Early detection and Advanced Targeted Drug Therapies for HER2 positive breast cancer
Baishakhee Bishoyi1, Harshita Jaiswal1, Yash Shah1, Manoj Dikkatwar2, Radhika Bindu1*
1Parul Institute of Pharmacy, Parul University, Vadodara, Gujarat, India.
2Amity Institute of Pharmacy, Amity University, Uttar Pradesh, Lucknow Campus, India.
*Corresponding Author E-mail: radhikasaddu94@gmail.com
ABSTRACT:
HER 2 positive breast cancers are the aggressive subtype of breast cancer which can be treated completely if early detected. According to the National Cancer Institute, localized or stage 1 female breast cancer patients have a relative survival rate of 99% and they can survive for more than 5 years after diagnosis but only 63.1% cases are diagnosed at this stage. In later stages when it's diagnosed, the relative survival rate becomes 29%. The overexpression of HER2 proteins can be detected by early diagnosis and screening through advanced technologies like 3D mammography, Positron Emission Mammography, Molecular breast imaging, Contrast-enhanced mammography. The specific diagnosis can be done by Immunohistochemistry (IHC) and Fluorescence in situ hybridization (FISH) for confirmation of this type of breast cancer. Biomarkers such as Her2 heterogenicity, Her2 expression, Her2 mutations, Hormone receptor (ER positivity, PR positivity), PIK3CA mutation, PTEN, PD-L1, TIL, BRCA, miRNA can be used for detection of breast cancer. With successful early detection, which will be used to diagnose early and start the treatment as early as possible. Recently FDA has approved various individual and combination medications for treating the HER2 positive breast cancer and there are further research studies and clinical trials are going on to get more impactful treatment for providing complete cure of the deadly disease.
KEYWORDS: HER2 Positive Breast Cancer, Early Detection, Screening Techniques, Specific Diagnosis, Advanced Targeted Drug Therapies.
INTRODUCTION:
What is Breast Cancer?
In 2020, Breast cancer has become the world’s most commonly diagnosed cancer according to the International agency for Research on Cancer . In India, it accounts for 26.3% of all cancers in women1,2. Women of age 25-40 have been greatly affected by this3. 1 in 28 women has a chance to develop breast cancer during their lifetime. 1 in 22 women are likely to develop breast cancer during their lifetime in urban areas, as compared to rural areas where 1 in 60 women will develop breast cancer in their lifetime4,5. Cancer is a disease in which certain body’s cells develop uncontrollably and spread to other parts of the body.
When this occurs in the breast tissues, it is known as Breast Cancer.
Burden of The Disease:
Among Indian women, breast cancer is the commonest cancer overall2. In 2018, 1,62,468 new cases and 87,090 deaths were reported for breast cancer in India3. A recent report published by National Cancer Registry Programme (NCRP) estimates that the number of cancer cases is likely to increase from 13.9 lakh in 2020 to 15.7 lakh by 2025, an increase of nearly 20% and 47% by 2040.1,4
Female breast cancer has now become the main cause of incidence of cancer in 2020 with the appearance of 2.3 million new cases. It accounts for 11.7% of all the cancers and holds 5th position for world’s total cancer mortality with 6.85 lakh deaths.1
What is Her2 Positive Breast Cancer?
Risk factors that one cannot change are getting older, race, genetic mutations (BRCA1 or 2), reproductive history, having dense breasts, personal history of breast cancer or certain non-cancerous breast diseases, family history of breast or ovarian cancer, previous treatment using radiation therapy, women who took drug diethylstilbestrol (DES)
Current Research on Early Detection:
Survival of breast cancer for at least 5 years after diagnosis ranges from more than 90% in high-income countries, 66% in India and 40% in South Africa12. Early detection and treatment have proven successful in high-income countries and should be applied in countries with limited resources where some of the standard tools are available. The three pillars toward achieving these objectives are, health promotion for early detection, timely diagnosis, and comprehensive breast cancer management. Breast cancer and related deaths can only be prevented and cured when it is early detected. When cancer is in an early stage and not metastasised, it can be cured completely and improve the patients’ outcomes. It can be done by various diagnostic methods and self-examination. Women at high risk must undergo screening process to avoid the severity of breast cancer.13,14,15
There is some research going on looking at ways to increase and develop breast cancer screening options. National Cancer Institute (NCI) is funding a large-scale randomised breast screening trial, the Tomosynthesis Mammographic Imaging Screening Trial (TMIST), to compare the number of advanced cancers detected in women screened for 5 years with 3D mammography with the number detected in women screened with 2D mammography.
NCI Supported Research Programs16
· Breast Specialised Programs of Research Excellence (Breast SPOREs)
· Cancer Intervention and Surveillance Modelling Network (CISNET)
· The Confluence Project, NCI’s Division of Cancer Epidemiology and Genetics
· Breast Cancer Surveillance Consortium (BCSC)
· Cancer Biomarkers Research Group; Early Detection Research Network (EDRN)
· The Consortium for Imaging and Biomarkers (CIB) and Consortium for Molecular Characterisation of Screen Detected Lesions
Traditional Diagnostic Technique17
Mammograms are the type of diagnosis in which low dose x-rays are done and it helps detect breast cancer at an early stage. But sometimes they miss certain types of cancers or it may lead to overdiagnosis. Recently a newer technique known as 3D mammography (digital breast tomosynthesis) is available in some diagnosis centres which can be helpful for better diagnosis of breast cancer. Women between 40- 44 have the option to start screening with a mammogram every year. Women above the age of 45 should get mammograms every year.
Breast Ultrasound:
Breast Ultrasounds are helpful in diagnosing cysts, lumps or any abnormal changes in breasts which cannot be identified by mammograms. This is done by using sound waves to picturise the breasts. This can differentiate between fluid filled cysts and solid masses. Ultrasound is also helpful in getting the biopsy results for cancer patients.
Automated Breast Ultrasound:
It is an advanced technology that allows you to take hundreds of images of the entire breast to get more pictures of suspicious areas.
Breast Magnetic Resonance Imaging (MRI):
Radio waves and strong magnets are used in Breast MRI to take detailed images of the breast from inside. It is helpful in determining the extent of breast cancer. Sometimes it gives false positive results that’s why it is not recommended in patients with average risk of breast cancer.
Advanced Empirical Breast Imaging Tests17
Molecular Breast Imaging (MBI)/ scintimammography/ breast-specific Contrast-enhanced mammography:
It is a nuclear medicine imaging process in which radioactive chemicals are injected into the blood and a special camera is used to see inside the breast. Mainly it is used for follow up on breast problems. It can also be helpful to determine the extent of breast cancer. But it exposes the whole body to radiation; so, cannot be used for screening every year.
Positron Emission Mammography:
This process uses a form of sugar attached to a radioactive particle which is injected into the blood for detection of cancer cells. It can detect small clusters of cancer cells within the breast in a better way.
Contrast-enhanced mammography (CEM)/ Contrast-enhanced spectral mammography (CESM)
This test uses a contrast dye containing iodine which is injected to the vein just before two sets of mammograms. This contrast can be helpful for showing the problems in the breast.
Optical Imaging Tests:
Light is passed through the breast tissues and then the measurement of light returns or passes through the tissues is the measure of abnormalities in this technique.
Electrical Impedance Imaging of Breasts:
This scans the breast for electrical conductivity because Breast cancer cells conduct electricity differently from the other normal cells. This test can be used to help in the classification of tumors that are found on screening with mammograms.
Elastography:
The breast cancers tend to be firmer and stiffer than the surrounding breast tissue. This test might prove to be useful in detection of the area that is cancerous or non-cancerous tumor.
Specific Diagnosis For Her2 Breast Cancer7
There are various tests used to detect HER2-positive breast cancer.
1. Immunohistochemistry (IHC): This test includes a chemical dye to detect the HER2 proteins. Scores from 0 to 3 shows presence of HER2 proteins. Score 0-1 indicates HER2 negative, score 2 indicates borderline and 3 indicates HER2 positive. If the score is borderline, then the FISH test is done for further confirmation.
2. Fluorescence in situ Hybridisation: This test involves special labels which link to HER2 proteins. Then specific chemicals are added which can further change the colour and glow when it comes in contact with HER2 proteins. In this test, either positive or negative results are shown. So, it is the most accurate test for HER2 positive breast cancer. But it is expensive and time taking so the IHC test is preferred first.
Some research results have shown that HER2 positive breast cancer can turn in to HER2 negative with time and vice versa. Biomarkers such as Her2 heterogenicity, Her2 expression, Her2 mutations, Hormone receptor (Estrogen Receptor, Progesterone Receptor), PIK3CA(phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) mutation, PTEN (Phosphatase and tensin homolog), PD-L1(Programmed Death Ligand 1), TIL(Tumor Infiltrating Lymphocytes), BRCA(Breast Cancer gene 1 or 2), miRNA(micro RNA) can be used for detection of breast cancer.18
New Targeted Treatment Options For Her2 Breast Cancer:
In about 1 in 5 women with breast cancer, the cancer cells have too much of a growth-promoting protein known as HER2 on their surface. These HER2-positive breast cancers grow and spread more aggressively. Different types of drugs have been developed that can target the HER2 protein and can treat the overexpression and amplification of HER2 gene.19
The FDA has approved a numerous targeted therapy for treatment of HER2 positive breast cancer including:
1. PHESGOTM, Genentech, Inc. (Pertuzumab, Trastuzumab and Hyaluronidase-Zzxf)
· It is a subcutaneous injection.
· The initial dose recommended for PHESGO is pertuzumab, trastuzumab, and hyaluronidase 1200 mg, 600mg, and 30,000 units respectively administered subcutaneously over approximately 8 minutes, followed every 3 weeks by a dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase administered subcutaneously over approximately 5 minutes.
· It got FDA approval on Jun 29,2020. It is indicated in Neoadjuvant, HER2-positive, locally advanced, inflammatory, or early stage along with chemotherapy.It can also be used with docetaxel to treat HER2 positive metastatic breast cancer that has not been treated with anti HER2 therapy or chemotherapy20,21.
2. Enhertu, AstraZeneca and Daiichi Sankyo (Fam-trastuzumab deruxtecan-nxki)
· The FDA approved this drug on 20 December 2019.22
· It is available in Intravenous infusion. The recommended dose is 5.4mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.
· It is used to treat unresectable and metastatic HER2 positive breast cancer that has been treated with 2 or more anti HER2 therapies.23
3. Tukysa, Seattle Genetics, Inc.(Tucatinib):
· FDA approved this drug on April 17, 2020 in combination with trastuzumab and capecitabine.
· Class – Tyrosine kinase inhibitor
· It is available in oral form. The recommended Dose of tucatinib is 300mg taken orally two times a day in combination with trastuzumab and capecitabine (1000mg/m 2 given orally twice daily on days 1-14 of a 21-day cycle) until disease progression or unacceptable toxicity .
· Main indication for adult patient with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases receiving one or more anti HER2 treatment regimen previously in the metastatic conditions.24,25
4. NERLYNX, Puma Biotechnology, Inc. (Neratinib Maleate)
· FDA approved this drug on February 25, 2020.
· In adult patients Neratinib is used in combination with capecitabine for either advanced or metastatic HER2 positive breast cancer who previously had two or more treatment regimens in the metastatic setting.
· Neratinib is available in oral dosage form.
· It is the irreversible inhibitor of EGFR, HER2, and HER4
· The dose recommended for neratinib in advanced or metastatic breast cancer is 240 mg (6 tablets) given orally once daily with food on days 1-21 of a 21-day cycle with capecitabine (750 mg/m2 given orally twice daily) on days 1-14 of a 21-day cycle until progression of disease or unacceptable toxicities.26,27,28
5. Kadcyla (Ado-trastuzumab emtansine)
· FDA-approved the drug on May 3, 2019.
· It is introduced for the treatment of advanced HER2 positive breast cancer
· Intravenous dosage form is available . The dose of ado-trastuzumab emtansine is 3.6mg/kg given in the form of intravenous infusion in every 3 weeks (cycle of 21- day) for a total of 14 cycles for EBC patients, until there is recurrence of disease or unacceptable toxicity.29,30
CONCLUSION:
HER2 breast cancer is a type of cancer in which HER2 proteins are overexpressed and turn to be an aggressive subtype. This may result in death of the patient if it is diagnosed in a later stage and treatment might not be sufficient to cure the patient. So, an early diagnosis and screening with mammograms and specific diagnosis with IHC (Immunohistochemistry) and FISH (Fluorescence in situ Hybridisation) is recommended for the women with high risk of breast cancer. Then the new FDA approved targeted advanced drug therapies such as Pertuzumab, Trastuzumab and Hyaluronidase-Zzxf (PHESGO™, Genentech, Inc.), fam-trastuzumab deruxtecan-nxki (ENHERTU), Tucatinib (Tukysa), Neratinib Maleate (Nerlynx), Ado-trastuzumab emtansine (Kadcyla) can be helpful in complete eradication of HER2 breast cancer. We hope for a better and healthy future for the survival of cancer patients and further research studies are going on for the same.
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Received on 08.01.2022 Modified on 17.06.2022
Accepted on 24.11.2022 © RJPT All right reserved
Research J. Pharm. and Tech 2023; 16(5):2205-2209.
DOI: 10.52711/0974-360X.2023.00362