Solving a Mystery to Fight a Rare Cancer

CARRIE BEST, patient, pictured with her son, Dylan - COURTESY CARRIE BEST

It was a few days after her son’s 6th birthday party four years ago when Carrie Best rolled over in bed and felt a pinch in her armpit. When she reached over and touched it, she jolted awake.

“I had a lump the size of a grape under my arm,” says Best, a 50-year-old school psychologist from Dublin, Ohio.

Because her mother was a breast cancer survivor, Best was already at high risk for cancer, and she called the oncologist she regularly saw for screenings. After an ultrasound, mammogram and biopsy, her oncologist delivered the good news and the bad news: “You don’t have breast cancer,” she told Best. “You have a cancer called neuroendocrine carcinoma with an unknown primary.” Based on that, the doctor estimated that Best had less than a 15 percent chance of surviving. .

The next several months became a frustrating roller- coaster of chemotherapy, a lumpectomy, scans, a genomic analysis revealing five mutations — and an aggressively progressing cancer that didn’t have a specific name. Best took matters into her own hands, setting up Google alerts for her mutations and obsessively reading every relevant research paper she could every chance she had, between meetings and even at long stoplights on her phone.

Things became tense with her oncologist, who dis- missed another doctor’s diagnosis of Best’s cancer as the extremely rare skin cancer Merkel cell carcinoma, which is neuroendocrine cancer of the skin. Her oncologist finally told Best she was in denial, that she had less than a 1 percent chance of surviving and needed to make peace with that reality and get her affairs in order.

Best was crushed — but they were going to have to “drag me kicking and screaming” into the grave, she says.

“Things happened and mistakes were made, but if those things hadn’t happened, I might not have fought so hard,” Best says. “If things in my journey had happened any differently, I might not be sitting where I am.”

Eventually, Best found a clinical trial for Bavencio (avelumab), an immunotherapy drug — but it didn’t start for another eight weeks. The primary investigator (PI) told her she didn’t have another eight weeks.

“I felt like I’d been punched in the gut,” Best says.

The PI made one more phone call. Rutgers Cancer Institute of New Jersey was opening enrollment the next day in a Bavencio trial being run by oncologist Howard L. Kaufman, M.D., Best was eligible, and her Merkel cell diagnosis was confirmed. She had five tumors through- out her body. Eight weeks later, she had none.

“It was one of the most powerful moments in my entire life,” she says. When she asked what would happen next, she wasn’t prepared for Kaufman’s answer: “I don’t know. You’re the first.”

MERKEL CELL CARCINOMA: WHAT SCIENTISTS KNOW

In Kaufman’s trial, she was first to enroll, first to be treated for Merkel cell with Bavencio, fastest to respond and first to become cancer-free, as she remains today. Kaufman’s trial led the FDA to fast-track Bavencio by granting it breakthrough designation. It was given the green light on March 23 of this year, the first drug approved for the treatment of Merkel cell carcinoma.

Best’s story featured several hallmarks of a typical Merkel cell carcinoma (MCC) experience. It took a long time, with some errors in the management of her cancer, for Best to receive a proper diagnosis. That’s largely because it’s so rare — only 1,600 to 2,000 cases occur each year in the U.S. — but the cancer also “looks alarmingly bland,” says Paul Nghiem, M.D., head of dermatology at the University of Washington School of Medicine in Seattle and an international leader in Merkel cell carcinoma research. “It has to grow a ways before it looks alarming enough to get biopsied.” That also means it has usually spread quite a bit by the time it is identified.

Best’s cancer also progressed rapidly, as it does in other patients. Despite being about 40 times less common than melanoma, mortality rates are far higher because it’s so aggressive: About 40 percent of patients will experience a recurrence, and, until the discovery of effective immunotherapy in 2016, more than 30 percent of patients died.

“It’s much more dangerous than having a mela- noma, and you don’t treat it the same way as melanoma,” says Nghiem. “That’s a big problem because there’s not awareness, and it’s often tragically and horrifyingly not treated the right way.”

But unlike most patients, Best was incredibly young for this cancer. Ninety percent of Merkel cell patients are over age 50, and risk continues increasing with age, even into the 70s, 80s and 90s, when risk for most other cancers levels out or decreases.

“We strongly believe the reason for that is the aging of the immune system, with less diversity and strength of their T cells,” Nghiem says. “The incidence is going up really fast for this cancer because the Baby Boomers are hitting the ages when risk of the cancer goes up,” Nghiem says.

Best’s younger age, which could have meant that her immune system was in better shape, may also be the reason she responded so quickly and completely, but much of her recovery, and the disease itself, remain shrouded in mystery. Even the function of Merkel cells, found in the skin’s epidermis, isn’t entirely understood. Scientists know they produce hormones, making them neuroendocrine cells, and they appear to play a role in the sense of touch.

The biggest breakthrough in understanding what causes the disease came in 2008, when scientists learned that about 80 percent of those who develop MCC have a newly discovered virus, the Merkel cell polyomavirus, present in their tumor. But then again, on any given day, about half of people in the general population have this virus on their normal skin, and the vast majority of them don’t develop MCC. The key to fighting this disease isn’t prevention of viral infection, Nghiem says, but detection and proper care after diagnosis of the rare cancer.

The immune system shouldn’t have a problem recognizing and fighting the virus, Nghiem says, but that’s somehow not the case in those with MCC. “Figuring out the tricks the cancer uses to hide from the immune sys- tem is at the core of progress in research,” he says.

Further, no one knows why some people develop it or why those without the virus develop MCC instead of melanoma or another skin cancer, says Jeffery Russell, M.D., Ph.D., an assistant professor of head and neck and cutaneous oncology at Moffitt Cancer Center in Tampa, Florida.

TREATING MERKEL CELL CARCINOMA

“We know that it’s a neuroendocrine tumor and similar to small cell lung cancer, which is also difficult to treat and is one of the most lethal cancers out there,” Russell says. Scientists also know the two most com- mon mutations are the tumor suppression regulators p53 and Rb (the retinoblastoma protein), as is true with many other cancers, but no evidence suggests that MCC is hereditary.

Even more so than with other diseases, this is one cancer that patients should learn as much about as possible, Nghiem says.

“They do need to take their care into their hands sometimes and realize that doctors are not familiar with this very often,” he says. “There’s a reason it’s mismanaged so often — because people don’t bother to actually read how to treat it and it’s complicated and depends on the patient.”

Best says she’s lost too many friends to the disease who never got a second opinion, often because they said they liked their doctor.

“It’s not about liking your doc- tor,” she says. “Make sure you know your genetic mutations, make sure you have a multidisciplinary team, make sure you advocate for yourself, and make sure you ask hard questions and get a second and a third opinion.”

Nghiem emphasizes the importance of going to a center that specializes in MCC and has a multidisciplinary team whose members work together to determine the best way to proceed; organizations including merkelcell.org can help steer patients in the right direction. Factors to con- sider in a treatment plan include whether the patient is immunosuppressed, the tumor’s size and location, whether the cancer has spread to the lymph nodes and whether the patient’s body makes certain antibodies to the virus. Only those with MCC make antibodies against the polyomavirus, and risk of recurrence is about 40 percent lower if a patient does make them, Nghiem says.

Typically, a combination of surgery and radiation is used for early-stage tumors, effectively treating about half the patients diagnosed with MCC, Nghiem says. Those who skip the radiation tend to have more relapses, adds Upendra Parvathaneni, M.D., a radiation oncologist who specializes in head and neck cancer treatment at University of Washington Medical Center and Seattle Cancer Care Alliance.

For the other half, with non-responsive or metastatic cancer, first-line treatment is now Bavencio, but if that drug is so new that some patients can’t get it yet, Russell says, off-label Keytruda (pembrolizumab) or Opdivo (nivolumab), which are similar immunotherapy drugs, may be options, based on results presented in April at the American Association for Cancer Research 2017 conference. All of these agents work on the PD-1/PD-L1 pathway that’s key to treating many other cancers.

They are known as checkpoint inhibitors because they interfere with the normal checks and balances that keep the immune system working at a measured level. This interference allows T cells the freedom to ramp up their activity against cancer. (Another checkpoint inhibi- tor, Yervoy [ipilimumab], is also under investigation as a treatment for Merkel cell, although it targets the protein receptor CTLA4 instead of the PD-1/PD-L1 pathway.) In general, these options are well tolerated. Most side effects include body aches, muscle aches, low- grade fevers and infusion-related reactions, although rare, more serious autoimmune side effects can also occur.

Chemotherapy agents used to treat MCC have included carboplatin or cisplatin with etoposide, topotecan, cyclophosphamide, doxorubicin and vincristine. But these rarely have shown long-term effectiveness, and chemotherapy is not recommended as a standard of care by two major organizations that set clinical practice guidelines for oncologists.

In fact, patients may respond better to immunotherapy if they haven’t first had chemotherapy. Kaufman’s clinical trial for Bavencio included 88 patients with metastatic stage 4 Merkel cell carcinoma who had previously been treated with chemotherapy; 9 percent of them experienced a complete response and 23 percent a partial response to the check- point inhibitor. The disease remained stable in another 10 percent. Most side effects involved fatigue or reactions related to infusion.

Whether patients responded to the Bavencio or not appeared unrelated to how much PD-L1 expression they had or whether they had the polyomavirus.

Yet, in a study led by Nghiem with 25 patients who hadn’t taken prior chemotherapy and received Keytruda, 56 percent either completely (16 percent) or partly (40 percent) responded.

Only two (14 percent) of those patients relapsed. One possible reason for a better response in those without previous chemotherapy is that cytotoxic drugs weaken the immune system, and a stronger immune system can respond better to immunotherapy.

Immunotherapy is also often used in conjunction with radiation.

“One of our goals is to find a way for radiation to work better in combination with these systemic agents,” Parvathaneni says. For reasons that aren’t well under- stood, using fewer radiation treatments (less than five) at a dose four or five times greater than usual appears to stimulate the immune system more than typical radiation therapy, increasing the likelihood that immunotherapy will be successful.

But current immunotherapy agents aren’t enough to satisfy the needs of all the patients whose cancer isn’t controlled by surgery and radiation.

“Those (agents) all probably give around a 60 percent response rate, and of those patients that respond, 80 percent or so will respond for a long time,” Nghiem says. “When you do that math, you’ve got about half of patients really benefiting from any one of these agents.” That leaves a quarter of all MCC patients without any effective treatment options, particularly those with suppressed immune systems.

So, what then? That’s what Nghiem and other researchers are exploring. One trial of Nghiem’s that is still recruiting patients focuses on adoptive T-cell therapy, where the patient’s T cells specific to the Merkel cell polyomavirus are drawn and isolated from their blood, grown to much larger numbers in the lab, and then re-injected with an immunotherapy agent. While that technology is “extremely promising,” Nghiem says, it’s also very expensive, and therefore efforts are ongoing to develop more efficient approaches to directly boost the anticancer immune response. It might seem that such a rare cancer is unlikely to generate enough research to find more answers, but studying MCC’s characteristics suggests otherwise, Russell says.

“On the surface, it seems like it’s a rare cancer, but Merkel cell might provide insight into other cancers,” Russell says. “If you look deeper, there are some really unique advantages to studying Merkel cell carcinomas.”

For one thing, it grows very rapidly and resembles small cell lung cancer. Its association with a virus means it could teach us more about other cancer-causing viruses. Because it’s a neuroendocrine tumor, findings about MCC may be applicable to a wide swath of other neuroendocrine cancers. And its two primary genetic mutations are shared by multiple other cancers.

“Its known genetic markers, neuroendocrine component and virus component make it a conglomerate of cancer risk factors,” Russell says.

As scientists learn more, Best hopes the data her experience provided will allow more to survive this unique cancer. “It was bizarre and surreal to go from eight weeks left to live to cancer-free in a two-month period,” Best says. “It was really hard for me to learn that there were no answers to the questions I had, and I was going to have to make peace with the unknown.”