Changes In Her2 Status After Neoadjuvant Chemotherapy
Neoadjuvant chemotherapy is currently considered as standard treatment for locally advanced breast cancer . Alteration of biomarker status after NAC is occasionally found in breast cancer . Hormone receptor status changed more often than HER2 status, and as for hormone receptors, positive to negative conversion was more common than negative to positive conversion . The frequency of HER2 change after NAC is reported in up to 15%, and both positive to negative conversion and negative to positive conversion were found with no preponderance . Previous studies on HER2 change after NAC are summarized in . In our study, HER2 status was altered after NAC in 3.4% with positive to negative conversion in 0.9% and negative to positive conversion in 2.5% . Most cases with negative to positive conversion of HER2 status after NAC showed low level of HER2 amplification, and the HER2/CEP17 ratio ranged from 2.2 to 4.4 . Cockburn et al. also reported the mean HER2/CEP17 ratio in resection specimens with HER2 positive conversion was 3.7. Although there are no guidelines about whether treatment should be modified based on altered biomarker status after NAC, the change of HER2 status may have an impact on the therapeutic management in certain patients. Accordingly, re-evaluation of biomarkers including HER2 after NAC is recommended for proper management.
Her2 Is A Protein That Accelerates Cell Growth
First, what do those letters mean? HER2 stands for human epidermal growth factor receptor 2, which is a gene that makes HER2 proteins, according to the National Institutes of Health. HER2 proteins are normally found on the surface of healthy breast cells to promote breast cell growth and repair, but when HER2 mutates, things go wrong. An excess of HER2 proteins causes cells to grow fast. When cancer cells have more HER2, this causes cancer cells to grow more rapidly, explains Swati Kulkarni, M.D., a breast surgeon at Northwestern Memorial Hospital in Chicago.
N Categories For Breast Cancer
N followed by a number from 0 to 3 indicates whether the cancer has spread to lymph nodes near the breast and, if so, how many lymph nodes are involved.
Lymph node staging for breast cancer is based on how the nodes look under the microscope, and has changed as technology has gotten better. Newer methods have made it possible to find smaller and smaller groups of cancer cells, but experts haven’t been sure how much these tiny deposits of cancer cells influence outlook.
Its not yet clear how much cancer in the lymph node is needed to see a change in outlook or treatment. This is still being studied, but for now, a deposit of cancer cells must contain at least 200 cells or be at least 0.2 mm across for it to change the N stage. An area of cancer spread that is smaller than 0.2 mm doesn’t change the stage, but is recorded with abbreviations that indicate the type of special test used to find the spread.
If the area of cancer spread is at least 0.2 mm , but still not larger than 2 mm, it is called a micrometastasis . Micrometastases are counted only if there aren’t any larger areas of cancer spread. Areas of cancer spread larger than 2 mm are known to influence outlook and do change the N stage. These larger areas are sometimes called macrometastases, but are more often just called metastases.
NX: Nearby lymph nodes cannot be assessed .
N0: Cancer has not spread to nearby lymph nodes.
N1c: Both N1a and N1b apply.
N3: Any of the following:
N3a: either:
N3b: either:
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Survival Rates For Her2
Cancer survival statistics are typically reported using a 5-year survival rate. This is the percentage of individuals that are still living 5 years after their diagnosis.
Survival rates can vary based off of the subtype of breast cancer that you have. A publication from the reports 5-year survival rates for HER2-negative breast cancers as:
- 92 percent for HER2-negative, HR-positive breast cancer
- 77 percent for triple-negative breast cancer
Keep in mind that HER2 and HR status arent the only factors that can influence outlook. Other important factors at diagnosis include:
- the stage of the cancer
- the specific type of breast cancer
- your age and overall health
Breast Cancer Research At Moffitt Cancer Center
Moffitt Cancer Center has been designated a Comprehensive Cancer Center by the National Cancer Institute, an achievement that speaks directly to our commitment to advancing research and treatment for this malignancy. We are researching the causes of HER2 positive breast cancer every day, and we wont be satisfied until there is a cure. To advance the treatment of this malignancy, Moffitt spearheads a robust clinical trials program where eligible patients can receive the latest breakthroughs in treatment before they are available elsewhere.
If you would like to learn more about the causes of HER2 positive breast cancer, or if you have been diagnosed with this malignancy and would like to explore the treatment options available to you at Moffitt, we encourage you to request an appointment. To do so, call or submit a new patient registration form. We accept patients with or without referrals.
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Breast Cancer Chemotherapy Can Use Agents Which Specifically Target Her
Sometimes medics will also treat HER-2 positive tumors with targeting agents such as
Physicians will also sometimes employ hormonal therapy, such as anthracylines, and taxanes, 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 useful in addition to trastuzumab-based neoadjuvant chemotherapy, and generally with good effect.
Effect On Tumor Growth In Xenograft Models
The ability of the HER2 mutations to increase tumor formation in xenografts was tested . NIH3T3-HER2 WT cells served as the control cell line. NIH3T3-HER2 V777L, D769H, and G309A-mutant cell lines had more rapid tumor growth than the HER2 WT control . The L755S, V842I, and R678Q cells showed tumor growth indistinguishable from the HER2 WT control cells . The NIH3T3-HER2 del.755â759 cells formed tumors slower than NIH3T3-HER2 WT cells . NIH3T3 cells have low levels of endogenous EGFR and HER3 and because the del.755â759 mutation seems to be more dependent on a heterodimer pattern like EGFR, the tumor formation ability of del.755â759 may be decreased in NIH3T3 cells. Similarly, MCF7-HER2 V777L cells formed tumors more rapidly in nude mice than MCF7-HER2 WT cells , indicating that HER2 mutations can increase tumor formation in this cell line as well. The strong effect of HER2 G309A seen in the tissue culture and xenograft experiments was surprising given the small effect of this mutation on HER2 phosphorylation . However, Greulich and colleagues recently showed that HER2 G309E can increase HER2 dimerization without increasing HER2 phosphorylation.
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Blocking Her2 Slows Or Stops Some Types Of Breast Cancer
NCI-funded researcher Dennis Slamon, M.D., was among the many scientists searching for genes that can lead to cancer. In 1987, he and his colleagues discovered that the growth factor receptor gene HER2, which produces HER2 proteins, might be a good candidate.
At the same time, a team of NCI researchers led by Stuart Aaronson, M.D., were among the first to show that the HER2 protein could cause normal cells to grow uncontrollably like aggressive cancer cells.
Dr. Slamons team found that the HER2 protein is present at high levels in about 30 percent of breast cancers. They also discovered that high levels of HER2 are linked to a greater likelihood of metastasis and relapse and an overall decrease in patient survival. The group concluded that HER2 might play a role in the development and growth of breast cancer.
NCI-funded researcher Dennis J. Slamon, M.D., discovered the genetic link between HER2 and breast cancer.
This led researchers to a groundbreaking hypothesis: If HER2 could be blocked, the growth of HER2-positive breast cancer might be slowed.
One way to block the action of a protein is to use laboratory-made monoclonal antibodies that attach to a specific protein and disrupt its function. With NCI support, Dr. Slamon and colleagues from the University of Texas Health Sciences Center had a breakthrough. They showed that an antibody specific to HER2 could slow the growth of metastatic breast cancer cells and other types of cancer in a laboratory dish.
What Tests Can Detect Breast Cancer Her2 Status
Doctors will typically look for a HER2 defect with a biopsy, which is a procedure to remove and test a sample of tumor tissue.
The two main types of tests used to detect breast cancer HER2 status are:
- Immunohistochemistry assay . This test uses a chemical dye to stain the HER2 proteins. It measures the amount of these proteins on the surface of the cells.
- Fluorescence in situ hybridization test . With a FISH test, special labels with chemicals added to them change color and glow in the dark when they attach to HER2 proteins. It looks for extra copies of the HER2 gene.
The FISH test is the most accurate. But itâs also the most expensive, and it takes a while to get your results. For these reasons, your doctor might first suggest that you have an IHC test.
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How Is The Stage Determined
The staging system most often used for breast cancer is the American Joint Committee on Cancer TNM system. The most recent AJCC system, effective January 2018, has both clinical and pathologic staging systems for breast cancer:
- The pathologic stage is determined by examining tissue removed during an operation.
- Sometimes, if surgery is not possible right away or at all, the cancer will be given a clinical stage instead. This is based on the results of a physical exam, biopsy, and imaging tests. The clinical stage is used to help plan treatment. Sometimes, though, the cancer has spread further than the clinical stage estimates, and may not predict the patients outlook as accurately as a pathologic stage.
In both staging systems, 7 key pieces of information are used:
- The extent of the tumor : How large is the cancer? Has it grown into nearby areas?
- The spread to nearby lymph nodes : Has the cancer spread to nearby lymph nodes? If so, how many?
- The spread to distant sites : Has the cancer spread to distant organs such as the lungs or liver?
- Estrogen Receptor status: Does the cancer have the protein called an estrogen receptor?
- Progesterone Receptor status: Does the cancer have the protein called a progesterone receptor?
- HER2 status: Does the cancer make too much of a protein called HER2?
- Grade of the cancer : How much do the cancer cells look like normal cells?
In addition, Oncotype Dx® Recurrence Score results may also be considered in the stage in certain situations.
Risk Of Recurrence: Early And Late
Research has shown the HER2-positive early breast cancers are two to five times more likely to recur than HER2-negative tumors. Even very small HER2-positive tumors with negative lymph nodes have a much higher risk of recurrence relative to tumors that are HER2-negative. Treatment with Herceptin can cut this risk by half.
The pattern of breast cancer recurrence may also differ. Small tumors are also more likely to have a metastatic recurrence if they are HER2-positive.
Despite the fact that HER2-positive and estrogen receptor-negative tuors are more likely to recur early on than estrogen receptor-positive and HER2-negative cancers, late recurrences are much less common.
With estrogen receptor positive breast cancers, the cancer is more likely to recur after five years than in the first five years, and the risk of recurrence remains steady each year for at least 20 years following the diagnosis. In contrast, those who have HER2 positive tumors and reach their five-year mark are much more likely to be “in the clear” and remain recurrence free.
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T Categories For Breast Cancer
T followed by a number from 0 to 4 describes the main tumor’s size and if it has spread to the skin or to the chest wall under the breast. Higher T numbers mean a larger tumor and/or wider spread to tissues near the breast.
TX: Primary tumor cannot be assessed.
T0: No evidence of primary tumor.
Tis: Carcinoma in situ
T1 : Tumor is 2 cm or less across.
T2: Tumor is more than 2 cm but not more than 5 cm across.
T3: Tumor is more than 5 cm across.
T4 : Tumor of any size growing into the chest wall or skin. This includes inflammatory breast cancer.
Her2s Genetic Link To Breast Cancer Spurs Development Of New Treatments
Single breast cancer cell and microenviornment visualized by transparent tumor tomography.
When NCI-supported researchers discovered that the HER2 gene is important for breast cancer growth, this led to the development of the drug trastuzumab and other targeted treatments that have improved survival for women with HER2-positive breast cancer.
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How Does Her2 Positive Breast Cancer Develop
While we are still learning about the causes of HER2 positive breast cancer, researchers have identified how HER2 positive breast cancer develops. In about 25 percent of breast cancers, the cancer cells have an excess of the HER2 protein. This is caused by a mutation in the HER2 gene. When the HER2 gene mutates, it causes cells in the breast to grow and divide at an uncontrolled rate, leading to tumor growth.
How Her2 Affects Treatment
Treatment for breast cancer depends in part on the stage and type and is different in each case, but typically involves some combination of surgery, radiation, chemotherapy, or other drug therapies. These other drug therapies depend partly on whether your cancer is HER2-positive. If it is, certain medications can work well, such as:
Monoclonal antibodies. These are lab-made versions of immune system substances designed to attach to HER2 protein on breast cancer cells.
Antibody-drug conjugates. These drugs target chemotherapy directly to HER2 protein on cancer cells.
Kinase inhibitors. These medications stop proteins like HER2 from sending signals.
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Her2 Overexpression In Human Cancer
Normal tissues have a low complement of HER2 membrane protein. Overexpression of HER2 is seen in 20% of breast and in some ovarian and gastric cancers, and it confers worse biological behavior and clinical aggressiveness in breast cancer . Breast cancers can have up to 2550 copies of the HER2 gene, and up to 40100 fold increase in HER2 protein resulting in 2 million receptors expressed at the tumor cell surface . The differential in HER2 expression between normal tissues and tumors helps to define HER2 as an ideal treatment target. Trastuzumab, the first treatment targeting HER2, is well-tolerated in patients with little toxicity, since its effects are relatively specific for cancer cells overexpressing HER2.
Soft Agar Colony Forming Assay
Statistical analysis of the colony count data were modeled using Poisson regression using the MCMCglmm package , of the R statistical environment using âGenotypeâ and a âGenotype:Treatmentâ interaction as fixed predictors. No intercept was included to force explicit measurements for each âGenotypeâ. MCMCglmm uses fully Bayesian modeling and parameter estimates generated using Gibbs sampling Markov Chain Monte Carlo with 100,000 iterations, a burn-in of 3,000, and a thin of 10. Diagnostics revealed the lack of autocorrelation and excellent chain mixing. The default prior was used for fixed effects, which is a multivariate normal distribution with a 0 mean vector and diagonal variance matrix with variances of 10â§10 and covariances of 0, as this ensures fixed effects are independent and estimated almost entirely from the data. Overdispersion and replicates were accounted for in the residual variance structure with an improper inverse-Wishart prior with nu = 0 and V = 1, which implicitly assumes each well is a random effect. Parameters and parameter contrasts were considered to be statistically significant when the 95% highest posterior density interval did not contain 0. The conclusions were robust to changes in the minimal colony size from 1 to 10 .
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Trastuzumab Targets Breast Cancer In Clinical Trials
Researchers launched three clinical trials of trastuzumab in the mid-1990s for patients with HER2-positive metastatic breast cancer. By 1998, the results of the phase 3 clinical trials showed that breast cancer in patients treated with trastuzumab and chemotherapy grew at a slower rate than in patients treated with chemotherapy alone. Subsequent clinical trials also showed positive outcomes among women with early-stage HER2-positive breast cancer.
On November 16, 2006, the US Food and Drug Administration granted approval to trastuzumab used with chemotherapy as an adjuvant treatment for women with HER2-positive breast cancer. The drug has improved survival rates for women with stage 1 to 3 HER2-positive breast cancer by more than 30 percent.
HER2 protein is expressed at high levels in several other cancers besides breast cancer, and in 2010, FDA approved the use of trastuzumab in combination with the chemotherapy drug cisplatin and a type of cancer drug called a fluoropyrimidine to treat some patients with HER2-positive gastric or gastroesophageal junction cancers.
Human Epidermal Growth Factor Receptor 2 In Cancers: Overexpression And Therapeutic Implications
Nida Iqbal
1Department of Medical Oncology, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India
2Department of Anaesthesia and Intensive Care Unit, Indraprastha Apollo Hospital, New Delhi 110076, India
Abstract
Human epidermal growth factor receptor 2 is a member of the epidermal growth factor receptor family having tyrosine kinase activity. Dimerization of the receptor results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways leading to cell proliferation and tumorigenesis. Amplification or overexpression of HER2 occurs in approximately 1530% of breast cancers and 1030% of gastric/gastroesophageal cancers and serves as a prognostic and predictive biomarker. HER2 overexpression has also been seen in other cancers like ovary, endometrium, bladder, lung, colon, and head and neck. The introduction of HER2 directed therapies has dramatically influenced the outcome of patients with HER2 positive breast and gastric/gastroesophageal cancers however, the results have been proved disappointing in other HER2 overexpressing cancers. This review discusses the role of HER2 in various cancers and therapeutic modalities available targeting HER2.
1. Introduction
2. Function
Figure 1 shows the main transduction pathways regulated by the four HER family membersEGFR, HER2, HER3, and HER4.
3. HER2 Overexpression in Cancers
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