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Ability to Generate Patient-Derived Breast Cancer Xenografts Is Enhanced in Chemoresistant Disease and Predicts Poor Patient Outcomes.

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 GB, Gonzalez-Angulo AM, Meric-Bernstam F - PLoS ONE (2015)

Bottom Line: One BCX model was cultured in vitro and re-implanted, maintaining its genomic profile.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.

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 hormone-receptor 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.

No MeSH data available.


Related in: MedlinePlus

Generating and maintaining patient-derived breast cancer xenografts (BCXs) and their time to passage.(A) After surgery, patient tumors (P0) were implanted into nude mice, creating a patient-derived BCX, passage 1 (P1). When tumors reached 1.5 cm diameter, they were harvested and implanted into 5 new mice (P2), and subsequent passages respectively. Patient tumors and BCXs were evaluated by STR and selected passages underwent molecular and histologic characterization. (B) Y-axis depicts time to reach 1.5 cm with each passage. The graph shows thirteen BCXs that were serially passage. (C) Time to passage (in months) at from implantation to first passage (P1), P1 to P2 (P2), and P1 to P3 (P3). Time to passage at P2 and P3 were compared to time to passage at from implantation to first passage (P1).
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pone.0136851.g001: Generating and maintaining patient-derived breast cancer xenografts (BCXs) and their time to passage.(A) After surgery, patient tumors (P0) were implanted into nude mice, creating a patient-derived BCX, passage 1 (P1). When tumors reached 1.5 cm diameter, they were harvested and implanted into 5 new mice (P2), and subsequent passages respectively. Patient tumors and BCXs were evaluated by STR and selected passages underwent molecular and histologic characterization. (B) Y-axis depicts time to reach 1.5 cm with each passage. The graph shows thirteen BCXs that were serially passage. (C) Time to passage (in months) at from implantation to first passage (P1), P1 to P2 (P2), and P1 to P3 (P3). Time to passage at P2 and P3 were compared to time to passage at from implantation to first passage (P1).

Mentions: Tumor from the surgical specimens (designated as “P0”) was implanted (Fig 1A) and mice with tumor growth at the site of implantation were considered to have successful engraftment. Tumors derived from 13 of the 48 specimens (27%) were successfully engrafted.


Ability to Generate Patient-Derived Breast Cancer Xenografts Is Enhanced in Chemoresistant Disease and Predicts Poor Patient Outcomes.

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 GB, Gonzalez-Angulo AM, Meric-Bernstam F - PLoS ONE (2015)

Generating and maintaining patient-derived breast cancer xenografts (BCXs) and their time to passage.(A) After surgery, patient tumors (P0) were implanted into nude mice, creating a patient-derived BCX, passage 1 (P1). When tumors reached 1.5 cm diameter, they were harvested and implanted into 5 new mice (P2), and subsequent passages respectively. Patient tumors and BCXs were evaluated by STR and selected passages underwent molecular and histologic characterization. (B) Y-axis depicts time to reach 1.5 cm with each passage. The graph shows thirteen BCXs that were serially passage. (C) Time to passage (in months) at from implantation to first passage (P1), P1 to P2 (P2), and P1 to P3 (P3). Time to passage at P2 and P3 were compared to time to passage at from implantation to first passage (P1).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556673&req=5

pone.0136851.g001: Generating and maintaining patient-derived breast cancer xenografts (BCXs) and their time to passage.(A) After surgery, patient tumors (P0) were implanted into nude mice, creating a patient-derived BCX, passage 1 (P1). When tumors reached 1.5 cm diameter, they were harvested and implanted into 5 new mice (P2), and subsequent passages respectively. Patient tumors and BCXs were evaluated by STR and selected passages underwent molecular and histologic characterization. (B) Y-axis depicts time to reach 1.5 cm with each passage. The graph shows thirteen BCXs that were serially passage. (C) Time to passage (in months) at from implantation to first passage (P1), P1 to P2 (P2), and P1 to P3 (P3). Time to passage at P2 and P3 were compared to time to passage at from implantation to first passage (P1).
Mentions: Tumor from the surgical specimens (designated as “P0”) was implanted (Fig 1A) and mice with tumor growth at the site of implantation were considered to have successful engraftment. Tumors derived from 13 of the 48 specimens (27%) were successfully engrafted.

Bottom Line: One BCX model was cultured in vitro and re-implanted, maintaining its genomic profile.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.

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 hormone-receptor 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.

No MeSH data available.


Related in: MedlinePlus