Tackling Questions on Genetic Testing

David R. Gandara, MD

Professor of Medicine Division of Hematology and Oncology Director, Thoracic Oncology Program Associate Director, Clinical Research UC Davis Cancer Center Sacramento, CA

Roy S. Herbst, MD, PhD

Chief of Medical Oncology Associate Director, Translational Research, Yale Comprehensive Cancer Center Smilow Cancer Hospital at Yale-New Haven, Yale School of Medicine New Haven, CT

The expansion of testing for genetic abnormalities in patients with advanced lung cancer is generating questions about which patients’ tumors should be tested, how they should be tested, and whether they should be retested.

In separate interviews, David R. Gandara, MD, and Roy S. Herbst, MD, PhD, the program directors for the 13th International Lung Cancer Congress, provided their thoughts on these questions.

Which patients should be tested?

Gandara: Whom to test is debatable among different people. To be most cost-effective, you could say I’m only going to test never-smoking patients with adenocarcinoma, and I’m going to test only for the EGFR mutation and ALK fusion. On the other hand, more and more, and I see this almost every week in my own practice, I have a patient who is a former smoker or a light smoker, and that patient turns out to have an ALK fusion or an EGFR mutation.

So I think, from an individual patient standpoint, it could easily be reconciled to test every patient with adenocarcinoma, and that’s what the new guidelines from the International Association for the Study of Lung Cancer and the College of American Pathologists will say.

In addition, we can say that some patients with squamous cell carcinoma have enough actionable abnormalities for which to test. I have several of my own patients, for example, who are never-smokers who have squamous cell carcinoma, including young Asian women, and they’ve turned out to have EGFR-activating mutations. And I can tell you their cancers are clearly squamous cell carcinoma.

Herbst: In my opinion, everyone who has advanced nonsmall cell lung cancer should be tested these days with molecular profiling. Certainly, patients with adenocarcinoma will have a host of actionable mutations such as the EGFR gene mutation, the ALK translocation, and ROS1, to name a few. So I think it is In my opinion, everyone who has advanced nonsmall cell lung cancer should be tested these days with molecular profiling. Certainly, patients with adenocarcinoma will have a host of actionable mutations such as the EGFR gene mutation, the ALK translocation, and ROS1, to name a few. So I think it is important to move forward to try to reflex-test all patients.

In the squamous cell patients, I would test them as well. In many cases, tumors are mixed. In many cases, the diagnosis of squamous versus adenocarcinoma is not entirely sound, so it’s my policy to try to test all patients. Clearly, we’re moving toward an era where we’ll discover new targets, and it will be important to test patients so that we can sort them into the right clinical trial.

I wouldn’t worry about whether someone smoked. I would test everyone, smokers and nonsmokers. Certainly, some of the mutations, such as EGFR mutations, are known to be more common in nonsmokers, but they’re not unheard of in smokers. It also depends on how much someone smoked and when they stopped smoking.

It’s quite clear that clinical characteristics are trumped by the molecular profile.

Which abnormalities or mutations should be included in the testing?

Gandara: There is a growing percentage of patients with non-small cell lung cancer who deserve molecular testing. The real message is to test simultaneously for the driver or actionable abnormalities, not sequentially.

For patients with non-small cell lung cancer, the most prominent drivers to test for—and where we have appropriate therapies right now—are the EGFR mutation and ALK fusion.

One of the newly described mutations is the ROS1 abnormality; those patients actually respond very well to crizotinib. In the past in non-small cell lung cancer, we tested for KRAS mainly as a negative test; that is, if the patient had a KRAS mutation, they were not as likely to respond to a drug like erlotinib. Now we have classes of agents, such as MEK inhibitors, which appear to be very active in KRAS mutations when those MEK inhibitors are given in combination with either chemotherapy or with other targeted agents. There are enough clinical trials that you can find one of these MEK agents for your patients.

Herbst: Certainly, multiplex testing is the future since tumor sample is limited. Clearly, the EGFR gene mutation and ALK translocation both are actionable with either erlotinib or crizotinib, respectively. ROS1 translocation also is treatable with crizotinib. That makes up about 18%, maybe 20% of patients with lung cancer. The other 80% will have mutations, for example, in PI3 kinase, BRAF, HER2. All those are on the order of a percentage or two, but if you knew the molecular profile of a patient, you could try to put them on the right clinical trial or the right combination of agents off trial.

What are the considerations in ensuring adequate tissue samples are available for testing?

Gandara: The evolution of the cancer genotype is a very important and new story. This is really Darwinism in action. What we mean by this is that clonal evolution occurs over time. We’ve been generally familiar with this but not to the extent that it occurs in reality and not to the extent that it occurs in non-small cell lung cancer.

Over time and under the influence of different therapies, there may be an evolution in the molecular profile in that patient. This could be acquisition of a secondary mutation, a so-called “resistance mutation” in EGFR mutation-positive patients or ALK fusion-positive patients, or it even could be development of a second driving oncogene in a patient who originally started with a different driving oncogene.

This raises the whole issue about, at the time of progressive disease, should you rebiopsy. More and more the answer is yes, you should.

Herbst: I will advocate for rebiopsy. The must frustrating thing, though expected, is that when you treat someone with the EGFR inhibitor erlotinib, or you treat someone with crizotinib, they are going to become refractory. The tumor becomes resistant, which we know happens with specific mechanisms, and the brain tends to be a sanctuary site for patients who have these abnormalities.

It will be important to rebiopsy at progression to understand exactly why the patient is resistant, so that that treatment can be delivered in a much more specific way, for example, targeting T790M for an EGFR mutation.