Stephanie Dunn Haney never felt a sense of urgency about the pain on the right side of her chest.
The discomfort only occurred when she coughed or sneezed, and she was trying to get pregnant with her second child. Once her second daughter was born, Dunn Haney didn’t want X-rays while she was nursing. Two years passed before she saw a doctor near her home in Bloomsburg, Pennsylvania. Test after test turned up nothing. After numerous X-rays and ultrasounds, doctors thought it was a condition caused by the metal from her underwire bra. She took high doses of anti-inflammatory drugs to combat the pain. Dunn Haney worked at her job as township manager, as two years turned into three.
By 2007, the pain was more prevalent, reaching along her back and shoulder blades. Dunn Haney says she worried that the pain could mean something serious, but nothing in her history or tests pointed toward cancer. “I thought, ‘This is making me nuts. We’ve got to do something,’” says Dunn Haney, now 46. Finally, a CT scan concerned her doctors. She saw a specialist who did a PET scan, an imaging test that detects spots with metabolic activity, such as when tumors are growing. Although many spots lit up, the specialist said he didn’t think it was cancer. To be certain, Dunn Haney underwent a biopsy on a lymph node under her collarbone. The biopsy result: positive for non-small cell lung cancer.
“We were really shocked,” Dunn Haney says. She had no risk factors commonly associated with lung cancer. She’d never smoked; she was young; she had no family history. Even though smoking accounts for up to 90 percent of lung cancers in the United States, 16,000 to 24,000 nonsmokers die every year from lung cancer. In addition to tobacco-related lung cancer, environmental exposures such as radon, secondhand smoke, and asbestos increase the risk for lung cancer. “Members of a family live in the same home and eat the same diet,” says Simon Spivack, chief of the division of pulmonary medicine at Albert Einstein College of Medicine and Montefiore Medical Center in Bronx, New York. “They might be exposed to dad’s cigarette smoke.”
There’s also likely an inherited genetic risk for lung cancer, but researchers are still working to pinpoint changes in specific genes that alone confer a strong risk in the way that, for example, the BRCA mutations increase the risk of certain breast cancers. It’s a crucial effort, because like other cancers, one of the biggest challenges is early detection. By the time a lung cancer patient develops symptoms, the cancers are usually stage 3 or 4, when the cancer is much more difficult to cure. In fact, most early-stage lung cancers are found by accident. “Somebody has a cough and gets an X-ray, and they find a nodule that wasn’t related to the cough,” Spivack says. “Or they get a CT scan of the abdomen and they got a few views of the lower lung, and sure enough they have a nodule there.”
Doctors can tell the types of lung cancers apart by looking at the biopsy under a microscope. Historically, there are two broad categories of lung cancer: non-small cell lung cancer (NSCLC) and small cell lung cancer. Most lung cancers (about 85 percent) are NSCLC. That group is further divided into three types, depending on where the cancer starts growing: adenocarcinoma, the most common of the NSCLC; squamous cell carcinoma; and large cell lung cancer (so-named because the cells are actually larger than the other cancers). While this description may sound simple, lung cancer is rich in molecular complexities and spurred by different molecular pathways. Increasingly, researchers have been able to exploit these unique pathways to develop targeted therapies. “Lung cancer is a great example of personalized medicine,” says Elaine Mardis, co-director of the Genome Institute at Washington University and a professor of genetics and molecular microbiology.
In fact, lung cancer is the poster child for precision medicine. Genetic discoveries over the past decade have transformed the way doctors treat and interpret the disease. On the treatment side, the idea behind precision medicine is to develop treatments that exploit weak spots in tumor cells to destroy only the cancer cells (as compared to traditional chemotherapy and radiation). Weak spots have been found in two genes, EGFR and ALK, both found in adenocarcinoma NSCLC. Mutations in these genes make them vulnerable to specific treatments that disable these genetic weak spots. These precision therapies are lengthening progression-free survival, an important surrogate for overall survival. On the diagnostic side, doctors are using mutations in EGFR, ALK, and a gene called KRAS to reclassify lung cancer. On the horizon are new treatments for lung cancer in clinical trials, including using the patient’s own immune system to block tumors. Clinical trials can offer people with lung cancer more treatment options.
LOOKING FOR LUNG CANCER’S WEAK SPOT
About 13 years ago, researchers thought they’d found a weak spot in lung cancer cells that would make them appropriate for precision treatment. A gene called EGFR helps cells grow and divide. Biopharmaceutical companies developed a class of drugs called tyrosine kinase inhibitors (TKIs) that block that signal, with the hopes that in lung cancer patients, the treatment would stop the tumors from growing.
The problem was that some patients responded very well to TKI therapy, but most others didn’t, and at the time, the doctors didn’t know why. When the researchers dug into the results, they discovered that patients who did respond to the first tyrosine kinase inhibitors tended to have similar features. They tended to be Asian, female, and younger than the average patient age. They also tended to be females who either never smoked or were light smokers who stopped a long time ago.
Researchers learned a lot more about which lung cancer patients best respond to EGFR inhibitors in 2004, once the Human Genome Project was published. With information about the sequence, or order of the bases of DNA that make up each and every gene, scientists figured out why only a select group of lung cancer patients responded to the inhibitors. They studied lung cancer tumors and found that some tumors had a change, or mutation, in the EGFR gene that made that particular tumor vulnerable to the kinase inhibitors. This change happens in about 10 percent of lung tumors, most commonly the NSCLC adenocarcinomas. “Researchers got lucky,” says Andrew Allen, chief medical officer of Clovis Oncology, a biopharmaceutical company headquartered in Boulder, Colorado. They found a single mutation — in EGFR — that keeps the cancer cells dividing and growing over and over again and targeted that mutation with the TKIs. “When you shut off the tumor growth, the tumor shrinks,” Allen says.
Researchers have discovered other genetic changes in lung tumors. A mutation in a gene called KRAS is common in lung cancer, but there’s no good therapy so far that can target this gene. Another genetic change found in some lung cancers is in the ALK gene, and it does have a precision treatment targeted at it. Today, by testing lung tumors for mutations in EGFR, ALK, and KRAS, doctors can identify patients who have the best chance of responding to these personalized therapies. The drugs developed for these tumor weak spots are Tarceva (erlotinib), Erbitux (cetuximab), Iressa (gefitinib), and Gilotrif (afatanib) for EGFR and Xalkori (crizotinib) for ALK.
Even though these drugs don’t work in every patient with non-small cell lung cancer, they do work well in patients whose tumors carry these genetic changes. The problem: Tumors usually find a way around the precision treatment, develop resistance, and come back. Researchers needed to find a new therapy for the lung tumor cells that developed resistance to the EGFR precision treatment. They studied the genes in the resistant lung tumors and found an acquired mutation called T790M in the EGFR gene. Drug companies went back to work and developed three drugs to block this new T790M mutation: AstraZeneca’s AZD9291, Hanmi’s HM61713, and Clovis’ CO-1686 (while drugs are under development, they’re often given a number before they’re named). All three companies presented results from their development efforts at the 2014 American Society of Clinical Oncology (ASCO) conference, a yearly meeting in which scientists present the latest results in cancer research.
Clovis’ CO-1686 increased progression-free survival, or how long the drug keeps the disease under control, 90 percent of the time. “This means that the tumor is not growing,” says Clovis’ Allen. The next step is to test CO-1686 as a first-line therapy (the first treatment tried for cancer) to see if it works as well as, or better than, existing therapies, such as Tarceva or Iressa.
Not only has the discovery of these new acquired tumor mutations changed how lung cancer is treated, but researchers have also learned more about tumor biology, which has allowed drug companies to develop precision therapy, based on a tumor’s genetic profile. Doctors can now use the precision therapies along with traditional treatment. Before these therapies, the one-year survival for people with stage 4 lung cancer was about 40 percent, and two-year survival was about 20 percent. “In the EGFR-mutated tumors, the majority of these patients, even with stage 4 disease, are living for at least two and half, three years, sometimes up to four years, when you get the right drug to the right patient,” says Bilal Piperdi, a lung cancer specialist at New York’s Montefiore Einstein Center for Cancer Care. “We’ve come a long way.”
Molecular profiling is also changing how many cancers are classified, including lung cancer. Doctors have always classified tumors by where they started — in the breast or colon or lung, for example. As researchers study the genomes of different types of cancers, they’re finding common mutations in cancers of different anatomic origins. A consortium of cancer researchers have been participating in a project called The Cancer Genome Atlas. Scientists have built libraries and have been scrutinizing the genomes of 12 types of cancer, and they have found mutations common to cancers that began in different parts of the body. For example, squamous cell lung cancer shared the same molecular marker with head and neck cancer and with a certain type of bladder cancer.
Pathologists are beginning to use a tumor’s mutational profile to reclassify lung cancers. Doctors previously divided NSCLC into three subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Now NSCLC is listed by molecular descriptions, according to the predominant genetic change in the tumor, including KRAS, EGFR, and ALK.
These distinctions will be important one day, says Washington University’s Mardis, because cancers will be defined less by their site of origin, such as breast or lung, and more by the molecular characteristics. Such changes open the door to new clinical trials based on treatments for the mutations, rather than the type of cancer.
In 2013, molecular testing for lung tumors became part of a nationally recognized protocol recommending that all adenocarcinoma lung cancers be tested for genetic mutations in EGFR and ALK before a treatment decision is made. Even with these recommendations, coming from four organizations, including the National Comprehensive Cancer Network (NCCN), not all eligible patients are tested. “Patients should talk to their physicians about molecular testing,” Piperdi says. “These tests are commercially available all throughout the United States.”
In a recent study published in the Journal of the American Medical Association, researchers tested lung tumors in 1,007 patients with stage 4 adenocarcinoma. Some tumors were tested for one mutation, others for 10. Doctors used the results to determine precision therapy in patients whose tumors had an actionable mutation. In 64 percent of the patients, molecular testing identified mutations that could be matched to a precision therapy. For patients who received such therapies, median survival was 1.1 years longer than those who did not receive precision therapy. The authors’ conclusion: “Although individuals with drivers receiving a matched targeted agent lived longer, randomized clinical trials are required to determine if selecting targeted therapy based on oncogenic drivers improves survival.”
One of the other challenges in lung cancer (and other tumors) is getting enough tissue during the biopsy for molecular testing. It is a challenge because the tumor may be very small or might be in a part of the body that’s difficult to access. Piperdi notes that patients need to be aware that an additional biopsy might be useful for molecular testing.
CONNECTING WITH ADVOCATES
With any kind of cancer, treatment alone isn’t enough. Patients need the help of advocacy groups. This is especially true with lung cancer because the disease carries the stigma that people brought the cancer on themselves. “It’s an unfair aspect of the disease,” Spivack says.
Websites such as Cancer Commons (cancercommons.org), a nonprofit organization, matches patient information with the best treatment for them. (See “Collective Action” in the summer/fall 2014 issue of Genome.) Also, the International Associations for the Study of Lung Cancer (iaslc.org) can connect lung cancer patients with conferences, the latest news, and with advocacy groups like the Bonnie J. Addario Lung Cancer Foundation (lungcancerfoundation.org).
The Addario Foundation offers lung cancer patients one-on-one support through programs, a patient handbook, and with personalized support for molecular testing. For patients who might benefit from a molecular profile of their tumor, the Addario Foundation offers several routes to testing. Because molecular testing is more common at large academic medical centers than it is at community hospitals, lung cancer patients may not be aware that this is an option for them, says Danielle Hicks, director of Patient Services and Programs at the foundation and Bonnie J. Addario’s daughter.
The foundation helps patients access the test in several ways. They make patients aware of the need for molecular testing, and they write letters to insurance companies on behalf of patients if they have trouble obtaining coverage. Testing can cost anywhere from $2,000 to $6,000, depending on the complexity of the test. The foundation also partners with diagnostic companies to help patients receive the test in a timely manner if there’s a delay in insurance coverage. Lung cancer patients can also get testing through the Addario Lung Cancer Medical Institute, a separate but related international research consortium. The institute conducts its own studies at 21 centers worldwide. Patients enrolled in these studies receive predictive and diagnostic testing at no cost to them.
“There are still unfortunately many patients who do not have their tumors tested for any genomic alterations, including EGFR and ALK,” says Foundation Medicine Chief Medical Officer Vincent Miller. “In many cases, patients who are tested are not tested up front, but only after other chemotherapy options have been tried.” Miller adds that there is an urgent need for physician education on the role of molecular testing in non-small cell lung cancer, noting that the most recent guidelines for NSCLC from the National Comprehensive Cancer Network state that the NCCN “strongly endorses broader molecular profiling with the goal of identifying rare driver mutations for which effective drugs may already be available, or to appropriately counsel patients regarding the availability of clinical trials.”
“This is an endorsement that all patients with stage 4 NSCLC (except squamous cell, in which case selected patients apply) should be tested up front with broader molecular profiling,” Miller says.
Lung cancer patient Dunn Haney is also a strong believer in molecular testing and in advocacy work, especially because lung cancer is so deadly that there aren’t enough survivors to speak out. She says she feels a responsibility to her daughters, now ages 1 and 11. “I want it to be clear that I fought hard against what is taking me from them and to teach them to do the same whether it’s lung cancer or something else they find important,” she says.
Dunn Haney encourages lung cancer patients to find doctors willing to do genetic testing on their tumors, even if it means getting second and third opinions. She says that in 2007, she gave her spiel about having young children to the first oncologist she saw, and she didn’t like his answer. She remembers the oncologist telling her that “fighters are great, but the only challenge is they don’t know when to stop fighting.” She interpreted that as the oncologist saying that she didn’t fully understand that he expected her to die in two years. “No one has the right to give you an expiration date,” Dunn Haney says.
She saw a second doctor and got the same message. She ended up seeing a third oncologist. Unlike the other doctors who kept saying over and over that her lung cancer wasn’t curable, the third doctor told her that lots of diseases are not curable, including heart disease and diabetes. This oncologist told her that her lung cancer didn’t have to be curable, that the disease instead could be managed, Dunn Haney recalls. “The science wasn’t different at any of those places,” she says. “But the third doctor talked to me in a different way, and that made a huge difference.”
Dunn Haney has continued treatment with that doctor, even though it’s a longer drive from her home. Converting lung cancer from a quickly fatal disease to a chronic disease is a major goal of the Addario Lung Cancer Foundation by finding ways to extend progression-free survival for each patient long enough to benefit from any new therapies, says Scott Santarella, Addario Foundation’s president and CEO. “At the end of the day we don’t care whether you smoke or not,” he says. “We want to help people get the treatment they need.”