Navigating the Molecular Testing Landscape in Lung Cancer

Roy Herbst, MD, PhD

Lung Cancer

Experts discuss how they use mutational testing

The expansion of tumor genetic profiling into the clinic has led to effective, targeted treatments for patients but created a daily dilemma for oncologists: What to do with the results of these tests?

At the 15th Annual International Lung Cancer Congress, a panel of lung cancer experts weighed in on the topic through a case discussion presented by Roy Herbst, MD, and Juliane M. Juergensmeier, PhD, of Yale Cancer Center, New Haven, CT. Dr Herbst is ensign professor of medicine, professor of pharmacology and chief of medical oncology. Dr Juergensmeier is research scientist in medical oncology and heads up the Yale Precision Medicine Tumor Board.

Yale Precision Medicine Tumor Board: Truly Multidisciplinary

At the Yale Precision Medicine Tumor Board, according to Juergensmeier, a multidisciplinary panel of experts comes together “to interpret complex genetic findings.” The board includes clinical medical oncologists, pathologists (anatomic and molecular), radiologists, surgeons, pharmacists, basic and translational researchers, geneticists, bioinformaticians, and advanced practice nurses.

In non–small cell lung cancer (NSCLC), the group currently evaluates the results of genetic profiling assays but expects to soon add gene expression profiling by immunohistochemistry and immune assays as well. Yale uses 3 levels of genetic profiling: an 8-gene panel, a 50-gene panel, and a 409-gene panel. Most involve next-generation sequencing; whole exome sequencing is also available.

“This information is submitted for discussion and treatment recommendations, primarily with a targeted agent or enrollment on a clinical trial based on the molecular profile,” she said. “But more often than not, we find mutations that are hard to interpret.”

While Yale is able to direct many eyes to one test result, oncologists in the community often lack for this expertise. A show of hands in the conference audience indicated few oncologists have access to on-site laboratories or molecular tumor boards.

A Typical Case: What Test Do You Order?

As a means of familiarizing the audience with gene expression profiling, Herbst and Juergensmeier presented a typical case from Yale and asked conference faculty to comment.

The 77-year-old patient was a former smoker with newly diagnosed early-stage NSCLC (T2N1). Imaging revealed a 25×14 irregular left upper lobe paramediastinal parenchymal lesion abutting the pleura. Tumor samples from lobectomy revealed a 4-cm moderate-to-well differentiated adenocarcinoma of the lung with 50% papillary, 30% acinar, and 20% micropapillary histologies.

The panel first discussed what genetic testing, if any, is warranted in this patient. According to Juergensmeier, either a limited genetic panel (primarily looking for EGFR mutations and ALK fusion) or broad genetic profiling would be appropriate.

Paul Bunn, Jr, MD, professor and James Dudley Chair in Cancer Research at the University of Colorado Denver School of Medicine, said his center’s policy is to perform molecular tests on such a patient at diagnosis. “The majority of such patients will relapse, and it’s good to know ahead of time how to treat this patient when that happens,” he said.

David Gandara, MD, professor of medicine and chief of the thoracic oncology program at the University of Davis Comprehensive Cancer Center in Sacramento, CA, commented on the tumor’s mixed histology, each with its own predilection for having an EGFR mutation or ALK fusion. “The issue is, which part of the tumor will you send for mutation testing?” he asked. The heterogeneity within the sample can be an issue in the case of multiple histologies, he said.

Bunn countered that this may not be an issue. Researchers from MD Anderson Cancer Center recently showed that in the presence of a driver mutation, heterogeneity tends to be low in NSCLC, he said. “While there can be some heterogeneity, it’s highly likely that in this patient you would find the same mutation in each of those histologic areas,” he maintained.

Corey Langer, MD, Professor of Medicine and Director of Thoracic Oncology at Abramson Comprehensive Cancer Center in Philadelphia, emphasized that this is an early-stage patient, and noted, “There’s no data that we alter outcomes in the early-stage, curable setting with any targeted agent. You are perfectly justified doing any gene profiling test, but doing none is also quite reasonable.”

Results of 409-Gene Panel

The 409-gene panel was run on this patient, and non-tumor DNA from a histologically normal lymph node was used as a reference, to exclude germine changes.

The molecular pathologist identified 4 gene alterations with significant frequency. These included mutations, and their tumor DNA frequencies, in ERCC4 (49%), CDKN4A (39%), EGFR (33%), and FGFR (26%). Both EGFR and CDKN4A mutations could have a major effect on the patient’s disease, but a targeted agent is currently available for only the EGFR mutation. ERCC4 would have a minor effect, and FGFR4 would have no effect on the cancer.

Herbst noted that this patient has the typical exon 19 EGFR mutation, for which EGFR inhibitors are available. The additional mutations could be of interest for this patient in the future, as new targeted agents become approved.

The Yale pathologist’s report on the actionable mutation (Table) describes the effects of the mutation and lists approved treatment options and relevant experimental agents.



“Clinicians need to get used to seeing these reports,” Bunn said. “Not all mutations are the same, and this will be even truer for KRAS than for EGFR. You will need to pay attention to
just what these mutations are.”

The Treatment of This Patient

Should this patient be treated with chemotherapy, a first-, second-, or third-generation EGFR inhibitor, an investigational agent (ie, targeting CDKN4A), or a combination of chemotherapy plus an EGFR inhibitor?

Bunn maintained that chemotherapy is the best option. He said he would discuss the results of genetic testing, and tell the patient: (1) there is evidence that treatment with an oral EGFR inhibitor will reduce the risk of recurrence, (2) with discontinuation of treatment the cancer will probably recur, (3) there is no evidence that this approach will improve survival over chemotherapy alone.

“Obviously, this is controversial,” he acknowledged. “Some oncologists would offer an EGFR inhibitor with or without chemotherapy, but I would discuss this with my patient, and my personal recommendation would be chemotherapy.”

Herbst agreed that adjuvant chemotherapy is recommended, with “consideration” of an EGFR inhibitor. He added that any treatment delay is not advisable. “The last thing we want is for whole exome testing to take so long that by 10 days we don’t have the results for EGFR and ALK testing, which we know are important.”

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