- Email: [email protected]
Clinical confirmation of higher exposure to niraparib in tumour vs plasma in patients with breast cancer
abstracts
Annals of Oncology Conclusions: 82% of pt of our series could avoid CT, however this proportion change after TAYLORx results in younger patients. Today 75% of these pt would had avoided CT. Ki67 > 25% and Progesterone Receptor 20% were the only pathological factors associated with an increased risk of RS > 25. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest. 210P
Impact of delayed neoadjuvant systemic chemotherapy on survival among breast cancer patients
Background: Delays in the initiation of therapy among patients with early stage and locally advanced breast cancer (BC), can negatively impact survival. Patients treated with neoadjuvant systemic chemotherapy (NSC) usually display tumors with high-risk features. Considering these high-risk characteristics, and the evidence supporting adverse outcomes associated with delays in adjuvant chemotherapy initiation, we sought to determine whether time to NSC is associated with survival outcomes. Methods: We identified patients diagnosed with invasive primary BC (stage I–III)be tween January 1995-December 2015. All patients were treated with NSC at MD Anderson Cancer Center. Patients were categorized according to their time from BC diagnosis to NSC (in days) into one of the three subgroups: 0-30, 31–60, and 61 days. Primary endpoint was overall survival (OS). Descriptive statistics and Cox Proportional Hazard models were used. Results: A total of5,137 patients were included. Median follow-up was 6.9 years. The 5-year OS estimates according to time to NSC were 87%, 85% and 83% in patients who received NSC within 0-30, 31-60 and 61 days after diagnosis, respectively (P ¼ 0.006). In multivariable analysis, compared to time to NSC of 0-30 days, delayed NSC 61 days was associated with an increased risk of death (31-60 days HR ¼ 1.05 [95%CI 0.92-1.19]; >61 days, HR ¼ 1.28 [95%CI 1.06-1.54]). In stratified analyses, the association between delay in NSC initiation and increased risk of death was statistically significant for patients with stage I, II (31-60 days: HR ¼ 1.22 [95%CI 1.02-1.47]; 61 days, HR ¼ 1.41 [95%CI 1.07-1.86]) BC and among patients with HER2þ tumors (61 days, HR¼1.86 [95%CI 1.21-2.86]). Conclusions: A delay in NSC initiation of more than 61 days after BC diagnosis is associated with an increased risk of death. Early initiation of NSC should be a priority; multidisciplinary teams must focus in coordination of care and patient-centered timely treatment planning and delivery. Legal entity responsible for the study: The authors. Funding: MD Anderson Cancer Center, Susan G Komen. Disclosure: All authors have declared no conflicts of interest.
211P
Clinical confirmation of higher exposure to niraparib in tumour vs plasma in patients with breast cancer
L. Spring1, M. Shan2, M.C. Liu3, E. Hamilton4, C.A. Santa-Maria5, H. Irie6, S. Isakoff1, J. Reeves7, L.W. Ellisen1, A. Liem8, A. Milillo Naraine9, J. Nangia10, D. Page11, P. Pan2, K. Sun2, J.R. Graham2, H. Han12 1 Massachusetts General Hospital, Boston, MA, USA, 2Tesaro: A GSK Company, Waltham, MA, USA, 3Mayo Clinic, Rochester, MN, USA, 4Sarah Cannon Research Institute/ Tennessee Oncology, Nashville, TN, USA, 5Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA, 6Icahn School of Medicine at Mount Sinai, New York, NY, USA, 7Florida Cancer Specialists-South, Fort Myers, FL, USA, 8Pacific Shores Medical Group, Long Beach, CA, USA, 9Memorial Health Care System, Hollywood, FL, USA, 10 Baylor College of Medicine, Houston, TX, USA, 11Providence Portland Medical Center, Portland, OR, USA, 12Moffitt Cancer Center-McKinley Outpatient Clinic, Tampa, FL, USA Background: Niraparib is a selective oral poly(ADP-ribose) polymerase 1/2 inhibitor (PARPi) approved as maintenance treatment of recurrent ovarian cancer. Previous studies revealed unique pharmacological properties of niraparib, including a large volume of distribution, suggesting higher tissue penetration of this drug. Preclinical studies have consistently demonstrated that niraparib tumor exposure is higher than plasma exposure, whereas another PARPi, olaparib, has demonstrated lower tumor exposure than plasma exposure in tumor xenograft models. In a clinical study, tumor concentrations of olaparib were on average 41% of plasma concentrations in patients with breast cancer (BC)1. Here we report for the first time the intra-tumoral concentration of niraparib in clinical samples. Methods: Tumor biopsies and plasma samples were collected from patients enrolled in a pilot study (NCT03329937) evaluating the antitumor activity and safety of niraparib as neoadjuvant treatment for HER2-negative, BRCA-mutated localized BC. Patients (N ¼ 9) received oral niraparib 200 mg once daily over two 28-day cycles; 2 patients in the analysis had dose reduction to 100 mg. Biopsies and plasma were obtained at the end of Cycle 2. Additional plasma samples were collected on Cycle 2/Day 1 at 0, 2, and 4 hours post dose to determine steady-state maximum concentration (Cmax).
Volume 30 | Supplement 5 | October 2019
A GSK Company. E. Hamilton: Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Genzyme; Travel / Accommodation / Expenses: Helsinn Therapeutics; Travel / Accommodation / Expenses: HERON; Travel / Accommodation / Expenses: Lexicon; Travel / Accommodation / Expenses: Medivation; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Sysmex; Travel / Accommodation / Expenses: Guardant Health; Travel / Accommodation / Expenses: Foundation Medicine. C. Santa-Maria: Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Medimmune. S. Isakoff: Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: PharmaMar; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck; Research grant / Funding (institution): OncoPep; Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar. D.B. Page: Honoraria (self): Novartis; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Syndax; Advisory / Consultancy: Nektar; Research grant / Funding (self): NanoString Technologies; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Puma Biotechnology; Speaker Bureau / Expert testimony: Genentech/Roche; Research grant / Funding (institution), Travel / Accommodation / Expenses: MedImmune; Research grant / Funding (institution): Merck; Speaker Bureau / Expert testimony: Philips Healthcare. P. Pan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Tesaro: A GSK Company. K. Sun: Shareholder / Stockholder / Stock options, Full / Part-time employment: Tesaro: A GSK Company. J.R. Graham: Shareholder / Stockholder / Stock options, Full / Part-time employment: Tesaro: A GSK Company. H.S. Han: Research grant / Funding (institution): Tesaro, Inc.; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Prescient; Research grant / Funding (institution): Horizon; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): TapImmune; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Department of Defense. All other authors have declared no conflicts of interest.
212P
The rationale for the effectiveness of systemic treatment of breast cancer depending on the body weight index
M.I.M. Hojouj Oncology and Medical Radiology, Dnipropetrovsk City Multidisciplinary Clinical Hospital n. 4, Dnipro, Ukraine Background: Breast cancer in the world in general and in Ukraine is steadily increasing. Epidemiological, experimental and clinical studies have shown that metabolic disturbances associated with BMI> 30 kg / m2 increase the risk of occurrence and worsen the clinical course of breast cancer. Thus, in patients with obesity, a decrease in the sensitivity of the tumor to systemic antitumor therapy, an increase in the frequency of postoperative complications and a decrease in the rates of general and non-recurrent survival. Methods: The aim of the study was to improve the results of neoadjuvant systemic antitumor therapy in breast cancer patients with abdominal obesity (BMI greater than 30 kg / m2) by administering levocarnitine in combination with neoadjuvant systemic anticancer therapy (NSAT) for the correction of metabolic disorders as the main pathogenetic part of obesity. Following randomization of all patients (n ¼ 108) with breast cancer with BMI> 30 kg / m2, depending on the appointment of levocarnitine during NSAT, were divided into 2 groups: comparison and observation. In the comparison group, patients (n ¼ 58) with BMI> 30 kg / m2 patients with breast cancer who did not receive levocarnitine during NSPT, and in the, observation group - patients (n ¼ 50) on breast cancer with BMI> 30 kg / m2 who received levocarnitine during NIST Results: After neoadjuvant systemic anticancer therapy, regardless of the purpose levocarnitine decreased residual tumor cell proliferation index (Ki-67) and increased incidence of Luminal A molecular type of breast cancer. Against neoadjuvant systemic anticancer therapy for breast cancer patients with a BMI over 30 kg / m2 to be additionally administered drugs that increases the incidence of complete morphological regression. This drug is levocarnitine in therapeutic doses (1500 mg / day), which has proven to be an effective means to increase the number of cases of clinically relevant responses (CR þ PR) to the treatment. Conclusions: Levocarnitine contributes to an increase in the number of cases of objective clinical (complete regression and partial regression) and morphological (therapeutic pathomorphosis IV and V degree) tumor response to cytotoxic breast cancer therapy in patients with BMI> 30 kg / m2 and frequency of organ-saving surgical interventions. Legal entity responsible for the study: The author. Funding: Has not received any funding. Disclosure: The author has declared no conflicts of interest.
doi:10.1093/annonc/mdz240 | v71
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz240.036/5578192 by guest on 26 October 2019
M. Chavez Mac Gregor1, X. Lei1, D. Gagliato2, V. Valero3, C. Barcenas3, G.N. Hortobagyi3, S.H. Giordano1 1 Health Services Research, The University of Texas MD Anderson Cancer Center, ao Paulo, Houston,TX, USA, 2Breast Medical Oncology, A Benefic^encia Portuguesa de S~ Sao Paulo, Brazil, 3Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Niraparib concentrations in plasma and tumor samples for each patient were quantified using a qualified liquid chromatography–tandem mass spectrometry method. Results: Niraparib concentrations in plasma from patients with BC (N ¼ 5) were within the reference range previously reported for solid tumors (steady state Cmax 3160þ/-2799 nM, Ctrough 1753þ/-1707 nM). In the same cohort of BC patients, niraparib concentrations in tumors ranged from approximately 4–131-fold higher than those in corresponding plasma samples after 2 months of niraparib treatment. Data for all patients will be presented at the meeting. Conclusions: These results provide the first clinical data of at least 4-fold higher intratumor concentration of niraparib compared with plasma concentration in patients with BC. Reference: Bundred N et al. Invest New Drugs 2013; 31: 949-58. Clinical trial identification: NCT03329937. Legal entity responsible for the study: Tesaro: A Gsk Company. Funding: Tesaro: A Gsk Company. Disclosure: M. Shan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Tesaro:
Annals of Oncology Conclusions: 82% of pt of our series could avoid CT, however this proportion change after TAYLORx results in younger patients. Today 75% of these pt would had avoided CT. Ki67 > 25% and Progesterone Receptor 20% were the only pathological factors associated with an increased risk of RS > 25. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest. 210P
Impact of delayed neoadjuvant systemic chemotherapy on survival among breast cancer patients
Background: Delays in the initiation of therapy among patients with early stage and locally advanced breast cancer (BC), can negatively impact survival. Patients treated with neoadjuvant systemic chemotherapy (NSC) usually display tumors with high-risk features. Considering these high-risk characteristics, and the evidence supporting adverse outcomes associated with delays in adjuvant chemotherapy initiation, we sought to determine whether time to NSC is associated with survival outcomes. Methods: We identified patients diagnosed with invasive primary BC (stage I–III)be tween January 1995-December 2015. All patients were treated with NSC at MD Anderson Cancer Center. Patients were categorized according to their time from BC diagnosis to NSC (in days) into one of the three subgroups: 0-30, 31–60, and 61 days. Primary endpoint was overall survival (OS). Descriptive statistics and Cox Proportional Hazard models were used. Results: A total of5,137 patients were included. Median follow-up was 6.9 years. The 5-year OS estimates according to time to NSC were 87%, 85% and 83% in patients who received NSC within 0-30, 31-60 and 61 days after diagnosis, respectively (P ¼ 0.006). In multivariable analysis, compared to time to NSC of 0-30 days, delayed NSC 61 days was associated with an increased risk of death (31-60 days HR ¼ 1.05 [95%CI 0.92-1.19]; >61 days, HR ¼ 1.28 [95%CI 1.06-1.54]). In stratified analyses, the association between delay in NSC initiation and increased risk of death was statistically significant for patients with stage I, II (31-60 days: HR ¼ 1.22 [95%CI 1.02-1.47]; 61 days, HR ¼ 1.41 [95%CI 1.07-1.86]) BC and among patients with HER2þ tumors (61 days, HR¼1.86 [95%CI 1.21-2.86]). Conclusions: A delay in NSC initiation of more than 61 days after BC diagnosis is associated with an increased risk of death. Early initiation of NSC should be a priority; multidisciplinary teams must focus in coordination of care and patient-centered timely treatment planning and delivery. Legal entity responsible for the study: The authors. Funding: MD Anderson Cancer Center, Susan G Komen. Disclosure: All authors have declared no conflicts of interest.
211P
Clinical confirmation of higher exposure to niraparib in tumour vs plasma in patients with breast cancer
L. Spring1, M. Shan2, M.C. Liu3, E. Hamilton4, C.A. Santa-Maria5, H. Irie6, S. Isakoff1, J. Reeves7, L.W. Ellisen1, A. Liem8, A. Milillo Naraine9, J. Nangia10, D. Page11, P. Pan2, K. Sun2, J.R. Graham2, H. Han12 1 Massachusetts General Hospital, Boston, MA, USA, 2Tesaro: A GSK Company, Waltham, MA, USA, 3Mayo Clinic, Rochester, MN, USA, 4Sarah Cannon Research Institute/ Tennessee Oncology, Nashville, TN, USA, 5Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA, 6Icahn School of Medicine at Mount Sinai, New York, NY, USA, 7Florida Cancer Specialists-South, Fort Myers, FL, USA, 8Pacific Shores Medical Group, Long Beach, CA, USA, 9Memorial Health Care System, Hollywood, FL, USA, 10 Baylor College of Medicine, Houston, TX, USA, 11Providence Portland Medical Center, Portland, OR, USA, 12Moffitt Cancer Center-McKinley Outpatient Clinic, Tampa, FL, USA Background: Niraparib is a selective oral poly(ADP-ribose) polymerase 1/2 inhibitor (PARPi) approved as maintenance treatment of recurrent ovarian cancer. Previous studies revealed unique pharmacological properties of niraparib, including a large volume of distribution, suggesting higher tissue penetration of this drug. Preclinical studies have consistently demonstrated that niraparib tumor exposure is higher than plasma exposure, whereas another PARPi, olaparib, has demonstrated lower tumor exposure than plasma exposure in tumor xenograft models. In a clinical study, tumor concentrations of olaparib were on average 41% of plasma concentrations in patients with breast cancer (BC)1. Here we report for the first time the intra-tumoral concentration of niraparib in clinical samples. Methods: Tumor biopsies and plasma samples were collected from patients enrolled in a pilot study (NCT03329937) evaluating the antitumor activity and safety of niraparib as neoadjuvant treatment for HER2-negative, BRCA-mutated localized BC. Patients (N ¼ 9) received oral niraparib 200 mg once daily over two 28-day cycles; 2 patients in the analysis had dose reduction to 100 mg. Biopsies and plasma were obtained at the end of Cycle 2. Additional plasma samples were collected on Cycle 2/Day 1 at 0, 2, and 4 hours post dose to determine steady-state maximum concentration (Cmax).
Volume 30 | Supplement 5 | October 2019
A GSK Company. E. Hamilton: Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Genzyme; Travel / Accommodation / Expenses: Helsinn Therapeutics; Travel / Accommodation / Expenses: HERON; Travel / Accommodation / Expenses: Lexicon; Travel / Accommodation / Expenses: Medivation; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Sysmex; Travel / Accommodation / Expenses: Guardant Health; Travel / Accommodation / Expenses: Foundation Medicine. C. Santa-Maria: Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Medimmune. S. Isakoff: Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: PharmaMar; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck; Research grant / Funding (institution): OncoPep; Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar. D.B. Page: Honoraria (self): Novartis; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Syndax; Advisory / Consultancy: Nektar; Research grant / Funding (self): NanoString Technologies; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Puma Biotechnology; Speaker Bureau / Expert testimony: Genentech/Roche; Research grant / Funding (institution), Travel / Accommodation / Expenses: MedImmune; Research grant / Funding (institution): Merck; Speaker Bureau / Expert testimony: Philips Healthcare. P. Pan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Tesaro: A GSK Company. K. Sun: Shareholder / Stockholder / Stock options, Full / Part-time employment: Tesaro: A GSK Company. J.R. Graham: Shareholder / Stockholder / Stock options, Full / Part-time employment: Tesaro: A GSK Company. H.S. Han: Research grant / Funding (institution): Tesaro, Inc.; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Prescient; Research grant / Funding (institution): Horizon; Research grant / Funding (institution): Karyopharm; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): TapImmune; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Department of Defense. All other authors have declared no conflicts of interest.
212P
The rationale for the effectiveness of systemic treatment of breast cancer depending on the body weight index
M.I.M. Hojouj Oncology and Medical Radiology, Dnipropetrovsk City Multidisciplinary Clinical Hospital n. 4, Dnipro, Ukraine Background: Breast cancer in the world in general and in Ukraine is steadily increasing. Epidemiological, experimental and clinical studies have shown that metabolic disturbances associated with BMI> 30 kg / m2 increase the risk of occurrence and worsen the clinical course of breast cancer. Thus, in patients with obesity, a decrease in the sensitivity of the tumor to systemic antitumor therapy, an increase in the frequency of postoperative complications and a decrease in the rates of general and non-recurrent survival. Methods: The aim of the study was to improve the results of neoadjuvant systemic antitumor therapy in breast cancer patients with abdominal obesity (BMI greater than 30 kg / m2) by administering levocarnitine in combination with neoadjuvant systemic anticancer therapy (NSAT) for the correction of metabolic disorders as the main pathogenetic part of obesity. Following randomization of all patients (n ¼ 108) with breast cancer with BMI> 30 kg / m2, depending on the appointment of levocarnitine during NSAT, were divided into 2 groups: comparison and observation. In the comparison group, patients (n ¼ 58) with BMI> 30 kg / m2 patients with breast cancer who did not receive levocarnitine during NSPT, and in the, observation group - patients (n ¼ 50) on breast cancer with BMI> 30 kg / m2 who received levocarnitine during NIST Results: After neoadjuvant systemic anticancer therapy, regardless of the purpose levocarnitine decreased residual tumor cell proliferation index (Ki-67) and increased incidence of Luminal A molecular type of breast cancer. Against neoadjuvant systemic anticancer therapy for breast cancer patients with a BMI over 30 kg / m2 to be additionally administered drugs that increases the incidence of complete morphological regression. This drug is levocarnitine in therapeutic doses (1500 mg / day), which has proven to be an effective means to increase the number of cases of clinically relevant responses (CR þ PR) to the treatment. Conclusions: Levocarnitine contributes to an increase in the number of cases of objective clinical (complete regression and partial regression) and morphological (therapeutic pathomorphosis IV and V degree) tumor response to cytotoxic breast cancer therapy in patients with BMI> 30 kg / m2 and frequency of organ-saving surgical interventions. Legal entity responsible for the study: The author. Funding: Has not received any funding. Disclosure: The author has declared no conflicts of interest.
doi:10.1093/annonc/mdz240 | v71
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz240.036/5578192 by guest on 26 October 2019
M. Chavez Mac Gregor1, X. Lei1, D. Gagliato2, V. Valero3, C. Barcenas3, G.N. Hortobagyi3, S.H. Giordano1 1 Health Services Research, The University of Texas MD Anderson Cancer Center, ao Paulo, Houston,TX, USA, 2Breast Medical Oncology, A Benefic^encia Portuguesa de S~ Sao Paulo, Brazil, 3Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Niraparib concentrations in plasma and tumor samples for each patient were quantified using a qualified liquid chromatography–tandem mass spectrometry method. Results: Niraparib concentrations in plasma from patients with BC (N ¼ 5) were within the reference range previously reported for solid tumors (steady state Cmax 3160þ/-2799 nM, Ctrough 1753þ/-1707 nM). In the same cohort of BC patients, niraparib concentrations in tumors ranged from approximately 4–131-fold higher than those in corresponding plasma samples after 2 months of niraparib treatment. Data for all patients will be presented at the meeting. Conclusions: These results provide the first clinical data of at least 4-fold higher intratumor concentration of niraparib compared with plasma concentration in patients with BC. Reference: Bundred N et al. Invest New Drugs 2013; 31: 949-58. Clinical trial identification: NCT03329937. Legal entity responsible for the study: Tesaro: A Gsk Company. Funding: Tesaro: A Gsk Company. Disclosure: M. Shan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Tesaro: