Breast cancer and the marvels of chemotherapy
Breast cancer is the second most commonly diagnosed cancer in women, just after skin cancer. The average risk of a woman in the United States developing breast cancer sometime during her life is about 12%. Despite the common misconception, both females and males can develop breast cancer. Patients have much more options and a significantly greater outlook today than they did 100 years ago when surgery was the only treatment option. Radiation, such as gamma rays, can now be used to treat breast cancer by causing physical breaks in the DNA. In cancerous cells with damaged DNA, cell division cannot occur, which results in the cell's death. Another treatment option available today is chemotherapy, which treats cancer by using different chemical compounds. This article will focus on explaining what chemotherapy is, how it applies to breast cancer, and an overview of some of the successful drugs to battle this aggressive cancer.
The Gruesome History of Breast Cancer Operations
In October 1877, William Halsted traveled to Europe as many aspiring American surgeons would do in order to learn refined European surgical techniques. During this same time period, German surgeon Richard von Volkmann was working on a technique to operate on breast cancer. While working at Volkmann's clinic in Germany, Halsted observed how Volkmann performed increasingly meticulous and aggressive surgeries to remove these breast tumors. Despite the surgeries being extensive and exhaustive, the breast cancer still relapsed and would recur months or years after the procedure.
During the 1880s at Johns Hopkins University, Halsted devised a surgical procedure that he termed a radical mastectomy to remove local malignant lumps in the breast. This radical mastectomy is a similar operation as Volkmann's, but would dig even deeper into the breast cavity. Halsted would remove the pectoralis major and minor (colloquially known as pecs), a large muscle group responsible for movement of the shoulder and hand. Even with his radical mastectomy procedure, the cancer would still recur leading him to cut even deeper into the chest. At this point, he would slice through the collarbone and remove a small cluster of lymph nodes located beneath it. This macabre operation would leave the breast cancer patient permanently disfigured with recovery often taking several years. Without the pectoralis major, the shoulders would cave inward making it impossible to move the arm forward or sideways. Additionally, removing the lymph nodes would block the flow of lymph, resulting in the arm to swell with accumulated fluid. What Halsted did not realize at this point in the late-1890s was that tumors could metastasize to other organs in the body. Someone with metastatic breast cancer would not be cured by a radical mastectomy regardless of how aggressive the operation is. In contrast, someone with a small, local breast tumor could benefit from the operation, but a far less invasive procedure would have been enough. Despite how painful and aggressive Halsted's radical mastectomy was, 20-year survival rates increased from 10% before its advent to 50%.
What is Chemotherapy?
The primary objective of chemotherapy is to kill cancer cells using drugs and various chemical compounds. Almost every chemotherapeutic drug has a unique way in which it kills cancer cells. Unlike radiation, chemotherapy reaches the entire body since it is usually administered by taking a pill or through an intravenous (IV) injection. The benefit of this is that it can reach cancer cells that have metastasized, or spread, to other parts of the body; however, this also means that healthy cells can be killed by using these chemotherapeutic methods. This is why there are many side effects associated with chemotherapy, although the benefits of this treatment option certainly outweigh those side effects.
Traditional chemotherapeutic agents interfere with mitosis, which is the division of cells, but cancer cells widely vary in their susceptibility to these agents. The most important cause of treatment failure when using chemotherapy is due to resistance. Cancerous cells produce significant amounts of pumps, called p-glycoprotein, that moves the drug from inside the cell to the outside. Another reason for the development of this resistance is because of gene amplification, where multiple copies of a gene are produced by cancer cells. This amplification overpowers the effect of drugs that reduce the expression of genes involved in replication. With greater copies of the gene, the drug will not be able to prevent all gene expression and therefore the cell can restore its proliferative, or cell-dividing, ability.
In 1965, James Holland, Emil Freireich, and Emil Frei hypothesized that cancer chemotherapy should be treated with a combination of several drugs, each with a different mechanism of action. The cancer cells could theoretically mutate and become resistant to one drug, but it would be much harder to develop resistance if a combination of drugs were concurrently active. This gave rise to what is now known as combination chemotherapy. Not only does combination chemotherapy reduce any potential resistance, but the drugs are often used at a lower concentration, which helps reduce its toxicity.
Application of Chemotherapy to Breast Cancer
Breast cancer is different from other cancers in that its proliferation, or growth, is partially driven by hormones like estrogen. Estrogen enters cells and binds to a receptor in the breast that tells it to grow. Many breast cancers take advantage of this receptor to snag the estrogen signal and use it to grow bigger. Tamoxifen is one chemotherapeutic drug that was synthesized in the 1990s. It functions by binding to the estrogen receptor in the breast so that estrogen can't bind to it and send its growth signal to the cancer cell. The primary disadvantage is that over time, the cancer cell becomes resistant to the estrogen receptor. This means that it continues to grow even without the estrogen signal, significantly reducing the efficacy of tamoxifen. Therefore, even with tamoxifen, patients might still require other chemotherapy treatments.
Trastuzumab (shown in orange) binds to domain iV of HER2 (depicted in blue). When bound, trastuzumab reduces the expression of HER2 that signals the cell to stop dividing.
Trastuzumab is another drug that was introduced in 1998 that has also been a huge breakthrough. It is a targeted therapy, meaning that the drug functions locally near the tumor so that fewer healthy cells are killed. This also means that there are fewer side effects when using these particular compounds. Trastuzumab acts like an antibody, which is molecules in our immune system used to target and bind to harmful invaders like bacteria and viruses. Trastuzumab binds to a molecule on the surface of some breast cancers called human epidermal growth factor receptor 2 (HER2). HER2 is another growth receptor receptor, similar to the estrogen receptor, that is overexpressed in one in five patients with breast cancer. Trastuzumab blocks HER2, similar to how tamoxifen blocks the estrogen receptor.
The last chemotherapeutic drug for breast cancer that will be talked about here is called docetaxel. This drug was approved for medical use in 1995 and is regarded as one of the most effective and safe drugs. Docetaxel functions by binding to microtubules, which play a major role in mitosis by moving chromosomes to the respective ends of a dividing cell. Since microtubules do not disassemble in the presence of docetaxel, they accumulate inside the cell. This buildup of microtubules can initiate apoptosis, or cell death. Since a hallmark feature of cancer is aberrant cellular division and growth, it is not surprising that doxetaxel is used in other kinds of cancer like head and neck cancer, stomach cancer, prostate cancer, and lung cancer. As mentioned earlier, combination chemotherapy is a very popular option in treating all types of cancers. With regards to breast cancer, it is common to see two or three chemotherapeutic drugs (like docetaxel and doxorubicin) being used in combination for local breast cancer cases.
Overall, the advances made in cancer research in the last century have been remarkable. Someone with breast cancer in the 1800s or early-1900s did not have much to look forward to other than a radical mastectomy with a low success rate that would leave them permanently disfigured. Today, breast cancer patients can expect much more, such as a combination of treatments tailored to the disease they have. The chemistry behind these modern treatments options, like chemotherapy, targets the biology of tumor cells with extreme accuracy and precision.
