Repeated Favorable Responses to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in a Case of Advanced Lung Adenocarcinoma
In December 2008, a 43-year-old Korean woman was admitted to our hospital with a 3-month history of dry cough and dyspnea. The patient had never smoked and had no recent history of travel or use of medications. Physical examination revealed some crackles on the left upper lung. Laboratory findings were within normal range, except for elevations of white blood cell count (26,600/mm3) and C-reactive protein (7.6 mg/dL). Chest radiograph () and computed tomography (CT) scans showed diffuse consolidations and ground glass opacities mixed with multiple hematogenous metastases in the left upper lobe (LUL) and left lower lobe. Pathologic results of transbronchial lung biopsy from the LUL showed a well-differentiated adenocarcinoma. We performed direct DNA sequencing for EGFR mutations in exon 18, 19, 20, and 21 with this specimen. The result indicated wild-type EGFR. First-line chemotherapy with gemcitabine and cisplatin was started on December 2008. After 6 cycles, second-line treatment with gefitinib 250 mg/day was initiated in May 2009 because of progressive disease. A follow-up CT showed partial response (). But, the time-to-progression of gefitinib was only 4 months (), so she received third-line pemetrexed for 6 cycles. After that the CT scan in July 2010 revealed aggravated pulmonary metastatic nodules, and we enrolled the patient in an ongoing clinical trial for evaluation of gefitinib reatreatment in advanced NSCLC patients who were controlled previously with gefitinib. The patient displayed marked improvement in symptoms and radiologic findings (). We attempted to obtain a gefitinib-resistant tumor biopsy sample at the end of this trial, but could not perform EGFR mutation analysis because of insufficient specimen. After 6 months, there were more progressed LUL nodule and hematogenous metastases (). On the suspicion of clinically defined acquired resistance to EGFR-TKI, we recruited the patient to a phase II trial with PF-00299804 (PF-00299804 in treating patients with stage IIIB or stage IV NSCLC that has not responded to standard therapy for advanced or metastatic cancer, ClinicalTrials.gov number, NCT0100-0025). In April 2011, the patient was started on PF-00299804 as fifth-line therapy. A radiologically evident partial response occurred once more (). The patient continued the experimental drug for 11 months before newly developed subcarinal lymphadenopathy was detected by CT imaging in March 2012 (). Endobronchial ultrasonography-guided transbronchial needle aspiration biopsy confirmed metastaic adenocarinoma. An EGFR mutation test with this specimen using the peptide nucleic acid (PNA) clamping method, revealed two mutations in exon 21 (L858R/L861Q) and exon 20 (T790M) (). With the progressive disease, sixth-line docetaxel chemotherapy was started beginning in April 2012.