HER-2 Status indicators for breast cancer diagnosis
One will often hear the words “HER-2 status” when a breast cancer lesion is being diagnosed and staged for treatment.
The HER-2 (Her2/neu, c-erb-2 or erb-2) is a gene which produces a protein that acts as a receptor on the surface of cells.
These receptors are very sensitive to hormonal/chemical ‘growth‘ signals in the body, and are therefore ‘growth factors‘. If a cancer tumor has cells which seem to have more of these HER2 proteins than normal, that means those cells are receiving more ‘messages‘ to grow and divide than normal cells. More specifically, HER-2/ neu, also known as c- erb B-2 (HER-2), is a a proto-oncogene located on chromosome 17. This gene is amplified therefore the protein (HER-2) overexpressed, in around 20-25% of invasive breast cancers.
I just want to let you know that I have created a newer version of this page with more up-to-date information on HER2 Status Indicators for Breast Cancer. However, this page has some great information, I would still use is as well.
Some proteins make breast tumors more receptive to certain hormones
Sometimes the phrase ‘hormone receptor status‘ is used along with terms like ‘protein status‘ and HER-2 status. These are all related terms; the presence of certain proteins is what makes a tumor more receptive to certain hormones.
Some hormones effect growth rates, such as the hormones attracted by HER-2 proteins, but other hormones might suppress growth or be associated with healing and blood flow. The ‘hormone receptor status‘ of a tumor is a composite of all the different proteins and associated hormones that might be influencing the behaviour a particular tumor in a particular patient, and the HER-2 status is a small subset of the overall hormonal picture, specifically related to the probable growth rate of the new cancer cells.
HER-2 gene amplification in breast cancer has been associated with increased cell mortility and cell proliferation, tumor invasiveness, accelerated angiogenesis, reduced apoptosis, and more progressive regional and distant metastases.
So, breast cancers presenting with a higher-than-average or ‘positive‘ HER-2 status will almost certainly be be more aggressive.
There are two ways to measure the HER-2 status of breast cancer tumors
The most common way to measure the HER-2 status of a suspected breast cancer tumor is through an immunohistochemisty (IHC) test. This will likely be part of an overall histological/pathological evaluation of the tumor.
Various tumor ‘markers‘, including the HER-2 status indicators, give the pathogist a characterization of the tumor, which helps to predict its future behavior and probable responses to different types of treatments. The immunohistochemistry test of the HER-2 status measures the ‘over-expression‘ of a particular protein, and is typically given a ‘score‘ of 0 to +3.
The pathologist will actually ‘count‘ the number of receptors on the surface of the cancer cells, and can ‘see‘ them microscopically because they are receptive to certain protein-based dyes, and change color. Scores of 0 and +1 are considered indicative of a ‘negative‘ status, while +2 and +3 are HER-2 positive. (So, the test measures whether the HER2 proteins are overexpressed, or not. There is no ‘in between‘ state).
Fluorescent in situ hybridization
The other method of measuring the HER-2 status of a breast tumor is by fluorescent in situ hybridization (FISH), which measures the amplification of the HER-2 gene (the number of copies of the HER-2 gene present in a cancer cell). Like the immunohistochestry test, results of the FISH test are reported as either positive or negative.
The overall hormone receptor status of a breast tumor helps predict behaviour and responsiveness to treaments
The hormone-receptor status of a tumor is really considered to be more of a predictive factor rather than a ‘prognostic‘ factor. It helps determine what you are up against, and how best to treat it. The outlook for a particular breast cancer is more likely to be influenced by the histological type and grade of the breast cancer tumor at the time it is discovered, and whether or not there is lymphatic involvement, and not the hormone receptor status.
It is true, however, that breast cancer tumors with a positive hormone receptor status have a more ‘indolent‘ course than do hormone receptor-negative tumors. Indolent is kind of a strange term to use, but it means that a tumor is less responsive or ‘lazy‘ in terms of normal treatments than in tumors which the hormone receptor status is negative. Some kind of extra intervention or ‘boost‘ is often required to really get a positive healing response from the cancer.
But certain kinds of hormone-receptor positive tumors are actually more responsive to endocrine therapy, so there is a positive aspect to this as well. In fact there is often a kind of ‘inverse‘ relationship between the HER-2 hormone receptor status, and the ER (estrogen receptor) and PR (progesterone receptor) status of a tumor. Higher ER and PR hormone receptor levels in a tumor usually have a negative HER-2 status, and a good outlook, while breast cancers with a high or positive HER-2 expression will tend to have a low expression of ER and PR, and also a poorer prognosis.
HER-2 positive status is associated with aggressive, fast growing breast cancers
Breast cancer tumors with a positive HER-2 status are usually fast growing and aggressive. There tends to be a higher level of HER-2 expression in higher grade tumors and in lower grade tumors. HER-2 receptors and also epidermal growth factor receptors are stimulants to cancer cell growth. Other hormonal factors of a tumor can also make the cancer more aggressive.
Some breast cancer tumors will have decreased levels of tumor-suppressor genes, such as p53, which make invasion beyond the breast ducts more likely. Decreased levels of metastasis-suppressor genes such as nm23 also make spread to the lymph nodes and other areas of the body more likely.
HER-2 positive breast cancers do appear to be more likely to spread early in the cancer course to major visceral sites such as the axillary lymph nodes, lungs, bone marrow, liver, ovaries, and the adrenal glands.
HER-2 may be higher for DCIS
There is also some evidence that HER-2 protein levels are significantly higher at the DCIS stage than in invasive-status breast cancers. The incidence of DCIS with HER-2 positivity ranges from about 24% to 38% in various studies, and that does appear to be a slightly higher rate than for invasive breast carcinoma.
This suggests that HER-2 signalling might be an important factor in the early stages of breast tumorigenesis. Of interest, the rate of HER-2 overexpression in colloid (mucinous) breast cancer is actually extremely low, and also tends to be very low in tubular and medullary breast carcinoma.
Treatment options for HER2 positive breast cancer tumors
Women with HER-2 positive breast cancer are usually offered treatment with trastuzumab (Herceptin Herceptin), which is the only FDA-approved therapy for women with breast cancer tumors over-expressing HER-2 proteins.
It is often the case that women with breast cancer tumors overexpressing HER-2 do not respond to tamoxifen (chemical/hormonal) therapy. But, the use of trastuzumab in combination with chemotherapy has lead to longer survival rates for women with metastatic HER-2 postive breast carcinomas.
The addition of herceptin when HER-2 is positive gives an amazing boost to the response and cure rates.
Herceptin is not really chemotherapy. Rather, it is a monoclonal antibody, and the use of cloned antibodies to combat breast cancer is sometimes referred to as ‘biologic therapy‘.
Specifically, trastuzumab binds the extracellular portion of the HER-2 transmembrane receptor, and it was initially targeted for patients with advanced, relapsed breast cancer with overexpression of the HER-2 protein.
Breast cancer chemotherapy can use agents which specifically target HER-2
Sometimes HER-2 positive tumors are also treated with HER-2 targeting agents such as pertuzumab, ertumaxomab, HER-2 vaccines (which improve T-cell immunity in the context of HER-2 overexpression) and tyrosine kinase inhibitors. Hormonal therapy, the use of anthracylines, and taxanes are also sometimes employed to minimize the growth-effect of HER-2 positive breast cancers. Since the rate of local recurrence is typically quite high with HER-2 postive tumors, radiation therapy is sometimes used in addition to trastuzumab-based neoadjuvant chemotherapy, and generally with good effect.
Overall prognosis for HER-2 positive breast cancer
Many studies have demonstrated the overexpression of HER-2 proteins with a poorer prognosis. It is difficult however to isolate just the HER-2 aspect of the tumor as the specific cause of this poorer outlook, or to find practical indications of just what is meant by ‘negative prognosis‘.
The HER-2 status is part of the picture, but so are tumor size and grade, lymph node status, other hormonal indicators (for example, reduced levels of the tumor suppressor gene p53 make the prognosis worse), and the type of cancer involved. However it is clear that a positive HER-2 overexpression does correspond to an increased likelihood for lymph node metastasis. HER-2 overexpression can also predict a poorer response to taximophen (hormonal/chemical therapy), though researchers are working on ways to combat this.
HER-2 overexpression can help predict the time until relapse of breast cancer
What an overexpression of HER-2 really tends to accurately predict is the time to relapse (the disease free interval), and consequently the overall survival time is also predictably decreased. Some studies have shown that the median survival time for patients with HER-2 positive breast cancer is reduced by just over 50%.
There are of course many factors that contribute to survival of breast cancer, but nonetheless, some studies have shown that only about 60% of patients with HER-2 positive status invasive breast cancer are disease free after 10 years, and about 65% survive overall (approx. 20 years or more). And, a greater number of HER-2 postive patients succumb to the illness during the first five years than those who are negative for HER-2 overexpression. At the same time, all other factors assumed to be equal, patients with negative HER-2 status tumors tend to be disease free at a rate of 75% over 10 years and have a slightly higher overall survival rate.
From this we can informally estimate that women with breast cancer which overexpresses HER-2 are about 10% more likely to have significant difficulties and ultimately succumb to the disease within the first five years, than those who do not.
Below are some Q&A on HER2 positive breast cancer:
- What are the treatment options for HER2 positive breast cancer? Treatments that specifically target HER2 are very effective. These treatments are so effective that the prognosis for HER2 positive breast cancer is actually quite good. These treatments include Trastuzmab (Herceptin), Lapatinib (Tykerb), Pertuzumab (Perjeta), and/or Ado-trastuzumab emtansine (kadcyla). In addition, there are several new medications being developed that also target HER2 and are being tested in clinical trials.
- Why is HER2 status testing done? HER2 status testing is done to find out the amount of HER2 produced by a tumor. HER2 status testing can vary across Canada. It is mostly done with breast cancer tumors but may also be done with advanced stomach cancers as well. HER2 status testing for breast cancer may be done on the main (primary) breast cancer tumor at the time of diagnosis, HER2 status may be done in combination with hormone receptor status testing, and if the breast cancer recurs or metastasizes.
- How is HER2 testing done? HER2 status testing is done on a tumor sample taken with a biopsy. Testing can be also done on stored tumor tissue. There are 3 techniques that can be used to determine HER status. These include Immunohistochemitry, fluorescent in situ hybridization, and chromogenic in situ hybridization. A HER2 blood test is also available, but it is not a substitute for tissue testing.
- What do the results mean? Results of HER2 status testing are reported as HER2 positive – the cancer cells are overexpressing HER2, and HER2 negative – the cancer cells are not overexpressing HER2. HER2 positive cancers are more aggressive and tend to grow and spread more quickly than cancers with a normal amount of HER2. They are often associated with a higher tumor grade. HER2 overexpression usually does not change throughout the course of the disease.
- What are some other important HER2 status information? About 20%-30% of invasive breast cancers overexpress HER2, and breast cancer cells that have BRCA1 mutations often do not overexpress HER2. HER2 positive breast cancers often contain lower levels of estrogen and progesterone receptors than HER2 negative tumors. Therefore, women with HER2 positive breast cancer may benefit less from certain types of hormonal therapy. Also, HER2 positive tumors respond best to certain types of chemotherapy drugs, in combination with trastuzumab.
- Jardines, L., Haffty, BG., Fisher, P.,Weitzel, J., Royce, M.,Breast cancer overview Risk factors, screening, genetic testing, and prevention . Chapter 8 in "Cancer Management: A multidisciplinary approach."
- Rilke F, Colnaghi MI, Cascinelli N, et al. Prognostic significance of HER-2/neu expression in breast cancer and its relationship to other prognostic factors. Int J Cancer. 1991;49:44-49.
- Lal, P., Tan, LK., Bhen, B., Correlation of HER-2 Status With Estrogen and Progesterone Receptors and Histologic Features in 3,655 Invasive Breast Carcinomas. American Journal of Clinical Pathology 2005;123(4):541-546.
- Tsuda H, Tsugane S, Fukutomi T, et al. Prognostic factors for recurrent breast cancer: univariate and multivariate analyses including histologic grade and amplification of the c-erbB-2 proto-oncogene. Jpn J Clin Oncol. 1992;22:244-249.
- Taucher P, Rudas M, Mader RM, et al. Do we need HER-2/neu testing for all patients with primary breast carcinoma? Cancer. 2003;98:2547-2553.
- Hoff ER, Tubbs RR, Myles JL, et al. HER2/neu amplification in breast cancer: stratification by tumor type and grade. Am J Clin Pathol. 2002;117:916-921.
- Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177-182.
- Seidman AD, Fornier M, Esteva FJ, et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER-2 immunophenotype and gene amplification. J Clin Oncol. 2001;19:2587-2595.
- Ravdin PM, Chamness GC. The c-erbB-2 proto-oncogene as a prognostic and predictive marker in breast cancer: a paradigm for the development of other macromolecular markers: a review. Gene. 1995;159:19-27.
- Porter PL, Garcia R, Moe R, et al. C-erbB-2 oncogene protein in in situ and invasive lobular breast neoplasia. Cancer. 1991;68:331-334.
- Zafrani B, Aubriot MH, Mouret E, et al. High sensitivity and specificity of immunohistochemistry for the detection of hormone receptors in breast carcinoma: comparison with biochemical determination in a prospective study of 793 cases. Histopathology. 2000;37:536-545.
- DiGiovanna MP, Chu P, Davison TL, Howe CL, Carter D, Claus EB, Stern DF. Active signaling by HER-2/neu in a subpopulation of HER-2/neu-overexpressing ductal carcinoma in situ: clinicopathological correlates. Cancer Res. 2002 Nov 15;62(22):6667-73.
- Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist. 2009 Apr;14(4):320-68. Epub 2009 Apr 3.
- Huston JS, George AJ. Engineered antibodies take center stage. Hum Antibodies
- Gullick WJ, Love SB, Wright C et al. c-erbB-2 protein overexpression in breast cancer is a risk factor in patients with involved and uninvolved lymph nodes. Br J Cancer 1991;63:434–438.
- Jacquemier J, Penault-Llorca F, Viens P et al. Breast cancer response to adjuvant chemotherapy in correlation with erbB2 and p53 expression. Anticancer Res 1994;14:2773–2778.
- Allred DC, Clark GM, Tandon AK et al. HER-2/neu node-negative breast cancer: Prognostic significance of overexpression influenced by the presence of in situ carcinoma. J Clin Oncol 1992;10:599–605.
- Andrulis IL, Bull SB, Blackstein ME et al. neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. J Clin Oncol 1998;16:1340 –1349.
- Pich A, Margaria E, Chiusa L. Oncogenes and male breast carcinoma: c-erbB-2 and p53 coexpression predicts a poor survival. J Clin Oncol 2000;18:2948 –2956.
- Thomas, E., Berner, G., Prognostic and predictive implications of HER2 status for breast cancer patients. European Journal of Oncological Nursing. (March 2000) Volume 4, Supplement A, Pages 10-17.
- Hait, WN., The Prognostic and Predictive Values of ECD-HER-2 Clin Cancer Res. 2001 Sep;7(9):2601-4.
- Hamilton A, Piccart M: The contribution of molecular markers to the prediction of response in the treatment of breast cancer: a review of the literature on HER-2, p53 and BCL-2. Ann Oncol 2000 , 11:647-663.