While most of us think of the U.S Food and Drug Administration (FDA) as simply an agency that approves drugs or regulates the foods and beverages sold in our grocery stores, less well-known is the impact the FDA could have on the prevention of major, life-threatening diseases such as melanoma, which is expected to kill more than 10,000 people in the United States this year alone.

The FDA took a major step forward in the treatment of metastatic melanoma in 2011, when it approved Yervoy (ipilimumab), the first new drug for melanoma in 13 years and the first until that time to generate phase 3 clinical trial data demonstrating an overall survival benefit. Since then, a dozen new drugs and combinations have been approved for the treatment of melanoma, with one immunotherapy combination showing a response rate of about 60 percent in patients with metastatic disease.

With a wide array of exciting new drugs and drug combinations currently in clinical trials, most notably in the immunotherapy space, the FDA will continue to play a critical role in providing patients with effective treatments for melanoma.

The FDA, however, can do more by addressing a couple of issues that would help prevent thousands of people from developing melanoma in the first place. The first is rethinking how we approve new sunscreen filter technology. Filters are the physical or chemical ingredients in sunscreen that block, absorb or reflect the sun’s harmful rays.

Most melanomas in the United States are a result of ultraviolet (UV) radiation causing damage to the DNA of skin cells. The damage to DNA triggers a reaction that leads to the creation of a pigment to protect cells from this radiation. We see that pigment as tanned skin. The same process that causes a tan also releases an addictive endorphin that can make us want to sunbathe more. This means that we crave the very substance that makes us sick — just like people who are addicted to tobacco.

Although consumers appear to have an infinite number of choices when it comes to products that protect the skin from the sun, sunscreens available in the United States are all based on technology that is more than a decade old. In fact, the FDA has not approved a new sunscreen filter in over 15 years, even though Europe and Canada have been safely using products that include newer filters for years. Some of the products available in other countries block a much broader range of UV radiation, particularly in the cancer-causing UVA (long-wave) bands.

In 2014, the Public Access to SunScreens (PASS) Coalition — comprised of industry and nonprofit partners, including the Melanoma Research Foundation (MRF) &mdash; worked with the FDA and Congress to come up with a solution to this problem. The effort resulted in a new law requiring the FDA to create and implement a timely process for evaluating sunscreen filters.

Unfortunately, the FDA’s recently released draft guidelines on sunscreen filters recommend a level of testing that is costly, timeconsuming and of questionable value. Companies can reduce this onerous burden, but only by sharing proprietary and confidential information in a public hearing, something no company would voluntarily do.

But sunscreen is just one prevention issue on which the FDA needs to focus. The other is stricter regulation of the tanning bed industry. The UV lamps in tanning beds are classified by the World Health Organization as a carcinogen in the same category as tobacco smoke. Unfortunately, these UV lamps are heavily marketed to teens and young adults, who may not be aware of their inherent dangers. Finally, late in 2015, after years of work by the MRF and others, the FDA released draft rules barring access to tanning beds for anyone under the age of 18, and requiring tanning salons to check and certify their equipment regularly. Unfortunately, a year later, those rules have still not been finalized. The delay is frustrating, inexplicable and irresponsible, and hampers melanoma prevention efforts.

Whether it’s regulating tanning beds, figuring out the best way to test and label sunscreens or approving new melanoma treatments, close and frequent conversations between the FDA, industry and advocates are important. These discussions must remain flexible and encourage innovation. Doing so will assure melanoma activists that the FDA plays just as strong a role in approving and regulating melanoma prevention products and protocols as it does in approving and regulating ground-breaking treatments.

As we continue to learn more about the causes of melanoma and its potential cure, an effective FDA will be critical to improving and protecting the health of our citizens. I encourage each of you to contact your congressional delegation and urge its members to work with the FDA to find a better process for evaluating sunscreen filters, and to support the FDA’s proposed restriction on tanning beds. Through your efforts, we can help change the melanoma landscape and save thousands of lives.

 Timothy Turnham, Ph.D., is executive director of the Melanoma Research Foundation. Prior to joining the MRF, Turnham served as chief executive officer of the Colon Cancer Alliance and director of development for United Cerebral Palsy Associations. He holds a B.A. in microbiology from the University of Tennessee, an M. Div. from the New Orleans Baptist Theological Seminary and a Ph.D. from the Southern Baptist Theological Seminary.

Articles

Speaking Out

To best help the melanoma community, the FDA must not only approve medications, but also focus on cancer prevention.

Covering All the Bases: FDA Must Focus on Cancer Prevention

Although immunotherapies have been an enormous advance for the treatment of many cancers, they come with their own set of toxicities. Patients should learn how to watch for these side effects and be ready to discuss them with oncology nursing professionals, who will know how to help.

This is the guidance shared by Jeffrey Weber, M.D., Ph.D., a medical oncologist and deputy director of the Perlmutter Cancer Center at NYU Langone Medical Center, in an interview with 

He spoke about the practical management of immune-related side effects, or adverse events (AEs), in melanoma therapy during the 34th Annual Chemotherapy Foundation Symposium held Nov. 9-11 in New York City.

Immunotherapies have their own set of AEs. What should patients and their nurses know about these conditions?

Weber detailed the side effects that might crop up in patients who are taking checkpoint inhibitors. He discussed both the broad areas of AEs for which patients and clinicians should monitor, as well as the more specific, potentially fatal AEs that can inflame individual organs.

Patients who get checkpoint inhibitors like ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and now atezolizamab (Tecentriq), which recently was approved for bladder cancer, have similarity in their immune-related AEs. There are three expected general side effects and five very specific side effects, where these drugs have the capacity to inflame an organ. Patients will get inflammation of an organ, such as the liver or the pancreas, whereas an organ right next door will be perfectly happy and unaffected, which makes it very strange.

The general side effects (patients and their) nurses should look out for are fatigue, feverishness and sweats, all of which come and go with treatment.

What are the organ-specific immune-related adverse events with these treatments?

Diffuse rashes and itchiness, and sometimes itchiness with no rash, are also a general side effect. If the rash is severe, it really must be looked at it, and if someone has desquamation (peeling) of the skin, pay special attention because — very rarely &mdash; the patient can get toxic epidermal necrolysis. This is a life-threatening condition, where the patient can die of sepsis (an invasion of bacteria). You basically slough (or shed) the skin. Finally, (patients should tell a nurse if their lymph nodes are swollen). I warn nurses that they may see diffuse swelling of lymph nodes, lymphadenopathy. If it is bilateral and diffuse, we don’t do anything about it, we just wait. If it is unilateral, we would worry about a relapse or a progression of disease, and that will get biopsied.

There is the possibility of inflammation of the liver, or hepatitis, with elevation of liver functions. We talk about elevation of pancreatic functions, amylase and lipase, which, strangely, can often be associated with no symptoms. And the patients won’t know it, but you’ll look at their labs and you’ll see the amylase and lipase very high. And if those go up high enough, you have to back off and hold (off on giving) the dose (of immunotherapy).

You can also see inflammation of the lung, or pneumonitis. And that’s a little scary. Especially with ipilimumab plus nivolumab, or with nivolumab alone, or pembrolizumab alone, you can see these fluffy, diffuse multilobar infiltrates. When patients get symptoms such as being out of breath, coughing, bringing up yellow or green sputum or spitting up blood, they need to be seen quickly. If they are developing pneumonitis on the X-ray, they need a CT scan. If the CT scan confirms it, the patient needs to be prescribed steroids. Pneumonitis is life-threatening. You need to jump on it.

You can also, not uncommonly, see inflammation of the pituitary, or direct inflammation of the thyroid. Sometimes you’ll see hyperthyroidism, followed by a burnt-out thyroid, and then the patient develops hypothyroidism that is just like Hashimoto’s thyroiditis — straight from the textbook. And you need to keep a close eye on those patients and find out what their symptoms are like, because when that thyroid burns out, they are going to need to go on (hormone) replacement levothyroxine (Synthroid). You don’t want to have that escape notice and then have all the negative side effects of having hypothyroidism that goes undetected.

Finally, the major life-threatening side effect — especially with the combination of ipilimumab and nivolumab, or with ipilimumab alone, and much less so with the PD-1 antibodies &mdash; is colitis, or inflammation of the colon. And that’s a potentially life-threatening side effect. You can have severe diarrhea, perforation of the gut, obstruction and &mdash; again &mdash; (patients need to report it, and nurses) need to jump on that.

Are there any other side effects that are cause for concern?

It’s easily treatable in its early stages, but (nurses, staff and patients must) stay in touch when (patients are) getting diarrhea. You have to aggressively manage the diarrhea.

There are the neurologic side effects. Weakness and numbness in the arms and legs means an immediate visit, because if a patient is developing Guillain-Barré or myasthenia gravis, you need to aggressively treat it. If the patient develops memory loss or behavior change, it could be encephalitis, or it could be hypopituitarism. A severe headache can be hypopituitarism and hypophysitis — way out of proportion to the swelling in the pituitary. The pituitary can go from 7 to 10 millimeters and you’ll get the worst headache of your life.

There is also inflammation of the kidneys and you can have elevated BUN/creatinine. You just have to be on the lookout for that. That’s usually easily managed by holding the drug and using steroids.

But the pneumonitis, the colitis, the neurologic symptoms — those are what give me pause. Clinicians need be on the alert and be willing to jump on toxicities quickly and not let them fester

Side Note

Immunotherapy agents have their own set of side effects, and managing them quickly and efficiently is key.

Managing Immunotherapy Side Effects in Melanoma: Quick Intervention Is Key

OVER THE PAST FIVE YEARS, the advancements in treating advanced melanoma have been staggering. Eight new drugs have been approved in that time period, including four immunotherapies and four targeted drugs.

As the cancer with perhaps the most mutations, melanoma is eminently treatable with both these types of drugs, and that has made it an excellent testing ground — and success story &mdash; when it comes to scientific innovation. In clinical trials, even more drugs are being tested today as treatments for melanoma.

But even before additional drugs reach the market, a challenge — the best kind possible &mdash; faces scientists and doctors. Every day, as they treat melanoma patients, they must decide: How do we best use and sequence this host of new drugs in the clinic? All the answers are not in yet, but experts in the field are using their experience to provide guidance. That’s the kind of wisdom that was passed along in a panel discussion hosted this summer by 

®, we present you with coverage of that talk, which outlines current questions in the treatment of advanced melanoma, along with a host of expert recommendations. This information is not just for doctors, but should also be very helpful to patients, who can consider the stage and location of their melanoma and ask informed questions of their health care teams: What mutations are expressed by my melanoma? Should I be treated with targeted drugs or immunotherapy? Should I get immunotherapy after surgery? Should I apply for inclusion in a clinical trial?

Elsewhere in this issue, we remind you that the need for melanoma prevention measures does not end in the winter, when, in many parts of the nation, the heat of the sun is at bay. We discuss a variety of strategies for keeping yourself safe from the sun’s ultraviolet rays.

In a third feature article, we look at the very rare condition of inherited melanoma. While this condition is not treated differently than other melanomas, we discuss the potential merits of knowing about a family history of the disease, and about any mutations that could predispose someone to additional types of cancer.

We round out this issue with articles on the side effects of novel melanoma treatments; some legislative efforts aimed at helping patients; a look at a measure that can increase the efficacy of at-home skin checks; and a report on whether the ultraviolet lamps used in gel manicures increase melanoma risk.

® gives you a well-rounded understanding of the issues associated with melanoma, from prevention to treatment to reducing the risk of recurrence. As always, thank you for reading.

From the Chairman

Keeping Treatment Practices Apace with Recent Scientific Breakthroughs: A Great Challenge to Face

WITH THREE “CHECKPOINT-INHIBITING” IMMUNOTHERAPIES NOW FDA-approved for the treatment of melanoma, we all need to be attuned to the unique grouping of side effects that can arise when patients take these medications.

It’s not a concern you need to dwell on if you haven’t experienced side effects that get in the way of your everyday life, but it’s something that you and your health care team should be aware of. In this special issue of 

®, we address the topic in an interview with medical oncologist Dr. Jeffrey Weber, who outlines the common and less common — but more potentially dangerous &mdash; side effects of these drugs. These drugs are relatively new, but in an unprecedented manner are rapidly expanding in use across many tumor types &mdash; faster than our ability to accurately quantify and characterize their side effects.

The approved immunotherapies for melanoma fall into the category of checkpoint inhibitors, which target certain proteins that are involved in keeping the immune system from going into overdrive. By releasing these “brakes,” the medications allow the immune system to gain power to fight the cancer. These drugs represent an incredible scientific breakthrough in the treatment of melanoma and many other cancers, but they can cause side effects, primarily due to immune activation working against normal tissue in addition to the intended cancer targets.

Typically, the immunotherapies Keytruda (pembrolizumab), Opdivo (nivolumab) and Yervoy (ipilimumab) do not cause discomfort as severe as that often sparked by systemic drugs like chemotherapies. But their side effects do have a unique and recognizable pattern. The most common are fatigue, fever and rash or itchiness. Swelling of the lymph nodes can also occur, which is not unexpected unless it’s focused in one specific area, which could indicate disease relapse. Inflammation of the lining of the gastrointestinal tract can lead to diarrhea. Check with your oncology nurse about any palliative therapies that could decrease the severity of these side effects and make you more comfortable.

Some symptoms may only be noticed by your doctor in lab tests: liver inflammation, kidney inflammation, elevated pancreatic functions or decreased functioning of the thyroid gland.

And then there are a group of more concerning symptoms. A much more serious incarnation of the typical immunotherapy rash can be a shedding of skin, which can invite bacterial infection and become lifethreatening. Other less common but potentially fatal side effects can include shortness of breath, which can signal lung inflammation, and an inflammation of the colon. Additional signs of potential danger are neurological symptoms, such as weakness in the extremities, memory loss or severe headache.

Most often, side effects can be handled with steroids or by delaying a dose of immunotherapy, in many cases temporarily. Although you may have reservations about reporting any side effects that could lead to an interruption in your treatment, your safety must be your primary concern. It’s up to you and your caregivers to contact your doctor or oncology nurse if you are having side effects from immunotherapy drugs that seem potentially serious, before they escalate into the danger zone. You are your own first line of defense when it comes to ensuring that your anticancer regimens are helping you — without causing serious and avoidable damage.

Editor's Page

WITH THREE “CHECKPOINT-INHIBITING” IMMUNOTHERAPIES NOW FDA-approved for the treatment of melanoma, we all need to be attuned to the unique grouping of side effects that can arise when patients take these medications.
 

In Watching for the Side Effects of Immunotherapy, You are Your Own First Line of Defense

Performing skin self-examinations with a partner can help with early detection of new or recurrent melanoma, according to a study conducted by researchers at Northwestern Medicine in Chicago and published online in the journal 

A total of 494 patients with a history of melanoma participated with a partner. The pairs in the study were trained on how to identify suspicious moles on the body.

“We delivered the intervention in three ways,” said June K. Robinson, research professor of dermatology and lead author on the study. “We delivered it with in-person training sessions with my research assistants using PowerPoint, a workbook that the two read in an office together and tablets that they looked at; then, they could discuss whatever they were reading or seeing.”

Pairs were randomized to one of four trial arms: control (no intervention), training with a workbook, in-person training or training with tablet. Informative sessions ranged from 20 to 45 minutes in length, and the patient-partner pairs on any of the three intervention arms learned how to recognize change in the border, color and diameter of moles. Together, they then gave the mole a score using a three-point system: 1 meaning normal, 2 meaning unsure and 3 meaning abnormal.

Robinson and her team reinforced the skills in four-month intervals over a two-year period. At each visit, data were collected through self-reported surveys that both patients and partners filled out separately, in different rooms. Both patients and partners received $20 for each assessment completed.

Among all 494 patients, 69 melanomas were identified in different individuals. Sixty-six were new melanomas and three patients had in-transit metastasis. Patient-partner pairs receiving an intervention (395 pairs) identified 43 of the melanomas successfully. However, patient-partner pairs in the control group were not able to identify any melanomas. Physicians identified melanoma in 16 different patients.

the study’s findings can be beneficial in two ways. First, skin self-examinations can decrease anxiety and reduce the number of physician visits because patients have better control and understanding of their bodies.

“Early in the diagnosis of melanoma, they are very anxious about every boo-boo being another melanoma, and so they ring the phone and try to get an appointment with the doctor to be seen immediately,” she said. “If we give them a system that they can use to enable and empower themselves, then the anxiety level starts to decrease, because they can make rational decisions about how fast they have to go see the doctor.”

The second benefit is getting the patients — who think they don’t have to worry anymore because they’re five years out from treatment &mdash; to do their own skin checks with partners. Robinson said this is crucial because the risk of developing another melanoma continues for at least an additional 10 years.

The idea of studying skin self-examinations with a partner came to life from an experience Robinson had with a male patient. The steel worker, of Irish descent, worked outside for years and had a suspicious mole on his back. While Robinson was explaining to him what to look for in the future, he said he didn’t care, and told her to “talk to [his] wife.”

It dawned on her at that moment that partners may be the best way to get people to actually check their skin. To move this study forward, Robinson hopes to make the program deliverable by an app to smartphones. It would include all the important information that can be used in recognizing a suspicious mole. Anyone who felt a mole looked peculiar could take a photo and send it to Robinson to examine. The app, she says, could promote better behaviors, since it is easily accessible.

“A lot of younger people who have melanoma are working people who don’t want to take off from work to go to the doctor over nothing,” said Robinson. “And the older people, they don’t want to travel through traffic to get to the doctor’s office for nothing. So, the reassurance that they can take and send an image with a smartphone in a way that's accessible and easy can take the program up a notch.”

Features

Checking skin with a trained partner can help to identify suspicious moles that may be skin cancer.

Partnering Up to Identify Melanoma

ERICA BRITTON has a genetic mutation associated with risk for both breast cancer and melanoma. - PHOTO BY RACHEL FESKO

WHEN ERICA BRITTON, 31, was diagnosed with melanoma at the age of 23, her family history of ovarian cancer prompted her physicians to test her for inherited mutations in the BRCA1 and BRCA2 genes. Inherited mutations in these genes, or germline mutations, are most commonly associated with increased risk for breast cancer and ovarian cancer; however, some research has also linked the mutations to an increased risk for certain skin cancers, including melanoma.

Melanoma is a form of skin cancer in which cancer cells form in melanocytes, or the cells that color the skin, such as moles. In 2016, it is estimated that more than 76,000 new cases of melanoma were diagnosed. The majority of cases are diagnosed at an early stage, and these patients have a five-year survival rate of greater than 90 percent. Although melanoma starts in the skin, it can spread, or metastasize, to other parts of the body. Patients diagnosed with metastatic melanoma have a five-year survival rate of about 18 percent.

About 8 percent of people diagnosed with melanoma have a first-degree relative who has also been diagnosed. Even fewer — about 1 to 2 percent &mdash; have two or more relatives with melanoma. These patients may have familial melanoma.

“Cases of inherited melanoma are extremely rare,” says Lynn M. Schuchter, M.D., chief of the division of hematology/ oncology and C. Willard Robinson Professor of Hematology-Oncology at Penn Medicine. “The vast majority of melanoma is sporadic.”

Everyone is at some risk for sporadic (non-inherited, or random) melanoma, but there are certain factors that increase the likelihood of getting the disease. People with fair skin that freckles or burns easily, people with blue, green or light-colored eyes, and those with red or blond hair are all at increased risk. In addition, long periods of exposure to natural sunlight or artificial ultraviolet (UV) radiation, like from a tanning bed, can increase risk. Finally, having several large or many small moles, or having a family history of unusual moles, can increase the risk for melanoma.

All of these risk factors are relevant in familial melanoma, but most familial or hereditary cancers are caused by certain germline (inherited) mutations.

“There is an increased risk for developing melanoma associated with gene mutations passed from generation to generation, but there is also risk associated with other things shared by families,” explains Pauline Funchain, M.D., a medical oncologist at Cleveland Clinic, in Ohio. “These shared things include other predisposing factors for melanoma like blond or red hair, fair skin, blue or green eyes, or shared activities like boating or other outdoor activities.”

“I am all about sunscreen and UPF clothing and hats. I don’t live my life in fear, but I am very careful about being outside.” — ROBYN COOK - Photo by PHOTO BY HEIDI SHUB

Robyn Cook, 48, and members of her family, fit many of these characteristics to a tee. Of Norwegian decent, Cook has blond hair, green eyes and fair skin, and can remember spending a lot of her childhood at a summer cabin being “fried” by the sun. Although she lives in Minnesota, she was still frequently exposed to UV radiation while she worked at a tanning salon in college. While on a vacation in Mexico in 2009, Cook’s mother questioned the suspicious look of a mole on the right side of her back. Her primary care doctor excised the mole and subsequent biopsy tests revealed that it was a stage 1 melanoma about 0.61 mm deep.

“When I was diagnosed, I had never really heard of melanoma. I didn’t know what it was,” says Cook. “My doctor told me that it was serious, but that I was OK after this first diagnosis and just had to get regular full body checks with a dermatologist.”

Cook says she drastically changed her sun behavior and that of her family, including her teenage daughter. “I am all about sunscreen and UPF clothing and hats,” Cook says. Designed to protect against the sun, such clothing is made of fabrics that absorb or reflect UV radiation, and is rated with an Ultraviolet Protection Factor (UPF) value. Clothing with a rating of UPF 40 or greater blocks 97.5 percent of UV radiation or more. “I don’t live my life in fear," Cook continues, "but I am very careful about being outside.”

Despite that, in September 2012, Cook noticed a lump in her left breast and immediately thought that she might have breast cancer. After undergoing a mammogram, ultrasound and needle biopsy, her doctors told her that she again had melanoma. However, this time, a scan of her whole body showed that the disease was stage 4 and had spread to other parts of her body. A second melanoma at a new site is called a second primary.

“When a patient has multiple primary melanomas, we often begin to wonder about the likelihood that patient has an inherited risk for melanoma,” Schuchter says. “We are also suspicious in patients with a young age of onset, those with family members with melanoma, or patients with atypical or dysplastic nevi.”

Atypical or dysplastic nevi are unusual-looking but noncancerous moles. People who have atypical moles are at an increased risk for melanoma that can develop in the mole or elsewhere on the body. The more moles they have, the higher their risk. Certain patients may be classified as having atypical mole syndrome. These patients have 100 or more moles, one or more moles that are 8 mm or larger in diameter, or one or more moles that are atypical. Other patients may be diagnosed with familial atypical multiple mole melanoma syndrome, or FAMMM. These people have atypical mole syndrome, but also have at least one first- or second-degree relative with melanoma.

Other than these risk factors, familial melanoma presents, is staged and is treated in the same way as sporadic melanoma.

“As far as we know now, familial melanoma does not alter prognosis — just the frequency with which someone may be diagnosed,” Schuchter says.

Even when clinicians are suspicious that a melanoma is familial, they do not always conduct tests to confirm whether a patient has a genetic predisposition, according to Schuchter and Jeffrey S. Weber, M.D., Ph.D., a specialist in melanoma management and cancer immunotherapy and deputy director of the Perlmutter Cancer Center at NYU Langone Medical Center.

“If someone has already had multiple melanomas and they are already undergoing intense melanoma screening or treatment, how does knowing that they have a genetic mutation help?” Weber asks. “Knowing does not change how melanoma is treated and it does not change the advice that is given to prevent future skin cancers.” Anyone diagnosed with melanoma should already be advised to practice sun-safe behaviors and to encourage these behaviors in members of their families.

However, Funchain encourages genetic testing in these patients.

“Although inherited melanoma is not typically very different from sporadic melanoma, the more important thing about identifying inherited melanoma is the ability to look for genes that may increase the risk for other cancers,” Funchain says. “By knowing what specific mutation a patient has, we have the opportunity to narrow down and more effectively address any risk for other cancers, and, potentially, save lives.”

For two decades, two genes have been linked to familial melanoma: CDKN2A and CDK4. Factors associated with an increased likelihood of having a CDKN2A mutation include an increased number of people with melanoma within a family, melanoma diagnosis at an early age and family members with multiple primary melanomas or pancreatic cancer. A study looked for these four features in 385 families in Australia, North America and Europe that included three or more people with melanoma. Researchers found that 39 percent of these families had CDKN2A mutations.

No drugs that target these mutations have been approved for the treatment of melanoma, but Ibrance (palbociclib) — which has been approved to target these genomic glitches in advanced breast cancer &mdash; is being tested in clinical trials.

After receiving her second primary melanoma diagnosis in 2012, Cook dug into the medical history of her family, including her deceased father. She found that, although it did not cause his death, her father had been diagnosed with melanoma earlier in his life.

To treat her stage 4 melanoma, Cook underwent a series of surgeries to remove metastases, began treatment with an immunotherapy drug called Yervoy (ipilimumab) and underwent Gamma Knife radiation. She also underwent testing for the CDKN2A mutation, but the tests were negative. During her recovery, her younger brother, a typically sun-safe athlete who lived in Arizona for much of his life, visited her to help. While visiting, he revealed to her that he felt a lump in his armpit, and she encouraged him to have it immediately checked out.

“He saw several physicians who said he was likely just sick and told him not to worry about it,” Cook says. “By a fourth visit to a surgical oncologist in April 2014, my brother was diagnosed with stage 4 melanoma.”

Yervoy, which worked to shrink Cook’s tumors, did not work for her brother, and he died from melanoma three days short of his 45th birthday.

Despite the fact that Cook was negative for the CDKN2A mutation, she may still have a germline mutation that makes her more susceptible to melanoma, according to Funchain. Alterations in CDKN2A and CDK4 account for only a small percentage of familial melanomas, and other genes involved are yet to be discovered.

“At the time when Cook was tested, the first papers on screening for CDKN2A had only just been published,” Funchain says. Since then, research has revealed a multitude of other genes that may increase the risk for familial melanoma, and new gene sequencing technology has made it cheaper and easier to test for multiple genetic mutations at the same time.

In Britton’s case, her diagnosis of melanoma and her family history of ovarian cancer led her physicians to suspect that she might have mutations in the BRCA genes.

One small study followed a group of 2,729 women with BRCA1 or BRCA2 mutations for an average of five years and found that women with the BRCA2 mutation had an 83 percent increased risk for developing skin cancer compared with women with a BRCA1 mutation.

Although Britton’s melanoma diagnosis was eventually downgraded to dysplastic nevus, her genetic testing showed that she was indeed positive for BRCA1, and she underwent a prophylactic bilateral mastectomy to lower her chances of getting breast cancer later in life. Her sister underwent genetic testing for BRCA mutations, as well.

Research is slowly emerging about other gene mutations associated with familial melanoma, including BAP1, MITF, POT1 and others. Each of these genes may also be associated with increased risk for other cancers. For example, mutated BAP1 has also been linked with a higher risk for mesothelioma and ocular melanoma.

According to Funchain, the most important thing that anyone can do if they may be predisposed to familial melanoma is connect with a genetic specialist or genetic counselor.

“Hereditary genetics is not a topic that many practitioners are fully versed in, so it is an important step to get hooked up with a genetic counselor,” Funchain says. “If you see someone who knows genetics really well, they can tell the patient about what other cancers might be involved with each mutation and can send them to the right people to be screened.”

Patients can also turn to organizations such as FORCE — Facing Our Risk of Cancer Empowered &mdash; a national non-profit organization that works to create awareness around and advocate for research to support people dealing with hereditary breast, ovarian and related cancers.

For Britton, knowledge about her BRCA mutation was able to inform her sister’s decision to get screened, and, if she has children in the future, will inform theirs as well. She also keeps a close watch on her skin and continues her regular visits to a dermatologist.

Cook has now gone almost three years without evidence of disease and is living a full and fulfilling life, she says. Although her screening for the CDKN2A mutation was negative, her experience has factored into her daughter’s decision-making when it comes to sun safety and skin cancer prevention.

Overall, for melanoma prevention, the advice is the same for someone with or without familial melanoma, according to Weber.

“Stay the heck out of the sun and see a dermatologist every six months,” he says.

A tiny fraction of melanoma is inherited.

A Rare Breed: Inherited Melanoma

CELINA McHUGH , PATIENT - PHOTO BY MARIA DeFORREST

Growing up along the Delaware Bay, Celina McHugh spent a lot of her time outdoors. Never did she think that, at 37 years old, she would be diagnosed with stage 1 melanoma. But that became her new reality when her doctor found a lesion on her shin. McHugh underwent surgery — a wide resection &mdash; and was followed every six months for about eight years with skin exams, chest X-rays and labs.

“When I was a kid, there was no sunscreen. It was basically suntan lotion,” says McHugh. While sunscreen did exist in America in the 1970s, there was little public awareness about its importance. “When I was a teenager, they came out with the Hawaiian Tropic oil, which is what I used,” she continues. “I grew up in Lewes (Delaware). I went to the beach a lot. I can’t tell you how many blistering sunburns I had. I mean, it takes one blistering sunburn (in childhood or adolescence) to increase your chances of melanoma by 50 percent — and I had several.”

Sunscreen is now something she wears every single day, 12 months of the year. It’s a strategy every person should add to their routine, she says, and dermatologists agree.

“I think there is a bit of a myth that sunscreen is only important when we go to the beach or take a tropical vacation in the winter,” says Jason Givan, M.D., a spokesperson for The Skin Cancer Foundation. “Really, you should be thinking about sunscreen on a daily basis.”

The sun gives off ultraviolet A (UVA) and ultraviolet B (UVB) rays all of the time. UVA is a longer-wave ray of light than UVB. It can be harmful because, unlike UVB, people often don’t realize they are being exposed to it. For instance, it can pass through clouds, rain and even windows of homes and cars. People won’t see a burn or tan with UVA, like they do from UVB, which is more prominent in the summer months.

The closer a person gets to the equator, the more direct and more intense the sun they receive. People who live in countries close to the equator often don’t see a lot of seasonal variation, and therefore may have more exposure, too.

Population studies and statistics show that 90 percent of all skin cancers are caused by overexposure to UV radiation.

“A major thing to remember is that, although we don’t have the levels of UVB in winter that we do in the summer, UVA is almost exactly the same, and so without the signals of either a burn or a tan developing, one isn’t really aware of the UVA, and that’s pretty constant,” adds Amy Newburger, M.D., a member of the American Academy of Dermatology. The face, ears and neck are the parts of the body most at risk during winter months, but skin cancer experts say the eyes, lips, hands and head also need protection in colder climates.

Much like a body of water in the summer, snow and ice are reflective. Snow reflects up to 80 percent of the sun’s UV light, so the rays hit you twice, further increasing your risk of skin cancer. This means that people who enjoy winter activities such as skiing, snowboarding and ice skating should take precautions. Further, the higher you are in altitude — for instance, on a mountain &mdash; the more exposure you will receive.

“When you’re at high altitudes, the ultraviolet radiation is greater,” says Newburger. “There’s less of the atmosphere to block it. They say that every thousand feet above sea level you’re going to have a 5 percent increase in the amount of ultraviolet radiation you get.”

Newburger also notes that people often think they aren’t getting too much sun because they don’t feel hot due to colder temperatures in winter months. That, she says, is a misconception.

Those who are most at risk of developing skin cancer, both in summer and winter, are people who work outside, are naturally fair-skinned, have previously had skin cancer and/or have a family history of the disease.

There are several tactics that can be easily applied in winter to help reduce a person’s risk. These include: wearing a broad-spectrum sunscreen with an SPF of 15 or higher every day; staying in the shade, especially between the hours of 10 a.m. and 4 p.m.; and covering skin that would otherwise be exposed with tightly woven clothing, wide-brimmed hats, scarves, gloves and UV-blocking sunglasses. Givan adds that thick denim, synthetic clothing and apparel in darker colors add a layer of protection. Newburger suggests opaque lipstick for women and lip sunscreens for men.

Skiers and snowboarders may want to consider wearing ski masks and goggles for greater protection, and covering their ears, as well. The larger the frames, the better protection to the sensitive skin around the eyes.

“After my first diagnosis, I was really careful and wore sunscreen every day on my face and my arms, even if I was just going in to work or to the store,” says McHugh. “I probably got less serious about it as the years progressed.”

She relapsed 13 years after her initial diagnosis — this time with metastatic melanoma. Her oncologist found a tumor in her groin, which was removed through a radical lymph node dissection. Another tumor was found in her back. With stage 4 melanoma, McHugh entered a clinical trial testing a combination of the immunotherapies Yervoy (ipilimumab)and Opdivo (nivolumab). While the drugs came with severe side effects, she says they worked.

“After my relapse, I now have sunscreen on my face, an SPF 25 at least, all year long,” she adds. “I also wear a hand cream that has an SPF 25. It might be 20 degrees outside, but you still need sunscreen.”

People can also reduce their risk of skin cancer by staying out of tanning beds. Often, people will try to get a “base tan” before leaving for a warm winter vacation or to keep a tan year-round, but each visit to an indoor tanning bed can increase the chances of getting melanoma, as well as non-melanoma skin cancers. Studies have found a nearly 60 percent increase in the risk of melanoma in people who have been exposed to UV radiation from indoor tanning. Tanning booths emit primarily UVA radiation.

The Skin Cancer Foundation recommends examining your own skin head-to-toe every month and seeing a physician once a year to have a professional skin exam done. Those people who have a family history of melanoma or who may have had several blistering sunburns in their lifetimes may want to go more frequently.

“The key is to get someone familiar with their own skin,” Givan says. “If you examine yourself every day, you may not notice a subtle change. Much like weight loss, if you see someone all the time you may not notice that they lost 10 pounds, but if you see them a month later, you will notice that.”

Newburger says people should watch out for a changing mole or a pimple that doesn’t heal, and persists and bleeds. They should also follow the ABCDE rules for recognizing a suspicious mole, which can be found on both the Skin Cancer Foundation and American Academy of Dermatology websites. The rules encourage people to consider suspicious any moles that are asymmetrical, have irregular borders, are not uniform in color, have a diameter greater than 6 mm and/or are evolving in size, shape or color.

Additionally, there are areas that a person can’t see themselves, like the scalp and back. This is where it can come in handy to have a friend or spouse take a look.

“You have to look out for yourself and, if there is something that makes you uncomfortable, make sure that it is biopsied, because I have seen a lot of doctors who say, ‘Oh, we’ll just watch it,’ and it turns out to be positive,” says McHugh. “I’d rather have a scar than have something I looked at for years and say, ‘Darn, I should have had it biopsied.’ ”

McHugh understands firsthand how a melanoma diagnosis can change your life. Her immunotherapy treatment and the steroids she was given left her extremely fatigued, with muscle pain and weakness in her arms and legs. She also was unable to work for a period of time. While she is now back to work, putting in half days, she still gets shortness of breath and has inflammatory arthritis.

As of January 2016, her scans were clear, and she has been classified as having no evidence of disease for 11 months. She has taken on two goals: to spread melanoma awareness and to grow old.

“It only takes one cell to become metastatic anytime later, and it’s there, it’s dormant in your body,” McHugh explains. “It’s one of those cancers where they don’t say ‘remission.’ They just say ‘no evidence of disease.’ It’s a waiting game. I know that mine will never be gone. I just have to keep waiting and see what my scans show.”

Even in winter and cold climates, you need to protect your skin from the sun’s ultraviolet rays which can lead to cancer.

A Ray of Truth: Protecting Skin from Melanoma in Cold Climates

The measures available for treating advanced melanoma were sparse in March 2011, when Yervoy (ipilimumab) became the first drug in 13 years to earn approval from the U.S. Food and Drug Administration (FDA) for treatment of the disease. Since then, the toolbox of drugs has rapidly expanded.

“In the last five years, there have been FDA approvals for 12 new agents and combination therapies for patients with advanced melanoma,” said Keith T. Flaherty, M.D., who moderated a Peer Exchange panel titled “Treatment of Advanced Melanoma and Basal Cell Carcinoma.” The panel was hosted over the summer by the website OncLive®, a sister publication to CURE®.

Novel melanoma treatments fall broadly into two categories. One encompasses agents that target cell signaling in the MAP kinase (MAPK) pathway, which is a chain of proteins inside a cell that transmits messages. The other category includes agents that target immune system proteins.

Several more melanoma treatments are poised to emerge from the pipeline. But even without additional advances, data on the optimal way to incorporate these novel drugs into practice lag far behind the breakneck pace of approvals. On the panel, experts in the field offered guidance based on their experience with the latest drugs.

What sets melanoma apart from other malignancies is its high mutational burden and immunogenicity, meaning its ability to react to certain substances by waging a strong immune response. Jeffrey S. Weber, M.D., Ph.D., explained how the interplay between these two factors makes melanoma highly susceptible to targeted therapies. “If you look at average mutational load, melanoma is No. 1 of all tumors, with a median of about 600 to 700 individual non-synonymous mutations,” he said.

Non-synonymous means the mutation is found only in tumor-cell DNA, where it encodes peptides and protein fragments not expressed by normal cells. This is important because melanoma grows from melanocytes, or pigmented skin cells, that have undergone dangerous changes, and one function of melanocytes is to present antigens, or foreign substances found in the body, to immune cells. When the melanoma melanocytes present the “alien” mutationencoded antigens to T cells, it triggers an immune response. “A lot of mutations means the cells grow out of control and make cancers, (but the cell) contains within it the potential seed of its own destruction…by the immune system,” Weber said.

Georgina Long, Ph.D., M.B.B.S., identified the three most common genetic drivers of melanoma as BRAF V600 mutations, NRAS mutations and NF1 alterations. Approximately 40 percent of patients with cutaneous melanoma (disease that occurs on the skin) have a BRAF mutation, up to 25 percent have an NRAS mutation and about 12 percent have an NF1 mutation. Other driver mutations include MEK1, KIT, CTNNB1 and GNAQ.

Long said BRAF V600 mutations are the most critical aberrations to test for when evaluating patients for treatment, since they are common and drugs exist that can target them. Long’s institution also routinely tests for RAS, NF1 and KIT aberrations, in case patients are eligible for clinical trials testing drugs that target those mutations. The frequency of driver mutations varies according to melanoma site and sun damage. As Jason J. Luke, M.D., explained, “There are melanocytic melanomas that can arise in other parts of the body, including acral lentiginous melanomas (which can occur on the palms or soles or under fingernails) or mucosal melanomas, as well as uveal melanomas (which occur in the eye), and we see a different mutational spectrum in those types of tumors.”

For example, while 40 percent of patients with cutaneous melanoma have a BRAF mutation, just 5 percent of patients with mucosal melanoma do. Conversely, 20 percent of patients with mucosal melanoma have a KIT mutation, compared with only 2 percent of patients with cutaneous melanoma. Clinical trials are evaluating therapies in melanoma patients that target mutations other than BRAF. “We haven’t cured melanoma, and there’s a lot of work still to be done,” Luke said.

Circling back to the interplay between mutational burden and immunogenicity, Luke said he and his colleagues are investigating whether certain genetic aberrations compromise the immune system’s ability to attack melanoma cells through pathway disruption. The findings could lead to novel targeted therapies that hone in on signaling pathways instead of driver mutations.

“The toughest issue right now in melanoma medical oncology (is) what to do with stage 3 patients,” Luke said. These are patients whose melanoma has spread to lymph nodes or lymphatic vessels in a region of the body close to the original cancer site. The first approach is excision of the primary tumor with wide margins and removal of regional lymph nodes.

Jonathan S. Zager, M.D., the lone surgeon on the panel, discussed how he weighs whether a patient with stage 3 or stage 4 (distant metastatic) melanoma is eligible for resection (surgery): Does the patient have bulky nodal disease or a tumor encroaching on an important vein or artery? “I can resect anything, but…you have to think about the functional and cosmetic consequences of the resection,” he said.

For patients with unresectable disease, clinicians must decide whether to use therapeutics to try to shrink the tumor until it becomes resectable; and for patients with resectable disease, clinicians must decide whether using an adjuvant, or post-therapy, regimen to reduce the chances of recurrence outweighs its toxicities. Outside of a clinical trial, the choice between targeted mutation therapy versus immunotherapy hinges on whether the tumor has a BRAF mutation.

According to Zager, BRAF inhibitors shrink unresectable melanoma faster than immunotherapy in patients with a BRAF mutation. “The tumor doesn’t have to go away — it just has to make surgery easier for the surgeon and for the patient,” he said. In the adjuvant setting, acquired resistance is a concern with targeted mutation therapies, but it’s less of a worry in the neoadjuvant, or pre-treatment, setting. Long said, “In the neoadjuvant setting, where you’ve got a patient and you need a quick reduction, you don’t worry so much about acquired resistance.”

For tumors that do not have BRAF mutations, Zager said he often uses the vaccine T-VEC. In a phase 3 trial that included patients with unresected stage 3b to 4 melanoma, T-VEC produced a significantly better durable response rate than a different immune-stimulating drug, granulocyte macrophage colony-stimulating factor (16.3 percent versus 2.1 percent, respectively). “It’s extremely well-tolerated,” he said, describing adverse effects as similar to mild or moderate flu symptoms that last for one or two days after injection.

Zager said T-VEC is a great option for patients who cannot or will not use systemic therapy. Weber described T-VEC as something of a “niche drug” that can help prime an immune response before administering a PD-1 checkpoint inhibitor alone, or added to other immunotherapies.

Immunotherapy combinations have shown good efficacy in trials, and the FDA has approved Yervoy plus Opdivo for patients with BRAF-positive disease. Long reviewed results from the phase 2 CheckMate-069 trial, which assessed a Yervoy/Opdivo combination in patients with stage 3 unresectable or stage 4 metastatic melanoma.

At the 2016 Annual Meeting of the American Association for Cancer Research, investigators reported that the two-year overall survival (OS) rate was 64 percent overall and 69 percent in patients whose melanoma did not include a BRAF mutation. “This is pretty incredible stuff,” Long said.

Ongoing trials are attempting to combine a BRAF inhibitor with immunotherapy. Luke said early data from phase 1 trials of such combinations have indicated lackluster response rates.

The panel had a spirited discussion about the risks and benefits of adjuvant high-dose Yervoy. In October 2015, the FDA expanded Yervoy’s indications to include a 10 mg/kg adjuvant regimen for completely resected melanoma in patients with cancer that had spread to lymph nodes near the original site, and was larger than 1 mm in those nodes. Approval was based on findings from a phase 3 trial that randomly assigned adults with stage 3 melanoma to highdose Yervoy (n = 475) or placebo (n = 476). Participants were required to have undergone complete resection and to have never received prior systemic therapy. Median recurrence-free survival was significantly longer in the Yervoy arm than in the placebo arm (26 months versus 17 months, respectively).

“That’s a 25 percent reduction in the risk of recurrence,” said Long, whose home country of Australia has not approved the adjuvant regimen. She also noted that OS data were not yet mature; but since then, updated findings from the trial demonstrated that, at a median of 5.3 years’ followup, the five-year overall survival rate was 65.4 percent with Yervoy compared with 54.4 percent in the control arm. Long pointed out that the high dose used in the trial was very toxic. Five treatment-related deaths occurred during the trial, but Weber noted that there were fewer deaths over time with Yervoy than in the placebo arm.

Although the two experts disagreed over the meaningfulness of the on-study deaths, they agreed that clinicians must weigh the study’s findings cautiously when making treatment decisions. Long said she doubted Australian oncologists would find that the benefits of using highdose Yervoy outweighed the serious risks.

Luke said that, even if the trial found an OS benefit with high-dose Yervoy, he was not sure the toxicities, some of which could make patients ineligible for subsequent therapies, would be worth it. “There are ongoing trials investigating agents in this space, so I would really prioritize the idea that patients should participate in those,” he said.

The paradigm for patients who have unresectable metastases is still evolving. Luke said the thinking used to be that mutation-targeting therapy was more suitable for high-volume BRAF-positive melanoma, which might be symptomatic, and that immunotherapy was better for low-volume disease. “I think our recent data are starting to say that at least there’s equipoise, or perhaps it’s the reverse,” he said. Luke explained that newer data show patients with less than three sites of disease, normal lactate dehydrogenase (LDH) levels (which indicate the health of the body's tissues) and good performance status have better longterm outcomes with mutation-targeting therapy than those with bulky disease. Recent studies have also found that patients with bulky disease and higher LDH levels fare better with immunotherapy combinations than many other patient groups.

On the mutation therapy front, Long discussed longterm data from the phase 3 COMBI-d trial that included 423 people, randomly assigning patients with BRAFpositive metastatic melanoma to Tafinlar plus Mekinist or to Tafinlar monotherapy. “The three-year survival in a normal LDH patient on dabrafenib and trametinib is 70 percent,” Long said. The panel concurred that trials of new immunotherapy regimens should perform posthoc analyses of OS data by LDH level and that, going forward, trials should include LDH breakdowns in their protocols.

“We need targeted therapy options for other patients,” Flaherty said. He brought up binimetinib, a MEK inhibitor being studied in patients with NRAS mutations. Long said a phase 3 study that compared binimetinib with the chemotherapy dacarbazine showed benefits in progression-free survival and response, but not in OS. “But it is a wonderful foundation, because there’s definitely a signal there,” she said. MEK inhibition also disrupts signaling along the MAPK pathway, which Long noted is “constitutively active in the majority of melanomas, even if they’re not BRAF-mutated.” Other molecular targets being explored are CDK4/6 and CDKN2A.

“Melanoma is an exciting cancer that’s really forging the way of treating cancer in a novel way. I’m really keen to continue to pursue that with clinical trials of novel combinations, because I would like to see the melanoma cure rate increase,” Long said, adding that she believes about one-third of patients are being cured.

Luke predicted that the best is yet to come, but said that progress depends on patients participating in clinical trials. Weber urged trial sponsors to let investigators mine their clinical trial data, which could lead to new discoveries.

Growing scientific insights have led to the swift development of treatments for advanced melanoma, leaving doctors to iron out details about their application.

Melanoma Dec. 2016 | CURE