title: Low residual proliferation after short-term letrozole therapy is an early predictive marker of response in high proliferative ER-positive breast cancer.
abstract: The gene expression grade index (GGI) is a 97-gene algorithm that measures proliferation and divides intermediate histological grade tumors into two distinct groups. We investigated the association between early changes in GGI and clinical response to neoadjuvant letrozole and compared this to Ki67 values. The paired gene expression data at the beginning and after 10-14 days of neoadjuvant letrozole treatment were available for 52 post-menopausal patients with estrogen receptor (ER)-positive breast cancer. Baseline values and changes in GGI, Ki67, and RNA expression modules representing oncogenic signaling pathways were compared to sonographic tumor volume changes after 3 months of treatment in the subsets of patients defined by high and low baseline GGI. The clinical response was observed in 80% genomic low-grade (24/30) and 59% genomic high-grade (13/22) tumors (P=0.10). Low residual proliferation after 10-14 days of neoadjuvant letrozole therapy, measured by either GGI or Ki67, was associated with sonographic response in genomic high-grade (GGI, P=0.003; Ki67, P=0.017) but not genomic low-grade (GGI, P=0.25; Ki67, P=1.0) tumors. The analysis of expression modules suggested that sonographic response to letrozole in genomic high-grade tumors was associated with an early reduction in IGF1 signaling (unadjusted P=0.018). The major conclusion of this study is that the early assessment of proliferation after short-term endocrine therapy may be useful to evaluate endocrine responsiveness, particularly in genomic high-grade ER-positive breast cancer.
authors: Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Hospital, University of Toronto, Ontario, Canada.
authors: Philippe L
authors: PL
authors: Bedard
authors: Sandeep K
authors: SK
authors: Singhal
authors: Michail
authors: M
authors: Ignatiadis
authors: Ian
authors: I
authors: Bradbury
authors: Benjamin
authors: B
authors: Haibe-Kains
authors: Christine
authors: C
authors: Desmedt
authors: Sherene
authors: S
authors: Loi
authors: Dean B
authors: DB
authors: Evans
authors: Stefan
authors: S
authors: Michiels
authors: J Michael
authors: JM
authors: Dixon
authors: William R
authors: WR
authors: Miller
authors: Martine J
authors: MJ
authors: Piccart
authors: Christos
authors: C
authors: Sotiriou
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D055088:Early Detection of Cancer; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077289:Letrozole; D046228:Microarray Analysis; D008875:Middle Aged; D018365:Neoplasm, Residual; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use*; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D000077289:Letrozole