K-P. Kim

Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation

Non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation shows good and rapid response to EGFR tyrosine kinase inhibitors (TKIs). We prospectively evaluated the efficacy of EGFR TKI for metastatic brain tumors in NSCLC patients harboring EGFR mutation. This was an open-label, single-institution, phase II study. Patients diagnosed with NSCLC harboring EGFR mutation and measurable metastatic brain tumors were eligible. They received either erlotinib or gefitinib once a day. Out of total 28 patients enrolled, 23 patients (83%) showed a partial response (PR) and 3 patients (11%) did stable disease (SD), giving a disease control rate of 93%. Median progression free survival (PFS) and overall survival (OS) were 6.6 months (95% CI, 3.8-9.3 months) and 15.9 months (95% CI, 7.2-24.6 months), respectively. There was no difference in PFS and OS according to EGFR TKIs used. After discontinuation of the treatment, 14 patients (50%) received local therapy for metastatic brain tumors during their disease course, either whole brain radiotherapy or radiosurgery, giving a local therapy-free interval of 12.6 months (95% CI, 7.6-17.6 months). EGFR TKI therapy might be the treatment of choice for metastatic brain tumors in NSCLC patients harboring an activating EGFR mutation.

3′-Deoxy-3′-18F-Fluorothymidine PET for the Early Prediction of Response to Leucovorin, 5-Fluorouracil, and Oxaliplatin Therapy in Patients with Metastatic Colorectal Cancer

The aim of this study was to evaluate 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) PET for early prediction of the standard anatomic response and survival outcomes in patients with metastatic colorectal cancer (mCRC) receiving leucovorin, 5-fluorouracil (5-FU), and oxaliplatin (FOLFOX). Methods: The main eligibility criteria included histologically confirmed mCRC, ≥1 extrahepatic measurable lesions, and no prior chemotherapy in a metastatic setting. Chemotherapy consisted of leucovorin on day 1, followed by the continuous infusion of 5-FU on days 1 and 2, and oxaliplatin on day 3. In the second and subsequent cycles of chemotherapy, oxaliplatin was administered simultaneously with leucovorin on day 1. 18F-FLT PET scans were obtained 3 times during the first cycle of chemotherapy: before chemotherapy, 24 h after infusion of 5-FU (day 2), and 48 h after completion of chemotherapy (day 5). The maximum standardized uptake value (SUVMAX) of 18F-FLT was measured. Treatment responses were assessed by CT after 3 cycles of FOLFOX. Results: Eighteen patients were included in the study. The response rate after 3 cycles of FOLFOX was 27.8% (5/18). The SUVMAX was increased in responders (P = 0.043) and nonresponders (P < 0.001) on day 2 and was decreased, compared with baseline values, on day 5 in responders only (P = 0.043). Receiver-operating-characteristic curve analysis indicated that the use of a threshold of an SUVMAX increase on day 2 of ≤45.8% resulted in a sensitivity of 100%, specificity of 69.2%, and relative risk of 2.250 (P = 0.029) for the diagnosis of responders. Use of a threshold of an SUVMAX decrease on day 5 of ≥10.6% resulted in a sensitivity of 100%, specificity of 76.9%, and relative risk of 2.667 (P = 0.007). Patients with low 18F-FLT flare tended to have longer survivals than patients with high flare (2-y overall survival rate, 77.8% vs. 44.4%; P = 0.051). Conclusion: The 18F-FLT flare observed during 5-FU infusion was associated with poor treatment response in patients with mCRC. The degree of 18F-FLT flare might be used to predict the outcome of patients who receive infusional 5-FU–based chemotherapy.

Abstract P3-07-34: Predictive role of stromal tumor infiltrating lymphocytes (TILs) in patients with metastatic HER2-positive breast cancer (BC) treated with trastuzumab

Background: Prognostic significance of stromal TILs in metastatic BC has been suggested in various BC subtypes. However, predictive role of stromal TILs for the efficacy of trastuzumab has not been established in patients with HER2-positive BC. This study was performed to evaluate whether the stromal TILs are associated with the efficacy of trastuzumab in patients with metastatic HER2-positve BC. Method: Between June 2006 and March 2013, a total of 60 women with recurrent or metastatic HER2-positive BC treated with trastuzumab were included in this retrospective analysis. In these patients, trastuzumab was administered either as single agent or combination with taxanes. Stromal TILs were assessed using immunohistochemistry in surgical specimen (n=39, 65%) and biopsy specimen of metastatic lesion (n=21, 35%) by the academic pathologist (HJL). Primary endpoint of this study was progression-free survival (PFS), and secondary endpoints were response rate and overall survival (OS). Result: Median age was 54 year old (range, 36-76), and all patients had invasive ductal carcinoma. Hormone receptor was positive in 34 patients (57%) and 18 patients (30%) initially presented with metastatic disease. Nine patients (15%) received cytotoxic chemotherapy without trastuzumab before the administration of trastuzumab. Patients were grouped according to the TILs ( 10% [n=10]), and there was no significant difference in age (p=0.68), histologic grade (p=1.00), metastatic sites (p>0.05), and number of lines of chemotherapy before the administration of trastuzumab(p=0.33) among patients with low and high stromal TILs. High TILs were more common in hormone receptor (HR)-negative tumor compared with HR–positive tumor (31% vs 6%; p=0.02). In overall, median PFS and OS were 15.0 months (95% CI, 9.7-20.2) and 35.0 months (95% CI, 29.8-40.2), respectively. Median PFS in patients with high stromal TILs were numerically longer than that in those with low TILs (22.0 months [95% CI, 9.6-34.4] vs 14.0 months [95% CI, 9.6-18.4]; p=0.057). There was no difference in response rates (p=0.43) and OS (p=0.94) according to the stromal TILs. FcR genotype was not significantly correlated with objective response rate, PFS and OS. Conclusion: This study suggests that the stromal TILs might be associated with the clinical outcomes of HER2-targeted therapy in patients with metastatic HER2-positive BC. Our finding should be validated in future studies based on a large sample size. Keywords: Breast cancer, tumor infiltrating lymphocyte. Trastzumab, HER2. Citation Format: Yoon JA, Yoo C, Lee HJ, Kim K-P, Kim J, Ahn J-H, Jung KH, Gong G, Kim S-B. Predictive role of stromal tumor infiltrating lymphocytes (TILs) in patients with metastatic HER2-positive breast cancer (BC) treated with trastuzumab. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-34.

Abstract P3-15-03: Prospective Evaluation of the Drug-Metabolizing Enzyme Polymorphisms and Toxicity Profile of Docetaxel in Korean Patients with Early-Stage Breast Cancer Receiving Adjuvant Chemotherapy

Background Interindividual variability of pharmacokinetics may account for unpredictable toxicity of docetaxel. Pharmacogenetic analysis on the metabolic pathway of docetaxel has been performed in hopes of identifying predicting factors related to docetaxel-related toxicities. Methods From March 2007 to June 2008, female patients with early-stage breast cancer receiving docetaxel-containing adjuvant chemotherapy were included in this study. The 4 cycles of planned dose of docetaxel (100 mg/m2) was performed as adjuvant chemotherapy, following 4 cycles of adriamycin and cyclophosphamide. We evaluated toxicity profile of docetaxel according to the drug-metabolizing enzyme or transporter polymorphisms reported to affect the pharmacokinetics of docetaxel. The single nucleotide polymorphisms (SNPs) of CYP3A5 gene (6986 A>G), ABCB1 gene (1236 C>T, 3435 C>T, 2677 G>T(A)), ABCC2 gene (-24C>T, 1249 G>A, 3972 C>T, rs1276549) and SCLO1B3 gene (334 T>G, 699 G>A, rs11045585) were sequenced from individuals. Toxicities including neutropenia was evaluated for the 1st cycle of docetaxel and defined according to the NCI CTCAE version 3.0. Results Pharmacogenetic analysis was performed in 218 Korean women who had received the planned chemotherapy. With regard to ABCB1 3435 C>T, ABCB1 3435 T/T had significantly higher risks of neutropenia (P=0.015). Meanwhile, allele frequencies for CYP3A5 6986 G and ABCB1 3435 T revealed a trend for neutropenia (P=0.107 and 0.068). We could not find any other association between genotypes and other toxicities. Discussion Although ABCB1 3435 T/T was significantly associated with docetaxel-related neutropenia in our study population, polymorphism of pharmacogenetic genes related to docetaxel metabolism did not appear to be evidently associated with docetaxel-related adverse events. Further external validation of these genes may be required to allow them to enter clinical practice. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-15-03.