was leading the typical student life as a sophomore at Penn State University. That quickly changed after she pulled a muscle in her back and got an X-ray that showed a dark spot on her lung. The 19-year-old was told she had stage 2 lung cancer.

“I thought, “Am I going to survive?” and “How is my family going to deal with this?” Murosky, now 27, recalls. “I even thought about how grateful I was that it was me receiving the diagnosis and not one of my two younger sisters.”

With no family history of lung cancer and no personal tobacco use, as well as believing that she was “too young” to get the disease, Murosky underwent genomic testing. The results revealed an ALK gene mutation. Her health care team decided that surgery followed by traditional chemotherapy and targeted radiation offered the best course of action.

Three years later, Murosky relapsed with stage 4 disease. She started on a therapy that directly targets her mutation and remains on it today.

“Unfortunately, until they develop a cure, I will never be cancer-free,” Murosky says. “But I do feel blessed that the therapy is working. Some days are more challenging than others, but there are times where I forget that I am a terminal lung cancer patient.”

Murosky’s story isn’t uncommon: More and more young people, especially women, are receiving a lung cancer diagnosis despite no history of tobacco use, a leading risk factor of the disease.

Months after her 50th birthday, Danielle Williams learned she had stage 4 lung cancer that spread to her lower spine, pelvis and right shoulder. Williams had put off going to the doctor even though she had pain in her lower back and had lost a lot of weight — she thought her five-day-a-week workouts were paying off.

By December 2018, Williams dwindled to 94 pounds during radiation treatment. The following month, she began chemotherapy, which she still receives every three weeks.

“It was numbing to hear that I have lung cancer,” says Williams, now 52. “I live a healthy lifestyle, with exercise being a major component of my life, and I have never smoked. I felt in the beginning like my body had betrayed me in some way.”

Murosky and Williams turned their diagnoses into purpose, each volunteering with the American Lung Association’s LUNG FORCE initiative to spread awareness. In addition to its education and advocacy efforts, the association works to expand lung cancer research. Every year, the nonprofit organization holds an Advocacy Day in Washington, where patient advocates meet with congress members on Capitol Hill to share their stories. The common goal: gain federal support to fund lifesaving research.

Although patients, advocates and loved ones from across the country typically take their message directly to the streets of Washington, the March 25th event, which had 115 participants, was conducted remotely via phone and video conference calls amid the coronavirus pandemic. However, COVID-19 didn’t slow the team down.

They were able to make 172 calls, including 98 Senate offices and 84 House offices. Attendees asked Congress to support $44.7 billion in funding for the National Institutes of Health and make sure that current health care protections, including those for patients with preexisting conditions, will continue. Protections under the Affordable Care Act ensure that millions of Americans can access, afford and retain quality and affordable health care, which is essential for patients with or at risk of lung diseases, including cancer.

“I can express to (congress members) that without the research that was done on the ALK gene mutation, there is a solid possibility that I would not be alive today,” two-time attendee Murosky says. “I can take a pill two times a day and continue with my life instead of having to use traditional IV chemotherapy.”

Others aim to eliminate the stigma that only people with a smoking history get lung cancer. Williams, who attended the event for the first time this year, felt compelled to be vocal about her diagnosis once she came to grips with it.

“I had what some might call an epiphany. I started to see the bigger picture, and I recognized why I had been diagnosed with lung cancer,” Williams says. “My goal is to dispel the misconceptions that smoking is the only cause of lung cancer; there are many other risk factors. I want to be the face of change.”

Articles

American Lung Association’s Advocacy Day attendees push Congress for better lung cancer research funding.
 

The Faces of Change: Advocating On Capitol Hill for Patients With Lung Cancer

Getting plenty of physical activity before radiation treatment can improve symptoms of fatigue and shortness of breath brought on by the therapy, according to recent study findings.

Researchers assessed quality of life in 130 patients with breast cancer, lung cancer or mediastinal lymphoma who were treated with radiation to the chest. Data was collected before radiation therapy was administered, immediately afterward and five to nine months after therapy ended.

Immediately after therapy, patients with lung cancer and lymphoma reported greater fatigue and dyspnea, which later improved. Patients with breast cancer, however, reported significantly increased physical activity and decreased fatigue over time.

For all patients, greater physical activity over time was significantly associated with concurrent improvements in fatigue and shortness of breath, according to the researchers.

“While our study is (small), it suggests that high levels of physical activity prior to initiation of radiation therapy for cancer are associated with better physical functioning and quality of life with cancer treatment,” Dr. Sheela Krishnan, a cardiologist at Penn Medicine in Philadelphia, said.

Exercise prior to radiation treatment can help patients better handle the side effects of treatment. 

Exercise Eases Treatment-Related Fatigue, Shortness of Breath

After Kenneth Felix fractured 12 ribs in a biking accident near his Erie, Pennsylvania, home in 2015, a CT scan of his chest revealed a suspicious-looking lesion in one lung. A biopsy showed that it was benign, but when Felix had it checked a year later, he received a scary diagnosis: stage 3 non-small cell lung cancer (NSCLC).

Felix traveled to Cleveland Clinic, where he underwent two chemotherapy cycles and 30 radiation treatments, followed by video-assisted thoracoscopic surgery (VATS), a procedure that allows surgeons to remove cancerous segments of the lung using a tiny camera and instruments that pass through small incisions in the chest wall.

The surgery was a seven-hour slog — Felix’s biking injuries, including five rib plates in the area to be operated on, had created scars that made the operation much more challenging &mdash; but he had a smooth recovery. “My biggest incision was just two inches,” says Felix, 72, a retired veterinarian. “I went home after four days and had zero pain, and within a week I was walking 15-minute miles.” Felix had another 10 radiation treatments after the surgery and has been cancer-free ever since.

Technology-assisted procedures like VATS or robotic surgery, coupled with advanced radiation techniques, are expanding the treatment choices for patients with lung cancer. A recent review of data from more than 288,000 patients in the United States treated for NSCLC over a nearly 10-year period showed that radiation therapy alone or combined with surgery correlated with increased overall survival. For patients with early-stage tumors confined to the lung, five-year survival rates after surgery are 68% or higher, and radiation produces three-year survival rates of 55% to 91%.

In fact, improvements in lung cancer treatments contributed to a 29% overall decline in cancer deaths between 1991 and 2017, according to the American Cancer Society. New diagnoses of lung cancer dropped by 5% a year in men and 4% in women between 2013 and 2017, thanks to a decline in smoking. For those who do face the diagnosis, a combination of improved screening and treatment techniques, including advanced surgery and radiation, has shortened treatment times and hospital stays.

“With the proliferation of CT screening technologies, we’re diagnosing patients earlier and having a chance to cure them,” says Dr. Daniel Raymond, a thoracic surgeon at Cleveland Clinic. “Formerly, 85% of lung cancer presented in stage 4, which was a terminal diagnosis.” The increasing number of patients receiving diagnoses earlier has “had a dramatic impact on survival,” he says.

NSCLC accounts for 80% to 85% of all lung cancer diagnoses, with the rest being more aggressive small-cell tumors. Patients with NSCLC are often good candidates for surgery, radiation or both. Radiation can be curative in early-stage NSCLC, slow the spread of metastatic

lung cancer and provide pain relief, says Dr. Shruti Jolly, professor and associate chair of community practices at the University of Michigan Rogel Cancer Center Michigan Medicine Medical School in Ann Arbor.

“There’s more data coming out showing that even in patients with metastasis if it’s limited to just a few areas outside of the lungs, there may be advantages to treating them aggressively with radiation,” Shruti says.

Lung cancer treatment is complex, requiring input from multiple physicians. That’s one reason most major cancer treatment centers review new diagnoses at a tumor board made up of radiologists, medical oncologists, pulmonologists, pathologists and lung surgeons, in addition to nurses, social workers and other supportive services. “We review the cases together,” Shruti says.

These multidisciplinary teams determine the best course of drug treatment, radiation and/ or surgery, depending on factors such as the location of the tumor, how far it has spread and whether or not the patient has other medical conditions that could complicate treatment.

Several types of surgeries can be used to remove lung tumors. The most common procedure is a lobectomy, removal of the entire affected lobe. Alternatively, in a segmentectomy or wedge resection, smaller segments of the tissues encompassing the tumors are removed. As a last resort, a pneumonectomy can be performed, removing the entire affected lung.

In the past, most patients facing surgery had to undergo a thoracotomy, an invasive procedure that involves dividing the muscles of the chest wall and spreading the ribs to reach and remove lung tumors. Some surgeons still prefer this technique, though the less invasive VATS can be equally effective, with shorter recovery times and less pain. At Cleveland Clinic, patients typically stay in the hospital for five to seven days after a thoracotomy, whereas patients who undergo VATS are sent home in two or three days.

VATS can be performed with one to three incisions ranging from one to three inches long, says Dr. Steven Kirtland, a pulmonary medicine specialist at Virginia Mason Medical Center in Seattle. A tiny fiber optic camera inserted into the chest through the incisions transmits images to a video monitor, guiding surgeons as they cut out cancerous tissues with scopes that also pass through the small incisions.

Some surgeons use robotic-assisted VATS, in which high-definition 3D cameras provide a full view of the chest. Robotic instruments are sent to the lungs through small incisions, and a surgeon sitting at a console directs the robot as it removes tumors. “The robot has complete 360-degree articulation, so we can reach areas that were challenging before, even if there are difficult angles,” Kirtland says. The advent of robotic surgery has lowered recovery times even more, he adds: “We often have patients who stay in the hospital just overnight. That used to be unheard of in lung surgery.”

Other emerging techniques also aim to make surgery less onerous for some patients with lung cancer. When CT scans detect very small nodules in the lungs, patients often are advised to wait and then repeat the imaging periodically to watch for growth. That might not be acceptable for some patients who are at high risk because of a history of cancer or smoking. At Cleveland Clinic, surgeons can offer those patients a hybrid imaging-surgery procedure called microcoil localization.

The procedure first involves a radiologist, who uses a needle to insert a tiny coil around a nodule revealed by a CT scanner. Then, using VATS, a surgeon removes a small segment of tissue containing the coil and nodule. The two specialists study the nodule while the patient is still in the surgery room; if they find it’s cancerous, they can proceed to a more involved surgery. Cleveland Clinic reported a 100% success rate, retrieving all the cancerous tissue using just the coil, in its first 20 uses of the technology.

“The standard of care for lung cancer is if you identify a spot in the lung and if it’s cancer, you take out the whole lobe in order to remove surrounding lymph nodes,” Raymond says. “But if the risk of spread to nodes is very small, you may not have to sacrifice the entire lobe.” As techniques such as microcoil localization evolve, he adds, more patients will be able to be treated successfully with minimally invasive surgery that sacrifices less lung tissue.

Radiation plays various roles in NSCLC treatment, including before surgery to shrink tumors and after surgery to ensure the eradication of the cancer. Radiation is also used to curatively treat lung cancer and is sometimes used in patients for whom surgery may be considered too risky.

Over the past 20 years, a type of abbreviated, highly focused radiation treatment called stereotactic body radiation therapy (SBRT) has become more widely used for early-stage

lung cancer than conventional radiation, which can require as many as 30 treatments. SBRT entails just one to five treatments and is less likely to damage healthy tissue nearby.

The patient is placed in an immobilization device, and breath motion is assessed to evaluate how much the tumor is moving. If motion is significant, the patient is instructed to hold their breath at certain intervals to make sure the radiation reaches the tumor safely and limit radiation dose to healthy tissues.

SBRT treats a smaller area and reduces the risk of side effects from radiation, such as difficulty swallowing and long-term lung and heart damage, Jolly says. For complex treatments, SBRT can be combined with intensity modulated radiation therapy (IMRT) to further conform dose to the tumor while avoiding normal tissues. With IMRT, radiation oncologists use advanced techniques to change the shape of photon beams throughout the treatment, making them even more precise. “When tumors are close to the heart, the chest wall or the esophagus, we can use IMRT to paint the doses around the areas that we want to avoid,” she says.

Recent studies have shown radiation therapy to be effective in the treatment of early-stage NSCLC, resulting in three-year rates of tumor control of 85% to 95%.

Patients with small tumors may benefit from radiofrequency ablation and microwave ablation, two new approaches that use imaging technologies such as ultrasound or CT to guide a needle with a probe directly into tumors.

Then either electrical currents or microwaves are sent through the probe, creating heat that kills the cancer cells. These procedures can be effective for patients who may have difficulty with surgery or aren’t candidates for surgery because their cancer has spread.

It may be possible in the future to use new technologies to diagnose and treat lung tumors in a single procedure, according to Kirtland. “Right now, all I can do is give patients the bad news that they have cancer, and then I have to send them to someone else who can cure them,” Kirtland says.

“With the advent of technologies that allow us to drive a probe out to these small lung nodules, my hope is we’ll be able to biopsy them, determine that it’s lung cancer that hasn’t spread, then ablate the tumor all in the same procedure.” Virginia Mason is putting together a small trial of this technique in patients with lung cancer who are eligible for surgery.

With so many advances in radiation and surgery techniques, it’s important that all newly diagnosed patients be evaluated by a multidisciplinary team of physicians, Raymond says. It may even be worth getting a second opinion, he adds, particularly for patients who are

told they are not candidates for the newer, minimally invasive techniques.

“Ideally, lung cancer patients should be at institutions with tumor boards, where their cases can be discussed amongst a panel of experts and a plan for care can be agreed upon,” Raymond says. “The team approach is really essential.”

Less invasive surgery and more focused radiation can ease treatment for patients with lung cancer &mdash; at any stage.
 

Precision Through Incision: Advances in Surgical Techniques to Treat Lung Cancer

is becoming more critical in cancer care. Patients who have a certain mutation or rearrangement may benefit from some of the targeted therapies that the Food and Drug Administration (FDA) approved in recent years.

In lung cancer, approved medications already address EGFR, ALK, ROS1, BRAF and NTRK gene alterations. But experts also anticipate targeted agents to help those with RET rearrangements, which occur in 1% to 2% of patients with lung cancer, mostly non-small cell disease.

®, Dr. Justin Gainor, director of the Center for Thoracic Cancers at Massachusetts General Hospital in Boston, discussed the gene rearrangement and treatments in the works.

Genetic changes in RET occur in various malignancies. There are two main types of genetic alterations. There can be RET mutations, which are essentially like a misspelling, and these are most common in a form of thyroid cancer.

Then there are RET fusions or RET rearrangements, which are similar. A RET rearrangement involves basically a piece of DNA breaking off and recombining with a different portion of the genome; hence, they’re fused together.

A RET fusion leads to active kinase enzyme, so it’s always sending growth signals to the cell. So, these are genetic alterations that are transforming and form a cancer.

How does knowing about a RET rearrangement help in determining treatment options?

RET fusions were first described around 2012 in lung cancer. There was a tremendous amount of hope at that time because biologically, they looked very similar to ALK and ROS1 fusions, where we already had this paradigm of developing a test to identify the fusion and then using a targeted therapy to treat it. What happened is that a number of drugs were repurposed.

They weren’t designed as RET inhibitors. They had an incidental RET function. They were repurposed and started being studied in RET fusion-positive lung cancers around 2013. We had a series of small phase 2 studies showing modest activity with these repurposed drugs, but our sense all along was that it wasn’t that the target was off, it was just that our drugs weren’t good enough.

In the past two years, we had two drugs that were specifically designed to target RET enter the clinic: pralsetinib, which is formerly known as BLU-667, and selpercatinib, formerly known as LOXO-292.

We entered with it being investigated in patients specifically with RET alterations, and there we have seen much higher response rates with these agents, including among patients with treatment-naive disease. From my perspective, I think a targeted therapy will become the standard of care for RET fusion-positive lung cancer.

Can you talk a little bit about what those two RET inhibitors have shown in clinical trial?

In the ARROW phase 1 study, we reported a response rate of 58% with pralsetinib. That was in 48 patients, most of whom had previously received chemotherapy and had stage 4 disease.

In terms of selpercatinib, there were 105 patients, and the overall response rate was 68% among those previously treated with chemotherapy and the progression free survival (the time from treatment to disease progression or worsening) was 18.4 months.

Collectively, this is really impressive data. Both drugs have received breakthrough therapy status by the FDA.

What are the implications for patients if these RET inhibitors get approved?

For one, it validates RET as a bona fide targetable oncogenic driver across the paradigm of targeted therapies. Second, we now know that for a given patient found to be RET fusion positive, it adds another layer of therapy. But we also know that these tumors are RET dependent and opens up a whole other area of investigation of developing new RET inhibitors.

We know with targeted therapies that at some point, cancers develop resistance. So, how can we overcome resistance? That strategy has played out for EGFR and ALK, where we now have multiple generations of drugs that were developed to overcome resistance. For patients, this is really important, because we want to keep expanding therapeutic options.

Where do you see the future of non-small cell lung cancer treatment going regarding RET?

I anticipate that we will have the first approved RET inhibitors for RET fusion-positive lung cancer by the end of the year and that these agents will become a standard of care. However, targeted therapies are only effective when we know that there’s an alteration.

This really underscores the need for testing. We absolutely need to be testing for these alterations as part of a broader strategy of doing comprehensive genetic profiling for patients with metastatic non-small cell lung cancer.

An expert explains how a better grasp of the gene alteration leads to better lung cancer treatments.
 

The Role of RET Rearrangements in Lung Cancer

Four years ago, Ronda Beaty was in the best shape of her life, so when she found herself winded just from walking up the stairs, she knew something was wrong. “My boyfriend and I were hiking in an Ohio state park one day, and I couldn’t even keep up with him,” says Beaty, who lives in Tipp City, Ohio. “And I was used to being the one in front.”

After two pneumonia diagnoses, Beaty was ordered to get a CT scan — and that’s when her life changed. On Dec. 23, 2016, she was told she had adenocarcinoma non- small cell lung cancer (NSCLC). “It was stage 4 with metastases to my brain, adrenal glands and lymph nodes,” she says.

Beaty began treatment in January 2017, and although she credits her medical team for saving her life, she struggled with anxiety and feeling helpless throughout her treatment.

“I have a huge group of friends and family and loved ones that are a support network, but none of them are lung cancer patients,” Beaty says. “I just felt like I really needed to talk to somebody that understood — (who) didn’t think they understood but really understood.”

But Beaty couldn’t find anyone like that. Time passed, and in December 2019 — almost three years to the date of her diagnosis &mdash; she felt ready to give up. Then she came across the website for GO2 Foundation for Lung Cancer, the world’s leading organization dedicated to extending and improving the lives of individuals who have or are at risk of lung cancer.

“I emailed them, and the very next morning, I had an email in my inbox — a personal introduction about who they were, what they were about and how they could help me,” she says.

Beaty was quickly connected with a woman through the organization’s Phone Buddy Program, which offers peer- to-peer support and matches patients with volunteers who have either been through or are going through lung cancer treatment. Beaty was surprised to learn that her mentor, Sandy Spears, was not only a stage 4 lung cancer survivor but also had no evidence of disease (NED). “I didn’t even know it was possible to be a stage 4 lung cancer patient with NED,” Beaty says.

The two exchanged texts for weeks, and then Spears asked if Beaty wanted to talk on the phone. “We spoke for about an hour-and-a-half on that first call,” Beaty says. “When I met Sandy, I had been battling for three years, and I was pretty ready to throw in the towel. But meeting her changed my whole attitude. I cried for three solid days because just meeting someone like that had given me newfound hope.”

Patients with lung cancer can get emotional, educational and social support through individual and group therapy sessions, online groups, and help hotlines, but options may be limited. “Even though lung cancer causes more deaths than breast, prostate and colorectal cancers combined,

the number of support groups formed for lung cancer survivors is surprisingly very small,” according to a study published in 

“There is still stigma out there, multiple types of stigma, that keeps people from getting support,” says Katie Brown, vice president of support and survivorship programs at LUNGevity, a national lung cancer-focused nonprofit organization. “That might be a deterrent for someone reaching out (for help), so maybe a peer mentor might appeal to them instead.”

Peer-to-peer support offers a unique benefit that other forms of support cannot: the ability to pair a patient with a mentor who has or has had lung cancer and is uniquely qualified to help them cope.

“The benefit is that you are specifically connecting with a peer mentor to talk about your disease,” Brown says. “A mentor is able to walk with you through it, encourage you and offer you hope, because they’ve been through it and came out on the other side.”

In addition to providing emotional support and sharing coping techniques, peer mentors can help shed light on treatment options, discuss how to deal with difficult conversations with doctors or family members, and help patients begin to visualize their life post-treatment.

LUNGevity’s LifeLine Support Partners program matches patients to mentors from a database of over 400 volunteers. Pairing is based on gender, age and diagnosis whenever possible. GO2’s Phone Buddy Program matches by stage, treatment plan, symptoms, side effects and profile, ensuring that patients and mentors are as compatible as possible.

“I was a little leery going into all of this,” Beaty says, “but it’s not intimidating at all. Sandy and I are the same age. She was diagnosed approximately at the same time I was. She had the same metastases that I have. We just had so much in common right away.”

Another benefit of customization: “It’s as personal as I want it to be,” Beaty says. “If I don’t feel up to it to respond, there’s no judgment there. You decide the level of commitment.” Although some patients prefer to converse only through text or email, others get close with their mentors, even meeting face-to-face.

Finally, mentors can open doors in ways that patients might never have imagined. In addition to helping Beaty find hope in her diagnosis, Spears introduced her to support programs, such as Lung Cancer Living Room, a GO2 Foundation support group that Beaty attends virtually through YouTube Live each month. Beaty’s involvement with GO2 Foundation and LUNGevity also led to a grant to attend LUNGevity’s annual International Lung Cancer Survivorship Conference, the world’s largest meeting of patients with lung cancer and caregivers, where she will be surrounded by even more patients, doctors and scientists.

“All of these people that I’ve met ... have instilled in me a new drive — a new reason, a new purpose to live,” Beaty says.

To become a mentor for GO2 Foundation and LUNGevity, volunteers simply need to have or have had lung cancer and be willing to speak with others about their experience. LUNGevity provides hopeful volunteers with online training videos, a manual and conference call training to ensure they are ready for the responsibility ahead.

Mentors choose to volunteer for a variety of reasons. Some want to pay it forward after receiving support of their own; others, like Spears, volunteer for the opposite reason — because they didn’t have support themselves.

“I decided to be a mentor in the Phone Buddy Program because when I was diagnosed with cancer, I didn’t have anybody to reach out to,” says Spears, who lives in Monroe, Georgia. “I felt totally alone.”

Lisa Zarov of Highland Park, Illinois, joined LUNGevity’s LifeLine Support Partners after surviving stage 1a adenocarcinoma NSCLC. A licensed clinical and school social worker, she felt uniquely qualified to help but also wished to stay connected to the cancer community.

“I just wanted to be able to do something, anything,” Zarov says. “I suppose it would have been easy enough to just have surgery, go on with my life and not look back, but I felt like in my position, as lucky as I was to have it caught early, there was no way I could just turn around and not look back.”

Nichelle Stigger, one of the patients Zarov came to support, received a diagnosis of stage 2b primary mucinous adenocarcinoma, one of the rarest types of lung cancer, at age 34. Stigger credits her relationship with Zarov as a major factor in her ability to work through her anger and shock at her diagnosis.

“It was really, really special,” says Stigger, who lives in Oak Park, Illinois. “I always tell Lisa, ‘I love you ... and know that I am better because you were able to love me through this process.’”

Anyone considering mentorship should consider a few factors, starting with their role in the relationship. “You are there to support the other person, not the other way around,” Zarov says. “Sometimes there’s a fine line between sharing your story and kind of crossing that line of leaning on the person you’re trying to support.”

In addition, there is also the possibility of a mentored patient dying — an unfortunate reality that Spears, whose first match died in November 2019, understands well. “The passing is always hard, because you do become close to them,” Spears says. “The way I look at that is that I want to be what I wanted somebody else to be for me. I want to give the support that I wanted in return &mdash; and at least I was there for her during that time to help her.”

Despite mentoring’s possible hardships, both Zarov and Spears agree that the benefits make the experience worthwhile. “Every time you share your story, even if it’s with one person, you’re being an advocate. You’re raising awareness,” Zarov says. “And to me, that’s so important. But also, I made a friend.”

Spears adds, “You build relationships with people who are like you. I’ve helped Ronda, but she’s helped me, too. She teaches me things, too. I can give her guidance, give her comfort ... but by giving somebody else comfort, you’re comforting yourself. You’re helping yourself.”

Although Beaty wishes she had found support sooner, she feels that everything happens when it’s supposed to. “It came at a time for me when I really needed it,” she says.

Beaty and Stigger have found a sense of comfort through peer-to-peer support. “It’s so powerful,” Stigger says. “I believe that’s part of the reason I was able to get through this process of cancer so successfully is because my mind was OK.”

“There is nothing more isolating than cancer,” Beaty says. “But there is also nothing better than a fellow lung cancer survivor saying, ‘I get it’ and knowing that they mean it, that they really do understand.”

Peer-to-peer connections bring unique benefits for patients coping with lung cancer.
 

Supporting Strangers With Lung Cancer

During winter 2013, Larry Gershon had a bad cold that he couldn’t shake. The then 65-year-old print broker took cold medicine and steroids to fight off the symptoms, but the illness persisted. When the wheezing and coughing got worse, he went to urgent care.

“The doctor thought it was best to take a chest X-ray to check for pneumonia. I didn’t have pneumonia, but it showed a spot in my right lung,” says Gershon, a resident of Palo Alto, California. After CT and PET scans revealed a mass in his upper right mediastinum, the chest area between the lungs, doctors surgically removed part of his lymph node for a tissue biopsy.

In late January, he learned he had adenocarcinoma of the lung, the most common type of non-small cell lung cancer (NSCLC). Initially, doctors thought it might be stage 3b because it had spread to his lymph nodes, but a subsequent MRI uncovered metastasis to the brain.

“I was told I had stage 4 lung cancer, and I was shocked — a deer in headlights,” says Gershon, now 72. “Because I was self-employed, one of my biggest concerns, when I was diagnosed, was if I would be able to continue to work.”

Gershon was first treated with chemotherapy in February 2013. A genomic test from his surgical biopsy revealed a mutation in the EGFR gene. In 2015, he moved on to Tarceva (erlotinib), an oral targeted therapy approved by the Food and Drug Administration (FDA) to treat patients whose cancer has spread to other parts of the body and have an EGFR mutation. After 20 months, Gershon’s disease progressed, so he switched to Tagrisso (osimertinib), another oral EGFR inhibitor, which he remains on.

About a year ago, he enrolled in a clinical trial to test a new diagnostic technology, known as liquid biopsy, in patients with previously diagnosed cancer. Instead of analyzing a piece of tissue, as a traditional biopsy does, a liquid biopsy looks for traces of cancer in the bloodstream, also known as circulating tumor DNA (ctDNA).

For the past two-and-a-half years, Gershon’s imaging scans have shown no signs of cancer. Every three months, he has blood drawn in hopes that a liquid biopsy will detect any recurrence as soon as it arises.

“When I progressed in 2016, I had bone metastases, and so they’re currently giving me bone density injections along with a blood draw to check my counts,” he says. “The liquid biopsy is a couple more vials of blood than I already do, so it’s a very simple test.”

In 2016, the FDA approved the first liquid biopsy to detect EGFR mutations, which are present in 10% to 20% of all NSCLCs and more commonly found in women, Asians and individuals who never smoked tobacco. Today, liquid biopsy has become the standard of care in clinics, either alone or alongside a tissue biopsy.

Although tissue biopsy remains the gold standard, doctors praise liquid biopsy for its many advantages, such as ease of administration, faster turnaround time and lower cost. In addition, even patients with hard-to-reach or small tumors can have blood drawn.

“In lung cancer, we are often dealing with very small tissue biopsies, and sometimes not even a biopsy but an aspirate, which is just a collection of cells, because it is too difficult to get a real tissue biopsy,” says Dr. Fred Hirsch, executive director of the Center for Thoracic Oncology

in The Tisch Cancer Institute at Mount Sinai. “With such limited tissue available, it is reasonable to do a liquid biopsy to test for molecular abnormalities like EGFR for the possibility of targeted therapy.”

Liquid biopsy research has focused on NSCLC, which represents 84% of all cases, because of its many molecular biomarkers that have been identified. This disease can exhibit changes not just in EGFR but also in the ALK, BRAF, NTRK and ROS1 genes. A patient with an identified biomarker may be able to be treated with a medication that targets the mutation, potentially working better than chemotherapy and causing fewer side effects.

The noninvasive nature of a liquid biopsy translates to a much lower risk of injury compared with a tissue biopsy. For the latter, samples of the lung tissue are removed with a needle or during surgery, and possible complications include air leak (pneumothorax), bleeding and infection.

A liquid biopsy requires a blood sample drawn from a vein in the arm with a standard needle. Typically, 20 milliliters of blood are taken, but some tests need as little as five milliliters, or about a teaspoon. A centrifuge spins the blood, separating it into its component parts. The plasma, which makes up the largest portion and excludes the blood cells and platelets, is then analyzed for ctDNA with a genetic test.

Study findings have shown that the amount of ctDNA correlates to the amount of cancer in the body, tumor response and survival outcome. It also provides molecular information about the specific mutations of the original tumor.

“For every patient who has advanced adenocarcinoma of the lung, you have to test for EGFR mutations, ALK mutations, BRAF mutations, ROS1 mutations— and that’s just the bare minimum,” says Dr. Nathan Pennell, a medical oncologist and director of the lung cancer medical oncology program at Cleveland Clinic’s Taussig Cancer Institute. “By the end of 2020, there will be approved drugs for RET and MET mutations, most likely, and there are lots of drugs in trials for KRAS and HER2 mutations.”

Genetic tests that analyze blood instead of tissue samples can detect the same kinds of mutations but with a much faster turnaround time. In a 2019 study, Dr. Bob T. Li, a medical oncologist at Memorial Sloan Kettering Cancer Center, and colleagues compared liquid biopsy with tissue biopsy in 210 patients with advanced lung cancer and found median turnarounds of nine days versus 20, respectively.

“It takes much longer to get tissue biopsy results, and sometimes patients can’t wait that long,” Li says. “Time matters, because there’s a risk of rapid deterioration, and you don’t want to miss the boat. Treating the patient expeditiously can mean the difference between life or death.”

Meanwhile, tissue biopsy remains the most accurate test. Medical test performance often is based on sensitivity, or the proportion of correctly identified true positives, and specificity, or the proportion of correctly identified true negatives. A blood-based biopsy’s specificity for ctDNA is very high, ranging from 95% to 100%, which means a positive result for a given mutation can be trusted and acted on immediately.

The sensitivity, on the other hand, varies from 60% to 85%. Therefore, a negative result cannot be fully trusted, and doctors will order a tissue biopsy to double-check.

“It’s very unlikely that you’re going to have a false- positive result with liquid biopsy, but you can have a false negative result,” Pennell says. “For EGFR mutations, the sensitivity is only about 80% compared with tissue. That means if 100 people have EGFR mutations, you’ll miss about 20 of them if you just do the blood-based test.”

In 2018, the International Association for the Study of Lung Cancer released a statement paper with recommendations on liquid biopsies for NSCLC. The association stated that liquid biopsy can be considered at the time of initial diagnosis in all patients who need tumor mutations identified but is particularly recommended when tumor tissue is scarce or unavailable or won’t be obtained for more than two weeks.

Ongoing research on liquid biopsies continues to improve on the test’s accuracy for diagnostics, but clinical trials like the one Gershon participated in aim to uncover new applications. Many experts foresee liquid biopsy as a tool for monitoring treatment or detecting cancer early, even before it shows up on imaging scans.

“In the near future, we would be able to use a blood test to see a molecular response based on the treatment. This would tell us whether the treatment is working or not before the CT scan,” Li says. “If the treatment is not working, we may be able to learn why and overcome it with another drug.”

These applications remain in the research phase and aren’t ready for prime time, but Li believes the field will get there within the next decade. “In the long term, perhaps we can have advanced technology that goes beyond ctDNA and looks at other genetic material to increase the sensitivity of detection,” Li says. “One day, we may be able to do a blood test, find cancer in its earliest form and eliminate it.”

For now, investigators in several studies are attempting to tackle a less ambitious goal: treatment monitoring. Because doctors can take many blood samples throughout the course of a patient’s treatment, they can use liquid biopsy to track tumor response and drug resistance. For instance, the T790M mutation in EGFR is found in about half of patients who develop resistance to EGFR-targeted drugs. Liquid biopsies conducted at certain intervals may reveal these mutations earlier.

“Even if a patient has a certain mutation at the start of treatment, this mutation can disappear and come back. Or it can disappear, and other mutations can come,” Hirsch says. “That is why repeated molecular characterization is important. But it is very difficult to get a new tissue biopsy, so there is a role here for liquid biopsy.”

Clinical trials like the one Gershon participated in are determining if liquid biopsy can detect minimum residual disease (MRD), a small number of cancer cells left in the body after treatment that may be too scarce to cause physical signs or symptoms.

Natera, the company that made Gershon’s liquid biopsy test for MRD, uses the unique mutational signature of a patient’s tumor from a tissue biopsy to determine the kinds of ctDNA most likely to show up in the bloodstream during progression.

The company hopes this personalized approach can find MRD far earlier than an imaging scan. For example, Natera used Gershon’s brain tumor biopsy from 2016 for the clinical trial to create a custom-built ctDNA monitoring assay to test his liquid biopsies.

“They take a blood draw and match it against the assay they did from my tumor biopsy based on what they think will indicate progression,” Gershon says. “If they see any circulating tumor DNA in my blood, it’ll be likely that I’ll progress at some point. I’ve had four of these blood draws so far, and thankfully, they have shown no circulating tumor DNA.”

Liquid biopsies are easier on patients, yield faster results and cost less than tissue biopsies, but these blood draws don’t yet replace traditional tests.
 

A Simpler Way to Sample: Liquid Biopsies in Lung Cancer

Patients with non-small cell lung cancer who have a high body mass index (BMI) have improved survival outcomes when they receive immune checkpoint inhibitor therapy, according to study results published in 

The findings add to the growing evidence of a so-called obesity paradox in patients with cancer, in which a high BMI is linked to an increased incidence of some malignancies but may offer protection from others, the researchers noted.

Researchers examined data from four clinical trials, known as OAK, POPLAR, BIRCH and FIR, in which participants were treated with Tecentriq (atezolizumab), a PD-L1 inhibitor, or docetaxel, a chemotherapy. The final analysis included 1,434 patients who received Tecentriq and 890 treated with docetaxel.

Nearly half (49%) were of normal weight, 34% were over- weight and 7% were obese. BMI, calculated by weight in kilo- grams divided by height in meters squared, was categorized

by the World Health Organization criteria: underweight (less than 18.5), normal weight (18.5-24.9), overweight (25-29.9) and obese (30 or higher). Many obese patients were white men who had previously smoked. The median age was 64 years.

When treated with Tecentriq, obese and overweight patients had an improved overall survival compared with those of normal BMI. In addition, patients considered overweight or obese had a greater survival advantage associated with PD-L1- positive tumors compared with PD-L1-negative tumors.

“This is an interesting outcome, and it raises the potential to investigate further with other cancers and other anticancer drugs,” lead investigator Dr. Ganessan Kichenadasse, a medical oncology researcher at Flinders Centre for Innovation in Cancer in Adelaide, Australia, said in a statement. “Our study provides new evidence to support the hypothesis that high BMI and obesity may be associated with response to immunotherapy.”

The findings of a new study add to the growing evidence of the "obesity paradox" in patients with cancer who have a high body mass index but have better outcomes on immunotherapy. 

Lung Cancer Special Issue (1) | CURE