Erin Youngerberg loves to travel. Over the past 15 years she and a group of her college friends have been to many places: several countries in Europe; London, for the Summer Olympics; Sochi, Russia, for the Winter Olympics; Singapore; and Thailand, twice. This year, the friends are considering Chile and Easter Island, more than 5,000 miles from Youngerberg’s home in Jersey City, New Jersey. On one of her trips in 2010, a mole she’d been concerned about displayed a worrying new symptom. She was in Australia, toweling off after a shower, when the mole on her back started to bleed. “This totally scared me,” she says. A pharmacist friend who was with her said, “You need to get that looked at,” Youngerberg recalls. “I swear it was growing daily.”
She had first noticed the mole about a year before, when it was an itchy pink bump. At the time, her primary-care physician said it was nothing to worry about and didn’t take a biopsy. When Youngerberg returned from Australia she saw a dermatologist, who biopsied the mole but didn’t suspect cancer and told Youngerberg as much. Within a week, the dermatologist called Youngerberg at work and asked her to come in to the doctor’s office. The timing couldn’t be worse. “The day I had the mole removed I had just resigned from my job in North Carolina to take a job in the New York City area,” she says.
Youngerberg went to her dermatologist’s office and learned that she had stage 3 nodular melanoma, meaning the cancer had already spread to her lymph nodes. She was 32 years old. Nodular melanoma can be difficult to diagnose, because these cancerous cells don’t always carry the telltale pigments melanomas usually show. Nodular melanomas can also be aggressive.
At the time, the standard treatment was a drug called interferon, which required people to go on the therapy for one year. Side effects of the drug are similar to influenza. Youngerberg chose not to take interferon and tried to join a clinical trial but didn’t qualify right away. Instead of moving back home to Minnesota to be with her family, Youngerberg started her new job in New York City. Her family and friends remained worried and kept getting in touch for updates.
Rather than answer the same questions over and over, Youngerberg started a blog called Melanoma and the City to keep everyone up to date on her treatments and progress. “I was getting overwhelmed with questions and people contacting me, so I figured it was the easiest way to say, ‘I’m okay,’ or ‘Here’s what’s going on,’ ” Youngerberg says.
Melanoma is a type of cancer in which skin cells called melanocytes — named because of their pigment — turn cancerous. They can grow on their own, or a mole that was benign can evolve into a melanoma. There are several types of melanoma. Cutaneous melanoma grows anywhere on the skin, including the palms of the hands or soles of the feet. The most common type of cutaneous melanoma, accounting for 70 percent of cases, is called superficial spreading melanoma (SSM) because it first grows horizontally across the surface of the skin. It can take months or years to form. Nodular melanoma, the type Youngerberg has, can start growing within a superficial spreading melanoma and then penetrate into the lower layers of skin. Melanomas can even grow in eye tissue. These uveal melanomas are usually detected when a person notices a change in vision, or are found during a routine eye exam.
On the skin, melanomas can look like a raised pink bump, like Youngerberg’s, but the majority are pigmented as bluish, black, or dark brown colors. (See “Camera Ready?,” page 60.) What usually triggers a call to the doctor is a change in size or color of a mole that’s been around for a while; a mole that starts to itch or bleed; or a new mole that grows very quickly. “Moles can also look uneven, like an egg in a frying pan, with a round, raised bump in the middle surrounded by flattened edges,” says Keith Flaherty, a medical oncologist at Massachusetts General Hospital and the director of developmental therapeutics.
Sunburns, indoor tanning, and a family history of skin cancer raise the risk for melanoma. Exposure to ultraviolet light is a major cause of melanoma. Even though people with lighter skin color are at higher risk, anyone can develop melanoma. The American Cancer Society expects that 76,380 people will be diagnosed with the disease in 2016 and projects that 10,130 will die from melanoma this year.
“A lot of people don’t realize how much damage a little mole can cause and how melanoma can metastasize to so many parts of the body,” says Youngerberg.
Melanoma does have several genetic links. According to the American Society of Clinical Oncologists, about 8 percent of people who receive a diagnosis of melanoma have a first-degree relative, such as a parent or sibling, with melanoma. In these familial melanomas, researchers have found mutations in two susceptibility genes, CDKN2A and CDK4, which put people at higher risk for melanoma.
“The increase in risk for individuals is very difficult to measure,” comments David Polsky, a dermatologist at NYU’s Langone Medical Center. Researchers estimate that CDKN2A mutations may be present in up to 25 percent of families, who have at least two first-degree relatives who have been diagnosed with melanoma. In families with three or four individuals diagnosed with melanoma, that figure rises up to 40 percent. “These ‘loaded’ families are very rare,” says Polsky. “Families with CDK4 mutations are also very rare. Among individuals lacking a family history of melanoma, CDKN2A mutations are also very rare, perhaps, less than 1 percent of individuals.”
In addition to familial melanoma, genetic diseases, such as retinoblastoma, xeroderma pigmentosum, and Li-Fraumeni syndrome, can put people at increased risk of melanoma. These conditions arise because of defects in genes that repair damage from UV light. Commercial genetic tests can identify these mutations.
Polsky says he doesn’t use commercial genetic tests for patients with familial melanomas because the results, whether negative or positive, won’t change how he plans patient care. “To me, extra surveillance is really the key,” says Polsky. “If doctors check people with a family history of melanoma twice a year instead of once a year because of their higher risk, we will still be able to catch melanoma early.” Polsky also authored a review article in 2015 in the British Journal of Dermatology, which assessed the link between melanoma risk and mutations in the BRCA1/2 genes, which are also involved in DNA repair. But Polsky says he didn’t find evidence that people with BRCA mutations should be under extra surveillance for melanoma.
Pathologists diagnose melanoma under the microscope by looking for special features in a skin biopsy, such as how many cells are dividing too quickly. What they look for above all is thickness. The deeper melanoma digs into the dermis, the layers under the skin, the greater the chance that some cancerous cells have reached nearby lymph nodes. Once melanoma spreads to nearby lymph nodes and beyond, the disease is considered metastatic, and life expectancy can decrease.
Most of the time, pathologists can diagnose melanoma without any problems. Unfortunately, that’s not always the case. Some researchers estimate that in 1.5 percent of suspected melanomas, which can account for 225,000 cases a year, even the most experienced pathologist can’t say with certainty that a biopsy is indeed melanoma. In these situations, pathologists refer the biopsies to dermatopathologists, physicians who are specially trained to diagnose skin disorders. These ambiguous biopsies can bring serious consequences. Doctors don’t want to say a mole is benign, when it’s actually cancer. Nor do they want patients to undergo extensive surgery and a sentinel node biopsy for a mole that turns out to be benign.
A diagnosis “can set a lot of bad things in motion, and you wouldn’t want to be wrong,” says Marcus Bosenberg, a dermatopathologist at the Yale University School of Medicine.
Myriad Genetics, of Salt Lake City, has a genetic test called myPath Melanoma that can help settle those difficult cases in which the diagnosis is uncertain. The test uses biopsy tissue to analyze a group of genes that are switched on in a very specific pattern. In a study designed to assess how well the gene assay works, the myPath test could distinguish melanoma in 90 percent of the biopsy samples. Thus far, dermatopathologists across the U.S. have ordered several hundred tests, says Loren Clarke, a dermatopathologist and vice president of medical affairs of dermatology at Myriad. “Even the most experienced dermatopathologists can disagree on whether some biopsies are benign or cancerous,” Clarke says. “We all know the stakes are high, because melanoma is potentially aggressive.”
In addition to assisting with diagnostics, genetic and genomic research is helping melanoma researchers reclassify the disease. The Cancer Genome Atlas (TCGA), a project of the National Institutes of Health to catalogue genetic and genomic changes in cancer, has been used by melanoma researchers recently to define four distinct categories of cutaneous melanoma, based on their most predominantly mutated genes. Another finding from this project shows just how much damage UV radiation can do to genes: More than 80 percent of the tumors analyzed had a UV signature, consistent with the known mutagenic effects of UV radiation in melanoma.
The area in which genomics has contributed the most to melanoma has been in the development of innovative and effective new treatments for patients with distant metastases, says Michael Davies, a medical oncologist and the deputy chairman of the Department of Melanoma Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston. Until 2011, only two treatments were approved by the Food and Drug Administration (FDA) for patients with metastatic melanoma: the chemotherapy dacarbazine and the immunotherapy interleukin-2. Benefits from both drugs were modest, and the risk of relapse was high, says Davies.
In the past five years, the FDA has approved seven new drugs for metastatic melanoma based on discoveries in the immune system or the cancer genome. (This number doesn’t include the many approvals of new combinations of existing drugs.) The turnaround started back in 2002, when a genetic variation in the BRAF gene was discovered in several cancers, including melanoma. Researchers estimate that BRAF mutations can be found in 45 percent of cutaneous melanomas. Researchers eventually developed a drug called Zelboraf (vemfurafenib), which blocks the mutation that tells cancer cells to grow and divide. By 2010, results of the first clinical trial on Zelboraf were published.
“BRAF inhibitors are the ultimate in personalized cancer therapy,” says Davies. The FDA initially approved two BRAF inhibitors, Zelboraf, which was cleared in 2011, and Tafinlar (dabrafenib), which was okayed in 2013, for the treatment of metastatic melanoma patients with a BRAF mutation in their tumor. “More recently, the FDA has also approved treatments in which these BRAF inhibitors are combined with inhibitors of the MEK gene, based on trials that showed that the combinations were more effective than treatment with the BRAF inhibitors alone,” says Davies. Both BRAF and MEK inhibitors work by blocking tumor cells from growing and dividing. However, these treatments are effective only in patients with a BRAF mutation.
“We always do the test for the BRAF mutation in the tumor before using these medications. If the BRAF test is positive, we know that these treatments have an almost 95 percent chance of slowing the growth of the tumors. However, if the BRAF test is negative, these same treatments can make the tumors grow faster. Thus, we know exactly who to use these treatments in, and who not to,” says Davies. Mutations in the BRAF genes are detected in approximately 50 percent of metastatic melanoma patients. Research is ongoing to identify and target other mutations based on the success with BRAF inhibitors.
The other group of new therapies is called checkpoint inhibitors, which work on the immune system. Checkpoint inhibitors trick a type of white blood cell, called a T cell, into attacking cancer. Normally, the immune system is kept in check by proteins that prevent it from attacking cells that it sees as “self,” even if those cells are cancerous. Immune therapies, such as Yervoy (ipilimumab), effectively release the brake on this control, making the cancer vulnerable to attack.
The FDA has recently approved a drug called Imlygic (talimogene laherparepvec), a genetically modified virus designed to destroy melanoma cells that can’t be removed by surgery. These treatments are called oncolytic virus therapies. Also in clinical trials are therapeutic vaccines that marshal the immune system against melanoma. The trend today in clinical trials is moving toward a combination of targeted therapies, immune therapies, or both, in the hopes of stopping progression or destroying melanoma completely.
“We have done so much better over the last couple of years, than previous years. Now, we are thinking of using the ‘C’ word. We’re talking about patients potentially being cured,” says Jeffrey Weber, a medical oncologist and the deputy director of the Laura and Isaac Perlmutter Cancer Center at the NYU Langone Medical Center.
Unfortunately, these therapies don’t work for everyone, and researchers still need to figure out why some people with melanoma survive and others do not. A team of researchers at the NYU Langone Medical Center recently discovered a genetic marker that may predict melanoma survival. The marker can be found in two genes that help guide the immune system. We inherit these gene defects from our parents, and while they won’t put us at risk for the disease, they may define whether people with melanoma survive or die from the disease. Melanoma thrives as a cancer because it can hide from cells in the immune system.
The study, published online in January 2016 in Clinical Cancer Research, used tissue samples from newly diagnosed melanomas to help predict how fast the cancer can progress. Senior author Tomas Kirchhoff, an assistant professor at NYU and a member of the Perlmutter Cancer Center, says the research could one day help doctors decide, for instance, how frequently to monitor people with worrisome tumors but who are not yet showing signs that the disease has spread.
“Any medical oncologist will tell you they have been puzzling their heads to identify patient prognosis on a personalized level, based on characteristics of early stage tumors,” says Kirchoff. Doctors want to know “whether patients are going to have a healthy life, or relapse soon with metastatic disease, or die of the disease,” he says.
Youngerberg has taken several of the new therapies, and she’s doing well on them. In May 2012, melanoma came back in her small intestines. When the tumor tested positive for the BRAF mutation, she took Zelboraf for five months. Although this is an oral drug, Youngerberg calls it a “horse pill” and says it was difficult to swallow. The tumors shrank for a while but started growing again. Youngerberg then took four doses of Yervoy (ipilimumab), the checkpoint inhibitor that works against a T cell protein called CTLA-4. Yervoy is given as once-monthly infusions. In between the monthly doses, surgeons removed eight inches of her small intestine because the tumor there was causing discomfort.
Four months of treatment with Yervoy didn’t succeed at removing all of the tumors in her small intestine. In January 2013, Youngerberg started a clinical trial for Keytruda (pembrolizumab), an immune therapy designed to block a T cell protein called PD-1. If cancer treatments are like a having a second job, then joining a clinical trial is like working overtime. Fortunately, Youngerberg’s employer allows flexible time, so she could work from home on treatment days, which came around every three weeks. Although the infusion took 30 minutes, the bloodwork, doctor visits, and wait times to get the drug from the pharmacy kept her at the hospital for at least half a day.
Youngerberg never let any of her cancer treatments dampen travel plans. She took her Zelboraf pill while attending the Summer Olympics in London. While she was on the trial for Keytruda, she took a treatment one day and flew to Russia the next. “I didn’t let them slow me down. As long as my doctor said I was okay to go, I still went,” she says.
After spending almost two and a half years and undergoing 41 infusions in the Keytruda trial, Youngerberg left the trial in May 2015. “I think my doctor would have liked to keep me in the trial, but I just needed to get a normal life back,” says Youngerberg.
Today, Youngerberg is more than five years out of diagnosis, and her disease remains stable. The fact that she’s not unusual shows just how far melanoma treatments have come and how innovative they are.
“A few years ago, for patients with metastatic melanoma, this was a really difficult conversation to have, because we really didn’t have any good treatments,” says MD Anderson’s Davies. “Now, when we have a patient with newly diagnosed metastatic melanoma, it’s still a difficult conversation, but we have multiple treatments that are very good.”
Youngerberg continues to cope with lymphedema, the aftermath of surgery to remove the lymph nodes under her right arm. She works with a physical therapist, because fluid collects in her armpit, causing swelling and soreness. “The therapist helps break up scar tissue and get things moving right again,” says Youngerberg.
On Tuesday, October 13, 2015, Youngerberg posted on her blog about being five years out of her melanoma diagnosis. She wrote about independence, enjoying the moment, about sharing her optimism, and about her decision to stay in New Jersey after her 2010 diagnosis.
That kind of choice might upset a parent anxious over a son or daughter with cancer, and eager to shepherd their child through treatment and its aftermath. Instead, Mary Zard, Youngerberg’s mom, knew that her daughter’s decision to remain in New Jersey was a good sign. When Zard’s own father was diagnosed with leukemia, she asked him to move in with her family so they could care for him. He refused, and Zard knew exactly why. He hadn’t given up. She felt that same relief when her daughter chose not to move home.
On Youngerberg’s blog post marking the five-year anniversary of her diagnosis, Mary Zard wrote the following:
“Actually, Erin, I was terrified that you WOULD pack up and move home. Let me explain … I felt that if you came home, you would have given up. You have a lot of me in you, and I understand your decisions. Friends and family kept telling me to tell you to move home, so I could ‘take care of you.’ I told them that if you moved home during your worst times, it would be your way of saying it was over. It ain’t over! While I have hated the miles between us, I have also been comforted by them. I know that is something you will understand. I love you to the moon and back!” ~Mom