Predictors of success in establishing orthotopic patient-derived xenograft models of triple negative breast cancer

Abstract

Patient-derived xenograft (PDX) models of breast cancer are an effective discovery platform and tool for preclinical pharmacologic testing and biomarker identification. We established orthotopic PDX models of triple negative breast cancer (TNBC) from the primary breast tumors of patients prior to and following neoadjuvant chemotherapy (NACT) while they were enrolled in the ARTEMIS trial (NCT02276443). Serial biopsies were obtained from patients prior to treatment (pre-NACT), from poorly responsive disease after four cycles of Adriamycin and cyclophosphamide (AC, mid-NACT), and in cases of AC-resistance, after a 3-month course of different experimental therapies and/or additional chemotherapy (post-NACT). Our study cohort includes a total of 269 fine needle aspirates (FNAs) from 217 women, generating a total of 62 PDX models (overall success-rate = 23%). Success of PDX engraftment was generally higher from those cancers that proved to be treatment-resistant, whether poorly responsive to AC as determined by ultrasound measurements mid-NACT (p = 0.063), RCB II/III status after NACT (p = 0.046), or metastatic relapse within 2 years of surgery (p = 0.008). TNBC molecular subtype determined from gene expression microarrays of pre-NACT tumors revealed no significant association with PDX engraftment rate (p = 0.877). Finally, we developed a statistical model predictive of PDX engraftment using percent Ki67 positive cells in the patient’s diagnostic biopsy, positive lymph node status at diagnosis, and low volumetric reduction of the patient’s tumor following AC treatment. This novel bank of 62 PDX models of TNBC provides a valuable resource for biomarker discovery and preclinical therapeutic trials aimed at improving neoadjuvant response rates for patients with TNBC.

Factors associated with engraftment success of patient-derived xenografts of breast cancer

“…Additionally, the statistical analysis of the NAC group, which included TDLUP, Miller-Payne grade, and Ki-67LI in the multivariate logistic regression analysis, also demonstrated an excellent predictive ability with an AUC of 0.89. Compared to the PDX graft studies in the literature, our score was higher than that reported by Echeverria et al who incorporated two variables, Ki-67LI and metastatic LNs, into a logistic regression model for TNBCs breast PDX survival (AUC 0.70) [ 18 ]. In the same context, Zhuo et al [ 30 ] used GPC3 expression and KI67LI to predict hepatocellular carcinoma PDX engraftment and found a good discriminatory power (AUC 0.828), which is similar to the score obtained in the current study.…”

“…In this study, high Ki-67LI, a cellular proliferation marker [ 16 – 18 ], emerged as a crucial factor for PDX engraftment. High histologic grade and TNBC subtype, often associated with elevated Ki-67LI, were consistently linked to increased PDX engraftment rates in prior studies [ 3 , 5 – 7 , 19 ].…”

Targeting neddylation and sumoylation in chemoresistant triple negative breast cancer

“…As part of the prospective neoadjuvant ARTEMIS trial (NCT02276443) 13 – 15 , we obtained fine needle aspirates or core biopsies at critical clinical decision-making time points (Fig. 1 ) including clinical presentation before NACT (denoted as pre ), from residual tumors after four cycles of Adriamycin (doxorubicin) and cyclophosphamide (AC; timepoint denoted as mid ), and at surgical resection of residual tumors after paclitaxel ± targeted therapy (denoted as post ).…”

Patient Characteristics Associated with Growth of Patient-Derived Tumor Implants in Mice (Patient-Derived Xenografts)

“…Several studies have tried to determine predictive factors for engraftment success. Reported success has ranged between 23% and 75%, depending mostly on the tumor type and proliferation rate [18][19][20][21][22][23]. Overall, colorectal (64-89%) and pancreatic (62%) tumors have had high engraftment rates, but low-proliferation tumors such as receptor-positive breast cancers [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] and neuroendocrine low-grade tumors have shown low success rates, even in the laboratories considered most successful in PDX engraftment in general [24].…”

“…Reported success has ranged between 23% and 75%, depending mostly on the tumor type and proliferation rate [18][19][20][21][22][23]. Overall, colorectal (64-89%) and pancreatic (62%) tumors have had high engraftment rates, but low-proliferation tumors such as receptor-positive breast cancers [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] and neuroendocrine low-grade tumors have shown low success rates, even in the laboratories considered most successful in PDX engraftment in general [24]. Likewise, aggressive and advanced (metastatic) cancers have shown high PDX model success rates compared to less-aggressive and nonmetastatic cancers [18,[25][26][27].…”