Aleix Prat1,2,3, Tomás Pascual1,2,3, Carmine De Angelis4,5, Carolina Gutierrez4,5, Antonio Llombart-Cussac6, Tao Wang4, Javier Cortés7,8, Brent Rexer9, Laia Paré1,2,3, Andres Forero10, Antonio C Wolff11, Serafín Morales12, Barbara Adamo1,2, Fara Brasó-Maristany1,2, Maria Vidal1,2, Jamunarani Veeraraghavan4,5, Ian Krop13, Patricia Galván1,2, Anne C Pavlick4, Begoña Bermejo14, Miguel Izquierdo15, Vanessa Rodrik-Outmezguine15, Jorge S Reis-Filho16, Susan G Hilsenbeck4,5, Mafalda Oliveira8,17, Maria Vittoria Dieci18,19, Gaia Griguolo18,19, Roberta Fasani8, Paolo Nuciforo8, Joel S Parker18, PierFranco Conte19,20, Rachel Schiff4,5,21,22, Valentina Guarneri19,20, C Kent Osborne4,5,21,22, Mothaffar F Rimawi4,5,21. 1. Department of Medical Oncology, Hospital Clínic de Barcelona, Spain. 2. Translational Genomics and Targeted Therapeutics in Solid Tumors Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. 3. Scientific Department, SOLTI Breast Cancer Cooperative Group, Barcelona, Spain. 4. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX. 5. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX. 6. Department of Medical Oncology, Hospital Arnau de Vilanova, Valencia, Spain. 7. IOB Institute of Oncology, Quironsalud Group, Madrid & Barcelona, Spain. 8. Breast Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. 9. Department of Medicine, Vanderbilt University, Nashville, TN. 10. Department of Medicine, University of Alabama-Birmingham, Birmingham, AL. 11. Johns Hopkins University, Baltimore, MD. 12. Department of Medical Oncology, Hospital Universitari Arnau Vilanova, Lleida, Spain. 13. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA. 14. Department of Medical Oncology, Hospital Clínico de Valencia, Valencia, Spain. 15. Novartis Oncology, Basel, Switzerland. 16. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY. 17. Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. 18. Department of Genetics, University of North Carolina, Chapel Hill, NC. 19. Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. 20. Medical Oncology 2, Istituto Oncologico Veneto, IRCCS, Padova, Italy. 21. Department of Medicine, Baylor College of Medicine, Houston, TX. 22. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.
Abstract
BACKGROUND: Identification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy. METHODS: A research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated. RESULTS: A total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab, the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest (44.5%, 95% confidence interval [CI] = 35.4% to 53.9% vs 11.6%, 95% CI = 6.9% to 18.0%; adjusted odds ratio [OR] = 6.05, 95% CI = 3.10 to 11.80, P < .001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P = .01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P < .001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P = .02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P = .01). CONCLUSIONS: Combining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer.
RCT Entities:
BACKGROUND: Identification of HER2-positive breast cancers with high anti-HER2 sensitivity could help de-escalate chemotherapy. Here, we tested a clinically applicable RNA-based assay that combines ERBB2 and the HER2-enriched (HER2-E) intrinsic subtype in HER2-positive disease treated with dual HER2-blockade without chemotherapy. METHODS: A research-based PAM50 assay was applied in 422 HER2-positive tumors from five II-III clinical trials (SOLTI-PAMELA, TBCRC023, TBCRC006, PER-ELISA, EGF104090). In SOLTI-PAMELA, TBCRC023, TBCRC006, and PER-ELISA, all patients had early disease and were treated with neoadjuvant lapatinib or pertuzumab plus trastuzumab for 12-24 weeks. Primary outcome was pathological complete response (pCR). In EGF104900, 296 women with advanced disease were randomized to receive either lapatinib alone or lapatinib plus trastuzumab. Progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) were evaluated. RESULTS: A total of 305 patients with early and 117 patients with advanced HER2-positive disease were analyzed. In early disease, HER2-E represented 83.8% and 44.7% of ERBB2-high and ERBB2-low tumors, respectively. Following lapatinib and trastuzumab, the HER2-E and ERBB2 (HER2-E/ERBB2)-high group showed a higher pCR rate compared to the rest (44.5%, 95% confidence interval [CI] = 35.4% to 53.9% vs 11.6%, 95% CI = 6.9% to 18.0%; adjusted odds ratio [OR] = 6.05, 95% CI = 3.10 to 11.80, P < .001). Similar findings were observed with neoadjuvant trastuzumab and pertuzumab (pCR rate of 66.7% in HER2-E/ERBB2-high, 95% CI = 22.3% to 95.7% vs 14.7% in others, 95% CI = 4.9% to 31.1%; adjusted OR = 11.60, 95% CI = 1.66 to 81.10, P = .01). In the advanced setting, the HER2-E/ERBB2-high group was independently associated with longer PFS (hazard ratio [HR] = 0.52, 95% CI = 0.35 to 0.79, P < .001); higher ORR (16.3%, 95% CI = 8.9% to 26.2% vs 3.7%, 95% CI = 0.8% to 10.3%, P = .02); and longer OS (HR = 0.66, 95% CI = 0.44 to 0.97, P = .01). CONCLUSIONS: Combining HER2-E subtype and ERBB2 mRNA into a single assay identifies tumors with high responsiveness to HER2-targeted therapy. This biomarker could help de-escalate chemotherapy in approximately 40% of patients with HER2-positive breast cancer.
Authors: Sara M Tolaney; William T Barry; Chau T Dang; Denise A Yardley; Beverly Moy; P Kelly Marcom; Kathy S Albain; Hope S Rugo; Matthew Ellis; Iuliana Shapira; Antonio C Wolff; Lisa A Carey; Beth A Overmoyer; Ann H Partridge; Hao Guo; Clifford A Hudis; Ian E Krop; Harold J Burstein; Eric P Winer Journal: N Engl J Med Date: 2015-01-08 Impact factor: 91.245
Authors: Kimberly L Blackwell; Harold J Burstein; Anna Maria Storniolo; Hope S Rugo; George Sledge; Gursel Aktan; Catherine Ellis; Allison Florance; Svetislava Vukelja; Joachim Bischoff; José Baselga; Joyce O'Shaughnessy Journal: J Clin Oncol Date: 2012-06-11 Impact factor: 44.544
Authors: Antonio Llombart-Cussac; Javier Cortés; Laia Paré; Patricia Galván; Begoña Bermejo; Noelia Martínez; Maria Vidal; Sònia Pernas; Rafael López; Montserrat Muñoz; Paolo Nuciforo; Serafín Morales; Mafalda Oliveira; Lorena de la Peña; Alexandra Peláez; Aleix Prat Journal: Lancet Oncol Date: 2017-02-24 Impact factor: 41.316
Authors: A Schneeweiss; S Chia; T Hickish; V Harvey; A Eniu; R Hegg; C Tausch; J H Seo; Y-F Tsai; J Ratnayake; V McNally; G Ross; J Cortés Journal: Ann Oncol Date: 2013-05-22 Impact factor: 32.976
Authors: Juan Miguel Cejalvo; Tomás Pascual; Aranzazu Fernández-Martínez; Fara Brasó-Maristany; Roger R Gomis; Charles M Perou; Montserrat Muñoz; Aleix Prat Journal: Cancer Treat Rev Date: 2018-05-07 Impact factor: 12.111
Authors: Aleix Prat; Cheng Fan; Aranzazu Fernández; Katherine A Hoadley; Rossella Martinello; Maria Vidal; Margarita Viladot; Estela Pineda; Ana Arance; Montserrat Muñoz; Laia Paré; Maggie C U Cheang; Barbara Adamo; Charles M Perou Journal: BMC Med Date: 2015-12-18 Impact factor: 8.775
Authors: Francesco Schettini; Tomás Pascual; Benedetta Conte; Nuria Chic; Fara Brasó-Maristany; Patricia Galván; Olga Martínez; Barbara Adamo; Maria Vidal; Montserrat Muñoz; Aranzazu Fernández-Martinez; Carla Rognoni; Gaia Griguolo; Valentina Guarneri; Pier Franco Conte; Mariavittoria Locci; Jan C Brase; Blanca Gonzalez-Farre; Patricia Villagrasa; Sabino De Placido; Rachel Schiff; Jamunarani Veeraraghavan; Mothaffar F Rimawi; C Kent Osborne; Sonia Pernas; Charles M Perou; Lisa A Carey; Aleix Prat Journal: Cancer Treat Rev Date: 2020-01-17 Impact factor: 12.111
Authors: Yun Shin Chun; Takashi Mizuno; Jordan M Cloyd; Min Jin Ha; Kiyohiko Omichi; Ching-Wei D Tzeng; Thomas A Aloia; Naoto T Ueno; Henry M Kuerer; Carlos H Barcenas; Jean-Nicolas Vauthey Journal: Eur J Surg Oncol Date: 2020-03-28 Impact factor: 4.424
Authors: Aranzazu Fernandez-Martinez; Ian E Krop; David W Hillman; Mei-Yin Polley; Joel S Parker; Lucas Huebner; Katherine A Hoadley; Jonathan Shepherd; Sara Tolaney; N Lynn Henry; Chau Dang; Lyndsay Harris; Donald Berry; Olwen Hahn; Clifford Hudis; Eric Winer; Ann Partridge; Charles M Perou; Lisa A Carey Journal: J Clin Oncol Date: 2020-10-23 Impact factor: 44.544
Authors: Aleix Prat; Valentina Guarneri; Laia Paré; Gaia Griguolo; Tomás Pascual; Maria V Dieci; Núria Chic; Blanca González-Farré; Antonio Frassoldati; Esther Sanfeliu; Juan M Cejalvo; Montserrat Muñoz; Giancarlo Bisagni; Fara Brasó-Maristany; Loredana Urso; Maria Vidal; Alba A Brandes; Barbara Adamo; Antonino Musolino; Federica Miglietta; Benedetta Conte; Mafalda Oliveira; Cristina Saura; Sònia Pernas; Jesús Alarcón; Antonio Llombart-Cussac; Javier Cortés; Luis Manso; Rafael López; Eva Ciruelos; Francesco Schettini; Patricia Villagrasa; Lisa A Carey; Charles M Perou; Federico Piacentini; Roberto D'Amico; Enrico Tagliafico; Joel S Parker; Pierfranco Conte Journal: Lancet Oncol Date: 2020-11 Impact factor: 41.316
Authors: Sandra M Swain; Gong Tang; Heather Ann Brauer; David S Goerlitz; Peter C Lucas; André Robidoux; Brent T Harris; Hanna Bandos; Yuqi Ren; Charles E Geyer; Priya Rastogi; Eleftherios P Mamounas; Norman Wolmark Journal: Clin Cancer Res Date: 2020-05-05 Impact factor: 12.531
Authors: Tomás Pascual; Aranzazu Fernandez-Martinez; Maki Tanioka; M Vittoria Dieci; Sonia Pernas; Joaquin Gavila; Valentina Guarnieri; Javier Cortes; Patricia Villagrasa; Núria Chic; Maria Vidal; Barbara Adamo; Montserrat Muñoz; Gaia Griguolo; Antonio Llombart; Pierfranco Conte; Mafalda Oliveira; Benedetta Conte; Laia Paré; Patricia Galvan; Lisa A Carey; Charles M Perou; Aleix Prat Journal: Clin Cancer Res Date: 2021-02-25 Impact factor: 12.531