- Email: [email protected]
0064 CYP2D6 pharmacogenetics stratifies tamoxifen treatment outcome
S34
Poster Session I. Predictive and prognostic factors
0063
Comparison of MammaPrint and TargetPrint results with clinical parameters in German patients (PATH) with early stage breast cancer
G. Kunz1 , T. Dimpfl2 , C. Jakisch3 , R. Buttner4 , F. de Snoo5 , O. Krijgsman6 , E. van Lienen7 , A. Glas6 , R. Bender8 . 1 Frauenklinik, St. Johannes Hospital Dortmund gGmbH, Dortmund, 2 IBZ Brustzentrum, Klinikum Kassel GmbH, Kassel, 3 Frauenklinik, Klinikum Offenbach ¨ ¨ Pathologie, Universitatsklinikum Bonn, GmbH, Offenbach, 4 Institut fur Bonn, Germany, 5 Medical Affairs, 6 Bioinformatics, 7 Project management, Agendia, Amsterdam, Netherlands, 8 Medical Affairs, Agendia, Huntington Beach, USA Goals: The 70-gene tumor expression profile “MammaPrint” was established as a powerful predictor of disease outcome in breast cancer patients. Also, a microarray based test called TargetPrint was developed as an objective and more quantitative assessment of tumor receptor status than IHC alone. TargetPrint measures the mRNA expression level of ER, PR and HER2. This study was performed as a validation of MammaPrint and TargetPrint in a German breast cancer population and to determine the degree of concordance with currently applied clinical measures. Methods: Frozen tumor samples were collected by ‘Patients Tumor bank of Hope’ (PATH), a German tumor bank, initiated by breast cancer patients. Patients were diagnosed with breast cancer stage I and II between November 2005 and April 2008 in Breast Centers in Germany. Frozen tumor samples from 140 patients were classified as being either good or poor prognosis signature by MammaPrint (at low or high risk for developing distant metastasis) and compared to actual adjuvant treatment management. Next, we compared IHC and fluorescent in situ hybridization (FISH) assessments of ER, PR and HER2 with gene expression readouts using TargetPrint. Results: Comparison of microarray receptor results with IHC/FISH performed at the local hospitals in Germany indicated highly similar results with a concordance of 97% for ER; 86% for PR; and 94% for HER2. Of 59 MammaPrint poor prognosis patients, 40 did not receive chemotherapy and are potentially undertreated; whereas 42 out of 77 good signature prognosis patients received chemotherapy and are potentially over treated. Conclusion: MammaPrint has been validated in multiple breast cancer populations and has been shown to provide improved prediction of recurrence risk than currently used guidelines. MammaPrint validates in this German study population and would have resulted in altered treatment advice in 60% of patients. TargetPrint shows high concordance for hormone and Her2 with IHC.
0064
CYP2D6 pharmacogenetics stratifies tamoxifen treatment outcome
W. Schroth1 , M.P. Goetz2 , U. Hamann1 , P.A. Fasching1 , M. Schmidt1 , S. Winter1 , P. Fritz1 , V.J. Suman2 , M.M. Ames2 , W. Simon1 , H. Ulmer1 , 1 , R. Strick1 , M.W. Beckmann1 , H. Kolbl ¨ 1 , J. Black2 , R. Avila2 , J. Bolander ¨ R. Weinshilboum2 , J.N. Ingle2 , M. Eichelbaum1 , M. Schwab3 , H. Brauch1 . 1 Dr. Margarete Fischer-Bosch Inst of Clinical Pharmacology, and University Tubingen, ¨ Stuttgart, Germany, 2 Dept of Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA, 3 Dr. Margarete Fischer-Bosch Inst of Clinical Pharmacology Stuttgart, Dept of Clin Pharmacology, University Hospital Tubingen, ¨ Stuttgart, Germany Goals: Tamoxifen has been attributed lower efficacy than aromatase inhibitors (AI) in postmenopausal hormone-receptor-positive breast cancer treatment. Genetically impaired CYP2D6 function has been shown to impact plasma levels of active tamoxifen metabolites and clinical outcome. We investigated effects of CYP2D6 genetic variants on tamoxifen efficacy in a sufficiently powered pharmacogenetic study to validate previous findings. Methods: A total of 1361 patients from 4 German hospitals and US NCCTG 89−30−52 trial were investigated. Median follow-up was 6.3 years and 95.4% were known to be postmenopausal. Inclusion criteria were adjuvant tamoxifen without chemotherapy, hormone receptor positivity, and no metastatic disease at diagnosis. DNA from tumor tissues or blood (N = 1325) was genotyped for CYP2D6 variants *3, *4, *5, *10, and *41 using Taqman real time quantitation and mass spectrometry. Results: Patients homozygous for non-functional CYP2D6 alleles *3, *4, and *5, predictive for poor metabolizer (PM) phenotype, had a higher recurrence risk (HR = 1.90, 95 CI 1.10−3.28; P = 0.022) than patients predicted
Thursday, 12 March 2009 to be extensive metabolizers (EM). The rate of recurrence at 9 years was 14.9% for EM, 20.7% for heterozygous variant carriers or intermediate metabolizer, and 28.3% for PM patients suggesting an allele-dose dependent impact. Decreased CYP2D6 activity was associated with worse event-free survival (HR = 1.33, 95 CI 1.06−1.68; P = 0.014) and disease-free survival (HR = 1.29, 95 CI 1.03−1.61; P = 0.024). Conclusion: Patients with unaffected CYP2D6 function, which make up 46% of all patients, have a maximum benefit from tamoxifen. This is superior to the outcome in patients unselected by genotype. Patients predicted for a lack of CYP2D6 metabolic capacity cannot benefit from tamoxifen and should be considered for alternative adjuvant endocrine therapy ab initio. WS and MPG contributed equally
0065
Predictive factors for response to fulvestrant − the impact of prior endocrine response on treatment outcome
W. Gradishar1 , J. Lindemann2 . 1 Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, USA, 2 Clinical Development, AstraZeneca, Macclesfield, United Kingdom Goals: It has previously been hypothesized that response to prior endocrine therapy (ET) may be a better indicator of potential responsiveness to subsequent endocrine treatment than hormone receptor (HR) status. A retrospective analysis of the second-line, ET-responsive patient subgroup from the Evaluation of Faslodex vs Exemestane Clinical Trial (EFECT) was supportive of this hypothesis for fulvestrant. A retrospective analysis of clinical trial and compassionate use program (CUP) data was conducted to further investigate which patients are more likely to respond to fulvestrant. Methods: Data were available from the CUP as well as from Phase II (Trials 004 and 0−15−22) and randomized Phase III trials of fulvestrant (Trials 0020 and 0021 [fulvestrant vs anastrozole post-anti-estrogen] and EFECT (fulvestrant vs exemestane post-non-steroidal aromatase inhibitor). ET-responsive patients were defined as those remaining disease-free on adjuvant ET for 2 years or progression-free for 6 months in the advanced setting. Outcome measures were: time to progression (TTP) and clinical benefit (CB [complete or partial response or stable disease lasting 6 months]). Results: Potential predictive factors for response to fulvestrant were identified from analysis of data from Trials 0020 and 0021: WHO performance status 1 (p = 0.0004); HR+ status (p < 0.0001); and response to prior ET (p = 0.0272). ET-responsive patients appeared to achieve longer TTP with fulvestrant than those who were not responsive to prior ET. Two earlier second-line trials (004 and 0−15−22) including only ET-responsive patients also showed high CB rates (60−69%) for fulvestrant. Data from the CUP indicated that fulvestrant-treated patients who achieved CB from their last ET more frequently achieved CB on fulvestrant (38.2%) compared with those who did not (29%). Retrospective analysis of CUP and clinical trial data also suggested that higher CB rates are achieved when fulvestrant is used earlier rather than later in the treatment sequence. Conclusion: A prior response to ET confers a greater likelihood of CB with fulvestrant treatment. Higher CB rates are achieved with fulvestrant when it is used earlier in the treatment sequence.
0066
Tailored adjuvant therapy for young women with breast cancer
M. Yoshida1 , C. Shimizu1 , T. Kinoshita1 , Y. Fujiwara1 . 1 Breast Cancer Division, National Cancer Center Hospital, Tokyo, Japan Goals: The current guideline according to risk categories of St. Gallen Consensus recommends consideration of adjuvant chemotherapy for the majority of young women with breast cancer. The objective of this study was to identify prognostic factors of recurrence and death and to assess the adequacy of applying adjuvant chemotherapy in young patients. Methods: All patients with invasive breast cancer aged under 40 at the time of diagnosis, who underwent surgical resection at our institution between 1990 and 2004 were identified from the database of National Cancer Center Hospital. The log-rank test and multivariate Cox regression analysis were used to determine clinicopathological factors associated with DFS and OS. Results: Of 222 patients, forty-two percent were under 35. In 22%, family history was noted. Pathological findings showed T1:T2:T3 (36:50:14%),
Poster Session I. Predictive and prognostic factors
0063
Comparison of MammaPrint and TargetPrint results with clinical parameters in German patients (PATH) with early stage breast cancer
G. Kunz1 , T. Dimpfl2 , C. Jakisch3 , R. Buttner4 , F. de Snoo5 , O. Krijgsman6 , E. van Lienen7 , A. Glas6 , R. Bender8 . 1 Frauenklinik, St. Johannes Hospital Dortmund gGmbH, Dortmund, 2 IBZ Brustzentrum, Klinikum Kassel GmbH, Kassel, 3 Frauenklinik, Klinikum Offenbach ¨ ¨ Pathologie, Universitatsklinikum Bonn, GmbH, Offenbach, 4 Institut fur Bonn, Germany, 5 Medical Affairs, 6 Bioinformatics, 7 Project management, Agendia, Amsterdam, Netherlands, 8 Medical Affairs, Agendia, Huntington Beach, USA Goals: The 70-gene tumor expression profile “MammaPrint” was established as a powerful predictor of disease outcome in breast cancer patients. Also, a microarray based test called TargetPrint was developed as an objective and more quantitative assessment of tumor receptor status than IHC alone. TargetPrint measures the mRNA expression level of ER, PR and HER2. This study was performed as a validation of MammaPrint and TargetPrint in a German breast cancer population and to determine the degree of concordance with currently applied clinical measures. Methods: Frozen tumor samples were collected by ‘Patients Tumor bank of Hope’ (PATH), a German tumor bank, initiated by breast cancer patients. Patients were diagnosed with breast cancer stage I and II between November 2005 and April 2008 in Breast Centers in Germany. Frozen tumor samples from 140 patients were classified as being either good or poor prognosis signature by MammaPrint (at low or high risk for developing distant metastasis) and compared to actual adjuvant treatment management. Next, we compared IHC and fluorescent in situ hybridization (FISH) assessments of ER, PR and HER2 with gene expression readouts using TargetPrint. Results: Comparison of microarray receptor results with IHC/FISH performed at the local hospitals in Germany indicated highly similar results with a concordance of 97% for ER; 86% for PR; and 94% for HER2. Of 59 MammaPrint poor prognosis patients, 40 did not receive chemotherapy and are potentially undertreated; whereas 42 out of 77 good signature prognosis patients received chemotherapy and are potentially over treated. Conclusion: MammaPrint has been validated in multiple breast cancer populations and has been shown to provide improved prediction of recurrence risk than currently used guidelines. MammaPrint validates in this German study population and would have resulted in altered treatment advice in 60% of patients. TargetPrint shows high concordance for hormone and Her2 with IHC.
0064
CYP2D6 pharmacogenetics stratifies tamoxifen treatment outcome
W. Schroth1 , M.P. Goetz2 , U. Hamann1 , P.A. Fasching1 , M. Schmidt1 , S. Winter1 , P. Fritz1 , V.J. Suman2 , M.M. Ames2 , W. Simon1 , H. Ulmer1 , 1 , R. Strick1 , M.W. Beckmann1 , H. Kolbl ¨ 1 , J. Black2 , R. Avila2 , J. Bolander ¨ R. Weinshilboum2 , J.N. Ingle2 , M. Eichelbaum1 , M. Schwab3 , H. Brauch1 . 1 Dr. Margarete Fischer-Bosch Inst of Clinical Pharmacology, and University Tubingen, ¨ Stuttgart, Germany, 2 Dept of Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA, 3 Dr. Margarete Fischer-Bosch Inst of Clinical Pharmacology Stuttgart, Dept of Clin Pharmacology, University Hospital Tubingen, ¨ Stuttgart, Germany Goals: Tamoxifen has been attributed lower efficacy than aromatase inhibitors (AI) in postmenopausal hormone-receptor-positive breast cancer treatment. Genetically impaired CYP2D6 function has been shown to impact plasma levels of active tamoxifen metabolites and clinical outcome. We investigated effects of CYP2D6 genetic variants on tamoxifen efficacy in a sufficiently powered pharmacogenetic study to validate previous findings. Methods: A total of 1361 patients from 4 German hospitals and US NCCTG 89−30−52 trial were investigated. Median follow-up was 6.3 years and 95.4% were known to be postmenopausal. Inclusion criteria were adjuvant tamoxifen without chemotherapy, hormone receptor positivity, and no metastatic disease at diagnosis. DNA from tumor tissues or blood (N = 1325) was genotyped for CYP2D6 variants *3, *4, *5, *10, and *41 using Taqman real time quantitation and mass spectrometry. Results: Patients homozygous for non-functional CYP2D6 alleles *3, *4, and *5, predictive for poor metabolizer (PM) phenotype, had a higher recurrence risk (HR = 1.90, 95 CI 1.10−3.28; P = 0.022) than patients predicted
Thursday, 12 March 2009 to be extensive metabolizers (EM). The rate of recurrence at 9 years was 14.9% for EM, 20.7% for heterozygous variant carriers or intermediate metabolizer, and 28.3% for PM patients suggesting an allele-dose dependent impact. Decreased CYP2D6 activity was associated with worse event-free survival (HR = 1.33, 95 CI 1.06−1.68; P = 0.014) and disease-free survival (HR = 1.29, 95 CI 1.03−1.61; P = 0.024). Conclusion: Patients with unaffected CYP2D6 function, which make up 46% of all patients, have a maximum benefit from tamoxifen. This is superior to the outcome in patients unselected by genotype. Patients predicted for a lack of CYP2D6 metabolic capacity cannot benefit from tamoxifen and should be considered for alternative adjuvant endocrine therapy ab initio. WS and MPG contributed equally
0065
Predictive factors for response to fulvestrant − the impact of prior endocrine response on treatment outcome
W. Gradishar1 , J. Lindemann2 . 1 Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, USA, 2 Clinical Development, AstraZeneca, Macclesfield, United Kingdom Goals: It has previously been hypothesized that response to prior endocrine therapy (ET) may be a better indicator of potential responsiveness to subsequent endocrine treatment than hormone receptor (HR) status. A retrospective analysis of the second-line, ET-responsive patient subgroup from the Evaluation of Faslodex vs Exemestane Clinical Trial (EFECT) was supportive of this hypothesis for fulvestrant. A retrospective analysis of clinical trial and compassionate use program (CUP) data was conducted to further investigate which patients are more likely to respond to fulvestrant. Methods: Data were available from the CUP as well as from Phase II (Trials 004 and 0−15−22) and randomized Phase III trials of fulvestrant (Trials 0020 and 0021 [fulvestrant vs anastrozole post-anti-estrogen] and EFECT (fulvestrant vs exemestane post-non-steroidal aromatase inhibitor). ET-responsive patients were defined as those remaining disease-free on adjuvant ET for 2 years or progression-free for 6 months in the advanced setting. Outcome measures were: time to progression (TTP) and clinical benefit (CB [complete or partial response or stable disease lasting 6 months]). Results: Potential predictive factors for response to fulvestrant were identified from analysis of data from Trials 0020 and 0021: WHO performance status 1 (p = 0.0004); HR+ status (p < 0.0001); and response to prior ET (p = 0.0272). ET-responsive patients appeared to achieve longer TTP with fulvestrant than those who were not responsive to prior ET. Two earlier second-line trials (004 and 0−15−22) including only ET-responsive patients also showed high CB rates (60−69%) for fulvestrant. Data from the CUP indicated that fulvestrant-treated patients who achieved CB from their last ET more frequently achieved CB on fulvestrant (38.2%) compared with those who did not (29%). Retrospective analysis of CUP and clinical trial data also suggested that higher CB rates are achieved when fulvestrant is used earlier rather than later in the treatment sequence. Conclusion: A prior response to ET confers a greater likelihood of CB with fulvestrant treatment. Higher CB rates are achieved with fulvestrant when it is used earlier in the treatment sequence.
0066
Tailored adjuvant therapy for young women with breast cancer
M. Yoshida1 , C. Shimizu1 , T. Kinoshita1 , Y. Fujiwara1 . 1 Breast Cancer Division, National Cancer Center Hospital, Tokyo, Japan Goals: The current guideline according to risk categories of St. Gallen Consensus recommends consideration of adjuvant chemotherapy for the majority of young women with breast cancer. The objective of this study was to identify prognostic factors of recurrence and death and to assess the adequacy of applying adjuvant chemotherapy in young patients. Methods: All patients with invasive breast cancer aged under 40 at the time of diagnosis, who underwent surgical resection at our institution between 1990 and 2004 were identified from the database of National Cancer Center Hospital. The log-rank test and multivariate Cox regression analysis were used to determine clinicopathological factors associated with DFS and OS. Results: Of 222 patients, forty-two percent were under 35. In 22%, family history was noted. Pathological findings showed T1:T2:T3 (36:50:14%),