of CYP2D6 status in women with familial breast cancer due to BRCA1 and BRCA2 mutations [38].We found a significant difference in overall survival (7 versus 28 years) in women with BRCA2-related breast cancer with low CYP2D6 activity and who had been treated with tamoxifen. A recent modelling analysis of the impact of CYP2D6*4 genotyping within the Breast International Group (BIG) 1-98 randomised trial of tamoxifen versus letrozole suggested that prospective CYP2D6 genotyping would remove any advantage of aromatase inhibitors over tamoxifen in the postmenopausal adjuvant breast cancer setting [39]. Retrospective genotyping of biological samples from BIG1-98 and the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trials will help to establish the true value of CYP2D6 genotyping in identifying patients likely to respond to tamoxifen. Further studies in premenopausal breast cancer cohorts are especially pertinent as tamoxifen is the adjuvant hormonal therapy of choice in this population because aromatase inhibitors are ineffective.

Summary

Recent large-scale GWAS have identified a number of genes that modestly increase the risk of sporadic breast cancer and modify the risk of cancer in individuals carrying BRCA1 or BRCA2 mutations. These genes were not previously implicated in breast cancer pathogenesis and provide new insights into the aetiology of the disease as well as a means of defining new potential therapeutic targets and refining risk estimates. Three categories of genes relevant to breast cancer aetiology can now be defined (see Table 1): highly penetrant genes (e.g. BRCA1 and BRCA2) that confer a high risk of cancer; rare mutations in genes (e.g. ATM and BRIP1) that moderately increase risk by 2- to 4-fold; and common variants in a number of genes mainly identified by GWAS (e.g. FGFR2) that increase cancer risk by less than 2-fold. Further genes that affect breast cancer risk exist and interrogation of the huge datasets generated by GWAS and in larger patient cohorts with different characteristics will provide more detailed molecular phenotypes to define breast cancer susceptibility and inform future clinical management strategies. It is likely that CYP2D6 genotyping will be introduced into mainstream clinical practice to determine tamoxifen efficacy. Pharmacogenetics will be increasingly used in breast cancer management to more accurately tailor medication to the individual, to reduce side effects and to optimise outcome.

References

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William G Newman and D Gareth Evans

Department of Medical Genetics, St Mary's Hospital and University of Manchester, UK

Correspondence to: William G Newman, Department of Medical Genetics, University of Manchester and St Mary's Hospital, Manchester, M13 0JH, UK (email: william.newman@manchester.ac.uk)
Table 1: Summary of genes associated with altered breast
cancer risk identified through different strategies over
the past 15 years.

Breast cancer risk         Genes                     References

Rare high-risk genes       BRC A1                    [1]
(x 10-20 lifetime risk)    BRC A2                    [2]
                           TP53                      [4]

Rare moderate-risk genes   ATM                       [6]
(x 2-4 lifetime risk)      BRIP1                     [8]
                           CHEK2                     [7]
                           PALB2                     [9,10]

Common low-risk genes      FGFR2                     [15,18]
(x <2 lifetime risk)       MAP3K1                    [15]
                           TNCR9                     [15]
                           LSP1                      [15]
                           CASP8*                    [12]
                           Variants in genes         [15,19-21]
                           at chromosomes 6q22.33,
                           2q35, 16q12 and 5p12

* CASP8 variant is protective.
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Title Annotation:Feature Article
Author:Newman, William G.; Evans, D. Gareth
Publication:Advances in Breast Cancer
Article Type:Report
Geographic Code:4EUUK
Date:Jun 1, 2008
Words:3349
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