Tumor Sequencing and Patient-Derived Xenografts in the Neoadjuvant Treatment of Breast Cancer

Abstract

Background: Breast cancer patients with residual disease after neoadjuvant chemotherapy (NAC) have increased recurrence risk. Molecular characterization, knowledge of NAC response, and simultaneous generation of patient-derived xenografts (PDXs) may accelerate drug development. However, the feasibility of this approach is unknown.Methods: We conducted a prospective study of 140 breast cancer patients treated with NAC and performed tumor and germline sequencing and generated patient-derived xenografts (PDXs) using core needle biopsies. Chemotherapy response was assessed at surgery.Results: Recurrent “targetable” alterations were not enriched in patients without pathologic complete response (pCR); however, upregulation of steroid receptor signaling and lower pCR rates (16.7%, 1/6) were observed in triple-negative breast cancer (TNBC) patients with luminal androgen receptor (LAR) vs basal subtypes (60.0%, 21/35). Within TNBC, TP53 mutation frequency (75.6%, 31/41) did not differ comparing basal (74.3%, 26/35) and LAR (83.3%, 5/6); however, TP53 stop-gain mutations were more common in basal (22.9%, 8/35) vs LAR (0.0%, 0/6), which was confirmed in The Cancer Genome Atlas and British Columbia data sets. In luminal B tumors, Ki-67 responses were observed in tumors that harbored mutations conferring endocrine resistance (p53, AKT, and IKBKE). PDX take rate (27.4%, 31/113) varied according to tumor subtype, and in a patient with progression on NAC, sequencing data informed drug selection (olaparib) with in vivo antitumor activity observed in the primary and resistant (postchemotherapy) PDXs.Conclusions: In this study, we demonstrate the feasibility of tumor sequencing and PDX generation in the NAC setting. “Targetable” alterations were not enriched in chemotherapy-resistant tumors; however, prioritization of drug testing based on sequence data may accelerate drug development.

Tumor Biology and Response to Chemotherapy Impact Breast Cancer-specific Survival in Node-positive Breast Cancer Patients Treated With Neoadjuvant Chemotherapy

“…This is consistent with other studies that have previously shown lower pCR rates in HR-positive disease. [7, 13, 37] Additionally, the number of breast cancer recurrences or deaths in the patients who achieved a pCR was so small that statistical comparison of the impact of pCR on outcome was limited. Since these patients are treated with adjuvant endocrine therapy for 5 years and in some instances 10 years after surgery, they remain at risk for future breast cancer events for over 10 years.…”

A Population of Heterogeneous Breast Cancer Patient-Derived Xenografts Demonstrate Broad Activity of PARP Inhibitor in BRCA1/2 Wild-Type Tumors

“…Efforts are therefore being taken to develop collections of heterogeneous patient-based models of TNBC that can be used to contrast therapeutic sensitivities and link antitumor responses to molecular traits that may only be present in subsets of patients (12–15). In particular, due to the poor outcomes for TNBC patients who harbor significant residual disease following neoadjuvant NeoCT, models derived from post-NeoCT, residual tumors are of particular importance.…”

Gene Sets Analysis using Network Patterns

“…To illustrate the utility of GeneSet MAPR, we report a detailed analysis of a gene set that is differentially expressed between triple negative breast cancer patients who exhibited pathological complete response (pCR) to a chemotherapy regimen and those who did not (non-pCR) (24). This gene set was derived from a longitudinal study named 'BEAUTY' at the Mayo Clinic and we refer to it as 'BEAUTY TRIPLE NEGATIVE RESPONSE' or 'BTNR' gene set.…”

“…While some members of these families were included in the BTNR set, they were not mentioned in the BEAUTY study (24). MAPR's ranking brought them to attention.…”

“…Kallikreins are cited by many studies as indicators of poor prognosis in cancer (28), and are often down-regulated and used as biomarkers in breast cancer patients (29). However, their presence as a family was not highlighted in the BEAUTY study (24), and MAPR's gene ranking drew attention to their potential importance in this context.…”