Tara Haelle

Every day while stuck in traffic heading home from work, Denise Lee saw the American Lung Association billboard along the highway, informing the 54-year-old lawyer that she should get screened for lung cancer if she smoked. But when she brought it up to her doctor, she learned she was a year too young for screening recommendations. After she turned 55, Lee talked to her doctor again and this time they made an appointment. She would be retiring soon and was about to spend a month vacationing in Sicily, so she scheduled the lung scan for the Monday after she returned.

The day after her scan, the pulmonologist called Lee and told her to come in immediately.

“At that point, in my head, I knew,” Lee says. “I couldn’t breathe.” But despite her insistence on getting screening as soon as she could, the news was a surprise: “They told me I had a mass on my lung.”

Denise Lee was enrolled onto the ALCHEMIST trial, a study assessing the efficacy of Keytruda plus chemotherapy in early-stage non-small cell lung cancer that had been removed by surgery.

She received the results of a biopsy on Valentine’s Day 2018: The mass was lung cancer but fortunately, scans suggested it was stage 2b or 3a, meaning they had caught it early enough for surgery. It wasn’t until surgeons removed the upper lobe of her lung and 17 lymph nodes that her cancer was downgraded to stage 1b. But Lee had risk factors that increased her likelihood of the cancer returning, so her oncologist recommended chemotherapy after surgery to increase her likelihood of survival. During her chemotherapy treatments, he told Lee she qualified for the ALCHEMIST clinical trials, a group of studies exploring different experimental treatment options in people who had early-stage non-small cell lung cancer (NSCLC) completely removed by surgery and treated with chemotherapy, but who still had a high risk of recurrence.

The ALCHEMIST trial Lee joined was testing a treatment that was unheard of for early-stage NSCLC just five or six years ago: immunotherapy.

One of the ways cancer takes over the body is by blocking the immune system’s ability to attack the cancer. Immunotherapy drugs are lab-grown antibodies that work by removing those roadblocks and teaching the immune system how to fight back. But until recently, immunotherapy had been used only in stage 4 metastatic lung cancer.

“The research tends to start in the metastatic setting because those patients have incurable disease,” says Dr. Catherine A. Shu, a thoracic medical oncologist at Columbia University Cancer Center in New York City. “If there is something that’s really promising and is approved in the metastatic setting, it is often brought into the earlier-stage setting. This is the traditional paradigm for all cancer research.”

For more than 30 years, the standard treatment for stage 3 NSCLC was daily radiation for six weeks plus chemotherapy, explains Dr. Neal Ready, a professor of medicine at Duke Cancer Institute in Durham, North Carolina.

“All sorts of things were done to improve on that and basically none of them worked,” he says. But immunotherapy has been moving into metastatic NSCLC for nearly a decade now and “it’s transformed the field,” Ready says.

Of note, immunotherapy is a standard now for stage 3 after a patient has completed chemotherapy and radiation. As it moves into earlier stages now, “the care for early-stage lung cancer is changing pretty rapidly,” he adds.

“This (immunotherapy) is changing our treatment options for patients with early-stage disease and actually leading to more cures, so it’s a really exciting time,” says Dr. Heather Wakelee, chief of the Division of Oncology at Stanford University and deputy director of the Stanford Cancer Institute in California. “We think immunotherapy is really going to change overall survival because immunotherapy changes the whole body’s response to the disease. If you get the body to recognize the tumor and mount an immune response, that can be permanent even when the drug is stopped.”

Aside from skin cancer, lung cancer is the second most common cancer after breast cancer in women and prostate cancer in men. More than 236,000 new cases are expected in 2022 and about 130,000 people die from the disease each year. Most cases (84%) are NSCLC and although new cases have been declining, five-year survival rates remain low, particularly for later stages, making early detection paramount. “Early” can refer to anything before stage 3b or 4, when the cancer has spread too far for resection — surgical removal. Stages 1 and 2 are resectable, and stage 3a can be, Wakelee says.

“The first really definitive new treatment in early lung cancer was adding an immune therapy for the treatment of stage 3 lung cancer,” Ready says. “The PACIFIC trial was the first trial that moved immune therapy into standard treatment for potentially curable non-small cell lung cancer.”

The PACIFIC trial tested the immunotherapy Imfinzi (durvalumab) in patients with stage 3 unresectable NSCLC. All patients received radiation and chemotherapy before randomly being assigned Imfinzi or placebo. Imfinzi improved five-year overall survival rates by 31%, which were 33% with placebo and 43% with Imfinzi. The Food and Drug Administration (FDA) 

 as the first NSCLC immunotherapy before stage 4.

Promising results from two other trials followed as researchers tested immunotherapy in patients with resectable cancer, both after surgery (adjuvant) and before surgery (neoadjuvant). The IMpower010 trial added Tecentriq (atezolizumab) after chemotherapy in people with resected stage 1b to 3a NSCLC. Researchers reported in October 2021 that 

 (length of time after primary treatment for a cancer ends that the patient survives without any signs or symptoms of that cancer) by 21% for all patients at three years and by 34% for a subset of patients whose genetic testing shows tumor expression of PD-L1 above 1%. PD-L1 is a protein produced by some tumor cells that acts as a “stop” signal to immune cells and dampens their attack on cancer cells.

Tecentriq, an anti-PD-L1 drug, blocks the protein, so it makes sense that a PD-L1 inhibitor would be more effective against tumors producing more PD-L1, although it is not a perfect biomarker. The FDA approved Tecentriq for patients with stage 2 to 3a NSCLC with tumors with at least 1% PD-L1 expression.

The CheckMate 816 trial tested Opdivo (nivolumab) as a neoadjuvant (presurgical) therapy: Patients with stage 1b to 3a resectable NSCLC received Opdivo with chemotherapy or chemotherapy alone before surgery. Adding Opdivo improved event-free survival (32 months vs. 21 months), with a complete pathologic response in 24% of patients compared with 2.2% receiving chemotherapy alone, 

 plus chemotherapy for neoadjuvant use in people with stage 1a to 3a NSCLC.

Lung cancer is very aggressive and can involve microscopic spread below what tests can detect, Ready says, and that’s what immunotherapy appears to help with. “The medical treatment can potentially wipe out whatever microscopic disease is left” after resection, he says. Ready adds that lung cancer experts are optimistic that the improvements they’re seeing in clinical trials “will translate into clearly better outcomes at three to five years — the gold standard in early stage lung cancer.”

So far that’s the case for Linda Cimino, a 60-year-old nurse practitioner in New Jersey who developed a dry cough in March 2020. Cimino tested negative for COVID-19 and knew dry coughs aren’t common with most infections. Because she’s otherwise active with yoga, Pilates and daily 5-mile runs, she already suspected cancer when she called her doctor.

But the pandemic delayed each appointment, first more than five weeks to get an X-ray and CT scan because radiology centers were closed, and then another couple of weeks before she got a biopsy in late April. The diagnosis: stage 3a NSCLC. Cimino couldn’t begin chemotherapy until July, and when she asked about genomic testing, the doctor at her small community hospital said they didn’t have enough tissue for it. So she switched to Memorial Sloan Kettering Cancer Center in New York City and a full genomic work-up revealed she had high PD-L1 levels and a high tumor mutation burden, both advantageous for success with immunotherapy.

Meanwhile, the chemotherapy she was receiving wasn’t working. The tumor continued to grow into her middle and lower lobe and surgery would have required the removal of most of her lung. So instead of surgery, she underwent three weeks of radiation in December that shrank her tumor by half. Before the PACIFIC trial, Cimino’s only options would have been radiation, surgery and chemotherapy. Now, immunotherapy was an option for Cimino. Given her relatively high PD-L1 levels (42%), she followed her oncology team’s advice to opt for immunotherapy and began receiving Opdivo plus Yervoy (ipilimumab) in January 2021. A month later, Cimino had no evidence of disease. She continued immunotherapy for nine months until she developed pancreatitis, an autoimmune complication that, like other autoimmune complications, can happen with immunotherapy. It stopped in September.

“With immunotherapy, I felt great. I had energy, I was functional,” Cimino says. “I’m not going to lie and say there aren’t side effects, but it’s not like chemo. I almost died from chemo. It doesn’t kill the good cells. It boosts the body’s natural defenses to fight cancer.”

Cimino was frustrated that her first cancer center said she wasn’t eligible for immunotherapy. It was joining the support network LUNGevity soon after diagnosis that prompted her to switch providers to get genomic testing, which doesn’t drive all immunotherapy decisions in early-stage lung cancer but is recommended for all patients at any stage of diagnosis, Wakelee says. “It’s very important that we know the mutations and the PD-L1 level before making a decision,” she says.

All the immunotherapy drugs currently approved for early-stage lung cancer are PD-1 or PD-L1 inhibitors, so patients with high PD-L1 expression in their tumors typically respond better to immunotherapy. People with the EGFR mutations or ALK genetic translocations typically have fewer overall mutations and it can be harder for the immune system to recognize the cancer and attack. That means patients with EGFR or ALK can benefit less from immunotherapy and are instead treated with therapies targeting the abnormal proteins resulting from EGFR and ALK genomic anomalies.

Many other trials are testing immunotherapy agents in early‑stage lung cancer. In addition to testing Opdivo, the ALCHEMIST trial that Lee was in is testing Keytruda (pembrolizumab), as are the PEARLS/KEYNOTE-091 trial and KEYNOTE-671 trial. In July 2021, results from the Impower030 trial — testing Tecentriq as both a pre- and postsurgery therapy — showed 90% of patients improved to the next lower stage. And the AEGEAN and MERMAID-1 trials are testing Imfinzi as pre- and postsurgery treatments. Other trials’ immunotherapy drugs have different targets, such as TIGIT, LAG3 and CTLA-4, which Yervoy inhibits.

The ultimate goal in using immunotherapy is to “improve cure rate and overall survival,” Shu says, but it takes years to collect those data, limiting disease recurrence and progression becomes a surrogate measure along the way. Meanwhile, the paradigm shift in treatment regimens has made it particularly important to have multidisciplinary oncology teams, including a medical oncologist, a pathologist, a radiation oncologist and a surgical oncologist, Shu says. A team looks at each person’s situation to determine the best treatment plan for them.

“It makes everything a little bit more complicated but also a lot more exciting” to individualize care for each patient, Shu says.

Among the barriers to immunotherapy use in early-stage lung cancer are patients’ lack of awareness of their options, inadequate insurance coverage for the drugs and not getting genomic testing done. Some patients may also struggle with a treatment schedule that involves coming in every week for infusions or taking a pill for several years, Shu says, “but most patients want the treatment if it’s been shown to work.” Side effects are usually less toxic than with chemotherapy, but toxicity may be an issue for some patients. Although rare, severe toxicities may prevent a patient from being able to undergo surgery.

But multidisciplinary teams help overcome other barriers. “Another challenge is that you’re changing a paradigm for surgeons: They usually take patients for surgery right away and now you’re telling them that you are going to give the patient this treatment first,” Shu says. “Sometimes there may be reluctance from the surgeons,” who worry the tumor will grow or they won’t be able to operate.

Patients can have those doubts, too. “A lot of patients just want their tumors out,” Shu says. “They don’t want to wait three months getting treatments before surgery.”

She explains that presurgery treatment with chemo and immunotherapy can often improve cure rates.

“We know that how necrotic (dead) the tumor looks at the time of surgery is much better with chemotherapy and immunotherapy, which we think means the cancer has less chance of spreading.”

And if the cancer does spread? Research and drug development are moving so quickly that patients may already have another option available to them by then.

“(With) all this research, we are actually seeing results in real time for patients,” Shu says. “Patients are always asking what’s next, and we’re coming up with it. I have patients who are on one line of treatment and by the time they’ve progressed, we’ve already come up with an FDA approval for another line of treatment for them. I have patients who have had metastatic disease for seven or eight years and are doing great.”

That was unheard of in the past, she says.

“The addition of the immune therapy in early-stage diseases is going to be transformative; it’s going to lead to improved progression free-survival and overall survival,” Ready says. “There’s still going to be a lot of biomarker analysis to identify patients who will benefit the most and patients (who) won’t benefit at all, so that’s not clear yet, but it’s clear it’s going to have a major impact.”

Despite stopping immunotherapy early last September after the pancreatitis, Cimino still has no evidence of disease, which she credits partly to immunotherapy.

“I think immunotherapy has a bigger role to play in future cancer therapies, especially for patients with other issues, because chemo is tough,” Cimino says. “All the chemo is doing is telling the body to kill everything. It’s not teaching the body anything.”

Lee also has no evidence of disease and got her last CT scan at the end of January. The only side effect she had from Opdivo was some stomach upset. She thinks it’s “fantastic” that immunotherapy is being used earlier in lung cancer treatment. It is important to note that patients may experience more side effects associated with immunotherapy use, some of which can be serious and permanent, even fatal.

“That’s one of the reasons I wanted to do the clinical trial,” Lee says. “The people who were suffering from lung cancer or any type of cancer before me, they went through a lot to test various drugs and basically made it easier for me. Somebody’s got to help with the research, so I wanted to do that.” 

Her reward has been seeing just how quickly progress is chugging along.

“For people just diagnosed with lung cancer, it is scary,” Lee says, “but there have been so many advances in the treatment of lung cancer that there’s a lot more hope now than there was, say 10, 15, 20 years ago.”

For more news on cancer updates, research and education, don’t forget to 

Articles

Instead of waiting until the disease has progressed, researchers have begun analyzing the effects of using immunotherapy before or after surgery in patients with early-stage lung cancer. The results, according to experts, may be transformative for patients.

A Paradigm Shift in the Treatment of Early-Stage Lung Cancer May Be Leading to More Cures

On the same day in March 2018, three things happened in the life of Lorenzo Cohen, professor and director of the Integrative Medicine Program at The University of Texas MD Anderson Cancer Center in Houston. First, he and his wife signed off on the final draft of their book “Anticancer Living: Transform Your Life and Health With the Mix of Six,” focused on cancer prevention and improving outcomes for those with cancer. Next, he received an email from the Melanoma Research Alliance telling him they would fund his study on lifestyle factors in patients with melanoma. Finally, he learned that the node that had been growing in his left armpit in recent weeks was stage 3 melanoma with unknown primary location.

“That means the immune system did what it had to do to knock out the (original tumor that began the cancer) but not soon enough before a few cells started to grow in the (armpit),” Cohen, who holds a postdoctorate degree, explains. He started taking a combination of Yervoy (ipilimumab) and Opdivo (nivolumab) as neoadjuvant immunotherapy — treatment given before surgery to shrink the tumor first. It was soon obvious the immunotherapy was working. “The nodes just started melting away,” he says.

But he wanted to do more for his therapy. Cohen is an expert on lifestyle habits that reduce risk of cancer and improve outcomes in those with cancer, and he had studied how psychological factors influence hormones that then affect the immune system. He knew, for example, that chronic stress weakens the immune system and can alter the microenvironment around a tumor, making it more hospitable to cancer growth.

“Stress was the first thing I knew I had to manage better,” he says. He doubled down on yoga, meditation and exercise because “the evidence is overwhelming that regular physical activity makes a huge difference on immune function and activation,” he says. He also started taking a beta-blocker, a drug that lowers heart rate and blood pressure by blocking the effects of a stress hormone and potentially reducing the effect of stress within the tumor microenvironment. He then turned to his diet. Cohen was familiar with the research of his colleague, Dr. Jennifer Wargo, a surgical oncologist at MD Anderson who studies how melanoma patients respond to immunotherapy based on the bacteria in their guts. He planned to use current evidence to improve his own gut bacteria, but he would discover that trying to manipulate the makeup of bacteria in our bodies can be tricky.

Wargo discovered early in her career that bacteria in pancreatic cancer tumors could break down chemotherapy into its inactive form. She began studying the millions of microbes that grow in a tumor alongside the cancerous cells, which is known as the tumor microbiome. Soon she was investigating the human gut microbiome, a community of organisms that has a far bigger effect on human health than researchers realized even a decade ago.

“In our bodies, there are hundreds of trillions of microbes that outnumber our cells,” Wargo says, adding that only a fraction of cells in our bodies are human. The rest are bacteria, viruses, fungi and other microbes. “There are more microbial genes in our body than there are stars in the galaxy,” she says. “It goes without saying that these microbes could have an impact on the way our body functions and how it may react to cancer treatment.”

Scientists have learned that these bacteria can help break down food and fight illness, or they can cause inflammation or contribute to chronic disease. It all depends on the balance of “good” and “bad” microbes in the gut, where the majority of the microbiome flourishes. Though researchers are still learning what makes a healthy microbiome, they know genetics, age, diet, lifestyle, medications, the environment and other factors can affect it. Antibiotics, for example, can wipe out good bacteria. Cancer treatments, including surgery, chemotherapy and radiation, also can disrupt the microbiome’s balance.

Research into the microbiome has touched nearly every area of medicine, from gastrointestinal disorders to heart disease, autism to Alzheimer disease, obesity to cancer. But scientists are in the earliest stages of learning how to alter the microbiome or restore imbalances. One way to modify gut bacteria is increasing or decreasing probiotic intake — the microorganisms themselves — or prebiotics, the fibrous foods that feed the bacteria. For example, taking probiotic supplements or eating fermented foods rich with bacteria can sometimes offset the negative effects of antibiotics that kill off too much good bacteria.

Another option is a fecal microbiota transplant, in which fecal matter of a healthy donor (first screened for harmful, infectious germs) is transplanted into another person’s gastrointestinal (GI) tract to restore the balance of healthy bacteria. This is done through a colonoscopy or through a pill or liquid. Fecal transplants are already the standard of care for recurrent Clostridium difficile infections, which occur in up to 10% of patients with cancer undergoing chemotherapy and 20% of all people with cancer.

But aside from those treatments, fecal transplants for other conditions are still only in trials, not treatment rooms, explains Dr. Saranya Chumsri, an oncologist specializing in breast cancer at Mayo Clinic in Jacksonville, Florida.

“We’re not quite there yet in the cancer world,” she says, but scientists are making headway. Chumsri has been conducting studies with over-the-counter probiotics to learn whether these supplements or other microbiome restoration products can improve treatment responses in patients with breast cancer, but it’s tricky to figure out the best combination of bacteria to offer.

“Studies show that if you have diverse gut microbiome — not just species but more diversity of the type of bacteria in the gut — it’s actually more protective for cancer,” she says. But it’s not always as simple as taking pills from the store.

“The problem with over-the-counter probiotic capsules is that they break apart in the stomach,” Chumsri explains. The stomach’s low pH can kill the bacteria before it reaches the rest of the gut, so researchers are looking at other options.

As scientists have learned how integral gut bacteria is to the immune system, the microbiome has received more attention in cancer research.

“Although our immune (system) originally evolved to fight microbes, it has actually become tolerant of some of them, and they shape how our immune system functions,” Wargo says. “Depending on what the bugs look like, your gut can influence your response to immunotherapy.”

Two studies in 2015 found that the microbiomes of mice can affect how well they respond to checkpoint inhibitor drugs and that researchers could change their microbiomes to improve the mice’s response. More recent research involving patients with cancer has found that differences in gut bacteria composition are linked to survival rates after bone marrow/stem cell transplants and may be able to reduce GI side effects from cancer treatment.

“I see a lot of patients referred to me with diarrhea and colitis,” says Dr. Pankaj Vashi, a gastroenterologist and vice chief of staff at Cancer Treatment Centers of America (CTCA) in Chicago. “If you give them doses of good bacteria (during) immunotherapy, it can reduce the incidence of colitis.” Vashi has seen other patients experience lower levels of toxicity to immunotherapy for kidney or lung cancer if their gut microbiome has the right mix of bacteria.

The question is whether it’s possible to modify patients’ microbiomes to achieve better response rates or less toxicity with cancer treatments. The most progress with these experiments is seen in patients with melanoma.

A study published in 2017 by Wargo and colleagues examined the gut microbiome of 112 patients with melanoma receiving anti-PD-1 immunotherapy, which not only kill cancer cells directly but block a pathway that protects tumor cells from the components of the immune system that fight cancer. Patients who responded to the therapy had higher rates of diversity and more Ruminococcaceae bacteria. It was research such as this that inspired Cohen to see if he could improve the diversity of his microbiome.

“Your microbiome is totally dependent on what you eat,” Vashi says. “If you eat a lot of fast foods and synthetic foods, you’re going to have issues with your gut microbiome.”

Those who eat lots of fruits, vegetables, lentils and legumes, however, tend to experience fewer side effects and have better outcomes overall.

Cohen was already eating a mostly whole food vegan diet, with occasional eggs or cheese. But after receiving his diagnosis, he increased his intake of probiotic-rich foods and reduced his carbohydrates, having read that spikes in insulin after eating carbs can negatively affect tumor microenvironments. He swapped out healthy grains such as oatmeal and quinoa for fermented foods such as miso, kombucha, sauerkraut, a liquid probiotic drink and nondairy yogurts fortified with extra bacteria.

He signed up as a participant in his own study — the one he was conducting with Wargo and others that had received funding the day he received his diagnosis — so he could analyze changes in his microbiome. Three months after his initial microbiome sample, he was startled to find less biodiversity in his gut than when he started. He stayed on the diet and analyzed another sample three months later: Again, it had less biodiversity than his first sample.

“I needed to do something, so I decreased the amount of probiotic food and increased healthy grains — quinoa, buckwheat, oatmeal, maybe 2 to 3 tablespoons a day of a healthy whole-grain mush,” he says. Another three months later, his microbiome’s diversity was better than it had been at the start of the study. Though he can’t be sure of the exact cause, it seemed that increasing his healthy microorganisms with extra food-based probiotics while decreasing prebiotics led to dysbiosis, an imbalance in his gut bacteria, and a decrease in the diversity of his gut bacteria.

Cohen, Wargo and their colleagues presented preliminary findings of that study in 2019. Among 46 patients with melanoma, those who ate a high-fiber diet rich in whole grains, fruits and vegetables were five times more likely to respond to anti-PD-1 therapy than those who had a low-fiber diet. And those who took probiotic supplements tended to have lower microbiome diversity.

“What’s interesting about the microbiome is that it’s far more complex than we know,” Cohen says. Cohen underwent surgery in June 2018 that removed the entire tumor and then continued taking Opdivo. He has had no evidence of disease since then.

The most recent breakthrough has replicated in humans a study previously done in mice. Two studies in February 2021 showed that fecal transplants from patients with melanoma who responded to checkpoint inhibitor therapy could turn some nonresponders into responders. In the phase 1 trial led by Dr. Gal Markel of the Sheba Institute in Israel, in which Wargo was involved, 10 patients with metastatic melanoma who had not responded to anti-PD-1 therapy received fecal transplants from patients who had responded. Two of the 10 patients then partially responded, and one had a complete response.

The other study, from the University of Pittsburgh Medical Center, involved 15 patients with advanced melanoma who had not responded to a combination treatment with Keytruda (pembrolizumab) and Opdivo.

After undergoing fecal transplants and then further treatment with Keytruda, six of the 15 saw a reduction in tumor size or no more progression. Those six had higher amounts of bacteria previously linked to immunotherapy response. The researchers suspect the changes to a patient’s gut microbiome may influence a tumor’s microenvironment to make it more susceptible to immunotherapy, but this is only one possible explanation for why changing the gut microbiome appeared to improve responses. Currently approximately 40% of patients with advanced melanoma do not respond to immunotherapy, so researchers hope larger trials will show this treatment can increase how many patients respond.

Research into modulating the microbiome has expanded to colorectal cancer, but doctors such as Vashi have been counseling their patients for years on how to find the right diet for their cancer, body type and health. One of those patients is Dwayne Copeland, a 57-year-old middle school teacher in Florence, Alabama. During the summer of 2010, while in Maryland for professional development, Copeland began feeling sick each afternoon. After he returned home, Copeland, also a football coach, began feeling sick during practice. When blood showed up in his stool, he called his family doctor. That October, he found out that he had colorectal cancer in all three parts of his large intestine. The first oncologist he saw recommended immediate surgery but told him he had only one to three years to live, so Copeland got a second opinion at CTCA.

“They told me I did not have an expiration date. That was really good to hear,” he says. He underwent 60 doses of chemo and 36 radiation visits before a total colectomy in January 2011, which left him with 3 inches of his rectum and 12-inch J-pouch — a surgery that allows a person to have control over their bowels without a complete colon — that enabled him to continue his active lifestyle without needing a colostomy bag. He also learned he has the hereditary condition MUTYH (MYH)-associated polyposis in which too many copies of the same cell are created, increasing the risk of colorectal cancer.

“It wasn’t if I’d have cancer again, it was when,” Copeland says. Vashi and his treatment team taught him what to eat to keep his microbiome balanced and reduce the likelihood of recurrence. As a science teacher, Copeland had read about the microbiome, “but I did not realize it was that important until I had cancer and needed to maintain a good gut balance,” he notes. Though he no longer coaches, he walks six days a week, maintains muscle mass with body weight and dumbbell exercises, takes a probiotic supplement, eats an apple and banana every day, and eats plenty of whole wheat bread and fish.

“The one thing I refrain from is sugar,” he says. “Anything (such as) desserts with a lot of sugar, that’s a risk-reward thing for me because I know it’ll cause problems with my gut bacteria.” He can tell within 45 minutes of eating if his gut is rebelling against what he ate.

As researchers continue exploring the relationship between the microbiome and cancer treatment, each discovery brings up more questions. It’s not clear how to determine which patients might benefit from a treatment that alters their microbiome, who the best donors are for fecal transplants, when patients should receive the transplant during treatment or what is the best method for fecal transplant. But it is clear from Cohen’s experience that even seemingly positive changes in diet can backfire. And over-the-counter probiotics aren’t necessarily beneficial, especially since they are not regulated by the Food and Drug Administration for quality.

“We haven’t yet figured out a magic pill that can work, and currently we focus more on a whole foods-based approach,” Wargo says. Her colleague, Nadim Ajami, executive director of scientific research for the Program for Innovative Microbiome and Translational Research at MD Anderson, points out that many probiotic supplements are a single organism. “We’re also seeing with cancer patients that diversity is good,” he says. “You wouldn’t want to miss the opportunity to increase diversity, but that is not the only ingredient.”

Vashi recommends that patients who want to learn more about ensuring a healthy microbiome should ask their oncologist for a referral. Many oncologists still haven’t recognized the importance of probiotics, prebiotics and microbiome balance to cancer care, but they should be willing to refer patients to dietitians or others who are familiar with the evidence.

Cohen pointed out the risks of making recommendations with incomplete evidence. After giving a lecture on the microbiome, he heard from a patient whose oncologist recommended taking probiotics based on Wargo’s early findings. That was before the findings that patients with melanoma taking probiotic supplements had less diversity were presented.

“This well-intentioned physician was potentially harming a patient because he was getting just a little bit ahead of what the evidence actually showed,” Cohen says. “There’s never been a clinical trial of probiotic supplementation with melanoma patients to say it helps the gut. Maybe the fecal microbiome transplant may help, but you can’t get that over the counter.”

The key appears to be a well-rounded diet that doesn’t tip too far in any direction. “Now the only recommendation we can really make is to try to achieve good gut health through a whole food, plant-centered, high-fiber diet,” he says. “Healthy gut bacteria for the majority of people will thrive and grow and proliferate in a positive way if they’re fed healthy foods.”

The gut microbiome plays an important role in how patients may respond to cancer treatments, and researchers are learning more about ways to alter it to benefit treatment outcomes.

Follow Your Gut: Advances in Understanding Microbiomes Are Transforming Cancer Care

Gareth Hughes’ life has always been a fast-paced adventure. As a producer for CBS Sports, the 41-year-old father of two frequently flew from his home in Brooklyn, New York, to various U.S. cities to cover the Super Bowl, the national semifinals for the NCAA Tournament known as the Final Four and other huge sports events.

But he wasn’t ready for the news he received shortly after working 2019’s regional semifinals for the NCAA Tournament known as the Sweet 16.

If the University of North Carolina (UNC) had won, he would have worked all weekend. When they lost to Auburn on Friday, Hughes headed home from the New York City studio and played with his kids. But he felt awful, and it had nothing to do with basketball. He recalls meeting with his psychiatrist the day before (on Thursday in NYC). “I curled up in a ball and cried, and I’d never done that before,” he says. Because Hughes continued having severe pain in his side on Saturday morning, his wife encouraged him to go to the hospital and get it taken care of before he flew to Minneapolis for the Final Four.

Given his youth and health — he’d quit drinking three years earlier — the doctors jumped to the obvious conclusion: time to take out his gallbladder. But after an ultra- sound, X-ray and additional imaging at the emergency department, the doctors changed their tune. “You could tell by the look on their faces that this was not going to be as easy as classic gallbladder problems,” Hughes says. The doctor sat on his bed and explained that there were spots on his liver, either from an infection or cancer. And infection didn’t seem likely.

After a CT scan and biopsy, Hughes knew he wouldn’t be covering the Final Four that year. Instead, he and his wife wrangled with news that changed their lives.

“You go from that Friday night, sitting on the stoop, listening to the music and playing buddy ball, a game we made up, with my 4-year-old son, and by Saturday evening, I’ve been admitted to the hospital and (I don’t know it yet), but my life is never going to be the same,” he says.

By the time he was discharged, it was clear that it was cancer. At an appointment with an NYU Langone Health oncologist, while fielding text messages from work about the Final Four set he’d worked a month to build, Hughes received an official diagnosis of intrahepatic cholangiocarcinoma — cancer of the bile ducts inside his liver. “It was a very strange moment where work and life collided,” he says.

After the appointment, he and his wife just rode the Second Avenue bus for a while, crying, talking and texting the news to friends. “In that initial moment you’re so lost. You don’t know anything,” he says.

The cancer hadn’t metastasized beyond Hughes’ liver, but it had gone too far for resection surgery. He had a grapefruit-sized tumor with satellites on the right side and two dots on the left — dots that essentially ruled out surgery because the risk of recurrence would be too high. He would begin chemotherapy treatment, the first-line standard of care for cholangiocarcinoma. Instead of receiving gemcitabine and cisplatin, however, Hughes sought a second opinion at Memorial Sloan Kettering Cancer Center in New York City, which prompted him to choose a pump that delivered floxuridine directly to an artery in his liver while he received gemcitabine and oxaliplatin. He also underwent testing to see if his tumors contained any mutations.

Hughes, like most Americans, had never heard of cholangiocarcinoma. He had also never heard of the FGFR2 fusion mutation, a gene alteration present in his tumor that broadened treatment options beyond standard chemotherapy — and an example of why doctors are increasingly encouraging people with hepatobiliary cancers to get genomic testing.

Hepatobiliary cancers include those in the liver, bile ducts and gallbladder. According to the National Cancer Institute, more than 42,000 people in the U.S. receive a diagnosis of liver or intrahepatic cholangiocarcinoma each year — a rate that has tripled since 1980 and continues to increase due to rising rates of hepatitis B and C infections, cirrhosis from alcohol consumption, and obesity and type 2 diabetes, which contribute to fatty liver disease. In addition, nearly 12,000 others, according to the American Cancer Society, are diagnosed with gallbladder cancer or extrahepatic cholangiocarcinoma, which occurs in the bile ducts outside the liver. The two extrahepatic types are perihilar, occurring in the bile ducts just outside the liver, and distal, occurring in the portion of the bile duct nearest the small intestine. Cholangiocarcinoma is rare — a couple of cases per 100,000 Americans each year — but intrahepatic cholangiocarcinoma is increasing, possibly due to increased detection as scans are done more readily and often.

Only surgery can cure hepatobiliary cancers when they’re caught early enough, but most patients don’t experience symptoms until the cancer has spread far enough to rule out curative surgery. Recurrence is common even after completely resecting a tumor that has spread, and post-surgery treatments vary greatly depending on where the cancer is.

For unresectable liver cancer, on the other hand, first-line treatment usually includes either the combination of the immunotherapy drug Tecentriq (atezolizumab) and the targeted drug Avastin (bevacizumab), or Nexavar (sorafenib) or Lenvima (lenvatinib), both targeted drugs. Second-line treatments include a range of immunotherapy and targeted drugs, including oral tyrosine kinase inhibitors, that have become available.

“With hepatocellular cancers, there has really been a sea change,” says Dr. Milind Javle, a professor of gastrointestinal oncology at The University of Texas MD Anderson Cancer Center in Houston. “Several agents (have been) approved in the last five years, whereas for a decade we had nothing other than sorafenib.” Those approvals include the immunotherapy drugs Keytruda (pembrolizumab), Opdivo (nivolumab) and Yervoy (ipilimumab) as well as the targeted drugs Stivarga (regorafenib), Cabometyx (cabozantinib) and Cyramza (ramucirumab).

For unresectable gallbladder and biliary cancers, however, not many options exist after first-line treatment with chemotherapy, nearly always gemcitabine and cisplatin. Without formal guidelines, most doctors use FOLFOX — folinic acid plus the chemo combo of fluorouracil and oxaliplatin — for second-line treatment of gallbladder cancer and cholangiocarcinoma.

Yet much of that is changing by the day. An increased understanding of tumor mutations across all hepatobiliary cancers is rapidly transforming patients’ treatment options, and doctors are increasingly encouraging patients to undergo genomic testing as the landscape of therapies expands to include more targeted drugs for these cancers.

Two types of testing that look at the genes are informative, says Dr. Kenan Onel, director of the Center for Cancer Prevention and Wellness at the Tisch Cancer Institute at Mount Sinai in New York City. Genetic testing looks at a person’s innate genetic code to see if they have any germ- line, or inherited, mutations that increase the risk of cancer developing. These mutations include ones familiar in other cancers, such as in the BRCA1 and BRCA2 genes.

Genomic testing, also called molecular profiling, on the other hand, looks only at the genes in the tumor itself that are not inherited, with the goal of finding mutations that can be targeted with specific drugs. No germline mutations have yet been linked to all gall bladder or bile duct cancers, Onel says, so genetic testing offers little insight for people with these cancers. But genomic testing, particularly with a method called next-generation sequencing, is already standard of care for biliary cancer and rapidly becoming so for liver cancer, Javle says.

“For both cancers, increasingly we are understanding that there are subgroups of the patients that have specific genomic alterations that render them more likely to respond to a specific treatment or more likely to be resistant to other treatments,” explains Dr. Lewis Roberts, a professor of medicine at Mayo Clinic who specializes in liver, biliary and gallbladder cancers. “That is perhaps more the case with bile duct cancer than with liver or gallbladder cancer.”

Only one targeted drug has been approved by the Food and Drug Administration (FDA) for cholangiocarcinoma — Pemazyre (pemigatinib). It was approved in April 2020 for advanced intrahepatic cholangiocarcinoma containing FGFR2 fusion or rearrangement mutations, the one Hughes had, after first-line standard chemotherapy. But additional targeted drugs may be coming soon as scientists learn more about genomic targets in biliary tumors, and more are avail- able in clinical trials — the direction Hughes ultimately took.

When his genetic and genomic testing results came back, Hughes learned he didn’t have any germline mutations that predisposed him to cancer, which also meant this cancer was unrelated to the testicular cancer he had at 11 months old that was cured by removal of one testicle. He also learned he hadn’t brought this cancer on himself with drinking, a fear he’d harbored since hearing the news. His doctor told him to “accept that this is random.”

The most important news from the testing was his having an FGFR2 fusion mutation, found in 15% of people with intrahepatic cholangiocarcinoma. That left open a door for oral therapies if chemotherapy failed. “From the get-go, they’re mentioning surgery, and that’s what I had in my head,” Hughes says. “What I should have had in my head were these pills.”

Hughes remained on the triplet chemotherapy regimen from May 2019 until Thanksgiving 2019, when scans showed the tumors were shrinking but his liver function had plummeted. While trying to kill the malignant cells, the chemotherapy had also killed too many healthy cells. Hughes had also developed a common allergy to oxaliplatin. While Hughes was on a long break from chemotherapy, his pain worsened, his pain medications increased, and he frequently visited the emergency department with pain and tumor fevers. By January 2020, his tumor markers had skyrocketed. He restarted chemotherapy, but because it continued to injure his liver, he stopped it in March 2020. It was time to try FGFR inhibitors.

Gene Targets in Cholangiocarcinoma and Gallbladder Cancer

An estimated 40% of patients with cholangiocarcinoma have tumor mutations that could potentially be treated with targeted therapies, but low enrollment in clinical trials has slowed progress in learning about effectiveness of these treatments.

Trials are currently investigating the FGFR inhibitors Balversa (erdafitinib), derazantinib, ponatinib, pazopanib, and Debio 1347, and researchers are testing Pemazyre or infigratinib against chemotherapy for first-line treatment. Another potential target in intrahepatic cholangiocarcinoma is the IDH1 mutation, occurring in approximately 10% to 20% of these tumors. IHD1 encodes an enzyme that can “turn off” the expression of certain cancer protection genes. Recent clinical trials showed improvements in progression- free survival with the IDH1 inhibitor Tibsovo (ivosidenib) in patients whose tumors harbor this mutation. Even the less common BRAF V600E mutation, which occurs in 5% of patients with cholangiocarcinoma, has shown some response in a trial testing the combination of the BRAF inhibitor Tafinlar (dabrafenib) with the MEK inhibitor Mekinist (trametinib). And tumors with HER2 mutations responded to the drug Nerlynx (neratinib) in a 2019 clinical trial.

Genomic testing can also benefit patients by offering insight into whether they’ll respond better — or more poorly — to different therapies. For example, some research suggests tumors with the IDH1 mutation respond to the TKI inhibitor Sprycel (dasatinib) even though it’s not specifically an IDH1 inhibitor. Meanwhile, tumors with FGFR2 mutations did not respond to Pemazyre if they also had TP53 mutations. Three mutations that occur in 15% to 20% of both intrahepatic and extrahepatic cholangiocarcinoma — KRAS, TP53 and ARID1A — lack approved drugs that target them, but emerging research still offers some hope. The ARID1A mutation may be susceptible to a group of drugs called poly (ADP-ribose) polymerase, or PARP, inhibitors, and recent results from a lung cancer trial heralded the first drug to successfully target KRAS, called sotorasib. Scientists have long sought drugs targeting KRAS mutations, which occur in several cancers, so sotorasib may offer benefit for other cancers with these mutations, too.

Though no targeted therapies for gallbladder cancer have been FDA approved yet, a number of mutations could soon have targeted drugs. One recent study by Javle found that 87% of 760 people with gallbladder cancer had a mutation that a drug may potentially target. The most common mutation was CDKN2A, followed by ERBB2, PIK3CA, MDM2, CCNE1, STK11, ERBB3, ATM and PTEN. Similarly, a recent study by Dr. Chirag Nepal and colleagues analyzed sequences from 92 tumors and found nearly a third (29%) had mutations in the TP53 gene, another gene that has attracted researchers’ attention because it’s so commonly mutated across many cancers. The researchers also found ELF3, ERBB2, CDC27, TGFBR2, PIK3CA, KIR2DL4, KIR2DL3 and ARID2 gene mutations, any of which might eventually help determine the most optimal therapies for tumors with these mutations.

With all these targets to investigate and all the experimental therapies out there, it takes additional research to discover what therapies might work against tumors with different mutations. Hughes started first with Balversa, the only other FGFR inhibitor approved by the FDA. However, because it’s approved only for advanced urothelial cancers with FGFR2/3 mutations, Hughes took it off-label. The most common side effect of FGFR inhibitor drugs is high phosphate levels in the blood, followed by fatigue, hair loss, diarrhea, constipation, losing nails, inflammation of the mouth and dry eye. Hughes vomited for a week after starting Balversa, took a brief break and started it again. It worked.

His tumors shrank by half until June, when treatment-related hand-foot syndrome (HFS) caused such painful sores on his feet that he couldn’t walk, and he had to stop the drug. “I became comfortable with the idea that taking breaks was going to be an important part of treatment,” Hughes says. “You have to build in breaks to give your body time to recover.” Hughes continued Balversa until October, when it was no longer working and the tumors began to grow again. He then enrolled in a trial for another FGFR inhibitor that didn’t even have a name yet. But he stopped that drug after just three weeks because his tumor marker doubled.

Fortunately, he qualified for a phase 1 trial with RLY-4008, a drug that targets FGFR2 mutations. Hughes began in December, and after one dose reduction so he could better tolerate it, his main tumor had shrunk 27% by the day after the Super Bowl. “Other drugs you feel drugged and stupid, but this one has kept me feeling normal,” he says, adding that he’s optimistic about his response so far. This drug still causes HFS and requires him to take breaks, but it isn’t as rough on his liver function.

Hughes wouldn’t have had access to this drug without genomic testing revealing the FGFR2 mutation and his choosing to enroll in a clinical trial.

“We should consider every patient as potentially someone who should be participating in a clinical trial,” Roberts says. “At every stage of cancer, there are trials that people can participate in that could potentially help them (and) increase the knowledge that we have and allow us to be offering better treatments over time.” The many trials investigating genomic targets also make Roberts optimistic about future treatments for hepatobiliary cancers.

“These biliary tract cancers are some of the most lethal cancers we have,” says Roberts, but FGFR inhibitors are already showing success in slowing them down — and that’s only one target. “Just knowing you have certain mutations gives us some idea about your likely outcomes because patients with different mutations seem to respond differently, and patients who respond to these treatments have substantially improved outcomes,” he says. “I think many of us are quite hopeful that with time, we’ll be able to continue to make progress and develop better and better treatments and cover a larger proportion of tumors with personalized treatment.”

That’s certainly Hughes’ hope as he’s come to accept the ups and downs of trying different therapies.

“My treatment has moved into a chronic phase, and that’s the most likely way I’ll be living with it for the rest of my life,” he says. “There’s a small possibility that things could break right and things could shrink. I don’t think the odds of that are that great.”

He prefers his odds with the new targeted drugs in development, such as RLY-4008. “I have this dream,” he says, “of this drug acting as my chronic answer.”

For more news on cancer updates, research and education, don’t forget to

Genomic testing has allowed patients to receive more specific drugs that target mutations in their tumors.

Genomic Testing Offers New Therapy Options for Hepatobiliary Cancers

Those who have inoperable pancreatic cancer are generally offered chemotherapy regimens that may extend life for just a couple of months at a high cost. That’s why many experts believe that clinical trials need to become the standard of care, allowing patients to benefit from the search for better therapies, especially targeted drugs and immunotherapies.

“We are just bombarding them with chemotherapy, which is of no use, and they go through so much pain and so much suffering,” says Pinku Mukherjee, Ph.D., a professor and chair of cancer biology and immunology at the University of North Carolina at Charlotte.

Roberta Luna, shown with her husband, Vic, would like clinical trial criteria loosened, so she can participate.

Yet only about 5 percent of patients nationally actually enter clinical trials, partly because of restrictive enrollment criteria, says Anirban Maitra, M.B.B.S., a professor of translational molecular pathology and scientific director of the Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research at The University of Texas MD Anderson Cancer Center in Houston. Having HIV or a history of another cancer, for example, should not be exclusions for most trials, he says, yet they are.

Roberta Luna, a 62-year-old commu&shy;nity volunteer and former paralegal in Santa Ana, California, knows firsthand how it feels to be excluded from myriad clinical trials. She wanted to find one that would offer something better than the 16 years of chemo&shy;therapy she has undergone to keep her stage 3 pancreatic cancer in check. “My tumor is inoperable because of the location — it’s entwined with the main artery like ivy,” Luna says. “There’s nothing they can do with it yet, so my hope is that they can keep the cancer at bay until they can do something to take it out.”

Her regimen has been “putting poison in my body, and it’s going to affect me at some point,” she says. She has known people who died from treatment toxicity, not their cancer, and she recently learned that years of chemotherapy appear to have affected her heart. But she has few options.

Luna has both types of pancreatic cancer — exocrine adenocarcinoma and a neuroendocrine tumor &mdash; and just one kidney. She was born with a nonfunctioning kidney that was removed when she was 3 years old. Her unique situation, plus over a decade of chemotherapy, excludes her from nearly all clinical trials.

“It is very frustrating, because you don’t know what might be out there that could possibly help you,” Luna says. “It makes you feel like they’re not even giving you a chance.”

She believes that when doctors keep those doors closed, it’s because both they and their patients consider clinical trials a last-ditch option. All the stake&shy;holders should instead look at clinical trials from the start, Luna says, particularly because any trial will provide at least the current standard of care.

“Especially for pancreatic cancer, we don’t have a whole lot of drugs out there, so trials are really something we should consider first,” she says. “It will help us, but it will also help others, because clinical trials are the only way we’re going to find out what drugs might work. This disease sometimes takes away so much control from you. … Helping somebody else is one little aspect you can control, and a major way to do that is (by) participating in a clinical trial.”

ROBERTA LUNA helps set up for the Pancreatic Cancer Action Network’s PurpleStride Orange County 2018 in Irvine, California, in November.

Both she and Scott Nelson, a Minneapolis resident who received a diagnosis of pancreatic cancer in 2004, say the disease’s low survival rate and rapid spread after detection can deter doctors from seeking options beyond standard care, and patients are hardly in a mental state to research trials themselves. “First you’re in shock, then you’re angry, then you decide you’re going to fight this, but you don’t know what to do,” Nelson says. “You’ve got to make these life or death decisions in a very short period of time.”

Nelson recommends that patients take two steps imme&shy;diately after diagnosis: Find a high-volume medical center that has many physicians special&shy;izing in pancreatic cancer, and call the Pancreatic Cancer Action Network (pancan.org), a nonprofit patient advocacy group that takes a patient’s information and searches for clinical trials for him or her. If patients struggle with the first step, the network can help them find a treatment center.

“They will walk you through what you have to do, and you keep that phone representative all the way through the process in future calls,” Nelson says.

Patients with pancreatic cancer face barriers to clinical trials as a standard of care.

Tara Haelle

A Paradigm Shift in the Treatment of Early-Stage Lung Cancer May Be Leading to More Cures

Follow Your Gut: Advances in Understanding Microbiomes Are Transforming Cancer Care

Genomic Testing Offers New Therapy Options for Hepatobiliary Cancers

Changing Our Standards

Latest News