Ability to generate patient-derived Breast cancer xenografts is enhanced in chemoresistant disease and predicts poor patient outcomes

Priscilla F. McAuliffe, Kurt W. Evans, Argun Akcakanat, Ken Chen, Xiaofeng Zheng, Hao Zhao, Agda Karina Eterovic, Takafumi Sangai, Ashley M. Holder, Chandeshwar Sharma, Huiqin Chen, Kim Anh Do, Emily Tarco, Mihai Gagea, Katherine A. Naff, Aysegul Sahin, Asha S. Multani, Dalliah M. Black, Elizabeth A. Mittendorf, Isabelle Bedrosian & 3 others Gordon Mills, Ana Maria Gonzalez-Angulo, Funda Meric-Bernstam

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background: Breast cancer patients who are resistant to neoadjuvant chemotherapy (NeoCT) have a poor prognosis. There is a pressing need to develop in vivo models of chemo resistant tumors to test novel therapeutics. We hypothesized that patient-derived breast cancer xenografts (BCXs) from chemo-naïve and chemotherapy-exposed tumors can provide high fidelity in vivo models for chemoresistant breast cancers. Methods: Patient tumors and BCXs were characterized with short tandem repeat DNA fingerprinting, reverse phase protein arrays, molecular inversion probe arrays, and next generation sequencing. Results: Forty-eight breast cancers (24 post-chemotherapy, 24 chemo-naïve) were implanted and 13 BCXs were established (27%). BCX engraftment was higher in TNBC compared to hormonereceptor positive cancer (53.8% vs. 15.6%, p = 0.02), in tumors from patients who received NeoCT (41.7% vs. 8.3%, p = 0.02), and in patients who had progressive disease on NeoCT (85.7% vs. 29.4%, p = 0.02). Twelve patients developed metastases after surgery; in five, BCXs developed before distant relapse. Patients whose tumors developed BCXs had a lower recurrence-free survival (p = 0.015) and overall survival (p<0.001). Genomic losses and gains could be detected in the BCX, and three models demonstrated a transformation to induce mouse tumors. However, overall, somatic mutation profiles including potential drivers were maintained upon implantation and serial passaging. One BCX model was cultured in vitro and re-implanted, maintaining its genomic profile. Conclusions: BCXs can be established from clinically aggressive breast cancers, especially in TNBC patients with poor response to NeoCT. Future studies will determine the potential of in vivo models for identification of genotype-phenotype correlations and individualization of treatment.

Original languageEnglish (US)
Article numbere0136851
JournalPLoS One
Volume10
Issue number9
DOIs
StatePublished - Sep 1 2015
Externally publishedYes

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Heterografts
breast neoplasms
Chemotherapy
Breast Neoplasms
Tumors
drug therapy
neoplasms
Drug Therapy
Neoplasms
Microsatellite Repeats
Surgery
genomics
Recurrence
Molecular Probes
somatic mutation
Protein Array Analysis
Identification (control systems)
Survival
DNA Fingerprinting
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ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

McAuliffe, P. F., Evans, K. W., Akcakanat, A., Chen, K., Zheng, X., Zhao, H., ... Meric-Bernstam, F. (2015). Ability to generate patient-derived Breast cancer xenografts is enhanced in chemoresistant disease and predicts poor patient outcomes. PLoS One, 10(9), [e0136851]. https://doi.org/10.1371/journal.pone.0136851

Ability to generate patient-derived Breast cancer xenografts is enhanced in chemoresistant disease and predicts poor patient outcomes. / McAuliffe, Priscilla F.; Evans, Kurt W.; Akcakanat, Argun; Chen, Ken; Zheng, Xiaofeng; Zhao, Hao; Eterovic, Agda Karina; Sangai, Takafumi; Holder, Ashley M.; Sharma, Chandeshwar; Chen, Huiqin; Do, Kim Anh; Tarco, Emily; Gagea, Mihai; Naff, Katherine A.; Sahin, Aysegul; Multani, Asha S.; Black, Dalliah M.; Mittendorf, Elizabeth A.; Bedrosian, Isabelle; Mills, Gordon; Gonzalez-Angulo, Ana Maria; Meric-Bernstam, Funda.

In: PLoS One, Vol. 10, No. 9, e0136851, 01.09.2015.

Research output: Contribution to journalArticle

McAuliffe, PF, Evans, KW, Akcakanat, A, Chen, K, Zheng, X, Zhao, H, Eterovic, AK, Sangai, T, Holder, AM, Sharma, C, Chen, H, Do, KA, Tarco, E, Gagea, M, Naff, KA, Sahin, A, Multani, AS, Black, DM, Mittendorf, EA, Bedrosian, I, Mills, G, Gonzalez-Angulo, AM & Meric-Bernstam, F 2015, 'Ability to generate patient-derived Breast cancer xenografts is enhanced in chemoresistant disease and predicts poor patient outcomes', PLoS One, vol. 10, no. 9, e0136851. https://doi.org/10.1371/journal.pone.0136851
McAuliffe, Priscilla F. ; Evans, Kurt W. ; Akcakanat, Argun ; Chen, Ken ; Zheng, Xiaofeng ; Zhao, Hao ; Eterovic, Agda Karina ; Sangai, Takafumi ; Holder, Ashley M. ; Sharma, Chandeshwar ; Chen, Huiqin ; Do, Kim Anh ; Tarco, Emily ; Gagea, Mihai ; Naff, Katherine A. ; Sahin, Aysegul ; Multani, Asha S. ; Black, Dalliah M. ; Mittendorf, Elizabeth A. ; Bedrosian, Isabelle ; Mills, Gordon ; Gonzalez-Angulo, Ana Maria ; Meric-Bernstam, Funda. / Ability to generate patient-derived Breast cancer xenografts is enhanced in chemoresistant disease and predicts poor patient outcomes. In: PLoS One. 2015 ; Vol. 10, No. 9.
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abstract = "Background: Breast cancer patients who are resistant to neoadjuvant chemotherapy (NeoCT) have a poor prognosis. There is a pressing need to develop in vivo models of chemo resistant tumors to test novel therapeutics. We hypothesized that patient-derived breast cancer xenografts (BCXs) from chemo-na{\"i}ve and chemotherapy-exposed tumors can provide high fidelity in vivo models for chemoresistant breast cancers. Methods: Patient tumors and BCXs were characterized with short tandem repeat DNA fingerprinting, reverse phase protein arrays, molecular inversion probe arrays, and next generation sequencing. Results: Forty-eight breast cancers (24 post-chemotherapy, 24 chemo-na{\"i}ve) were implanted and 13 BCXs were established (27{\%}). BCX engraftment was higher in TNBC compared to hormonereceptor positive cancer (53.8{\%} vs. 15.6{\%}, p = 0.02), in tumors from patients who received NeoCT (41.7{\%} vs. 8.3{\%}, p = 0.02), and in patients who had progressive disease on NeoCT (85.7{\%} vs. 29.4{\%}, p = 0.02). Twelve patients developed metastases after surgery; in five, BCXs developed before distant relapse. Patients whose tumors developed BCXs had a lower recurrence-free survival (p = 0.015) and overall survival (p<0.001). Genomic losses and gains could be detected in the BCX, and three models demonstrated a transformation to induce mouse tumors. However, overall, somatic mutation profiles including potential drivers were maintained upon implantation and serial passaging. One BCX model was cultured in vitro and re-implanted, maintaining its genomic profile. Conclusions: BCXs can be established from clinically aggressive breast cancers, especially in TNBC patients with poor response to NeoCT. Future studies will determine the potential of in vivo models for identification of genotype-phenotype correlations and individualization of treatment.",
author = "McAuliffe, {Priscilla F.} and Evans, {Kurt W.} and Argun Akcakanat and Ken Chen and Xiaofeng Zheng and Hao Zhao and Eterovic, {Agda Karina} and Takafumi Sangai and Holder, {Ashley M.} and Chandeshwar Sharma and Huiqin Chen and Do, {Kim Anh} and Emily Tarco and Mihai Gagea and Naff, {Katherine A.} and Aysegul Sahin and Multani, {Asha S.} and Black, {Dalliah M.} and Mittendorf, {Elizabeth A.} and Isabelle Bedrosian and Gordon Mills and Gonzalez-Angulo, {Ana Maria} and Funda Meric-Bernstam",
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T1 - Ability to generate patient-derived Breast cancer xenografts is enhanced in chemoresistant disease and predicts poor patient outcomes

AU - McAuliffe, Priscilla F.

AU - Evans, Kurt W.

AU - Akcakanat, Argun

AU - Chen, Ken

AU - Zheng, Xiaofeng

AU - Zhao, Hao

AU - Eterovic, Agda Karina

AU - Sangai, Takafumi

AU - Holder, Ashley M.

AU - Sharma, Chandeshwar

AU - Chen, Huiqin

AU - Do, Kim Anh

AU - Tarco, Emily

AU - Gagea, Mihai

AU - Naff, Katherine A.

AU - Sahin, Aysegul

AU - Multani, Asha S.

AU - Black, Dalliah M.

AU - Mittendorf, Elizabeth A.

AU - Bedrosian, Isabelle

AU - Mills, Gordon

AU - Gonzalez-Angulo, Ana Maria

AU - Meric-Bernstam, Funda

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Background: Breast cancer patients who are resistant to neoadjuvant chemotherapy (NeoCT) have a poor prognosis. There is a pressing need to develop in vivo models of chemo resistant tumors to test novel therapeutics. We hypothesized that patient-derived breast cancer xenografts (BCXs) from chemo-naïve and chemotherapy-exposed tumors can provide high fidelity in vivo models for chemoresistant breast cancers. Methods: Patient tumors and BCXs were characterized with short tandem repeat DNA fingerprinting, reverse phase protein arrays, molecular inversion probe arrays, and next generation sequencing. Results: Forty-eight breast cancers (24 post-chemotherapy, 24 chemo-naïve) were implanted and 13 BCXs were established (27%). BCX engraftment was higher in TNBC compared to hormonereceptor positive cancer (53.8% vs. 15.6%, p = 0.02), in tumors from patients who received NeoCT (41.7% vs. 8.3%, p = 0.02), and in patients who had progressive disease on NeoCT (85.7% vs. 29.4%, p = 0.02). Twelve patients developed metastases after surgery; in five, BCXs developed before distant relapse. Patients whose tumors developed BCXs had a lower recurrence-free survival (p = 0.015) and overall survival (p<0.001). Genomic losses and gains could be detected in the BCX, and three models demonstrated a transformation to induce mouse tumors. However, overall, somatic mutation profiles including potential drivers were maintained upon implantation and serial passaging. One BCX model was cultured in vitro and re-implanted, maintaining its genomic profile. Conclusions: BCXs can be established from clinically aggressive breast cancers, especially in TNBC patients with poor response to NeoCT. Future studies will determine the potential of in vivo models for identification of genotype-phenotype correlations and individualization of treatment.

AB - Background: Breast cancer patients who are resistant to neoadjuvant chemotherapy (NeoCT) have a poor prognosis. There is a pressing need to develop in vivo models of chemo resistant tumors to test novel therapeutics. We hypothesized that patient-derived breast cancer xenografts (BCXs) from chemo-naïve and chemotherapy-exposed tumors can provide high fidelity in vivo models for chemoresistant breast cancers. Methods: Patient tumors and BCXs were characterized with short tandem repeat DNA fingerprinting, reverse phase protein arrays, molecular inversion probe arrays, and next generation sequencing. Results: Forty-eight breast cancers (24 post-chemotherapy, 24 chemo-naïve) were implanted and 13 BCXs were established (27%). BCX engraftment was higher in TNBC compared to hormonereceptor positive cancer (53.8% vs. 15.6%, p = 0.02), in tumors from patients who received NeoCT (41.7% vs. 8.3%, p = 0.02), and in patients who had progressive disease on NeoCT (85.7% vs. 29.4%, p = 0.02). Twelve patients developed metastases after surgery; in five, BCXs developed before distant relapse. Patients whose tumors developed BCXs had a lower recurrence-free survival (p = 0.015) and overall survival (p<0.001). Genomic losses and gains could be detected in the BCX, and three models demonstrated a transformation to induce mouse tumors. However, overall, somatic mutation profiles including potential drivers were maintained upon implantation and serial passaging. One BCX model was cultured in vitro and re-implanted, maintaining its genomic profile. Conclusions: BCXs can be established from clinically aggressive breast cancers, especially in TNBC patients with poor response to NeoCT. Future studies will determine the potential of in vivo models for identification of genotype-phenotype correlations and individualization of treatment.

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