유방암에서 EGFR/HER2 Tyrosine Kinase 억제제인 Lapatinib에 대한 반응 및 내성에 관한 연구

Lapatinib is a dual tyrosine kinase inhibitor of EGFR and HER2. Lapatinib plus capecitabine is an effective treatment option in trastuzumab-refractory HER2-Positive (+) metastatic breast cancer. However, not all patients benefit from the treatment and patients who benefit eventually develop acquired resistance to the treatment. In order to identify optimal patients for the treatment and elucidate mechanism of resistance, 1) tumor specimen for biomarker identification predicting treatment outcome, and 2) in vitro acquired resistance model were investigated. Total HER2 (H2T), p95HER2 (p95), and total HER3 (H3T) expression were quantified in formalin-fixed paraffin-embedded samples using the VeraTag assay and correlations with treatment outcomes of lapatinib and capecitabine in HER2+, trastuzumab-refractory metastatic breast cancer patients were analyzed. SK-BR-3 cell line, which is a HER2-positive lapatinib-sensitive breast cancer cell line, was continuously exposed to lapatinib and lapatinib-resistant (LR) cell line was generated. Various representative targeted agents of key signaling pathways were tested in addition to lapatinib to test inhibition of which pathway could restore the sensitivity to lapatinib in the LR cell line. A total of 52 patients were evaluable for protein expression and clinical outcome. H2T level was significantly higher in responders (median 93.49 in partial response, 47.66 in stable disease, and 17.27 in progressive disease p = 0.020). Longer time-to-progression (TTP) was observed in patients with high H2T [p = 0.018, median 5.2 months in high (>14.95) vs. 1.8 in low (0.605) vs. 2.2 in low (<0.605)]. Patients having both high H2T and high H3T had significantly longer TTP [adjusted hazard ratio (HR) 0.38 (95% CI 0.20 – 0.73), p = 0.004] and overall survival [adjusted HR 0.46 (95% CI 0.24 – 0.89), p = 0.020]. No significant association between p95 and response or survival was observed. SK-BR-3 cell line, which is a HER2-positive lapatinib-sensitive breast cancer cell line, was continuously exposed to lapatinib. The IC50 value of lapatinib in the LR cells was 3.03 uM compared to 0.13 of the parental cells. Lapatinib was unable to inhibit p-STAT3 expression and p-Akt expression was only partly inhibited in the LR cell line. Among the various agents tested, NVP-BEZ235, a dual inhibitor of PI3K and mTOR, inhibited the persistent PI3K/Akt/mTOR pathway activation in the LR cell line and restored sensitivity to lapatinib. In conclusion, overexpression of HER2 and HER3 is associated with sensitivity to lapatinib, whereas persistent PI3K/Akt/mTOR pathway activation can lead to acquired resistance.Docto

Gefitinib을 투여 받은 비소세포폐암 환자에서 EGFR 돌연변이의 의의

Thesis(master`s)--서울대학교 대학원 :의학과 분자종양의학전공,2005.Maste

The Impact of Primary Tumor Resection on the Survival of Patients with Stage IV Breast Cancer

Purpose The main treatment for stage IV breast cancer is currently systemic therapy. Surgical resection of the primary tumor is usually done for treating the tumor-related complications Recent studies have suggested that surgery may improve the long-term survival of stage IV breast cancer patients We evaluated the impact of the primary surgical resection site on the survival of stage IV breast cancer patients. Methods We reviewed the records of the stage IV breast cancer patients who were treated at Seoul University Hospital between April 1992 and December 2007 The tumor and clinical characteristics, the type of treatments and the overall survival were compared between the surgically versus nonsurgically treated patients. Results. Of the 198 identified patients, 110 (55 8%) received surgical excision of their primary tumor and 88 (44 2%) did not The mean survival was 67 months vs. 42 months for the surgically treated patients vs the patients without surgery, respectively (p=0 0287) On a multivariate analysis with using the Cox model and after adjusting for the estrogen receptor status, visceral metastases, the number of metastatic sites and trastuzumab treatment, surgery was an independent factor for improved survival (hazard ratio, 0.55; 95% confidence interval, 0.31-0.97; p=0.041). Conclusion Surgical resection of the primary tumor in stage IV breast cancer patients was independently associated with improved survival. Randomized prospective trials are needed to firmly recommend surgical resection of the primary tumor in stage IV breast cancer patients본 연구는 폐암, 유방암/난소암 유전체 연구센터의 연구비를 지원받아 수행 되었음(01-PJ3-PG6-01GN07-0004).Bafford AC, 2009, BREAST CANCER RES TR, V115, P7, DOI 10.1007/s10549-008-0101-7Blanchard DK, 2008, ANN SURG, V247, P732, DOI 10.1097/SLA.0b013e3181656d32*KOR BREAST CANC S, 2008, BREAST CANC FACTS FI, V1, P5Fields RC, 2007, ANN SURG ONCOL, V14, P3345, DOI 10.1245/s10434-007-9527-0Gnerlich J, 2007, ANN SURG ONCOL, V14, P2187, DOI 10.1245/s10434-007-9438-0Rapiti E, 2006, J CLIN ONCOL, V24, P2743, DOI 10.1200/JCO.2005.04.2226Morrow M, 2006, J CLIN ONCOL, V24, P2694, DOI 10.1200/JCO.2006.05.9824Babiera GV, 2006, ANN SURG ONCOL, V13, P776, DOI 10.1245/ASO.2006.03.033Hotta T, 2006, ANTICANCER RES, V26, P1377Abe O, 2005, LANCET, V366, P2087Andre F, 2004, J CLIN ONCOL, V22, P3302, DOI 10.1200/JCO.2004.08.095Giordano SH, 2004, CANCER, V100, P44, DOI 10.1002/cncr.11859Khan SA, 2002, SURGERY, V132, P620, DOI 10.1067/msy.2002.127544Flanigan RC, 2001, NEW ENGL J MED, V345, P1655Demicheli R, 2001, BRIT J CANCER, V85, P490Dauplat J, 2000, SEMIN SURG ONCOL, V19, P42Overgaard M, 1999, SEMIN RADIAT ONCOL, V9, P292DOGHETTO GB, 1999, AM SURGEON, V65, P352BLAND KI, 1998, BREAST COMPREHENSIVE, V2Ragaz J, 1997, NEW ENGL J MED, V337, P956OREILLY MS, 1994, CELL, V79, P315FISHER B, 1989, CANCER RES, V49, P1996*NAT CANC I, BREAST CANC TREATM P