Herceptin as a targeted therapy for breast cancer

As cancers are becoming more and more resistant to standard chemotherapy and other forms of treatments, different kinds of drugs have to be developed to more specifically tackle these issues. One treatment that is becoming more prevalent is targeted cancer therapy.

Targeted cancer therapy blocks a specific molecular target, either by inhibiting a specific protein or gene that is important for cancer cell growth, progression, or metastases (spread of cancer). [1] In contrast to the traditional chemotherapy that targets all rapidly-proliferating cells, be it normal or cancer cells, targeted therapy explicitly thwarts cancer cells, and does not cause damage to rapidly-dividing normal cells. [1]

Like standard chemotherapy, targeted therapies also consist of many different subtypes, including hormonal therapies, signal transduction inhibitors, gene expression modulators, apoptosisA type of cell death in which a series of molecular steps in a cell lead to its death. This is one method the body uses to get rid of unneeded or abnormal cells. The process of apoptosis may be blocked in cancer cells. Also called programmed cell death. (cell-death) inducers, angiogenesis (new blood vessel formation) inhibitors, immunotherapies, and toxin delivery molecules. [1]

Immunotherapies

One of the more common and readily available types of targeted therapy is the immunotherapies, which are monoclonal antibodies that exhibit inhibitive effects on over-amplified genes, such as human epidermal growth factor receptor 2 or simply referred to as HER-2. [2] This gene is known to be up-regulated on the surface of epithelial cells and is responsible for cellular growth, differentiation, as well as tumorigenicity, especially in gastric and breast cancer cells. [2–6]

Over-expression or gene amplification of HER2 is implicated in approximately 20-25% of all invasive breast cancer and typically associated with poorer prognosis.2 HER2-positive breast cancer is regarded as the second-poorest prognosis as compared to the other subtypes and is also generally corresponded with poorer disease-free and overall survival rates. [3]

Since up-regulation of HER2 is observed in many types of cancer — especially breast cancer, which is also associated with poorer prognosis — treatment that specifically targets this gene may be of particular interest and will confer great therapeutic benefits for these groups of patients. Trastuzumab, or Herceptin, a recombinant humanized monoclonal antibody that directly targets the extracellular domain IV of HER2 was the first targeted cancer therapy ever to be approved by the Food and Drug Administration (FDA), with clinical evidence showing high success rates for treating breast cancer. [3, 5]

Herceptin has been approved by more than 125 countries as standard therapy for HER2-positive patients with locally advanced or metastatic breast, gastric or gastroesophageal junction (GEJ) cancer. [7]

Herceptin can be administered either intravenously (into a vein) or subcutaneously (under the skin); many clinical studies have revealed that serum concentration of the subcutaneous Herceptin is on par to that of the intravenous counterpart, both of which could achieve a complete pathological response. [8] Based on recent statistical reports, more than two million breast cancer patients were treated with Herceptin, 80,000 of which received it subcutaneously. [9]

Furthermore, the subcutaneous forms of Herceptin can also either be delivered via a hand-held syringe from a subcutaneous vial or a single-use injection device (SID), which is less time-consuming and associated with less pain, discomfort and other related side-effects according to patients’ feedbacks. [9]

As an adjuvant therapy

Herceptin is typically administered as adjuvant therapy in patients who either display over-amplified HER2 with positive nodal status alone or negative nodal and hormone-receptor status (ER/PR negative) together with one high-risk feature. High-risk features include tumor size more than 2cm, tumor grade 2 or 3 and age less than 35 years. Adjuvant Herceptin is generally given as a regimen consisting of Doxorubicin, Cyclophosphamide, and either Paclitaxel or Docetaxel. It can also be administered in conjunction with Docetaxel and Carboplatin or solely after receiving multi-modal Anthracycline-based treatments. [10]

In patients with over-amplified HER2 metastatic breast cancer, Herceptin is to be administered in conjunction with Paclitaxel as the first-line therapy, while it is to be delivered as a single agent for HER2-positive patients who had undergone at least one chemotherapeutic regimen. [11] Moreover, those with HER2-positive metastatic gastric or gastroesophageal junction adenocarcinomaCancer that begins in glandular (secretory) cells. Most cancers of the breast, pancreas, lung, prostate, and colon are adenocarcinomas. without prior treatment are recommended to have Herceptin along with Cisplatin and Capecitabine or 5-Fluorouracil.

According to research studies, Herceptin should be administered for one year with a one-week or three-week interval, depending on the regimen. [10]

Three mechanisms of Herceptin on cancer cells have been proposed: [3,10]

• It can lead to degradation of HER2 on cancer cells;
• It can lure immune cells to HER2-over-expressed tumor sites, referred to as antibody-dependent cellular cytotoxicity (ADCC);
• The most established action of this drug is its ability to inhibit MAPK and PI3K/Akt pathway, which eventually leads to cell cycle arrest and termination of cell growth and proliferation.

Are there side effects?

Side effects commonly found in breast cancer patients receiving Herceptin include fatigue, fever, increased cough, difficulty breathing, nausea, vomiting, infusion reactions, diarrhea, headache, rash, neutropenia (low number of neutrophils), anemia and muscle pain. [12] In the worst-case scenario, it can result in cardiotoxicity but is typically reversible. [13]

The most common side effects related to Herceptin for metastatic gastric cancer include diarrhea, fatigue, neutropenia (low number of neutrophils), anemia, stomatitis (inflammation of mouth and lips), weight loss, upper respiratory tract infections, fever, thrombocytopenia (low number of platelets) and mucosal-related inflammation. [12]

Targeted cancer therapy, such as Herceptin, serves as a promising therapeutic option since it can specifically impede certain over-expressed proteins or genes in malignancy, especially in breast and gastric cancers. This drug is typically delivered post-chemotherapy or an adjunctAnother treatment used together with the primary treatment. Its purpose is to assist the primary treatment. to chemotherapy, which leads to cancer cell death via several cellular mechanistic actions.

Adverse side effects are typically mild, and mostly are gastrointestinal-related symptoms; however, in the worst-case scenario, it can lead to cardiac problems. Thus, prevention of such adverse events can be avoided by close monitoring of the patient throughout and after the course of the therapy. [14]

Despite the possible occurrences of adverse side effects, clinical evidence has shown that Herceptin is well-tolerated. [7] It also has been approved as the standard treatment in treating HER2-positive cancers along with other chemotherapeutic agents due to the increased disease-free, progression-free, as well as overall survival rates of this drug. [2,5]