Advances in breast cancer: pathways to personalized medicine

Abstract

Breast cancer is a complex disease caused by the progressive accumulation of multiple gene mutations combined with epigenetic dysregulation of critical genes and protein pathways. There is substantial interindividual variability in both the age at diagnosis and phenotypic expression of the disease. With an estimated 1,152,161 new breast cancer cases diagnosed worldwide per year, cancer control efforts in the postgenome era should be focused at both population and individual levels to develop novel risk assessment and treatment strategies that will further reduce the morbidity and mortality associated with the disease. The discovery that mutations in the BRCA1 and BRCA2 genes increase the risk of breast and ovarian cancers has radically transformed our understanding of the genetic basis of breast cancer, leading to improved management of high-risk women. A better understanding of tumor host biology has led to improvements in the multidisciplinary management of breast cancer, and traditional pathologic evaluation is being complemented by more sophisticated genomic approaches. A number of genomic biomarkers have been developed for clinical use, and increasingly, pharmacogenetic end points are being incorporated into clinical trial design. For women diagnosed with breast cancer, prognostic or predictive information is most useful when coupled with targeted therapeutic approaches, very few of which exist for women with triple-negative breast cancer or those with tumors resistant to chemotherapy. The immediate challenge is to learn how to use the molecular characteristics of an individual and their tumor to improve detection and treatment, and ultimately to prevent the development of breast cancer. The five articles in this edition of CCR Focus highlight recent advances and future directions on the pathway to individualized approaches for the early detection, treatment, and prevention of breast cancer.

Fig. 1

Genetic susceptibility to breast cancer. Familial breast cancer comprises approximately 20% to 30% of all breast cancers. BRCA1 and BRCA2 are two major highpenetrance genes associated with hereditary breast and ovarian cancer syndrome and explain less than 10% of all breast cancer cases. Mutations in CHEK2 contribute to a substantial fraction of familial breast cancer. Carriers of TP53 mutations develop Li-Fraumeni syndrome and are at high risk of developing early-onset breast cancer, but these mutations are very rare. Susceptibility alleles in other genes, such as PTEN, ATM, STK11/LKB1, and MSH2/MLH1, are also rare causes of inherited breast cancer. About half of the familial clustering of breast cancer is unexplained. The susceptibility to breast cancer in this group is presumed to be due to either additional high-penetrance susceptibility genes (which remain to be identified) or variants at many moderate or low-penetrance loci, each conferring a moderate risk of the disease (polygenic susceptibility; ref. 110). Eight low penetrance variants recently identified by whole genome association studies account for a small proportion (about 5%) of familial cases. The majority of women with breast cancer (so-called sporadic) do not have inherited mutations but may carry common low-penetrance genetic risk variants. The presence of such multiple genetic risk variants in the same individual may predispose to the development of breast cancer, independent of family history. Seven (FGFR2, TNRC9, MAP3K1, LSP1, 2q35, 5p12, 8q24) of the eight variants discovered thus far together account for 60% of breast cancer in the general population of women of European Ancestry (19). Adapted with permission from Lippincott, Williams & Wilkins (110).

Fig. 2

Who has BRCA1 and BRCA2 mutations? Women with breast cancer diagnosed before age of 40 y, categorized according to the number of affected first- or second-degree female relatives (0, 1, 2, or >2) from the Australian Breast Cancer Family Study (6). Sporadic cases have no family history of breast cancer. Familial cases have one or more affected first- or second-degree relatives and make up about 30% of all breast cancer cases. Hereditary cases have a germline mutation in either BRCA1 or BRCA2 and are more likely to occur within the familial cohort; however, in absolute numbers, 60% of cases testing positive for a deleterious mutation have no family history and are in the “sporadic” group. The proportion of mutation carriers identified in each category of family history, in terms of 1 in x, is shown in the right side of the pyramid. The proportion of mutation carriers for each category of family history, in terms of a percentage of all identified mutation carriers, is shown on the right side of the figure. Only 1in 2cases from families with >2 affected relatives have identifiable BRCA1/2 mutation and they make up <1% of mutation carriers. Adapted with permission from J Natl Cancer Inst Monogr (6).

Fig. 3

Distribution of breast cancer subtypes across different populations. The clear gradient in the proportion of intrinsic molecular breast cancer subtypes across different populations may influence etiology, pathogenesis, and prognosis of breast cancer in patients of various races/ ethnicities. This diagram was constructed based on the analysis of data from the Carolina Breast Cancer Study (47), the Polish Breast Cancer Study (48), the Japanese Breast Cancer Study (46), and the Nigerian Breast Cancer Study (49). Subtypes were defined using immunohistochemical surrogates (44) and were as follows: luminal A (estrogen receptor positive and/or progesterone receptor positive, HER2 negative), luminal B (estrogen receptor positive and /or progesterone receptor positive, HER2 positive), HER2-like (estrogen receptor negative, progesterone receptor negative, HER2 positive), basal-like (estrogen receptor negative, progesterone receptor negative, HER2 negative, cytokeratin 5/6 positive, and/or epidermal growth factor receptor positive), unclassified (negative for all five markers).

Fig. 4

The epigenetic progenitor model of cancer. Cancer arises in three steps: (a) polyclonal epigenetic disruption of progenitor cells; (b) an initiating monoclonal mutation, and (c) acquisition of genetic and epigenetic plasticity. First is an epigenetic alteration of stem/progenitor cells within a given tissue, which is mediated by aberrant regulation of tumor-progenitor genes (TPG). For example, in breast cancer, the first step could be methylation of the BRCA1 promoter as a result of events within the stem cells themselves, the influence of the stromal compartment, or environmental damage or injury. Second step is a gatekeeper mutation (GKM) in a tumor suppressor gene (TSG) such asTP53 or oncogene amplification (ONC) such as MYC amplification. Although these gatekeeper mutations are themselves monoclonal, the expanded or altered progenitor compartment increases the risk of cancer when such a mutation occurs and the frequency of subsequent primary tumors (shown as separately arising tumors). Third is genetic and epigenetic instability, which leads to increased tumor evolution. Many of the properties of advanced tumors (invasion, metastasis, and drug resistance) are inherent properties of the progenitor cells that give rise to the primary tumor and do not require other mutations (highlighting the importance of epigenetic factors in tumor progression). Adapted by permission from MacMillan Publishers Ltd: Nature Reviews Genetics (ref. 111), copyright 2006.