Breast Center Pathology Laboratory
SERVICES/RESOURCES - CLINICAL
Prognostic Biomarkers - HER2/neu by IHC
Indications for use
The proto-oncogene HER-2/neu (c-erbB-2) resides on chromosome 17q and
encodes a trans-membrane tyrosine kinase growth factor receptor.
Amplification of the HER-2/neu gene, or overexpression of the HER-2/neu
protein, is found in 20-30% of breast cancers. Amplified or overexpressed
HER-2/neu is a weak unfavorable prognostic factor in untreated breast
cancer patients. The predictive implications of HER-2 alterations
are more complex and include resistance to hormonal therapy (1, 2),
resistance to CMF chemotherapy (3, 4), responsiveness to doxorubicin
(5-7), and responsiveness to Trastuzumab (Herceptin®) therapies
(8, 9). The primary indication for assessing HER-2/neu today is to
identify patients who might benefit from trastuzumab therapy.
Scoring/interpretation
Many systems have been used to score HER-2/neu results, such as the
one endorsed by the Dako HercepTest™, which scores the intensity
of membrane staining on a scale of 0-3. Currently, patients with
tumors showing 2+ or 3+ HER-2/neu signals by HercepTest™ criteria
are selected for trastuzumab therapy, and recent studies in the metastatic
setting suggest that the benefit is primarily limited to 3+ patients.
Clinical trials (NSABP B31, INT N9831 and BCIRG 006) assessing adjuvant
trastuzumab therapy are ongoing and restrict enrollment to patients
with tumors showing 3+ staining by HercepTest™ or greater than
one-third positive cells using alternative methods of scoring (10,
11).
In our laboratory, HER-2/neu immunostaining is scored using the “Allred Score” which is a microscopic method conveying the estimated proportion and intensity of positive tumor cells (range from 0-8). This scoring system was developed in our laboratory over a decade ago and has been used and validated for several markers, including, ER, PR, HER-2/neu, and p53. We define a “positive” test as scores >4, which is highly correlated with a 3+ HercepTest™ score.
Selected Bibliography
1. Elledge RM, Green S, Ciocca D, Pugh R, Allred DC, Clark GM, et al.
HER-2 expression and response to tamoxifen in estrogen receptor-positive
breast cancer: a Southwest Oncology Group Study. Clin Cancer Res
1998;4(1):7-12.
2. Love RR, Duc NB, Havighurst TC, Mohsin SK, Zhang Q, DeMets DL, et al. Her-2/neu overexpression and response to oophorectomy plus tamoxifen adjuvant therapy in estrogen receptor-positive premenopausal women with operable breast cancer. J Clin Oncol 2003;21(3):453-7.
3. Allred DC, Clark GM, Tandon AK, Molina R, Tormey DC, Osborne CK, et al. HER-2/neu in node-negative breast cancer: prognostic significance of overexpression influenced by the presence of in situ carcinoma. J Clin Oncol 1992;10(4):599-605.
4. Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Koerner F, et al. c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 1994;330(18):1260-6.
5. Ravdin PM, Green S, Albain KS, Boucher V, Ingle JN, Pritchard K, et al. Initial report of the SWOG biological correlatine study of CerbB2 expression as a predictor of outcome in a trial comparing adjuvant CAF T with Tamoxifen (T) alone. Proc Am Soc Clin Oncol 1998;17:97a (#374).
6. Paik S, Bryant J, Park C, Fisher B, Tan-Chiu E, Hyams D, et al. erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 1998;90(18):1361-70.
7. Thor AD, Berry DA, Budman DR, Muss HB, Kute T, Henderson IC, et al. erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 1998;90(18):1346-60.
8. Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999;17(9):2639-48.
9. Chang J, Mohsin SK, Weiss H, Hilsenbeck SG, Lucci AJ, Gutierrez MC, et al. Induction of apoptosis and decrease in proliferation in primary breast cancers with neoadjuvant Herceptin. Breast Cancer Res Treat 2003:(abstract).