Heather Stringer

After giving blood in 1998, Terri Milton received a call from the donor organization alerting her that her liver enzymes were elevated. She saw her doctor, and results from a CT scan and an ultrasound showed that her liver was storing excess fat, which can be a symptom of drinking too much alcohol. But Milton, a Houston resident who was 37 at the time, never imbibed. Her doctor explained that she had nonalcoholic fatty liver disease (NAFLD), a condition that affects about 25% of the U.S. population.

The doctor described the disease as very common and nothing to worry about, and Milton experienced no symptoms at the time. Eight years later, she received a diagnosis of type 2 diabetes. Then, in 2016, she felt pain in her upper right torso and underwent surgery to remove her gallbladder. During the procedure, her surgeon discovered that Milton’s liver had a rough texture. He ordered three biopsies, which revealed advanced cirrhosis, or late-stage scarring of the liver. Eight days after the surgery, she was hospitalized because fluid was accumulating in her abdomen, leading to a 40-pound weight gain. She was experiencing ascites, a symptom of cirrhosis and impaired liver function.

Over the years, Milton’s untreated liver disease had progressed to nonalcoholic steatohepatitis (NASH), an aggressive form of fatty liver disease that leads to liver inflammation and increases

the risk of cirrhosis. In 2018, likely as a result of her progressive liver disease, Milton received the devastating news that she had liver cancer, or hepatocellular carcinoma.

To treat the cancer, her hepatologist suggested transarterial chemoembolization, which blocks the blood supply to the tumor and infuses it with chemotherapy. Now her liver shows no signs of cancer, but she still experiences fatigue and frequent infections as a result of cirrhosis. Eventually, she will need a transplant, which is possible in a small minority of patients whose cancer has not spread beyond the liver or only affects certain portions of the organ.

“I wish my doctor had explained 20 years ago that NAFLD is reversible,” says Milton, 56. “Just losing 10% to 15% of my body weight could have made a significant difference in reversing my fatty liver disease.”

The urgent need to spread this message is gaining momentum nationwide because NAFLD is the fastest- rising cause of liver cancer in Western countries.

More than 42,000 people will receive a liver cancer diagnosis this year in the United States, and data suggests that more than 14% of cases will be associated with NAFLD. Alcohol-related cirrhosis is another major risk factor for liver cancer, but a third is becoming less of a threat: hepatitis B and C infections are causing fewer cases of liver cancer due to advances in antiviral therapies that reduced the progression of these conditions to cirrhosis. The risk factors for NAFLD include obesity, type 2 diabetes and high cholesterol, and researchers are still trying to understand why certain people with this disease progress to NASH, cirrhosis and cancer and others do not.

Findings from a new study also showed a 91% higher risk of developing several forms of cancer in people with NAFLD compared with those without the disease, with the highest risk associated with liver, pancreatic, stomach, colon and uterine cancers.

The researchers were interested in understanding whether the combination of obesity and NAFLD influenced cancer risk, and they found that people with a high body mass index (BMI) and NAFLD faced double the risk of cancer compared with people who were obese only. “This raises questions about the impact of fatty liver,” says study author Dr. Alina Allen, a gastroenterologist at Mayo Clinic in Rochester, Minnesota. “It could be a biomarker for cancer.”

Cancer risk may increase in part because excess fat in the liver, known as steatosis, can stimulate inflammatory cytokines, which are proteins important in cell signaling,

says Dr. Arthur McCullough, a hepatologist at Cleveland Clinic. “This inflammation creates oxidative stress, which can cause alterations in cell growth and tumor suppressor genes,” he explains.

Studies also suggest that the gut microbiome may be linked to NAFLD and NASH. “We know that the nature of the gut bacteria in the intestines can have profound effects on liver function,” says Dr. Scott Friedman, dean for therapeutic discovery and chief of the division of liver diseases at Icahn School of Medicine at Mount Sinai in New York City. “Bacteria can produce different products that activate inflammation in the liver, and we are still trying to understand which bacteria and products produce liver injury.”

Although the evidence linking NAFLD to cancer is sobering, researchers like Allen make it clear to the people they treat that fat and even scar tissue in the liver can disappear if patients lose weight, limit sugar and exercise more.

“I think the reversibility of many forms of fatty liver disease needs greater attention in primary care settings, and we will make the biggest gains by educating the public,” says Dr. Julia Wattacheril, director of the NAFLD program at New York-Presbyterian/Columbia University Irving Medical Center in New York City. “I’ve found that a significant number of patients lose weight when they are told that they have earlier stages of fatty liver disease that are most likely reversible.”

She gathers details about a patient’s nutrition and exercise habits and discusses any barriers to implementing lifestyle changes. “Some patients may not have a safe place to walk or experience food insecurity, which is why it’s so important to get a good history first,” Wattacheril says. If needed, she can refer them to a nutritionist who provides education and guidance in developing a plan to make changes.

Early intervention is also the goal of a project led by Dr. Jessica Hawng, a professor of general internal medicine at The University of Texas MD Anderson Cancer Center in Houston. In August 2019, her team received $2.4 million in funding from the Cancer Prevention & Research Institute of Texas to screen 1,000 patients for liver cancer risk factors including hepatitis B, hepatitis C and alcohol use and metabolic conditions such as obesity and diabetes. The participants are patients at Hope Clinic in Houston, a health center for low-income, uninsured

The patients will undergo a FibroScan with the ultrasound imaging machine that detects fat, stiffening (fibrosis) and hardening (cirrhosis) of the liver. The researchers will analyze the data to determine which risk factors predict fibrosis and then develop a risk tool to help primary care providers and specialists deter- mine which patients have a high likelihood of developing NAFLD and NASH.

“The future of fatty liver disease hinges upon diagnosis, but right now there are no clear screening recommendations for physicians,” Hwang says. “We hope to change that problem with the risk tool that would be developed in our study.”

One of the challenges in the effort to reduce liver cancer is the fact that patients with underlying liver disease that can lead to cancer typically experience no symptoms until the disease has progressed. “The earlier stages of liver disease usually get detected only if patients are having a liver blood test or an abdominal imaging test for some other health issue,” Friedman says.

Tony Villiotti, 73, is trying to raise awareness about the silent disease because his NAFLD progressed to NASH, cirrhosis and ultimately liver cancer. In 2018, he founded NASH Knowledge, a nonprofit organization that provides information and resources related to liver disease, including a link to a documentary Villiotti produced to share his story. He got a diagnosis of NAFLD in 2005 at the age of 59, but his doctor didn’t raise any concerns. “He encouraged me to lose some weight, but I had been told that many times in my life,” says Villiotti, who also has type 2 diabetes. “I didn’t realize high BMI could increase my risk of developing NASH.”

After a routine blood test nine years later, Villiotti was told that his liver enzymes were highly elevated, and an  MRI showed that his condition had progressed to cirrhosis. “My first reaction was that cirrhosis was a drinker’s disease, so I thought they had the wrong person,” says Villiotti, who lives in Pittsburgh. “I felt fine, and my diabetes was under control.” He started seeing a hepatologist, who suggested that he consider getting a transplant, but Villiotti resisted the idea because he had heard that people with diabetes had difficulty tolerating the anti-rejection drugs.

In 2017, he was told he had liver cancer. He also started experiencing cirrhosis symptoms, including hepatic encephalopathy, or mental confusion caused by excess toxins in his blood. “I had a foggy brain, so I couldn’t drive or read a book, and sometimes I wandered around in the middle of the night,” Villiotti says.

He was ready to join the national transplant waiting list but unsure whether he would get a donor liver before it was too late. In March 2018, his doctor called with the good news that a liver was available. Villiotti was weak for the first few months after the trans- plant, but now he has more energy than he had in 15 years.

“I wish I had known more about this disease earlier,” he says. “Now I’m trying to help others understand that they need to talk to their doctors about NAFLD.”

Research also suggests that, along with obesity, diabetes and high cholesterol, certain gene variations can increase the chances of developing fatty liver disease. One of the earliest studies that revealed a genetic risk was the 2008 Dallas Heart Study, which included 6,000 residents of Dallas County ages 18 to 65.

The researchers found that the PNPLA3 variant was associated with steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Forty-nine percent of Hispanics in the study had the gene compared with 17% of African Americans and 23% of European Americans, and these findings prompted researchers to explore drugs that target this variant.

“It’s important to understand that there may be other ancestry groups with undetected variants that have not yet been studied,” Wattacheril says. “Patients who are thin, seemingly fit and do not have diabetes may still be at risk of NAFLD.” For example, South Asians and East Asians tend to accumulate fat in the liver at a lower BMI, yet these groups have not been studied systematically, according to Wattacheril. “The need for longitudinal studies in diverse populations is critical,” she says.

Standard treatments for liver cancer include surgery, transplant, embolization, radiation and medications such as chemotherapy or targeted drugs.

Doctors may also have a new option for treating patients who have NASH. Recent phase 3 clinical trial results were encouraging for participants who took Ocaliva (obeticholic acid), a drug that reduces inflammation in the liver. Participants took either a placebo or 10 or 25 milligrams of the medication daily for 18 months, and fibrosis improved more frequently in the groups that took the drug. “I’m excited about these results because many trials of other drugs targeting the liver have not worked,” McCullough says.

Even patients who progress to liver cancer have more treatment options than ever, says Dr. Ghassan Abou- Alfa, a medical oncologist specializing in liver cancer at Memorial Sloan Kettering Cancer Center in New York City. Tyrosine kinase inhibitors, for example, block proteins that help tumor cells grow or form new blood vessels, and the Food and Drug Administration approved three of these medications to treat liver cancer within the past few years, and another in 2007.

In 2017, the agency approved the first immunotherapy treatment for liver cancer, Opdivo (nivolumab); Keytruda (pembrolizumab) got the OK a year later. “Now we are finding that if you combine two forms of treatment, such as immunotherapy with a biologic or two immunotherapies, patients are having good outcomes,” Abou-Alfa says.

Although the number of treatments is rising, hepatologists like Dr. Sonali Paul, of The University of Chicago Medicine, are eager to, when possible, prevent liver cancer from developing. That’s why education should start early, she says. NAFLD has become the most common cause of chronic liver disease among children and adolescents, which comes as no surprise to Paul, because the obesity epidemic also affects youth.

“For now, there is no pill to treat fatty liver, and it is best to talk to patients about the risks before scarring takes effect,” she says. “If we explain to kids and adults that their livers are sick, they have a chance to change their eating and exercise habits for the long run.”

Articles

Nonalcoholic fatty liver disease can lead to cancer. Patients can reverse the damage through diet and exercise, but how can they know if they have the common condition?
 

Reversing The Course Of Nonalcoholic Fatty Liver Disease and Liver Cancer Risk

Sally Palles had just undergone a mammogram in 2015 when the radiologist entered her room and delivered upsetting news: She most likely had breast cancer. “I felt both devastated and foolish because I hadn’t scheduled a mammogram in four years, even though I’m a nurse,” says Palles, who was working at what was then called Carolinas Hospital in Florence, South Carolina.

Palles later learned that she had hormone receptor-positive (HR-positive), HER2-negative breast cancer: The disease was fueled by the hormone estrogen and expressed little or no HER2 protein, which can contribute to the growth of some breast cancers. She had a left breast mastectomy and took an anti-estrogen (also termed hormonal) medication to prevent the cancer from recurring, but eventually stopped these treatments because of severe nausea — and the fact that the disease was not progressing. “I thought the cancer was all gone and not coming back,” says Palles, now 68.

Then, in 2017, she visited an orthopedic physician after hurting her right shoulder. An X-ray revealed that the injury was caused by cancer, which had spread to bones in her arm, back and upper chest. Historically, patients with newly diagnosed metastatic HR-positive cancer have been treated with hormone therapy followed by chemotherapy once anti-estrogen medications stop working. Now these patients have an option that is successfully delaying the transition to chemotherapy: a new biological therapy known as CDK4/6 inhibitors in combination with hormone therapy.

“These targeted medications have transformed the care of HR-positive positive breast cancer,” says Dr. Payal Shah, an assistant professor at the Abramson Cancer Center at the University of Pennsylvania. “They not only improve progression-free survival (meaning they delay the time until disease worsens), but they are also well-tolerated and allow many patients to maintain a higher quality of life than they would on chemotherapy.” Furthermore, recent research is showing that these drugs can also prolong survival.

Three CDK4/6 inhibitors — Ibrance (palbociclib), Kisqali (ribociclib) and Verzenio (abemaciclib) &mdash; have been approved by the Food and Drug Administration (FDA) in the past five years to treat HR-positive, HER2-negative meta- static breast cancer in both women and men. For metastatic disease, the drugs are combined with hormonal therapies as initial or subsequent (called second-line) treatments, so pre-menopausal women must first be treated with ovarian suppression medications to induce menopause, says Dr. Michelina Cairo, a breast oncologist with Texas Oncology- Houston Memorial City.

Other types of targeted drugs also have made an appearance. Piqray (alpelisib) targets the PI3K protein, which is expressed in breast tumors that harbor a PIK3CA gene mutation, one of the more common mutations in breast cancer. The drug was approved in May in combination with Faslodex (fulvestrant), a medica- tion that blocks the action of estrogen in cancer cells. The drug duo is used to treat postmenopausal women or men with HR-positive, HER2-negative cancer that has a PIK3CA mutation and has progressed on or after initial hormonal therapy. Trial results show that it lengthens the amount of time before disease progresses. New targeted treatments are also benefiting patients with other forms of metastatic breast cancer, including those with triple-negative disease or BRCA gene mutations. Lynparza (olaparib) and Talzenna (talazoparib) were both recently approved to treat BRCA gene-mutated, HER2-negative breast cancer.

In June 2017, Palles started taking Kisqali along with Arimidex (anastrozole), a hormone therapy; this time, nausea was not a problem, because she discovered that the side effect could be mitigated by stopping her antidepressant medication. Though she felt fatigued from the treatment, the cancer was in remission for one year. Then, in spring 2018, it started growing in her cervical spine. Her tumor tested positive for the PIK3CA mutation and she recently started taking Piqray. “My hope is that I can stay on this for a long period of time, and by then something new will be available for me to try,” Palles says.

Ibrance, initially approved by the FDA in 2015 for certain patients with metastatic breast cancer, was the first CDK4/6 inhibitor to add language to its label broadening the group of patients eligible to use it: In 2017, it was approved as an initial treatment for HR-positive, HER2- negative metastatic breast cancer. Targeted treatments in this class interrupt the cancer cell cycle. “The cell cycle includes various steps, and one of those steps is a checkpoint in which the cell basically evaluates whether it has everything needed to successfully divide,” Shah says. “CDK4/6 inhibitors switch off the CDK protein and ultimately decrease the growth and division of cancer cells.”

Data from a recent phase 3 trial showed that more than 70% of previously untreated pre- and peri- menopausal patients with metastatic HR-positive, HER2-negative disease who received a combination of Kisqali and anti-estrogen therapy were alive after 42 months versus 46% of patients who received anti- estrogen therapy alone.

At a recent oncology conference, Kisqali’s manufacturer announced that, in a separate trial, the combination of Kisqali and Faslodex significantly improved overall survival as a first- and second-line treatment (used initially upon diagnosis or after the disease has progressed on another treatment) in postmenopausal women with HR-positive and HER2-negative breast cancer. Faslodex plus Verzenio has also shown improvement in overall survival based on recent trial results.

“The fact that we are seeing an improvement in overall survival is encouraging,” says Dr. Tufia Haddad, a breast oncologist at Mayo Clinic in Rochester, Minnesota. “Ultimately, what we’d like to see is a trend toward moving these drugs into the early-stage breast cancer setting.”

Researchers are studying the potential benefits of treating patients with the combination of CDK4/6 inhibitors and anti-estrogens before the disease has spread.

Physicians who regularly prescribe CDK4/6 inhibitors have also been encouraged by the minimal side effects. All three drugs, for example, can lower white blood cell counts, but this rarely leads to infections, Shah says. “These drugs are generally effective even when doses are reduced to help with side effects.”

Verzenio is more likely to cause diarrhea, which can be severe but manageable. One patient told CURE® that taking the medication halfway through her meal, rather than afterwards, made a big difference in easing diarrhea.

Though CDK4/6 inhibitors have revolutionized care for patients with metastatic HR-positive breast cancer, the disease ultimately develops resistance to these medications, says Dr. Dejan Juric, a breast oncologist and director of the Henri and Belinda Termeer Center for Targeted Therapies at Massachusetts General Hospital. “Our main goal is to develop a better understanding of the mechanisms of resistance and develop treatments to achieve longer disease control,” he says.

Juric recently was the senior author on the study that led to the approval of Piqray, the first precision oncology agent to target the PIK3CA mutation in breast cancer. About 40% of patients with HR-positive, HER2-negative breast cancer have these mutations, which usually develop early in the course of the disease, Juric says. The mutation can be detected in the tumor, but also with a blood test (known as a liquid biopsy), and the study showed that the combination of Piqray and Faslodex increased progression-free survival by more than five months in patients who had the mutation compared with the control group.

About one-third of the study participants experienced hyperglycemia (high blood sugar). “The medication targets an important pathway in normal cells that is involved in glucose metabolism, which is why patients can experience elevated levels of glucose in the blood,” says Dr. Francisco Esteva, a professor at NYU School of Medicine and director of the breast oncology program at Perlmutter Cancer Center at NYU Langone Health. He regularly tests blood sugar levels of patients on Piqray and, if needed, prescribes diabetes medications or temporarily stops the cancer treatment.

TACKLING OTHER FORMS OF ADVANCED BREAST CANCER

Targeted therapies known as AKT inhibitors are attracting attention as a possible treatment for patients with both hormone receptor-positive as well as triple-negative breast cancer, a form of the disease that does not respond to hormonal therapies or drugs that target the HER2 protein. A phase 2 study showed a median overall survival of more than 23 months when the experimental AKT inhibitor ipatasertib was added to Taxol (paclitaxel), a chemotherapy treatment, compared with 18 months for Taxol alone.

Triple-negative breast cancer also recently became the first form of the disease that could be officially treated with immunotherapy. In March, the FDA approved Tecentriq (atezolizumab), which can help the immune system recognize and attack cancer cells, in combination with the chemotherapy drug Abraxane (nab-paclitaxel) for patients with triple-negative disease whose tumors are infiltrated by immune cells expressing the protein PD-L1.

The combination was approved based on the results of a phase 3 trial that tested Abraxane with or without Tecentriq, with 451 patients assigned to each regimen. The median progression-free survival was 7.2 months versus 5.5 months among those who took the combination versus Abraxane alone, respectively. In patients whose tumors expressed the protein PD-L1, progression-free survival was 7.5 months with the combination versus 5.0 months with Abraxane alone. At an interim analysis, median overall survival was 21.3 months with the combination compared with 17.6 months with Abraxane alone. For patients whose tumors expressed PD-L1, overall survival was 25 months with the combination versus 15.5 months with Abraxane alone. Most side effects were due to chemotherapy, but there was a bit more nausea and coughing in patients who took the combination regimen. Hypothyroidism occurred in 17.3% of patients taking the combination versus 4.3% receiving chemotherapy alone.

“New studies are also exploring whether using immunotherapy earlier may be more effective,” says Dr. William Gradishar, chief of the hematology/oncology division at Northwestern University Feinberg School of Medicine and director of the Maggie Daley Center for Women’s Cancer Care in Chicago. A recent phase 3 clinical trial known as KEYNOTE- 522 showed promising results when patients with triple- negative breast cancer received the immunotherapy Keytruda (pembrolizumab) and chemotherapy before having surgery.

Researchers are also exploring how to use antibody-drug conjugates, which employ antibodies to deliver chemotherapy to cancer cells, as a potential treatment for triple-negative breast cancer. Sacituzumab govitecan (IMMU-132) is one such drug that may have potential as a future treatment for triple-negative breast cancer. “The preliminary data has shown proof of principle,” Gradishar says.

Oncologists are also seeing the benefits of targeted treatments known as PARP inhibitors for patients who have inherited BRCA1 or BRCA2 gene mutations, which includes about 5% of those with breast cancer. These mutations make it difficult for damaged DNA to repair itself, which increases the risk of developing breast cancer. PARP inhibitors interfere with an enzyme known as poly ADP-ribose polymerase (PARP), which cancer cells depend on to repair DNA. This further interferes with DNA repair and can lead to cancer cell death.

In January 2018, the FDA approved a first PARP inhibitor to treat breast cancer, Lynparza (olaparib), based on a trial that showed longer remission times and higher response rates compared with chemotherapy. The drug is used for patients with HER2-negative metastatic breast cancer in the presence of a germline (inherited) BRCA mutation. Later that year a similar drug, Talzenna (talazoparib), was approved for patients with HER2-negative disease that also tested positive for BRCA mutations. Now researchers are exploring the benefits of combining PARP inhibitors with immunotherapy, says Dr. Vandana Abramson, an assistant professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee. “These are exciting combinations because we may be able to use one drug to unleash the potential of another drug,” she says. “DNA damage caused by PARP inhibitors may create an environment that is conducive for immunotherapy to work.”

Although there is still no cure for metastatic breast cancer, oncologists like Abramson are optimistic as they see patients living longer. “We are able to offer less toxic treatments that are more effective,” she says. “Breast cancer is increasingly becoming a chronic disease because patients have effective treatment options once they develop resistance to one drug.”

Helen Black, 54, who learned in 2017 that she has metastatic breast cancer, is hopeful that she can enjoy a high quality of life for years. She was surprised by her diagnosis because the initial symptom was a tickle in the back of her throat. Black was first treated with antibiotics because an X-ray suggested pneumonia, but, in fact, breast cancer had spread to her left lung. She started chemotherapy to stabilize her lung and sought a second opinion from an oncologist at The University of Texas MD Anderson Cancer Center in Houston. Black was premenopausal, so her oncologist suggested that she have a hysterectomy before starting Ibrance combined with hormone therapy.

Black, a mother of nine, has no evidence of disease in her body now and continues working as a professional advocate for people with developmental disabilities. She took time off briefly when she was recovering from her hysterectomy and exercises regularly by biking, practicing yoga and walking. When she’s tempted to fear the future, Black remembers the woman in her breast cancer support group who has been taking Ibrance for seven years.

“When I asked my doctor what happens after Ibrance, he explained that his answer would have been very different five years ago because there were fewer treatment options,” says Black, who lives in Spokane, Washington. “He said my job is to live, and when this one stops working, we will have others to try.”

New treatments are lengthening life and improving its quality for some with metastatic breast cancer.

A Brighter Outlook for Metastatic Breast Cancer

In 2012, Brenda Berchtold was running out of breast cancer treatment options when her oncologist in Baltimore suggested one other possibility: immunotherapy. Dr. Leisha Emens was leading a clinical trial for Tecentriq (atezolizumab), and Berchtold would receive infusions once every three weeks for nearly a year.

The 55-year-old mother of two had received a diagnosis of cancer in her right breast in 1986 after she felt a pea-size lump during a self-exam. Results of a biopsy showed that the cancer was estrogen receptor negative, progesterone receptor negative and HER2 negative, which meant she had an aggressive form of disease known as triple-negative breast cancer. She underwent a lumpectomy followed by radiation and enjoyed seven years of remission. But then the cancer returned.

Triple-negative breast cancer does not respond to hormonal therapies or drugs that target the HER2 protein, and Berchtold endured multiple rounds of chemotherapy over the years only to see the cancer eventually return in her right breast. In 2009, she underwent a bilateral mastectomy, but a year later, scans showed evidence of cancer in her lymph nodes and sternum. Emens, who is now co-leader of the UPMC Hillman Cancer Center’s Immunology and Immunotherapy Program in Pittsburgh, Pennsylvania, suggested that Berchtold enroll in a vaccine trial, but her cancer progressed while she was on the trial. That’s when Emens suggested the Tecentriq trial.

Finally, in 2013, Berchtold received good news after 12 weeks of treatment. The results of a CT scan revealed a significant reduction in the size of her tumors. She was also relieved that the side effects she experienced from the immunotherapy, such as muscle weakness, fatigue and facial swelling, were much more tolerable than what she had experienced during chemotherapy. The symptoms were the result of a common side effect known as hypothyroidism and could be treated with medication. By 2016, the scans showed no evidence of disease in her body.

“It was like hitting the lottery,” Berchtold says. “For years I had felt fatigued and sick because I was in and out of chemotherapy, but now I know what it’s like to feel normal. I have energy again.”

Berchtold was part of a phase 1 clinical trial that prompted further clinical trials for Tecentriq, a programmed death-ligand 1 (PD-L1) checkpoint inhibitor that prevents cancer cells from hiding from the immune system. Although she took the medication as a single agent, later studies showed the drug to be more effective combined with chemotherapy. In March, the drug became the first immunotherapy approved by the Food and Drug Administration (FDA) in combination with Abraxane (nab-paclitaxel), a type of chemotherapy, for patients with triple-negative breast cancer that cannot be surgically removed and is locally advanced or metastatic. The other requirement for receiving the drug is that immune cells in the tumor must test positive for the PD-L1 protein.

The approval was based on the results of the phase 3 IMpassion 130 trial, which included 902 patients with metastatic triple-negative breast cancer who received chemotherapy with either Tecentriq or a placebo. The study showed that in patients who were PD-L1 positive, the median overall survival for the immunotherapy group was 25 months compared with 18 months for the placebo group.

“We haven’t had very good treatment strategies for triple-negative breast cancer, and to see more than a nine-month improvement in overall survival for a population that is typically given 12 to 18 months to live is really compelling,” says Dr. Heather McArthur, medical director of breast oncology at Cedars-Sinai Medical Center in Los Angeles. “There is incredible enthusiasm in the medical community about immunotherapy strategies.”

Although the approval is being celebrated by the breast cancer community, immunotherapies were available years earlier for patients with melanoma and lung, kidney or bladder cancer. “This is because these cancers are more likely to have highly mutated proteins that could be recognized as foreign by the immune system,” Emens says. “Breast cancer is less likely to have a lot of mutations.” The cancers that have more mutations are typically induced by exposure to environmental factors like sunlight or smoking. Breast cancer does not have such a clear carcinogen exposure, Emens says.

Triple-negative breast cancer, which accounts for about 15% to 20% of all breast cancers, has traditionally been treated with chemotherapy, which can cause side effects including hair loss, nausea, fatigue, peripheral neuropathy and low blood counts. Triple-negative breast cancer was the first form of the disease targeted for immunotherapy trials because these tumors have higher levels of T cells known as tumor-infiltrating lymphocytes that can become activated by checkpoint inhibitor drugs. In the early studies when immunotherapy was used as a single agent, the response rate was about 10%, but then researchers started combining Tecentriq with chemotherapy and response rates improved.

“The IMpassion data showed that immunotherapy has a role in breast cancer,” says Dr. Jennifer Litton, a breast medical oncologist at The University of Texas MD Anderson Cancer Center in Houston. “Now researchers are exploring the potential benefits of combining immunotherapy with other treatments like radiation, different chemotherapies, vaccines and other immunotherapies.”

McArthur has been studying the combination of the checkpoint inhibitor Keytruda (pembrolizumab) with radiation in patients with metastatic triple-negative disease. “In this process, the tumor is being broken down by the radiation into tumor fragments, and this triggers a response as the immune system tries to clean up the debris,” McArthur says. Of the 17 patients in her recent study, 33% experienced a partial response, and one woman had such an exceptional response that she has no evidence of disease. She finished treatment more than a year ago and does not require maintenance therapy. The encouraging results from the metastatic study motivated McArthur and her colleagues to explore whether radiation with immunotherapy could benefit patients who receive the combination in the early stages of the disease.

Researchers have also studied the potential advantages of combining Keytruda with chemotherapy in women with early-stage breast cancer. In one phase 2 study, women with stage 2 or 3 locally advanced triple-negative or hormone receptor-positive/HER2-negative breast cancer received chemotherapy alone or with Keytruda before surgery.

“We found that adding immunotherapy to chemotherapy tripled the likelihood of a complete response,” says Dr. Rita Nanda, associate professor of medicine and director of breast medical oncology at University of Chicago Medicine. “That meant there was no cancer left at the time of surgery.” The results led to an ongoing phase 3 trial, and if this study confirms the earlier results, this could become a new standard of care for early-stage breast cancer, Nanda says.

Although the side effects of immunotherapies usually are less debilitating than those of chemotherapies, some patients may experience serious toxicities because of these novel drugs, cautions Dr. Elizabeth Mittendorf, director of the Breast Immuno-Oncology Program at Dana-Farber/Brigham and Women’s Cancer Center in Boston. Diarrhea or abdominal pain may be a sign of colitis, and worsening cough, shortness of breath or chest pain may be symptoms of pneumonitis. Hormone gland problems and hepatitis are also possible side effects. These patients may need to temporarily stop immunotherapy until their problems are resolved, or they may require treatment with steroid. “The health personnel answering the phones for these patients need to have a different threshold than for symptoms resulting from chemotherapy,” Mittendorf says.

Breast cancer vaccines have also garnered attention as another strategy for stimulating an immune response. Cancer cells often have molecules known as antigens on their surfaces, and the vaccines help T cells “remember” these proteins when it’s time to launch an attack to prevent recurrence. “By themselves, the T-cell-eliciting vaccines that our group has been studying are not enough to stimulate an immune response that can eliminate a tumor, but we’ve presented some data suggesting that vaccines might work nicely with trastuzumab,” Mittendorf says. Herceptin (trastuzumab) is a monoclonal antibody that targets the HER2 protein in breast cancer.

Although Tecentriq has been approved as initial therapy in combination with chemotherapy to treat PD-L1 positive metastatic breast cancer, researchers are also investigating novel approaches to the timing of immunotherapy during treatment. Dr. Antoinette Tan, chief of breast medical oncology at Levine Cancer Institute at Atrium Health in North Carolina, was interested in exploring the potential benefits of administering chemo- therapy alone before starting the combination of chemo- therapy and immunotherapy. She is leading a clinical trial for patients with HER2-negative metastatic breast cancer, and one group is receiving chemotherapy alone for two cycles before including Keytruda. The second group is taking both treatments upfront.

Participants are also providing biopsy samples before and after treatment so the researchers can test for biomarkers like PD-L1 and tumor-infiltrating lymphocytes. “Using the tumor tissue samples, we hope to identify which biomarkers can be used to predict who will respond better to the different treatment sequences,” Tan says.

Janet Frazier, 63, recently joined this clinical trial after multiple rounds of different chemotherapies failed to stop a recent progression of the disease. Frazier, who received a triple-negative breast cancer diagnosis in 2009, had enjoyed six years of remission following chemotherapy, surgery and radiation, but then she discovered a bump on the back of her head and another one on her abdomen.

“I had been told that if triple-negative cancer responds to treatment and doesn’t come back for five years, then the odds of recurrence decrease,” Frazier says.

She saw her family doctor and a general surgeon, and both believed she had a cyst on the back of her head and a fatty lipoma — a benign tumor &mdash; on her abdomen. But Frazier’s dermatologist urged her to have the lumps biopsied due to her history of cancer. In 2016, Frazier learned that the lumps tested positive for triple-negative breast cancer, and scans revealed that the cancer had spread to her lungs, brain, abdomen and lymph nodes.

“I had never dreamed that my cancer would come back as skin bumps,” says Frazier, who lives in Davidson, North Carolina. “It was devastating news.”

Tan considered the Keytruda trial, but Frazier was ineligible due to the tumors in her brain. After two years of chemotherapy, multiple radiation treatments to individual brain tumors and, finally, whole brain radiation, she was able to participate. Frazier started receiving the chemotherapy drug Taxol (paclitaxel) for six weeks and added Keytruda in December 2018. After six weeks of immunotherapy, she heard good news for the first time in 18 months: The tumors were either stabilizing or shrinking. That trend has continued.

In 2009, Frazier’s prayer was to live long enough to see her son, a senior in high school, graduate. Since then, she’s had the opportunity to attend his U.S. Naval Academy graduation and her daughter’s wedding. “I’m just so happy that I’m on the right track,” Frazier says. “I have hope.”

Though stories like hers encourage further exploration of immunotherapies, researchers acknowledge that many unanswered questions remain, and many patients do not respond to the currently approved immunotherapy. In the IMpassion study, most of the original 900-plus enrolled have not yet reached 25 months of follow-up, Mittendorf says, and must continue to be followed for clinical outcomes.

“We need an improved understanding of who is and is not responding to immunotherapy, who will develop toxicities, how to treat patients once they progress on immunotherapy, and how to make other subtypes of cancer susceptible to immunotherapy,” she says. “But the recent FDA approval has reinvigorated enthusiasm in the field to continue investigating these treatment strategies.”

Immunotherapy takes on a new role in treating patients with triple-negative disease.

Breast Cancer Gets a Boost From Immunotherapy

When Jason Campbell, D.D.S., started having neck pain in July 2017, he suspected it was the consequence of spending hours each week hunched over the mouths of patients in his dental practice. But six months later, during a marathon training run, Campbell, 45, experienced double vision, nausea and head pain and rushed to the hospital. MRI results revealed a golf ball-size tumor near his brainstem, and his doctors suspected that the growth was chordoma, a rare type of cancer in the cells at the base of the skull.

A biopsy revealed a different source: Campbell’s cancer had originated in the squamous cells near the upper part of his throat and then spread to the base of the skull. For his diagnosis of stage 4 nasopharyngeal head and neck cancer, Campbell received chemotherapy with docetaxel and 5-fluorouracil (5-FU) for one week, followed by radiation treatment combined with the platinum-based chemotherapy cisplatin for two months.

“It was the hardest thing I’ve ever done physically,” says Campbell, of Orem, Utah. Eating was painful and he lost 50 pounds, but Campbell was determined to avoid using a feeding tube. He performed physical therapy five times a day to maintain his ability to swallow. By November, there was no evidence of cancer on scans, and Campbell celebrated with his wife and five children.

Jason Campbell, fourth from left, has received support from his family during treatment for head and neck cancer. Family members are, from left: MARLEY (17), his wife MOLLY, AUDREY (8), RACHEL (13), CALEB (15). Not shown is MORGAN (22).

Six months later, a routine scan showed that the cancer had spread to his lungs. Doctors gave Campbell six months to live.

Campbell prayed for guidance and started searching for clinical trials. A friend suggested that he seek out Ezra Cohen, M.D., a specialist in head and neck cancer at the University of California, San Diego (UC San Diego). Cohen, associate director of translational science at Moores Cancer Center there, was just starting a clinical trial that included a combination of one immunotherapy — Bavencio (avelumab) &mdash; and two targeted therapies, Erbitux (cetuximab) and Ibrance (palbociclib). Each drug would target the cancer cells, either by directly inhibiting growth or by preventing cancer growth via the immune system.

Campbell was the first patient to start the trial. He began in June 2018 with more than 35 lung tumors that were doubling in size every two months. After eight months of weekly infusions, just eight small tumors remained — and the side effects of treatment were minimal.

“I feel very lucky to be the first person in the world to receive this treatment, and other than a little fatigue the first few days after my infusions, I feel good,” Campbell says.

This ability to help patients like Campbell represents a dramatic shift in head and neck cancer treatment, according to Cohen. “This is probably the most active period of drug development in head and neck cancer — possibly ever,” he says.

Although surgery, radiation and chemotherapy are at the heart of standard care for this disease, Erbitux started to generate excitement when it was approved for head and neck cancer in 2006. The drug interferes with the activity of a protein called epidermal growth factor receptor (EGFR), which drives some head and neck cancers. However, results were not impressive. “The response rate was less than 10 percent, and the duration of response was in months,”

The latest Food and Drug Administration approvals related to the disease came in 2016: the immunotherapies Keytruda (pembrolizumab) and Opdivo (nivolumab), which target the PD-1 receptor protein on the surface of immune cells. By targeting this protein, these drugs can prevent cancer cells from hiding from the immune system and enable T cells to attack the cancer. “Now, we are seeing patients who can have a durable response for years, and we had not seen that before,” Cohen says.

Head and neck cancer accounts for about 4 percent of all cancers in the United States and is more common in men. Although the greatest risk factors historically involve use of tobacco and alcohol, this form of cancer is increasingly linked to HPV, which 80 percent of sexually active people contract at some point. Researchers predict that by 2030, half of all head and neck cancers will be attributed to this virus, but oncologists are already seeing that percentage. “About half of my patients with head and neck cancer have HPV-related disease,” says Robert Ferris, M.D., Ph.D., director of University of Pittsburgh Medical Center’s Hillman Cancer Center.

The good news is that people with the HPV-derived type usually have a better prognosis than other patients with head and neck cancer, even though all get the same kinds of treatments. This may be because the virus produces a good target for the immune system and most HPV-associated head and neck cancers express PD-L1, making them more sensitive to immunotherapy, Cohen says.

HPV-related tumors usually reside in the oropharynx, the part of the throat at the back of the mouth behind the oral cavity, and the cancer often starts in the tonsils. Patients may notice symptoms such as a lump in the neck or throat, swallowing problems, bleeding or a persistent earache.

Non-HPV-related head and neck cancers are often found at the front of the mouth or down in the neck, where the larynx and vocal cords are located. Symptoms include trouble breathing or speaking, pain when swallowing, persistent pain in the neck or throat or a change in voice.

Two-thirds of head and neck cancers are diagnosed in advanced, but rarely metastatic, stages, Cohen says.

Treatment depends on the stage and location of the cancer, and physicians weigh the potential benefits of surgery, radiation and chemotherapy. “With early-stage disease, we use as few modalities as possible, because each treatment causes side effects,” Ferris says. “In the later stages, we tend to intensify treatments by combining radiation with chemotherapy and sometimes using immunotherapy.”

Standard treatments can produce a number of side effects, some long-lasting or permanent. Surgically removing parts of the head or neck can result in trouble speaking, eating or swallowing, as well as disfigurement; choosing doctors who are experts in this kind of surgery helps minimize these effects. Radiation can cause mouth and gum sores and difficulty swallowing, and chemotherapy such as cisplatin can cause vomiting, fatigue and hair loss.

When Erbitux was approved in combination with radiation, the drug was considered a less-toxic alternative to cisplatin. However, the recent results of a clinical trial in patients with HPV-positive oropharyngeal cancer showed better survival rates with cisplatin plus radiation — and the overall toxicity was similar between the two combinations.

“There is a lot of active research looking at alternatives to cisplatin, because the combination of this drug plus radiation is some of the hardest cancer treatment we put patients through in the outpatient setting, in terms of acute toxicity and long-term side effects,” says Rom Leidner, M.D., medical co-director of the head and neck cancer program at Earle A. Chiles Research Institute in Portland, Oregon. “But for now, cisplatin plus radiation has been proven to have superior survival outcomes.”

The longer-term side effects of cisplatin plus radiation, Cohen notes, can include difficulty speaking and/or swallowing, tightness and/or pain in the neck, dry mouth and dental decay.

Until Keytruda and Opdivo were approved for recurrent or metastatic head and neck cancer, patients with advanced disease had few options after receiving the standard Erbitux plus 5-FU and either cisplatin or carboplatin. Now, studies are showing that these immunotherapies may also have benefits as treatments for newly diagnosed disease.

In one study, Barbara Burtness, M.D., compared patients who received Keytruda alone with those who received Erbitux and a platinum-based chemotherapy (cisplatin or carboplatin) plus 5-FU. A third group received Keytruda with a platinum agent and 5-FU. Her team also tested the level of PD-L1 expression in tumor cells. In patients with high levels of PD-L1 expression, Keytruda lengthened survival by 4.2 months compared with patients who received Erbitux plus chemotherapy. The results also showed that Keytruda plus chemotherapy helped patients regardless of whether their tumors expressed PD-L1.

“The implication is that patients who have PD-L1-expressing cancers should receive Keytruda as a first-line treatment instead of two chemotherapy drugs plus cetuximab,” says Burtness, co-director of the developmental therapeutics research program and team leader of disease-aligned research for head and neck cancer at Yale Cancer Center. “But we do not have all the information yet. We need to find out who should get Keytruda alone versus Keytruda with chemotherapy.”

Burtness is now investigating whether Keytruda could help patients who do not have a complete response to chemotherapy and radiation and are left with the option of surgeries that could affect the tongue or voice box.

JOSEPH FRANCHI discovered his cancer had spread to his brain after he lost the ability to juggle five objects.

Joseph Franchi says he believes that trying immunotherapy earlier might have helped him avoid serious side effects from treatment. Franchi, of Westport, Connecticut, thought he had strep throat in 2012, but even after a round of antibiotics, he felt scratchiness for months. His physician later discovered a tumor wrapped around Franchi’s right tonsil, and biopsy results revealed squamous cell carcinoma. By far the most common type of head and neck cancer, it begins in the cells that line the moist areas inside the head and neck. After a combination of surgery and radiation treatment, the cancer was in remission for three years.

Then, in 2015, it returned in his lungs and pericardium, the membrane surrounding his heart. Franchi was referred to Burtness, who recommended a combination of chemotherapy and Erbitux.

“I had a reaction to the carboplatin during the chemotherapy infusion and my palms became extremely itchy, and it felt like bees were stinging the bottoms of my feet,” says Franchi, 52, who until recently worked at a financial software company. He stopped taking the drug, but then his lungs developed inflammation as a result of the second chemotherapy, paclitaxel. He stopped the chemotherapy drugs and continued taking Erbitux.

The cancer was in remission for more than six months, but then a change caught his attention. An experienced juggler, Franchi suddenly lost his ability to juggle five objects simultaneously. He returned to the doctor and discovered that cancer had spread to his brain, which prompted Burtness to suggest that he start taking Keytruda in early 2017.

“The scans are now showing no new growth of the cancer,” Franchi says. “Although I feel tired, overall I feel pretty good.”

Even though Keytruda is helping patients like Franchi, researchers are studying how to raise response rates to these drugs. Currently, about 15 percent of eligible patients with head and neck cancer respond to the approved immunotherapies, but a strategy that Cohen used has doubled this number by combining the PD-1 inhibitors with a drug that targets STAT3, a protein in the body that transmits signals to trigger the maturation of immune cells. In studies in mice and cell lines, he has also experimented with combining a PD-1 inhibitor with molecules that turn on “toll-like receptors” involved in the first step of an immune response.

Cohen is also working with Kathryn Gold, M.D., an associate professor at UC San Diego Health, to investigate the benefit of combining two targeted therapies — one that blocks EGFR to prevent cancer cell growth and one that inhibits the proteins CDK 4 and 6 &mdash; with a PD-1-inhibiting immunotherapy. Campbell is a patient in this trial, and Cohen hopes to understand why he’s benefiting from the combination. “We are discovering that these drugs may complement one another,” Cohen says. “Disrupting the EGFR signaling can make the PD-1 antibodies work better, so the combination helps both drugs work better.”

Researchers are also exploring whether HPV vaccines could boost immune responses in patients with HPV-related head and neck cancer. “The virus is still expressed in the cancer, and a vaccine may also complement existing therapies,” Cohen says.

Compared with chemotherapy, immunotherapies tend to have fewer and different side effects — rash, diarrhea, low thyroid hormone, fatigue &mdash; and researchers are exploring whether using less radiation could further reduce unwanted effects. In one recent study, investigators decreased the dose given to patients with low-risk HPV-positive cancers. They also tried administering chemotherapy plus a reduced amount of radiation in patients with more aggressive HPV-positive cancers. “The survival outcomes were excellent, and people recovered significantly faster (and) had less pain, and the functional outcomes were better,” says Tanguy Seiwert, M.D., director of the head and neck cancer program at the University of Chicago and first author of the study.

Patients like David Simmons, a pastor in Greenville, South Carolina, can attest to the benefits of less radiation. Simmons was 54 when doctors discovered a malignant squamous cell carcinoma the size of an orange in his neck. He had been experiencing ear pain and passed out as a result of pressure from the tumor on his vagus nerve. In 2013, Simmons started receiving a combination of chemotherapy and radiation, but the treatment shrank his vocal cords and permanently constricted his throat. Simmons now uses a feeding tube to eat and has difficulty speaking.

DAVID SIMMONS is doing well on immunotherapy for recurrent head and neck cancer.

“The treatment was successful at the time, but I paid the price in other ways,” says Simmons, who lost 85 pounds during the treatment and struggled with comprehension while reading for months afterward. “I lost my voice for four weeks, and people still have trouble understanding me.”

Simmons remained cancer-free for more than two years, but the disease returned in his right knee, prompting his oncologist to recommend a regimen of cisplatin and 5-FU. The 5-FU caused neutropenia and a blood count problem that put him at high risk of infections, and later he had an anaphylactic reaction to cisplatin. In January 2018, the oncologist suggested a new approach: infusions of Keytruda once every three weeks. His response far exceeded his physician’s expectations. After three months, the tumors were shrinking in his leg; six months later, the cancer was almost gone.

Now that he’s no longer as vulnerable to infections, Simmons is enjoying the freedom to visit hospitalized members of his congregation. He also felt strong enough for summertime travel to Yellowstone National Park and the Grand Canyon.

“Earlier during treatment, I felt like I was going to die several times, and I spent many days in the hospital,” Simmons says. “Since I started immunotherapy, I feel like I have a new lease on life, and I’m grateful for the extra time with my wife and grandchildren.”

Patients with head and neck cancer may soon have more effective, less toxic choices as immunotherapy moves into first-line treatment and novel targeted drugs are explored.
 

Heather Stringer | Contributors

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