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

Abstract

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). 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. 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. 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.