ONCAlert | Upfront Therapy for mRCC
Lung Cancer Case Studies

Mutation Testing in NSCLC

Sarah Goldberg, MD
Published Online:Mar 29, 2018
Sarah Goldberg, MD, discusses a case scenario of a 66-year old woman with EGFR-positive metastatic lung adenocarcinoma.

Treatment of NSCLC With Uncommon EGFR Mutations


Sarah Goldberg, MD: This patient has an EGFR mutation, so it’s not at all unexpected that she’s wild-type for KRAS and ALK. In general, we do test for many mutations at the diagnosis of advanced or stage 4 NSCLC, specifically lung adenocarcinoma. And looking for EGFR and ALK are 2 of the most important genes to look at because we have targeted therapies that can work very well for those. There are other genes that are very important to look for mutations in, including RAS1, BRAF. There’s many others. MET is actually also an important one. KRAS is an interesting one to talk about because we don’t have targeted therapies for KRAS. One important reason to check it might be that typically if there’s a mutation in KRAS, the other ones are usually negative, although sometimes you can see multiple alterations in genes. But typically, if one is positive, the others are negative if they’re mutually exclusive. So, again, in this patient, it’s not surprising that since she does have an EGFR mutation that the ALK and KRAS are negative.

There are 2 types of EGFR mutations that are, by far, the most common in NSCLC, specifically lung adenocarcinoma. That’s the exon 19 deletion and the L858R point mutation in exon 21. So, those 2 types of mutations make up, again, the vast majority of EGFR mutations, probably around 90% of the mutations. When we see a patient with an EGFR mutation, that’s typically what we see. And those 2 types of mutations typically make the cancer very sensitive to EGFR inhibitors. And so, when we find that, it’s usually a very good thing for the patient because we have drugs that can work very, very well for their treatment.

There are several drugs that we have now that are EGFR inhibitors that are options for patients, but those are the common mutations—that’s what they’re typically called, the common EGFR mutations—and they are sensitizing as well, meaning they sensitize the cancer to the EGFR inhibitors.

EGFR mutations can be in this rare category, or uncommon category. About 10% of them fall into that category. And this patient has one of them, the G719 mutation. There are about 10% of EGFR mutations that fall into uncommon category. And what’s important to note about the uncommon EGFR mutation is that some of them still are sensitizing. So, uncommon doesn’t necessarily mean that the drugs won’t work, the EGFR inhibitors won’t work. Uncommon can be sensitizing to the drug, and that’s the case with this patient’s mutation. This is the type of mutation that is uncommon; it’s rare in EGFR but still can make the cancer sensitive to the EGFR inhibitors.

Transcript edited for clarity.
  • A female patient, Chinese descent, aged 66, is referred from primary care with persistent cough, sputum with blood, shortness of breath and chest pain
  • History
    • Never smoked
    • Recurrent bronchitis over past 5 years
    • Has never been screened for lung cancer (by radiography or low-dose CT [LDCT])
    • Hypertension controlled on HCTZ; no diabetes, renal impairment
    • Family history
      • Grew up in China, moved to US at age 29; married for 30 years
      • Grew up in family with heavy smokers
      • Husband is current smoker
  • LDCT reveals multiple tumors in left lung with pleural metastases
  • Biopsy reveals non-small cell lung cancer
  • Molecular analysis:
    • EGFR mutation: G719X
    • Negative for ALK rearrangement
    • Wild-type KRAS
  • The patient was started on afatinib, 40 mg once daily
  • After one month on therapy, she reported having rather severe diarrhea (5 times/day)
  • Treatment was discontinued, then re-started treatment at 30 mg/day
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