H.S. Kim

Single monosomy as a relatively better survival factor in acute myeloid leukemia patients with monosomal karyotype.

Monosomal karyotype (MK) defined by either ⩾2 autosomal monosomies or single monosomy with at least one additional structural chromosomal abnormality is associated with a dismal prognosis in patients with acute myeloid leukemia (AML). It was detected in 174 of 3041 AML patients in South Korean Registry. A total of 119 patients who had received induction therapy were finally analyzed to evaluate the predictive factors for a positive prognosis. On multivariate analysis, single monosomy, the absence of abn(17p), ⩾10% of cells with normal metaphase and the achievement of a complete remission (CR) after induction therapy were significant factors for more favorable outcomes. Especially, single monosomy remained as a significantly independent prognostic factor for superior survival in both patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) in CR and who did not. Allo-HSCT in CR improved overall survival significantly only in patients with a single monosomy. Our results suggest that MK-AML may be biologically different according to the karyotypic subtype and that allo-HSCT in CR should be strongly recommended to patients with a single monosomy. For other patients, more prudent treatment strategies should be examined. Furthermore, the biological mechanism by which a single monosomy influences survival should be investigated.

WASH-IN RATE ON THE BASIS OF DYNAMIC CONTRAST-ENHANCED MR IMAGING: USEFULNESS FOR PROSTATE CANCER DETECTION AND LOCALISATION

Materials and Methods: In 53 patients, the wash-in rate was measured in the cancer area and in three normal areas (the peripheral zone, inner portion of the transitional zone, and outer portion of the transitional zone). On the basis of these data, parametric imaging was generated and then its accuracy for cancer detection and location was evaluated compared to that of T2-weighted imaging without the use of an endorectal coil. For that purpose the entire prostate was divided into 18 segments.

Abstract OT3-1-08: The PROCEED trial KCSG BR11-01: Phase III multicenter randomized open label study of irinotecan plus capecitabine versus capecitabine in patients previously treated with anthracycline and taxane for HER2 negative metastatic breast cancer

Background: Most patients with metastatic breast cancer (MBC) experience disease progression after being treated with an anthracycline or taxane. Irinotecan, a semisynthetic agent derived from the natural alkaloid camptothecin is metabolized to the active metabolite SN-38 which targets topoisomerase I leading to single and double strand DNA breaks. Irinotecan as a single agent demonstrated tumor activity with an objective response rate ranging from 5 to 23% in patients with MBC refractory to taxane and anthracycline. Irinotecan increased the activity of 5-FU, the active metabolite of capecitabine, and overcomes the negative effect of thymidylate synthase overexpression, which is the main target of an active metabolite of 5-FU. A phase II study that evaluated the efficacy and safety of irinotecan and capecitabin combination (IX) showed that the median progression free survival (PFS) was 7.6 months (95% CI, 5.0-10.2months), and the median OS was 22.6 months (95% CI, 15.4 – 29.8 months) with good tolerability in anthracycline and taxane pretreated MBC patients. Based on these results, we planned to conduct a multicenter, randomized phase III study which assesses the efficacy of irinotecan and capecitabine combination therapy compared with capecitabine alone in patients with anthracycline and taxane resistant MBC. Methods: In this trial, patients with HER2 normal tumor who previously received anthracycline and taxane based chemotherapies are enrolled. Eligible patients are randomly assigned in a 1:1 ratio to receive irinotecan plus capecitabine or capecitabine alone. The primary end point of this trial is PFS and a total number of accrual patients will be 222. Randomization is done using a random block size permutation method and stratified by hormone receptor status (negative vs. positive), first line vs. ≥second lines, visceral metastasis (negative vs. positive). Patients receive irinotecan at 80 mg/m2 on day 1 and 8 every 3 weeks and capecitabine 1000mg/m2 bid from day 1 to day 14 every 3 weeks. In control arm, patients receive capecitabine 1250mg/m2 bid from day 1 to day 14 every 3 weeks. Response will be assessed using RECIST1.1 criteria and toxicity will be graded according to NCI-CTCAE 4.0 criteria. Study Status: A total of 107 patients consented for the study since June 2011, and accrual is ongoing. Clinical trial information: NCT01501669. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-08.

P3-14-03: ABCB1 Single Nucleotide Polymorphismas a Possible Prognostic Factor in Breast Cancer Patients Receiving Docetaxel and Doxorubicin Neoadjuvant Chemotherapy on Systemic Treatment.

Background Expression of the adenosine triphosphate-binding cassette B1 (ABCB1) transporter and P-glycoprotein are associated with resistance to anticancer drugs. The purpose of this thesis was to investigate the role of single nucleotide polymorphism (SNP) in the ABCB1 and CYP3A genes in breast cancer patients who were treated with neoadjuvant docetaxel and doxorubicin chemotherapy. Material and Methods : Patients with histologically confirmed breast cancer, Stage II or III, referred for neoadjuvant chemotherapy were enrolled. Patients were treated with 3 cycles of neoadjuvant and adjuvant chemotherapy with docetaxel and doxorubicin. The polymorphisms of ABCB1 (C3435T, G2677T/A, and C1236T) were genotyped by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) assays. The genotyping of CYP3A was done by the GoldenGate assay (Illumina Inc). The correlation of genetic polymorphisms of ABCB1, CYP3A, and clinical outcomes was analyzed. Results : A total of 216 patients were enrolled, and the median age was 44 years (range 25–69 years). The overall radiological response rate (RR) was 76.8% while 8.3% of the patients achieved a pathologically complete response. After a follow-up duration of 48.8 months, the median relapse-free survival (RFS) and overall survival (OS) were not reached. ABCB1 3435TT genotype had a longer OS than CT/TT genotype ( p =0.045) and a trend toward a lower relapse rate (p=0.284) although it is statistically insignificant. With univariate analysis of the OS, good performance status (PS), invasive ductal carcinoma, initial operable stages, estrogen receptor (ER)-positive, non-triple negative, and the TT genotype of ABCB1 C3435T were associated with a lower risk of death. Multivariate analyses for the OS revealed that PS (HR 4.670, 95% CI=1.066−10.468; p =0.041), initial clinical stage (HR 3.198, CI=1.480−6.907; p =0.003), and triple negative phenotype (HR 3.091, 95% CI=1.245−6.570; p =0.004) were significantly associated with the OS. ABCB1 3435TT genotype was also associated with a lower risk of death with marginal significance not shown to be an independent prognostic factor (HR 0.295 95% CI=0.121−1.122; p =0.071). ABCB1 3435TT genotype had a higher AUC than CC/CT genotype for docetaxel with marginal significance ( p =0.054). These higher AUCs in the C3435TT genotype was associated with increased toxicities of neutropenia ( p =0.037) and diarrhea ( p =0.017). AA (*1/*1)/AG (*1/*3) genotypes of CYP3A5 had a higher AUC than GG (*3/*3) for docetaxel with statistical significance ( p =0.024). However, these higher AUCs of CYP3A5*1 allele carrier did not affect the survival and toxicities. Discussion : This study showed that the genetic polymorphism of ABCB1 C3435T might be associated with a longer OS and have predictive roles after the treatment with the neoadjuvant docetaxel/doxorubicin for stage II and III breast cancer. Our results also suggest that the prediction of docetaxel toxicity might be possible for ABCB1 C3435T polymorphism. Larger prospective studies as well as functional studies in human subjects are warranted. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-03.