It starts as a tiny dark spot on your calf or the crook of your neck or your back. It’s probably blotchy, like a Rorschach test, and if a doctor notices it, she is likely to take a second look. “I’d like to examine this one more closely,” she might say about the mark on your skin that you’d perhaps never even noticed. And it’s often good news to hear a doctor say that, because if you catch this little mass of dark, feisty cells before they spread, the inkblot can’t seep into your body and stain your liver or bones or brain with cancer.
While relatively rare, with 21 new cases per 100,000 people in the United States each year, melanomas are the most dangerous form of skin cancer that humans develop. They begin when melanocytes, cells that produce and contain the pigment melanin and dictate the tone of a person’s skin, mutate and start dividing too quickly, forming these telltale blotches. But once a melanoma has advanced from being an isolated group of cells on the skin and has sent scouts to other parts of the body, it’s notoriously hard to treat, despite its small size.
“Gram for gram, melanoma is the most deadly form of skin cancer,” says Stanford dermatologist and melanoma program director Susan Swetter, MD. “Differences in survival drop dramatically with only a few millimeters of increased tumor thickness on the skin.”
Over the past five years, however, a new generation of melanoma drugs has emerged that may change the cancer’s deadly reputation. At Stanford and around the country, basic researchers are revealing weak spots in melanoma cells that treatments can target, and physicians like Swetter are shepherding these new approaches through trials and into their clinics, extending patients’ lives.
“This is absolutely the most exciting time in my career for treating melanoma,” says Paul Khavari, MD, PhD, the chair of dermatology at Stanford.
At the same time, scientists are learning more about what makes people more prone to developing melanoma and — time and time again — placing the majority of the blame squarely on exposure to ultraviolet radiation, mainly the sun and artificial sources of ultraviolet light, such as tanning beds. Fortunately, regulations on tanning beds are tightening, public health initiatives on the dangers of tanning are ramping up, and compounds are being discovered that lessen the damage ultraviolet radiation can wreak on cells. For the first time in recent memory, scientists are hopeful that both the incidence and mortality of melanoma could soon start declining, after steadily increasing for the past four decades.
When they’re taught how to recognize potential melanomas among the constellation of dots on patients’ bodies, medical students are often told to think of the cancers as the “ugly ducklings” of skin spots. While small, regularly brown moles rarely pose a threat, spots that are asymmetric with uneven borders and various colors are more alarming.
For Trista McNeill, a director at eBay and an active runner and swimmer, concerning-looking moles were nothing new: She has fair, freckled skin; spent her childhood outside (often without sunscreen); and had two moles removed from her face as a teenager. But in 2007, when she was 37, an odd-looking spot on her skin started bleeding. In cases like McNeill’s, a biopsy of the suspicious spot sent off to the lab will reveal whether it’s cancer. If it is melanoma, its thickness, some microscopic features, and, mostly, whether it’s begun to spread to draining lymph nodes will dictate what happens next. The earliest stages of melanoma, when confined to the skin, as McNeill’s was in 2007, are straightforward to treat: Simply removing the cells from where they’ve nestled into the skin and checking the region’s lymph nodes to see if melanoma has spread is usually enough. And about 84 percent of melanomas are diagnosed when they’re still in this contained stage, according to the National Cancer Institute.
For some patients, though, the story doesn’t end here. Take McNeill: She had occasional skin checks to ensure her melanoma wasn’t reemerging. She went scuba diving in Mexico, the Philippines and Palau, diligently slathering sunscreen all over herself before each dive to prevent another episode of cancer. Nothing ever appeared. But in early 2014, nearly seven years after her initial diagnosis, McNeill — while attending the South by Southwest art and technology conference in Austin, Texas — felt an ache in her side. “It started hurting so badly that I thought I must have a gallstone or something,” she recalls. In an emergency room in Austin, scans revealed that her liver and lungs were dotted with melanoma. “It was completely shocking,” McNeill says. “It had been seven whole years, so I thought I was pretty much in the clear.”
Once melanoma has moved to other organs, at which point it is termed metastatic, the news is often dire for patients — or at least it was. “Metastatic melanoma has been known as the chemotherapy-resistant cancer, and we previously had extremely ineffective therapies for advanced disease,” says Swetter. “To see a cure in patients whose melanoma had spread was extremely rare, until now.”
For the latter part of the 20th century, metastatic melanoma was most often treated with the chemotherapeutic drug dacarbazine. But dacarbazine works in only about 15 percent of patients, and it shrinks their tumors only temporarily. Among those people with the most advanced melanomas who were treated with the drug, only 2 percent were alive six years later, a 1984 study found.
In 1998, the Food and Drug Administration approved interleukin-2, which treats metastatic melanoma by revving up the activity of the patient’s immune system to fight tumors. But, once again, the drug works for only a select few: Trials conducted before the drug was approved found that less than 7 percent of patients went into remission after taking IL-2. And it carries with it a host of serious side effects.
But just after the turn of the millennium, some of the first large, genetic studies of melanoma started to be published. About half of all skin melanomas, researchers found, had mutations in a gene called BRAF. The protein encoded by the mutated gene makes cells divide too quickly and prevents them from dying. If they could block that protein, scientists realized, they might be able to put the brakes on melanomas. At the same time, other research teams started to learn more effective ways of harnessing the power of the immune system to fight cancers like melanoma.
Over the past five years, that research has paid off. In 2011, the FDA approved ipilimumab, an immune drug, and vemurarenib, which blocks mutated BRAF, for use in metastatic melanoma. In 2013, the regulatory agency approved two more drugs targeting pathways related to BRAF: dabrafenib and trametinib. Then, in September 2014, another immune-based melanoma treatment won approval: pembrolizumab, followed by nivolumab in March 2015.
For McNeill, the timing of her metastatic disease couldn’t have been better. “If you have to have melanoma, now’s the best time,” one doctor told her. Back at Stanford, after her emergency room diagnosis in Texas, McNeill saw not only Swetter, but a team of doctors from multiple disciplines, including medical oncology to guide drug selection and coax her tumors to shrink, and surgery to remove her ovaries when they became affected by the cancer. But things kept looking worse: In June, only a few months after her cancer had returned, she started having trouble controlling one of her feet. An MRI revealed that the melanoma had spread to her brain and was affecting her motor cortex — the part of the brain that oversees the movement of the rest of the body.
“I realized at that point that I had a formidable foe and that I still had a lot of fighting to do,” says McNeill. Radiation oncology was added to the list of departments teaming up on her case; they gave her a 15-day course of whole-brain radiation. Luckily, the tumor began to shrink. That’s when McNeill started to get good news. Genetic testing revealed that her melanoma cells had mutations in BRAF and expressed PD-L1, a protein involved in the immune system. Knowing this helped her doctors choose the right drugs to attack her tumors. She was started on two of the targeted therapies that have been approved only since 2013: dabrafenib and trametinib.
“In the past, the median survival for stage-4 disease has been six to nine months,” Swetter says. “Now, I have patients who are four or five years out with advanced melanoma on the newer targeted drugs and immunotherapies and still in complete remission.” At least 40 percent of her patients are surviving for the first few years after a stage-4 melanoma diagnosis, she estimates. There’s still room for improvement, though, and luckily, there are a growing number of clinicians turning their attention toward developing next-generation drugs for melanoma.
“After decades of treatment failures, melanoma has become a cancer that’s being actively studied again,” Swetter says. “Prior to the last decade, researchers and clinicians alike became discouraged with the dismal response to treatment for advanced disease, and fortunately for patients this has changed.”
Driven by basic research
Research in a Stanford basic biology lab has provided a better understanding of why melanoma is so good at evading most treatments. In 2010, Irving Weissman, MD, the director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine, discovered that a subset of melanoma cells have a protein called CD271 jutting out of their surface.
To study these CD271-studded cells further, Weissman’s research group turned to samples from patients’ melanomas, rather than mice with the cancer. “Almost everybody uses a line of mice prone to melanoma that’s been bred for so many generations it doesn’t resemble anything you see in humans,” he explained.
Weissman and postdoctoral scholar Alex Boiko, PhD, took the CD271-studded cells from human melanoma biopsies performed at Stanford (depending on the patient, 2-40 percent of the total melanoma cells carried CD271) and implanted them in immune-deficient mice. Almost three-quarters of the CD271-carrying cells took root in the rodents, causing melanoma. But less than one in 10 of the non-CD271-containing cells could do the same. CD271, Boiko and Weissman concluded, was a marker for cancer stem cells — cells that are able to give rise to a new tumor.
But that wasn’t all Weissman and his colleagues found about the newly identified melanoma stem cells. They went on to show why cells with CD271 escaped most existing melanoma treatments: They lacked a number of markers that other tumor cells have. In fact, Weissman found, they lacked the proteins that most classic immune therapies were designed to seek out and destroy. The observation explained why these therapies hadn’t been hugely successful. While immunotherapies might eliminate some melanoma cells, they missed targeting the cells with CD271 — the very cells that can best spread a cancer.
But in the process of his research, Weissman also found a marker — a protein called CD47 — that all tumor cells appear to have, including the stem cells. Now, his group is developing a drug that blocks CD47, making the tumor cells suddenly susceptible to attacks from certain immune system cells, known as macrophages. Macrophages eat the tumor cells and present the digested materials to killer T cells, which go on to attack not only tumor cells that lack CD271 but also those that carry it. This “cross-presentation” to killer T cells should activate more effective immune responses, Weissman says. He hopes to test it as a treatment in melanoma patients some day soon.
And while immune approaches like Weissman’s progress, research continues on the genetics underlying melanomas, aiming to find genes outside of the BRAF pathway that cause the other half of the melanomas. In his lab, Khavari is developing new strains of mice that have the same genetic mutations that can cause melanoma in humans.
“In cancer sequencing, there have been a huge number of genes discovered, but people don’t know which of those are really driving the tumors,” Khavari says. By mutating the same genes in mice, his research team can investigate their biological consequences and — they hope — find more targets for drugs that block melanoma’s formation, growth and spread.
The end of the Bronze Age?
While the newest melanoma drugs aim to decrease the mortality rate attributed to metastatic melanoma, most researchers agree that there’s another, more powerful way to lower the number of people who die from the disease: keep people from getting it in the first place.
“Despite all the encouraging research in therapies, what would make the most impact on improving survival is better prevention,” says Swetter.
In 1903, a German medical company accidentally discovered that ultraviolet lamps tanned people’s skin and started manufacturing tanning beds. Slow to catch on at first, tanning beds didn’t reach the United States until the late 1970s. At that point — thanks to a few celebrities with bronzed looks and an already growing trend of tanning outdoors — tanning beds rapidly took off. By the 1980s, indoor tanning was widespread in the United States and Europe; it offered a new, easy way to get that coveted tan, even in mid-winter. But in the mid-1990s, data started building up that the more time people spent in tanning beds — or in the sun without sunscreen — the more likely they were to develop melanoma, as well as other forms of skin cancer. The natural or artificial UV rays that darken skin also cause mutations in the DNA of skin cells. And the more mutations accumulate, the more likely one will affect BRAF or another melanoma-linked gene, flipping a cell from healthy to cancerous. Tanning beds accelerate this process because they provide a more concentrated dose of UV rays — around 15 times stronger than those from the sun.
Tanning in a UV bed a single time increases a person’s risk of developing melanoma by 20 percent, a 2012 study in the British Medical Journal reported. If indoor tanning starts in young adulthood — before age 35 — or if a person has had more than five sunburns, that risk is at least doubled, studies have found. While most cases of melanoma are in light-skinned Caucasians, dark-skinned people can also get the cancer; they also have increased odds the more times they sunburn and the more time they spend in tanning beds. In all, researchers estimated in 2011 that about 86 percent of melanomas in fair-complexioned individuals are due to ultraviolet exposure.
Yet despite the evidence that tanning significantly boosts melanoma risk, tanning salons stay in business and beachgoers continue forgoing sunscreen to darken their skin. The American Academy of Dermatology reports that more than a million people a day visit tanning salons in the United States, and nearly 30 million people tan indoors a year. More than 70 percent of these are Caucasian females, mostly under the age of 30. And the rates of melanoma in the United States reflect these numbers: While rates of the cancer in women decreased from 1978 to 1987, then remained steady for five years, they’ve been climbing ever since. Much of that rise has been attributed to the increased use of tanning beds beginning in the 1980s.
So what can be done to stop these climbing rates? Queensland — an Australian state with the highest rates of melanoma in the world — launched massive public health campaigns beginning in the 1980s aimed at educating the public on the risks of sun exposure and tanning, as well as how to recognize early melanoma, Swetter says. Since then, they’ve seen the rates of melanoma in Queensland start to drop.
In the United States, word is starting to get out — 11 states have now banned tanning beds for minors (with more considering similar legislation), and the FDA has upped its regulation of the devices. But with 55 percent of current college students having tanned indoors at least once, more education is needed. Swetter has been involved in studies that probe what makes people less likely to tan: Using sunless tanning lotions that artificially darken your skin helps avoid harmful ultraviolet radiation, and educating tanning salon workers in cancer risks makes it more likely they’ll tell their patrons about these risks.
“But it’s really difficult to change tanning behaviors,” is how Swetter sums up much of the data.
Catching melanoma early, though, is another matter. Swetter’s research has found that if someone routinely has skin exams — either using a mirror (or a partner) at home to examine moles on the back or hard-to-see areas, or visiting a doctor’s office — they’re more than three times as likely to be diagnosed with an early, curable melanoma than a more advanced form of the cancer. Indeed, when a region in Germany launched a statewide skin-cancer-screening program in the mid-2000s, its death rates from melanoma were nearly 50 percent lower five years later. Routine skin exams, Swetter argued in a 2014 commentary in Nature, should be implemented more widely by primary care providers in the United States, following appropriate training to enhance skin cancer detection and triage. (Well under a quarter of U.S. adults receive a skin exam in any given year, she says.)
If people are going to tan, though, another project that Swetter’s involved in could help ward off cancer. Jean Tang, MD, PhD, an associate professor of dermatology, is heading up the research, which searches for compounds that decrease melanoma risk. One promising candidate so far: vitamin D supplements.
“When you add vitamin D to melanoma cells growing in the lab, it reduces their growth,” Tang explains. “And when you give vitamin D to mice with melanoma, it also shrinks their tumors.” In 2011, Tang published a study in the Journal of Clinical Oncology that retrospectively compared vitamin D intake among the population of women enrolled in the Women’s Health Initiative. Indeed, those with a history of skin cancer who had received the vitamin were less likely to develop melanoma. Now, she’s just completed a trial in which women were randomly selected to either receive 4,000 IU of vitamin D a day (a much higher dose than most multivitamins contain) or none of the vitamin. The results are still being analyzed.
With Swetter, she’s also studied the protective effects of aspirin and other pain relievers — some studies have found that a daily aspirin for five years lowers a person’s risk of melanoma — but more work is needed before recommendations are made to routinely take either vitamin D or aspirin.
For now, she echoes Swetter’s advice that protecting one’s skin from the dangers of the sun, learning the clinical warning signs for melanoma and other skin cancer, and regular skin exams, are the best medicine to prevent melanoma. But she knows not everyone hears her.
“It’s frustrating,” Tang says. “I think sometimes it’s like fighting obesity. I can tell you what’s good for you, but people are looking for the magic pill.” And for now, at least, there’s no magic pill — just a pile of evidence against tanning, and drugs to treat melanoma that are getting better every year.
Trista McNeill, the patient who is being helped by the new melanoma drugs, is hesitant to say she’s cured, but she knows from her regular checkups that her body has few signs left of her cancer. “In many ways, I can’t believe that I have cancer, and coming to grips with the fact that life will never really be the same is a tough pill to swallow,” says McNeill. “But I’m hardly ever overwhelmed because I have such a strong support team. I feel pretty lucky.”