TY - JOUR
T1 - Tumor Sequencing and Patient-Derived Xenografts in the Neoadjuvant Treatment of Breast Cancer
AU - Goetz, Matthew P.
AU - Kalari, Krishna R.
AU - Suman, Vera J.
AU - Moyer, Ann M.
AU - Yu, Jia
AU - Visscher, Daniel W.
AU - Dockter, Travis J.
AU - Vedell, Peter T.
AU - Sinnwell, Jason P.
AU - Tang, Xiaojia
AU - Thompson, Kevin J.
AU - McLaughlin, Sarah A.
AU - Moreno-Aspitia, Alvaro
AU - Copland, John A.
AU - Northfelt, Donald W.
AU - Gray, Richard J.
AU - Hunt, Katie
AU - Conners, Amy
AU - Weinshilboum, Richard
AU - Wang, Liewei
AU - Boughey, Judy C.
AU - Goetz, Matthew P.
AU - Kalari, Krishna R.
AU - Suman, Vera J.
AU - Moyer, Ann M.
AU - Yu, Jia
AU - Visscher, Daniel W.
AU - Dockter, Travis J.
AU - Vedell, Peter T.
AU - Sinnwell, Jason P.
AU - Tang, Xiaojia
AU - Thompson, Kevin J.
AU - Barman, Poulami
AU - Mahoney, Douglas W.
AU - Carlson, Erin
AU - Hart, Steven N.
AU - Yin, Ping
AU - Qin, Bo
AU - Felten, Sara J.
AU - McLaughlin, Sarah A.
AU - Copland, John A.
AU - Northfelt, Donald W.
AU - Gray, Richard J.
AU - Hunt, Katie
AU - Conners, Amy
AU - Sicotte, Hugues
AU - Eckel-Passow, Jeanette E.
AU - Kocher, Jean Pierre
AU - Ingle, James N.
AU - Ellingson, Marissa S.
AU - McDonough, Michelle
AU - Wieben, Eric D.
AU - Wang, Liewei
AU - Boughey, Judy C.
N1 - Publisher Copyright:
© 2017 The Author.
PY - 2017/7/1
Y1 - 2017/7/1
N2 - 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.
AB - 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.
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U2 - 10.1093/jnci/djw306
DO - 10.1093/jnci/djw306
M3 - Article
C2 - 28376176
AN - SCOPUS:85016204307
SN - 0027-8874
VL - 109
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 7
ER -