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Metabolite-guided vs CYP2D6 genotype-guided long-term prediction of outcome in breast cancer patients treated adjuvantly with tamoxifen
15th St.Gallen International Breast Cancer Conference / The Breast 32S1 (2017) S22–S77
presentation. Age, clinical staging, ER status, BRCA1/2 mutation status, tamoxifen use, recurrence (local, regional and distant) as well as mortality were noted. CYP2D6 genotyping was performed using DNA extracted from whole blood. Results: From the 86 samples available for the study, 2 patients had unknown ethnicity and were excluded. Of the 84 patients, 53 (63.1%) were found to have ER-positive disease. 44/53 patients were confirmed to be on tamoxifen. The CYP2D6*3/*4/*5 alleles were detected in 10 of the 44 patients on tamoxifen. Within this group with ER-positive disease on tamoxifen, follow-up over 10 years showed a trend towards poorer outcomes with regards to both recurrence (HR 1.4) and overall survival (HR 2.2) in those with the CYP2D6*3/*4/*5 alleles. Conclusion: The trends observed in a small subgroup of ER-positive breast cancer patients corresponded with the expected poorer clinical outcomes in tamoxifen-treated patients with CYP2D6 variants. Small sample size, poor follow-up data beyond 3 years and genotyping of only three CYP2D6 variants were important limiting factors in achieving adequate statistical power. National combined databases are warranted for monitoring of clinical outcome in breast cancer patients subjected to comprehensive pharmacogenetic analysis. Disclosure of Interest: No significant relationships. P004 Patient-reported assessment and objective assessment of edema among breast cancer patients receiving docetaxel plus cyclophosphamide (TC) M. Hattori*, K. Sugino, A. Yoshimura, M. Sawaki, J. Ishiguro, N. Gondo, H. Kotani, A. Kataoka, S. Oonishi, H. Iwata. Department of Breast Oncology, Aichi Cancer Center, Nagoya, Japan Aims: To investigate the time course and severity of edema by using both subjective and objective outcome measures among breast cancer patients receiving 4 cycles of docetaxel and cyclophosphamide (TC) every 3 weeks as adjuvant therapy. Methods: The incidence and severity of edema was prospectively evaluated at each cycle of TC at 4 and 12 weeks after TC using CTCAE and the ratio of extracellular water (ECW) to total body water (TBW) measured by multi-frequency bioelectrical impedance analysis. Patient’s quality of life was assessed using Functional Assessment of Cancer Therapy-taxane (FACT-T) scale scores at the same time points. We also evaluated the scores of FACT-T items regarding edema as indicators of patient-reported assessment of edema. Results: Between July 2015 and September 2016, 26 patients were enrolled in this study. Of 26 patients, three did not complete 4 cycles of TC due to allergy (n = 2) and infection (n = 1), leaving 23 patients for the analysis. The incidence of edema assessed by CTCAE and ECW/ TBW ratio increased from cycle 3, markedly at 4 weeks after TC, and decreased, but was still higher than at baseline level at 12 weeks after TC. Grade 2 and higher arm edema occurred in 4 patients (17%) and leg edema in 2 patients (8%). All four patients with grade 2 and higher arm edema had undergone axillary lymph node dissection. The scores of FACT-T items (Tax1, Tax2 and Tax3) started to decrease in cycle 2, markedly at 4 weeks after TC, and increased but were still lower than at baseline level at 12 weeks after TC. The mean Tax2 scores (edema of hands) were relatively better than the scores of Tax1 (anasarca) and Tax 3 (edema of legs and feet). Conclusions: There was no apparent discordance in the time course of TC-induced edema between patient-reported assessment and objective assessment. In both subjective and objective assessment, TC-induced edema had markedly worsened at 4 weeks after TC, and although improving at 12 weeks, was still present. Disclosure of Interest: No significant relationships.
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P005 Metabolite-guided vs CYP2D6 genotype-guided long-term prediction of outcome in breast cancer patients treated adjuvantly with tamoxifen T. Helland1 *, N. Henne2,3, B. Naume4,7, E. Borgen5, V. Kristensen9, S. Hustad2,3, E. Janssen6,8, E. Lien1,2, G. Mellgren1,2, H. Soiland2,10. 1 Hormone Laboratory, Haukeland University Hospital, Bergen, Norway, 2 Department of Clinical Science, University of Bergen, Bergen, Norway, 3 Core Facility of Metabolomics, University of Bergen, Bergen, Norway, 4 Department of Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway, 5Pathology Department, Radium Hospital, Oslo University Hospital, Oslo, Norway, 6Department of Pathology, Stavanger University Hospital, Stavanger, Norway, 7Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway, 8Department of Mathematics and Natural Science, University of Stavanger, Oslo, Norway, 9 Department of Genetics, Institute for Cancer Research, Radium Hospital, Oslo University Hospital, Oslo, Norway, 10Department of Breast and Endocrine Surgery, Stavanger University Hospital Stavanger, Stavanger, Norway Aim: This retrospective observational study aims to investigate the predictive value of concentrations of active tamoxifen metabolites and CYP2D6 genotype on breast cancer outcome in 106 ER positive patients with a long-term follow-up. Method: From 1995 to 1998, 817 patients were included in an observational study and treated according to the national guidelines at the time [1]. Serum samples were drawn at 3-year follow-up from 356 relapse-free patients, 106 of these were treated with tamoxifen. The median follow up time for breast cancer death was 16.8 years (3.5–19.4). An LC-MS/MS method was developed to determine the concentration levels of the two active tamoxifen metabolites, endoxifen and 4OHtam. The method was validated according to FDA guidelines and can detect and quantify tamoxifen and 9 of its metabolites in human serum. Importantly, the method separates the inactive isomers of 4OHtam and endoxifen from its active isomers. CYP2D6 genotyping is being performed using an FDA approved Luminex test in which 16 allele variants including duplications and deletions are analyzed. Results: The previously observed endoxifen level of 10 nM in poor metabolizers [2] was used as cut-off for the grouping of patients. Univariate survival analysis did not show a significant association between breast cancer specific survival and endoxifen levels. ( p = 0.15). However, for the period beyond 10-years of follow-up the breast cancer survival differed between the high endoxifen group (>10 nM) and the low endoxifen group (<10 nM). For patients surviving the first 10 years the breast cancer specific survival was 94.2% vs. 77.8% for the high endoxifen group and low endoxifen group, respectively ( p = 0.020, logrank and p = 0.017, Breslow, HR = 4.5, CI 95 = 1.1–17.9). In the multivariate analysis endoxifen ≤/>10 nM remained the only factor in the final model. The results on CYP2D6 genotyping is pending in the lab, but will arrive in time for the conference. Conclusion: Low concentrations of endoxifen are associated with worse long-term survival beyond 10 years. A comprehensive analysis addressing the relationship between genotyped based and metabolite based prediction of long-term outcome in tamoxifen treated breast cancer patients will be presented on the poster. References [1] Wiedswang G, et al. Clin Ca Res; 2004. [2] Mürdter TE, et al. Clin Pharmacol Ther; 2011. Disclosure of Interest: No significant relationships. P006 Clinicopathological factors and prognosis according to subtype in elderly breast cancer patients older than 75-years-old M. Ishida*, S. Akiyoshi, H. Ijichi, T. Masuda, J. Tanaka, Y. Nakamura, E. Tokunaga. National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
presentation. Age, clinical staging, ER status, BRCA1/2 mutation status, tamoxifen use, recurrence (local, regional and distant) as well as mortality were noted. CYP2D6 genotyping was performed using DNA extracted from whole blood. Results: From the 86 samples available for the study, 2 patients had unknown ethnicity and were excluded. Of the 84 patients, 53 (63.1%) were found to have ER-positive disease. 44/53 patients were confirmed to be on tamoxifen. The CYP2D6*3/*4/*5 alleles were detected in 10 of the 44 patients on tamoxifen. Within this group with ER-positive disease on tamoxifen, follow-up over 10 years showed a trend towards poorer outcomes with regards to both recurrence (HR 1.4) and overall survival (HR 2.2) in those with the CYP2D6*3/*4/*5 alleles. Conclusion: The trends observed in a small subgroup of ER-positive breast cancer patients corresponded with the expected poorer clinical outcomes in tamoxifen-treated patients with CYP2D6 variants. Small sample size, poor follow-up data beyond 3 years and genotyping of only three CYP2D6 variants were important limiting factors in achieving adequate statistical power. National combined databases are warranted for monitoring of clinical outcome in breast cancer patients subjected to comprehensive pharmacogenetic analysis. Disclosure of Interest: No significant relationships. P004 Patient-reported assessment and objective assessment of edema among breast cancer patients receiving docetaxel plus cyclophosphamide (TC) M. Hattori*, K. Sugino, A. Yoshimura, M. Sawaki, J. Ishiguro, N. Gondo, H. Kotani, A. Kataoka, S. Oonishi, H. Iwata. Department of Breast Oncology, Aichi Cancer Center, Nagoya, Japan Aims: To investigate the time course and severity of edema by using both subjective and objective outcome measures among breast cancer patients receiving 4 cycles of docetaxel and cyclophosphamide (TC) every 3 weeks as adjuvant therapy. Methods: The incidence and severity of edema was prospectively evaluated at each cycle of TC at 4 and 12 weeks after TC using CTCAE and the ratio of extracellular water (ECW) to total body water (TBW) measured by multi-frequency bioelectrical impedance analysis. Patient’s quality of life was assessed using Functional Assessment of Cancer Therapy-taxane (FACT-T) scale scores at the same time points. We also evaluated the scores of FACT-T items regarding edema as indicators of patient-reported assessment of edema. Results: Between July 2015 and September 2016, 26 patients were enrolled in this study. Of 26 patients, three did not complete 4 cycles of TC due to allergy (n = 2) and infection (n = 1), leaving 23 patients for the analysis. The incidence of edema assessed by CTCAE and ECW/ TBW ratio increased from cycle 3, markedly at 4 weeks after TC, and decreased, but was still higher than at baseline level at 12 weeks after TC. Grade 2 and higher arm edema occurred in 4 patients (17%) and leg edema in 2 patients (8%). All four patients with grade 2 and higher arm edema had undergone axillary lymph node dissection. The scores of FACT-T items (Tax1, Tax2 and Tax3) started to decrease in cycle 2, markedly at 4 weeks after TC, and increased but were still lower than at baseline level at 12 weeks after TC. The mean Tax2 scores (edema of hands) were relatively better than the scores of Tax1 (anasarca) and Tax 3 (edema of legs and feet). Conclusions: There was no apparent discordance in the time course of TC-induced edema between patient-reported assessment and objective assessment. In both subjective and objective assessment, TC-induced edema had markedly worsened at 4 weeks after TC, and although improving at 12 weeks, was still present. Disclosure of Interest: No significant relationships.
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P005 Metabolite-guided vs CYP2D6 genotype-guided long-term prediction of outcome in breast cancer patients treated adjuvantly with tamoxifen T. Helland1 *, N. Henne2,3, B. Naume4,7, E. Borgen5, V. Kristensen9, S. Hustad2,3, E. Janssen6,8, E. Lien1,2, G. Mellgren1,2, H. Soiland2,10. 1 Hormone Laboratory, Haukeland University Hospital, Bergen, Norway, 2 Department of Clinical Science, University of Bergen, Bergen, Norway, 3 Core Facility of Metabolomics, University of Bergen, Bergen, Norway, 4 Department of Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway, 5Pathology Department, Radium Hospital, Oslo University Hospital, Oslo, Norway, 6Department of Pathology, Stavanger University Hospital, Stavanger, Norway, 7Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway, 8Department of Mathematics and Natural Science, University of Stavanger, Oslo, Norway, 9 Department of Genetics, Institute for Cancer Research, Radium Hospital, Oslo University Hospital, Oslo, Norway, 10Department of Breast and Endocrine Surgery, Stavanger University Hospital Stavanger, Stavanger, Norway Aim: This retrospective observational study aims to investigate the predictive value of concentrations of active tamoxifen metabolites and CYP2D6 genotype on breast cancer outcome in 106 ER positive patients with a long-term follow-up. Method: From 1995 to 1998, 817 patients were included in an observational study and treated according to the national guidelines at the time [1]. Serum samples were drawn at 3-year follow-up from 356 relapse-free patients, 106 of these were treated with tamoxifen. The median follow up time for breast cancer death was 16.8 years (3.5–19.4). An LC-MS/MS method was developed to determine the concentration levels of the two active tamoxifen metabolites, endoxifen and 4OHtam. The method was validated according to FDA guidelines and can detect and quantify tamoxifen and 9 of its metabolites in human serum. Importantly, the method separates the inactive isomers of 4OHtam and endoxifen from its active isomers. CYP2D6 genotyping is being performed using an FDA approved Luminex test in which 16 allele variants including duplications and deletions are analyzed. Results: The previously observed endoxifen level of 10 nM in poor metabolizers [2] was used as cut-off for the grouping of patients. Univariate survival analysis did not show a significant association between breast cancer specific survival and endoxifen levels. ( p = 0.15). However, for the period beyond 10-years of follow-up the breast cancer survival differed between the high endoxifen group (>10 nM) and the low endoxifen group (<10 nM). For patients surviving the first 10 years the breast cancer specific survival was 94.2% vs. 77.8% for the high endoxifen group and low endoxifen group, respectively ( p = 0.020, logrank and p = 0.017, Breslow, HR = 4.5, CI 95 = 1.1–17.9). In the multivariate analysis endoxifen ≤/>10 nM remained the only factor in the final model. The results on CYP2D6 genotyping is pending in the lab, but will arrive in time for the conference. Conclusion: Low concentrations of endoxifen are associated with worse long-term survival beyond 10 years. A comprehensive analysis addressing the relationship between genotyped based and metabolite based prediction of long-term outcome in tamoxifen treated breast cancer patients will be presented on the poster. References [1] Wiedswang G, et al. Clin Ca Res; 2004. [2] Mürdter TE, et al. Clin Pharmacol Ther; 2011. Disclosure of Interest: No significant relationships. P006 Clinicopathological factors and prognosis according to subtype in elderly breast cancer patients older than 75-years-old M. Ishida*, S. Akiyoshi, H. Ijichi, T. Masuda, J. Tanaka, Y. Nakamura, E. Tokunaga. National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan