Hormone receptor (ER, PR, HER2/neu) status and proliferation index marker (Ki-67) in breast cancers: Their onco-pathological correlation, shortcomings and future trends
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0975-2870.194180
Estrogen receptor (ER) and progesterone receptor (PR) are hormone receptors found on breast cells that pick up hormone signals resulting in cell growth. Similarly, positive human epidermal growth factor receptor-2 (HER2/neu) status of the breast carcinoma means that HER2/neu gene is making too many HER2/neu proteins, which acts as receptors on the cell surface and helps the cells to grow and divide. Hormone receptor studies such as ER, PR, and HER2/neu are routinely done in breast carcinoma. It not only helps in the prognosis of the tumor but also helps in deciding its treatment. The goal of doing this receptor status is to provide right treatment to the right patient. This hormone receptor status is graded using Allred scoring and grading system. Depending on the hormone status, breast carcinomas can be divided into a number of different categories ranging from triple positive through triple negative. Another marker of proliferation (Ki-67) is also being used which is a proliferation index marker. This scoring system has its own limitation and shortcomings, which depends on a lot of pre- and post-analytical factors. Certain new techniques such as genomic assays, PAM50, and HALO screening test are being used nowadays for breast cancer detection. Keywords: Allred system, breast cancer, hormone receptors
Hormone receptor studies such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2/neu) are routinely done in breast carcinoma. It not only helps in the prognosis of the tumor but also helps in deciding its treatment. The goal of doing this receptor status is to provide right treatment to the right patient. The role of the pathologist is to accurately assess these biomarkers, and the role of the oncologist is to treat the patient with one of the several established therapies, depending on the hormone status. ER and PR are hormone receptors found on breast cells that pick up hormone signals resulting in cell growth. Cancer is called ER-positive (ER + ) if it has receptors for hormone estrogen which receives the signals from estrogen and promotes its growth, just like normal cells. Similarly, the cancer is PR-positive (PR + ) if it has receptors for hormone progesterone. Again, this means that the cancer cells may receive signals from progesterone that could promote their growth. Similarly, HER2/neu positive (HER2/neu + ) status of the breast carcinoma mean that HER2/neu gene is making too many HER2/neu proteins. HER2/neu proteins are receptors on breast cells. Normally, HER2/neu receptors control healthy breast cell growth, division, and repair. However, in about 30% of breast cancers, the HER2/neu gene does not work correctly and makes too many copies of it (known as HER2/neu gene amplification). These extra HER2/neu gene copies tell breast cells to make too many HER2/neu receptors (HER2/neu protein overexpression). This ultimately makes breast cells to grow and divide in an uncontrolled way. [1],[2] Biomarkers can be prognostic, predictive, or both. Prognostic biomarkers measure prognosis independently of other factors. The presence or absence of these biomarkers is directly associated with disease recurrence or mortality. Predictive biomarkers, on the other hand, predict whether or not a patient will respond to a given therapy. The presence of the hormone receptors ER, PR in a patient's breast cancer is an example of a weak prognostic but strong predictive biomarker. If a patient's tumor expresses ER and/or PR, we can predict that this patient will positively benefit from endocrine therapy such as tamoxifen. The overexpression of the oncogene HER2/neu in a patient's breast cancer is an example of both a prognostic and predictive biomarker. HER2/neu expression is associated with poor prognosis (high risk of recurrence [ROR]); however, it also predicts that a patient will more likely benefit from anthracycline and taxane-based chemotherapies and therapies that target HER2/neu (trastuzumab), but not to endocrine-based therapies. [1],[2]
Allred system of scoring for estrogen receptor and progesterone receptor ER and PR are nuclear receptors. In Allred system of scoring, score 0-5 is given to the cells depending on the proportion of cells which are stained (proportion score [PS]) and score 0-3 is given depending on the intensity of staining (intensity score [IS]) [Table 1] and [Table 2]. By adding the PS and IS, we can calculate the final Allred score (PS + IS = AS) [Table 3]. [3]
Scoring for human epidermal growth factor receptor 2/neu overexpression HER2/neu is a cell membrane receptor and depending on the intensity of staining a score of 0-3 is given to the cells [Table 4].
A positive HER2/neu result is:
In Allred scoring system, only the invasive tumor cells should be assessed as ER/PR staining is present in normal breast epithelial cells as well. Here, the normal breast epithelial cells act as internal positive control. Any positive test result, whether just for ER, PR, or both means that the breast cancer is considered "hormone-receptor-positive." Hormone therapy helps to slow or stop the growth of hormone receptor-positive breast cancers by lowering the body's estrogen levels or blocking the effects of estrogen. These medications also may reduce the ROR. Likewise if HER2/neu receptor is present in large amount on the cancer cells; it confers a more aggressive biologic behavior of the tumor cell. We can use a very effective targeted therapy against HER2/neu such as Herceptin. Herceptin is a biologic treatment, not a chemotherapy drug; rather an antibody that blocks the HER2/neu receptor on the cancer cells and shuts down the signal from HER2/neu, hence stopping the growth of cancer cells. [1],[2] Besides, Allred scoring system, another scoring system in use for ER and PR is "quick score system," However, there is no worldwide consensus on the scoring system. A few other histological scoring systems in use for breast cancers are Nottingham Histologic Score ("Elston Grade") and Bloom-Richardson Grade. Ki-67 in breast cancer Ki-67 protein in humans is encoded by MK167 gene and is a cellular marker for proliferation. This is a nuclear protein and is expressed in proliferating cells but is not detected in resting cells. The Ki-67 expression as detected by immunohistochemistry is one of the most reliable indicators of the proliferative status of cancer cells. The most important parameters that define the treatment and prognosis in breast cancer are ER, PR, and HER2/neu status although some people report Ki-67 in addition to ER, PR, and HER2/neu. The existing guidelines of the American Society of Clinical Oncology do not include Ki-67 in the list of required routine biological markers. However, the advent of new genetic tests has emphasized the role of proliferative genes, including Ki-67, as prognostic and predictive markers. [4] The most commonly used method to detect Ki-67 positivity is by staining with MIB-1 antibody. The Ki-67 score is defined as the percentage of total number of tumor cells with nuclear staining, whereas others count several hundred nuclei in different areas of tumors to give an overall average index. This can be a reason for the considerable interlaboratory and intraobserver variability. A standardization of Ki-67 pathological assessment has not yet been accomplished. [5] This lack of consistency across laboratories has limited the role of Ki-67, till the time, it will be properly standardized.
Based on hormone receptor status and HER2/neu, breast cancers are divided into four different groups. Luminal type A or estrogen receptor positive, progesterone receptor positive, human epidermal growth factor receptor 2/neu negative These types of cancers, as the name describes, are positive for hormone receptors (ER and PR) and negative for HER2/neu and/or low Ki67 index [Figure 1]. About 80% of breast cancers are ER + , and about 65% of these are also PR + , which means that they grow in response to estrogen and progesterone, respectively. These tumors are more responsive to hormone therapy than hormone receptor-negative tumors. They have an overall tumor grade of 1 or 2. Only about 15% of these tumors have p53 gene mutations, which have a poor prognosis.
Luminal Type B or triple positive or estrogen receptor positive, progesterone receptor positive, human epidermal growth factor receptor 2/neu positive, or human epidermal growth factor receptor 2/neu negative with high Ki-67 breast cancers This term is used to describe cancers that are ER + , PR + , HER2/neu + , and/or high Ki-67 index [Figure 2]. They are referred to as luminal because the tumor cells arise from the inner (luminal) cells lining the mammary ducts. These cancers can be treated with hormone therapy as well as drugs that target HER2/neu.
Estrogen receptor negative, progesterone receptor negative, human epidermal growth factor receptor 2/neu positive, or simply human epidermal growth factor receptor 2/neu positive breast cancers About 20% of breast cancers are HER2/neu + [Figure 3]. These cancers are very aggressive and fast growing with a high tumor grade. They do not respond to hormone therapies instead they are treated with antibodies against HER2/neu receptors (Herceptin) blocking their action, as described above. Women with HER2/neu + type tumors may be diagnosed at a younger age than luminal A and B tumors.
Basal-like or triple negative phenotype, estrogen receptor negative, progesterone receptor negative, and human epidermal growth factor receptor 2/neu negative breast cancers Almost 10-20% of breast cancers are triple negative. They are referred to as basal-like because the tumor cells have features similar to those of the outer (basal) cells surrounding the mammary ducts. Most breast cancers associated with BRCA-1 gene are triple negative and most of them contain p53 gene mutations. Although these cancers respond fairly well to chemotherapy but they tend to recur. No perfect therapy has been devised so far, but several promising strategies are being aimed at triple-negative breast cancers. However, it should be noted that most triple negative breast tumors are not basal-like and vice versa. Triple negative phenotype (TNP) breast cancers can be further subclassified into two categories by adding epidermal growth factor receptor (EGFR) and cytokeratin 5/6 (CK-5/6) immunostaining information. The two subcategories are core basal and 5 negative phenotype (5-NP). The core basal group in addition to TNP is positive for EGFR and CK-5/6. While as the 5-NP group, which as the name suggests is TNP and also EGFR and CK-5/6 negative. It is seen that the core basal group has significantly worse prognosis, with an absolute 10% lower 10-year breast cancer specific survival than 5-NP. [6]
It has been shown that some hormone status (ER, PR, and HER2/neu) test results may sometimes be wrong (false positive or false negative). This is probably because different laboratories have different regulations for classifying positive and negative test results. The different sources of variation are shown in detail in [Table 5]. [7],[8] Errors in most cases happen when the test results are borderline, meaning they are not strongly hormone receptor-positive or negative. In other cases, tissue from one area of breast cancer can test HER2/neu + and tissue from a different area of cancer can test HER2/neu negative (HER2/neu− ). [1],[2]
The need for writing this article is to inform all the stakeholders that despite the usefulness of this hormone status/scoring system, it has its own shortcomings and limitations. Interobserver variations, different protocols adopted by different laboratories, quality of different reagents, time of fixation, staining, etc., are some of the common errors besides others as described in [Table 5]. Hence, there is a need to standardize this system so as to cover these fallacies and make this ER, PR, HER2/neu, and Ki-67 system more accurate and authentic. It can be achieved partly by close association between oncologists and pathologists and regular oncologists-pathologists meetings and case discussions, besides of course standardizing these procedures and results.
Some recently introduced investigations in breast cancer detection and their treatment which opens a whole new era of investigations against breast cancers are listed below. Tests of ploidy These tests are being done routinely nowadays to predict the behavior of tumor growth. Diploidy means that a proportion of cancer cells have the same number of chromosomes as normal, healthy cells. They tend to be slower-growing, less aggressive cancers. Aneuploidy means that a proportion of cancer cells have too many or too few chromosomes. When cancer cells are rapidly dividing, mistakes in the distribution of chromosomes can happen, resulting in some cells having too many chromosomes and others too few. An aneuploid cancer may be more aggressive than diploid cancer. Tests of gene patterns or genomic assays: Oncotype DX, MammaPrint, and Mammostrat These tests use a sample of the breast cancer tissue to analyze the activity of a group of genes, rather than just a single gene. Knowing whether certain genes are present or absent, overly active or not active enough, can help us predict the risk of breast cancer recurrence. The Oncotype DX test analyzes the activity of 21 genes and then calculates a recurrence score number between 0 and 100; the higher the score, the greater the ROR. The MammaPrint test analyzes 70 genes to see how active they are and then calculates either a high-risk or low-risk recurrence score. It is also used to estimate a women's recurrence risk for early-stage breast cancer. MammaPrint results can also help us decide about whether to use chemotherapy to reduce recurrence risk. The Mammostrat test measures the levels of five genes in breast cancer cells. These measurements are used to calculate a risk index score. The higher the risk index, the more likely the cancer is to recur. Women are assigned to a risk category (high, moderate, or low) based on their risk index score. [9]
PAM 50 assay detects the activity of 58 genes (called the PAM50 gene signature) to estimate the risk of distant recurrence of hormone-receptor-positive breast cancer from 5 to 10 years after diagnosis after 5 years of hormonal therapy treatment in postmenopausal women. Based on these activity levels, these assay results are reported as a ROR score from 0 to 100 in two ways: Node-negative cancers are classified as low (0-40), intermediate (41-60), or high (61-100) risk, and node-positive cancers are classified as low (0-40) or high (41-100) risk. [9]
HALO or breast cytological evaluation test is FDA approved for the collection of nipple aspirate fluid (NAF) for cytological evaluation. The collected fluid can be used in the determination and/or differentiation of normal versus premalignant versus malignant cells. The HALO breast cytological evaluation test is the only fully automated, noninvasive, NAF collection system. It is now recognized that almost all breast cancers begin within the breast milk ducts. Clinical studies have also confirmed the ability to detect early cellular changes within the breast ducts, similar to the Pap test detection of early cervical cellular changes through analysis of NAF. [10]
Scintimammography uses small amounts of radioactive materials called radiotracers (technetium 99 sestamibi), a gamma camera and a computer to help investigate an abnormality discovered on mammography. It is used when the detection of breast abnormalities is not possible or not reliable on the basis of mammography and ultrasound.
Newer targeted therapies beside Herceptin such as pertuzumab (Perjeta), ado-trastuzumab emtansine (Kadcyla), lapatinib (Tykerb), etc. Anti-angiogenic drug such as bevacizumab (Avastin). Other targeted therapies such as everolimus (Afinitor), exemestane (Aromasin). Bisphosphonates therapies such as zoledronic acid and denosumab. Vitamin D therapy Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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