May 14, 2013 / By Turna Ray
Smoking, most people have come to accept, is a major cause of lung cancer. But each year in the US, up to 24,000 men and women who have never smoked still end up dying from the disease.
Researchers led by Geoffrey Oxnard of the Dana-Farber/Brigham and Women’s Cancer Center have a hypothesis that for some never smokers who get lung cancer, an underlying, inherited genetic mutation called T790M significantly increases their chances of getting the disease. Now, in an effort to gain a clearer picture of why some carriers of this mutation develop lung cancer, Oxnard and his colleagues have devised a strategy for finding people and their families with this very rare mutation and following them through a registry called INHERIT EGFR.
Jimmie Bandgren, a 77-year-old non-smoker, and her two children carry the inherited T790M mutation and are enrolled in INHERIT EGFR. Bandgren was first diagnosed with breast cancer in 1989. When the cancer recurred and spread to her lymph nodes more than a decade later, her doctor also detected multiple nodules in her lungs. In 2012, after a few of the slow-growing nodules had become large enough to be biopsied, Bandgren’s doctor diagnosed her with non-small cell lung cancer.
Upon analyzing the tissue from her biopsies, Bandgren’s oncologist in Huntsville, Ala., reported that her lung tumors had the T790M mutation. However, this was unusual since this type of mutation usually shows up in patients after they have become resistant to treatment with a tyrosine kinase inhibitor, such as Tarceva (erlotinib), but Bandgren had never been on this kind of treatment.
Her oncologist referred her to a lung cancer specialist, David Carbone, then at Vanderbilit-Ingram Cancer Center in Nashville. “Dr. Carbone was sure it was the inherited gene,” Bandgren recalled. A genetic test confirmed that her tumors indeed had the T790M mutation and also revealed that she had inherited a germline T790M mutation, meaning the mutation is present in all the cells in her body, not just in the cancer tumor.
After that, Bandgren’s two children were genetically tested, which revealed that 50-year-old Nancy Capelli, a non-smoker, and 48-year-old Mike Bandgren, a smoker for more than three decades, had inherited the mutation. Although Capelli had no symptoms of lung cancer at the time of testing, based on the results, she got a CT scan, which found several nodules in her lungs. Earlier this year, she had the largest pre-cancerous nodule surgically removed.
Capelli “went ahead and got a screening CT scan even though she was totally asymptomatic, a never smoker, and not technically eligible for a screening CT based on [current guidelines],” said Carbone, now at Ohio State University’s Comprehensive Cancer Center. The nodule “was found to be early stage. And it was documented only because I had identified this mutation in her mother, and then found it in her.”
Meanwhile, the test results for Bandgren’s son have come to light more recently and his doctors haven’t determined a course of action yet. He has three children, who may also be tested for the T790M mutation once they come of age to give consent.
There is a strong history of cancer in Bandgren’s family. Both of her sisters died of cancer ─ Frankie from leukemia at the age of 32 and Johnnie from lung cancer at the age of 71. Bandgren’s mother survived uterine cancer and lived until age 94. Based on her own experience and her family history, Bandgren is trying to encourage other family members to get tested and enroll in the INHERIT EGFR registry.
“We know that some families carry these germline EGFR mutations. There are a handful that have been described in the literature,” Oxnard said. “The point of [INHERIT EGFR] is to go beyond the anecdotal descriptions of these individual families and try to team up to try to describe a larger series. The challenge is that it has not been possible to find these patients because they are … extraordinarily rare.”
T790M mutations, which occur in the epidermal growth factor receptor kinase, most commonly occur in patients’ tumors after they have been treated with inhibitors of this kinase, such as Tarceva, and have become resistant to therapy. Around half of lung cancer patients who acquire resistance to EGFR-inhibiting drugs are found to harbor T790M mutations in their tumors. An even smaller number of lung cancer patients, between 1 percent and 4 percent, harbor T790M mutations in their tumors when their lung cancer is first diagnosed.
In this already small group of lung cancer patients with baseline T790M tumor mutations, researchers have observed an even more exclusive subset who have inherited germline T790M mutations. Through anecdotes, researchers have noted patterns that lead them to believe that carriers of the germline mutation, particularly those who are non-smokers, may have a heightened risk for lung cancer than do non-carriers.
Germline EGFR T790M mutations were first identified in lung cancer in 2005, but the rarity of the marker in lung cancer patients has made it difficult for researchers to track it in the population. Previously, investigators have searched for the germline mutation in families with a history of lung cancer and have come up empty handed. Looking for the mutation in non-smokers still casts too wide a net and picks up a miniscule number of carriers.
“So, we don’t even know about prevalence,” Oxnard said. “We don’t know about penetrance much except anecdotal reports here and there. And it’s only the [mutation] positive families [with cancer] that you find described in the literature. The families walking around with these mutations but not affected by lung cancer don’t get described.”
In INHERIT EGFR, instead of using family history or smoking history to home in on lung cancer patients with germline T790M mutations, Oxnard and his colleagues are using the baseline tumor genotype.
“This is the first study to my knowledge where performance of germline genetic testing is based upon the tumor genomics,” Oxnard said. “That’s the innovation. The idea that finding a tumor genotype means that a patient should get germline testing has not previously been described.” The investigators aim to enroll 100 people with germline T790M mutations over a three year period. They will start by screening lung cancer patients who have T790M mutant tumors, since previous research published by Oxnard suggests that patients in this subset have a 50 percent chance of carrying a germline mutation.
In a paper published last year in the Journal of Thoracic Oncology, study investigators from Memorial Sloan-Kettering and Vanderbilt Ingram Cancer Center described screening more than 500 patients with EGFR-mutant lung cancer over a seven-year period and finding 11 unrelated lung cancer patients who had T790M mutations in their tumors at diagnosis. Of these, 10 patients had benign tissue available for diagnosis and five were found to have a germline T790M mutation.
After screening lung cancer patients with T790M-mutated tumors, Oxnard and colleagues will also test relatives of germline EGFR mutation carriers for inherited T790M mutations. Participants will be followed for two years to study their health. Investigators will discuss the possibility of getting a CT scan for those with a germline mutation. “We’re teaming up with advocacy groups to try to get scans paid for if they don’t get reimbursed by insurers,” Oxnard said.
As of April 3, researchers had enrolled six people in INHERIT EGFR and were screening eight of their relatives. Currently, there are 15 sites around the country recruiting patients into INHERIT EGFR. Carbone at OSU is also the chair of the scientific advisory board at the Addario Lung Cancer Medical Institute, which has agreed to fund the registry. The Conquer Cancer Foundation of the American Society of Clinical Oncology has also provided grant funding for the effort.
Molecular diagnostic firm Response Genetics has agreed to help recruit patients for the registry. The Los Angeles-based company markets genetic tests that gauge whether cancer patients have certain mutations that will make them likely to respond to various treatments. If the company finds a patient with a T790M mutated tumor, they inform the patient’s doctor about the INHERIT EGFR study.
“We have identified numerous potential study subjects,” Stephanie Astrow, VP of R&D at Response Genetics, told PGx Reporter. “However, as our analysis is performed on the tumor tissue, we do not know whether the mutation is somatic or germline. That determination is subsequently made if the patient decides to go forward with screening for the INHERIT study and is protected health information.”
So far, Response Genetics is the only commercial lab helping recruitment efforts for INHERIT EGFR. “One in 1,000 lung cancer patients probably carries T790M in their lung cancer; when you find it, I recommend that those patients get referred to this study,” Oxnard said. “It would make a huge difference if other companies felt that this is important for their patients too, so when they found patients with a T790M mutation, they referred them to our effort to learn more about this condition.”
Patients can remotely partake in the registry. INHERIT EGFR has a research coordinator who reviews whether patients might be right for the study over the web; genetic counselors can provide free counseling over the phone; and investigators can collect saliva specimens via the mail to conduct the genetic analysis. Testing is performed in a CLIA-certified lab, and participants’ test results will not be reported to their physician.
“No one has to worry about the burden of this,” Oxnard said. “If you just tell patients we’re out here, and they visit the website, then we will take them through the process.”
Not just in smokers
After Carbone recommended Capelli get tested for T790M mutations, she looked into the services at Stanford University near Palo Alto, Calif., since she lives in the area. She got in touch with medical oncologist and geneticist James Ford, whose lab is focused on researching the role of tumor suppressor genes p53 and BRCA1 in cancer. Even the experts at Stanford weren’t too familiar with germline T790M mutations in lung cancer, Capelli recalled, but they worked with her to get her genetically tested.
Bandgren’s oncologist in Huntsville also didn’t know about the inherited T790M mutation, but she is thankful that he was able to guide her to Carbone. “We tell people we have this inherited gene, and even doctors haven’t heard of it,” Bandgren said.
Because there isn’t that much information out there about the link between lung cancer in non-smokers and the inherited T790M mutation, Bandgren and Capelli have had a hard time convincing their relatives to get tested. Some family members smoke or have worked around toxic fumes, and they feel that if they do get lung cancer it will likely be because of their exposure to these environmental factors.
But Capelli, Bandgren, and many others like them, can’t blame their cancer on smoking. “My cousins may be indifferent, but I feel they would want to know if their kids have the mutation,” Capelli said. “If their kids are clear, that would be a kind of peace of mind.”
The knowledge that Capelli has inherited this mutation has placed her on a track to get more frequent CT scans to monitor the growth of her other lung nodules. After her lung tumor biopsy last year, Bandgren received radiation treatments for one of the tumors and a recent PET scan has shown that she is stable.
“We really would like for more information to be out there” about the T790M mutation, “so people realize it’s a step forward and that something can be done if there is any inkling that they have this [inherited] gene mutation,” Bandgren said.
“Look at all the work on breast cancer and the [inherited] breast cancer genes,” Capelli said. “I’m sure it started like this.”
Germline BRCA1/2 mutations are rare, accounting for only 5 percent of breast cancers and between 10 percent and 15 percent of ovarian cancers. Women who inherit these mutations have up to an 85 percent risk of developing breast cancer by age 70 and up to 60 percent risk of developing ovarian cancer by age 85. Since geneticist Mary-Claire King first described the link between germline BRCA1 mutations and heightened risk of breast cancer in 1990, BRCA1 and BRCA2 have been the most heavily studied disease-linked genes. Myriad Genetics, the only firm that markets a diagnostic that gauges BRCA mutations for hereditary breast and ovarian cancer, boasts having tested a million patients to date.
Through INHERIT EGFR, Oxnard and his colleagues are trying to figure out the same types of information about germline T790M mutations: In whom does it occur? How often? And what kind of cancer risk does it confer in carriers? Inherited T790M mutations “represent an example like BRCA mutations where you’re likely to have very high risk of lung cancer if you inherit this gene,” Carbone said.
Although genetics research on inherited cancer syndromes may help dispel the commonly held view of lung cancer as a smokers’ disease, it could take many years beyond the length of the INHERIT EGFR trial to pinpoint exactly why some T790M mutation carriers develop lung cancer and why some don’t. In his research, Oxnard has seen an elderly man with germline T790M mutation who died of cancer but never had lung cancer, observed lung cancer patients who carry the mutation but have no family history of the disease, seen germline carriers in their 20s with lung nodules, and described one patient who had six resected lung cancers each characterized by a different genotype in addition to T790M.
“The penetrance [of germline T790M] is going to be a little mysterious,” he said. “Clearly, it’s highly penetrant in some instances but not in others. We have to understand why that occurs.”
Ultimately, a better characterization of how germline EGFR mutations are linked to lung cancer can help experts refine screening guidelines that currently only focus on smokers. The NCI’s National Lung Screening Trial showed that annual screening with low-dose CT scans in high-risk people – those with a long smoking history – can reduce lung cancer mortality by 20 percent. Based on data from this study, the American Cancer Society issued an initial guideline this year that clinicians at high-volume cancer treatment centers should discuss low-dose CT screening with healthy patients between age 55 and 74 years who have at least a 30-pack-per-year smoking history.
“The problem is that the EGFR mutation carriers, as [Bandgren's] daughter [Capelli] demonstrates, may not have any smoking history,” OSU’s Carbone said. “There are about 20,000 deaths every year from lung cancer … [among patients] who have never smoked. So, those people wouldn’t be eligible for any typical screening program, but what we’re hoping to do is develop evidence that these people who inherit this abnormality should be screened because they are at very high risk of developing lung cancer even in the absence of smoking.”
If INHERIT EGFR can show that people with the germline T790M mutation have pulmonary nodules at the same rate as smokers in lung cancer screening trials, for example, then Oxnard believes that may be a starting point for suggesting that this patient subset deserves to at least be followed more closely until more is known about the cancer risk associated with this inherited marker.
“Lung cancer has that bad connotation that if you smoked, you did it to yourself,” Capelli said. “Anybody that has lungs can get lung cancer. There are a lot of non-smokers that get it, and there are no mammograms or [measures] in place to catch it early. By the time somebody figures out they have it, it’s too late.”
Turna Ray / Editor, PGx Reporter / GenomeWeb LLC / 212.651.5626 (P)