Abstract
Inhibition of proliferation in estrogen receptor-positive (ER+) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER+/human epidermal growth factor receptor 2-negative (HER2) early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10 to 21 days before surgery. Twenty-one percent of tumors remained highly proliferative, suggesting that these tumors harbor alterations associated with intrinsic endocrine therapy resistance. Whole-exome sequencing revealed a correlation between 8p11-12 and 11q13 gene amplifications, including FGFR1 and CCND1, respectively, and high Ki67. We corroborated these findings in a separate cohort of serial pretreatment, postneoadjuvant chemotherapy, and recurrent ER+ tumors. Combined inhibition of FGFR1 and CDK4/6 reversed antiestrogen resistance in ER+ FGFR1/CCND1 coamplified CAMA1 breast cancer cells. RNA sequencing of letrozole-treated tumors revealed the existence of intrachromosomal ESR1 fusion transcripts and increased expression of gene signatures indicative of enhanced E2F-mediated transcription and cell cycle processes in cancers with high Ki67. These data suggest that short-term preoperative estrogen deprivation followed by genomic profiling can be used to identify druggable alterations that may cause intrinsic endocrine therapy resistance.
| Original language | English (US) |
|---|---|
| Article number | aai7993 |
| Journal | Science Translational Medicine |
| Volume | 9 |
| Issue number | 402 |
| DOIs | |
| State | Published - Aug 9 2017 |
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ASJC Scopus subject areas
- Medicine(all)
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Genomic profiling of ER+ breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance. / Giltnane, Jennifer M.; Hutchinson, Katherine E.; Stricker, Thomas P.; Formisano, Luigi; Young, Christian D.; Estrada, Monica V.; Nixon, Mellissa J.; Du, Liping; Sanchez, Violeta; Ericsson, Paula Gonzalez; Kuba, Maria G.; Sanders, Melinda E.; Mu, Xinmeng J.; Van Allen, Eliezer M.; Wagle, Nikhil; Mayer, Ingrid A.; Abramson, Vandana; Gómez, Henry; Rizzo, Monica; Toy, Weiyi; Chandarlapaty, Sarat; Mayer, Erica L.; Christiansen, Jason; Murphy, Danielle; Fitzgerald, Kerry; Wang, Kai; Ross, Jeffrey S.; Miller, Vincent A.; Stephens, Phillip J.; Yelensky, Roman; Garraway, Levi; Shyr, Yu; Meszoely, Ingrid; Balko, Justin M.; Arteaga, Carlos L.
In: Science Translational Medicine, Vol. 9, No. 402, aai7993, 09.08.2017.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Genomic profiling of ER+ breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance
AU - Giltnane, Jennifer M.
AU - Hutchinson, Katherine E.
AU - Stricker, Thomas P.
AU - Formisano, Luigi
AU - Young, Christian D.
AU - Estrada, Monica V.
AU - Nixon, Mellissa J.
AU - Du, Liping
AU - Sanchez, Violeta
AU - Ericsson, Paula Gonzalez
AU - Kuba, Maria G.
AU - Sanders, Melinda E.
AU - Mu, Xinmeng J.
AU - Van Allen, Eliezer M.
AU - Wagle, Nikhil
AU - Mayer, Ingrid A.
AU - Abramson, Vandana
AU - Gómez, Henry
AU - Rizzo, Monica
AU - Toy, Weiyi
AU - Chandarlapaty, Sarat
AU - Mayer, Erica L.
AU - Christiansen, Jason
AU - Murphy, Danielle
AU - Fitzgerald, Kerry
AU - Wang, Kai
AU - Ross, Jeffrey S.
AU - Miller, Vincent A.
AU - Stephens, Phillip J.
AU - Yelensky, Roman
AU - Garraway, Levi
AU - Shyr, Yu
AU - Meszoely, Ingrid
AU - Balko, Justin M.
AU - Arteaga, Carlos L.
PY - 2017/8/9
Y1 - 2017/8/9
N2 - Inhibition of proliferation in estrogen receptor-positive (ER+) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER+/human epidermal growth factor receptor 2-negative (HER2) early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10 to 21 days before surgery. Twenty-one percent of tumors remained highly proliferative, suggesting that these tumors harbor alterations associated with intrinsic endocrine therapy resistance. Whole-exome sequencing revealed a correlation between 8p11-12 and 11q13 gene amplifications, including FGFR1 and CCND1, respectively, and high Ki67. We corroborated these findings in a separate cohort of serial pretreatment, postneoadjuvant chemotherapy, and recurrent ER+ tumors. Combined inhibition of FGFR1 and CDK4/6 reversed antiestrogen resistance in ER+ FGFR1/CCND1 coamplified CAMA1 breast cancer cells. RNA sequencing of letrozole-treated tumors revealed the existence of intrachromosomal ESR1 fusion transcripts and increased expression of gene signatures indicative of enhanced E2F-mediated transcription and cell cycle processes in cancers with high Ki67. These data suggest that short-term preoperative estrogen deprivation followed by genomic profiling can be used to identify druggable alterations that may cause intrinsic endocrine therapy resistance.
AB - Inhibition of proliferation in estrogen receptor-positive (ER+) breast cancers after short-term antiestrogen therapy correlates with long-term patient outcome. We profiled 155 ER+/human epidermal growth factor receptor 2-negative (HER2) early breast cancers from 143 patients treated with the aromatase inhibitor letrozole for 10 to 21 days before surgery. Twenty-one percent of tumors remained highly proliferative, suggesting that these tumors harbor alterations associated with intrinsic endocrine therapy resistance. Whole-exome sequencing revealed a correlation between 8p11-12 and 11q13 gene amplifications, including FGFR1 and CCND1, respectively, and high Ki67. We corroborated these findings in a separate cohort of serial pretreatment, postneoadjuvant chemotherapy, and recurrent ER+ tumors. Combined inhibition of FGFR1 and CDK4/6 reversed antiestrogen resistance in ER+ FGFR1/CCND1 coamplified CAMA1 breast cancer cells. RNA sequencing of letrozole-treated tumors revealed the existence of intrachromosomal ESR1 fusion transcripts and increased expression of gene signatures indicative of enhanced E2F-mediated transcription and cell cycle processes in cancers with high Ki67. These data suggest that short-term preoperative estrogen deprivation followed by genomic profiling can be used to identify druggable alterations that may cause intrinsic endocrine therapy resistance.
UR - http://www.scopus.com/inward/record.url?scp=85027421288&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85027421288&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aai7993
DO - 10.1126/scitranslmed.aai7993
M3 - Article
C2 - 28794284
AN - SCOPUS:85027421288
VL - 9
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 402
M1 - aai7993
ER -