Tilak K Sundaresan1,2,3, Taronish D Dubash1,3, Zongli Zheng1,4,5,3, Aditya Bardia1,6,3, Ben S Wittner1,3, Nicola Aceto1,7,3, Erin J Silva1,3, Douglas B Fox1,3, Matthew Liebers1,3, Ravi Kapur8, John Iafrate1,4,3, Mehmet Toner1,9,10,11,3, Shyamala Maheswaran12,13,14, Daniel A Haber15,16,17,18. 1. Cancer Center, Massachusetts General Hospital, Bldg 149, 13th Street, Charlestown, MA, 02129, USA. 2. Division of Oncology, San Francisco Medical Center, San Francisco, CA, USA. 3. Harvard Medical School, Boston, MA, 02115, USA. 4. Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA. 5. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China. 6. Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA. 7. Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland. 8. MicroMedicine, Inc., Waltham, MA, 02451, USA. 9. Department of Surgery, Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA. 10. Shriners Hospitals for Children, Boston, MA, 02114, USA. 11. Department of Surgery, Massachusetts General Hospital, Boston, MA, 02114, USA. 12. Cancer Center, Massachusetts General Hospital, Bldg 149, 13th Street, Charlestown, MA, 02129, USA. maheswaran@helix.mgh.harvard.edu. 13. Department of Surgery, Massachusetts General Hospital, Boston, MA, 02114, USA. maheswaran@helix.mgh.harvard.edu. 14. Harvard Medical School, Boston, MA, 02115, USA. maheswaran@helix.mgh.harvard.edu. 15. Cancer Center, Massachusetts General Hospital, Bldg 149, 13th Street, Charlestown, MA, 02129, USA. dhaber@mgh.harvard.edu. 16. Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA. dhaber@mgh.harvard.edu. 17. Howard Hughes Medical Institute, Bethesda, MD, 20851, USA. dhaber@mgh.harvard.edu. 18. Harvard Medical School, Boston, MA, 02115, USA. dhaber@mgh.harvard.edu.
Abstract
PURPOSE: Therapeutic efficacy of hormonal therapies to target estrogen receptor (ER)-positive breast cancer is limited by the acquisition of ligand-independent ESR1 mutations, which confer treatment resistance to aromatase inhibitors (AIs). Monitoring for the emergence of such mutations may enable individualized therapy. We thus assessed CTC- and ctDNA-based detection of ESR1 mutations with the aim of evaluating non-invasive approaches for the determination of endocrine resistance. PATIENTS AND METHODS: In a prospective cohort of 55 women with hormone receptor-positive metastatic breast cancer, we isolated circulating tumor cells (CTCs) and developed a high-sensitivity method for the detection of ESR1 mutations in these CTCs. In patients with sufficient plasma for the simultaneous extraction of circulating tumor DNA (ctDNA), we performed a parallel analysis of ESR1 mutations using multiplex droplet digital PCR (ddPCR) and examined the agreement between these two platforms. Finally, we isolated single CTCs from a subset of these patients and reviewed RNA expression to explore alternate methods of evaluating endocrine responsiveness. RESULTS: High-sensitivity ESR1 sequencing from CTCs revealed mono- and oligoclonal mutations in 22% of patients. These were concordant with plasma DNA sequencing in 95% of cases. Emergence of ESR1 mutations was correlated both with time to metastatic relapse and duration of AI therapy following such recurrence. The Presence of an ESR1 mutation, compared to ESR1 wild type, was associated with markedly shorter Progression-Free Survival on AI-based therapies (p = 0.0006), but unaltered to other non-AI-based therapies (p = 0.73). Compared with ESR1 mutant cases, AI-resistant CTCs with wild-type ESR1 showed an elevated ER-coactivator RNA signature, consistent with their predicted response to second-line hormonal therapies. CONCLUSION: Blood-based serial monitoring may guide the selection of precision therapeutics for women with AI-resistant ER-positive breast cancer.
PURPOSE: Therapeutic efficacy of hormonal therapies to target estrogen receptor (ER)-positive breast cancer is limited by the acquisition of ligand-independent ESR1 mutations, which confer treatment resistance to aromatase inhibitors (AIs). Monitoring for the emergence of such mutations may enable individualized therapy. We thus assessed CTC- and ctDNA-based detection of ESR1 mutations with the aim of evaluating non-invasive approaches for the determination of endocrine resistance. PATIENTS AND METHODS: In a prospective cohort of 55 women with hormone receptor-positive metastatic breast cancer, we isolated circulating tumor cells (CTCs) and developed a high-sensitivity method for the detection of ESR1 mutations in these CTCs. In patients with sufficient plasma for the simultaneous extraction of circulating tumor DNA (ctDNA), we performed a parallel analysis of ESR1 mutations using multiplex droplet digital PCR (ddPCR) and examined the agreement between these two platforms. Finally, we isolated single CTCs from a subset of these patients and reviewed RNA expression to explore alternate methods of evaluating endocrine responsiveness. RESULTS: High-sensitivity ESR1 sequencing from CTCs revealed mono- and oligoclonal mutations in 22% of patients. These were concordant with plasma DNA sequencing in 95% of cases. Emergence of ESR1 mutations was correlated both with time to metastatic relapse and duration of AI therapy following such recurrence. The Presence of an ESR1 mutation, compared to ESR1 wild type, was associated with markedly shorter Progression-Free Survival on AI-based therapies (p = 0.0006), but unaltered to other non-AI-based therapies (p = 0.73). Compared with ESR1 mutant cases, AI-resistant CTCs with wild-type ESR1 showed an elevated ER-coactivator RNA signature, consistent with their predicted response to second-line hormonal therapies. CONCLUSION: Blood-based serial monitoring may guide the selection of precision therapeutics for women with AI-resistant ER-positive breast cancer.
Entities:
Keywords:
AI resistance ER + breast cancer; Acquired ESR1 mutations; Circulating tumor DNA (ctDNA); Circulating tumor cells (CTCs); High-sensitivity ESR1 sequencing
Authors: Shunqiang Li; Dong Shen; Jieya Shao; Robert Crowder; Wenbin Liu; Aleix Prat; Xiaping He; Shuying Liu; Jeremy Hoog; Charles Lu; Li Ding; Obi L Griffith; Christopher Miller; Dave Larson; Robert S Fulton; Michelle Harrison; Tom Mooney; Joshua F McMichael; Jingqin Luo; Yu Tao; Rodrigo Goncalves; Christopher Schlosberg; Jeffrey F Hiken; Laila Saied; Cesar Sanchez; Therese Giuntoli; Caroline Bumb; Crystal Cooper; Robert T Kitchens; Austin Lin; Chanpheng Phommaly; Sherri R Davies; Jin Zhang; Megha Shyam Kavuri; Donna McEachern; Yi Yu Dong; Cynthia Ma; Timothy Pluard; Michael Naughton; Ron Bose; Rama Suresh; Reida McDowell; Loren Michel; Rebecca Aft; William Gillanders; Katherine DeSchryver; Richard K Wilson; Shaomeng Wang; Gordon B Mills; Ana Gonzalez-Angulo; John R Edwards; Christopher Maher; Charles M Perou; Elaine R Mardis; Matthew J Ellis Journal: Cell Rep Date: 2013-09-19 Impact factor: 9.423
Authors: Xianzhou Song; Jianwei Chen; Mingkun Zhao; Chengwei Zhang; Yang Yu; David M Lonard; Dar-Chone Chow; Timothy Palzkill; Jianming Xu; Bert W O'Malley; Jin Wang Journal: Proc Natl Acad Sci U S A Date: 2016-04-15 Impact factor: 11.205
Authors: Rinath Jeselsohn; Roman Yelensky; Gilles Buchwalter; Garrett Frampton; Funda Meric-Bernstam; Ana Maria Gonzalez-Angulo; Jaime Ferrer-Lozano; Jose A Perez-Fidalgo; Massimo Cristofanilli; Henry Gómez; Carlos L Arteaga; Jennifer Giltnane; Justin M Balko; Maureen T Cronin; Mirna Jarosz; James Sun; Matthew Hawryluk; Doron Lipson; Geoff Otto; Jeffrey S Ross; Addie Dvir; Lior Soussan-Gutman; Ido Wolf; Tamar Rubinek; Lauren Gilmore; Stuart Schnitt; Steven E Come; Lajos Pusztai; Philip Stephens; Myles Brown; Vincent A Miller Journal: Clin Cancer Res Date: 2014-01-07 Impact factor: 12.531
Authors: C Kent Osborne; Valerie Bardou; Torsten A Hopp; Gary C Chamness; Susan G Hilsenbeck; Suzanne A W Fuqua; Jiemin Wong; D Craig Allred; Gary M Clark; Rachel Schiff Journal: J Natl Cancer Inst Date: 2003-03-05 Impact factor: 13.506
Authors: Dan R Robinson; Yi-Mi Wu; Pankaj Vats; Fengyun Su; Robert J Lonigro; Xuhong Cao; Shanker Kalyana-Sundaram; Rui Wang; Yu Ning; Lynda Hodges; Amy Gursky; Javed Siddiqui; Scott A Tomlins; Sameek Roychowdhury; Kenneth J Pienta; Scott Y Kim; J Scott Roberts; James M Rae; Catherine H Van Poznak; Daniel F Hayes; Rashmi Chugh; Lakshmi P Kunju; Moshe Talpaz; Anne F Schott; Arul M Chinnaiyan Journal: Nat Genet Date: 2013-11-03 Impact factor: 38.330