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Peritoneal metastasis of colorectal cancer (pmCRC): Identification of predictive molecular signatures by a novel preclinical platform of matching pmCRC PDX/PD3D models

ABSTRACT: 14 PDX models of pmCRC were established, including 9 matched PD3D/PDX models, and treatment response to 17 SoC and targeted therapies was monitored, which resulted in drug-dependent inter- and intra-patient specific growth inhibition. Analysis of the molecular data of the models and patient tissue resulted in the identification of predictive biomarkers for treatment with 5-FU, irinotecan, trametinib, erlotinib, cetuximab and avastin, oxaliplatin, selumetinib, docetaxel and everolimus. Conclusions: The establishment of a preclinical drug testing platform based on in vitro and in vivo matched pmCRC models, molecularly characterized by multi-omics technology, facilitated the identification of predictive biomarkers for treatment response, as well as cancer relevant signatures for effective therapies, ready for validation in clinical cohorts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180790 | GEO | 2021/10/27

REPOSITORIES: GEO

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Project description:Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer, with approximately 50% of patients having residual disease after neoadjuvant chemotherapy (NACT) and worse prognosis with higher residual cancer burden (RCB). Patient-derived xenograft (PDX) models of breast cancer are an effective discovery platform and tool for preclinical pharmacologic testing and biomarker identification. There is a need for PDX models encompassing the heterogeneity of TNBC both pre- and post- therapy and for identifying clinical and molecular features of patient’s tumors that are associated with success in establishing these models. Using fine-needle aspirates (FNAs), we established orthotopic PDX models of TNBC from the primary breast tumors of patients prior to and following neoadjuvant systemic therapy while enrolled in the ARTEMIS trial (NCT02276443). ARTEMIS is a prospective neoadjuvant clinical trial for women with primary TNBC who are treated with four cycles of Adriamycin combined with cyclophosphamide (AC) followed by taxane +/- different experimental therapies. Serial biopsies were obtained from patients prior to treatment (pre-therapy), from poorly responsive disease after four cycles of AC (mid-NACT), and in cases of AC-resistance, after a three-month course of different experimental therapies and/or additional chemotherapy (post-NACT). Our study cohort includes a total of 269 FNA biopsies from 217 women, generating a total of 62 successful PDX models (overall success-rate = 23%). This cohort includes five serial pre- and mid-NACT PDX pairs, as well as one serial pre-, mid-, post-NACT triplet. Success of PDX engraftment was generally higher from cancers that proved to be treatment-resistant: whether poor response to AC determined by ultrasound measurements mid-NACT (p=0.063), RCB II/III status after NACT (p=0.046), or metastatic relapse within two years of surgery (p=0.008). TNBC molecular subtype determined from gene expression microarrays of pre-NACT tumor 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.

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Peritoneal metastasis of colorectal cancer (pmCRC): Identification of predictive molecular signatures by a novel preclinical platform of matching pmCRC PDX/PD3D models

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