Receptor tyrosine-protein kinase erbB-2
The HER2 protein, also known amongst other names as, ErbB2 or neu, and coded for by the ERBB2 gene at 17q12 derives its name from human epidermal growth factor receptor 2, indicating its similarity to epidermal growth factor receptor (EGFR). HER2 interacts with other members of the EGFR family and functions as a co-receptor for epidermal growth factor or equivalent ligands.
Activation of the co-receptor complex transduces a signal, which in turn, stimulates tyrosine kinase activity in the intracellular domain. In normal cells, HER2 is a proto-oncogene, conveying the signal downstream where it stimulates cell growth and differentiation.
Abnormal expression of HER2 protein is thought to result in excess growth stimulation, converting HER2 into an oncogene. About 20-25% of breast cancers are strongly HER2 positive and are associated with a more aggressive phenotype. 10-15% of gastric adenoacarcinoma as positive.
HER2 can be blocked using a synthetic humanised monoclonal antibody called trastuzumab, although the mechanisms of action may be more complex than just receptor antagonism. Pertuzumab is also a monoclonal antibody that interferes with Her2 dimerisation. There is on-going research into using both agents synergistically.
Histological Assessment of Her2 in Breast Cancer
Both immunohistochemistry and FISH can be used. The results of either method are either positive, negative or equivocal. A single method will suffice if the result is positive or negative, but equivocal results should be corroborated with the other method.
Her2 immunohistochemistry is graded as follows:
- No staining or <10% membrane staining in tumour cells
- Faint membrane staining is detected in >10% of tumour cells, but cells are only stained in part of the membrane
- Weak to moderate staining of the entire membrane in >30% of tumour cells
- Uniform intense staining of the entire membrane in >30% of tumour cells.
Histological Assessment of Her2 in Gastric Cancer
~20% of gastric adenocarcinomas are positive, increasing in proportion to about a third in gastro-oesophageal junction tumours and intestinal-type tumours. Unlike breast cancer, there is more heterogeneity within the tumours. Following preliminary assessment, the recommended scoring system differs from breast cancer: completely circumferential staining is not required, i.e. basolateral staining will suffice, background dysplasia can be counted (whereas breast DCIS is not) and only a small group of cells is sufficient for positive staining. Intensity also follows the breast scoring system with the rule of thumb that score 3 staining is visible at ~5x, score 2 visible at 10-20x and 1+ visible requiring 40x magnification. Immunohistochemistry is the first-line modality with recourse to FISH only in scores of 2. One issue is that different antibody clones result in differing levels of staining.
- ↑ Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Archives of pathology & laboratory medicine. 2007; 131(1):18-43.([18:ASOCCO2.0.CO;2 Link to article] – subscription may be required.)
- ↑ Hofmann M, Stoss O, Shi D, Büttner R, van de Vijver M, Kim W, Ochiai A, Rüschoff J, Henkel T. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008 Jun; 52(7):797-805.(Link to article – subscription may be required.)
- ↑ Albarello L, Pecciarini L, Doglioni C. HER2 testing in gastric cancer. Advances in anatomic pathology. 2011 Jan; 18(1):53-9.(Link to article – subscription may be required.)