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Early Study Results Find High Proportion of Young Lung Cancer Patients With Targetable Mutations

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NEW YORK (GenomeWeb) – Researchers hoping to uncover the genetic factors underlying lung cancer in young and otherwise healthy adults have reported preliminary results showing that 76 percent of participants in a study had druggable driver mutations in their tumors.

At the World Conference on Lung Cancer earlier this month, researchers led by Barbara Gitlitz of the University of Southern California and Geoffrey Oxnard from the Dana-Farber Cancer Institute discussed the experiences of the first 68 subjects, most of whom had adenocarcinomas and were all younger than 40 years of age. After assessing these patients' tumor tissue on Foundation Medicine's FoundationOne next-generation sequencing test, researchers found 44 percent of patients had ALK rearrangements, 26 percent had EGFR mutations, and 6 percent had ROS1 rearrangements.

Drugs, such as the ALK inhibitor Xalkori (crizotinib) and EGFR inhibitors Tarceva (erlotinib) and Gilotrif (afatinib), are approved for non-small cell lung cancers characterized by these mutations. In the case of lung cancers with ROS1 rearrangements, studies have shown that patients respond to Xalkori.

In the study, 7 percent of patients had tumors characterized by other markers, such as EGFR-RAD1, EGFR-KDD, HER2, ATM, BRCA2, TP53/PTEN, and TP53. Specifically, EGFR-RAD1 and EGFR-KDD are fusions that haven't previously been seen in lung cancer patients.

Gitlitz's team launched the so-called Genomics of Young Lung Cancer Study (GoYLC) last year wanting to find out if there is a different biology driving the lung tumors occurring in those under 40, a historically understudied group. The American Cancer Society estimates that two out of three lung cancer patients are diagnosed when they are 65 years or older. Fewer than 2 percent of cases occur in those younger than 45.

The median age of diagnosis in GoYLC was 35 years, with some diagnosed as young as 16. "Anybody can get lung cancer. You don't have to be 75 and a lifetime smoker to get it," Steven Young, president of the Addario Lung Cancer Medical Institute (ALCMI), told GenomeWeb.

Young people who get lung cancer are often healthy, athletic, and don't smoke. "It's very perplexing," Young said. "Why would someone like this develop lung cancer?"

The Bonnie J. Addario Lung Cancer Foundation, a philanthropic organization with a track record of supporting research through ALCMI that's hard to do or isn't being pursued, began asking why the disease occurs in younger people following the death of Jill Costello. In 2009, the University of California, Berkeley student and a star member of the crew team was diagnosed with Stage IV small cell lung cancer at age 21. At the time of diagnosis, Costello's cancer had spread to both her lungs, several other organs, and her bones.

She passed away a year later, but her death led to the formation of Jill's Legacy, an advisory committee within the foundation that aimed to educate the younger population about the risks of lung cancer. Costello's story struck a chord and a lot of young people began reaching out to the foundation for support.

Last year, Gitlitz's group launched the GoYLC in order to systematically study the genomic profile of younger lung cancer patients for the first time and create a registry of such patients. The preliminary results have exceeded the targetable mutations researchers had expected to find.

Earlier work by the Lung Cancer Mutational Consortium suggested researchers could find twice the number of actionable mutations in younger study subjects compared to older patients. "The study to date has shown an incredible preponderance of [targetable] mutations in this younger population," Young said.

In the study, researchers found ALK, EGFR, and ROS1-positive tumors in more women than men — 95 percent versus 74 percent, respectively. There was a high prevalence of EGFR and ALK alterations among patients with Stage IV adenocarcinomas.

Based on their tumor markers, all of these patients, who otherwise would get chemotherapy, have been referred for targeted drugs, either on or off label, or to clinical trials. Researchers will follow these patients to track how they do on these treatments, and whether NGS profiling and a precision medicine strategy benefits them.

It's very perplexing. Why would someone like this develop lung cancer?

Young highlighted that one lung cancer patient in the US who had a never-before-seen EGFR-RAD1 fusion received Gilotrif, which is approved for metastatic NSCLC patients with EGFR exon 19 deletions or exon 21(L858R) substitutions. This patient has been on the drug without disease progression for more than half a year. Researchers are in the process of following up on how another patient in Italy with the EGFR-KDD fusion fared and what treatment he received.

Despite these promising initial results, significant questions still remain: Why do younger patients have more targetable mutations than older patients? Why do they develop cancer without a lifetime of exposure to carcinogens, like tobacco smoke or radon? "That's still the mystery," Young said, emphasizing that the GoYLC results are preliminary. "We don't really know the answer to that."

Researchers will continue to search for answers, though. They will recruit patients in to GoYLC for at least another year, aiming to enroll more than 200 patients. Young noted that researchers are also pursuing a parallel study of 1,000 patients that will investigate lung cancers affecting the young from a global perspective.

Since younger patients represent a small slice of the overall lung cancer population, researchers are enrolling volunteers through clinical sites and through the web. The latter approach has been successful, with 30 percent of subjects in GoYLC recruited via a web-based portal that facilitates online consenting, screening, and shipping of biospecimen kits.

In addition to receiving testing on Foundation Medicine's NGS panel for actionable mutations that can inform treatment, GoYLC participants will also receive whole-exome analysis, so researchers can search for insights into germline and somatic markers. They will also look for clues in cell-free DNA. Young noted that this additional testing may very well reveal inherited markers that confer heightened risk for lung cancer.

Another study led by GoYLC co-leader Oxnard, called INHERIT EGFR, is exploring whether inheriting a germline EGFR T790M mutation increases familial risk of lung cancer, particularly among non-smokers. Although, Oxnard's team needs to study many more cancer patients and their families before drawing more definitive conclusions, early results do suggest a correlation between having a germline T790M mutation and heightened familial lung cancer risk.

Based on data presented at the American Society of Clinical Oncology's annual meeting this year, Stanford University oncologist James Ford said clinicians might consider germline testing for patients whose somatic test results show a T790M mutation. Although the prevalence of this marker in the population hasn't yet been pinned down, Ford also backed germline testing for T790M in families with multiple non-smoking lung cancers.

Although NGS testing had failed to identify actionable markers for Costello, the first results from GoYLC suggest that a high proportion of young lung cancer patients may have targetable mutations, which could give them a better shot at living longer. This, according to Young, bodes well so far for NGS as a precision medicine tool for this population.

He recounted a joke about a person who loses his keys in the parking lot at night, and when someone asks why he is only searching under the street lights, he responds, "Because that's the only place I can see." When it comes to lung cancer, "we need to look into the unlighted portions of the parking lot," Young said.

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