TOP2A gene copy gain predicts response of epithelial ovarian cancers to pegylated liposomal doxorubicin: TOP2A as marker of response to PLD in ovarian cancer

J. Erriquez, P. Becco, M. Olivero, R. Ponzone, F. Maggiorotto, A. Ferrero, M. S. Scalzo, E. M. Canuto, A. Sapino, L. Verdun Di Cantogno, P. Bruna, M. Aglietta, M. F. Di Renzo, G. Valabrega

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Abstract

Objective The treatment of platinum resistant/refractory epithelial ovarian cancer (EOC) is a challenge for oncologists. One of the most utilized drugs in these patients is pegylated liposomal doxorubicin (PLD). As PLD is active only in a small subset of patients and causes side effects, selection of responsive patients is an unmet need and might be guided by the status of the DNA topoisomerase II alpha (TOP2A) that is poisoned by the drug. Methods From 176 ovarian cancers treated in three institutions, we selected 38 patients treated with PLD monotherapy as second/third line of treatment. TOP2A gene copies were measured using Fluorescent In Situ Hybridization (FISH) and expression evaluated using immunohistochemistry. Patients' derived xenografts (PDXs) of ovarian cancers were used to assess the correlation between TOP2A protein expression and response to PLD. Results Clinical data showed that TOP2A gene gain that is paralleled by increased expression of the protein, was associated with a higher probability of clinical benefit from PLD. Treatment of PDXs demonstrated that only xenografts showing a high percentage of TOP2A expressing cells underwent tumor shrinkage when treated with PLD. Conclusions These data show that TOP2A gene gain and protein over-expression might predict activity of PLD in platinum resistant/refractory EOC.

Original languageEnglish
Pages (from-to)627-633
Number of pages7
JournalGynecologic Oncology
Volume138
Issue number3
DOIs
Publication statusPublished - Sep 1 2015

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Ovarian Neoplasms
Genes
Heterografts
Platinum
liposomal doxorubicin
Ovarian epithelial cancer
Fluorescence In Situ Hybridization
Pharmaceutical Preparations
Patient Selection
Proteins
Therapeutics
Immunohistochemistry
Neoplasms

Keywords

  • Doxorubicin
  • PDX (patient derived xenografts)
  • Predictive biomarkers
  • Topoisomerases

ASJC Scopus subject areas

  • Obstetrics and Gynaecology
  • Oncology
  • Medicine(all)

Cite this

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title = "TOP2A gene copy gain predicts response of epithelial ovarian cancers to pegylated liposomal doxorubicin: TOP2A as marker of response to PLD in ovarian cancer",
abstract = "Objective The treatment of platinum resistant/refractory epithelial ovarian cancer (EOC) is a challenge for oncologists. One of the most utilized drugs in these patients is pegylated liposomal doxorubicin (PLD). As PLD is active only in a small subset of patients and causes side effects, selection of responsive patients is an unmet need and might be guided by the status of the DNA topoisomerase II alpha (TOP2A) that is poisoned by the drug. Methods From 176 ovarian cancers treated in three institutions, we selected 38 patients treated with PLD monotherapy as second/third line of treatment. TOP2A gene copies were measured using Fluorescent In Situ Hybridization (FISH) and expression evaluated using immunohistochemistry. Patients' derived xenografts (PDXs) of ovarian cancers were used to assess the correlation between TOP2A protein expression and response to PLD. Results Clinical data showed that TOP2A gene gain that is paralleled by increased expression of the protein, was associated with a higher probability of clinical benefit from PLD. Treatment of PDXs demonstrated that only xenografts showing a high percentage of TOP2A expressing cells underwent tumor shrinkage when treated with PLD. Conclusions These data show that TOP2A gene gain and protein over-expression might predict activity of PLD in platinum resistant/refractory EOC.",
keywords = "Doxorubicin, PDX (patient derived xenografts), Predictive biomarkers, Topoisomerases",
author = "J. Erriquez and P. Becco and M. Olivero and R. Ponzone and F. Maggiorotto and A. Ferrero and Scalzo, {M. S.} and Canuto, {E. M.} and A. Sapino and {Verdun Di Cantogno}, L. and P. Bruna and M. Aglietta and {Di Renzo}, {M. F.} and G. Valabrega",
year = "2015",
month = "9",
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doi = "10.1016/j.ygyno.2015.06.025",
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pages = "627--633",
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TY - JOUR

T1 - TOP2A gene copy gain predicts response of epithelial ovarian cancers to pegylated liposomal doxorubicin

T2 - TOP2A as marker of response to PLD in ovarian cancer

AU - Erriquez, J.

AU - Becco, P.

AU - Olivero, M.

AU - Ponzone, R.

AU - Maggiorotto, F.

AU - Ferrero, A.

AU - Scalzo, M. S.

AU - Canuto, E. M.

AU - Sapino, A.

AU - Verdun Di Cantogno, L.

AU - Bruna, P.

AU - Aglietta, M.

AU - Di Renzo, M. F.

AU - Valabrega, G.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Objective The treatment of platinum resistant/refractory epithelial ovarian cancer (EOC) is a challenge for oncologists. One of the most utilized drugs in these patients is pegylated liposomal doxorubicin (PLD). As PLD is active only in a small subset of patients and causes side effects, selection of responsive patients is an unmet need and might be guided by the status of the DNA topoisomerase II alpha (TOP2A) that is poisoned by the drug. Methods From 176 ovarian cancers treated in three institutions, we selected 38 patients treated with PLD monotherapy as second/third line of treatment. TOP2A gene copies were measured using Fluorescent In Situ Hybridization (FISH) and expression evaluated using immunohistochemistry. Patients' derived xenografts (PDXs) of ovarian cancers were used to assess the correlation between TOP2A protein expression and response to PLD. Results Clinical data showed that TOP2A gene gain that is paralleled by increased expression of the protein, was associated with a higher probability of clinical benefit from PLD. Treatment of PDXs demonstrated that only xenografts showing a high percentage of TOP2A expressing cells underwent tumor shrinkage when treated with PLD. Conclusions These data show that TOP2A gene gain and protein over-expression might predict activity of PLD in platinum resistant/refractory EOC.

AB - Objective The treatment of platinum resistant/refractory epithelial ovarian cancer (EOC) is a challenge for oncologists. One of the most utilized drugs in these patients is pegylated liposomal doxorubicin (PLD). As PLD is active only in a small subset of patients and causes side effects, selection of responsive patients is an unmet need and might be guided by the status of the DNA topoisomerase II alpha (TOP2A) that is poisoned by the drug. Methods From 176 ovarian cancers treated in three institutions, we selected 38 patients treated with PLD monotherapy as second/third line of treatment. TOP2A gene copies were measured using Fluorescent In Situ Hybridization (FISH) and expression evaluated using immunohistochemistry. Patients' derived xenografts (PDXs) of ovarian cancers were used to assess the correlation between TOP2A protein expression and response to PLD. Results Clinical data showed that TOP2A gene gain that is paralleled by increased expression of the protein, was associated with a higher probability of clinical benefit from PLD. Treatment of PDXs demonstrated that only xenografts showing a high percentage of TOP2A expressing cells underwent tumor shrinkage when treated with PLD. Conclusions These data show that TOP2A gene gain and protein over-expression might predict activity of PLD in platinum resistant/refractory EOC.

KW - Doxorubicin

KW - PDX (patient derived xenografts)

KW - Predictive biomarkers

KW - Topoisomerases

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