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Mucinous bronchioloalveolar carcinoma of lung and ALK mutation

Posted Jul 19 2010 9:06pm

Last month I received a generous note from a patient who responded to a previous post on molecular markers in lung cancer from the USCAP 2010 meeting.  I made the statement that "every adenocarcinoma should be tested for EGFR mutation (with the exception of mucinous ACa/BAC which are always KRAS mutants)."  This patient's experience should cause us to not be so categorical about such statements.  Moreover, as we develop testing algorithms, we should consider an approach which will allow us to detect "exceptions to the rule."

The patient was diagnosed with mucinous BAC.  But not only was the tumor wild-type for KRAS mutation (i.e., no mutation was detected) but instead an ALK mutation identified in the tumor.  The patient subsequently received the drug crizotinib, an inhibitor of the fusion protein EML4/ALK, and has had a sustained response to treatment.  

This is the drug that generated so much attention at the recent ASCO 2010 meeting in Chicago.  In an international phase I study of advanced, heavily pretreated NSCLC patients selected for ALK protein expression, crizotinib produced a 57% response rate with a 6-month PFS predicted to be 72%.  This data was presented at the Plenary Session.  Moreover, it was noted that the majority of patients showed some kind of response (63% including objective and unconfirmed partial responses), the response often occurred dramatically within the first 2 weeks of treatment, and the responses were often durable.  In this study, 96% of responders had adenocarcinoma histology--primarily signet ring morphology.

This is surely a very exceptional case since mucinous ACa/BAC is a very distinctive histological subtype and has been also characterized at the molecular level as being associated with KRAS mutation.  The point is that histology is not a perfect predictor of potentially druggable molecular pathologies.  If targeted therapy is being contemplated in NSCLC, we should adopt a systematic approach to all NSCLC regardless of histology.  At this point, while we are identifying patients who may potentially benefit from targeted therapy, we are building a database that will allow a more full appreciation of the relationship between histological type and molecular pathology.

Thanks to the patient who took the time to respond to my blog and for helping to edify us all!

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