Mechanism Of Action Of Her2
As discussed above, the HER2 receptor is a transmembrane tyrosine kinase receptor that belongs to the human epidermal growth factor receptors . It is expressed at a low level on the surface of epithelial cells, and is needed for development in several tissue types, such as the breast, ovary, central nervous system, lung, liver and kidney . It is overexpressed in 2530% of breast cancer cells. As shown in Figure 1, HER2 forms homodimers or heterodimers with other members of the human epidermal growth factor receptors. The HER2 protein can exist in an inactivated state, and dimerize independent of the binding of a ligand. The binding of a ligand induces phosphorylation of the receptors, which in turn activates the MAPK pathway and the PI3K pathways.
HER2 signaling pathway, mechanism of action of targeted therapies, and resistance mechanisms. 1. The truncated P95HER2 isoform results in the loss of the extracellular binding site for trastuzumab. 2.3. Overexpression of other tyrosine kinase receptors, such as IGF1-R and C-met, can continue to trigger downstream signaling despite blockade by trastuzumab. 4. Mutations or loss of PTEN constitutively activates the PI3K signaling pathway.
Patients With Residual Disease After Neoadjuvant Anti
In a subset of patients, systemic neoadjuvant treatment of early HER2-positive breast cancer does not result in pCR and there is residual disease present in the breast and/or axilla. CTNeoBC meta-analysis showed that pCR is associated with an improvement in long-term clinical outcome and those patients with residual disease after NAT have a higher risk of disease recurrence . In such patients with residual cancer after systemic NAT, therapy should be escalated and 14 cycles of trastuzumab emtansine should be administered.
The recommendation for this approach is based on the results of the KATHERINE trial, which showed that adjuvant treatment with T-DM1 in patients who had residual disease after neoadjuvant chemotherapy and HER2-targeted therapy reduced the risk of recurrence of invasive breast cancer or death by 50% compared with those who continued treatment with trastuzumab alone .
The estimated percentage of patients without invasive disease at 3 years was 88.3% in the T-DM1 versus 77.0% in the group that received trastuzumab alone . A clear and consistent treatment benefit was observed in all key clinically relevant subgroups, regardless of the size of the residual tumor, hormone receptor status, lymph node status, and previous use of dual HER2 blockade .
Optimal adjuvant anti-HER2 treatment approach based on response to systemic NAT is shown in Figure 5.
Neoadjuvant Systemic Therapy For Patients With Early And Locally Advanced Her2
Treatment of early breast cancer may begin either by surgery followed by adjuvant systemic treatment or by neoadjuvant systemic therapy. Neoadjuvant systemic therapy can help convert tumor from inoperable to operable stage, increase the chance of breast-conserving surgery and less radical axillary dissection, reduce the morbidity associated with breast surgery, and assist, along with other risk factors, in assessing the prognosis of the disease. In general, studies have shown that there is no difference in overall survival if the same systemic treatment protocol is administered neoadjuvantly or adjuvantly, but achieving pathologic complete response after administration of neoadjuvant systemic therapy is associated with an improvement in survival . HER2-positive status, along with other factors such as negative hormonal status, G3, N0, cT1/cT2, is a strong predictive factor for the response to neoadjuvant therapy , and therefore anti-HER2 therapy should preferably be initiated already at the neoadjuvant stage, to increase the chance of achieving pCR.
All patients with HER2-positive early and locally advanced breast cancer that are candidates for adjuvant systemic therapy are also candidates for neoadjuvant systemic anti-HER2 therapy regardless of tumor size, especially in the following cases:
- N-positive tumor
- Patients desire for BCS, which is not possible without reducing the tumor size with systemic therapy first
- Inoperable tumor
- Inflammatory breast cancer .
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What Are The Symptoms Of Her2
Its not possible to self-determine whether you have HER2-positive breast cancer. If your doctor suspects cancer, further testing will reveal whether you are HER2-positive.
Overall, its important to see your doctor right away if you notice any of the following symptoms:
- any new or changing lumps in your breast or armpit areas
- clear, colored, or bloody nipple discharge
- unexplained pain in your breasts
- changes in your nipples or breast skin, such as dimpling, reddening, or scaliness
- nipples that turn inward
Hormone treatments may be an option for cancer thats also HR-positive.
Monitoring Cardiac Function During Administration Of Anti
In the administration of drugs that inhibit HER2 receptor activity, a well-described side effect is a cardiotoxicity, which may manifest either as an asymptomatic decrease in LVEF or as a symptomatic failure of cardiac function. For this reason, evaluation of cardiac function, i.e., measurement of LVEF before the initiation of anti-HER2 therapy and every 3 months during anti-HER2 therapy, is recommended .
Treatment with trastuzumab-pertuzumab may be initiated if the initial LVEF is > 50%. If LVEF drops by 10 or more points below baseline or to < 50% during treatment with trastuzumab-pertuzumab, therapy should be temporarily withheld. LVEF evaluation should be repeated within 3 weeks and, if the LVEF value recovers to > 50% or to < 10 units compared to pre-treatment value, trastuzumab-pertuzumab therapy may be resumed. If LVEF does not improve or decreases even further, and if symptomatic congestive heart failure develops, permanent discontinuation of anti-HER2 therapy should be considered. All such patients should be referred for cardiac specialist .
It should be noted that cardiotoxicity associated with the administration of anti-HER2 therapy is reversible in nature and that standard ACE inhibitor therapy in most cases leads to an improvement in cardiac function and recovery of LVEF, after which most patients can resume planned anti-HER2 therapy.
The recommendations for the management of patients receiving trastuzumab-pertuzumab based on LVEF measurements are shown in Table 4.
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Starting With Neoadjuvant Therapy
Most often, these cancers are treated with neoadjuvant chemotherapy. For HER2-positive tumors, the targeted drug trastuzumab is given as well, often along with pertuzumab . This may shrink the tumor enough for a woman to have breast-conserving surgery . If the tumor doesnt shrink enough, a mastectomy is done. Nearby lymph nodes will also need to be checked. A sentinel lymph node biopsy is often not an option for stage III cancers, so an axillary lymph node dissection is usually done.
Often, radiation therapy is needed after surgery. If breast reconstruction is planned, it is usually delayed until after radiation therapy is done. For some, additional chemo is given after surgery as well.
After surgery, some women with HER2-positive cancers will be treated with trastuzumab for up to a year. Many women with HER2-positive cancers will be treated first with trastuzumab followed by surgery and then more trastuzumab for up to a year. If after neoadjuvant therapy, any residual cancer is found at the time of surgery, ado-trastuzumab emtansine may be used instead of trastuzumab. It is given every 3 weeks for 14 doses. For women with hormone receptor-positive cancer that is in the lymph nodes, who have completed a year of trastuzumab, the doctor might also recommend additional treatment with an oral targeted drug called neratinib for a year.
Targeting The Immune Microenvironment
TNBC and HER2-positive groups present immunogenic features for BC, with a large number of tumor-infiltrating lymphocytes and higher levels of PD-L1, which are potential immunotherapy candidates . Given the anti-tumor activity that HER2-targeted therapy can exert through the immune-mediated mechanism, immunotherapy and targeted therapy are being studied together.
3.3.1. HER2-Derived Peptide Vaccine
Vaccinations are a form of active immunotherapy in which the immune system recognizes antigens on the surface of cells. Directly attacking tumor cells and tumor stroma or indirectly resetting the immune system to antitumor detection mode are the principles of action, which enhance the sustained effectiveness of the antitumor immune response . Tumors can benefit from vaccination when conventional cytotoxic or targeted drug therapies fail .
Tumor-associated antigens , including HER2, are the basis of many vaccines used for BC. Current immunogenic HER2-derived peptides derive from different parts of HER2 molecules, such as E75 from the extracellular domain, GP2 from the transmembrane domain and AE37 from the intracellular domain . Their tumor killing effects are usually achieved by triggering the immune system to target HER2-expressing cells and induce a tumor-specific immune response .
3.3.2. Immune Checkpoint Inhibitor
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Breast Cancer: Types Of Treatment
Have questions about breast cancer? Ask here.
ON THIS PAGE: You will learn about the different types of treatments doctors use for people with breast cancer. Use the menu to see other pages.
This section explains the types of treatments, also known as therapies, that are the standard of care for early-stage and locally advanced breast cancer. Standard of care means the best treatments known. When making treatment plan decisions, you are encouraged to discuss with your doctor whether clinical trials are an option. A clinical trial is a research study that tests a new approach to treatment. Doctors learn through clinical trials whether a new treatment is safe, effective, and possibly better than the standard treatment. Clinical trials can test a new drug and how often it should be given, a new combination of standard treatments, or new doses of standard drugs or other treatments. Some clinical trials also test giving less drug or radiation treatment or doing less extensive surgery than what is usually done as the standard of care. Clinical trials are an option for all stages of cancer. Your doctor can help you consider all your treatment options. Learn more about clinical trials in the About Clinical Trials and Latest Research sections of this guide.
Escalating Therapy In The Curative Intent Settingadjuvant Treatment
Although many patients have excellent oncologic outcomes after receipt of adjuvant HER2-directed therapy and chemotherapy, others remain at considerable risk of local and/or distant BC recurrence. Therefore, subsequent clinical trials focused on strategies to further improve DFS and OS outcomes for higher risk patients . Adjuvant trials evaluating an extended course of trastuzumab , lapatinib , or bevacizumab in combination with standard chemotherapy and trastuzumab did not result in a statistically significant increase in OS compared with chemotherapy and trastuzumab alone., , The ExteNET trial noted a 2.5% DFS advantage in patients with stage II and stage III, HER2-positive EBC who received 1 year of adjuvant neratinib after the completion of chemotherapy and adjuvant trastuzumab the DFS benefit was greater in those with HR-positive, HER2-positive EBC . These results led to FDA approval of adjuvant neratinib in 2017. However, there are limited data to support the use of neratinib in patients who received pertuzumab and T-DM1 postoperatively. Furthermore, the incidence of severe diarrhea in ExteNET participants was considerable , although the development of prophylactic antidiarrheal regimens has mitigated this toxicity. Results of the landmark KATHERINE trial, which led to the FDA approval of adjuvant T-DM1, are described above.
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New Drugs And Treatment Strategies In Her2
This section reviews emerging combination therapies in HER2-positive MBC, for which HER2 is not the target. There is good preclinical rationale and early-phase clinical trials to support the study of checkpoint inhibitors, CDK4/CDK6 inhibitors , and PIK3CA inhibitors in this setting., ,
HER2-enriched tumors are immunogenic they have a higher mutational burden compared with luminal tumors, and approximately 50% are programmed deathligand-1 positive., Preclinical data were suggestive of a synergistic effect of antiprogrammed cell death protein 1 /antiPD-L1 agents with trastuzumab. Therefore, studies to determine the role of immunotherapy in HER2-positive MBC have been conducted. To date, clinically meaningful improvements in oncologic outcomes have not been noted, although research is ongoing.
Anti-HER2mTOR/PI3K inhibitor combinations
Whats The Difference Between Her2
HER2 proteins can indicate whether breast cancer cells are likely to divide and replicate. HER2-negative breast cancer is more common and means that cancer cells are not producing a lot of HER2.
HER2-positive breast cancer, on the other hand, means that the cells are producing a large number of these hormone receptors, indicating a more aggressive cancer.
- having a history of receiving radiation therapy in your chest area
- smoking or using other tobacco products
Also, while having a family history of breast cancer generally increases your personal risk of breast cancer development, HER2-positive breast cancer is not hereditary.
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What Is Targeted Therapy For Her2
When a cancer is HER2-positive, it means that the cancer cells make too much HER2 protein, which can cause tumors to grow more rapidly than with other forms of breast cancer.
Drugs that target the HER2 proteins are the primary treatment for this type of breast cancer, given along with chemotherapy. Your oncology team may refer to these medications as targeted therapy or HER2-directed therapy.
Trastuzumab and pertuzumab are the most commonly used drugs used to treat HER2-positive breast cancer. Neratinib is another drug that is sometimes given after trastuzumab.
Some other targeted therapy drugs, such as lapatinib or ado-trastuzumab emtansine , are mainly used to treat more advanced HER2-positive breast cancers.
Herceptin and Perjeta are given at the same time as chemotherapy through an IV. HER2-directed therapy is usually given over a longer period of months than chemotherapy.
Herceptin alone is usually continued after chemotherapy has finished, every three weeks for a total of one year.
Side effects for HER2-targeted therapies may include:
- sleep problems
- redness at the IV site
What To Expect When Taking Herceptin
Herceptin can only be given by intravenous infusion, which means it is delivered directly into your bloodstream through an IV or a port. The first dose of Herceptin takes about 90 minutes. After that, it only takes about 30 minutes to get other doses of Herceptin. Your Herceptin treatment schedule will depend on whether you are receiving it with other medicines. You can talk to your doctor about your treatment schedule options.
If youve been diagnosed with early-stage HER2-positive breast cancer, youll likely receive Herceptin together with a chemotherapy regimen. You will receive it for a specific amount of time.
If youve been diagnosed with metastatic HER2-positive breast cancer, you will keep being treated with Herceptin as long as you are getting benefits from the medicine and arent having troubling side effects.
Its important to know that women who are pregnant or planning to get pregnant should not take Herceptin. Herceptin can harm the developing fetus. If there is any chance you can become pregnant, you must use effective birth control while youre taking Herceptin and for at least 7 months after your last dose.
Also, women who are breastfeeding or plan to breastfeed shouldnt take Herceptin. Together, you and your doctor will decide if you should take Herceptin or breastfeed.
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Should All Her2 + Breast Cancers Be Treated
- All invasive and metastatic HER 2 positive breast cancers benefit from HER2 directed therapy. Even very small cancers appear to benefit. A U.S. study evaluated the records of 965 women with small cancers that had not been treated with HER2-targeted therapy or chemotherapy. By the end of five years, 6% of women with HER2-negative breast cancer had a recurrence compared with 23% of women with HER2-positive breast cancer.
The Approach To The Diagnosis And Treatment Of Her2
As breast cancer is a very complex disease, and the final outcome depends on the stage of the disease, the biological characteristics of the tumor itself and the initial treatment protocol, patient treatment should be optimally performed at certified Breast Units . Recommendations from the EUSOMA for the establishment of Breast Units require at least 150 newly discovered breast cancers per year . The organization of breast cancer diagnosis and treatment is based on the teamwork of different specialties gathered in a multidisciplinary tumor board whose decisions are based on current professional guidelines. The MTB comprises at least of:
- Medical oncologist
- Radiation oncologist/radiotherapist/oncology and radio-therapy specialist.
If this can be provided at the institution level, it would be optimal for the Board to include an oncology nurse, a physiatrist, and a psychologist/psychiatrist. Given the importance of the surgical oncologist for the final outcome of breast cancer treatment, the panel strongly supports and recommends the introduction of specialization in the field of surgical oncology into the curriculum of specializations for medical doctors in Bosnia and Herzegovina.
The MTB bases diagnosis and treatment decisions on current guidelines and submits them in writing to the patient and her family doctor.
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Bcbm And Leptomeningeal Disease
Going forward, urgent improvements to the current standard of care are required. Innovation in drug development and clinical trial design is essential, including further studies of HER2-targeted TKIs, optimized HER2 monoclonal antibodies that cross the BBB effectively, trials focusing on brain metastasis prevention , novel preclinical models, drug combinations, and therapeutic targets. The onus is on oncologists to enroll suitable patients on clinical trials, including those with progressive or untreated brain metastasis. Furthermore, thoughtful trial designs by experienced researchers incorporating appropriate CNS endpoints and relevant patient-reported outcomes are required.
Patients Material And Methods
A group of Austrian breast cancer specialists met in December 2020 to establish a comprehensive clinical benefit-risk profile of available HER2-targeted therapies based on recent data and to develop an updated treatment algorithm by consensus over several months in 2021.
The basis of the scientific-clinical review of the therapeutic options were data from the following sources: all studies included in the consensus statement, regulatory information on established and new compounds, scientific updates of the last years from the following symposia/congresses: San Antonio Breast Cancer Symposium, the American Society of Clinical Oncology Annual Meetings, the European Society for Medical Oncology Annual Meetings, safety profiles and efficacy data of the respective compounds, current treatment recommendations for patients with metastatic HER2+ breast cancer from various guidelines, and comprehensive clinical practice experiences of the respective experts, their teams and institutions.
A total of four scenarios were developed in which treatment strategies appropriate for specific patient profiles were evaluated. Consensus was established by detailed discussions of each scenario and by reaching full consensus .
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