A Rare Case of Adenocarcinoma of the Lung Harboring EGFR, BRAF, and ALK Activating Mutations.

SESSION TITLE: Cancer Global Case ReportsSESSION TYPE: Global Case ReportPRESENTED ON: Tuesday, October 28, 2014 at 01:30 PM - 02:30 PMINTRODUCTION: Personalized target therapy of non-small cell lung cancer (NSCLC) is based on the mutation status of EGFR, KRAS, BRAF, and EML4-ALK fusion gene, and different mutations have different treatment. Herein, a rare case of adenocarcinoma of the lung harboring EGFR，BRAF and ALK activating mutations simultaneously was reported.CASE PRESENTATION: A 68-year-old male who is a light smoker (4 cigarettes per day) was admitted to our hospital in July 2013 because of chest distress and shortness of breath lasting > 2 years. He had nothing remarkable in his medical and family history; physical examination also did not reveal any significant abnormalities. X-ray showed an abnormal shadow in the right lower field on chest. Contrast-enhanced computed tomography (CT) revealed one nodular shadow in the right lower lobe (measured 1.8 cm in the largest dimension in the S3 segment. Head MRI, isotope bone scan, abdominal ultrasound, bronchoscopy and laboratory tests showed normal results. We conducted trans-bronchial lung biopsy (TBLB). The pathological diagnosis of the TBLB specimen was moderately differentiated adenocarcinoma (T1aN0M0). Since there was no surgical contraindication, the patient started with a wedge resection of the right lower lobe of the lung. Fresh surgical specimen was sent for molecular analysis. This confirmed the tumor harbor EGFR mutation (19-del). An ALK rearrangement and BRAF (V600E) mutation was also detected by Fluorescence PCR within the tumor. The final pathology revealed the nodule in the right S3 segment was moderately differentiated adenocarcinoma, no tumor invasion in the lymph nodes. The patient was currently faring well in the outpatient follow-up and discharged in view of satisfactory recovery. Based on the presence of an ALK rearrangement, it was proper to receive Crizotinib. But, given the tumor harbor EGFR mutation as well, it was a good choice to choose EGFR-tyrosine kinase inhibitor (TKI) gefitinib and erlotinib. Considering the tumor present with BARF mutation too, the patient may resistant to TKI. The doctor found themselves in a dilemma.DISCUSSION: We report an unusual case of a gentleman with adenocarcinoma of lung harboring EGFR (19-del), ALK rearrangement and BRAF (V600E) mutation, which is considered an uncommon phenomenon. To our knowledge, this is the first report of a case of lung adenocarcinoma of this combination. Concurrent somatic BRAF mutations and ALK rearrangements have not been reported. A molecular analysis of mutations in non-small cell lung cancer reported that no BRAF mutations were identified in conjunction with ALK, KRAS or EGFR. This also confirms that harboring either one of these mutations in adenocarcinoma of lung is rare1. Recent advances in molecular status analyses of lung adenocarcinoma specimens have revealed active mutations of EGFR gene are often associated with well differentiated adenocarcinoma of the lung. Patients with non-small cell lung cancer (NSCLC) harboring mutations in the EGFR gene have dramatic response to the EGFR- tyrosine kinase inhibitor (EGFR-TKI)2. Mutations in downstream signaling effectors of EGFR could result in resistance to EGFR inhibitors. Fortunately, several specific small-molecule BRAF V600E inhibitors are currently under pre-clinical or clinical investigation and mutated BRAF V600E protein may be a promising therapeutic target. EML4-ALK fusion gene positive lung adenocarcinoma typically occurs in young subjects with non- or low smoking habits, mucinous cribriform pattern is shown to be frequently associated with EML4-ALK positive lung adenocarcinoma3. Crizotinib is a good choice for the patients with NSCLC harboring ALK arrangement.CONCLUSIONS: In this case, the patient has three mutation genes, EGFR (19-del)，EML4-ALK fusion and BRAF (V600E). Now the tumor was resected completely, and no post-operative adjuvant therapy, but we all know that these three mutations are in different pathways and have different target therap. This is a challenge to doctors in the treatment of the patients harboring three mutations and needing target therapy.Reference #1: Paik PK, Arcila ME, Fara M, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol 2011; 29:2046-2051Reference #2: Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010; 362:2380-2388Reference #3: Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012; 18:378-381DISCLOSURE: The following authors have nothing to disclose: Yang Yang, Xiao Song, Junjie Zhu, Xiao ZhouNo Product/Research Disclosure Information.