title: A PAM50-Based Chemoendocrine Score for Hormone Receptor-Positive Breast Cancer with an Intermediate Risk of Relapse.
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.
authors.affiliation: Department of Medical Oncology, Hospital Clínic i Provincial, Barcelona, Spain. alprat@clinic.ub.es.|Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.|Translational Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
authors.forename: Aleix
authors.initials: A
authors.lastname: Prat
authors.affiliation: Department of Medical Oncology, Valencia University Hospital, Valencia, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Lluch
authors.affiliation: University of Edinburgh Cancer, Research UK Centre, Edinburgh.
authors.forename: Arran K
authors.initials: AK
authors.lastname: Turnbull
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand.
authors.forename: Anita K
authors.initials: AK
authors.lastname: Dunbier
authors.affiliation: Department of Medical Oncology, A Coruña University Hospital Complex, A Coruña, Spain.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Calvo
authors.affiliation: Department of Medical Oncology, Hospital del Mar Medical Research Institute-IMIM and Pompeu Fabra University, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Albanell
authors.affiliation: Department of Medical Oncology, Biomedical Research Institute-IMIBIC, Reina Sofía Hospital Complex, Córdoba, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: de la Haba-Rodríguez
authors.affiliation: Department of Medical Oncology, Consorci Sanitari de Terrassa, Barcelona, Spain.
authors.forename: Angels
authors.initials: A
authors.lastname: Arcusa
authors.affiliation: Department of Medical Oncology, Virgen de la Salud Hospital, Toledo, Spain.
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Chacón
authors.affiliation: Department of Medical Oncology, Jaén Hospital Complex, Jaen, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Sánchez-Rovira
authors.affiliation: Department of Medical Oncology, Onkologikoa, Donostia, Spain.
authors.forename: Arrate
authors.initials: A
authors.lastname: Plazaola
authors.affiliation: Department of Medical Oncology, Hospital Clínic i Provincial, Barcelona, Spain.|Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Muñoz
authors.affiliation: Translational Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Paré
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.affiliation: Department of Medical Oncology, Virgen de la Victoria University Hospital, Málaga, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Ribelles
authors.affiliation: Department of Medical Oncology, Virgen de la Victoria University Hospital, Málaga, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Jimenez
authors.affiliation: University of Edinburgh Cancer, Research UK Centre, Edinburgh.
authors.forename: Abdul Aziz
authors.initials: AA
authors.lastname: Bin Aiderus
authors.affiliation: GEICAM (Spanish Breast Cancer Research Group), Madrid, Spain.
authors.forename: Rosalía
authors.initials: R
authors.lastname: Caballero
authors.affiliation: Department of Medical Oncology, Hospital Clínic i Provincial, Barcelona, Spain.|Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
authors.forename: Barbara
authors.initials: B
authors.lastname: Adamo
authors.affiliation: Academic Department of Biochemistry, Royal Marsden Foundation Trust, London, United Kingdom.
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.affiliation: GEICAM (Spanish Breast Cancer Research Group), Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Carrasco
authors.affiliation: Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Martín
authors.affiliation: University of Edinburgh Cancer, Research UK Centre, Edinburgh.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Dixon
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.|Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.|Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Department of Medical Oncology, Virgen de la Victoria University Hospital, Málaga, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Alba
mesh_terms: D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000009:adverse effects; D009363:Neoplasm Proteins / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D012008:Recurrence
chemical_list: D018931:Antineoplastic Agents, Hormonal; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human