HER2 Positive Breast Cancer: New Treatment Horizon
05 May 2018
Breast cancer (BC) is one of the major cancers, second most common, in females worldwide. 1.7 billion Breast cancer Cases were reported in 2012 .The ERBB gene family, known as proto-oncogene, is one of the major risk factors for BC. The protein human epidermal growth factor receptor (HER) 2, localized on chromosome 17q, is part of this family. These receptors are present on normal breast cells, the over expression or growth of these are found in nearly 30% of all BCs and is termed HER-2 positive BC. A single HER2-positive cancer cell has nearly two million HER2 proteins on its surface, which is 100 times more than a normal healthy cell. This over expression causes cells to grow and multiply more rapidly. Dimerisation (pairing) of this HER proteins is a vital step in the signalling pathway which ultimately leads to cancer cell growth in particular tissue. The HER2 have an important role in the regulation of the tumour initiating cells in BC.
The techniques currently used to evaluate HER-2/neu status in BREAST CANCER(BC) are gene-based assays like PCR or southern and slot blotting methods, non fluorescent in situ hybridization, and the latest one – fluorescent in situ hybridization technique.
- IHC test: The ImmunoHisto Chemistry test counts the number of HER2 proteins available on the cancerous cells, and rates from 0 to 3, 0 to 1+: HER2 negative; 2+: borderline; 3+: HER2 positive.
- SPoT-Light HER2 CISH test or The SPoT-Light test- “Subtraction Probe Technology Chromogenic In Situ Hybridization” is being used on fresh biopsy tissue to stain the HER2 genes, and being observed under microscope for extra copies and extra receptors on the cells. The test result could be either positive or negative.
- FISH test: The Fluorescence In Situ Hybridization test identifies the HER2 gene amplification in cancer cells and performed on biopsy tissues. It compares the HER2 gene copy to the CEP17. The FISH test ratio is 2.2 or more consider as positive and if the ratio is 1.8 or less will be considered as negative.
- Inform HER2 Dual ISH test: The In Situ Hybridization for HER2 is also used to diagnose the number of HER2 gene amplifications. the result could either positive or negative.
For HER2 positive BC, treatment is based on the diagnosis, stage of the cancer, whether it is localized or metastasized. If the cancer is localised, the first line treatment option is to remove tumour by surgical methods. Treatment option such as radiotherapy, chemotherapy, and hormonal therapy are also being used, to prevent recurrence of the tumour.
In general, among all types of cancer, chemotherapy is preferable for pre- and post- surgery by doctors (oncologists) to reduce chances of cancer recurrence. Post surgical chemotherapy is known as adjuvant therapy, and before surgery as neo adjuvant therapy.
Chemotherapy can be given in combination with an anti-HER2/neu–directed therapy trastuzumab which has evidenced reduced risk of recurrence. The HER2 positive cancer is often treated with anthracylines and taxanes along with other drugs, usually in combinations. Anthracycline and trastuzumab may cause cardiac complications; hence the combination is avoided. Drugs like paclitaxel (taxens),and docetaxel are generally given. Other cytotoxic drugs like cyclophosphamide, flurouracil capecitabine, methotrexate are also in practise.
Trastuzumab is a monoclonal antibody that specifically acts by targeting specific receptors or proteins present on the surface of cancerous cells while not affecting other normal cells. Trastuzumab binds to HER2 protein and blocks that receptor to inhibit further growth. Cardiac function needs to be monitored before starting trastuzumab and after initiating therapy as this drug have side effects on heart function.
Trastuzumab is usually given once in every three weeks usually for a year, but can vary as per patient’s condition and history of cancer.
Adverse effects include flu-like symptoms; and pounding heart beats . A major negative effect is that it can increase p27 protein which is responsible for halting cell proliferation.
Lapatinib is also a targeted therapy for the treatment of HER2 positive breast cancer. It blocks the signal transduction to cells resulting in the cell’s death. Lapatinib is given with the drug Capecitabine.
Capecitabine is a pro-drug and metabolised to 5-FluroUracil. It is a thymidylate synthatase inhibitor. This molecule inhibits the synthesis of thymidine monophosphate (active form of thymidine that is required for the de novo synthesis of DNA).
Lapatinib is a new treatment option and is still being investigated in clinical trials.
It’s another molecule with targeted therapy (MAb) mechanism just like trastuzumab. Usually, it is given with trastuzumab and docetaxel. Pertuzumab, in the pivotal phase III CLEOPATRA trial, met with limited success in prostate, ovarian and breast cancers. Trastuzumab in combination with pertuzuab and docetaxel possibly leads to less cardiac toxicity as reported.
All above drugs are currently being used in the management of HER2 BC, but some patients do not respond to the drugs different regimens are being tried in clinical trials. The use of anti-HER- 2/neu antibody therapy may have significant potential as trials are ongoing for them.
More research on trastuzumab and pertuzumab molecules is ongoing in NEOSPHERE, MARIANNE TRYPHAENA and APHINITY trials for different stages/types of breast cancer.