Siddhartha Devarakonda, MD
The arrival of next-generation sequencing, specifically for patients with non–small cell lung cancer (NSCLC), has allowed physicians to identify molecular abnormalities and potential therapies to match those targets. Though the turnaround time is longer than the standard panel to test for EGFR/ALK/ROS1
mutations, it has the potential to unravel additional mutations that will provide even more information about a patient’s prognosis and likelihood of therapeutic response.
“The biggest point is that lung cancer is not the same as it was 10 years before,” said Siddhartha Devarakonda, MD. “Testing is very important, and if you don’t test, you will not find alterations. Some of these drugs have very good clinical efficacy in inducing responses and prolonging patient longevity. It is really important to test for these alterations.”
Devarakonda, MD, a senior fellow at Washington University School of Medicine in St. Louis, lectured on biomarker testing in NSCLC during the 2017 OncLive®
State of the Science Summit in Advanced Non–Small Cell Lung Cancer. In an interview, he shared insight on the importance of testing for these molecular markers, some of the rarer mutations, and what work lies ahead for the field in this area.
OncLive: Can you provide an overview of your presentation?
Just like you wouldn’t treat breast cancer without knowing if a patient is estrogen receptor–positive, progesterone receptor–positive, or HER2-positive in 2017, it is very important to look for biomarkers in lung cancer.
Some of these have a bearing on patient prognosis, and help to identify the right therapy. One thing to remember is that lung cancer is a molecularly heterogeneous disease; you have small cell lung cancer, squamous cell carcinoma, and adenocarcinoma. These are the most common subtypes. Each of them have a distinct biology, and that is 1 thing we have learned with a lot of sequencing studies.
Adenocarcinomas are typically characterized by alterations in the RAS/RAF pathway. In SCLC, on the other hand, you typically have your TP53 retinoblastoma mutation, but squamous cell carcinoma differentiation and a few structure alterations is what characterizes them.
Of these, the 1 thing that’s clinically important as of today is the receptor TKI pathway in adenocarcinoma, because that is the 1 we have medications for. This can be through EGFR
mutations, translocations in ALK/ROS1/RET
, and so on. The bottom line of this is you have a lot of alterations in lung cancer; in adenocarcinoma, you have the receptor TKI signaling pathway. It is important to pick up these alterations because a lot of these can be targeted today with TKIs, so that is one of the big take-home messages here.
Alterations in the RAS pathway tend to be mutually exclusive. One good analogy for that is if you have lights turned on in a room, you don’t have to turn it on a second time. The reason this is important is that sometimes even KRAS
is not a targetable alteration. Sometimes, we don’t end up testing for those alterations because if you find it, it is often very unlikely that you will find something else. You don’t have to delay treatment unless the next-generation sequencing panel comes back and your EGFR/ALK/ROS1
—the ones that you often test first-line for—are negative.
How do you test for these alterations? The right tests to pick depends on what you’re trying to look for. For mutations, PCR has been the standard test but next-generation sequencing is becoming more popular. The one advantage is if you are trying to do a PCR test, you need to have prior knowledge of what you're looking for. That is easier for KRAS
, because KRAS
is typically activated by mutations in 3 spots. EGFR
, however, is a pretty large gene and then you find a variety of alterations in it about 90% of the time. It is usually the exon 21 point mutation, or exon 19 deletion, but every now and then you do find these rare mutations such as exon 20 and exon 18, some of which you can target with drugs. For instance, afatinib (Gilotrif) has good clinical data from the LUX Lung studies.