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Melinda L. Telli - One of the best experts on this subject based on the ideXlab platform.

  • Association of a four-gene decision tree signature with response to platinum-based chemotherapy in patients with triple negative breast cancer.
    Journal of Clinical Oncology, 2017
    Co-Authors: Jelmar Quist, Melinda L. Telli, Hasan Mirza, Maggie C.u. Cheang, Christopher J. Lord, Andrew Tutt, Anita Grigoriadis
    Abstract:

    1006Background: Approaches to capture the molecular complexity of triple negative breast cancers (TNBCs) are lacking. We sought to classify TNBCs into subgroups with common biological features based on transcriptomic and genomic data using a Bayesian algorithm. Methods: Matched gene expression and copy number microarray data was available for the Guy’s (n = 88) and METABRIC (n = 112) TNBC cohorts. CONEXIC was used to derive a decision tree signature for classification. Performance of the signature was tested in 7 TNBC cohorts (total n: 1,368), including 2 clinical trials assessing the efficacy of gemcitabine and carboplatin with and without Iniparib. In the early-stage PrECOG 0105 Phase II neoadjuvant trial (n = 43), subtypes were evaluated in relation to response by residual cancer burden (RCB). In the metastatic Sanofi Phase III trial (n = 224), subtypes were assessed by RECIST. Results were compared to the BL1 TNBCtype-4 subtype and assessed using a multivariate analysis. Results: The integrative analy...

  • homologous recombination deficiency hrd score predicts response to platinum containing neoadjuvant chemotherapy in patients with triple negative breast cancer
    Clinical Cancer Research, 2016
    Co-Authors: Melinda L. Telli, Kristin C. Jensen, Kirsten Timms, Julia Reid, Bryan T Hennessy, Gordon B Mills, Zoltan Szallasi, William T Barry, Eric P Winer, Nadine Tung
    Abstract:

    Purpose: BRCA1/2 -mutated and some sporadic triple-negative breast cancers (TNBC) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed on the basis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). Experimental Design: We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy. We then tested the association of HR deficiency, defined as HRD score ≥42 or BRCA1/2 mutation, with response to platinum-based therapy. Results: In a trial of neoadjuvant platinum, gemcitabine, and Iniparib, HR deficiency predicted residual cancer burden score of 0 or I (RCB 0/I) and pathologic complete response (pCR; OR = 4.96, P = 0.0036; OR = 6.52, P = 0.0058). HR deficiency remained a significant predictor of RCB 0/I when adjusted for clinical variables (OR = 5.86, P = 0.012). In two other trials of neoadjuvant cisplatin therapy, HR deficiency predicted RCB 0/I and pCR (OR = 10.18, P = 0.0011; OR = 17.00, P = 0.0066). In a multivariable model of RCB 0/I, HR deficiency retained significance when clinical variables were included (OR = 12.08, P = 0.0017). When restricted to BRCA1/2 nonmutated tumors, response was higher in patients with high HRD scores: RCB 0/I P = 0.062, pCR P = 0.063 in the neoadjuvant platinum, gemcitabine, and Iniparib trial; RCB 0/I P = 0.0039, pCR P = 0.018 in the neoadjuvant cisplatin trials. Conclusions: HR deficiency identifies TNBC tumors, including BRCA1/2 nonmutated tumors more likely to respond to platinum-containing therapy. Clin Cancer Res; 22(15); 3764–73. ©2016 AACR .

  • Association of tumor BRCA1 reversion mutation arising during neoadjuvant platinum-based therapy in breast cancer (BC) with therapy resistance.
    Journal of Clinical Oncology, 2015
    Co-Authors: Anosheh Afghahi, Shaveta Vinayak, Kristin C. Jensen, James M. Ford, Kirsten Timms, Pei-jen Chang, Anne-renee Hartman, Melinda L. Telli
    Abstract:

    1094 Background: In germline BRCA1 or BRCA2 mutation carriers, restoration of tumor BRCA1/2 function by a secondary mutation in these genes has been recognized as a mechanism of acquired resistance to platinum and PARP inhibitors, primarily in ovarian cancer. We set out to evaluate this mechanism of resistance in newly diagnosed BRCA1/2-mutant BC patients (pts) with a poor response to platinum-based therapy. Methods: PrECOG 0105 was a single-arm phase II study in pts with clinical stage I-IIIA triple-negative (TN) or BRCA1/2 mutation-associated BC. Pts received neoadjuvant therapy with gemcitabine, carboplatin and Iniparib every 21 days for 6 cycles (n = 80). The primary endpoint was pathologic complete response, defined as no invasive carcinoma in the breast and axilla. In addition to comprehensive germline BRCA1/2 testing, all pts underwent tumor BRCA1/2 genotyping using pre-treatment biopsies. For mutation carriers with unfavorable response (moderate or extensive residual disease at surgery), tumor BRC...

  • Abstract P5-04-03: Deconvoluting immune cell populations using ‘in silico flow cytometry’ with CIBERSORT: Association with neoadjuvant therapy response and genomic instability in TNBC
    Poster Session Abstracts, 2015
    Co-Authors: Shaveta Vinayak, Sylvia Adams, Kristin C. Jensen, Anosheh Afghahi, James M. Ford, Sunil Badve, Aaron M. Newman, Ash A. Alizadeh, Melinda L. Telli
    Abstract:

    Background: Increased tumor infiltrating lymphocytes (TILs) are prognostic and predictive of therapy response in TNBC. CIBERSORT, a highly novel ‘in silico flow cytometry’ gene expression-based method, can assess the overall immune content and relative levels of distinct leukocyte subsets in tumors. Methods: We applied CIBERSORT to PrECOG 0105, a neoadjuvant trial of carboplatin, gemcitabine and Iniparib for patients with clinical stage I-IIIA TN or BRCA1/2 mutation-associated BC. HE R 0.70, p Conclusions: Neoadjuvant platinum-based therapy response significantly associates with both iTILs and CIBERSORT immune score. A measure of global genomic instability (HRD score) significantly associates with immune score alone. Enumeration of 23 leukocyte subsets in therapy-naive TNBC by CIBERSORT revealed three distinct cell types that significantly predict pCR, two of which also associate with genomic instability. These results suggest an intimate interplay between genomic instability and immune infiltration, potentially shaping adaptive anti-tumor humoral immune responses, and thereby affecting neoadjuvant response in TNBC. Citation Format: Shaveta Vinayak, Aaron Newman, Sylvia Adams, Anosheh Afghahi, Kristin C Jensen, Sunil S Badve, James M Ford, Ash A Alizadeh, Melinda L Telli. Deconvoluting immune cell populations using ‘in silico flow cytometry’ with CIBERSORT: Association with neoadjuvant therapy response and genomic instability in TNBC [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-04-03.

  • phase ii study of gemcitabine carboplatin and Iniparib as neoadjuvant therapy for triple negative and brca1 2 mutation associated breast cancer with assessment of a tumor based measure of genomic instability precog 0105
    Journal of Clinical Oncology, 2015
    Co-Authors: Melinda L. Telli, Shaveta Vinayak, Kristin C. Jensen, Allison W Kurian, Jafi A Lipson, Patrick Flaherty, Kirsten Timms, Victor Abkevich, Elizabeth A Schackmann, Irene L Wapnir
    Abstract:

    Purpose This study was designed to assess efficacy, safety, and predictors of response to Iniparib in combination with gemcitabine and carboplatin in early-stage triple-negative and BRCA1/2 mutation–associated breast cancer. Patients and Methods This single-arm phase II study enrolled patients with stage I to IIIA (T ≥ 1 cm) estrogen receptor–negative (≤ 5%), progesterone receptor–negative (≤ 5%), and human epidermal growth factor receptor 2–negative or BRCA1/2 mutation–associated breast cancer. Neoadjuvant gemcitabine (1,000 mg/m2 intravenously [IV] on days 1 and 8), carboplatin (area under curve of 2 IV on days 1 and 8), and Iniparib (5.6 mg/kg IV on days 1, 4, 8, and 11) were administered every 21 days for four cycles, until the protocol was amended to six cycles. The primary end point was pathologic complete response (no invasive carcinoma in breast or axilla). All patients underwent comprehensive BRCA1/2 genotyping, and homologous recombination deficiency was assessed by loss of heterozygosity (HRD-L...

Luis Manso - One of the best experts on this subject based on the ideXlab platform.

  • SOLTI NeoPARP: a phase II randomized study of two schedules of Iniparib plus paclitaxel versus paclitaxel alone as neoadjuvant therapy in patients with triple-negative breast cancer
    Breast cancer research and treatment, 2015
    Co-Authors: Antonio Llombart-cussac, Hervé Bonnefoi, Cristian Villanueva, Suzette Delaloge, S Morales, J Balmana, Kepa Amillano, Begoña Bermejo, Ana Casas, Luis Manso
    Abstract:

    Iniparib is an investigational agent with antitumor activity of controversial mechanism of action. Two previous trials in advanced triple-negative breast cancer (TNBC) in combination with gemcitabine and carboplatin showed some evidence of efficacy that was not confirmed. This phase II randomized neoadjuvant study was designed to explore its activity and tolerability with weekly paclitaxel (PTX) as neoadjuvant treatment in TNBC patients. 141 patients with Stage II–IIIA TNBC were randomly assigned to receive PTX (80 mg/m2, d1; n = 47) alone or in combination with Iniparib, either once-weekly (PWI) (11.2 mg/kg, d1; n = 46) or twice-weekly (PTI) (5.6 mg/kg, d1, 4; n = 48) for 12 weeks. Primary endpoint was pathologic complete response (pCR) in the breast. pCR rate was similar among the three arms (21, 22, and 19 % for PTX, PWI, and PTI, respectively). Secondary efficacy endpoints were comparable: pCR in breast and axilla (21, 17, and 19 %); best overall response in the breast (60, 61, and 63 %); and breast conservation rate (53, 54, and 50 %). Slightly more patients in the PTI arm presented grade 3/4 neutropenia (4, 0, and 10 %). Grade 1/2 (28, 22, and 29 %), but no grade 3/4 neuropathy, was observed. There were no differences in serious adverse events and treatment-emergent adverse events leading to treatment discontinuation among the three arms. Addition of Iniparib to weekly PTX did not add relevant antitumor activity or toxicity. These results do not support further evaluation of the combination of Iniparib at these doses plus paclitaxel in early TNBC.

  • solti neoparp a phase ii randomized study of two schedules of Iniparib plus paclitaxel and paclitaxel alone as neoadjuvant therapy in patients with triple negative breast cancer tnbc
    Journal of Clinical Oncology, 2012
    Co-Authors: A Llombart, Hervé Bonnefoi, Ana Lluch, Cristian Villanueva, Suzette Delaloge, S Morales, J Balmana, Kepa Amillano, Ana M Casas, Luis Manso
    Abstract:

    1011 Background: Iniparib is an anticancer agent with a mechanism of action still under investigation. A phase 2 randomized neoadjuvant study in patients (pts) with TNBC was designed to explore the activity and tolerability of two schedules of Iniparib with weekly paclitaxel (PTX). Here we report the efficacy and safety results from a planned interim analysis (IA). Methods: The trial accrued a total of 141 pts in October 2011, of whom, 74 are included in this IA. All were chemo-naive, histologicallyconfirmed Stage II-IIIA TNBC (IIA 47%; IIB 35%; IIIA 16%) with a median age of 50 yr. Triple negative status was centrally confirmed [ER/PR <10%, HER2 IHC (0+, 1+) or FISH negative]. Pts were randomized (1:1:1) to receive weekly PTX (80 mg/m2, IV, d 1; N=25) alone or in combination with Iniparib, either on a once weekly (QW) (11.2 mg/kg, IV, d 1; N=25) or twice weekly (BIW) (5.6 mg/kg, IV, d 1, 4; N=24) schedule. The total planned treatment duration was 12 wks. The IA endpoint is pathological complete response ...

  • SOLTI NeoPARP: A phase II, randomized study of two schedules of Iniparib plus paclitaxel and paclitaxel alone as neoadjuvant therapy in patients with triple-negative breast cancer (TNBC).
    Journal of Clinical Oncology, 2012
    Co-Authors: A Llombart, Hervé Bonnefoi, Ana Lluch, Cristian Villanueva, Suzette Delaloge, S Morales, J Balmana, Kepa Amillano, Ana M Casas, Luis Manso
    Abstract:

    1011 Background: Iniparib is an anticancer agent with a mechanism of action still under investigation. A phase 2 randomized neoadjuvant study in patients (pts) with TNBC was designed to explore the activity and tolerability of two schedules of Iniparib with weekly paclitaxel (PTX). Here we report the efficacy and safety results from a planned interim analysis (IA). Methods: The trial accrued a total of 141 pts in October 2011, of whom, 74 are included in this IA. All were chemo-naive, histologicallyconfirmed Stage II-IIIA TNBC (IIA 47%; IIB 35%; IIIA 16%) with a median age of 50 yr. Triple negative status was centrally confirmed [ER/PR

Carey K. Anders - One of the best experts on this subject based on the ideXlab platform.

  • TBCRC 018: phase II study of Iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases
    Breast cancer research and treatment, 2014
    Co-Authors: Carey K. Anders, Rita Nanda, Vandana G. Abramson, Anna Maria Storniolo, Allison M. Deal, Minetta C. Liu, John T. Carpenter, Shannon Puhalla, Amal Melhem-bertrandt, Nan Lin
    Abstract:

    Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of Iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and Iniparib every 3 weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14 months and median OS was 7.8 months. Intracranial RR was 12 %, while intracranial CBR was 27 %. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 diarrhea was rare (3 %). Intrinsic subtyping revealed 19 of 21 tumors (79 %) were basal-like, and intracranial response was associated with high expression of proliferation-related genes. This study suggests a modest benefit of irinotecan plus Iniparib in progressive TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease.

  • TBCRC030: A randomized, phase II study of preoperative cisplatin versus paclitaxel in patients (pts) with BRCA1/2-proficient triple-negative breast cancer (TNBC)—Evaluating the homologous recombination deficiency (HRD) biomarker.
    Journal of Clinical Oncology, 2014
    Co-Authors: Erica L. Mayer, Carey K. Anders, Vandana G. Abramson, Nadine Tung, Ines Vaz-luis, Andrea L. Richardson, Charles M. Perou, Andres Forero-torres, P. Kelly Marcom, Kathy D Miller
    Abstract:

    TPS1145 Background: Both platinum and taxane chemotherapy have activity in TNBC, however biomarkers predictive for activity of either agent are lacking. The HRD assay detects impaired double strand DNA break repair, and may identify BRCA1/2-proficient tumors with a ‘BRCA-like’ phenotype suitable for treatment with DNA repair targeted therapies. A significant correlation between HRD score and response to platinum was reported in a preoperative study of gemcitabine, carboplatin and Iniparib for TNBC. The current trial will prospectively determine the association between HRD score and response to platinum or taxane preoperative chemotherapy in TNBC, as well as explore other potential novel biomarkers of response. Methods: This is a phase II multicenter study randomizing pts with BRCA1/2-proficient, stage I (T1 > 1.5 cm)-III TNBC to preoperative cisplatin 75 mg/m2 q3 wks x 4 or paclitaxel 80 mg/m2 weekly x 12 wks, followed by surgery. Mandatory tissue collection will occur at baseline and surgery. Pts with si...

  • tbcrc 018 phase ii study of Iniparib plus chemotherapy to treat triple negative breast cancer tnbc central nervous system cns metastases mets
    Journal of Clinical Oncology, 2013
    Co-Authors: Carey K. Anders, Rita Nanda, Vandana G. Abramson, Anna Maria Storniolo, Allison M. Deal, John T. Carpenter, Shannon Puhalla, Amal Melhembertrandt, P K Marcom, Catherine Van Poznak
    Abstract:

    515 Background: Nearly half of women with advanced TNBC develop CNS mets. This study evaluated the safety and efficacy of Iniparib, a small molecule anti-cancer agent that penetrates the blood brain barrier (BBB), and the topoisomerase I inhibitor, irinotecan, in patients (pts) with TNBC CNS mets. Methods: Eligible pts had TNBC with new or progressive CNS mets with at least 1 measurable (> 5mm) lesion. Pts received irinotecan 125mg/m2 IV days (d) 1, 8 and Iniparib (initial dose 5.6mg/kg, later changed to 8mg/kg) IV d 1, 4, 8, 11 every 21d. Tumor response rate (RR) was assessed by brain MRI and body CT every 9 weeks. The Kaplan Meier method estimated the primary endpoint of time to progression (TTP, intracranial [modified RECIST] or extracranial [RECIST 1.1]). Secondary endpoints were RR, PFS, OS, quality of life (QOL) and correlative endpoints. Results: Of 37 pts who began treatment, 34 were evaluable for efficacy. Mean age was 48 yrs (34 – 80 yrs). BRCA status was known for 16 patients of whom 5 had a mu...

  • TBCRC 018: Phase II study of Iniparib plus chemotherapy to treat triple-negative breast cancer (TNBC) brain metastases (BM).
    Journal of Clinical Oncology, 2011
    Co-Authors: Carey K. Anders, Rita Nanda, Mohan Liu, K. L. Blackwell, C. H. Van Poznak, Vandana G. Abramson, Anna Maria Storniolo, Nu Lin, Vered Stearns, A. Melhem
    Abstract:

    TPS127 Background: TNBC is an aggressive subset of BC with high rates of BM and poor survival. Iniparib, an anticancer agent with poly (ADP-ribose) polymerase (PARP) inhibitory activity, in combination with DNA-damaging chemotherapy appears to be effective in advanced TNBC. Iniparib penetrates the blood brain barrier. We are evaluating the efficacy and safety of Iniparib plus irinotecan, a topoisomerase I inhibitor with activity in primary and secondary central nervous system (CNS) tumors, in pts with TNBC BM. Methods: Pts with TNBC BM measuring > 0.5cm are eligible for enrollment. There are no limits to prior therapies, including Iniparib; stable or decreasing steroids ≥ 7 days prior to study entry. Pts with leptomeningeal disease are excluded. Cohort 1: new and/or progressive BM following CNS radiation; Cohort 2: asymptomatic, CNS-radiation therapy naive patients. Pts receive irinotecan (125 mg/m2 IV D 1, 8) prior to Iniparib (5.6mg/kg IV D 1, 4, 8, 11) of a 21 day cycle. Intra- and extracranial disease...

Hervé Bonnefoi - One of the best experts on this subject based on the ideXlab platform.

  • Iniparib administered weekly or twice-weekly in combination with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: a phase II randomized open-label study with pharmacokinetics
    Breast Cancer Research and Treatment, 2019
    Co-Authors: Veronique Dieras, Agnes Jager, Stefania Zambelli, Bruno Coudert, J Gligorov, Xavier Pivot, Enrique Alba, Hervé Bonnefoi, Ahmad Awada, Geoffrey J. Lindeman
    Abstract:

    PurposeMetastatic triple-negative breast cancer (TNBC) is a phenotypic breast cancer subgroup with a very poor prognosis, despite standard treatments. Combined twice-weekly Iniparib and gemcitabine/carboplatin (GC+tw-Iniparib) showed benefit over gemcitabine/carboplatin in a randomized phase II trial, and a phase III was initiated comparing these regimens. The present phase II study was initiated to compare GC+tw-Iniparib with a more practical once-weekly schedule (GC+w-Iniparib) in TNBC.MethodsMetastatic TNBC patients were randomized to receive Iniparib weekly (11.2 mg/kg on days 1 and 8) or twice-weekly (5.6 mg/kg on days 1, 4, 8, and 11) with gemcitabine (1000 mg/m2) and carboplatin (area under the curve 2 on days 1 and 8), every 3 weeks. The primary endpoint was the overall response rate (ORR). Pharmacokinetics of Iniparib and its two metabolites were analyzed.ResultsA total of 163 patients were randomized, 82 GC+w-Iniparib and 81 GC+tw-Iniparib. Demographic and baseline characteristics were well balanced. ORR was 34.1% (95% CI 23.9–44.4%) vs. 29.6% (95% CI 19.7–39.6%) and median progression-free survival was 5.5 months (95% CI 4.2–5.7) vs. 4.3 months (95% CI 3.0–5.8) for GC+w-Iniparib and GC+tw-Iniparib, respectively. Safety was similar across treatment arms in terms of event severity and type. Iniparib plasma concentrations and exposure were two-fold higher with w-Iniparib compared to tw-Iniparib. Iniparib and its metabolites were cleared rapidly with a terminal half-life of 

  • Iniparib administered weekly or twice weekly in combination with gemcitabine carboplatin in patients with metastatic triple negative breast cancer a phase ii randomized open label study with pharmacokinetics
    Breast Cancer Research and Treatment, 2019
    Co-Authors: Veronique Dieras, Agnes Jager, Stefania Zambelli, Bruno Coudert, J Gligorov, Xavier Pivot, Hervé Bonnefoi, Ahmad Awada, Emilio Alba, Geoffrey J. Lindeman
    Abstract:

    PURPOSE Metastatic triple-negative breast cancer (TNBC) is a phenotypic breast cancer subgroup with a very poor prognosis, despite standard treatments. Combined twice-weekly Iniparib and gemcitabine/carboplatin (GC+tw-Iniparib) showed benefit over gemcitabine/carboplatin in a randomized phase II trial, and a phase III was initiated comparing these regimens. The present phase II study was initiated to compare GC+tw-Iniparib with a more practical once-weekly schedule (GC+w-Iniparib) in TNBC. METHODS Metastatic TNBC patients were randomized to receive Iniparib weekly (11.2 mg/kg on days 1 and 8) or twice-weekly (5.6 mg/kg on days 1, 4, 8, and 11) with gemcitabine (1000 mg/m2) and carboplatin (area under the curve 2 on days 1 and 8), every 3 weeks. The primary endpoint was the overall response rate (ORR). Pharmacokinetics of Iniparib and its two metabolites were analyzed. RESULTS A total of 163 patients were randomized, 82 GC+w-Iniparib and 81 GC+tw-Iniparib. Demographic and baseline characteristics were well balanced. ORR was 34.1% (95% CI 23.9-44.4%) vs. 29.6% (95% CI 19.7-39.6%) and median progression-free survival was 5.5 months (95% CI 4.2-5.7) vs. 4.3 months (95% CI 3.0-5.8) for GC+w-Iniparib and GC+tw-Iniparib, respectively. Safety was similar across treatment arms in terms of event severity and type. Iniparib plasma concentrations and exposure were two-fold higher with w-Iniparib compared to tw-Iniparib. Iniparib and its metabolites were cleared rapidly with a terminal half-life of < 1 h, without accumulation. CONCLUSIONS Despite a doubled maximum concentration with weekly Iniparib, no detectable differences in safety or efficacy were observed between the weekly and twice-weekly administration schedules in this population. TRIAL REGISTRATION ClinicalTrial.gov Identifier NCT01045304.

  • SOLTI NeoPARP: a phase II randomized study of two schedules of Iniparib plus paclitaxel versus paclitaxel alone as neoadjuvant therapy in patients with triple-negative breast cancer
    Breast cancer research and treatment, 2015
    Co-Authors: Antonio Llombart-cussac, Hervé Bonnefoi, Cristian Villanueva, Suzette Delaloge, S Morales, J Balmana, Kepa Amillano, Begoña Bermejo, Ana Casas, Luis Manso
    Abstract:

    Iniparib is an investigational agent with antitumor activity of controversial mechanism of action. Two previous trials in advanced triple-negative breast cancer (TNBC) in combination with gemcitabine and carboplatin showed some evidence of efficacy that was not confirmed. This phase II randomized neoadjuvant study was designed to explore its activity and tolerability with weekly paclitaxel (PTX) as neoadjuvant treatment in TNBC patients. 141 patients with Stage II–IIIA TNBC were randomly assigned to receive PTX (80 mg/m2, d1; n = 47) alone or in combination with Iniparib, either once-weekly (PWI) (11.2 mg/kg, d1; n = 46) or twice-weekly (PTI) (5.6 mg/kg, d1, 4; n = 48) for 12 weeks. Primary endpoint was pathologic complete response (pCR) in the breast. pCR rate was similar among the three arms (21, 22, and 19 % for PTX, PWI, and PTI, respectively). Secondary efficacy endpoints were comparable: pCR in breast and axilla (21, 17, and 19 %); best overall response in the breast (60, 61, and 63 %); and breast conservation rate (53, 54, and 50 %). Slightly more patients in the PTI arm presented grade 3/4 neutropenia (4, 0, and 10 %). Grade 1/2 (28, 22, and 29 %), but no grade 3/4 neuropathy, was observed. There were no differences in serious adverse events and treatment-emergent adverse events leading to treatment discontinuation among the three arms. Addition of Iniparib to weekly PTX did not add relevant antitumor activity or toxicity. These results do not support further evaluation of the combination of Iniparib at these doses plus paclitaxel in early TNBC.

  • solti neoparp a phase ii randomized study of two schedules of Iniparib plus paclitaxel and paclitaxel alone as neoadjuvant therapy in patients with triple negative breast cancer tnbc
    Journal of Clinical Oncology, 2012
    Co-Authors: A Llombart, Hervé Bonnefoi, Ana Lluch, Cristian Villanueva, Suzette Delaloge, S Morales, J Balmana, Kepa Amillano, Ana M Casas, Luis Manso
    Abstract:

    1011 Background: Iniparib is an anticancer agent with a mechanism of action still under investigation. A phase 2 randomized neoadjuvant study in patients (pts) with TNBC was designed to explore the activity and tolerability of two schedules of Iniparib with weekly paclitaxel (PTX). Here we report the efficacy and safety results from a planned interim analysis (IA). Methods: The trial accrued a total of 141 pts in October 2011, of whom, 74 are included in this IA. All were chemo-naive, histologicallyconfirmed Stage II-IIIA TNBC (IIA 47%; IIB 35%; IIIA 16%) with a median age of 50 yr. Triple negative status was centrally confirmed [ER/PR <10%, HER2 IHC (0+, 1+) or FISH negative]. Pts were randomized (1:1:1) to receive weekly PTX (80 mg/m2, IV, d 1; N=25) alone or in combination with Iniparib, either on a once weekly (QW) (11.2 mg/kg, IV, d 1; N=25) or twice weekly (BIW) (5.6 mg/kg, IV, d 1, 4; N=24) schedule. The total planned treatment duration was 12 wks. The IA endpoint is pathological complete response ...

  • SOLTI NeoPARP: A phase II, randomized study of two schedules of Iniparib plus paclitaxel and paclitaxel alone as neoadjuvant therapy in patients with triple-negative breast cancer (TNBC).
    Journal of Clinical Oncology, 2012
    Co-Authors: A Llombart, Hervé Bonnefoi, Ana Lluch, Cristian Villanueva, Suzette Delaloge, S Morales, J Balmana, Kepa Amillano, Ana M Casas, Luis Manso
    Abstract:

    1011 Background: Iniparib is an anticancer agent with a mechanism of action still under investigation. A phase 2 randomized neoadjuvant study in patients (pts) with TNBC was designed to explore the activity and tolerability of two schedules of Iniparib with weekly paclitaxel (PTX). Here we report the efficacy and safety results from a planned interim analysis (IA). Methods: The trial accrued a total of 141 pts in October 2011, of whom, 74 are included in this IA. All were chemo-naive, histologicallyconfirmed Stage II-IIIA TNBC (IIA 47%; IIB 35%; IIIA 16%) with a median age of 50 yr. Triple negative status was centrally confirmed [ER/PR

Shaveta Vinayak - One of the best experts on this subject based on the ideXlab platform.

  • Tumor BRCA1 Reversion Mutation Arising during Neoadjuvant Platinum-Based Chemotherapy in Triple-Negative Breast Cancer Is Associated with Therapy Resistance
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2017
    Co-Authors: Anosheh Afghahi, Shaveta Vinayak, Kristin C. Jensen, Allison W Kurian, Kirsten Timms, Elizabeth A Schackmann, Robert W. Carlson, Pei-jen Chang, Anne-renee Hartman, James M. Ford
    Abstract:

    Purpose: In germline BRCA1 or BRCA2 (BRCA1/2) mutation carriers, restoration of tumor BRCA1/2 function by a secondary mutation is recognized as a mechanism of resistance to platinum and PARP inhibitors, primarily in ovarian cancer. We evaluated this mechanism of resistance in newly diagnosed patients with BRCA1/2-mutant breast cancer with poor response to neoadjuvant platinum-based therapy.Experimental Design: PrECOG 0105 was a phase II neoadjuvant study of gemcitabine, carboplatin, and Iniparib in patients with stage I-IIIA triple-negative or BRCA1/2 mutation-associated breast cancer (n = 80). All patients underwent comprehensive BRCA1/2 genotyping. For mutation carriers with moderate or extensive residual disease after neoadjuvant therapy, BRCA1/2 status was resequenced in the residual surgical breast tumor tissue.Results: Nineteen patients had a deleterious germline BRCA1/2 mutation, and four had moderate residual disease at surgery. BRCA1/2 sequencing of residual tissue was performed on three patients. These patients had BRCA1 1479delAG, 3374insGA, and W1712X mutations, respectively, with LOH at these loci in the pretreatment tumors. In the first case, a new BRCA1 mutation was detected in the residual disease. This resulted in a 14-amino acid deletion and restoration of the BRCA1 reading frame. A local relapse biopsy 4 months later revealed the identical reversion mutation, and the patient subsequently died from metastatic breast cancer.Conclusions: We report a BRCA1 reversion mutation in a patient newly diagnosed with triple-negative breast cancer that developed over 18 weeks of platinum-based neoadjuvant therapy. This was associated with poor therapy response, early relapse, and death. Clin Cancer Res; 23(13); 3365-70. ©2017 AACR.

  • Association of tumor BRCA1 reversion mutation arising during neoadjuvant platinum-based therapy in breast cancer (BC) with therapy resistance.
    Journal of Clinical Oncology, 2015
    Co-Authors: Anosheh Afghahi, Shaveta Vinayak, Kristin C. Jensen, James M. Ford, Kirsten Timms, Pei-jen Chang, Anne-renee Hartman, Melinda L. Telli
    Abstract:

    1094 Background: In germline BRCA1 or BRCA2 mutation carriers, restoration of tumor BRCA1/2 function by a secondary mutation in these genes has been recognized as a mechanism of acquired resistance to platinum and PARP inhibitors, primarily in ovarian cancer. We set out to evaluate this mechanism of resistance in newly diagnosed BRCA1/2-mutant BC patients (pts) with a poor response to platinum-based therapy. Methods: PrECOG 0105 was a single-arm phase II study in pts with clinical stage I-IIIA triple-negative (TN) or BRCA1/2 mutation-associated BC. Pts received neoadjuvant therapy with gemcitabine, carboplatin and Iniparib every 21 days for 6 cycles (n = 80). The primary endpoint was pathologic complete response, defined as no invasive carcinoma in the breast and axilla. In addition to comprehensive germline BRCA1/2 testing, all pts underwent tumor BRCA1/2 genotyping using pre-treatment biopsies. For mutation carriers with unfavorable response (moderate or extensive residual disease at surgery), tumor BRC...

  • Abstract P5-04-03: Deconvoluting immune cell populations using ‘in silico flow cytometry’ with CIBERSORT: Association with neoadjuvant therapy response and genomic instability in TNBC
    Poster Session Abstracts, 2015
    Co-Authors: Shaveta Vinayak, Sylvia Adams, Kristin C. Jensen, Anosheh Afghahi, James M. Ford, Sunil Badve, Aaron M. Newman, Ash A. Alizadeh, Melinda L. Telli
    Abstract:

    Background: Increased tumor infiltrating lymphocytes (TILs) are prognostic and predictive of therapy response in TNBC. CIBERSORT, a highly novel ‘in silico flow cytometry’ gene expression-based method, can assess the overall immune content and relative levels of distinct leukocyte subsets in tumors. Methods: We applied CIBERSORT to PrECOG 0105, a neoadjuvant trial of carboplatin, gemcitabine and Iniparib for patients with clinical stage I-IIIA TN or BRCA1/2 mutation-associated BC. HE R 0.70, p Conclusions: Neoadjuvant platinum-based therapy response significantly associates with both iTILs and CIBERSORT immune score. A measure of global genomic instability (HRD score) significantly associates with immune score alone. Enumeration of 23 leukocyte subsets in therapy-naive TNBC by CIBERSORT revealed three distinct cell types that significantly predict pCR, two of which also associate with genomic instability. These results suggest an intimate interplay between genomic instability and immune infiltration, potentially shaping adaptive anti-tumor humoral immune responses, and thereby affecting neoadjuvant response in TNBC. Citation Format: Shaveta Vinayak, Aaron Newman, Sylvia Adams, Anosheh Afghahi, Kristin C Jensen, Sunil S Badve, James M Ford, Ash A Alizadeh, Melinda L Telli. Deconvoluting immune cell populations using ‘in silico flow cytometry’ with CIBERSORT: Association with neoadjuvant therapy response and genomic instability in TNBC [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-04-03.

  • phase ii study of gemcitabine carboplatin and Iniparib as neoadjuvant therapy for triple negative and brca1 2 mutation associated breast cancer with assessment of a tumor based measure of genomic instability precog 0105
    Journal of Clinical Oncology, 2015
    Co-Authors: Melinda L. Telli, Shaveta Vinayak, Kristin C. Jensen, Allison W Kurian, Jafi A Lipson, Patrick Flaherty, Kirsten Timms, Victor Abkevich, Elizabeth A Schackmann, Irene L Wapnir
    Abstract:

    Purpose This study was designed to assess efficacy, safety, and predictors of response to Iniparib in combination with gemcitabine and carboplatin in early-stage triple-negative and BRCA1/2 mutation–associated breast cancer. Patients and Methods This single-arm phase II study enrolled patients with stage I to IIIA (T ≥ 1 cm) estrogen receptor–negative (≤ 5%), progesterone receptor–negative (≤ 5%), and human epidermal growth factor receptor 2–negative or BRCA1/2 mutation–associated breast cancer. Neoadjuvant gemcitabine (1,000 mg/m2 intravenously [IV] on days 1 and 8), carboplatin (area under curve of 2 IV on days 1 and 8), and Iniparib (5.6 mg/kg IV on days 1, 4, 8, and 11) were administered every 21 days for four cycles, until the protocol was amended to six cycles. The primary end point was pathologic complete response (no invasive carcinoma in breast or axilla). All patients underwent comprehensive BRCA1/2 genotyping, and homologous recombination deficiency was assessed by loss of heterozygosity (HRD-L...

  • Phase II Study of Gemcitabine, Carboplatin, and Iniparib As Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation–Associated Breast Cancer With Assessment of a Tumor-Based Measure of Genomic Instability: PrECOG 0105
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2015
    Co-Authors: Melinda L. Telli, Shaveta Vinayak, Kristin C. Jensen, Allison W Kurian, Jafi A Lipson, Patrick Flaherty, Kirsten Timms, Victor Abkevich, Elizabeth A Schackmann, Irene L Wapnir
    Abstract:

    Purpose This study was designed to assess efficacy, safety, and predictors of response to Iniparib in combination with gemcitabine and carboplatin in early-stage triple-negative and BRCA1/2 mutation–associated breast cancer. Patients and Methods This single-arm phase II study enrolled patients with stage I to IIIA (T ≥ 1 cm) estrogen receptor–negative (≤ 5%), progesterone receptor–negative (≤ 5%), and human epidermal growth factor receptor 2–negative or BRCA1/2 mutation–associated breast cancer. Neoadjuvant gemcitabine (1,000 mg/m2 intravenously [IV] on days 1 and 8), carboplatin (area under curve of 2 IV on days 1 and 8), and Iniparib (5.6 mg/kg IV on days 1, 4, 8, and 11) were administered every 21 days for four cycles, until the protocol was amended to six cycles. The primary end point was pathologic complete response (no invasive carcinoma in breast or axilla). All patients underwent comprehensive BRCA1/2 genotyping, and homologous recombination deficiency was assessed by loss of heterozygosity (HRD-L...