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Melatonin and metformin in neoadjuvant chemotherapy in locally advanced breast cancer
abstracts
295P
Melatonin and metformin in neoadjuvant chemotherapy in locally advanced breast cancer
T.Y. Semiglazova1, M. Osipov2, P. Krivorotko3, V. Semiglazov3, S. Protsenko1, L. Berstein4, E. Tsirlina4, V. Klimenko1, R. Donskih5, V. Anisimov6, A. Belyaev7 1 Innovative Methods of Therapeutic Oncology and Rehabilitation, N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russian Federation, 2Innovative Methods of Therapeutic Oncology and Rehabilitation, Federal State Budget Institution "National Medical Research Center of Oncology na N.N. Petrov" Ministry of Healthcare of Russian Federation, St. Petersburg, Russian Federation, 3Breast Cancer Department, N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russian Federation, 4 Endocrinology, Federal State Budget Institution "National Medical Research Center of Oncology na N.N. Petrov" Ministry of Healthcare of Russian Federation, St. Petersburg, Russian Federation, 5Breast Cancer, Federal State Budget Institution "National Medical Research Center of Oncology na N.N. Petrov" Ministry of Healthcare of Russian Federation, St. Petersburg, Russian Federation, 6Cancerogenesis and Aging, Federal State Budget Institution "National Medical Research Center of Oncology na N.N. Petrov" Ministry of Healthcare of Russian Federation, St. Petersburg, Russian Federation, 7Federal State Budget Institution "National Medical Research Center of Oncology na N.N. Petrov" Ministry of Healthcare of Russian Federation, St. Petersburg, Russian Federation Background: According to in vitro/in vivo studies both melatonin (MLT) and metformin (MTF) may exhibit an antitumor effect. Furthermore, in accordance to epidemiological studies MTF reduces the risk of developing breast cancer (BC) among patients with diabetes mellitus; as well as “light at night”can inhibit endogenic MLT synthesis and increase risk of breast cancer. Thus, MLT and MTF need to be investigated in clinical oncology. Methods: A total of 53 patients with locally advanced BC (ER positive/HER2 negative 68%, ER positive/HER2 positive -25% and ER negative/HER2 negative -7%), were included in the study of MLT or MTF efficiency in combination with anthracyclin and taxan-containing neoadjuvant chemotherapy (NACT) (clinicalTrials.gov NCT02506777). The average patients’ age was 56 years. All patients had no history of diabetes mellitus. All patients were randomized into 3 groups. The first group (n ¼ 20) received NACT, the second one (n ¼ 21) received NACT in combination with 3 mg overnight dose of oral MLT, the third group (n ¼ 12) received NACT in combination with oral MTF (850 mg twice a day). For all patient groups the NACT duration was 6 cycles, then surgery was performed. Results: An objective response rate for three studied groups was 85%, 85.7% and 75% respectively. According to multivariate analysis of results the NACT combination with MLT and MTF does not lead to increase of pathomorphological response (pCR) rate compared to NACT group (OR 0.482 [95% CI 0,083-2,792], p¼0.416; OR 0.602 [95% CI 0,085-4,284], p¼0.612). pCR rate was in 25%, 14,2% b 16,6% accordingly. The quality of life was assessed by EORTC-QLQ-C30. In the group of patients who received NACTþMLT, in contrast to the group of patients who received only NACT, the values on the role functioning (RF), fatigue (FA) and sleep (SL) scales did not decrease during the treatment (p ¼ 0.008, p ¼ 0.004, p ¼ 0.014 respectively). Conclusions: MLT and MTF did not show influence on pCR and objective response rates, however, MLT used during NACT may improve the quality of life. Legal entity responsible for the study: T. Semiglazova. Funding: Federal State Budget Institution "National Medical Research Center of Oncology na N.N. Petrov" Ministry of Healthcare of Russian Federation. Disclosure: All authors have declared no conflicts of interest.
v100 | Breast Cancer, Locally Advanced
296P
Patient-tailored tamoxifen dosing based on an increased quantitative understanding of its complex pharmacokinetics: A novel integrative modelling approach
A. Mueller-Schoell1, L. Klopp-Schulze1, W. Huisinga2, M. Joerger3, P. Neven4, S.L. Koolen5, R.H.J. Mathijssen6, S. Schmidt7, C. Kloft1 1 Department Of Clinical Pharmacy And Biochemistry, Freie Universitaet Berlin, Berlin, Germany, 2Institute of Mathematics, University of Potsdam, Potsdam, Germany, 3 Medical Oncology & Hematology, Kantonsspital St. Gallen, St. Gallen, Switzerland, 4 Vesalius Research Center - VIB, University Hospitals Leuven, KU Leuven, University of Leuven, Leuven, Belgium, 5Medical Oncology and Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, Netherlands, 6Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands, 7Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, AL, USA Background: About 20% of breast cancer (BC) patients do not attain tamoxifen’s (TAM) active metabolite endoxifen (ENDX) target concentrations when receiving 20 mg TAM once daily (q.d.). Thus, individualised dosing of up to 120 mg TAM q.d. for ENDX target attainment (TA) has been proposed. Combining concentrations and antiestrogenic activities of ENDX and its 3 precursors, the antiestrogenic activity score (AAS) has been developed as alternative TA metric. We aimed to integrate experimental and clinical data from diverse sources in an innovative modelling approach to identify patient groups at risk of treatment failure and to assess whether ENDX- or AASguided dosing would be more favourable for TA applying in silico simulation. Methods: In vitro data from enzyme kinetic experiments, pharmacokinetic (PK) parameters from previous clinical studies and in vivo data from three clinical trials were synthesised into a minimal nonlinear mixed-effects physiologically-based pharmacokinetic (NLME-PBPK) model. Using simulation, lowest doses needed for TA, applying either the ENDX (5.97 ng/mL) or the AAS (1798) threshold, were investigated in a representative virtual BC population with various CYP2D6 activity scores (AS) and age. Results: The developed NLME-PBPK model captured individual TAM and 3 metabolite concentration profiles from 406 BC patients well. Bioactivation to ENDX was 4.5fold higher in CYP2D6 normal (NM) than in poor metabolisers (PM). Patients with low CYP2D6 activity and young age showed highest risks for ENDX non-TA. Among all patients, 76% received the same dose irrespective of the TA metric used. For the remaining 23% with different dose selections, applying the AAS instead of the ENDX target, TA increased in NM and intermediate metabolisers (IM) (þ21.7% and þ6.9%, respectively), while TA decreased in PM (-11.7%). Conclusions: Our modelling approach combined pharmacogenetic factors, physiological changes and variability on PK parameters in a quantitative manner and allowed to translate PK information on TAM and its three major metabolites into individualised dosing. While ENDX-guided dosing was preferable for PM in our simulation, AASguided dosing was superior for NM and IM. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: L. Klopp-Schulze: Full / Part-time employment: Merck Healthcare KGaA. S.L. Koolen: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Cristal Therapeutics; Travel / Accommodation / Expenses: Ipsen. R.H.J. Mathijssen: Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Servier. C. Kloft: Research grant / Funding (institution), Grants received outside the submitted work: DDMoRe; Research grant / Funding (institution), Grants received outside the submitted work: Industry consortium (AbbVie Deutschland GmbH & Co. KG, Boehringer Ingelheim Pharma GmbH & Co. KG, Gruenenthal GmbH, F. Hoffmann-La Roche Ltd., Merck KGaA and SANOFI); Research grant / Funding (institution), Grants received outside the submitted work: Federal Ministry of Education and Research; Research grant / Funding (institution), Grants received outside the submitted work: Diurnal Ltd. All other authors have declared no conflicts of interest.
297P
Lack of benefit of neoadjuvant pertuzumab in high risk HER2 positive breast cancer: A retrospective case-control study of 355 cases with biomarker analysis
M. Tiako Meyo1, M. Lavigne2, P. Leclerc3, M.-L. Tanguy4, Y. Kirova5, A. Hurgon6, A. Lalli6, V. Fourchotte7, A. Vincent-Salomon2, L. Escalup3, P.H. Cottu1 1 Medical Oncology, Institut Curie, Paris, France, 2Pathology, Institut Curie, Paris, France, 3 Pharmacy, Institut Curie, Paris, France, 4Radiotherapy, Institut Curie, Paris, France, 5 Radiotherapy, Paris, France, 6Pharmacy, Institut Curie, Paris, France, 7Surgical Oncology, Institut Curie, Paris, France Background: The NEOSPHERE trial suggested that pertuzumab (P) added to a combination of docetaxel and trastuzumab (T) as a neoadjuvant therapy in HER2 positive breast cancer (HER2þ BC) patients (pts) significantly enhances pathological complete response (pCR) rates. Here, we report our institution experience, focusing on stage III tumors.
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz241.003/5576755 by guest on 25 October 2019
NCT02506790). The average patients’ age was 68 years. All patients had no history of diabetes mellitus. All patients were randomized for 1:1:1 ratio. The first group (n ¼ 19) received 120 mg of oral TOR daily, the second one (n ¼ 16) received TOR in combination with 3 mg overnight dose of oral MLT, the third group (n ¼ 19) received TOR in combination with oral MTF (850 mg twice a day). For all patient groups the hormone therapy duration was 4 months, then surgery was performed. Results: An objective response rate for three studied groups was 31.6%, 86.7%. and 47.3% accordingly. Adding MLT to TOR lead to significant increase in response rate compared to TOR monotherapy group (v2 ¼ 10.32, p¼0.001). The decrease in Ki67 expression in TOR group was observed in 42%, TORþ MLT group in 56%, and TORþMTF group in 74% of patients. According to multivariate analysis of results the TOR combination with MTF leads to 4.2-fold higher Ki-67 expression decrease probability compared to TOR group (OR 4.23 [95% CI 1.044-17.139], p¼0.043). Also this group is the only one to display a significant correlation (Spearman) between Ki67 expression decrease dynamics and abnormal BMI values (p¼0.015). No pathomorphological response (pCR) was observed. Adding MLT or MTF to standard hormone therapy did not lead to decrease in the quality of life (EORTC-QLQ-C30), about 50% of TORþMLT therapy recipients had better sleep quality. Conclusions: MLT and MTF showed encouraging results in combination with neoadjuvant hormonotherapy. However, these data require confirmation in larger randomized studies. Legal entity responsible for the study: T. Semiglazova. Funding: Federal State Budget Institution "National Medical Research Center of Oncology na N.N. Petrov" Ministry of Healthcare of Russian Federation. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
295P
Melatonin and metformin in neoadjuvant chemotherapy in locally advanced breast cancer
T.Y. Semiglazova1, M. Osipov2, P. Krivorotko3, V. Semiglazov3, S. Protsenko1, L. Berstein4, E. Tsirlina4, V. Klimenko1, R. Donskih5, V. Anisimov6, A. Belyaev7 1 Innovative Methods of Therapeutic Oncology and Rehabilitation, N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russian Federation, 2Innovative Methods of Therapeutic Oncology and Rehabilitation, Federal State Budget Institution "National Medical Research Center of Oncology na N.N. Petrov" Ministry of Healthcare of Russian Federation, St. Petersburg, Russian Federation, 3Breast Cancer Department, N.N. Petrov National Medical Research Center of Oncology, St. Petersburg, Russian Federation, 4 Endocrinology, Federal State Budget Institution "National Medical Research Center of Oncology na N.N. Petrov" Ministry of Healthcare of Russian Federation, St. Petersburg, Russian Federation, 5Breast Cancer, Federal State Budget Institution "National Medical Research Center of Oncology na N.N. Petrov" Ministry of Healthcare of Russian Federation, St. Petersburg, Russian Federation, 6Cancerogenesis and Aging, Federal State Budget Institution "National Medical Research Center of Oncology na N.N. Petrov" Ministry of Healthcare of Russian Federation, St. Petersburg, Russian Federation, 7Federal State Budget Institution "National Medical Research Center of Oncology na N.N. Petrov" Ministry of Healthcare of Russian Federation, St. Petersburg, Russian Federation Background: According to in vitro/in vivo studies both melatonin (MLT) and metformin (MTF) may exhibit an antitumor effect. Furthermore, in accordance to epidemiological studies MTF reduces the risk of developing breast cancer (BC) among patients with diabetes mellitus; as well as “light at night”can inhibit endogenic MLT synthesis and increase risk of breast cancer. Thus, MLT and MTF need to be investigated in clinical oncology. Methods: A total of 53 patients with locally advanced BC (ER positive/HER2 negative 68%, ER positive/HER2 positive -25% and ER negative/HER2 negative -7%), were included in the study of MLT or MTF efficiency in combination with anthracyclin and taxan-containing neoadjuvant chemotherapy (NACT) (clinicalTrials.gov NCT02506777). The average patients’ age was 56 years. All patients had no history of diabetes mellitus. All patients were randomized into 3 groups. The first group (n ¼ 20) received NACT, the second one (n ¼ 21) received NACT in combination with 3 mg overnight dose of oral MLT, the third group (n ¼ 12) received NACT in combination with oral MTF (850 mg twice a day). For all patient groups the NACT duration was 6 cycles, then surgery was performed. Results: An objective response rate for three studied groups was 85%, 85.7% and 75% respectively. According to multivariate analysis of results the NACT combination with MLT and MTF does not lead to increase of pathomorphological response (pCR) rate compared to NACT group (OR 0.482 [95% CI 0,083-2,792], p¼0.416; OR 0.602 [95% CI 0,085-4,284], p¼0.612). pCR rate was in 25%, 14,2% b 16,6% accordingly. The quality of life was assessed by EORTC-QLQ-C30. In the group of patients who received NACTþMLT, in contrast to the group of patients who received only NACT, the values on the role functioning (RF), fatigue (FA) and sleep (SL) scales did not decrease during the treatment (p ¼ 0.008, p ¼ 0.004, p ¼ 0.014 respectively). Conclusions: MLT and MTF did not show influence on pCR and objective response rates, however, MLT used during NACT may improve the quality of life. Legal entity responsible for the study: T. Semiglazova. Funding: Federal State Budget Institution "National Medical Research Center of Oncology na N.N. Petrov" Ministry of Healthcare of Russian Federation. Disclosure: All authors have declared no conflicts of interest.
v100 | Breast Cancer, Locally Advanced
296P
Patient-tailored tamoxifen dosing based on an increased quantitative understanding of its complex pharmacokinetics: A novel integrative modelling approach
A. Mueller-Schoell1, L. Klopp-Schulze1, W. Huisinga2, M. Joerger3, P. Neven4, S.L. Koolen5, R.H.J. Mathijssen6, S. Schmidt7, C. Kloft1 1 Department Of Clinical Pharmacy And Biochemistry, Freie Universitaet Berlin, Berlin, Germany, 2Institute of Mathematics, University of Potsdam, Potsdam, Germany, 3 Medical Oncology & Hematology, Kantonsspital St. Gallen, St. Gallen, Switzerland, 4 Vesalius Research Center - VIB, University Hospitals Leuven, KU Leuven, University of Leuven, Leuven, Belgium, 5Medical Oncology and Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, Netherlands, 6Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands, 7Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, AL, USA Background: About 20% of breast cancer (BC) patients do not attain tamoxifen’s (TAM) active metabolite endoxifen (ENDX) target concentrations when receiving 20 mg TAM once daily (q.d.). Thus, individualised dosing of up to 120 mg TAM q.d. for ENDX target attainment (TA) has been proposed. Combining concentrations and antiestrogenic activities of ENDX and its 3 precursors, the antiestrogenic activity score (AAS) has been developed as alternative TA metric. We aimed to integrate experimental and clinical data from diverse sources in an innovative modelling approach to identify patient groups at risk of treatment failure and to assess whether ENDX- or AASguided dosing would be more favourable for TA applying in silico simulation. Methods: In vitro data from enzyme kinetic experiments, pharmacokinetic (PK) parameters from previous clinical studies and in vivo data from three clinical trials were synthesised into a minimal nonlinear mixed-effects physiologically-based pharmacokinetic (NLME-PBPK) model. Using simulation, lowest doses needed for TA, applying either the ENDX (5.97 ng/mL) or the AAS (1798) threshold, were investigated in a representative virtual BC population with various CYP2D6 activity scores (AS) and age. Results: The developed NLME-PBPK model captured individual TAM and 3 metabolite concentration profiles from 406 BC patients well. Bioactivation to ENDX was 4.5fold higher in CYP2D6 normal (NM) than in poor metabolisers (PM). Patients with low CYP2D6 activity and young age showed highest risks for ENDX non-TA. Among all patients, 76% received the same dose irrespective of the TA metric used. For the remaining 23% with different dose selections, applying the AAS instead of the ENDX target, TA increased in NM and intermediate metabolisers (IM) (þ21.7% and þ6.9%, respectively), while TA decreased in PM (-11.7%). Conclusions: Our modelling approach combined pharmacogenetic factors, physiological changes and variability on PK parameters in a quantitative manner and allowed to translate PK information on TAM and its three major metabolites into individualised dosing. While ENDX-guided dosing was preferable for PM in our simulation, AASguided dosing was superior for NM and IM. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: L. Klopp-Schulze: Full / Part-time employment: Merck Healthcare KGaA. S.L. Koolen: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Cristal Therapeutics; Travel / Accommodation / Expenses: Ipsen. R.H.J. Mathijssen: Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Servier. C. Kloft: Research grant / Funding (institution), Grants received outside the submitted work: DDMoRe; Research grant / Funding (institution), Grants received outside the submitted work: Industry consortium (AbbVie Deutschland GmbH & Co. KG, Boehringer Ingelheim Pharma GmbH & Co. KG, Gruenenthal GmbH, F. Hoffmann-La Roche Ltd., Merck KGaA and SANOFI); Research grant / Funding (institution), Grants received outside the submitted work: Federal Ministry of Education and Research; Research grant / Funding (institution), Grants received outside the submitted work: Diurnal Ltd. All other authors have declared no conflicts of interest.
297P
Lack of benefit of neoadjuvant pertuzumab in high risk HER2 positive breast cancer: A retrospective case-control study of 355 cases with biomarker analysis
M. Tiako Meyo1, M. Lavigne2, P. Leclerc3, M.-L. Tanguy4, Y. Kirova5, A. Hurgon6, A. Lalli6, V. Fourchotte7, A. Vincent-Salomon2, L. Escalup3, P.H. Cottu1 1 Medical Oncology, Institut Curie, Paris, France, 2Pathology, Institut Curie, Paris, France, 3 Pharmacy, Institut Curie, Paris, France, 4Radiotherapy, Institut Curie, Paris, France, 5 Radiotherapy, Paris, France, 6Pharmacy, Institut Curie, Paris, France, 7Surgical Oncology, Institut Curie, Paris, France Background: The NEOSPHERE trial suggested that pertuzumab (P) added to a combination of docetaxel and trastuzumab (T) as a neoadjuvant therapy in HER2 positive breast cancer (HER2þ BC) patients (pts) significantly enhances pathological complete response (pCR) rates. Here, we report our institution experience, focusing on stage III tumors.
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz241.003/5576755 by guest on 25 October 2019
NCT02506790). The average patients’ age was 68 years. All patients had no history of diabetes mellitus. All patients were randomized for 1:1:1 ratio. The first group (n ¼ 19) received 120 mg of oral TOR daily, the second one (n ¼ 16) received TOR in combination with 3 mg overnight dose of oral MLT, the third group (n ¼ 19) received TOR in combination with oral MTF (850 mg twice a day). For all patient groups the hormone therapy duration was 4 months, then surgery was performed. Results: An objective response rate for three studied groups was 31.6%, 86.7%. and 47.3% accordingly. Adding MLT to TOR lead to significant increase in response rate compared to TOR monotherapy group (v2 ¼ 10.32, p¼0.001). The decrease in Ki67 expression in TOR group was observed in 42%, TORþ MLT group in 56%, and TORþMTF group in 74% of patients. According to multivariate analysis of results the TOR combination with MTF leads to 4.2-fold higher Ki-67 expression decrease probability compared to TOR group (OR 4.23 [95% CI 1.044-17.139], p¼0.043). Also this group is the only one to display a significant correlation (Spearman) between Ki67 expression decrease dynamics and abnormal BMI values (p¼0.015). No pathomorphological response (pCR) was observed. Adding MLT or MTF to standard hormone therapy did not lead to decrease in the quality of life (EORTC-QLQ-C30), about 50% of TORþMLT therapy recipients had better sleep quality. Conclusions: MLT and MTF showed encouraging results in combination with neoadjuvant hormonotherapy. However, these data require confirmation in larger randomized studies. Legal entity responsible for the study: T. Semiglazova. Funding: Federal State Budget Institution "National Medical Research Center of Oncology na N.N. Petrov" Ministry of Healthcare of Russian Federation. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology