Because of headway in the development of treatments for patients with thyroid and other difficult-to-treat rare cancers, the American Society of Clinical Oncology (ASCO) selected progress in treating rare cancers as its 2018 Advance of the Year.

ASCO made the announcement in January as part of “Clinical Cancer Advances 2019: ASCO’s Annual Report on Progress Against Cancer.” The update on oncology treatment highlights the most impactful clinical research milestones and policy developments achieved over the past year.

ASCO’s past president, Dr. Monica M. Bertagnolli, said in a press release that federal investment is critical for furthering progress in the cancer space as a whole but especially in rare cancers, where there is a great deal of unmet need. Rare cancers account for approximately 20% of all cancers diagnosed annually in the United States.

“It’s exciting to see such substantial progress over the course of a single year, particularly against rare cancers,” Bertagnolli said. “With U.S. cancer cases set to rise by roughly a third over the next decade, we must continue to advance research that saves lives. ... We need to prioritize federal funding of cancer research in the years to come. Americans are counting on it.”

In January 2018, the Food and Drug Administration (FDA) approved the radioactive agent Lutathera (lutetium Lu 177 dotatate) for treating patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). These tumors develop in the pancreas or elsewhere in the gastrointestinal tract, forming from cells that make hormones.

The agency approved the targeted drug combination of Tafinlar (dabrafenib) and Mekinist (trametinib) for patients with BRAF-mutated anaplastic thyroid carcinoma — the first treatment in almost 50 years for the disease &mdash; in May 2018. This unusually aggressive, fast-growing type of thyroid cancer tends to spread quickly to other parts of the body and is typically resistant to chemotherapy. Anaplastic thyroid carcinomas that carry a BRAF gene mutation may be sensitive to the drug combination: Tafinlar inhibits the activity of the mutated proteins made by the BRAF gene, and Mekinist interferes with the MEK protein, which is part of the cell signaling pathway that includes BRAF.

The targeted drug Nexavar (sorafenib), a tyrosine kinase inhibitor, was shown, for the first time, to improve progression-free survival (the length of time after treatment when disease does not progress) in patients with desmoid tumors. These noncancerous masses form in the connective tissue of the abdomen, arms and legs. Nexavar helps block the development of blood vessels that desmoid tumors need to grow.

The targeted drug Herceptin (trastuzumab), originally approved to treat breast cancer, was found to slow the progression of HER2-positive uterine serous carcinoma, a rare and aggressive form of endometrial cancer. Herceptin blocks the activity of the protein HER2, a growth factor receptor overexpressed by some cancers.

The experimental CSF1R inhibitor Turalio (pexidartinib) became the first agent to show promise in patients with tenosynovial giant cell tumors, which form in the joints or tendon sheaths of young adults and, although not malignant, can be debilitating. The drug prevents inflammation and boosts activity of the immune system’s T cells against the condition.

NETTER-1 Trial Leads to Approval in GEP-NETs

Lutathera received the FDA’s OK based on positive results from two clinical trials. The first, the phase 3 NETTER-1 trial, compared Lutathera with long-acting high-dose versus lower- dose octreotide (an inhibitor of some hormones) and showed that using Lutathera led to a 79% reduced risk of disease progression or death.

Researchers also evaluated Lutathera’s effectiveness in a subset of 360 patients with GEP-NETs who were enrolled in the ERASMUS Medical Center study. Initially, this experimental drug was provided through expanded access at one trial site based in the Netherlands. The overall response rate (the proportion of patients whose tumors had any response to the drug) was 16% (58 patients), including three complete responses (the disappearance of any signs of cancer due to the treatment).

First Anaplastic Thyroid Cancer Drug in 50 Years

The FDA approval of Tafinlar plus Mekinist for treating patients with inoperable or metastatic anaplastic thyroid cancer driven by a BRAF V600E mutation was based on positive results from an open-label clinical trial (in which patients and their doctors know which treatment is being given). Among 23 patients who could be evaluated, 57% had a partial response and 4% achieved a complete response. Of these 14 responders, 64% (nine) were not found to have significant tumor growth for at least six months.

In previously published data, seven in 10 patients with locally advanced or metastatic BRAF V600E-mutated anaplastic thyroid cancer responded to the combination. In that study, the overall response rate was 69% (11 of 16), with one complete and 10 partial responses. Seven patients were showing continued response to the combination when the analysis took place.

Tafinlar and Mekinist are also approved by the FDA to be used alone or together in patients with BRAF V600 mutation-positive melanoma. The agents also can be used in combination for the treatment of patients with BRAF V600E mutation-positive, metastatic non-small cell lung cancer.

First Drug to Delay Desmoid Tumor Progression

In a phase 3 trial (NCT02066181), Nexavar delayed the time after treatment until disease worsened in patients with desmoid tumors whose disease had been progressing, resisting treatment or producing symptoms.

Researchers randomly assigned 87 patients to get 400 milli- grams once daily of either oral Nexavar or placebo. Patients receiving placebo could cross over to the Nexavar group if their disease progressed.

At a median follow-up of 27.2 months, the two-year progres- sion-free survival rate in the Nexavar group was 81% compared with just 36% in the placebo group. Prior to crossover, the overall response rate in those who received Nexavar was 33% versus 20% in those who were given placebo. Further, responses happened faster in the Nexavar group than in the placebo group, taking a median of 9.6 months versus 13.3 months, respectively.

Nexavar has not yet been approved to treat this rare form of sarcoma, although it is approved for patients with certain types of advanced kidney, liver and thyroid cancers.

Slowing A Rare Endometrial Cancer’s Progression

Findings from a small randomized trial showed that the use of Herceptin plus chemotherapy resulted in a more than 50% improvement in progression-free survival in patients with HER2-positive uterine serous carcinoma compared with chemotherapy alone.

The median progression-free survival increased to 12.6 months with the addition of Herceptin from eight months with only chemotherapy. Further, patients with advanced disease experienced a twofold increase in median progression- free survival, going from 9.3 months with chemotherapy to 17.9 months with added Herceptin.

A preliminary survival analysis reported at the 2018 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer demonstrated a trend favoring the Herceptin group, which seemed greater for those with more advanced disease and those who had received the combination as initial systemic therapy.

Turalio Shows Promise in Giant Cell Tumor

In results of the phase 3 ENLIVEN trial, oral Turalio showed promise in patients with tenosynovial giant cell tumor. The analysis was based on central review of magnetic resonance imaging scans.

Patients were randomized to get 1,000 milligrams of either Turalio or placebo daily for two weeks followed by 800 milligrams daily for 22 weeks. After completing part one, participants had the option to continue into an open-label Turalio extension. Of the 120 patients treated, 61 received Turalio and 59 placebo. Overall response rate was 39.3% in the Turalio group versus 0% in the placebo group at the end of part one. After a median six-month follow-up, none of the responders experienced disease progression.

Liver toxicities occurred more often in those who received Turalio. Eight patients discontinued treatment with the agent because of side effects; four experienced serious nonfatal side effects with increased bilirubin (which can indicate liver problems or excessive destruction of red blood cells), with one case lasting around seven months. Other side effects included changes in hair color, vomiting, fatigue, dysgeusia (distorted sense of taste) and swelling around the eyes.

The researchers concluded that, despite these side effects, Turalio offers a relevant treatment option for which the benefits outweigh the side effects for certain patients with this rare cancer of the joints.

On May 15, the FDA’s Oncologic Drugs Advisory Committee recommended that the agency approve Turalio to treat adults with symptomatic tenosynovial giant cell tumor. The FDA approved the drug on Aug. 2.

For the first time, ASCO identified priorities for future research efforts in oncology, including:

Identifying tests (or assays) that better predict response to immunotherapies.

Determining which patient groups will derive the most benefit from postoperative treatment.

Testing, in solid tumors, of advances made with cellular therapies.

Exploring more precision medicine approaches in pediatric cancers.

Improving care for older adults with cancer.

Minimizing the long-term consequences of cancer treatment.

Reducing obesity and its impact on cancer incidence and patient outcomes.

Developing strategies to identify and treat those with premalignant lesions.

“These priorities represent our vision for finding the next generation of cancer cures and reducing cancer’s impact on patients’ lives,” Dr. Richard L. Schilsky, senior vice president and chief medical officer of ASCO, said in a press release.

Articles

Drugs in the News

Progress in treating rare cancers represents the most significant oncology advance of last year, ASCO says.

New Therapies Making Progress in Rare Cancers

When it comes to treating relapsed or therapy-resistant Waldenstrom’s macroglobulinemia (WM), the watchword is “personalization.”

“Every patient is different — the clinical features of (their cases), their genomic profiles, as well as comorbidities and medications &mdash; and we need to take all those factors into account to choose the best therapies after initial treatment,” said Dr. Jorge J. Castillo, clinical director of the Bing Center for Waldenstrom’s Macroglobulinemia at Dana-Farber Cancer Institute in Boston and an associate professor at Harvard Medical School.

Castillo and several others discussed progress in the treatment of WM before an audience of 1,300 from 29 countries during an April 10 webcast. The event was sponsored by the 

International Waldenstrom’s Macroglobulinemia Foundation

, a nonprofit organization that provides supportive services to people affected by any type of cancer.

A rare blood cancer, WM is a type of non-Hodgkin lymphoma. In this disease, cancer cells, specifically malignant plasma cells that normally make antibodies, produce an abnormal protein that crowds out normal cells in bone marrow, thickens the blood and can cause anemia, bleeding, bruising and infection.

In some cases, newly diagnosed WM needs no treatment beyond careful observation. If symptoms warrant treatment, the choices are clear: either chemotherapy paired with the targeted drug Rituxan (rituximab) or the targeted drug Imbruvica (ibrutinib) given by itself or with Rituxan, explained Dr. Stephen M. Ansell, a professor of medicine at Mayo Clinic College of Medicine and Science in Rochester, Minnesota and a consultant with the department of internal medicine there.

It’s when the disease stops responding to initial therapy or comes back after a remission that treatment decisions become more complicated.

CHOOSING TREATMENTS AFTER RELAPSE OR DRUG RESISTANCE

When determining treatment, oncologists have patients’ quality of life in mind, Castillo said.

“The reason we begin treatments for WM is because quality of life is affected or threatened by recurring infections, anemia, hyperviscosity (thickness) of blood or fluid in the lungs that could lead to meningitis,” he said. “Improved quality of life is the outcome we’d like to see when we treat patients.”

Castillo outlined the three main treatment courses he considers when a patient’s disease recurs or becomes resistant to initial therapies:

The chemotherapies bendamustine and cyclophosphamide (or others) combined with Rituxan, which kills blood cells marked with the protein CD20, most of which are cancerous.

A targeted drug known as a proteasome inhibitor — usually, Velcade (bortezomib), Kyprolis (carfilzomib) or Ninlaro (ixazomib). These drugs stop a process inside cells that clears away unneeded proteins; without that process, the proteins accumulate and the cells blow up.

A targeted drug known as a Bruton tyrosine kinase (BTK) inhibitor, such as Imbruvica, alone or with Rituxan. This type of drug inhibits the multiplication rate of cancer cells.

Although there is no established order for trying these options, Castillo said he prefers to start with chemotherapy/Rituxan and then, if necessary, move to a proteasome or BTK inhibitor — or the two combined. If the cancer grows after that, he typically treats it with chemotherapy, using symptoms and other indices of cancer burden to make decisions on treatment timing and type.

“Those are the three big options that are safe (and) effective and provide patients with good quality of life and good response, moving forward, for years,” he said. “Sequencing of these is less under- stood, but in our experience, we’ve seen that patients who respond very well to initial therapies and then lose response do respond to the next line of treatments.”

Ansell mentioned another option for relapsed or resistant disease: Venclexta (venetoclax), which blocks the activity of the protein BCL-2, sending a message to cancer cells to self-destruct. Although it is approved by the Food and Drug Administration for use in relapsed or resistant WM, it’s likely to soon be OK’d for use as an initial treatment, according to Ansell.

“What’s exciting is that it is now being used in combination with BTK inhibitors and has been shown to be highly effective and well tolerated,” he said. “In the future, it may be used more in combination with other, more standard therapies to get very durable remissions.”

Finally, stem cell transplant using a patient’s own stem cells can be a treatment option for WM. “The role of that in WM is not defined,” Castillo said. “Some doctors feel it needs to be used earlier in treatment, and some feel it should be used later.” In his opinion, stem cell transplant should be considered in patients whose disease has progressed despite several previous courses of treatment.

Patients with WM should not undergo allogeneic stem cell transplant, which uses donor cells, except within the confines of a clinical trial, he said.

Additional drugs fill the WM toolbox, but they can cause more troublesome side effects. “We use the agents we feel are more effective and less toxic early and then leave the less effective, more toxic drugs for later,” Castillo said.

To further personalize treatment, oncologists use genetic profiling of patients’ cancers to determine which drugs are likely to work the best. Castillo said that 90% of patients with WM have a mutation in the MYD88 gene and about one-third carry a mutation in the CXCR4 gene.

“It seems that patients who don’t carry MYD88 mutations might not respond as well to ibrutinib as patients with the MYD88 mutation,” he said. “Similarly, patients with the CXCR4 mutation might have a shorter, more superficial response to ibrutinib compared (with) patients without it. So, with ibrutinib, knowing the genetic profile of a patient’s cancer could help inform decisions about which drug to use next.”

Castillo noted that genetic profiling does not help in decisions about whether to give chemotherapy, Rituxan or proteasome inhibitors in WM.

Future clinical trials of treatments for WM are likely to be driven by genetic profiling, he added: “We have a clinical trial running at Dana-Farber in which we are combining an antibody against CXCR4 with ibrutinib. In the future, more clinical trials might have these components (to help identify the patients) we believe might be better suited.”

It’s reasonable for patients and their doctors to consider potential side effects of medications when choosing treatments, Castillo said. “Some treatments (including Rituxan, Imbruvica and bendamustine) are more problematic, giving patients low blood counts so that they may need transfusions or growth factors (which cause bone marrow to produce more blood cells),” he said. “Other combinations cause nausea or constipation, and knowing that in advance helps us take measures to stay ahead of the game.”

Some medications, such as Velcade, result in neuropathy — nerve damage that causes numbness and weakness of the extremities, he added: “We need to be careful about decreasing the dose or spacing the cycles to minimize those problems.”

Castillo noted that neuropathy can also be caused by the disease, and affects one in four patients he treats for WM.

It’s important to determine the reason for the neuropathy before treating it in patients with WM, according to Castillo. “We need to prove that neuropathy is related to the disease,” he said. “Clinicians may assume there’s a connection, but when they go deeper, (they) find that a patient has diabetes or vitamin B12 deficiency or Lyme disease.” Those conditions can also lead to neuropathy.

Castillo suggested that patients with neuropathy see both a specialist in WM and a neurologist who specializes in neuropathy so that thorough testing will be done. When patients have neuropathy, care teams should avoid WM treatments that may worsen it, he said.

Overall, Castillo said, there is a lot of hope on the horizon for the WM community. “We’re collecting data every year at the national level, and we’ve been encouraged by seeing that the survival of patients with WM keeps getting longer,” he said. “The future is very bright, and what’s coming out of clinical trials and our labs and clinics will help to move the field forward and make patients feel better, live longer and enjoy their lives as much as they can.”

Features

Treating relapsed Waldenstrom’s macroglobulinemia takes an individualized approach from a growing list of options.

Making It Personal With Waldenstrom's Macroglobulinemia

Shannon Vits was 16 when her menstrual periods stopped in 2015. She wasn’t worried, attributing the problem to her athletic activity with the poms dance team, but after the season ended, her periods didn’t return.

She consulted her doctor; blood tests confirmed an elevated testosterone level and a pelvic ultrasound showed a small mass on her right ovary. Vits was referred to a gynecologic surgical oncologist, who ultimately removed the ovary after finding an 8.4-centimeter Sertoli-Leydig cell tumor (SLCT) there.

The condition, which is exceedingly rare, is thought to develop in hormone- releasing ovarian cells that build connective tissue (made up of different cells that can develop into more common ovarian cancer). Standard treatment is surgery, sometimes followed by chemotherapy.

“Short of a tertiary referral center (where specialists practice), any oncologist will see (just) a handful of malignant Sertoli-Leydig cell tumors,” says Dr. Steven A. Vasilev, a gynecologic oncologist in Santa Monica, California. “They will see many more benign (SLCTs), but those are still rather rare, too.”

After her surgery, Vits was monitored every four months with blood tests and ultrasounds. During a January 2018 follow-up, the doctor found a growth on her left ovary, along with a slightly elevated testosterone level. By March, the growth had almost doubled in size. The doctor removed it along with most of Vits’ left ovary, leaving enough of the reproductive organ to retrieve eggs for future in vitro fertilization.

“It was my first year in college, and I was getting used to being away from home — that threw me for a big loop,” Vits says. She missed five weeks of classes and returned just before final exams. The remainder of her left ovary was removed in July after two rounds of egg retrieval.

Those familiar with SLCT might have recognized the cessation of Vits’ periods as a symptom. Up to half of these tumors can stop menstruation by releasing testosterone. Elevated levels of the hormone can also sometimes cause the development of male characteristics, such as a deepening voice and facial hair.

Vits had something else in common with most others who develop SLCT: a young age. Unlike most ovarian tumors, SLCT is generally a young person’s disease, affecting women under 30. The fact that Vits’ mother had her left ovary removed in 1979 after receiving a diagnosis of a rare granulosa cell tumor might be meaningful, too: Both types of ovarian masses are stromal cell tumors that can be caused by an inherited mutation of the DICER1 gene.

There are more than 30 types of ovarian cancer, classified by cell type. SLCTs likely arise from sex cord-stromal cells, which release hormones and build connective tissue for the ovarian structures. Both Sertoli and Leydig cells are typically found in the testes. Sertoli cells support sperm cells, and Leydig cells produce testosterone. Leydig cells are also found in the ovaries, where they rarely cause problems.

As a category, sex-cord stromal tumors make up 7% of all primary ovarian tumors. SLCTs represent just 0.5% of all ovarian tumors, making them a small percentage even of stromal tumors.

Almost all SLCTs — 98% &mdash; are found in just one ovary, and at surgery, 80% are considered stage 1 and have not spread. Patients with stage 1 SLCT tumors have a five-year survival rate of 92.3%, which drops to 33.3% at stage 2 or greater. Those with well-differentiated tumors &mdash; the cells in the mass look close to normal &mdash; have almost a 100% five-year survival rate compared with 77.8% for patients with moderately or poorly differentiated tumors, in which cells appear more abnormal and aggressive.

Women with tumors that are poorly differentiated or have heterologous elements (tissues from areas other than the cancer’s site of development, such as immature cartilage or skeletal muscle components) have a greater risk of relapse than those with well-differentiated tumors, who are usually cured with surgery alone, says Dr. David M. Gershenson, a professor of gynecologic oncology at The University of Texas MD Anderson Cancer Center in Houston. Tumors with a heterologous element have a relapse rate of around 20%, whereas poorly differentiated tumors — even early-stage ones &mdash; have a 50% to 60% risk of relapse. “The degree of differentiation is probably the most important factor in prognosis and risk of relapse,” he says.

Opinions differ as to whether an SLCT is cancer. The National Institutes of Health lists it as a cancer, and Gershenson agrees with that definition. “Essentially all SLCTs are malignant; none are benign,” he says — there are simply differences in their aggressiveness.

Dr. Kris Ann Schultz, a pediatric hematologist and oncologist and principal investigator and founder of the International Ovarian and Testicular Stromal Tumor (OTST) Registry at Children’s Minnesota, encourages patients to not think of SLCT in terms of cancer or not cancer but, instead, to consider any form of it to be serious.

About 75% of SLCTs are diagnosed in women age 30 and younger. Between 30% and 50% of the tumors release testosterone, which in one-third of cases leads to symptoms of virilization, or the development of male characteristics — a deepening voice, enlarged clitoris, facial hair, decreased breast size and cessation of menstrual periods.

Some symptoms, such as hair growth and vocal changes, may reverse after treatment, but others, such as an enlarged clitoris and smaller breasts, may remain.

The tumor can also cause pelvic pain and swelling, fatigue and acne. “You don’t have to have all those symptoms, but if you have (any of) those symptoms and you see an ovarian mass, think of this,” Schultz says.

Jennifer Nickle, who was 43 when she received her diagnosis in 2015, did not fall into the expected age group. Perhaps that — along with the rarity of the tumor type &mdash; is why she received an initial misdiagnosis of early menopause, for which she was prescribed iron supplements for anemia.

She had already seen her doctor for a year because of mild pelvic pain, chronic diarrhea and fatigue, as well as her period ending. Unhappy with the continued symptoms, Nickle switched doctors in 2015. By that point, she felt a golf ball-size mass when she pressed on her abdominal area. Her new gynecologist could not see a mass on an ultrasound — it was blocked by what the doctor thought was a large fibroid &mdash; but it was visible on a CT scan. Surgery was scheduled to remove both ovaries and the uterus as a precaution.

Before surgery, Nickle’s doctor did a workup to learn more about the mass. She ordered a blood test to screen for elevated levels of a protein called cancer antigen 125, which can indicate ovarian cancer. Nickle’s levels were only slightly elevated, so her doctor ruled out that diagnosis. Patients like Nickle, who have symptoms of virilization, should also get their androgen and testosterone levels checked before and after surgery; rarely, estrogen may be elevated. “Even if they’re not displaying virilization, they still may have elevated levels,” Vasilev says. If an SLCT is not suspected before the operation but diagnosed afterward, hormone levels should then be checked to use as a baseline, he says; this must be done as soon as possible, before the patient leaves the hospital, because levels drop quickly after surgery.

During an operation, a surgeon may ask pathologists to analyze tumor tissue to help determine the type of disease. Even well-versed pathologists may not be comfortable making an SLCT diagnosis during surgery, but if they do suspect SLCT at that time, the surgeon can biopsy other areas or sample fluid to look for cell spread outside the ovarian mass; this staging process can affect the type of treatment a patient receives. It’s important that the tumor remain intact during removal, because rupture will advance its staging and require chemotherapy that may not otherwise have been needed, Vasilev says.

Unless a patient has a simple cyst, he recommends choosing a hospital over an outpatient surgicenter, which won’t be able to have a pathologist analyze tissue during surgery. Also, surgicenters have limited access to surgeons and pathologists who have experience with rare tumors.

Even in the hospital, not all gynecologists, OB/GYNs or oncologists have that experience. Gershenson recommends that patients see a surgeon who is a gynecologic oncologist for their tumor workup and removal, if possible, and get treatment from someone familiar with SLCT. “If somebody doesn’t have expertise in dealing with ovarian malignancies, a number of errors can be made with management of surgery,” he says. Not only can the tumor rupture, but an ill-informed surgeon may remove the remaining ovary and uterus even if it’s not involved in the illness, rather than perform fertility-sparing surgery, he adds.

SLCTs that some consider benign are often found incidentally, after treatment for some- thing else, Vasilev says. He estimates that in those cases, less than half of patients get the appropriate workup and staging. The concern in overlooking this, he says, is that a nonaggressive but larger SLCT could develop malignant features if left in place.

Identifying any genetic mutations that contribute to an SLCT’s development and growth is important, according to Vasilev. In the near future, he says, a routine way to determine this may involve blood tests, done before surgery, to check levels of circulating tumor DNA. This kind of test, known as a liquid biopsy, analyzes the DNA shed into the bloodstream by tumor cells as they die, making it possible to identify mutations associated with the cancer. This testing is available now, and although it is not considered ready for routine use, its role is being evaluated.

In many cancer types, knowing which mutations are present can help doctors choose treatments that target those aberrations. These kinds of treatments are not yet available for SLCTs, but identifying a patient’s DICER1 gene mutation can help establish the diagnosis by process of elimination: “Gynandroblastoma is the only other ovarian tumor that is associated with this mutation at any significant frequency,” says Dr. Anthony N. Karnezis, a gynecologic pathologist and an associate professor at the University of California, Davis. Knowing that a patient has the mutation can also help advance research and show that family members should be screened with the help of a genetic counselor, he says.

An inherited DICER1 mutation, present in more than half of SLCT cases, is also associated with a higher chance of developing other kinds of tumors, including pleuropulmonary blastomas of the lung and masses in the thyroid, kidney brain and cervix. Because 80% of people born with the DICER1 mutation inherited it from their parents, Schultz says, other family members may also have the mutation. Screening protocols for various tumors are available to check family members with the DICER1 mutation, from childhood through adulthood. “For some, (the mutation) is an entry point into surveillance that can be lifesaving,” Schultz says.

For example, she says, one woman with a DICER1 mutation in the OTST Registry had her 3-month-old son tested. He was positive for the mutation and underwent lung imaging, which revealed a lung cyst. Surgeons found it was a type 1 pleuropulmonary blastoma and removed it before it could turn into a more dangerous type 2 or 3 solid tumor, requiring more treatment.

Nickle is negative for the DICER1 mutation, so her family did not need testing. Vits tested positive, as did her mother and maternal uncle.

Another recently identified mutation associated with SLCT is FOXL2, which does not appear in people who have the DICER1 mutation. Karnezis says that just two publications to date identified FOXL2 mutations in SLCT and more research is needed, but one study found the mutations in 19% of these tumors. People with this mutation receive SLCT diagnoses at a median age of 79.5, much later in life than those with DICER1 mutations.

In cases of SLCT, FOXL2 mutations are not inherited, so these patients do not need genetic counseling.

In its clinical guidelines for treating SLCT, the National Comprehensive Cancer Network (NCCN) recommends fertility-sparing surgery in stages 1a to 1c and removal of the affected ovary in all other stages. If the risk of relapse is 20% or greater, Gershenson says, additional (adjuvant) treatment is considered. The NCCN suggests platinum-based chemotherapy after surgery in stages 2 to 4 and possibly stage 1 intermediate- or high-risk disease. Gershenson says there is no absolute standard, because no reported randomized clinical trials have been completed due to the extreme rarity of the condition.

Now, however, Dr. Jubilee Brown, professor and associate director of gynecologic oncology at Levine Cancer Institute in Charlotte, North Carolina, is enrolling women with newly diagnosed ovarian sex cord tumors in a study, GOG-0264, which will compare the effectiveness of various chemotherapy regimens, Schultz says.

 is also studying this tumor type, as is the 

International Pleuropulmonary Blastoma/DICER1 Registry

. “The goals of both registries are to further understand what causes these tumors, how to detect them at the earliest possible time and how to treat them in the most effective way with the least toxicity,” Schultz says.

The most common chemotherapy regimens for SLCT are paclitaxel plus carboplatin and the regimen of bleomycin, etoposide and cisplatin, known as BEP. “In general, SLCTs are not that sensitive to chemotherapy. Chemotherapy is only moderately effective,” Gershenson says. A recent study in the Journal of Gynecologic Oncology showed that adjuvant chemotherapy for patients with SLCT had no clear benefit for early-stage disease but was associated with improved survival for those with advanced disease.

Patients whose disease relapses after primary treatment may get additional surgery followed by high-dose chemotherapy, although surgery may not be appropriate if the disease has spread widely. Clinical trials may also be options in those cases.

Radiation is not typically used instead of chemotherapy, Gershenson says, unless metastatic disease causes symptoms in a specific area and surgery isn’t an option. “We don’t have any meaningful information on immunotherapy for SLCT at this point,” he adds.

Based on her tumor’s characteristics and in-depth discussions with experts, Vits decided to forgo chemo- therapy. Although she had a second incidence of SLCT, it was not a recurrence but a new tumor, on which several pathologists weighed in. One said it was moderately differentiated, and another believed it was well differentiated. Her doctors recommended adjuvant chemotherapy, but Vits felt that because the tumor was completely removed, chemotherapy side effects were not worth the risk. She continues to get her blood and testosterone levels checked every four months and also undergoes pelvic and thyroid ultrasounds.

Nickle’s 12-centimeter tumor was poorly differentiated with heterologous elements, and she followed her doctors’ recommendations for three rounds of postsurgical BEP. She had a difficult time with the chemotherapy and has some continuing side effects that could be associated with that treatment, her surgery and/or menopause: chemo brain, swelling in her hands and feet, and elevated cholesterol and liver enzymes. She follows up with her local gynecologist every four to six months for lung and abdominal/pelvic CT scans and bloodwork.

Nickle said she’s learned not to ignore any symptoms, no matter how small. Her advice for those with a new SLCT diagnosis: Fully research chemotherapy before agreeing to it. She recognizes that the treatment may be why she hasn’t had a recurrence, and she does not necessarily regret receiving it, but she says, “I wish I had researched it a little more before jumping in. I was not fully aware of the side effects and problems I would have going through chemo.”

A rare type of ovarian tumor can raise testosterone levels, causing women to develop male characteristics. The main treatments: surgery and chemotherapy.

Hormones Gone Mad in a Rare Type of Ovarian Cancer

Terry Diaz is sorry she ever got breast implants.

She had them placed in 2006 due to changes in her breasts after nursing three sons, and her surgeon told her they were safe saline implants that would last a lifetime without side effects, except for potential rupture if she was hit hard in the chest.

Two months later, Diaz began having migraines and unexplained weight gain — and that was just the start of her problems.

“Breast implant illness has cost me everything,” she told a Food and Drug Administration (FDA) public advisory committee that heard testimony in March about the dangers of breast implants and considered how to regulate the industry so that women are better protected. In addition to patients, surgeons and implant manufacturers testified.

Diaz described being “bedridden and waiting to die” and said she couldn’t climb stairs after she developed a group of autoimmune symptoms that many patients refer to as breast implant illness. “l had to close my thriving business, and I’m in the process of being accepted into Chapter 13 and home loan modification, but still may lose my home. I can no longer afford health insurance or medical care. Today, I’m no longer bedridden and about 85% better, and the only medical procedure I had was explantation of my implants. I lost 10 years of my life due to ‘safe’ implants.”

Diaz was one of many who gave emotional testimony during the two-day hearing, including others with breast implant illness and some who said their implants gave them a new kind of cancer called breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). The patients called for better informed consent for women considering implants, and some asked that the type of implant most associated with these illnesses — which has a textured surface &mdash; be taken off the U.S. market.

While the FDA declined to ban any implants, it issued a call July 24 for implant maker Allergan to voluntarily recall specific models of textured implants associated with cases of the cancer, as well as two types of tissue expanders.

“Although the overall incidence of BIA-ALCL appears to be relatively low, once the evidence indicated that a specific manufacturer’s product appeared to be directly linked to significant patient harm, including death, the FDA took action to alert the firm to new evidence indicating a recall is warranted to protect women’s health,” said Dr. Amy Abernethy, the FDA’s principal deputy commissioner. 

As of July 24, the FDA had records of 573 cases of BIA-ALCL and 33 patient deaths from it across the globe; of these cases, 481 are associated with Allergan implants.

“FDA analysis demonstrates that the risk of BIA-ALCL with Allergan BIOCELL textured implants is approximately six times the risk of BIA-ALCL with textured implants from other manufacturers marketing in the U.S., and continued distribution of Allergan’s BIOCELL textured breast products/implants would likely cause serious, adverse health consequences and potentially death from BIA-ALCL,” the FDA wrote in a 

Allergan responded to the FDA’s request and has notified the agency that it is issuing a worldwide recall of its BIOCELL textured breast implant products, including: Natrelle Saline-Filled breast implants, Natrelle Silicone-Filled breast implants, Natrelle Inspira Silicone-Filled breast implants and Natrelle 410 Highly Cohesive Anatomically Shaped Silicone-Filled breast implants. The recall also includes tissue expanders used by patients prior to breast augmentation or reconstruc- tion, including: Natrelle 133 Plus Tissue Expander and Natrelle 133 Tissue Expander with Suture Tabs.

In its safety communication statement to patients who have or are considering breast implants — as well as their health care professionals &mdash; the FDA outlined the known risks of implants and what patients should know when checking for symptoms of BIA-ALCL, such as swelling and pain in their breasts. “The FDA does not recommend removal (of implants) for patients without symptoms due to potential risks, but we provide helpful information for patients and providers to consider when discussing next steps,” said Dr. Jeff Shuren, director of the FDA’s Center for Devices and Radiological Health.

In the spring, prior to the FDA’s request for the voluntary recall, Canada, France and the Netherlands banned some textured implants as a precaution.

At its March hearing, the FDA promised to further study the issue of breast implant dangers while making sure that women who plan to get implants are aware of these concerns.

In a statement, the FDA pledged to better inform women and their doctors that the risk of BIA-ALCL rises when textured implants are used and that there seems to be an autoimmune syndrome tied to implants in general. The agency may call for a boxed warning and patient decision checklist to be included with product labeling and will seek to incorporate ingredient lists into implant labels, it said in the statement by Abernethy and Shuren.

The FDA also said it will continue to inform health care providers through a letter about BIA-ALCL and other breast implant risks and will educate pathologists about when to test for the cancer.

The agency plans to publicly share reports made about cases of BIA-ALCL and breast implant illness. Manufacturers used to report medical problems associated with their implants in summary form but now will file individual reports in the Manufacturer and User Facility Device Experience (

) database, where past data summarized in reports will also be made available.

Finally, the FDA will partner with registries such as 

, which collects data on patients with BIA-ALCL, and the 

, which collects data on the safety and performance of implants. Both are run by the Plastic Surgery Foundation. The agency has called on organizers of such registries to encourage more health care providers to participate and contribute information about patient health history, as well as to make the data more public and transparent.

During the hearing, the committee also agreed that more research must be done regarding breast implants’ role in the development of cancer and autoimmune conditions. Dr. Josef Zundorf of the German Federal Institute for Drugs and Medical Devices testified that an international consortium will prepare research proposals on these topics to be considered in the second half of this year.

First identified about 20 years ago, BIA-ALCL is a rare type of non-Hodgkin lymphoma that arises specifically in women with implants. The FDA first warned women about BIA-ALCL in 2011.

Breast implant illness, meanwhile, involves a constellation of autoimmune issues that can include chronic fatigue, fevers, brain fog and joint pain. Either can affect women who get implants after mastectomy due to breast cancer or a predisposition to the disease.

“Four years ago, I was diagnosed with BIA-ALCL, stage 4, from six-year-old implants, and life as I knew it ceased to exist,” Terri McGregor, of Ontario, Canada, said at the meeting. McGregor said she was treated with chemotherapy, the targeted drug Adcetris (brentuximab vedotin) and a stem cell transplant — which gave her another type of cancer. “The isolation and betrayal

of our cancer is compounded by the dismissive PR campaign of industry. They stayed silent, and when our existence could no longer be denied, we were merely portrayed as anomalies.”

Textured implants, as opposed to uniformly smooth ones, have been associated with BIA-ALCL, although in some cases the type used is unknown. The disease can arise from implants filled with either saline or silicone, according to the American Society for Aesthetic Plastic Surgery.

The chances that a woman with a breast implant will develop BIA-ALCL are between 1 in 3,000 and 1 in 30,000, and the disease typically occurs about a decade after implant, said experts who testified.

There are several theories about what causes the cancer, said Raina Dauria of implant manufacturer Mentor. One is that the increased surface area on textured implants provides a foothold for bacteria introduced during surgery, which can result in long-term inflammation and eventually disease. Another theory blames particulates in the breast capsule — tissue that forms around an implant in about half of women who use them &mdash; or free silicone particles on implant surfaces. Experts testified that some women may be genetically susceptible to BIA-ALCL but added that more research is needed.

Representatives of breast implant manufacturers called BIA-ALCL a slow-growing T-cell cancer and noted that it’s usually curable through removal of implants and any affected surrounding tissue. When health insurance doesn’t cover BIA-ALCL-related expenses, “we’ve committed internal resources to assist surgeons for patients in these circumstances,” Brown said. “We give financial assistance for evaluation and any treatment associated with BIA-ALCL.”

A patient, however, accused the representatives of trivializing what she called a “manmade cancer.”

Jennifer Cook of Georgia, who received a diagnosis of BIA-ALCL in 2017, said that surgeons should be required to provide informed consent about the risk of the disease. Cook said she received her implants as part of a clinical trial and signed a consent form stating that there was no established scientific evidence linking them with cancer. Over many years, she said, no one informed her that a risk had been established, and she found out only by watching a play on the topic at the middle school where she taught.

“I was shocked and thought I would need to reprimand the students for making false statements, and then I learned the horrifying truth,” Cook said. “Shortly thereafter, I recognized that I had symptoms. I was blindsided. I was deceived, and I don’t want anyone else to go through that.”

Breast implant illness, meanwhile, seems to occur more often in women who have a personal or family history of autoimmune conditions, experts said, suggesting that more research is needed and that these women should be warned before getting implants. One expert said that this group should opt against implants.

Patients called on authorities to officially name the condition, formally tie it to breast implants and stop dismissing women who complain of symptoms. Although the syndrome is not recognized by many doctors or health insurers, Facebook has more than 170 groups and communities devoted to it; the largest includes more than 70,000 members, according to Jamee Cook, of Breast Implant Victim Advocacy.

Some members of the public, including some surgeons and a breast cancer survivor who has them, testified in favor of implants, saying that they are largely safe and give a meaningful psychological boost to women who have deformities or have undergone mastectomy and seek augmentation.

Patients, however, told horror stories of declining health, hospitalizations and lost jobs. Some suggested that the implants that sickened them also left their children — conceived or breastfed while the implants were in place &mdash; with lasting health problems.

The patients who testified said that surgeons should be more upfront about potential side effects and the high likelihood that reoperation — an expense that may not be covered by health insurance &mdash; will be needed over time due to leakage, rupture, capsular contracture (a sometimes painful complication that can occur in the tissue that forms around an implant) or other health problems. Some surgeons urged the FDA to authorize high-resolution ultra- sound as a cheaper, more reliable way of checking for breast implant rupture than the only modality currently approved &mdash; MRI, which can cost women $2,600 out of pocket and is therefore inaccessible to many. They cited studies supporting the accuracy and feasibility of ultrasound for this purpose.

Patient requests also included research about the safety of implants during breastfeeding, an FDA requirement that manufacturers reveal the ingredients in their implants and the removal of textured models from the market.

In 2018, less than 10% of the breast implants used in the United States were textured, and the rest were smooth, the FDA said in its statement. Stephanie Manson Brown, a representative of implant manufacturer Allergan, noted that the opposite is true outside the United States.

Brown stated that textured implants have a role to play because they are anatomically shaped, stay in place better than smooth models (which are round) and may be associated with a lower rate of capsular contracture. One panelist questioned whether even smooth implants provide a safe option, since many surgeons — in a practice not approved by the FDA &mdash; wrap mesh around the implants to better keep them in place.

Manufacturers also discussed their efforts to track patients and their outcomes in FDA-mandated company registries. Registries have been required since 2006, when silicone gel implants were put back on the market after being removed in 1992 due to concerns that they were tied to illnesses.

Two companies, Mentor and Sientra, recently received letters from the FDA citing them for insufficient follow-up with users of their products. In addition, panelists complained that the studies the companies submitted to the FDA have different formats and timelines and can’t be compared.

Manufacturers’ representatives said that it’s challenging to collect this information because many women choose to leave the studies. Some patients countered that they had remained engaged in follow-up studies — until manufacturers canceled them.

“These post-approval studies were required by the FDA, but they’ve been flawed and incomplete and not reliable,” Jamee Cook said. “There’s been a failure to complete studies. Some women got lymphoma that would have been documented (if the studies had continued). Some women were told a study stopped or that the doctor had dropped out, or women were dropped after reporting symptoms. We’re missing data because of this.”

A national registry should track issues including patient and family health history and prior use of breast implants, said Dr. Binita Ashar of the Center for Diseases and Radiological Health. Zundorf said it would be helpful to develop a national system for classifying the surface texture of implants, making it possible to compare the findings of registries tracking BIA-ALCL across the world.

Before getting breast implants, women should know about a cancer (breast implant-associated anaplastic large cell lymphoma) and an autoimmune syndrome associated with them.

The Truth About Implants

After Nichol Miller was diagnosed with a high-grade soft tissue sarcoma in her leg in the fall of 2014, she underwent broad-spectrum chemotherapy and surgery at Oregon Health and Science University Hospital, near her home in Portland. Neither treatment stopped the fast-spreading cancer.

Her physicians rechecked the results of the next-generation genomic testing that was conducted on her tumor samples. They discovered that her tumor had a rare mutation called NTRK gene fusion — and told her about a clinical trial opening in Denver for a drug targeting that abnormality. In March 2015, Miller was the first patient with such a fusion to enroll in the trial; by then, she was in a wheelchair and relied on supplemental oxygen to breathe because tumors filled 90% of her lungs.

"The testing that detected the NTRK gene fusion is what really made the difference between life and death,” says survivor Nichol Miller.

Within three days of starting the drug, a twice-daily pill, Miller could sit up and talk in complete sentences. A month later, she was off the oxygen; by six weeks, she could go horseback riding. Her scans have shown no evidence of cancer for the past three years, and she remains on the drug, now called Vitrakvi (larotrectinib). Unlike chemotherapy, Vitrakvi doesn’t cause many side effects — Miller has mild body aches once in a while, she says &mdash; so she can stay on the drug as long as it keeps her cancer at bay.

“The testing that detected the NTRK gene fusion is what really made the difference between life and death,” says Miller, 45, a mother of three teenagers who now travels throughout the country telling her story at cancer-related conferences. “It speaks to the efficacy of targeted therapies.”

The Food and Drug Administration approved Vitrakvi in November 2018 to treat adults and children with solid tumors of any type originating anywhere in the body if the patients have fusions in one of three NTRK (neurotrophic receptor tyrosine kinase) genes. It was the first drug on the market to target NTRK fusions and the second FDA approval based on the biological characteristics of tumors rather than their location in the body. The initial one was the immune-activating drug Keytruda (pembrolizumab), approved for patients with solid tumors characterized as microsatellite instability (MSI)-high or mismatch repair deficient. Tumors with these genetic abnormalities have trouble repairing their own DNA when it’s damaged.

An NTRK fusion occurs when a piece of the chromosome that contains a coding part of an NTRK gene splits off and connects to an unrelated gene on a different chromosome.

That sparks the production of a chimeric — or fusion &mdash; protein composed of uncontrolled TRK enzymes, which promote cancer growth. NTRK fusions are rare: A recent sampling of more than 13,000 tumors found the abnormality in just 0.31% of adult cancers and 0.34% of pediatric tumors. Each year, an estimated 5,000 patients receive this diagnosis. NTRK fusions appear in some common cancers, such as non-small cell lung, sarcoma and colon, as well as some rare cancers, including secretary breast carcinoma and cellular or mixed congenital mesoblastic nephroma.

NTRK fusions in cancer were discovered in the 1980s, and at first, oncology researchers feared they couldn’t be targeted with drugs. That’s because three NTRK genes play critical roles in the development and survival of nerve cells, raising the possibility that altering the genes could cause dangerous neurological side effects. But as researchers continued to study gene fusions, they realized those fears were unfounded.

“Gene fusions are unique to cancer cells,” says Dr. George Demetri, director of the sarcoma center at Dana- Farber Cancer Institute in Boston. That makes them ideal targets, because drugs designed to block the effects of protein that arises from gene fusions are unlikely to affect healthy tissues, he explains. The side effects reported during the Vitrakvi trials included mild fatigue, dizziness and digestive issues, but for the most part, “the drug is remarkably well tolerated,” Demetri says.

Vitrakvi was approved by the FDA based on data from three studies involving 55 patients with NTRK fusions who had run out of treatment options. The drug produced a 75% overall response rate — the proportion of patients who responded partially or completely to the therapy &mdash; across a range of tumor types, including thyroid cancer, lung cancer and soft tissue sarcoma. Of those responses, 39% lasted a year or longer.

In May 2019, researchers presented updated results from two of the Vitrakvi trials. At that point, 83 adults had received the drug, and among the 74 patients who could be evaluated, the response rate was 76%.

Children fared even better. Of 34 pediatric patients who could be evaluated, the overall response rate was 94%. Most of the children had stayed on the drug for more than

a year, with some still taking it two years after the trial began.

Kayley Leeds says the drug Vitrakvi has given her son, Ashton, “his life back” after thyroid cancer. Here, Leeds and her husband, Shayne, are pictured with their son

Ashton Leeds was eight years old and battling stage 4 thyroid cancer when he was admitted into a clinical trial of Vitrakvi at Seattle Children’s Hospital. Ashton, who is from Claresholm, Alberta, received his diagnosis in the fall of 2014, when he was just 5, and was treated with surgery in Toronto and then with radioactive iodine at a children’s hospital in Calgary. But his cancer had spread to his lungs and kept coming back, and his doctors ran out of treatment options by early 2017.

Then Ashton’s mother, Kayley Leeds, got a phone call from a researcher who asked to test her son’s tumor samples and include the results in a database of rare tumors. She agreed. A few months later, she got a call informing her of Ashton’s NTRK gene fusion. Ashton’s doctors matched him with the clinical trial in Seattle.

Ashton started the drug in July 2017, and within two months, most of his tumors disappeared. He has a few spots in his lung, but “he’s able to play soccer again and run and play with his friends,” his mother says. “It has given him his life back.”

Several tools can detect NTRK fusions in tumor samples. Reasonably inexpensive immunohistochemistry tests can identify proteins made by fused genes, and other laboratory assays can spot abnormal genes and chromosomes. Many oncologists favor more comprehensive next-generation sequencing (NGS) of tumor tissue, which can detect several gene alterations, including NTRK fusions, in a single test.

“These days, with advances in technology, we can check more than 400 cancer-related genes in one shot, including NTRK,” says Dr. Shumei Kato, a medical oncologist with Moores Cancer Center at University of California, San Diego Health and an assistant professor of medicine at the UC San Diego School of Medicine. If an NTRK fusion is detected, “that can be life-changing for certain patients,” Kato says.

The advantage of using NGS testing over other methods, he adds, is that it may turn up abnormalities in other genes, such as ROS1 and ALK in lung cancer, which can be targeted with different drugs.

Dr. Benjamin Levy, clinical director of medical oncology at Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital in Washington, D.C., believes that most patients with lung cancer should have NGS testing because of the potential of targeted drugs like Vitrakvi to improve their prognosis. But arranging this for every patient can be challenging: Sometimes there isn’t enough tumor tissue collected during a biopsy to complete NGS testing, he says, or physicians become overwhelmed by the logistics involved in ordering the tests.

“That has to change,” Levy says, adding that patients should insist on NGS testing of their tumors: “Now we have these wonderful therapies that are emblematic of precision medicine.” To help oncologists choose therapies based on the results of NGS tests, many cancer centers have put together molecular tumor boards, groups of physicians who work together to interpret the data and recommend personalized treatments based on the results.

Drug developers are working on the next generation of NTRK-inhibiting drugs, which could help patients who initially respond well to Vitrakvi but whose cancers then become resistant. One of those drugs, Loxo-195, was designed to counteract a common mechanism of resistance called TRK kinase mutations. An ongoing clinical trial of the drug is recruiting children and adults with advanced, NTRK fusion-positive solid tumors that have stopped responding to Vitrakvi.

Acra Samuels, whose liver tumors responded extremely well to Vitrakvi, walks near her Montana home with her husband, Chris, and their sons, Chase, Holden and Austin. 

Acra Samuels obtained both Vitrakvi and Loxo-195 on a trial basis, the first drug in 2016 and the follow-up medicine a year later, when tumors in her liver became resistant to Vitrakvi and spread throughout her abdominal cavity. “I had not been able to eat, I could hardly walk and there were tumors protruding from my abdomen,” says Samuels, who traveled from her home in Big Sky, Montana, to Dana-Farber for treatment. “It was clear I wouldn’t have long at all if there wasn’t another solution.”

One day after starting Loxo-195, Samuels started eating again; five days later, virtually all the tumors had receded. Samuels remains on the drug with no evidence of cancer in her body. Her only side effect is a bit of dizziness that prevents her from driving at night. “It’s nothing short of a miracle,” says Samuels, 48, a mother of three who owns a vacation rental business with her husband.

Data from an early trial of Loxo-195 reported in April showed a 34% response rate to the drug. Twenty patients had TRK kinase mutations, and nine had a complete or partial response. The three patients in the trial who grew resistant to Vitrakvi for other reasons did not respond to Loxo-195.

Patients can become resistant to targeted drugs in many ways, Kato says, which makes treating NTRK- fusion-driven cancers challenging. “Unfortunately, cancer can be smart,” he says. “Tumors create new mutations in NTRK that allow the cancer to survive.” Another potential problem: There are other NTRK aberrations, including amplifications, or abnormal increases in the number of copies of the gene. “We need to find out what role they play in cancer,” Kato says.

A new drug can break the circuit of cancer-causing effects that develop when certain genes fuse.

Rare Cancers Special Issue | CURE

New Therapies Making Progress in Rare Cancers

Making It Personal With Waldenstrom's Macroglobulinemia

Hormones Gone Mad in a Rare Type of Ovarian Cancer

The Truth About Implants

Blowing a Fuse: Fighting NTRK Gene Fusions in Cancer

Studying Rare Diseases Is Difficult, But Innovation Drives Results

Seeking Immunity: Exploring Kaposi's Sarcoma

Patients Need Facts About Rare Cancers, Like Lymphoma Associated With Breast Implants

A Rare Opportunity for Patients With Brain and Spinal Cancers

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