Laia Capdevila

Targeting EML4-ALK driven non-small cell lung cancer (NSCLC)

Recently, due to key discoveries relating to the molecular biology of many cancers and the development of effective and specific targeted treatments, the ability to personalize cancer therapy based on individual patient genotypes has become a reality in clinical practice (1). Some examples of this genotype-specific approach to anti-cancer therapeutics are BCR-ABL targeted therapy in chronic myelogenous leukemia, C-KIT inhibition in gastrointestinal stromal tumors, the use of Kristen rat sarcoma (KRAS) to negatively select EGFR inhibitors in colon cancer, HER2-directed therapy in breast cancer, and BRAF inhibitors in melanoma (2-13). Several other therapies are currently under investigation in clinical trials and will likely soon broaden this list further.

The epidermal growth factor receptor (EGRF) in lung cancer

In the last decade, important advances have been made in understanding of cancer biology, particularly non-small-cell lung cancer (NSCLC) with the discovery of oncogenic drivers of the disease. The epidermal growth factor receptor (EGFR) gene and its pathways was the first oncogenic driver discovered to be mutated and treatable in lung cancer. Treatment with EGFR tyrosine kinase inhibitors (TKIs) is the standard of care for molecularly selected EGFR-mutant patients, while its role in unselected lung cancer patients is nowadays controversial. This review will provide an overview of the EGFR pathway and options for its treatment of lung cancer.

Interstitial Lung Disease Arising From Erlotinib Treatment in a Caucasian Patient

Nonesmall-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations have better response and survival when they are treated with EGFR tyrosine kinase inhibitors (TKI). The most common adverse events associated with EGFR TKI therapy are rash and diarrhea. Interstitial lung disease (ILD) is also a possibility. ILD, although less common, can be severe. We describe a patient treated at our center with erlotinib. The patient was diagnosed with ILD 1 month after treatment initiation. Given the known benefits of treatment with EGFR TKI in EGFRmutated patients, as well as the wishes of our patient, erlotinib was reintroduced along with corticosteroids. To date, there are only 10 cases reported with reintroduction of EGFR TKI therapy after ILD. We report a case of retreatment with erlotinib after ILD both alone and with chemotherapy.

靶向EML4-ALK 驱动的非小细胞肺癌

近年来，得益于多种肿瘤分子生物学研究和 有效特异性靶向治疗发展的重大发现，根据患者 基因型的肿瘤个体化治疗已在临床实践中成为可 能[1]。这种基因型特异性抗肿瘤治疗方法有很多， 比如BCR-ABL靶向治疗慢性粒细胞白血病，C-KIT 抑制剂治疗胃肠道间质瘤，KRAS在EGFR抑制剂 无反应的结肠癌中的应用，乳腺癌的HER2导向治 疗以及BRAF抑制剂治疗黑色素瘤[2-13]。其他一些 治疗方案正在临床研究中，这将在不久的将来有 可能拓宽基因个体化治疗的这个范围。

1148 POSTER DAB2 Interactive Protein (DAB2IP) Methylation in Serum DNA of Non-Small-Cell Lung Cancer (NSCLC) Patients (p) With Epidermal Growth Factor Receptor (EGFR) Mutations

7593 Background: DAB2IP loss promotes primary tumor growth by activating Ras and drives metastasis through NFkB, serving as a signaling scaffold to coordinately regulate these pathways. DAB2IP is frequently methylated in lung cancer, and methylation in the m2a region is a key regulatory factor for DAB2IP expression in prostate cancer. We examined DAB2IP methylation in cell lines and in serum from erlotinib-treated NSCLC p with EGFR mutations. METHODS In human lung, breast and colorectal cancer cell lines, we analyzed DAB2IP promoter methylation in regions m2a and m2b by methylation-specific PCR (MSP) and bisulfite genomic sequencing. In circulating serum DNA from 152 erlotinib-treated NSCLC p with EGFR mutations, we analyzed methylation in the m2a and m2b promoter regions of DAB2IP by MSP. Methylation status was correlated with clinical outcome. RESULTS Methylation was detected in the m2a region of 42 (27.63%) p, and in the m2b region in 51 (33.55%) p. There were no major differences in clinical characteristics (age, gender, smoking history, EGFR mutation type, metastatic sites) between p with methylation in the m2a region and p with methylation in the m2b region. Overall progression-free survival (PFS) was 15 months (m), and median survival (MS) 28 m for all 152 p. For the 41 p with bone metastases (mets), PFS was 14 m for 30 p without methylation in the m2a region vs 8 m for 11 p with methylation in the m2a region (P=0.01), and MS was 23 m vs 10 m, respectively (P=0.19). For the 57 p with distant mets but no lung mets, PFS was 18 m for 36 p without methylation in the m2a region vs 10 m for 21 p with methylation in the m2a region (P=0.01), and MS was 24 m vs 16 m, respectively (P=0.03). No differences in either PFS or MS were observed according to the methylation status of the m2b region. CONCLUSIONS Methylation in the m2a region of DAB2IP in serum DNA correlates with PFS and MS to erlotinib in NSCLC p with EGFR mutations with non-lung mets. Surveillance of DAB2IP methylation status in circulating DNA could be a useful tool to predict outcome to erlotinib in EGFR-mutated NSCLC p with non-lung mets.