Breast Cancer—Her2/neu
* Amplification of the HER2/Neu (ERBB2) gene, with associated HER2 protein overexpression and constitutive activation of its tyrosine kinase activity, is more frequent in ER/PR-negative breast cancers and is an independent indicator of poor prognosis.
* More importantly, ERBB2 is a target of, and ERBB2 amplification is a marker of, sensitivity to treatment with trastuzumab (Herceptin). In addition, the small tyrosine kinase inhibitor (TKI) lapatinib, and the new anti-HER2 antibody, pertuzumab, which targets a different HER2 epitope, have been shown to be effective in HER2 amplified breast cancer. The latter has been shown to improve progression-free survival rate by almost 50% in patients with advanced breast cancer, when added to docetaxel and trastuzumab.
* Although semiquantitative immunohistochemical tests for protein expression, such as Herceptest, are convenient, variability of antigen preservation and retrieval, as well as interobserver variability in interpretation, make immunohistochemistry a less reliable predictor of response than FISH. The American Society of Clinical Oncology and College of American Pathologists have issued guidelines for evaluating the HER2 status of breast tumors.
* Resistance to trastuzumab is poorly understood, and many mechanisms may be involved, including loss of the ERBB2 external domain, overexpression of MUC4, increased transcription of ERBB2, and bypassing EGFR signaling by activation of downstream pathways, especially the PI3-kinase/mTOR pathway, including activating PIK3CA mutations and loss of PTEN.
* One means of overcoming resistance is treatment with mTOR pathway inhibitors, such as everolimus. Although modest responses have been shown in pretreated patients, clinical trials to evaluate the drug in combination with chemotherapy and trastuzumab are underway.
* Trastuzumab has also been shown to be active in HER2 amplified/overexpressing adenocarcinoma of the stomach and distal esophagus. The criteria for immunohistochemical and FISH evaluation from the ToGA trial that showed this benefit differed from the CAP/ASCO criteria, although a recent publication from Memorial Sloan Kettering shows that the CAP/ASCO criteria may be adequate.