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

Melinda L. Telli, Kristin C. Jensen, Shaveta Vinayak, Allison W. Kurian, Jafi A. Lipson, Patrick J. Flaherty, Kirsten Timms, Victor Abkevich, Elizabeth A. Schackmann, Irene L. Wapnir, Robert W. Carlson, Pei Jen Chang, Joseph A. Sparano, Bobbie Head, Lori J. Goldstein, Barbara Haley, Shaker R. Dakhil, Julia E. Reid, Anne Renee Hartman, Judith Manola & 1 others James M. Ford

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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-LOH) in pretreatment core breast biopsies. Results: Among 80 patients, median age was 48 years; 19 patients (24%) had germline BRCA1 or BRCA2 mutations; clinical stage was I (13%), IIA (36%), IIB (36%), and IIIA (15%). Overall pathologic complete response rate in the intent-to-treat population (n = 80) was 36% (90% CI, 27 to 46). Mean HRD-LOH scores were higher in responders compared with nonresponders (P = .02) and remained significant when BRCA1/2 germline mutations carriers were excluded (P = .021). Conclusion: Preoperative combination of gemcitabine, carboplatin, and iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer. The HRD-LOH assay was able to identify patients with sporadic triple-negative breast cancer lacking a BRCA1/2 mutation, but with an elevated HRD-LOH score, who achieved a favorable pathologic response. Confirmatory controlled trials are warranted.

Original languageEnglish (US)
Pages (from-to)1895-1901
Number of pages7
JournalJournal of Clinical Oncology
Volume33
Issue number17
DOIs
StatePublished - Jun 10 2015

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gemcitabine
Neoadjuvant Therapy
Genomic Instability
Carboplatin
Breast Neoplasms
Mutation
Neoplasms
Triple Negative Breast Neoplasms
Axilla
Germ-Line Mutation
Loss of Heterozygosity
Homologous Recombination
Progesterone Receptors
Estrogen Receptors
Area Under Curve
iniparib
Breast
Biopsy
Safety

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Telli, Melinda L.; Jensen, Kristin C.; Vinayak, Shaveta; Kurian, Allison W.; Lipson, Jafi A.; Flaherty, Patrick J.; Timms, Kirsten; Abkevich, Victor; Schackmann, Elizabeth A.; Wapnir, Irene L.; Carlson, Robert W.; Chang, Pei Jen; Sparano, Joseph A.; Head, Bobbie; Goldstein, Lori J.; Haley, Barbara; Dakhil, Shaker R.; Reid, Julia E.; Hartman, Anne Renee; Manola, Judith; Ford, James M.

In: Journal of Clinical Oncology, Vol. 33, No. 17, 10.06.2015, p. 1895-1901.

Research output: Contribution to journalArticle

Telli, ML, Jensen, KC, Vinayak, S, Kurian, AW, Lipson, JA, Flaherty, PJ, Timms, K, Abkevich, V, Schackmann, EA, Wapnir, IL, Carlson, RW, Chang, PJ, Sparano, JA, Head, B, Goldstein, LJ, Haley, B, Dakhil, SR, Reid, JE, Hartman, AR, Manola, J & Ford, JM 2015, '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, vol. 33, no. 17, pp. 1895-1901. https://doi.org/10.1200/JCO.2014.57.0085
Telli, Melinda L. ; Jensen, Kristin C. ; Vinayak, Shaveta ; Kurian, Allison W. ; Lipson, Jafi A. ; Flaherty, Patrick J. ; Timms, Kirsten ; Abkevich, Victor ; Schackmann, Elizabeth A. ; Wapnir, Irene L. ; Carlson, Robert W. ; Chang, Pei Jen ; Sparano, Joseph A. ; Head, Bobbie ; Goldstein, Lori J. ; Haley, Barbara ; Dakhil, Shaker R. ; Reid, Julia E. ; Hartman, Anne Renee ; Manola, Judith ; Ford, James M. / 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. In: Journal of Clinical Oncology. 2015 ; Vol. 33, No. 17. pp. 1895-1901.
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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-LOH) in pretreatment core breast biopsies. Results: Among 80 patients, median age was 48 years; 19 patients (24{\%}) had germline BRCA1 or BRCA2 mutations; clinical stage was I (13{\%}), IIA (36{\%}), IIB (36{\%}), and IIIA (15{\%}). Overall pathologic complete response rate in the intent-to-treat population (n = 80) was 36{\%} (90{\%} CI, 27 to 46). Mean HRD-LOH scores were higher in responders compared with nonresponders (P = .02) and remained significant when BRCA1/2 germline mutations carriers were excluded (P = .021). Conclusion: Preoperative combination of gemcitabine, carboplatin, and iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer. The HRD-LOH assay was able to identify patients with sporadic triple-negative breast cancer lacking a BRCA1/2 mutation, but with an elevated HRD-LOH score, who achieved a favorable pathologic response. Confirmatory controlled trials are warranted.",
author = "Telli, {Melinda L.} and Jensen, {Kristin C.} and Shaveta Vinayak and Kurian, {Allison W.} and Lipson, {Jafi A.} and Flaherty, {Patrick J.} and Kirsten Timms and Victor Abkevich and Schackmann, {Elizabeth A.} and Wapnir, {Irene L.} and Carlson, {Robert W.} and Chang, {Pei Jen} and Sparano, {Joseph A.} and Bobbie Head and Goldstein, {Lori J.} and Barbara Haley and Dakhil, {Shaker R.} and Reid, {Julia E.} and Hartman, {Anne Renee} and Judith Manola and Ford, {James M.}",
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TY - JOUR

T1 - 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

T2 - PrECOG 0105

AU - Telli, Melinda L.

AU - Jensen, Kristin C.

AU - Vinayak, Shaveta

AU - Kurian, Allison W.

AU - Lipson, Jafi A.

AU - Flaherty, Patrick J.

AU - Timms, Kirsten

AU - Abkevich, Victor

AU - Schackmann, Elizabeth A.

AU - Wapnir, Irene L.

AU - Carlson, Robert W.

AU - Chang, Pei Jen

AU - Sparano, Joseph A.

AU - Head, Bobbie

AU - Goldstein, Lori J.

AU - Haley, Barbara

AU - Dakhil, Shaker R.

AU - Reid, Julia E.

AU - Hartman, Anne Renee

AU - Manola, Judith

AU - Ford, James M.

PY - 2015/6/10

Y1 - 2015/6/10

N2 - 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-LOH) in pretreatment core breast biopsies. Results: Among 80 patients, median age was 48 years; 19 patients (24%) had germline BRCA1 or BRCA2 mutations; clinical stage was I (13%), IIA (36%), IIB (36%), and IIIA (15%). Overall pathologic complete response rate in the intent-to-treat population (n = 80) was 36% (90% CI, 27 to 46). Mean HRD-LOH scores were higher in responders compared with nonresponders (P = .02) and remained significant when BRCA1/2 germline mutations carriers were excluded (P = .021). Conclusion: Preoperative combination of gemcitabine, carboplatin, and iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer. The HRD-LOH assay was able to identify patients with sporadic triple-negative breast cancer lacking a BRCA1/2 mutation, but with an elevated HRD-LOH score, who achieved a favorable pathologic response. Confirmatory controlled trials are warranted.

AB - 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-LOH) in pretreatment core breast biopsies. Results: Among 80 patients, median age was 48 years; 19 patients (24%) had germline BRCA1 or BRCA2 mutations; clinical stage was I (13%), IIA (36%), IIB (36%), and IIIA (15%). Overall pathologic complete response rate in the intent-to-treat population (n = 80) was 36% (90% CI, 27 to 46). Mean HRD-LOH scores were higher in responders compared with nonresponders (P = .02) and remained significant when BRCA1/2 germline mutations carriers were excluded (P = .021). Conclusion: Preoperative combination of gemcitabine, carboplatin, and iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer. The HRD-LOH assay was able to identify patients with sporadic triple-negative breast cancer lacking a BRCA1/2 mutation, but with an elevated HRD-LOH score, who achieved a favorable pathologic response. Confirmatory controlled trials are warranted.

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DO - 10.1200/JCO.2014.57.0085

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JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

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