Heather Stringer

For patients who have undergone surgery to remove colon cancer, one of the significant stressors is waiting to see if CT scans show that the cancer has recurred.

Now, new technology to detect cancer much earlier may alleviate the agonizing wait and lead to better outcomes. In 2020, Medicare recommended coverage for a new test that detects small amounts of circulating tumor DNA (ctDNA) in the blood of patients who previously received a diagnosis of certain types of cancer.

The Signatera test, developed by Natera, is being used in a clinical trial looking at how well the ctDNA testing works to predict the benefit of chemotherapy treatment after surgery for stage 3 colon cancer.

® spoke with Dr. Scott Kopetz, a professor in the department of gastrointestinal medical oncology at the University of Texas MD Anderson Cancer Center in Houston, about the test’s potential value for patients.

“In early stage 2 colon cancer, for example, we do not typically recommend chemotherapy, but what if the test came back positive for cancer in the blood?” he said. “Then we might suggest chemotherapy.”

In patients with stage 3 disease, chemotherapy is usually prescribed, but a negative ctDNA test result might indicate that this treatment is not needed, Kopetz explains. The new blood test detects unique mutations in a patient’s tumor and has been shown in clinical studies to identify residual disease up to two years earlier than standard imaging.

“The challenge now is learning what to do with the information we gather from the test, but ultimately I think this technology will dramatically accelerate our ability to cure more patients,” Kopetz says.

To read more on how the identification of rare genomic alterations in patients with colorectal cancer has given oncologists the opportunity to treat patients who otherwise might not have many options, 

®’s recent special gastrointestinal cancers issue.

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Articles

A new technology that can detect small amounts of circulating tumor DNA in the blood of patients who previously received a diagnosis of certain types of cancer may dramatically accelerate the ability to cure more patients, says an expert from the University of Texas MD Anderson Cancer Center.

A New Frontier: Identifying Traces of Colorectal Cancer in the Blood

When Mia Balko, 48, started experiencing an ongoing cough in early 2019, her primary care doctor treated her with medication for acid reflux disease, but the cough persisted. Then she noticed that her abdomen was becoming increasingly distended and firm, and she asked to see a gastroenterologist.

Balko, who lives in Waco, Texas, was shocked when she later learned that the cough had been triggered by stage 4 colon cancer. The disease had spread to her abdomen and caused fluid retention, which in turn pressed on her lungs. Balko initially received two different chemotherapy regimens over the course of a year, but despite each treatment, the disease continued to grow.

The cancer tested positive for a specific gene mutation known as KRAS G12C, which made Balko eligible to participate in a clinical trial at The University of Texas MD Anderson Cancer Center in Houston for a new targeted therapy known as AMG 510 (sotorasib). She started taking eight pills daily that contained a small molecule equipped to bind to a region of the KRAS G12C protein. Initially the only side effect was headaches, but once she started taking the medication before bed, the headaches disappeared. After nearly a year on the new targeted treatment, her scans showed that the cancer was stable.

“My quality of life improved when I switched to the targeted therapy,” Balko says. “I had a lot more stamina to work and do activities I enjoy.”

Although a recent scan showed a new lesion on her liver, she is grateful she can continue taking AMG 510 as she adds a new chemotherapy treatment to her regimen to address the growth.

For years, the only main targeted therapy available to patients with colorectal cancer was a medication that blocked the function of a protein called epidermal growth factor receptor (EGFR), but this treatment was not effective for patients with the KRAS mutation, which is present in approximately 40% of colorectal cancers. Now researchers are uncovering new treatments that are improving outcomes for people with colorectal cancer who have this mutation and other genetic aberrations, including the BRAF mutation and HER2 amplification.

“Compared (with) other forms of cancer, results of targeted therapy agents have not been as impressive in colorectal cancer, but we have learned from many negative trials,” explains Dr. Afsaneh Barzi, a gastrointestinal medical oncologist at City of Hope Comprehensive Cancer Center in Duarte, California. “With the new clinical trials, we are right on the cusp of seeing significant changes in outcomes for this population of patients.”

Colorectal cancer is the third-leading cause of cancer deaths in the United States, and Barzi notes it is critical for patients to receive molecular testing at diagnosis to identify potential genetic targets. “Sometimes doctors wait to do this testing until patients have failed on standard therapy, but this is too late,” she says. “We need this information early on to identify potential clinical trials.”

For patients who do not have the KRAS mutation, which is known as KRAS wild-type, EGFR inhibitors combined with chemotherapy can slow progression of the disease, but more recent studies have shown that there is one more element to consider for these patients: the cancer’s location.

“When scientists analyzed the study results, they discovered that EGFR inhibition with first-line chemotherapy only worked with people who had left-sided colon cancers,” says Dr. Alfred Neugut, co-director of the Cancer Prevention Center at New York Presbyterian Hospital and Columbia University Medical Center’s Herbert Irving Comprehensive Cancer Center. For right-sided tumors, the better option for first-line treatment is chemotherapy plus Avastin (bevacizumab).

New Strategies for Treating BRAF and HER2 Cancers

The BRAF mutation — which occurs in approximately 10% of colorectal cancers — is another biomarker that has historically been difficult to target in patients with colorectal cancer, but researchers have started to uncover new ways to improve outcomes for this population.

“More than a decade ago, we recognized that this group of patients was not responding to traditional therapies, so initially we tried targeting the BRAF mutation,” notes Dr. Scott Kopetz, a professor in the department of gastrointestinal medical oncology at MD Anderson. “This strategy had worked in patients with melanoma, but we found that this was not the case for people with colorectal cancer.”

Researchers discovered that when they used a drug to block a receptor on BRAF-mutated cells, the cells increased EGFR signaling to compensate and continue cancer growth. Then Kopetz launched clinical trials in which patients received either one or two BRAF inhibitors in addition to an EGFR inhibitor, and this was more successful. In April 2020, the Food and Drug Administration (FDA) approved Braftovi (encorafenib), a BRAF inhibitor, in combination with Erbitux (cetuximab), an EGFR inhibitor, for patients with metastatic colon cancer. Findings from the recent BEACON CRC study showed that these combinations increased overall survival by more than four months. The most common side effects included diarrhea, acne and nausea.

Now researchers are exploring benefits of adding chemotherapy to this regimen or combining BRAF inhibitors with immunotherapy. Mary DeForest, 59, recently enrolled in a clinical trial for a combination of Braftovi and Erbitux plus the immunotherapy drug Opdivo (nivolumab) to treat stage 4 colon cancer, and she has been impressed by the results. After four months on the combination, the tumor in her liver has shrunk 75% and the cancer in her colon decreased 25%. “I feel so good that I don’t think about having cancer anymore,” DeForest, from Bay City, Texas, says.

Another promising target in colorectal cancer is the HER2 amplification, which means the cancer has too many copies of the HER2 gene. The amplification occurs in approximately 3% to 5% of colorectal cancers, and clinical trials combining two HER2-targeted therapies have shown that this strategy can have impressive results, according to Dr. James Cleary, a senior physician at Dana-Farber Cancer Institute in Boston.

One of Cleary’s patients has been taking a combination of Herceptin (trastuzumab) and Tykerb (lapatinib) for four years with an excellent quality of life, and now there is a second option for her if the cancer starts to grow.

Enhertu (trastuzumab deruxtecan) is an antibody-drug conjugate that binds to cells with the HER2 amplification and then delivers a toxin into these cancer cells. Results of a recent study showed that, among patients with the highest levels of HER2 expression, the response rate to this drug was 45% and the median progression-free survival (the time from treatment to disease progression or worsening) was seven months.

Genomic testing of cancer cells can reveal not only the presence of KRAS, BRAF and HER2 alterations but also the level of microsatellite instability (MSI). People who are MSI-high are deficient in the mismatch repair (MMR) proteins that find mistakes in DNA. These MSI high cancers accumulate DNA mutations that are felt to make tumors more recognizable, which is good news now that immunotherapy is an option for treatment.

“Immunotherapy uses the body’s own immune system to fight off cancers, and tumors with more mutations are easier to identify as invaders,” Cleary says. “The challenge is that only about 3% to 4% of people with metastatic colon cancer are MSI-high, so not many patients can benefit from immunotherapy at this point.”

Rodnell Workman, 47, was among the patients with stage 4 colon cancer who were eligible for immunotherapy. His symptoms began in 2016, when he felt as though he had the flu and later discovered that his appendix had ruptured. The surgical team identified abnormalities on his appendix and a colonoscopy showed that he had a large mass in his colon. Biomarker testing revealed that he had Lynch syndrome, an inherited condition associated with high levels of MSI and increased cancer risk. The doctors prescribed chemotherapy to shrink the tumor before removing it surgically, and they also recommended three months of the immunotherapy Keytruda (pembrolizumab) to ensure that the cancer was eradicated.

“I had no side effects from the immunotherapy and I’ve had clean scans ever since,” says Workman, who lives in New Jersey.

Although Workman received immunotherapy after chemotherapy, in June 2020 the FDA approved Keytruda as a first-line treatment for patients with colorectal cancer that is MSI-high, MMR deficient or unresectable. Researchers also have started to investigate whether immunotherapy in combination with Stivarga (regorafenib), which inhibits growth of blood vessels needed for tumor growth, could benefit the many patients with tumors that are not MSI-high.

Although oncologists have more targeted therapy options for patients with colorectal cancer than in the past, the treatments are still limited to a somewhat small percentage of patients who have certain mutations, says Dr. Suneel Kamath, a medical oncologist who specializes in the treatment of gastrointestinal cancers at Cleveland Clinic in Ohio. “The biggest area of need is finding more mutations and developing drugs to target them,” he says.

For example, fibroblast growth factor receptor (FGFR) mutations in bile duct and bladder cancer have also been found in colon cancer. Clinical trials are underway to test whether Pemazyre (pemigatinib), an FGFR inhibitor that targets this mutation, blocks tumor growth in people with metastatic colon cancer.

Moreover, mutations in the RAS gene family have been known to be bad actors for decades — associated with more aggressive behavior in many tumor types — and were considered “undruggable” until recently.

Cleary said he hopes to see more studies that explore repurposing targeted treatments for other forms of cancer to help people with colorectal cancer. As part of one study, Cleary and his Dana-Farber colleague Dr. Harsh Singh treated two patients with colon cancer who tested positive for gene translocations seen in lung cancer: ROS1 and ALK. They prescribed targeted therapies that have been effective in lung cancer, and the results were encouraging. The treatment was beneficial for seven months for the patient with the ALK translocation, and the patient with the ROS1 translocation continues to do well after more than a year of targeted treatment.

“To me, this was very exciting,” Cleary says. “Seeing (patients with colorectal cancer) with these rare genomic alterations benefit from nontraditional therapies gives me hope that additional targetable alterations can be found and exploited, and, hopefully, this is just the beginning.”

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The identification of rare genomic alterations in patients with colorectal cancer gives oncologists the opportunity to treat patients who otherwise might not have many options.

Overcoming Obstacles to Targeted Therapy in Colon Cancer

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.”

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.

Heather Stringer

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