BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin

Tamar Safra, Lucia Borgato, Maria Ornella Nicoletto, Linda Rolnitzky, Sharon Pelles-Avraham, Ravit Geva, Martin Edward Donach, John Curtin, Akiva Novetsky, Tal Grenader, Wei Chu V Lai, Alberto Gabizon, Leslie Boyd, Franco Muggia

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Abstract

Epithelial ovarian cancer (EOC) patients with BRCA mutations (BRCA+) benefit from platinum-based treatment more than noncarriers. Impaired ability to repair DNA by homologous recombination increases their chemosensitivity. We investigated whether BRCA+ predicts for improved outcome following pegylated liposomal doxorubicin (PLD) for recurrence. Recurrent EOC patients receiving second- or third-line PLD from 1998 to 2009 in 4 institutions (Tel Aviv, New York, Padua, and Jerusalem) were subjected to retrospective comparisons between 40 (25.8%) patients who were BRCA+, and 115 (74.2%) deemed nonhereditary (NH). Median age was 59 years (range 31-83); 111 (72%) had a platinum-free interval more than 6 months [PLD alone (n = 65) and PLD plus platinum (n = 90)]; 104 received PLD in second-line and 51 in third-line. BRCA+ versus NH comparisons: median time to treatment failure (TTF) 15.8 months [95% confidence interval (CI): 11.4-21.6] versus 8.1 months (95% CI: 6.1-10.3; P=0.009); overall survival (OS) 56.8 months (95% CI: 32.5-indeterminate) versus 22.6 months (95% CI: 17.0-34.1; P = 0.002). In multivariate Cox models BRCA status was significantly associated with TTF (HR = 1.66; 95% CI: 1.08-2.55; P = 0.02) and OS (adjusted HR 2.07; 95% CI: 1.18-3.60; P = 0.01). Adjusted HR relating platinum sensitivity to OS was 1.58 (95% CI: 0.93-2.68; P = 0.09); no significant association found with age at diagnosis, line of PLD or combinations, or institution. In this retrospective analysis, recurrent EOC BRCA mutation carriers treated with PLD had an improved outcome, and this result seemed to be independent of platinum sensitivity. Tumors arising in a background of defective BRCA function are more sensitive than other EOCs to DNA-damaging agents such as PLD, even after acquiring platinum resistance.

Original languageEnglish (US)
Pages (from-to)2000-2007
Number of pages8
JournalMolecular Cancer Therapeutics
Volume10
Issue number10
DOIs
StatePublished - Oct 2011
Externally publishedYes

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Platinum
Confidence Intervals
Mutation
Treatment Failure
Survival
Recombinational DNA Repair
Ovarian epithelial cancer
liposomal doxorubicin
Proportional Hazards Models
Recurrence
DNA
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin. / Safra, Tamar; Borgato, Lucia; Nicoletto, Maria Ornella; Rolnitzky, Linda; Pelles-Avraham, Sharon; Geva, Ravit; Donach, Martin Edward; Curtin, John; Novetsky, Akiva; Grenader, Tal; Lai, Wei Chu V; Gabizon, Alberto; Boyd, Leslie; Muggia, Franco.

In: Molecular Cancer Therapeutics, Vol. 10, No. 10, 10.2011, p. 2000-2007.

Research output: Contribution to journalArticle

Safra, T, Borgato, L, Nicoletto, MO, Rolnitzky, L, Pelles-Avraham, S, Geva, R, Donach, ME, Curtin, J, Novetsky, A, Grenader, T, Lai, WCV, Gabizon, A, Boyd, L & Muggia, F 2011, 'BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin', Molecular Cancer Therapeutics, vol. 10, no. 10, pp. 2000-2007. https://doi.org/10.1158/1535-7163.MCT-11-0272
Safra, Tamar ; Borgato, Lucia ; Nicoletto, Maria Ornella ; Rolnitzky, Linda ; Pelles-Avraham, Sharon ; Geva, Ravit ; Donach, Martin Edward ; Curtin, John ; Novetsky, Akiva ; Grenader, Tal ; Lai, Wei Chu V ; Gabizon, Alberto ; Boyd, Leslie ; Muggia, Franco. / BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin. In: Molecular Cancer Therapeutics. 2011 ; Vol. 10, No. 10. pp. 2000-2007.
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abstract = "Epithelial ovarian cancer (EOC) patients with BRCA mutations (BRCA+) benefit from platinum-based treatment more than noncarriers. Impaired ability to repair DNA by homologous recombination increases their chemosensitivity. We investigated whether BRCA+ predicts for improved outcome following pegylated liposomal doxorubicin (PLD) for recurrence. Recurrent EOC patients receiving second- or third-line PLD from 1998 to 2009 in 4 institutions (Tel Aviv, New York, Padua, and Jerusalem) were subjected to retrospective comparisons between 40 (25.8{\%}) patients who were BRCA+, and 115 (74.2{\%}) deemed nonhereditary (NH). Median age was 59 years (range 31-83); 111 (72{\%}) had a platinum-free interval more than 6 months [PLD alone (n = 65) and PLD plus platinum (n = 90)]; 104 received PLD in second-line and 51 in third-line. BRCA+ versus NH comparisons: median time to treatment failure (TTF) 15.8 months [95{\%} confidence interval (CI): 11.4-21.6] versus 8.1 months (95{\%} CI: 6.1-10.3; P=0.009); overall survival (OS) 56.8 months (95{\%} CI: 32.5-indeterminate) versus 22.6 months (95{\%} CI: 17.0-34.1; P = 0.002). In multivariate Cox models BRCA status was significantly associated with TTF (HR = 1.66; 95{\%} CI: 1.08-2.55; P = 0.02) and OS (adjusted HR 2.07; 95{\%} CI: 1.18-3.60; P = 0.01). Adjusted HR relating platinum sensitivity to OS was 1.58 (95{\%} CI: 0.93-2.68; P = 0.09); no significant association found with age at diagnosis, line of PLD or combinations, or institution. In this retrospective analysis, recurrent EOC BRCA mutation carriers treated with PLD had an improved outcome, and this result seemed to be independent of platinum sensitivity. Tumors arising in a background of defective BRCA function are more sensitive than other EOCs to DNA-damaging agents such as PLD, even after acquiring platinum resistance.",
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AU - Safra, Tamar

AU - Borgato, Lucia

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AU - Pelles-Avraham, Sharon

AU - Geva, Ravit

AU - Donach, Martin Edward

AU - Curtin, John

AU - Novetsky, Akiva

AU - Grenader, Tal

AU - Lai, Wei Chu V

AU - Gabizon, Alberto

AU - Boyd, Leslie

AU - Muggia, Franco

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N2 - Epithelial ovarian cancer (EOC) patients with BRCA mutations (BRCA+) benefit from platinum-based treatment more than noncarriers. Impaired ability to repair DNA by homologous recombination increases their chemosensitivity. We investigated whether BRCA+ predicts for improved outcome following pegylated liposomal doxorubicin (PLD) for recurrence. Recurrent EOC patients receiving second- or third-line PLD from 1998 to 2009 in 4 institutions (Tel Aviv, New York, Padua, and Jerusalem) were subjected to retrospective comparisons between 40 (25.8%) patients who were BRCA+, and 115 (74.2%) deemed nonhereditary (NH). Median age was 59 years (range 31-83); 111 (72%) had a platinum-free interval more than 6 months [PLD alone (n = 65) and PLD plus platinum (n = 90)]; 104 received PLD in second-line and 51 in third-line. BRCA+ versus NH comparisons: median time to treatment failure (TTF) 15.8 months [95% confidence interval (CI): 11.4-21.6] versus 8.1 months (95% CI: 6.1-10.3; P=0.009); overall survival (OS) 56.8 months (95% CI: 32.5-indeterminate) versus 22.6 months (95% CI: 17.0-34.1; P = 0.002). In multivariate Cox models BRCA status was significantly associated with TTF (HR = 1.66; 95% CI: 1.08-2.55; P = 0.02) and OS (adjusted HR 2.07; 95% CI: 1.18-3.60; P = 0.01). Adjusted HR relating platinum sensitivity to OS was 1.58 (95% CI: 0.93-2.68; P = 0.09); no significant association found with age at diagnosis, line of PLD or combinations, or institution. In this retrospective analysis, recurrent EOC BRCA mutation carriers treated with PLD had an improved outcome, and this result seemed to be independent of platinum sensitivity. Tumors arising in a background of defective BRCA function are more sensitive than other EOCs to DNA-damaging agents such as PLD, even after acquiring platinum resistance.

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