Ability to Generate Patient-Derived Breast Cancer Xenografts Is Enhanced in Chemoresistant Disease and Predicts Poor Patient Outcomes.
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.
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Priscilla F
PF
McAuliffe
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Kurt W
KW
Evans
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Argun
A
Akcakanat
Department of Bioinformatics and Computational Science, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Ken
K
Chen
Department of Bioinformatics and Computational Science, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Xiaofeng
X
Zheng
Department of Bioinformatics and Computational Science, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Hao
H
Zhao
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Agda Karina
AK
Eterovic
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Takafumi
T
Sangai
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Ashley M
AM
Holder
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Chandeshwar
C
Sharma
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Huiqin
H
Chen
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Kim-Anh
KA
Do
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Emily
E
Tarco
Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Mihai
M
Gagea
Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Katherine A
KA
Naff
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Aysegul
A
Sahin
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Asha S
AS
Multani
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Dalliah M
DM
Black
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Elizabeth A
EA
Mittendorf
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Isabelle
I
Bedrosian
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Gordon B
GB
Mills
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Ana Maria
AM
Gonzalez-Angulo
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America; Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
Funda
F
Meric-Bernstam
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017024:Chemotherapy, Adjuvant / Q000379:methods; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D005260:Female; D064593:Heterografts / Q000473:pathology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism
D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen