Genetic mutations help fuel the growth of cancer tumors in patients. And, in recent years, experts in the medical field have begun to better understand how targeting those mutations can knock out the spread of the disease.

For non-small cell lung cancer (NSCLC), the most frequent diagnosis in this disease type, genetic testing is now recommended and can help pinpoint if a patient has one of these gene mutations.

, we feature an article on new targeted therapies that have been approved in the treatment of NSCLC. Leading experts in the field share their insight into the 

 that exist now, as well as how this type of therapy is revolutionizing the treatment of the disease. We hear from two patients about how their lives have been changed by finding the right targeted treatment. We also take a closer look at 

 and if it plays a role in the development of lung cancer. A recent study compared people with lung cancer with those without disease. It showed that those with lung cancer had more stressful life events. We offer tips on how to create more serenity and decrease stress.

Many patients say one of the most stressful situations is travel for medical care. Often, the best oncology treatment can be found at major medical centers, which are found in larger cities. This limits access to patients who live far away or in rural areas. They may have longer commutes to the center or can’t get there at all. Two experts discuss how 

Also in this issue, updated treatment guidelines for advanced disease, stem cell research and personalized care, and how the American Lung Association is working to end stigma surrounding lung cancer.

The treatment of lung cancer is constantly evolving, we hope you find this special issue helpful in your quest to understand what awaits in the future. As always, thank you for reading.

Articles

From the Chairman

Determining the Target to Find the Right Treatment

THE TERM “BIOPSY” DATES to the 1800s. Tissue biopsies have served as the definitive way to confirm a diagnosis of cancer. However, much like cancer drug development is evolving, so is the way we can detect the disease, categorize it more precisely and, more recently, even pinpoint how to treat it.

A term fairly new to most patients — “liquid biopsy” &mdash; is changing the way patients obtain clarity on their tumor and may actually influence therapy. The first liquid biopsy in the United States was approved in 2016 by the Food and Drug Administration (FDA) for the detection of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancers (NSCLC).

Compared with a tissue biopsy, which requires surgery or a needle penetrating the body, this is a less invasive procedure for patients. A liquid biopsy is done with a blood draw, and results are back roughly in a few days versus a week or more. The information gained may determine whether the cancer will respond to already approved or newer investigational cancer therapies.

Although we hope that liquid biopsies may one day help detect lung cancer early on in disease, as of now, they may help with monitoring patients in the treatment process.

Liquid biopsies can be particularly useful when a mutation becomes apparent after treatment has started. If this is accompanied by disease progression, the liquid biopsy results could potentially influence therapy.

For instance, in some cases, this biopsy is picking up the T790M mutation, which becomes more detectable as patients develop resistance to EGFR-targeted therapies in a process termed “clonal selection.” A newer drug, Tagrisso (osimertinib), is approved specifically for this mutation. Interestingly, the results of the recent phase 3 FLAURA trial found that Tagrisso proved superior as frontline therapy, compared with the standardof- care use of Tarceva (erlotinib) or Iressa (gefitinib) for EGFR-mutated NSCLC, and is being reviewed by the FDA on the breakthrough therapy designation track for this indication.

Trials like this highlight the use and importance of gene sequencing technologies for decision-making among medical experts.

In the cover story, you will hear from some of those experts and meet a patient who had a liquid biopsy — on the day he tested positive for EGFR gene mutation, he walked out of the cancer institute with a targeted therapy in tow. We are very optimistic that this trend toward less invasive ways for more personalized and effective treatment will continue.

Chair, Department of Breast Medical Oncology

The University of Texas MD Anderson Cancer Center

Editor's Page

A Little Blood Goes a Long Way

Implementation of telehealth into cancer centers across the United States has allowed for outreach to patients in many locations that are often far from large, urban medical centers.

The development of modern multidisciplinary treatment of patients with cancer with the coordination of medical oncologists, radiation oncologists and surgical oncologists has led to regionalization of treatment teams within specialized care centers in some areas.

These medical centers are commonly located in large, urban areas, leading to significant hurdles for patients in rural areas to access specialized treatment teams. Many studies have demonstrated that greater geographic distance from urban advanced-care centers worsens patient survival.

Rural patients tend to have diminished access to appropriate, routine cancer screening studies, leading to patients with cancer being diagnosed with more advanced stage disease.

Advanced-stage cancers, which are often associated with disease spread to other organs or lymph nodes beyond the original tumor, are invariably associated with decreased patient survival and are more difficult to treat. In the past decade, there have been several Australian studies demonstrating that mortality is higher in patients with lung cancer who live farther from specialty hospitals with thoracic surgeons on staff.

Improved lung cancer survival is linked to earlier stage at diagnosis. One study found that those patients treated at these specialty hospitals were more likely to undergo surgical excision of their lung cancer, leading to improved overall survival.

Data from the United Kingdom corroborates these findings, showing that greater geographic distance from a facility with a thoracic surgeon has an even larger effect on patient survival than the patient’s cancer stage at diagnosis.

Although there is inconclusive evidence that U.S. rural patients have worse survival rates than their urban counterparts, data from the American Society of Clinical Oncology indicate that only 3 percent of medical oncologists work in rural areas, resulting in significantly higher travel times for rural patients to be seen by medical and radiation oncologists. In addition, oncologists find it more difficult to enroll these patients in clinical trials of novel therapies.

To overcome these discrepancies in urban and rural patient outcomes, health care systems are turning toward multidisciplinary tumor teleconferences to link community cancer treatment centers with regional specialist hospitals.

These telehealth conferences tap video conference technology to provide real-time discussions between oncologists on the front line of patient cancer care in a rural setting and specialists in urban tertiary care centers.

A patient’s oncologist often is instrumental in coordinating a patient’s care leading up to and after surgery or specialized radiation therapy.

As such, it is vital that oncologists communicate frequently and directly with those specialists in the tertiary care center.

Regular telehealth video tumor conferences allow real-time decision-making with a large group of specialists to consider each patient’s case individually. Each patient with cancer is unique. Collaborative discussion between specialists facilitates optimization and personalization of each patient’s cancer care.

Often, tertiary or quaternary medical centers participate in clinical trials to study novel chemotherapeutic agents or treatment regimens. Many community oncology centers may have limited access for patient enrollment in these clinical trials, but the collaboration of a virtual tumor board allows some patients in rural areas to participate in therapeutic clinical trials to which they may not have otherwise been exposed.

As cancer therapy, especially lung cancer care, becomes more individualized with analysis of genes expressed by tumors, it is important for all patients with cancer to have access to such trials.

Lung cancer screening with low-dose computed tomography scanning of the chest has recently been recommended in select patients with significant smoking history. However, it is thought that a majority of patients in the community who would benefit from such screening will never receive it for various reasons.

Lung cancer continues to be responsible for the largest numbers of cancer deaths in the U.S. and is the second most commonly diagnosed cancer in both men and women.

As such, it is even more important to reach these rural patients who more often have advanced-stage lung cancer for enrollment in trials that could provide them potentially lifelengthening therapies.

The multidisciplinary cancer center at University of California, Davis has regular telehealth video conferences with surrounding community oncology groups to discuss all avenues of our patients’ care.

By nurturing this network of satellite oncology sites with our thoracic oncology specialists, our medical and radiation oncologists, surgeons, pathologists and radiologists are able to personalize the treatment plans for each patient.

In an era when oncology is becoming more and more individualized with identification of unique tumor characteristics, the advent of telehealth is an excellent adjunct to the care of patients with lung cancer, especially for rural patients whose access to specialized care may be limited.

JAMES CLARK, M.D., is a general surgery resident at the University of California, Davis. He plans to specialize in general thoracic surgery with an interest in surgical management of advanced stage lung cancer.

ELIZABETH DAVID, M.D., MAS, FACS, specializes in general thoracic surgery, with a particular interest in thoracic surgical oncology at the University of California, Davis. She is interested in minimally invasive thoracic surgery, including robotic surgery, tracheal and airway procedures, esophageal resection and stenting and palliative oncologic procedures. David has a special interest in surgical management of advanced stage lung cancer.

Speaking Out

Telehealth Can Expand Lung Cancer Treatment Options in Rural Areas

A NEW DRUG COMBINATION in testing could hit non-small cell lung cancer (NSCLC) with a one-two punch: simultaneously suffocating tumor cells and preventing new ones from forming.

Plinabulin, an angiogenesis inhibitor that prevents growth of new blood vessels, is being tested in combination with the chemotherapy drug Taxotere (docetaxel) as an option for patients with advanced stage 4 NSCLC who have progressed after treatment with standard-of-care therapy. The investigators intend to determine the overall survival (OS) benefit of plinabulin for patients receiving second- or third-line chemotherapy.

For patients treated solely with chemotherapy, OS is often very short, with a median survival of 7 to 8 months, according to Goetz H. Kloecker, M.D., M.S.P.H., MBA, FACP, an associate professor of medicine and director of the Thoracic Oncology and Hematology/Oncology Fellowship programs at the University of Louisville in Kentucky. “In the initial trials, [for patients who had] larger tumors — more than 3 centimeters &mdash; OS and progression-free survival (PFS) was significantly improved, and significant for lung cancer means the median survival was improved by more than 2 months. It may not sound like much, but for lung cancer, a median of 2 months often translates that there are more people alive 1 or 2 years later,” Kloecker said.

This drug could represent a big step forward in helping patients with lung cancer who have received standard-of-care therapies in the first- or second-line setting. There are currently two approved antiangiogenetic therapies for this patient population — Avastin (bevacizumab) and Cyramza (ramucirumab) &mdash; and adding another option to be combined with Taxotere could lead to treating more patients for a longer period.

“Tumors need a lot of blood, since they live on oxygen,” Kloecker said. “Plinabulin blocks blood vessels from growing and kills tumor blood vessels. It does this by blocking the inner microtubules of the blood vessels, killing them and depriving the tumor cells of oxygen, causing cell death.” Adding Taxotere, which blocks the mitosis of cancer cells, creates a “double hit” to the tumor’s system, he said, and the cancer cells can no longer replicate.

The combination thus targets the environment surrounding the cancer, the blood vessels and the cells all at the same time. “Combining standard docetaxel with something that brings more punch, like blocking the blood vessels, makes sense,” Kloecker said. “You suffocate the cancer cells because there is no oxygen, and you make them stop replicating with the chemotherapy.”

The trial will randomize approximately 550 participants to receive either the combination of plinabulin and Taxotere, or Taxotere alone with a placebo. Eligible patients will have metastatic, stage 4 NSCLC and have progressed after initial treatment with standard therapy, including chemotherapy or immunotherapy, with no severe heart problems or brain metastases. Patients also must have an Eastern Cooperative Oncology Group performance status of zero to 2, and at least one lesion larger than 3 centimeters in diameter in the lung parenchyma. Since it is a large phase 3 trial, the investigators will be assessing OS, PFS and duration of response (DoR).

In a previous phase 2 study of plinabulin and Taxotere in patients with advanced NSCLC, the median OS was 11.3 months, with a PFS of 3.7 months, compared with 6.7 months and 2.9 months, respectively, with Taxotere alone. The DoR of the combination was 12.7 months versus 1 month. The investigators concluded that adding plinabulin to Taxotere improves the efficacy versus Taxotere alone.

The two drugs do not have overlapping toxicities or side effects and it tends to be well tolerated.

Notably, lesion size does seem to matter in terms of plinabulin’s efficacy.

Although this drug is not a “sure thing,” Kloecker said, he added that patients tend to do better when enrolled in clinical trials and encourages people with NSCLC to ask their physicians if a trial center is near their area. U.S. trial locations are in California, Colorado, Georgia, Illinois, Kentucky, Mississippi, Ohio and Tennessee. The majority of the enrollment is taking place in China.

Features

For patients with advanced disease, median survival was improved.

Novel Drug Combination Hits Non-Small Cell Lung Cancer With Double Punch

In early 2016, Matthew Tobin came down with a headache and persistent cough that lasted for months. When his doctor ordered an X-ray to test for pneumonia, it revealed a spot on his lung. After a tissue biopsy, doctors gave him the devastating diagnosis: lung cancer.

But to know the exact type of lung cancer — what its genetic characteristics were &mdash; Tobin’s oncology team at Dana-Farber Cancer Institute in Boston would have to wait a week or more to get results from the tissue sample. They suggested a relatively new option: a liquid biopsy, or blood sample, from which they might be able to quickly isolate the cancer’s genetic markers.

“We had results within a couple days of my giving the blood sample,” says Tobin, 50, a Massachusetts attorney in private practice. He tested positive for epidermal growth factor receptor (EGFR) gene mutation and also had metastatic disease, which made him a good candidate for a drug, Tarceva (erlotinib), that targets this receptor. “The day I got my results, I walked out of Dana-Farber with a targeted drug. Within days, I felt better. Within weeks, we had started to turn the tide.”

Not long ago, liquid biopsies were once the province of theory and hope. Now they are becoming part of the standard of care in lung cancer.

“We’ve been making a ton of headway on precision therapies and genomics,” explains Geoffrey Oxnard, M.D., Tobin’s oncologist at Dana-Farber and an assistant professor of medicine at Harvard Medical School. “But it’s not that easy to connect a patient to a drug. It’s not that easy to get tumor to test in all patients. With the convenience of liquid biopsy, there’s no excuse not to offer precision therapy and genomics to all your patients with lung cancer.”

In 2016, the Food and Drug Administration approved the first liquid biopsy test, to screen the blood plasma of patients with metastatic non-small cell lung cancer who may have particular mutations in the EGFR gene. But experts say this technique is being used in many different lung cancer scenarios. Specific genetic drivers, or suspected drivers, can be detected in more than half of lung cancers, studies show.

Second- and even third-line therapies have increased median progression-free survival rates two to three times longer than in patients receiving traditional chemotherapy. And liquid biopsies make it easier to test whether the cancer of a patient will react well to these new anti-tumor agents, experts say.

“Liquid biopsies are just another way of identifying molecular markers,” says Philip Mack, Ph.D., director of molecular pharmacology at the University of California, Davis. “But with a liquid biopsy, you can take a sample anytime. You can look to see how a tumor has evolved over time. You can test whether the tumor is developing resistance. It’s the next frontier of cancer research. We need to put a lot more energy into doing rigorous clinical trials that take advantage of liquid biopsies.”

Lung cancer is the leading cause of cancer deaths overall. Each year, more people die of lung cancer than of colon, breast and prostate cancers combined. Unfortunately, most cases of the disease are not diagnosed in early stages, when the disease typically causes no symptoms. And treatment options remain confusing for stage 3, locally advanced lung cancers. It’s unclear how to predict when and whether these patients will progress and whether it makes sense to use treatments designed for patients with metastatic disease.

In the past several years, researchers have made great strides in understanding the biology of lung cancer. This, in turn, has identified several genetic mutations — BRAF, EGFR &mdash; and genetic rearrangements &mdash; ALK and ROS1 &mdash; that mutation-specific drugs have been designed to target, usually in metastatic, or stage 4, patients. Other genetic aberrations, such as MET, HER2, NTRK and RET, may indicate drugs that can be used off-label in some patients with lung cancer.

However, most tumors develop resistance to these new agents. In some instances, there are then specific treatment options for patients who have developed certain genetic markers.

The challenge in all of this is that until recently, each treatment crossroad required a tissue biopsy. And tissue biopsies are limited by location and quantity.

With tissue biopsies, it may be difficult to get a clear picture of a person’s systemic disease burden. What if there’s not enough tissue to do all the tests needed? (According to experts, this happens in 25 percent of cases.) What if the genetics, and thus the drug markers, differ within one tumor or between different metastatic sites? What if the tumor location or locations — say, in the bone or liver &mdash; make tissue biopsy dangerous or impossible, as is the case for 31 percent of patients with lung cancer? What if a patient is too sick to endure a stressful tissue biopsy?

“If we do a liquid biopsy and find markers in the blood, we can put the patient on a particular drug. This avoids repeat (tissue) biopsies. That is really being used every day clinically,” says Maximilian Diehn, M.D., Ph.D., assistant professor at Stanford University School of Medicine.

So how does a liquid biopsy differ from a more traditional tissue biopsy? Most patients with cancer have experienced a tissue biopsy, and it’s never very pleasant: a local or general anesthetic, sometimes positioned uncomfortably in some sort of imaging machine, incisions or instruments that remove a small cylinder of tissue, soreness, recovery time. Then both patient and oncology team must wait for laborious lab work: setting, staining, slicing, then microscopic analysis and second opinions that may take a week or two.

As with any surgical procedure, there is always the risk of infection and bleeding when a tissue biopsy is taken. And in some patients with lung cancer, tissue biopsies may be impossible because of the location of the tumor, or there may be too great a risk of serious side effects, such as a collapsed lung.

Liquid biopsies, in contrast, simply mean a needle stick in the vein.

KAREN LOSS threw the first pitch at the Washington Nationals game in August to raise lung cancer awareness. - COURTESY KAREN LOSS / THE WASHINGTON NATIONALS

Karen Loss, 58, pushed for a liquid biopsy when her pathology team ran out of tumor tissue to test, and they felt a second tissue biopsy was too risky. “It was just a few vials of blood,” says Loss, a security specialist from McLean, Virginia. “It was an easy prep on my part, no fasting. In the end, I came up negative for any markers, but I’m glad I did it.”

The test requires a sample of blood, or in some cases urine or cerebrospinal fluid, to scan for pieces of circulating tumor DNA (ctDNA) that have sloughed off when tumor cells die. Then technicians can use techniques that make the ctDNA replicate, or amplify, certain sections of DNA with a lab procedure called polymerase chain reaction. Once the marker is amplified, it can be detected.

There are various methods for doing this: Some use fluorescence or a panel of several dozen genes thought to drive cancer growth.

Next-generation sequencing (NGS) analyzes millions or billions of DNA sequences that can provide a broad picture of the cancer’s genetic makeup. If you think of DNA as a book with a lot of sentences, NGS scans billions of lines of DNA code for a spelling or grammar error that may tag it as tumor DNA.

If the lab techs run out of tumor sample, it’s not difficult to go back for more because the liquid biopsy procedure is not very invasive, specialists say. Even better, clinicians can test more frequently and safely to see how a cancer may be changing in response to treatment or other factors.

“This sounds complicated, but the genetics of metastases in the bone can differ from the mets in liver,” says Mack. “With liquid biopsy, you can get a more global picture of the mutations out there.”

This can be particularly useful for patients with lung cancer. Patients eventually develop resistance to targeted therapies, but now oncologists can scan ctDNA for certain changes, such as the T790M mutation in the EGFR gene, which can be treated with Tagrisso (osimertinib).

Tobin took Tagrisso after his tumor became resistant and harbored the T790M mutation. He has since started a course of traditional chemotherapy.

While lung cancer specialists are optimistic about the role of liquid biopsy in lung cancer treatment, they caution that a lot of work remains. The NGS tests are still expensive, and not all insurance plans cover this technique. And liquid biopsies still detect ctDNA only about 70 to 80 percent of the time. If possible, oncologists try to compare the results of liquid biopsy with a more traditional tissue sample.

“You can’t trust a negative result,” says Oxnard. “You need to fall back on the tumor sample as backup.”

Further, the scans aren’t yet sensitive enough to reliably detect ctDNA when the cancer is still early-stage. And in some studies, people whose liquid biopsy showed a cancer driver did not end up developing a full-blown malignancy. And for those who do, not all types of lung cancer shed DNA that can be detected by liquid biopsy.

Even more confounding, when ctDNA is compared with DNA from a tissue sample, studies have shown that there are often differences. Experts aren’t yet sure what this means: Is it because the cancer is spinning out different DNA changes? Is it a problem with the test? Or is it something else?

More clinical studies are needed to answer these and many other questions and to provide enough data to prove the usefulness of liquid biopsies in different areas of lung cancer care, says Diehn.

“Going forward, we need to simultaneously go in two directions,” Oxnard says. “In one direction, we need to make liquid biopsy more sensitive, more broad. And the other direction we need is to make liquid biopsy cheaper, more focused, more nimble.”

Either way, patients with lung cancer and, over time, a growing number of malignancies are likely to encounter more liquid biopsies in the clinic.

Newer, less invasive tests are helping scientists isolate genomic alterations.

Liquid Biopsies: A Lung Cancer Game-Changer?

DAVE KARLIN (second from left) celebrates with his family at the Bonnie J. Addario Lung Walk/Run event in September at Lake Merced in San Francisco. - COURTESY DAVE KARLIN

The word “lucky” isn’t generally associated with a stage 4 cancer diagnosis. But Dave Karlin knows that in his case it applies.

Karlin, 60, of Belmont, California, was diagnosed in March 2017 with stage 4 non-small cell lung cancer (NSCLC). He is among the 10 to 15 percent of patients with NSCLC who test positive for a mutation in the epidermal growth factor receptor (EGFR) gene, which provides instructions for making a receptor protein found on the surface of certain cells, including cancer cells, that causes them to grow and divide. The mutation makes him a candidate for targeted therapy, an emerging class of drugs that focus on blocking cancer’s growth at the cellular level.

“I got a call from my oncologist, saying I was EGFR-positive,” Karlin recalls. “She told me I was in the ‘lucky 10 percent’ and that my cancer could be treated with Tarceva (erlotinib).”

Karlin has adenocarcinoma, a type of NSCLC that begins in the cells that line the alveoli, tiny air sacs inside the lungs. Other main types include squamous cell carcinoma and large cell carcinoma, in addition to rarer types such as pleomorphic, carcinoid tumor, salivary gland carcinoma and unclassified carcinoma. How NSCLC is treated and whether targeted therapy is an option depend on the type and how advanced the cancer is.

“Targeted therapy has revolutionized how lung cancer is treated,” says Roy Herbst, M.D., Ph.D., professor of medicine, professor of pharmacology and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Connecticut. “It’s extraordinary. We’ve gone from ‘one therapy fits all’ to precise treatments based on molecular profiling.”

When NSCLC is diagnosed, oncologists stage the cancer to determine if it has metastasized to other parts of the patient’s body and the best course of treatment, including surgical options and more traditional treatments, such as chemotherapy and radiation.

But oncologists also use testing known as molecular profiling to look for particular genetic arrangements that can be targeted during treatment. There are four different genetic signatures for which the Food and Drug Administration has approved targeted therapies for use in lung cancer: EGFR, ALK, ROS1 and BRAF.

Guidelines recommend genetic testing in patients with nonsquamous NSCLC, says Geoffrey Oxnard, M.D., thoracic oncologist at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School, both in Boston. “If you find a mutation, there are treatment options,” he says.

Currently, those include the oral EGFR inhibitors Tarceva, Gilotrif (afatinib), Iressa (gefitinib) and Tagrisso (osimertinib), as well as the oral ALK-protein-targeted therapies Xalkori (crizotinib), Zykadia (ceritinib), Alecensa (alectinib) and Alunbrig (brigatinib). BRAF gene mutations may be targeted with the oral medications Tafinlar (dabrafenib) and Mekinist (tramentinib).

It’s important for patients to realize that there’s a difference between a person’s inherited genes and their tumor genetics, Oxnard says. Molecular profiling of a tumor is about understanding what makes the cancer think. “It doesn’t tell us why the patient got lung cancer,” says Oxnard.

Treatment for lung cancer varies by disease stage, but for patients with genetic mutations, targeted therapy is used as a first-line treatment. “In some lung cancers, we see particular mutations that are acquired, and we have developed excellent inhibitors that target the proteins affected by mutations,” says Jyoti Patel, M.D., professor in the department of medicine and director of thoracic oncology at the University of Chicago Medicine. “We see dramatic and durable responses in patients.”

Approximately 5 percent of patients with NSCLC have ALK mutations. Most recently, the Food and Drug Administration approved Alecensa to treat patients with ALK-positive metastatic NSCLC in the frontline. Results of the phase 3 ALEX study showed that compared with Xalkori, Alecensa improved progression-free survival by 47 percent.

In addition to ALK, mutations in BRAF or ROS1 are experienced by 1 to 2 percent of patients, Patel says, adding that the majority of patients with targetable mutations have adenocarcinoma, the most common kind of NSCLC. “We know far less about mutations that cause squamous cell cancer to grow,” she says.

Molecular profiling can be a vital first step toward getting the right treatment. “If you have a mutation, you will do better if you have one of these inhibitors instead of chemotherapy,” says Patel. “Targeted therapies improve outcomes and overall survival. They can cause tumor regression, often within weeks. Patients can live more normal lives.”

Oxnard agrees. “If a patient has a mutation, pill therapy with an EGFR inhibitor is better than chemotherapy. There are less side effects,” he says. That’s been Karlin’s experience.

After he was diagnosed with a main tumor in his lung, a smaller tumor in a lymph node near his chest and a smaller tumor in his chest wall, an MRI showed six lesions in his brain. “With stage 4 cancer, surgery is out of the question,” Karlin says. His brain lesions were treated with five days of stereotactic radiosurgery, and he takes Tarceva daily.

A scan three months after Karlin began Tarceva showed no tumor in his lymph node or chest wall, and the main tumor in his lung was down 50 percent. A second scan, done in September 2017, revealed no change in the main tumor but also no new tumor growth.

“In some ways, I feel better than I have in years,” Karlin says. However, he has experienced some of the common side effects seen with targeted therapy drugs, such as a facial rash, fatigue and a sensitive stomach. Diarrhea is also a common side effect of targeted therapies, and patients using ALK inhibitors sometimes have leg swelling, Patel says.

“These drugs hit cancer at its most vulnerable point without hitting the body,” says Oxnard.

For Karlin, Tarceva’s side effects are usually manageable, he says. “Chemotherapy and radiation is the image we have of cancer,” he says. “If the cancer doesn’t kill you, the treatment will. As long as the Tarceva is effective, I’ll be on it.”

Targeted therapy does have drawbacks. For instance, cancer cells can become resistant to them.

“These drugs are quite specific, and cancer can often outwit them,” says Patel. “It’s important for people to consider what’s next when they are on targeted therapy.”

MATT HIZNAY dances with his wife, Ally, during their wedding reception on June 14, 2014. - COURTESY MATT HIZNAY / CIRINO PHOTOGRAPHY

Matt Hiznay, 30, of Lakewood, Ohio, knows about developing resistance to targeted therapy. Diagnosed with stage 4 ALKpositive adenocarcinoma in August 2011, he started on Xalkori that September. By November, he was told he’d had a complete response to the drug. He stayed on it until May 2012, when he had his first recurrence. His oncologist then treated him with the second-generation ALK inhibitor Zykadia, followed by chemotherapy and another complete response in March 2013.

But in April 2014, Hiznay’s cancer came back. After two months of radiation, his doctor again treated him with Xalkori.

That controlled the disease until April 2015, when he entered a phase 1 clinical trial of lorlatinib, a third-generation ALK inhibitor, which he continues to take.

“Some people have a diabetes pill once a day,” he says. “I have a cancer pill.”

“I’ve met people who’ve been on Tarceva for three years, six years, but cancers can mutate,” he says. “That cancer cell wants to stay alive and keep progressing.

“Treatment is like the game whack-amole,” Karlin adds. “If something comes up, we whack it. If nothing comes up, we wait. I’m a candidate for immunotherapy as a second-line treatment.”

Immunotherapy is a class of drugs that boost the body’s natural defenses to fight cancer by interfering with how cancer cells grow and spread. About onethird of patients with NSCLC have high levels of a biomarker known as PD-L1, indicating that an immunotherapy drug, such as Keytruda (pembrolizumab), would be appropriate, Oxnard says.

Still, new targeted therapies are emerging, such as an EGFR inhibitor for patients who develop resistance to first-line EGFR-targeted therapies. Tagrisso, approved for patients with a type of resistance known as the T790M mutation, has been shown to be very promising as the first therapy for patients with EGFR mutations, as well.

For patients with ALK mutations, Zykadia, Alecensa and Alunbrig are approved as second-line treatments for those who have developed resistance to Xalkori, says Oxnard. In addition, he says, randomized trials in EGFR and ALK show encouraging results in newer targeted therapies.

The search for new first-line and second-line treatments holds great promise for researchers and clinicians. The Addario Lung Cancer Medical Institute (ALCMI) in San Carlos, California, is collaborating with Champions Oncology and the ROS1ders, a group of patients with the ROS1 expression, on the Global ROS1 Initiative launched last year.

According to Guneet Walia, Ph.D., senior director of research and medical affairs for the Bonnie J. Addario Lung Cancer Foundation and ALCMI, the initiative has built an open data repository of ROS1-positive patients across seven cancer types in 19 countries. It is now building a bio repository of tumor tissue donated by the ROS1ders after biopsies and surgeries to help generate cancer models to identify new resistance mechanisms and drug targets.

With the advent of precision medicine, Walia says, patient populations in each molecular subtype — EGFR, ALK, ROS1 &mdash; get smaller, particularly considering second-, third- and further lines of therapy. “We need to rally resources to find these patients and study disease evolution,” she says. “That’s why we worked to identify patients from all over the world and bring them together under the Global ROS1 Initiative.”

The field has seen an explosion of advances in the past two to three years, Walia says, adding that because the EGFR and ALK patient populations are so much larger, people with ROS1 typically feel neglected in the development of targeted therapies.

“It’s so important to know the genetic makeup of your tumor so you get the right drug at the right time,” Walia says. In addition to getting molecular testing upfront, it’s important to get testing at each NSCLC cancer progression, she says: “Cancer always finds a way to grow and evolve, despite therapy. Getting another biopsy and round of molecular testing can tell you if your drivers have evolved.”

Molecular testing can take a while for some patients because their biopsy may have been done elsewhere or there may not be enough tissue left, Oxnard says. That may change with the development of liquid biopsies, which allow medical experts to examine blood for free-floating DNA.

“Things are rapidly changing,” Patel says. “These incremental gains add up to leaps forward in our treatment of lung cancer. We’re learning how to outwit cancer and how to develop drugs that have long-lasting efficacy.”

New targeted therapies are rapidly changing the landscape of non-small cell lung cancer.

Approaching Lung Cancer With Precision

JILL FELDMAN says her lung cancer diagnosis helped her realize she needed to get control of her stress to maximize her life. - PHOTO BY CARISSA HODGES

Jill Feldman began her journey with lung cancer 34 years ago, although not as a patient.

“When I was 13 years old, I had a grandparent on each side of the family die within weeks of their lung cancer diagnosis — and within weeks of each other,” Feldman says. “Six months later, my dad was diagnosed. He died three months later.”

Feldman later lost her mother and her aunt within two years of each other, also both to lung cancer.

“Needless to say, I was bitter and angry,” she says. “I was 28 years old, pregnant with my second child and basically orphaned by this disease.”

Over the years, Feldman’s stress continued to mount. She had two more children; became the primary caregiver for her brother, who suffers from schizophrenia; and worried about everyday stressors like work and finances. However, her family history with lung cancer loomed largest of all.

“My greatest fear was that my four kids would go through what I went through,” she says. “Stress has certainly been kind of a roller coaster ride for most of my life.”

When her fears came true in 2005, Feldman couldn’t help but wonder whether all that stress contributed to her own non-small cell lung cancer (NSCLC) diagnosis. Although her personal experience is purely anecdotal, a recent study published in the 

 which examined major stressful life events and the risk of developing the disease, suggests she may have been on to something.

Everyone experiences stress, which Syed H. Jafri, M.B.B.S., assistant professor of medicine in the Division of Oncology at McGovern Medical School in Houston, describes as the body’s response to a perceived physical or psychological threat. “When you perceive a threat, your body reacts by trying to restore homeostasis,” Jafri says. The body releases adrenaline, which can actually be beneficial during acute, or “on the spot” stress, because it helps the body function at a higher level in the short term. “But if that response is activated for weeks or months on end, that can have negative effects on your body, which then affects your immune system,” Jafri says.

Chronic stress results from repeated exposure to situations that lead to the release of cortisol, a stress hormone. Many scientists believe that the stress response system was not designed to be constantly activated, which could lead to the breakdown of bodily systems.

Jafri first wondered about a correlation between chronic stress and lung cancer when he watched a friend’s parent — a nonsmoker &mdash; die from the disease two years after the unexpected death of that person’s spouse.

Several years later, Jafri took note as actor Christopher Reeve suffered a paralyzing injury. Within two years of Reeve’s death of cardiac arrest, his wife, another nonsmoker, suddenly died of lung cancer.

“It intrigued me,” Jafri says. “Are these two events linked?”

To answer that question, Jafri conducted a study that assessed the amount of stressful life events experienced by patients with lung cancer and controls of similar age, gender and lifestyle.

Patients were enrolled between May 2015 and December 2016, and 301 people were included in the final analysis. In both groups, the majority were men in their 60s who had smoked.

“Over their lifetime, there was no difference between the two groups,” Jafri says. “But those with lung cancer had more stressful life events within the last five years before their diagnosis.” Jafri and his team found that for patients with cancer, the most common of those situations included the life-threatening illness of an immediate family member and retirement.

Feldman’s grandparents died in 1983. Her father followed six months later. Her mother passed away in 1998, then her aunt in 2000. Five years later, Feldman received troubling news from a routine computerized tomography, or CT, scan: Two nodules were growing on her lung.

She underwent testing for the T790M germline mutation, which can predispose someone to developing lung cancer. It came back negative.

To measure stress, many in the medical field rely on the Holmes-Rahe Life Stress Inventory, a scale that rates life events based on their potential stress level. Events like “death of a spouse” sit at the top, while more common ones like “traffic tickets” sit at the bottom. “Death of a close family member” sits fifth from the top.

Over the course of her life, Feldman experienced the death of five close family members; within five years of her diagnosis, other stressors included “major changes in the health of a family member,” “gaining a family member” and “death of a close friend.” Based on those factors, the Holmes-Rahe statistical prediction model estimates that Feldman was 80 percent more likely than the general public to develop a “major stress-induced health breakdown.” “It’s still surreal,” Feldman says. “To be diagnosed with the same disease that I watched kill both of my parents … it was just surreal. My biggest fear was becoming my reality.”

MARC RAPP says he believes work-related stress contributed to his diagnosis of non-small cell lung cancer. - PHOTO BY EMILY MCCLURE

Seemingly smaller everyday issues, such as workplace changes, can add up and also have a negative effect on overall health. Marc Rapp considers himself a classic example of this. An otherwise healthy marathon runner, Rapp was startled to receive a metastatic NSCLC diagnosis in 2016 at age 38. Looking back, he recalls many “normal” yet stressful life events that could have played a role in the development of his cancer: job changes, family issues, relocations and organizational restructuring.

One event in particular sticks out in his mind.

“Literally 12 months prior to my diagnosis, I accepted an expanded role that put me in a 24/7 high-stress environment,” Rapp says. “I personally think the level of stress I had over that last year to 18 months was a significant cause or at least an influencer in all of this. It’s just too coincidental.”

Risk factors for lung cancer include family history, smoking (Feldman and Rapp are both nonsmokers), exposure to secondhand smoke, radon, asbestos, arsenic, and diesel exhaust, as well as radiation to the chest. Many experts agree that the list should include the presence of chronic stress, because it makes the body more hospitable to cancer growth. But more evidence needs to be gathered.

“It’s the seed and soil hypothesis,” says Tsonwin Hai, Ph.D., a professor in the department of biological chemistry and pharmacology at The Ohio State University Comprehensive Cancer Center in Columbus. “You have the seed — the cancer cell &mdash; but it’s not just the cancer cell you need to worry about. It’s the surrounding environment. Without fertile soil, nothing’s going to grow.”

Two types of stressors can create this “fertile soil” in the body: psychological and physical. Psychological stressors include situations that can be interpreted as threatening, such as the death of a loved one. Physical stressors places strain on the body, such as injury or chronic illness. The body reacts to both types in a variety of ways, including physical reactions such as muscle tenseness, digestive disorders, weight gain, headache, heavy or rapid breathing, increased heart rate, high blood pressure, a weakened immune system, high blood sugar, heartburn and stomachache. Emotional reactions include insomnia, depression and withdrawal.

And here lies the conundrum: Chronic psychological stressors may make the body more hospitable for lung cancer, and physical stressors that often accompany the disease may make the prognosis worse, Hai says.

To combat the side effects of stress and improve both quality of life and prognosis, stress management should be a priority for all patients with lung cancer, according to Hai, Jafri and other experts, including Kathleen Hall, founder and CEO of The Stress Institute. “The minute you change your perspective, you change the chemistry of your brain,” says Hall, who holds a master’s in divinity from Emory University and a doctorate in spirituality from Columbia Theological Seminary.

Hai agrees. “Stress is unavoidable in life,” she says, “but if you can dampen it, if you can calm your nerves, then you can reduce the detrimental effect.”

After Feldman’s diagnosis, she experienced what she describes an epiphany moment: She realized she needed to get control of her stress to maximize the life she still had. “I could hear my mom’s voice in my head,” Feldman recalls. “Maybe a year after my dad died, she had said: ‘Jill, your dad is dead, but you are alive. Life is for the living, and right now, you are not living.’ It was a wake-up call. I realized that I was wasting my time.”

Throwing herself into advocacy work, connecting with others and learning to compartmentalize helped Feldman take control over her stress, which has drastically improved her life. “When I have appointments with my oncologist, we go through the scans, then I go home, take a hard copy of the scan and look at it myself,” Feldman says. “I allow myself a couple of days to kind of obsess over it, then I put it in a box and I tape it up. I had to figure out how to compartmentalize, because it was consuming me and taking over my life, and the stress was not worth it. Doing this gives me the opportunity to mentally decide what role lung cancer is going to play in my life, because physically, I don’t have that control.”

For Rapp, being intentional and focused with his time has injected more life into his years. “As crazy as it sounds, there’s a side of me that wouldn’t change this,” he says. “Because as scary as this is, I’ve lived more in the last year. I’ve traveled more. I’ve spent more time with my kids. I’ve been more intentional with things than I ever was in the other 37 years. Now, I realize that this is what life is about.”

“Things happen,” Hai says. “We’re all going to go into unknowns in our life, but we need to treasure the moments we have. If you think in that way, you won’t worry about what’s going to happen in the next day, next week or next year. You’ll realize that every minute counts.”

When her fears came true in 2005, Feldman couldn’t help but wonder whether all that stress contributed to her own non-small cell lung cancer (NSCLC) diagnosis.

Lung Special Issue (2) | CURE