Her-2/neu Gene Amplification
Her-2/neu Gene Amplification
We compared the incidence of Her-2/neu amplification in patients with and without a family history of breast cancer and correlated gene status with clinicobiologic and prognostic features in sporadic and familial cases.
Of 108 patients, 28.7% had gene amplification. Among 96 cases with family history information available, 28 had an affected first-degree relative. The gene was amplified more frequently in familial than in sporadic cases (13/28 [46%] vs 14/68 [21%]; P = .01). Among familial cases, amplification was associated with adverse clinicobiologic features (poorly differentiated tumors [P = .05], larger tumors [P = .05], more lymph nodes involved [P = .04], and DNA aneuploid [P = .02] and highly proliferative tumors [P = .005]), and the relapse (P = .02) and disease-related death (P = .05) rates were higher than in cases without amplification. Among sporadic cases, amplification was not associated with significantly different disease features, except for a higher incidence of DNA aneuploid tumors (P = .01), percentage of S-phase tumor cells (P = .006), and lower proportion of estrogen (P = .001) and progesterone (P = .002) receptors.
Her-2/neu amplification was observed more frequently among patients with a family history of breast cancer, in whom it was associated with adverse clinicobiologic features and a worse clinical outcome.
Breast cancer is the most common type of cancer in women. It is expected that in every 9 to 11 women, 1 will be affected by breast cancer during her lifetime; the trend has shown an increase during the past years. Although the exact nature and pathogenesis of breast cancer remains largely unknown, it is estimated that up to 13% of women with breast cancer have a familial history of the disease in a mother, sister, or daughter.
As in other tumors, multiple genetic changes have been identified in breast carcinomas that might be involved in uncontrolled tumor cell growth. Among other genes, the human epidermal growth factor receptor-2 (also known as the Her-2/neu or c-erb-b2 gene), which is the human analog of the neu gene identified in rat neuroblastomas in the early 1980s, is one of the genes involved in human breast cancer.
The Her-2/neu gene is located at 17q12-21.32 and encodes a p185 transmembrane glycoprotein with tyrosine kinase activity, closely related to the epidermal growth factor receptor. The Her-2/neu protein is one of a family of 4 closely related transmembrane growth factors designated Her-1 to Her-4 that constitute the type I growth factor receptor gene family. Transmembrane Her-2/neu molecules are expressed as inactive monomers on the cell surface; ligand binding to the Her-2/neu receptor is associated with dimerization and stabilization of the formed dimers. Once formed, both homodimers and heterodimers induce mitogenic signals. The interaction between Her-2/neu and its ligands is involved in cell-to-cell interactions during organogenesis and, thereafter, in regulating cell growth, survival, and differentiation.
The most frequent abnormality involving Her-2/neu in breast cancer consists of the amplification of the gene and subsequent overexpression of the protein. Accordingly, the Her-2/neu gene is expressed at abnormally high levels in 10% to 40% of primary breast cancers, and in most of these (>90%) an increased number of copies per cell of the Her-2/neu gene is found in association with raised concentrations of its messenger RNA.
Reports suggest that in breast cancer, Her-2/neu gene amplification is associated with adverse prognostic factors such as absence of expression of hormonal receptors, poorly differentiated histologic subtypes, the presence of DNA aneuploidy, and high proliferation. Despite this, the relationship between the Her-2/neu gene status and other relevant prognostic factors (ie, tumor size, patient age, lymph node status, and survival) remains unclear. Accordingly, the initial association found by Slamon et al among node-positive patients between Her-2/neu gene amplification and a significantly reduced overall survival could not be confirmed by others. Despite the increasingly high number of reports in which the Her-2/neu gene status is analyzed in patients with breast cancer, few studies have explored its potential association with a genetic background; information currently available in this regard is inconclusive, with findings of no association or an inverse correlation between BRCA1/BRCA2 gene mutation status and the amplification of the Her-2/neu gene.
The aim of the present study was to explore the potential link between the presence of Her-2/neu gene amplification and a familial history of breast cancer and its correlation with disease characteristics and prognosis in sporadic vs familial breast cancer.
We compared the incidence of Her-2/neu amplification in patients with and without a family history of breast cancer and correlated gene status with clinicobiologic and prognostic features in sporadic and familial cases.
Of 108 patients, 28.7% had gene amplification. Among 96 cases with family history information available, 28 had an affected first-degree relative. The gene was amplified more frequently in familial than in sporadic cases (13/28 [46%] vs 14/68 [21%]; P = .01). Among familial cases, amplification was associated with adverse clinicobiologic features (poorly differentiated tumors [P = .05], larger tumors [P = .05], more lymph nodes involved [P = .04], and DNA aneuploid [P = .02] and highly proliferative tumors [P = .005]), and the relapse (P = .02) and disease-related death (P = .05) rates were higher than in cases without amplification. Among sporadic cases, amplification was not associated with significantly different disease features, except for a higher incidence of DNA aneuploid tumors (P = .01), percentage of S-phase tumor cells (P = .006), and lower proportion of estrogen (P = .001) and progesterone (P = .002) receptors.
Her-2/neu amplification was observed more frequently among patients with a family history of breast cancer, in whom it was associated with adverse clinicobiologic features and a worse clinical outcome.
Breast cancer is the most common type of cancer in women. It is expected that in every 9 to 11 women, 1 will be affected by breast cancer during her lifetime; the trend has shown an increase during the past years. Although the exact nature and pathogenesis of breast cancer remains largely unknown, it is estimated that up to 13% of women with breast cancer have a familial history of the disease in a mother, sister, or daughter.
As in other tumors, multiple genetic changes have been identified in breast carcinomas that might be involved in uncontrolled tumor cell growth. Among other genes, the human epidermal growth factor receptor-2 (also known as the Her-2/neu or c-erb-b2 gene), which is the human analog of the neu gene identified in rat neuroblastomas in the early 1980s, is one of the genes involved in human breast cancer.
The Her-2/neu gene is located at 17q12-21.32 and encodes a p185 transmembrane glycoprotein with tyrosine kinase activity, closely related to the epidermal growth factor receptor. The Her-2/neu protein is one of a family of 4 closely related transmembrane growth factors designated Her-1 to Her-4 that constitute the type I growth factor receptor gene family. Transmembrane Her-2/neu molecules are expressed as inactive monomers on the cell surface; ligand binding to the Her-2/neu receptor is associated with dimerization and stabilization of the formed dimers. Once formed, both homodimers and heterodimers induce mitogenic signals. The interaction between Her-2/neu and its ligands is involved in cell-to-cell interactions during organogenesis and, thereafter, in regulating cell growth, survival, and differentiation.
The most frequent abnormality involving Her-2/neu in breast cancer consists of the amplification of the gene and subsequent overexpression of the protein. Accordingly, the Her-2/neu gene is expressed at abnormally high levels in 10% to 40% of primary breast cancers, and in most of these (>90%) an increased number of copies per cell of the Her-2/neu gene is found in association with raised concentrations of its messenger RNA.
Reports suggest that in breast cancer, Her-2/neu gene amplification is associated with adverse prognostic factors such as absence of expression of hormonal receptors, poorly differentiated histologic subtypes, the presence of DNA aneuploidy, and high proliferation. Despite this, the relationship between the Her-2/neu gene status and other relevant prognostic factors (ie, tumor size, patient age, lymph node status, and survival) remains unclear. Accordingly, the initial association found by Slamon et al among node-positive patients between Her-2/neu gene amplification and a significantly reduced overall survival could not be confirmed by others. Despite the increasingly high number of reports in which the Her-2/neu gene status is analyzed in patients with breast cancer, few studies have explored its potential association with a genetic background; information currently available in this regard is inconclusive, with findings of no association or an inverse correlation between BRCA1/BRCA2 gene mutation status and the amplification of the Her-2/neu gene.
The aim of the present study was to explore the potential link between the presence of Her-2/neu gene amplification and a familial history of breast cancer and its correlation with disease characteristics and prognosis in sporadic vs familial breast cancer.
