By now, most patients (and hopefully, all oncologists!) are familiar with the significance of EGFR mutations in non-small cell lung cancer (NSCLC). The discovery of ALK mutations and the successful use of crizotinib in this setting has also been big news in the lung cancer world. I'd like to bring everyone up to date on two lesser known abnormalities that can occur in non-small cell lung cancer: HER2 and BRAF mutations. This post will cover HER2 mutations in NSCLC, and I will cover BRAF in a companion post to follow shortly. Dr. West alluded to these mutations in his recent post on the Lung Cancer Mutation Consortium study, and you can see in the figure he previously presented the relatively low frequencies of these mutations compared to more common mutations such as EGFR and KRAS.

(click on image to enlarge)

BRAF and HER2 mutations are important because, like EGFR and ALK, we have therapies that target them, and we think that we would have similar successes by tailoring treatment to these mutations. Furthermore, we have already seen successes in other cancers where BRAF (melanoma) and HER2 (breast and stomach cancers) have been targeted.

HER2 is actually a member of the same family of tyrosine kinase receptors as EGFR. Similar to the story for EGFR, there are differences between HER2 overexpression, gene amplification and mutations in the HER2 gene. In breast cancer, overexpression of HER2 occurs in about 20% of cases; mutations in the HER2 gene are much less common. HER2-targeted therapy has been used very successfully in breast cancer patients whose tumors overexpress HER2 or have gene amplification. The most commonly used drugs targeting HER2 in breast cancer are Herceptin (a.k.a. trastuzumab, an antibody that is administered intravenously) and Tykerb (a.k.a. lapatinib, an oral drug). These drugs can be combined with chemotherapy or can be used alone in breast cancer. Herceptin typically causes few side effects when given alone and some patients with breast cancer remain on the drug for years. There is a small but real risk of heart dysfunction so the heart function must be monitored with echocardiograms and the drug has to be stopped if this occurs.

In lung cancer, it's a little more complicated. While HER2 is overexpressed in about 20% of lung cancers, mutations in HER2 occur in only about 2-3% of non-small cell lung cancers. Like EGFR and ALK, HER2 mutations typically occur in adenocarcinomas and appear to be more frequent in women and never-smokers.

Mutations in HER2 lead to continuous activation of the HER2 receptor, similar to the situation with EGFR. Early trials of Herceptin combined with chemotherapy in lung cancer patients with HER2 overexpression did not show a benefit for patients, in stark contrast to what we saw in breast cancer. But HER2 mutations may be a different story. There are case reports of lung cancer patients with HER2 mutations who have responded to treatment with Herceptin plus chemotherapy. BIBW 2992 (a.k.a. afatanib, previously covered by Dr. West) is a small molecule inhibitor of EGFR and HER2. This drug has also shown evidence of activity in lung cancer patients with HER2 mutations. Most of the patients described had cancers that had shown resistance to chemotherapy and/or EGFR inhibitors. However, I think the number of patients described to date is too small to draw firm conclusions about the clinical behavior of HER2-mutated NSCLC.

So why aren't we testing for HER2 mutations in all patients with lung cancer? I think we may in the future. In breast cancer, overexpression is pretty easy to test, and since overexpression correlates with response to treatment, patients can easily be funneled towards appropriate therapy or clinical trials. In lung cancer, it looks like we have to do mutational analysis because it does not appear that overexpression correlates with response. Mutational analysis is not done routinely, and the number of patients with these mutations is small, making it challenging for one or a couple of institutions to do clinical trials. The Lung Cancer Mutation Consortium is testing for HER2 mutations, and the eventual goal is for participating institutions to join forces to complete clinical trials for these uncommon mutations. At present, these patients would typically be treated with front-line chemotherapy, with HER2-directed trials being designed for second-line or greater treatment. Some patients who are identified as HER2-mutant may be able to get access to off-label Herceptin or Tykerb when clinical trials are not available; however, both of these drugs are expensive, and it may be challenging to get these treatments paid for.

The questions that I still have are:

• Will the responses to HER2-directed therapy in these patients be as dramatic as those we have seen with EGFR or ALK targeted therapy?
• Should HER2-directed therapy be incorporated into frontline chemotherapy in this group of patients? Can we find an easier and faster way of identifying patients than through mutational analysis?
• Which HER2-targeted therapy will be best for these patients?
• Is it important to also block EGFR?

There is still a lot to learn but I am looking forward to finding answers to these questions.