A PAM50-Based Chemoendocrine Score for Hormone Receptor-Positive Breast Cancer with an Intermediate Risk of Relapse

Aleix Prat ¹, Ana Lluch ², Arran K Turnbull ³, Anita K Dunbier ⁴, Lourdes Calvo ⁵, Joan Albanell ⁶, Juan de la Haba-Rodríguez ⁷, Angels Arcusa ⁸, José Ignacio Chacón ⁹, Pedro Sánchez-Rovira ¹⁰, Arrate Plazaola ¹¹, Montserrat Muñoz ¹², Laia Paré ¹³, Joel S Parker ¹⁴, Nuria Ribelles ¹⁵, Begoña Jimenez ¹⁵, Abdul Aziz Bin Aiderus ³, Rosalía Caballero ¹⁶, Barbara Adamo ¹², Mitch Dowsett ¹⁷, Eva Carrasco ¹⁶, Miguel Martín ¹⁸, J Michael Dixon ³, Charles M Perou ¹⁴, Emilio Alba ¹⁵

Affiliations

¹ Department of Medical Oncology, Hospital Clínic i Provincial, Barcelona, Spain. alprat@clinic.ub.es.
² Department of Medical Oncology, Valencia University Hospital, Valencia, Spain.
³ University of Edinburgh Cancer, Research UK Centre, Edinburgh.
⁴ Department of Biochemistry, University of Otago, Dunedin, New Zealand.
⁵ Department of Medical Oncology, A Coruña University Hospital Complex, A Coruña, Spain.
⁶ Department of Medical Oncology, Hospital del Mar Medical Research Institute-IMIM and Pompeu Fabra University, Barcelona, Spain.
⁷ Department of Medical Oncology, Biomedical Research Institute-IMIBIC, Reina Sofía Hospital Complex, Córdoba, Spain.
⁸ Department of Medical Oncology, Consorci Sanitari de Terrassa, Barcelona, Spain.
⁹ Department of Medical Oncology, Virgen de la Salud Hospital, Toledo, Spain.
¹⁰ Department of Medical Oncology, Jaén Hospital Complex, Jaen, Spain.
¹¹ Department of Medical Oncology, Onkologikoa, Donostia, Spain.
¹² Department of Medical Oncology, Hospital Clínic i Provincial, Barcelona, Spain.
¹³ Translational Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
¹⁴ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
¹⁵ Department of Medical Oncology, Virgen de la Victoria University Hospital, Málaga, Spain.
¹⁶ GEICAM (Spanish Breast Cancer Research Group), Madrid, Spain.
¹⁷ Academic Department of Biochemistry, Royal Marsden Foundation Trust, London, United Kingdom.
¹⁸ Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain.

PMID: 27903675
41 References
9 citations

Abstract

Purpose: Hormone receptor-positive (HR+) breast cancer is clinically and biologically heterogeneous, and subgroups with different prognostic and treatment sensitivities need to be identified.Experimental Design: Research-based PAM50 subtyping and expression of additional genes was performed on 63 patients with HR+/HER2- disease randomly assigned to neoadjuvant multiagent chemotherapy versus endocrine therapy in a phase II trial. The biology associated with treatment response was used to derive a PAM50-based chemoendocrine score (CES). CES's predictive ability was evaluated in 4 independent neoadjuvant data sets (n = 675) and 4 adjuvant data sets (n = 1,505). The association of CES, intrinsic biology, and PAM50 risk of relapse (ROR) was explored across 6,007 tumors.Results: Most genes associated with endocrine sensitivity were also found associated with chemotherapy resistance. In the chemotherapy test/validation data sets, CES was independently associated with pathologic complete response (pCR), even after adjusting for intrinsic subtype. pCR rates of the CES endocrine-sensitive (CES-E), uncertain (CES-U), and chemotherapy-sensitive (CES-C) groups in both data sets combined were 25%, 11%, and 2%, respectively. In the endocrine test/validation data sets, CES was independently associated with response. Compared with ROR, >90% of ROR-low and ROR-high tumors were identified as CES-E and CES-C, respectively; however, each CES group represented >25% of ROR-intermediate disease. In terms of survival outcome, CES-C was associated with poor relapse-free survival in patients with ROR-intermediate disease treated with either adjuvant endocrine therapy only or no adjuvant systemic therapy, but not in patients treated with (neo)adjuvant chemotherapy.Conclusions: CES is a genomic signature capable of estimating chemoendocrine sensitivity in HR+ breast cancer beyond intrinsic subtype and risk of relapse. Clin Cancer Res; 23(12); 3035-44. ©2016 AACR.

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