Meeri Kim, Ph.D.

Flori Hendron was taking a shower when she felt a tiny lump near her armpit. She was 38 with no family history of breast cancer, so she figured the growth would be benign. To be safe, she scheduled a doctor’s appointment.

“I followed up on it, and that launched my adventure with breast cancer back in 1996,” says Hendron, now 62, a resident of Los Angeles. The mother of two endured a lymph node dissection, a lumpectomy, radiation and chemotherapy to treat her early-stage disease. “I went into that year of treatment like a warrior, even though it beat me up so badly. My kids were 6 and 8, so there was no way I was going to die.”

Afterward, she assumed she had won her hard-fought battle with cancer. Instead, it turned out that first small lump marked the beginning of an agonizing, decades-long war.
In 2002, a large spongy lump appeared in the same breast, leading to a double mastectomy with reconstruction. In hindsight, Hendron wishes she had skipped the reconstruction. The surgery left her extremely sick with multiple infections, and at the same time, the cancer continued to spread.

Later that year, after a horrible bout with several chemotherapies that didn’t work and spread of the cancer through lymphatic vessels in the skin, Hendron finally started taking Herceptin (trastuzumab), a targeted therapy for patients with HER2-positive breast cancer. She’d known from the start that her cancer was HER2-positive, she says, but was considered ineligible for the drug until 2002 because her tumor was too small and her disease wasn’t advanced enough. The drug kept her cancer-free, and after 20 months of treatment, she stopped taking it in April 2004.

“I used to race forward and get things done quickly in my career, and in breast cancer, I did the same thing but with blindfolds,” says Hendron, who spent most of her professional life in product design, brand development and marketing. “I should have never stopped the Herceptin, but I just didn’t know enough yet.”

In 2007, she received a stage 4 breast cancer diagnosis. The disease had spread to her lungs and sternum, and although Hendron also asked for brain imaging to check for metastases, her oncologist at the time dismissed her request as it was not the standard of care in the absence of symptoms. After she switched to a new oncologist, an MRI scan revealed a single brain metastasis in her frontal lobe.

“Over the years, I’ve learned that if a doctor belittles you or is unsupportive, it’s time for a new doctor,” she says. “Be a fully active participant in your own survival and insist on what you need.”

Nunny Reece, who also is living with stage 4 breast cancer, agrees that patients must advocate for themselves and pay attention to their bodies. She first found a lump in her breast in 2015 at age 37, but her doctor told her that she simply had dense breasts and shouldn’t worry.

Two years later, in June 2017, Reece discovered a new lump under her arm. She also noticed blotches on her skin and experienced pain throughout her body. Even though her doctor gave her a diagnosis of lupus, she decided to schedule a mammogram because the pain wasn’t going away.

“First they told me I needed to see a surgeon because I have breast cancer. At that time,
I had no information other than that it was breast cancer, so I assumed it was early stage,” says Reece, now 42, a resident of Hope Mills, North Carolina. “I was so shocked when the doctor told me, with tears in her eyes, that they (couldn’t) do surgery because I (was) already at stage 4.”

Having lost her father to stage 4 colon cancer just a year earlier, the mother of three felt devastation and heartbreak. The disease — which was hormone receptor (HR)-positive but HER2-negative — had spread to her lungs, lymph nodes and bones. Her doctors first tried hormone therapy, a treatment for breast cancers that are fueled by hormones, but it didn’t work. They moved on to oral, then IV chemotherapy drugs, which helped for a while.

In December 2019, Reece experienced frequent headaches and dizziness, common symptoms of brain metastases. An MRI confirmed that the cancer had spread to her brain.

“Brain metastasis is quite common in the metastatic breast cancer setting (in which cancer has spread beyond the breast and nearby lymph nodes), and it is becoming more problematic as we’re getting more novel drugs to the market that are doing a better job of controlling systemic disease,” meaning cancer throughout the body, says 

Dr. Rashmi K. Murthy, assistant professor of breast medical oncology at The University of Texas MD Anderson Cancer Center in Houston. “For patients with HER2-positive, metastatic breast cancer, for example, up to 50% of individuals can develop brain metastases during the course of their disease.”

More women like Hendron and Reece are living longer with metastatic breast cancer and will at some point require treatment for brain metastasis. Current options, such as radiation and surgery, aren’t a possibility for all patients, depending on the number of tumors, and can have lingering side effects. For many patients, the development of brain metastases greatly limits life quality and expectancy.

Fortunately, new targeted therapies and immunotherapies show promise for brain metastases. These innovations have the potential to treat secondary tumors while minimizing harm to healthy brain tissue and reducing the possibility of negative long-term side effects.

“We’re all taught in medical school that the brain doesn’t regenerate, so it’s very difficult once you have a neurologic symptom to have full recovery, unless it’s very short-lived,” says Dr. Carey K. Anders, medical director of the Brain and Spine Metastases Program at the Duke Cancer Center in Durham, North Carolina. “We don’t want our patients to have to live with a neurologic symptom that could alter their daily life, whether it affects driving, caring for themselves and their family, (or) doing their work or the hobby that they love.”

Despite all the new therapies that have emerged, breast cancer remains the second most common cause of death in women. Most of those deaths are caused by metastatic breast cancer. Although just 6% of patients have metastatic breast cancer at initial diagnosis, nearly 30% with early-stage breast cancer will eventually develop metastatic disease.

The brain, bones, lungs and liver are common sites of breast cancer metastases. Breast cancer is the second leading source of brain metastases after lung cancer, and 10% to 15% of all patients with the disease will develop at least one secondary brain tumor.

Among patients with metastatic breast cancer, the risk of spread to the brain can be higher depending on the disease’s subtype. Those with HER2-positive disease are the most susceptible, with about half of all patients developing brain metastases. About 25% to 45% of women with triple-negative metastatic breast cancer will develop brain metastases, which also represents an elevated risk of brain metastases compared with non-triple-negative breast cancer. Breast cancers with estrogen receptors, called ER-positive cancers, that are also HER2-negative tend to have a lower risk.

Brain metastases are associated with a poor prognosis. After diagnosis, overall survival ranges from three months 

to just over two years. Metastases are most often discovered using MRI with a contrast solution delivered intravenously to improve image clarity. Physicians watch for common symptoms of brain metastases in patients when deciding whether to order a scan.

“Symptoms that we look out for are headaches, especially if they happen with nausea and vomiting that can’t be really well explained by a patient’s chemotherapy, for example,” says Dr. Nancy Lin, director of the Metastatic Breast Cancer Program at Dana-Farber Cancer Institute in Boston. “We also worry about seizures, or if someone has weakness on one side of their body.”

Treatment may involve local therapies directed at the brain metastases, such as surgery and radiation therapy, as well as systemic therapies that treat cancer throughout the body. Surgery could be a viable option for a single, large brain tumor, depending on its location. But for most patients, initial treatment involves either focused radiation or whole brain radiation, depending on the number of metastases and how early diagnosis occurs.

Because she had a single tumor, Hendron had a noninvasive procedure in February 2008 called Gamma Knife stereotactic radiosurgery, which uses 3D imaging to deliver a powerful, precise dose of radiation to a targeted area. It took just a single outpatient session without any incisions or anesthesia to successfully treat her lesion. Side effects of stereotactic radiosurgery can include fatigue, swelling, headache, nausea and vomiting and usually last for a few weeks after treatment.

“Gamma Knife was the easiest treatment I ever had and the most effective,” Hendron says. “I was in the hospital at 7 a.m. and home by 11 a.m. I wore my own clothes and didn’t need any pre-meds or post-meds.”

Reece had a very different and much more harrowing experience. She had 12 metastases throughout her brain and was treated with 10 rounds of whole brain radiation. Because it delivers radiation to the entire brain, including healthy tissue, this type of treatment can lead to serious problems later in life, such as memory loss, strokelike symptoms and poor brain function. Patients also suffer from painful short-term side effects such as head- ache, nausea, vomiting, fatigue and hair loss.

“Treatment has not been good to me. It has been a struggle; really, really tough,” Reece says. “The side effects from the whole brain radiation were bad. I was nauseous, throwing up, dizzy. 

The MRI showed that it did help, though, and some of the metastases in my brain decreased in size.” Fortunately, advances in local therapies aim to help more patients like Reece reap the benefits of radiation therapy without the harsh side effects. For example, a modification to whole brain radiation that avoids damage to the hippocampus, a region of the brain associated with memory, is now the standard of care at many institutions. Study findings have also shown that Namenda (memantine), a drug originally used to treat Alzheimer’s disease, can help protect the brain and may improve cognitive outcomes in patients undergoing whole brain radiotherapy.

In addition, the number of metastases that can be treated with stereotactic radiosurgery instead of whole brain radiation continues to increase as the technology improves. “When the original radiosurgery studies came out, the number of lesions was three to four that could be treated safely with radiosurgery at one time, and anything more than that required whole brain. We’re now up into the teens,” Anders says. “There is data to support irradiating 10-plus lesions, and I know we’ve been doing 

that routinely at our cancer institute to try to avoid whole brain radiation therapy.”

Perhaps the most exciting advance lies in the results of the phase 3 HER2CLIMB clinical trial of Tukysa (tuca- tinib), a new HER2 kinase inhibitor used to treat HER2- positive breast cancer, in patients with brain metastases. Tukysa crosses the blood-brain barrier, a membrane that separates circulating blood from the brain, which most cancer therapies can’t do. Patients who received Tukysa along with chemotherapy and Herceptin experienced a higher rate of tumor shrinkage, including metastases in the brain, and also had a longer period of time where they lived without worsening disease, and lived longer overall, compared with patients who received only standard chemotherapy and Herceptin.

In April 2020, the Food and Drug Administration 

combination with Herceptin and Xeloda (capecitabine) based on these findings for previously treated patients with advanced inoperable or metastatic HER2-positive breast cancer. 

Several clinical trials
focusing on new treatments trastuzumabor combinations for brain metastases are recruiting or plan to recruit patients with breast cancer. For instance, an upcoming phase 2 study will involve genetic testing of the brain lesion to check for alterations that could be matched to a therapeutic target. A phase 3 trial in the recruiting stage will see if combining Tukysa with Kadcyla (T-DM1; ado-trastu- zumab emtansine), a targeted therapy for HER2-positive breast cancer, improves survival.

As similar treatments gain FDA approval, improved guidelines around screening will likely emerge to catch and treat brain metastases earlier. Right now, the standard is to screen only patients who have symptoms.

“We are definitely evaluating patients who have any kind of neurological symptoms for brain metastases, but it’s not necessarily an immediate part of their diagnostic work-up,” Murthy says. “As we get more and more therapeutics that show efficacy across the blood-brain barrier, I certainly think that is going to change. The approval of tucatinib has certainly changed my practice to evaluate patients for brain metastases.”

The topic of screening for brain lesions has become controversial in the field of breast cancer, mostly because of 

a lack of evidence. However, multiple studies in the works will attempt to disentangle the effects of regular brain MRIs on patients with breast cancer.

“We don’t have definitive data to say that screening is useful, and screening has the potential to be harmful if it’s done in a way that leads to treatment changes that may or may not be necessary,” says Lin, who does not routinely screen patients but has a very low threshold for ordering a brain scan. “People could end up getting (potentially harmful) treatments that they don’t necessarily need or getting switched off the treatments that would otherwise have worked. That’s the argument against universal screening for brain metastases.”

Hendron and Reece get regular brain MRIs to check for the appearance of new secondary tumors. In 2019, Hendron’s doctors uncovered three more brain metastases, 

which were treated with stereotactic brain radiation therapy. Since then, her scans have been stable.

“I often say cancer is a mind game. The body game is what the doctors and medicine
do, but the mind game is the work we have to do,” she says. “The biggest piece of advice is: You just have to learn to be present. All we have is this moment, and each person has to find what works for them to be in the moment.”

For her, the best self-care activities are art and writing. Hendron started painting while recovering from her bilateral mastectomy in 2002 and never stopped. She even developed and facilitated an art program at Cedars-Sinai Medical Center, where she taught other cancer survivors how to connect with the healing process through art expression.

Reece, whose cancer remains active in her liver and lungs, started her eighth line of treatment with Halaven (eribulin), a type of chemotherapy used to treat metastatic breast cancer, in September. If that doesn’t work, she plans to consider any clinical trials that she might be eligible for. The driving force behind trying treatment after treatment, despite the excruciating side effects and risk of disappointment, is her family: her husband of 20 years and three sons.

“Day-to-day life is a struggle. Some days I’m OK, but my OK is different from everyone else’s OK. I’m able to get out of bed today, wash my face, brush my teeth,” says Reece. “But through my relationship with God, I trust that one day we’ll have a miracle and be able to beat this thing. I’ll have a good quality of life again and do things with my family like I used to.”

Articles

Two women living with metastatic breast cancer that has spread to the brain describe the tools that are helping to keep them alive.

Beyond the Breast: How Some Patients Combat Brain Metastases

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

T.J. and JEN SHARPE searched for immunotherapy clinical trials to treat his stage 4 melanoma. - Photo by KIM RUOFF

One weekend in August 2012, while his wife and two children visited family out of town, T.J. Sharpe was stuck at home nursing a high fever that just wouldn’t quit. He tried every trick in the book to lower his body temperature — Advil, Gatorade, soup &mdash; but it continued to spike up to 103.8 degrees Fahrenheit.

Sharpe reluctantly went to his local hospital’s emergency department, where a doctor told him an X-ray showed spots on his lungs that were likely cancerous. Over the next few days, tests confirmed the presence of tumors in his lungs, spleen, liver and abdomen. What Sharpe assumed would be a quick trip to the emergency department led to a diagnosis of stage 4 melanoma and a 16-day hospital stay.

“I was originally diagnosed with stage 1b melanoma that I had removed when I was 25 years old, and then 12 years later I get diagnosed with stage 4,” says Sharpe, a resident of Fort Lauderdale, Florida. “It was a difficult diagnosis, since my son was only 4 weeks old at the time.”

Sharpe lost 30 pounds in two weeks, had the large tumor in his abdomen removed and started researching the best course of treatment. His initial oncologist offered chemotherapy, which was then a standard, but said he’d be surprised if Sharpe survived two years. For the 37-year-old husband and father of two young children, that prognosis simply wasn’t good enough.

“My wife and I had a couple of friends who were familiar with the pharmaceutical space, and they knew that there was a ton of good research being done on immunotherapy, especially with checkpoint inhibitors,” Sharpe says. “We continued to look for something better than chemotherapy and eventually found two clinical trials that could give us the response that we were hoping for.”

Unlike traditional treatments such as chemotherapy or radiation therapy, immunotherapy helps stimulate a patient’s own immune system to fight cancer. Many types exist, but the most promising options for patients across a wide array of cancers today include immune checkpoint inhibitors. The job of proteins called immune checkpoints, such as PD-1 and CTLA-4, is to prevent the immune system from being overly aggressive in attacking invaders, but cancer cells can also use them to hide. When checkpoints are blocked with inhibitors, the immune system becomes more aggressive and can do more to kill cancer cells.

Many experts believe that checkpoint inhibitors have the potential to fight cancer more effectively and with fewer side effects than traditional therapies. “Immune checkpoint blockade was initially thought to be a narrow therapy confined to melanoma, and it wasn’t even completely clear if it worked in melanoma, so why should the average oncologist care about it?” recalls Jeffrey S. Weber, M.D., Ph.D., deputy director of Perlmutter Cancer Center at NYU Langone Health in New York City. “But then PD-1 and PD-L1 blockade worked well in melanoma and in other cancers, and so now it finally has respect. It’s a major sea change in the way people with cancer are treated.”

Sharpe was initially treated by Weber in a clinical trial at Moffitt Cancer Center, in Tampa, Florida, that combined the CTLA-4 inhibitor Yervoy (ipilimumab) with tumorinfiltrating lymphocyte therapy. The latter immunotherapy type involves multiplying a patient’s own tumor-fighting T cells in a lab and then infusing them into the body so they can work as an army to fight cancer.

Unfortunately, the trial didn’t work out for Sharpe as he had hoped. Four months in, CT scans revealed that three out of his five tumors had grown, and some new tumors had appeared. But Sharpe is not alone — in fact, just 20 percent of patients with advanced melanoma achieve long-term overall survival with Yervoy.

Research has found that better responses generally occur with checkpoint drugs that inhibit PD-1 or PD-L1 (another protein) as opposed to CTLA-4. But even with these drugs, the rate of response varies from 15 to 65 percent, depending on the cancer type and treatment setting (first-line versus later-line therapy for metastatic disease).

An active area of cancer research involves finding out why these often very effective drugs work for just a minority of patients. So far, there are a lot of questions and not very many answers.

For instance, ideally, patients would get tested for various biomarkers before treatment to predict their individual clinical response to many different checkpoint inhibitors. While a couple of biomarkers have been identified, an extensive test does not yet exist, so how should doctors assess patients’ eligibility for these novel therapies? And what does the future hold for checkpoint inhibitors and finding related biomarkers?

“By studying tumors from patients who are treated and by studying events ongoing in their blood, we hope to be able to find more highly predictive biomarkers,” says Suzanne Topalian, M.D., associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University in Baltimore. “A combination of factors may need to be tested in order to give us a better idea of which patients are likely to respond.”

Doctors do have at least some information to go on. Whether and when an oncologist decides to use a checkpoint inhibitor for treatment depends largely on the kind of cancer involved. Some types, such as head and neck cancer, stomach cancer and Hodgkin lymphoma, have effective therapies that do not include immunotherapy, so checkpoint blockade would typically not be employed as first-line treatment, although that’s being explored in clinical trials.

For instance, one trial is testing chemoradiation with and without the PD-1 inhibitor Keytruda (pembrolizumab) in patients with locally advanced head and neck squamous cell carcinoma. Other subtypes of the disease — for instance, prostate cancer and pancreatic cancer &mdash; have not so far responded to checkpoint inhibitors.

On the other hand, advanced melanoma lacked good treatment options in the past, so when checkpoint inhibitor immunotherapy began to show efficacy, physicians jumped on it. Even in melanoma, where immunotherapy has shown great promise, a large number of factors come into play when deciding on a particular treatment plan: What stage is the cancer? Has it been surgically removed?

Has it spread throughout the body? Is there evidence that it is rapidly growing? Does the cancer express a BRAF mutation, making it likely to respond to a targeted drug? Does the patient have time to try a second or third option? All those considerations must be taken into account.

As with many cancer therapies, trying these treatments without knowing if they will work comes with risks in the areas of both health and financial cost. Immunerelated side effects of PD-1 and PD-L1 inhibitors include fatigue, nausea, rash, diarrhea, cough, itching, decreased appetite and musculoskeletal pain. And although physicians want these drugs to be available to all patients who need them, treatment regimens with checkpoint inhibitors can cost hundreds of thousands of dollars. One doctor estimated that a combination treatment involving two drugs would total $300,000, with the patient’s out-of-pocket cost being upward of $60,000.

Combining checkpoint inhibitors with other immunotherapies or traditional treatments may be the key to improving the probability and quality of response. A recent analysis of eight studies found that higher values of response, survival and time until disease progression were observed in combination therapy compared with single-agent therapy. Already, the FDA has approved Keytruda in combination with chemotherapy for previously untreated metastatic nonsquamous non-small cell lung cancer, as well as the PD-1 inhibitor Opdivo (nivolumab) plus Yervoy for adults with metastatic melanoma.

And studies are being conducted on a variety of combinations across cancer types. For example, a reduced dose of Yervoy combined with Keytruda, has demonstrated promising results in patients with melanoma and renal cell carcinoma. Other trials are examining checkpoint inhibitors used in different combinations or together with cancer vaccines, chemotherapy, radiation and T-cell therapies.

“Right now, most of our clinical trials involve giving new drugs in combination with one of the PD-1 inhibitors,” says Beth Buchbinder, M.D., a medical oncologist at Dana-Farber Cancer Institute in Boston. “We have a really exciting trial in lung cancer and melanoma that takes a piece of the tumor to the lab, where we create a vaccine out of it. If the patient isn’t getting a good response after surgery and Opdivo, then we can add the vaccine as a backup plan.”

Meanwhile, Topalian and others continue to research ways to deliver precision immunotherapy that is tailored to individual patients. Physicians hope that the discovery of robust biomarkers will pave the way for this type of treatment in the future. “Today, we sometimes make a seat-of-the-pants assessment in terms of trying a checkpoint inhibitor, but I think in the future, there will be less art and more science,” Weber says. “If we had biomarkers to predict outcome with great accuracy, we could take a blood sample and then (be able to tell) our patients who will do well and who won’t.”

Two biomarker tests now exist to guide doctors about a patient’s response: PD-L1 and a genetic fingerprint called microsatellite instability (MSI). A PD-L1 test requires sending a piece of tumor tissue to a lab that measures how much of the protein it expresses. Patients with tumors high in PD-L1 are more likely to respond to checkpoint blockade, although those lower in PD-L1 could still see a response. MSI is a biomarker that signifies whether the cancer has many or few gene mutations, and those with many — MSI-high cancers &mdash; seem to have a greater likelihood of response to checkpoint inhibitors. In fact, the FDA has approved Opdivo for metastatic colorectal cancers that are MSI-high and have progressed after other treatments, as well as Keytruda to treat any metastatic, MSI-high solid tumor that progressed on previous treatments. Now, scientists are exploring the use of drugs that might cause cancers to express more mutations, thus making them more responsive to immunotherapies.

Neither biomarker test is perfect, however, and there doesn’t always seem to be a direct correlation between the result and an individual patient’s response to anti-PD-1.

Also, test results could change over the lifetime of a tumor or even based on the location from which the tissue sample is taken.

“I think a lot of these tests are helpful but not yet to the point where you would make a patient decision based off of them,” Buchbinder says. “Eventually, there might be some algorithm where you combine all of these factors to help pick immune therapies, but we’re not quite there yet.”

Meanwhile, researchers are in the midst of discovering and testing immune checkpoint proteins beyond CLTA-4 and PD-1/PD-L1. Other targets with drugs in development include IDO, LAG3, KIR and TIM-3. “There are probably two or three dozen different checkpoint pathways, and they are all unique. Some of them act early in the immune response against cancer; some of them act later; some of them act together,” Topalian says. “There is a lot of very interesting scientific research going on and much we still need to learn about how these pathways work.”

Sharpe, who discovered that his cancer responded to one type of checkpoint inhibitor but not another, is a case in point.

Although disappointed with his results in the clinical trial of Yervoy, Sharpe wasted little time feeling sorry for himself and began looking into a plan B. In April 2013, he joined a clinical trial of then-experimental Keytruda. By July, his follow-up CT scans showed that the overall tumor size had shrunk 30 percent, and more than half of the tumors from his last scan were no longer seen. After remaining on Keytruda for years, Sharpe received his last dose in August 2017 and is now considered cancer-free.

Sharpe, who doesn’t recall his tumor ever being tested for PD-L1 expression, is not certain why Keytruda worked for him when Yervoy didn’t. One possibility he discussed with doctors is that Keytruda reinforced the tumor-infiltrating lymphocytes that remained in his system from the first trial.

He may never have a definitive understanding of why, but Sharpe credits his survival to the Keytruda clinical trial and feels extremely fortunate that he was eligible to participate. Still, his journey isn’t over, and he now dedicates much of his life to helping other patients educate themselves about cancer. He has written 200 posts detailing his battle with melanoma for a Philly.com blog called Patient #1 and serves as a patient expert consultant to the biopharma and clinical research industries.

“When my first oncologist told me I had less than two years to live, it really gave me the motivation to look at the pictures of my two young children and say, ‘That’s not good enough for me,’” Sharpe says. “People are going to live long, happy, healthy lives because immunotherapy and checkpoint inhibitors were able to activate their immune systems to fight cancers that would have otherwise killed them.”

Checkpoint inhibitors can be extremely effective for the right patients, but identifying who will benefit remains an imprecise science.

The Jury Is Out

MICHAEL LEVIN, 72, has faced lung cancer twice and was diagnosed with a third or possible recurrence of the disease. - PHOTO BY COURTNEY GOLDMAN

Michael Levin first noticed the unbearable pain while on a golf trip in Mexico during winter 2007. On the second day of practice rounds, he started to experience an ache from his knees down to his feet. Levin tried to mask it by taking ibuprofen but still felt miserable.

A month or two later, back home in Atlanta, Levin went to the doctor after his feet had swollen excessively. He was sent to a rheumatologist, who performed a chest X-ray and a bone scan. The next morning, the physician broke the news to Levin that he had a mass on the upper part of his right lung. He received a diagnosis of stage 2 non-small cell lung cancer (NSCLC), which had spread to nearby lymph nodes.

“When I picked up the phone and heard it was my doctor, I was delighted at first because I thought we were getting to the bottom of it,” recalls Levin, now 72 years old. “Then, when he said I had a mass, I went blank for about 10 minutes. The hardest part was telling my family.”

His treatment consisted of surgery and chemotherapy followed by regular surveillance. Every three months, Levin went back in for a chest CT scan along with an MRI of his brain. A few years later, the routine surveillance uncovered four metastatic tumors in his brain. Levin was treated successfully with gamma knife radiosurgery — he underwent this procedure three times &mdash; which uses beams of highly focused gamma rays to treat small- to medium-size lesions.

In 2014, a second lung cancer was diagnosed after doctors found a tumor on his left side. A new, unrelated cancer that develops in someone with a previous diagnosis of the disease is known as a second cancer.

Although a second cancer can occur anytime during survivorship, some studies show they commonly appear five to nine years after treatment. It differs from a recurrence, which refers to the initial cancer coming back after a period of time when it could no longer be detected. In particular, survivors of lung cancer remain at increased risk for second cancers, such as lung, esophageal, stomach, small intestine, colon, bladder and pancreatic.

“All patients with cancer hear about is the five-year survival rate, so you think that’s the end goal,” says Levin. “But that’s not really the goal. What isn’t communicated is that once you survive five years, the chance of a recurrence or second cancer increases.”

Once again, the regular scans led to the new tumor being found early, and surgeons successfully removed it. Levin did experience some complications during treatment — he contracted an infection of Clostridium difficile, which is a bacterium that causes inflammation of the colon, in the hospital &mdash; but still considers himself extremely fortunate to have survived all that he did. “My survival can be attributed to early diagnosis, and that’s really what gave me the best possible chance for a good outcome,” he says.

Nearly 1 in 5 cancers diagnosed today occur in a person who has survived a previous cancer. While improvements in early detection and treatment mean that people are living longer, the possibility of cancer striking again becomes a serious concern. People should consider certain actions like getting regular follow-up exams, which will allow doctors to catch and act on the disease earlier.

Lung cancer survivors remain at risk for developing second cancers. The most common in this population is a new lung cancer. Overall, the rate of developing second lung cancers and tumors in the aerodigestive tract — consisting of the combined organs and tissues in the respiratory tract and the upper part of the digestive tract &mdash; for these patients is about 10 times greater than that of other adults who smoke.

“This is about empowering individuals who have had lung cancer and may very well get a second cancer,” says James Mulshine, M.D., a professor in the Department of Internal Medicine at Rush Medical College in Chicago. “For example, improving their lifestyle can have significant positive benefits and staying in regular touch with a care provider who is aware of such possibilities is a good thing for these patients.”

Although the disease can occur in a person who has never smoked, smokers are at greatest risk. Physicians divide lung cancer into two major types based on the appearance of tumor cells when looked at under a microscope. Small cell lung cancer (SCLC) accounts for about 10 to 15 percent of all lung cancers. It develops almost exclusively in heavy smokers and spreads much more quickly than NSCLC. NSCLC is an umbrella term for three disease subtypes — squamous cell carcinoma, adenocarcinoma and large cell carcinoma &mdash; and makes up 80 to 85 percent of lung cancers.

Bruce Johnson, M.D., chief clinical research officer at Dana-Farber Cancer Institute in Boston and 2017- 2018 American Society of Clinical Oncology President, performed an extensive review of studies looking at survivors of lung cancer and their rates of second cancer. For patients who underwent surgical resection for NSCLC, the risk of a second lung cancer is approximately 1 to 2 percent per year and appears to increase over time. Those treated with chemotherapy and chest radiation for locally advanced lung cancer have a higher risk of a second lung cancer than those treated with a surgical resection alone. Johnson favors following patients at risk for a second lung cancer with chest CT scans. The patients followed with clinical examinations and chest radiographs rather than chest CT scans had a two-year survival of only 25 percent, so more intensive follow-up is warranted.

Data are much more limited for patients who had SCLC because only 7 percent of them survived for two years or longer. According to Johnson’s analysis, the risk of a second lung cancer for SCLC survivors rises from about 2 percent per year to rates approaching 10 percent per year after the passage of a decade.

The second lung cancers are typically NSCLC — namely, adenocarcinomas and squamous cell carcinomas &mdash; arising in a different anatomic site from the initial tumor.

The review paper and other studies also noted different factors that could possibly increase or decrease one’s risk of a second cancer. For example, Johnson looked at whether the studies included the effect of continued cigarette smoking, the type of initial and secondary treatment administered and the continuing surveillance of patients. “We published that the vast majority of people who get diagnosed with lung cancer no longer smoke, but those who keep smoking double their risk of getting a second tumor compared with those who quit smoking,” Johnson says. “So one thing that people can do if they’re still smoking is to quit.”

Tobacco products not only are a risk factor for developing cancer but also can exacerbate illnesses like heart disease and chronic obstructive pulmonary disease, more commonly known as COPD. In a study published in the Journal of the National Cancer Institute, of 611 SCLC survivors examined, no second lung cancers occurred in the small number of patients who were nonsmokers. Relative risk remained stable over time for patients who had stopped smoking before receiving a diagnosis of SCLC, but those who quit at the time of diagnosis had increasing likelihood of a second lung cancer over time.

“For our patients who have had a lung cancer, the most important thing that we tell them is to stop tobacco use or smoking because that’s usually the most common risk factor for developing lung cancer,” says Rathi Pillai, M.D., an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta.

“Plus, it can be a driver for developing another lung cancer or other types, such as head and neck or bladder cancer.”

The same study also investigated the contribution of initial treatment type to the development of second cancer. For instance, radiation is known to cause damage to healthy cells and possibly contribute to a second cancer. Patients who received chest irradiation had a thirteenfold greater risk compared with the general population, while those who got other types of treatment had a sevenfold greater risk. Overall, the type of chemotherapy used to treat the latter group was not associated with a significant difference in risk.

Generally, the risk of getting a second cancer after radiation therapy goes up as the dose increases. The area treated and the age of the patient when they were treated also affect cancer risk. Solid tumors take time to develop, and many are not seen for at least 10 years after initial treatment. Lastly, smoking increases the risk of a second cancer after radiation.

Survivors can lower the risk of developing second cancers by eliminating tobacco, maintaining a healthy weight, staying physically active, following a healthy diet and limiting alcohol consumption. They can also find out more about their family history and receive genetic testing to see if any predispositions or conditions exist that would further increase their cancer risk.

Making changes like these may help people sleep and eat better, which is important for people who want to maximize their quality of life after a first lung cancer, says Mulshine. Disease experts also emphasize regular surveillance to make sure there hasn’t been a recurrence or a second cancer. Many doctors recommend follow-up visits and CT scans every 6 to 12 months for the first two years after treatment, followed by yearly visits and CT scans. But no standardized guidelines exist for what the surveillance procedure should be for a lung cancer survivor. “There’s a lot of debate in the lung cancer community in regard to how to monitor a patient after being treated for early-stage lung cancer,” says Pillai. “Given the fact that we do find second lung cancers or recurrences, surveillance is certainly warranted, but what exactly that surveillance should be, and how frequently it should be performed, varies among providers.”

She suggests getting CT scans at least once a year to monitor for recurrence and the development of a second tumor. Also, survivors should make sure to keep up with other routine tests like mammograms and colonoscopies.

“I’ve had terrific quality of life despite the cancer, and much of it is due to the regular surveillance,” says Levin. “All my cancer diagnoses, after the initial one, happened early and resulted in fast treatment.”

Unfortunately, Levin recently received a diagnosis with what is likely to be his third lung cancer but could also be a recurrence, as well as prostate cancer. Despite the many setbacks, he isn’t ready to give up. Levin, who has been married for 51 years and is a father and grandfather, considers himself blessed to have his loved ones for support. He has also become heavily involved with patient advocacy and outreach with the Lung Cancer Alliance since his initial diagnosis.

“I’m happy to be here. I have a wonderful family, many friends and a terrific medical team,” says Levin. “Plus, I have some financial means to walk away from work for a while. I’m lucky in that respect.”

Second cancers are common among patients with lung cancer, so how can risk be lowered?

Meeri Kim, Ph.D.

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