Relapse-free survival of statistically standardized continuous RT-PCR estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2): NCIC CTG MA.14.
Recent ASCO/CAP guidelines focus on decision making associated with the presence/absence of continuous breast biomarkers. Statistical standardization (SS) is demonstrated as a method to evaluate the effects of continuous RT-PCR biomarker expression levels on breast cancer outcomes. MA.14 allocated 667 postmenopausal patients to tamoxifen based on locally determined ER/PR. Of 299 available patient tumor samples, 292 passed internal quality control. All tumors were centrally assessed by RT-PCR ER/PR/HER2 with each biomarker's z-scores categorized: ≥1.0 standard deviation (SD) below mean; <1.0 SD below mean; ≤1.0 SD above mean; >1.0 SD above mean. Log-rank statistics tested univariate differences in breast cancer relapse-free survival (RFS). Continuous SS-ER/PR/HER2 were assessed in multivariate Cox step-wise forward regression, adding a factor if p ≤ 0.05. Sensitivity analyses examined an external HER2+ cut-point of 1.32. Patients whose tumors were tested were representative of the MA.14 population (p values = 0.18-0.90). At 9.8 years median follow-up, SS-ER did not univariately impact RFS (p = 0.31). SS-PR values above the mean (z ≥ 0.0) had the best univariate RFS (p = 0.03). SS-HER2 also univariately impacted RFS (p = 0.004) with lowest (z-scores ≤ -1.0) and highest (z-scores > 1.0) having shortest RFS. Multivariate stratified/unstratified Cox models indicated patients with T1 tumors (p = 0.02/p = 0.0002) and higher SS-PR (p = 0.02/p = 0.01) had longer RFS; node-negative patients had better RFS (in unstratified analysis, p < 0.0001). Local ER/PR status did not impact RFS (p > 0.05). Patients with SS HER2+ ≥ 1.32 had worse RFS (univariate, p = 0.05; multivariate, p = 0.06). We demonstrated that higher SS-PR, and SS HER2 levels, measured by RT-PCR impacted breast cancer RFS outcomes. Evaluation in other trials may provide support for this methodology.
Canadian Cancer Trials Group (Formerly, NCIC Clinical Trials Group), Queen's University, 10 Stuart St, Kingston, ON, Canada. jachapma@aol.com.
Judith-Anne W
JA
Chapman
Massachusetts General Hospital, Harvard University, Boston, MA, USA.
Dennis C
DC
Sgroi
Massachusetts General Hospital, Harvard University, Boston, MA, USA.
Paul E
PE
Goss
Massachusetts General Hospital, Harvard University, Boston, MA, USA.
Elizabeth
E
Zarella
Massachusetts General Hospital, Harvard University, Boston, MA, USA.
Shemeica
S
Binns
bioTheranostics Inc, San Diego, CA, USA.
Yi
Y
Zhang
bioTheranostics Inc, San Diego, CA, USA.
Catherine A
CA
Schnabel
bioTheranostics Inc, San Diego, CA, USA.
Mark G
MG
Erlander
Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, Canada.
Kathleen I
KI
Pritchard
Canadian Cancer Trials Group (Formerly, NCIC Clinical Trials Group), Queen's University, 10 Stuart St, Kingston, ON, Canada.
Lei
L
Han
Massachusetts General Hospital, Harvard University, Boston, MA, USA.
Tanja
T
Badovinac-Crnjevic
Canadian Cancer Trials Group (Formerly, NCIC Clinical Trials Group), Queen's University, 10 Stuart St, Kingston, ON, Canada.
Lois E
LE
Shepherd
McGill University, Montreal, QC, Canada.
Michael N
MN
Pollak
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008875:Middle Aged; D015282:Octreotide / Q000008:administration & dosage / Q000627:therapeutic use; D017698:Postmenopause; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics*; D011980:Receptors, Progesterone / Q000235:genetics*; D016019:Survival Analysis; D013629:Tamoxifen / Q000008:administration & dosage* / Q000627:therapeutic use; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D015282:Octreotide; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; C508053:ERBB2 protein, human
Biomarker standardization; Centrally assessed breast cancer biomarkers; RT-ER; RT-HER2; RT-PR