Melanoma 2013: Update on Anti-Cancer Therapies
About the Lecture
Melanoma is the 4th most common cancer in men and 5th most common cancer in women. Melanoma is a cancer of the skin but can also occur in the eye. When small and local it can be treated with surgery and is often cured. Melanoma can sometimes recur and spread to other organs, called metastatic melanoma and then needs systemic treatment. Chemotherapies have been less effective in this type of cancer with a great need for more targeted approached. Some of the newest targeted approaches including those that boost the patient’s own immune system are discussed. This is a disease in which research is a key to solving some of the mysteries and there are many ongoing studies that are revealing more about the molecular nature of the disease as well as specific mechanism to block its growth. The newest treatments, clinical trials, successes and failures are discussed along with hope for future treatments.
John A.Glaspy, MD, MPH, is board certified in internal medicine, hematology and oncology. He is a Professor of Medicine, Division of Hematology Oncology at the David Geffen School of Medicine at UCLA. He is the Associate Chief of the Division of Hematology-Oncology in the UCLA Department of Medicine and also the Vice-Chair for UCLA’s Jonsson Comprehensive Cancer Center Scientific Protocol Review Committee. He holds the Estelle, Abe, and Marjorie Sanders Endowed Chair in Cancer Research. During the course of his career, Dr. Glaspy has authored more than 300 articles, abstracts, and book chapters and conducted numerous studies in a variety of areas including stem-cell transplant diseases, diet, cancer-related anemia and fatigue, ovarian cancer and melanoma.. He has received numerous awards and honors, including being named one of the “Best Doctors in America.” Dr. Glaspy has many important roles at UCLA that include seeing patients. He has specialties in a variety of cancers including women’s cancers, breast and ovarian, as well as in melanoma.
This is a summary of a presentation presented on July 9, 2013.
For a long time, research into treatment approaches for malignant melanoma seemed to make little progress. However, over the last five years we have made tremendous strides in understanding this disease, and we are very hopeful that over the next five years our efforts will continue to lead to more effective and durable treatment approaches.
There was a 619% increase in the incidence of melanoma between the years of 1950 and 2000. Within this same period, the mortality rate also increased by 165%. The good news is that over the past decade although the incidence of melanoma is increasing, most likely due to more early-stage forms that are diagnosed, we have been able to treat these early stage melanomas with surgery, and there has been a decline in mortality. There are 55,000 new cases of melanoma annually, which makes it fifth most common cancer in men and the seventh most common cancer in women. There are approximately 7,900 deaths per year due to melanoma. It is the second leading cause of loss of productive years due to cancer because it tends to occur in younger people.
Up until recently, melanoma was differentiated into four categories: (1) acral-lentiginous melanoma, which occurs on the hand or food only, (2) superficial spreading melanoma, (3) lentigo maligna melanoma, and (4) nodular melanoma. Some of this categorization is changing as we learn more about the molecular nature of melanoma.
Risk Factor and Causes
We have known for a long time that ultraviolet radiation (UV) exposure from the sun is a factor in the development of melanoma. Individuals with a history of sunburns are at higher risk. It is Interesting to note that men in the United States tend to get melanoma on their left arms and women tend to get it on their right arms; however, in the United Kingdom, the reverse is true. This is presumably from sun exposure to the arms when riding in cars. Also, melanoma has been diagnosed among psoriasis patients treated with UVA light exposure approximately 15 years earlier.
There are also genetic risk factors, which include fair skin, red hair, and individuals who are unable to tan. This is especially true of people whose ancestors may have migrated from higher latitude places with less sunlight such as the Nordic countries. Individuals who have multiple nevi (moles) are also at higher risk. If there is a family history of melanoma, you have twice the risk of developing it, which accounts for about 10% of all melanoma patients. There are also specific gene mutations, e.g., the CDKN2A (cyclin-dependent kinase inhibitor 2A) or CDK4 genes, which are associated with familial atypical multiple mole melanoma (FAMM). In addition, mutations in the melanocortin-1 receptor are also associated with increased risk of melanoma. Individuals with a personal history of melanoma are, unfortunately, at increased risk for additional melanomas.
Melanoma develops as abnormal melanocytes, which are those cells in the skin that protect the body. Melanocytes are designed to be resistant to damage because they are the cells on the outside of the body that come face-to-face with the “harsh environment” of the world. When your skin is exposed to the damaging rays of the sun, your melanocytes produce melanin (pigmentation) to protect the body. You can think of melanocytes as our bodies’ “armor;” thus, they are built to be tough and indestructible. It is exactly this feature that makes abnormal melanocytes (melanoma cancer cells) difficult to kill. As with normal melanocytes, the malignant melanocytes are quite resistant to destruction.
Education can be very important in preventing melanoma. Because Australia has a very high incidence of melanoma, they have made a concerted effort to inform their citizens about the importance of protecting their skin from the sun. The country has done an outstanding job of educating the population about exposure to the sun; it has even built covers over school playgrounds to provide shade and reduce sun exposure to children. Why does Australia have such a high incidence of melanoma? We do know that there is high UV exposure in the southern hemisphere, and there is a hole in the environmental ozone layer, but that hole sits over Antarctica, not over Australia. The most probable reason for the high rate of melanoma in Australia is that it is a racially homogenous population of very light-skinned people who are more susceptible to the harmful effects of the sun and developing melanoma. The indigenous people who might have been more protected are close to being extinct; the continent is now primarily inhabited by immigrants who migrated from Northern climates with cloudy weather and are not genetically prepared for the elements.
The sun emits different kinds of light: visible light you see, infrared light you feel as heat, and invisible ultraviolet (UV) radiation. It is the UV radiation part of light that affects our skin the most. There are 3 types of UV rays:
- UVA: A stands for Aging. UVA radiation penetrates deep into the skin and is responsible for premature aging of the skin and skin cancer. Tanning beds can emit 2 to 5 times more UVA radiation than the sun.
- UVB: B stands for Burning. UVB radiation is stronger than UVA radiation. It mainly affects the outer layers of the skin, causing sunburns, premature aging of the skin, and skin cancer. These rays are strongest during the summer months – especially between 11 a.m. and 4 p.m.
- UVC: UVC radiation is the strongest, most dangerous form of UV light. However, they are stopped by the earth’s atmosphere and do not reach earth’s surface.
We have learned that UV radiation can trigger two distinct mutagenic (cancer causing) activities related to the development of melanoma. UVA causes a G to T transversion and UVB and UVC causes transition mutations at cytosine containing dipyrimidines (e.g., p53 and CDKN2a). These mechanisms are important in the development of melanoma and are both crucial; understanding these mutations provides important data that researchers previously did have and allows us to develop new treatments.
Familial melanoma has been an important source for understanding more about the genetic problems that cause melanoma. Specifically, xeroderma pigmentosum is associated with difficulty in repairing genetic (DNA) damage after the skin has been affected. The familial atypical mole melanoma (FAMM) syndrome is linked to a CDN2a mutation and a CDK4 mutation. Both of these affect the regulation of proteins relevant in tumor growth and suppression and identify potential targets for treatment.
Staging and Prognosis
There is an elaborate staging system for melanoma. Stage I and stage II melanomas are treated with surgery. To avoid a local recurrence of the melanoma a wide margin of clear, clean tissue around the site, is necessary. Based on the results of multiple clinical trials, the standard of care for this margin is one inch or three centimeters. Depending on the size and depth of the melanoma, these surgeries can be more extensive than other surgical procedures and often require plastic surgery to repair the damage. Stage II melanoma patients are sometimes offered other treatment, known as an adjuvant treatment to help stave off the development of widespread disease that may come from microscopic cells that have already escaped from the original tumor prior to surgery, depending on prognostic factors. In stage III melanoma, we know that cancer cells have escaped from the primary tumor because there are positive lymph nodes, meaning microscopic cancer cells have reached the lymph nodes. It is unclear whether these cells have gone beyond the lymph nodes; in some cases they have and in others not. As researchers, we want to develop adjuvant treatments for stage III patients to prevent the disease progressing to stage IV. In Stage IV, the disease has already spread to other parts of the body or organs. When we stage melanoma, we look at a number of prognostic factors, including tumor thickness, ulceration, presence of lymph nodes, LDH (lactate dehydrogenase) levels, and the site of metastases. The stage of disease does accurately predict the length of survival: the lower the stage, the greater the chance of long-term disease-free survival; the higher the stage, the greater the chance of mortality from the disease.
Treatment and New Understanding of Melanoma – A Paradigm Shift
Research oncologists are currently undergoing a paradigm shift in how we think about classifying cancer. Rudolf Ludwig Karl Virchow (1821-1902) was the first person to review rationally and organize cancerous tumors. He evaluated thousands of tumors cells and wrote a book that classified them. His classification recognized that the tumor of origin was the defining characteristic of the disease, thus breast cancer when it metastasized to the lung or liver is not treated as a lung or liver cancer, but still as a breast cancer. This classification led to many advances and understandings in treatments. However, as we have advanced in our understanding of molecular biology, we have learned that tumors have their own molecular identities apart from the site of origin. As such, tumors from different organs of origin may have more similarities than differences, and we may need to undergo a significant shift in the paradigm that has existed for the past 100 years in how we conceptualize tumors. Our goal is to have a molecular understanding that will lead to different and more targeted treatments.
For many years patients with stage IIb through stage III melanoma received high-dose alpha interferon therapy, which is a biochemotherapy; they were just observed, or they were put on one of several clinical trials. Around 2004, researchers concluded that no randomized clinical trial had demonstrated superiority of treatment over the best supportive care. Biochemotherapy was determined not to be superior to chemotherapy. Researchers determined that high-dose interleukin 2 (IL-2) could have a role. High dose IL-2 has not had any randomized control trials, but it was approved by the FDA because we observed that long-term survival was higher for those patients who received it. It has high toxicity and high costs associated with it. IL-2 has more side effects than interferon, and it must be given in the intensive care unit. Our conclusion has been that clearly there is a need to understand the disease biology and develop rational therapies.
The paradigm shift underway artificially breaks down two approaches to the treatment of melanoma. In the first approach, research is focused on what is going wrong in the cells that produce the melanoma and treatments are investigated that will target the tumor, thus altering its ability to replicate and progress. The second approach has been to see how to make the host for the disease as inhospitable as possible by using immunotherapy to help the body’s immune system to eradicate the disease. There is no reason to believe that one or the other of these approaches are mutually exclusive and, in fact, as the secrets of melanoma are uncovered there may well be different approaches for different kinds of disease and also combinations.
There have been a variety of targets identified across the continuum of the development of abnormal cell growth in melanoma. Some of these include BRAF, CDKN2A loss, PTEN loss, increased CDI, and other changes such as the loss of E-cadherin and increased expression of N-cadherin, αVβ3 integrin, and matrix metalloproteinase 2 (MMP-2). All of these may be potential targets where interventions can occur throughout the continuum of melanoma development. It is very complicated, and we are just beginning to understand how these work. However, there have been a couple of pathways that have been identified in the signaling of cancer cells to grow and/or fail to die when they are supposed to die. The signaling can occur at the level of receptors that sit on the surface of the cell like antennae, and there can be signaling from proteins within the cell. There is a receptor called the tyrosine kinase receptor that when turned on it sends signals to RAS that, in turn, sends signals to two branches. One is the mitogen-activated protein kinase pathway (MAPK), which is important in the proliferation of cell growth. The other is the phosphatidyl-inositol 3 kinase (PI3K) pathway that is important to the survival of cells and apoptosis (planned cell death). The RAS is stimulated, and it also turns on BRAF. What is important in this molecular model is that approximately half of all melanomas have a mutation in RAS and turns on BRAF permanently.
A large amount has been learned over the past few years. Some of the initial drugs were not effective but did not disapprove the theory. There is a lower chance of BRAF mutations in melanomas that come from chronic sun damage. What has become clear is that different types of targets will be needed for different types of melanomas. Several of the drugs have shown dramatic responses in their ability to turn off BRAF. However, there have also been side effects such as more squamous cell cancers, as many cells have BRAF, and it clearly has a role in other domains as well. So far, the main problem with the drugs developed for BRAF inhibition has been that patients develop an “acquired resistance,” which means that the cells find ways around the BRAF inhibition, and the cancer begins to progress again. The average time to progression is about eight months. There is ongoing research at UCLA by Dr. Roger Lo, who is investigating the pathways of resistance. He does this by doing repeated biopsies on patients’ tumors that have progressed. This research is helping us understand how tumors can resist the drug vemurafenib and is helping us develop drugs that will block these resistances. The other toxicities in these drugs include joint pains (60%) skin rash (50%), fatigue (50%) and skin squamous cell carcinomas/keratoacanthomas (25%). Another drug has been identified that blocks the development of squamous cells and also extends the time to progression. One issue that we need to resolve is how to develop combinations of drugs that have optimally desirable outcomes. We know that if too many drugs are given the toxicities can add up, so our goal is to develop drugs that combine targets without increased toxicities. The good news is that there are many of targets in melanoma, and only some of these have been exploited.
The other line of research has been focused on how to make the patient (host) less hospitable to the cancer. The idea behind this is to enable your immune system to work better in its ability to destroy cancer cells. T-cells can, when they want to, kill a cancer cell. However, if the T-cell recognizes the cell as part of the body, then it will not attack and kill it. Bodies have dendritic cells which are supposed to take information from the environment of a person (or host), break it down and tell the T-cell which cell is an enemy/foreign cell, thus directing the body to send T-cells after it and destroy it. One problem has been that the body often recognizes cancer cells as “not the enemy” and thus they are left to grow and develop. The approaches that have been tested have included creating vaccines that help the dendritic cells better recognize the cancer cells from normal cells.
Another approach has been directed at understanding how cancer cells tell T-cells to turn off their response. CTLA-4 appears to be the mechanism involved in telling T-cells to stop identifying and sending out directions to kill cancer cells, thus diminishing the immune’s response to melanomas. Research has been focused on developing CTLA-4 blocking antibodies. Ipilimumab is one of these. It is less toxic that interleukin 2. About 20% of patients receiving this drug are doing well, which is about one in five patients. The problem right now is that the researchers have not identified which patients will do well and who will not. This is an important area for additional research. Recently we have determined that the mechanism, PD-1, tells T-cells to stop killing the cancer cells. In clinical trials, an anti-Pd-1 antibody is being tested. There are many more approaches like these being evaluated.
Our next steps are to develop better predictors of which patients get which approach, targeted or immune therapy. Another goal is to develop more targeted treatments and figure out how to keep the cancer cells from getting around the treatment approaches. Most likely, it will not be targeted versus an immune approach, but rather a combinatorial therapy–improvements in immunotherapy in addition to better-targeted approaches. A lot has happened in the past five years, and we expect that even more advances in the next five years as we better understand this disease at a molecular level. In addition, treatment approaches that apply to specific subtypes of melanoma will probably also apply to various subtypes of other cancers and vice-a-versa, allowing a shift in how cancers are characterized but, more important, the creation of therapies that can be applied to multiple types of cancers based on their molecular structure. We are very hopeful in that research in other cancers will lead to innovations into melanoma.