title: Effect of continuous statistically standardized measures of estrogen and progesterone receptors on disease-free survival in NCIC CTG MA.12 Trial and BC Cohort.
abstract: BACKGROUND
  We hypothesized improved inter-laboratory comparability of estrogen receptor (ER) and progesterone receptor (PgR) across different assay methodologies with adjunctive statistical standardization, akin to bone mineral density (BMD) z-scores. We examined statistical standardization in MA.12, a placebo-controlled pre-menopausal trial of adjuvant tamoxifen with locally assessed hormone receptor +/- tumours, and in a cohort of post-menopausal British Columbia (BC) tamoxifen-treated patients.
  
  
  METHODS
  ER and PgR were centrally assessed for both patient groups with real time quantitative reverse transcription polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Effects on disease-free survival (DFS) were investigated separately for 345 MA.12 and 673 BC patients who had both qPCR and IHC assessments. Comparisons utilized continuous laboratory units and statistically standardized z-scores. Univariate categorization of ER/PgR was by number of standard deviations (SD) above or below the mean (z-score ≥1.0 SD below mean; z-score <1.0 SD below mean; z-score ≤1.0 SD above mean; z-score >1.0 SD above mean). Exploratory multivariate examinations utilized step-wise Cox regression.
  
  
  RESULTS
  Median follow-up for MA.12 was 9.7 years; for BC patients, 11.8 years. For MA.12, 101 of 345 (29%) patients were IHC ER-PgR-. ER was not univariately associated with DFS (qPCR, P = 0.19; IHC, P = 0.08), while PgR was (qPCR, P = 0.09; IHC, P = 0.04). For BC patients, neither receptor was univariately associated with DFS: for ER, PCR, P = 0.36, IHC, P = 0.24; while for PgR, qPCR, P = 0.17, IHC, P = 0.31. Multivariately, MA.12 patients randomized to tamoxifen had significantly better DFS (P = 0.002 to 0.005) than placebo. Meanwhile, jointly ER and PgR were not associated with DFS whether assessed by qPCR or by IHC in all patients, or in the subgroup of patients with IHC positive stain, for pooled or separate treatment arms. Different results by type of continuous unit supported the concept of ER level being relevant for medical decision-making. For postmenopausal BC tamoxifen patients, higher qPCR PgR was weakly associated with better DFS (P = 0.06).
  
  
  CONCLUSIONS
  MA.12 pre-menopausal patients in a placebo-controlled tamoxifen trial had similar multivariate prognostic effects with statistically standardized hormone receptors when tumours were assayed by qPCR or IHC, for hormone receptor +/- and + tumours. The BC post-menopausal tamoxifen cohort did not exhibit a significant prognostic association of ER or PgR with DFS. Adjunctive statistical standardization is currently under investigation in other NCIC CTG endocrine trials.
authors: Judith-Anne W
authors: JA
authors: Chapman
authors: Torsten O
authors: TO
authors: Nielsen
authors: Matthew J
authors: MJ
authors: Ellis
authors: Phillip
authors: P
authors: Bernard
authors: Stephen
authors: S
authors: Chia
authors: Karen A
authors: KA
authors: Gelmon
authors: Kathleen I
authors: KI
authors: Pritchard
authors: Aurelie
authors: A
authors: Le Maitre
authors: Paul E
authors: PE
authors: Goss
authors: Samuel
authors: S
authors: Leung
authors: Lois E
authors: LE
authors: Shepherd
authors: Vivien H C
authors: VH
authors: Bramwell
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D015331:Cohort Studies; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D009367:Neoplasm Staging; D017698:Postmenopause; D017697:Premenopause; D011379:Prognosis; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*
chemical_list: D011960:Receptors, Estrogen; D011980:Receptors, Progesterone
references: Clin Cancer Res. 2012 Aug 15;18(16):4465-72
references: 22711706
references: Comp Funct Genomics. 2005;6(3):123-31
references: 18629220
references: J Clin Pathol. 2000 Sep;53(9):688-96
references: 11041059
references: J Clin Oncol. 2012 Mar 1;30(7):729-34
references: 22291085
references: J Clin Oncol. 2011 Aug 1;29(22):2978-84
references: 21709197
references: J Steroid Biochem Mol Biol. 1996 Mar;57(5-6):323-8
references: 8639468
references: J Clin Oncol. 2008 Mar 1;26(7):1059-65
references: 18227529
references: Nat Med. 2002 Nov;8(11):1323-7
references: 12389040
references: Breast J. 2000 May;6(3):189-196
references: 11348363
references: Mod Pathol. 1998 Feb;11(2):155-68
references: 9504686
references: Stat Med. 2008 May 20;27(11):1944-59
references: 18300332
references: Ann Oncol. 2010 Feb;21(2):283-290
references: 19628570
references: Breast J. 2006 Jan-Feb;12(1):37-47
references: 16409585
references: Breast Cancer Res Treat. 1998;52(1-3):261-88
references: 10066087
references: J Clin Pathol. 2000 Feb;53(2):125-30
references: 10767828
references: Semin Oncol. 2001 Feb;28(1):53-67
references: 11254867
references: J Clin Oncol. 2011 Apr 20;29(12):1531-8
references: 21422407
references: Clin Cancer Res. 2010 Nov 1;16(21):5222-32
references: 20837693
references: J Natl Cancer Inst. 2005 Dec 21;97(24):1808-15
references: 16368942
references: J Clin Pathol. 2000 Apr;53(4):292-301
references: 10823126
references: J Steroid Biochem Mol Biol. 1993 May;45(5):367-73
references: 7684604
references: Eur J Cancer. 1993;29A(9):1293-7
references: 8343271
references: J Clin Oncol. 2010 Jun 1;28(16):2784-95
references: 20404251