1933MO - TransFAL: Establishment of clinical trial-matched luminal breast cancer patient-derived xenografts (PDX) for translational studies

Background

PARSIFAL was a randomized phase II trial aimed at evaluating the efficacy of palbociclib (P) plus either fulvestrant (F) or letrozole (L) in Estrogen Receptor[+]/Human Epidermal Growth Factor Receptor 2[-] metastatic breast cancer. The present study focused on establishing luminal breast cancer PDX models from a cohort of enrolled patients in an effort to develop preclinical models that recapitulate the disease before and after treatment with P and endocrine therapy (ET).

Methods

14 pre- and 18 post-treatment tumors were transplanted into immunocompromised mice. Xenografts were profiled using a capture-based exome sequencing panel and analyzed by immunohistochemistry as well as for the in vivo antiproliferative activity of P plus the patient-matched ET. Models of acquired resistance were generated from responder models and characterized. Predictive markers of response were analyzed and, in the case of non-responder models, additional treatments were tested in vivo and/or ex vivo.

Results

Successful engraftments were established in 3 of the 32 tumors (take rate 9%, 95% CI 1.8% -23.1%). Of those, PDX426 and PDX446 derived from pre-treatment tumors of patients receiving P+L and P+F, respectively, and PDX450 from a post-treatment tumor of a patient treated with P+L. PDX426 harbored an FGFR1 amplification and PDX446 harbored concomitant PIK3CA and PTEN mutations. Both PDXs expressed normal levels of pRb and cyclin E1. PDX446 showed sensitivity to P+F or P+L for >95 days, resembling the patient’s clinical response. Of note, PDX446 was also sensitive to single-agent F or L. The model of acquired resistance to P+F exhibited lower expression of pRb than the sensitive model. PDX450 harbored concomitant ESR1, PIK3CA, and PTEN mutations and expressed low pRb. Despite an initial response, all tumors progressed to P+L after 80 days, matching the clinical disease progression. The P+L-resistant tumors were also resistant to P+F in vivo but sensitive to the PI3K-α inhibitor alpelisib plus F ex vivo.

Conclusions

PDX models showed comparable treatment responses to those observed clinically, providing information about the additional benefit of P to ET alone as well as effective treatment options in the post-P setting.

Clinical trial identification

NCT02491983.

Editorial acknowledgement

Legal entity responsible for the study

MedSIR.

Funding

Pfizer.

Disclosure

M. Scaltriti: Leadership role: medendi.org; Research grant/Funding (institution): Menarini Richerche, AstraZeneca, Daiichi Sankyo, Regeneron, BD Therapeutics, Puma Biotechnology, Immunomedics, Targimmune ; Advisory/Consultancy: Lilly, Menarini Richerche, AstraZeneca, Daiichi Sankyo. C. Saura: Advisory/Consultancy: AstraZeneca, Celgene, Daiichi Sankyo, F. Hoffmann - La Roche Ltd, Genomic Health, Merck, Sharp and Dhome España S.A., Novartis, Odonate Therapeutics, Pfizer, Philips Healthwork, Pierre Fabre, prIME Oncology, Puma, Synthon and Sanofi Aventis; Honoraria (institution): AstraZeneca, Daiichi Sankyo, Eli Lilly and Company, Genentech, Immunomedics, Macrogenics, Merck, Sharp and Dhome España S.A., Novartis, Pfizer, Piqur Therapeutics, Puma, Roche, Synthon and Zenith Pharma. M. Capelán: Non-remunerated activity/ies, Participation in the video shooting organised by Novartis: Novartis. M. Gil-Gil: Honoraria (self): Novartis, Pfizer. A. Llombart Cussac: Leadership role: Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, MSD; Shareholder/Stockholder/Stock options: MedSIR, Initia-Research; Advisory/Consultancy: Lilly, Roche, Pfizer, Novartis, Pierre-Fabre, GenomicHealth, GSK; Speaker Bureau/Expert testimony: Lilly, AstraZeneca, MSD; Research grant/Funding (self): Roche, Foundation Medicine, Pierre-Fabre, Agendia; Travel/Accommodation/Expenses: Roche, Lilly, Novartis, Pfizer, AstraZeneca. J. Cortés: Advisory/Consultancy: Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology; Honoraria (self): Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo; Research grant/Funding (institution): Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London; Shareholder/Stockholder/Stock options: MedSIR. J.M. Perez Garcia: Advisory/Consultancy: Roche, Lilly; Travel/Accommodation/Expenses: Roche. M. Del Campo: Advisory/Consultancy: Pfizer. M. Bellet Ezquerra: Advisory/Consultancy: Novartis, Pfizer, Lilly; Speaker Bureau/Expert testimony, Non-remunerated activity/ies: Novartis, Pfizer, Lilly; Non-remunerated activity/ies, Contracted Research. Site PI clinical trials: Novartis, Pfizer, Lilly, Genentech. V. Serra: Non-remunerated activity/ies, Support for non-commercial research: Novartis, Genetech and AstraZeneca. All other authors have declared no conflicts of interest.