Abstract
BackgroundBreast cancer is a heterogeneous disease and patients with similar pathologies and treatments may have different clinical outcomes. Identification of molecular alterations associated with disease outcome may improve risk assessment and treatments for aggressive breast cancer.MethodsAllelic imbalance (AI) data was generated for 122 invasive breast tumors with known clinical outcome. Levels and patterns of AI were compared between patients who died of disease (DOD) and those with ≥5 years disease-free survival (DFS) using Student t-test and chi-square analysis with a significance value of P<0.05.ResultsLevels of AI were significantly higher in tumors from the 31 DOD patients (28.6%) compared to the 91 DFS patients (20.1%). AI at chromosomes 7q31, 8p22, 13q14, 17p13.3, 17p13.1 and 22q12.3 was associated with DOD while AI at 16q22–q24 was associated with DFS. After multivariate analysis, AI at chromosome 8p22 remained an independent predictor of breast cancer mortality. The frequency of AI at chromosome 13q14 was significantly higher in patients who died ≥5 years compared to those who died <5 years from diagnosis.ConclusionTumors from DOD compared to DFS patients are marked by increased genomic instability and AI at chromosome 8p22 is significantly associated with breast cancer morality, independent of other clinicopathological factors. AI at chromosome 13q14 was associated with late (>5-years post-diagnosis) mortality but not with death from disease within five years, suggesting that patients with short- and long-term mortality may have distinct genetic diseases.
Highlights
Mortality rates from breast cancer have decreased since 1990, it is estimated that,40,000 women in the United States died from breast cancer in 2011 [1]
To identify chromosomal alterations associated with poor prognosis, we subjected primary breast tumors from patients who died of disease (DOD) or were disease-free (DFS) .5 years postdiagnosis to allelic imbalance (AI) analysis
When comparing clinicopathological factors between DOD and disease-free survival (DFS) patients, ethnicity, histological type and HER2 status did not differ significantly, tumors in DOD patients were diagnosed at a younger age and were significantly larger, of higher stage and grade, and more likely to have positive lymph node status and to be hormone receptor negative or of the triple negative subtype (Table 1)
Summary
Mortality rates from breast cancer have decreased since 1990, it is estimated that ,40,000 women in the United States died from breast cancer in 2011 [1]. Breast tumors have additional levels of variability, with at least five breast subtypes based on patterns of differential gene expression [2,3] This pathological and molecular heterogeneity influences prognosis and treatment: in a study of 2,929 breast cancer patients, despite use of identical treatment modalities for patients with similar pathological characteristics, clinical outcomes were highly variable [4]. Molecular profiling has improved pathological classification of tumors; molecular tests such as MammaPrintH and Oncotype DXTM can provide estimates of the odds of recurrence and be used to discriminate those patients requiring aggressive treatment from those who would not benefit from cytotoxic regimens [5,6,7]. Identification of molecular alterations associated with disease outcome may improve risk assessment and treatments for aggressive breast cancer
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