title: Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population.
abstract: BACKGROUND
  Biomarkers to improve the risk-benefit of extended adjuvant endocrine therapy for late recurrence in patients with oestrogen-receptor-positive breast cancer would be clinically valuable. We compared the prognostic ability of the breast-cancer index (BCI) assay, 21-gene recurrence score (Oncotype DX), and an immunohistochemical prognostic model (IHC4) for both early and late recurrence in patients with oestrogen-receptor-positive, node-negative (N0) disease who took part in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) clinical trial.
  
  
  METHODS
  In this prospective comparison study, we obtained archival tumour blocks from the TransATAC tissue bank from all postmenopausal patients with oestrogen-receptor-positive breast cancer from whom the 21-gene recurrence score and IHC4 values had already been derived. We did BCI analysis in matched samples with sufficient residual RNA using two BCI models-cubic (BCI-C) and linear (BCI-L)-using previously validated cutoffs. We assessed prognostic ability of BCI for distant recurrence over 10 years (the primary endpoint) and compared it with that of the 21-gene recurrence score and IHC4. We also tested the ability of the assays to predict early (0-5 years) and late (5-10 years) distant recurrence. To assess the ability of the biomarkers to predict recurrence beyond standard clinicopathological variables, we calculated the change in the likelihood-ratio χ(2) (LR-Δχ(2)) from Cox proportional hazards models.
  
  
  RESULTS
  Suitable tissue was available from 665 patients with oestrogen-receptor-positive, N0 breast cancer for BCI analysis. The primary analysis showed significant differences in risk of distant recurrence over 10 years in the categorical BCI-C risk groups (p<0·0001) with 6·8% (95% CI 4·4-10·0) of patients in the low-risk group, 17·3% (12·0-24·7) in the intermediate group, and 22·2% (15·3-31·5) in the high-risk group having distant recurrence. The secondary analysis showed that BCI-L was a much stronger predictor for overall (0-10 year) distant recurrence compared with BCI-C (interquartile HR 2·30 [95% CI 1·62-3·27]; LR-Δχ(2)=22·69; p<0·0001). When compared with BCI-L, the 21-gene recurrence score was less predictive (HR 1·48 [95% CI 1·22-1·78]; LR-Δχ(2)=13·68; p=0·0002) and IHC4 was similar (HR 1·69 [95% CI 1·51-2·56]; LR-Δχ(2)=22·83; p<0·0001). All further analyses were done with the BCI-L model. In a multivariable analysis, all assays had significant prognostic ability for early distant recurrence (BCI-L HR 2·77 [95% CI 1·63-4·70], LR-Δχ(2)=15·42, p<0·0001; 21-gene recurrence score HR 1·80 [1·42-2·29], LR-Δχ(2)=18·48, p<0·0001; IHC4 HR 2·90 [2·01-4·18], LR-Δχ(2)=29·14, p<0·0001); however, only BCI-L was significant for late distant recurrence (BCI-L HR 1·95 [95% CI 1·22-3·14], LR-Δχ(2)=7·97, p=0·0048; 21-gene recurrence score HR 1·13 [0·82-1·56], LR-Δχ(2)=0·48, p=0·47; IHC4 HR 1·30 [0·88-1·94], LR-Δχ(2)=1·59, p=0·20).
  
  
  CONCLUSIONS
  BCI-L was the only significant prognostic test for risk of both early and late distant recurrence and identified two risk populations for each timeframe. It could help to identify patients at high risk for late distant recurrence who might benefit from extended endocrine or other therapy.
  
  
  BACKGROUND
  Avon Foundation, National Institutes of Health, Breast Cancer Foundation, US Department of Defense Breast Cancer Research Program, Susan G Komen for the Cure, Breakthrough Breast Cancer through the Mary-Jean Mitchell Green Foundation, AstraZeneca, Cancer Research UK, and the National Institute for Health Research Biomedical Research Centre at the Royal Marsden (London, UK).
authors.affiliation: Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, Boston, MA, USA; Center for Cancer Research, Massachusetts General Hospital, Charlestown, Boston, MA, USA. Electronic address: dsgroi@partners.org.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Sgroi
authors.affiliation: Centre for Cancer Prevention, Queen Mary University, London, UK.
authors.forename: Ivana
authors.initials: I
authors.lastname: Sestak
authors.affiliation: Centre for Cancer Prevention, Queen Mary University, London, UK.
authors.forename: Jack
authors.initials: J
authors.lastname: Cuzick
authors.affiliation: bioTheranostics, San Diego, CA, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: bioTheranostics, San Diego, CA, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Schnabel
authors.affiliation: bioTheranostics, San Diego, CA, USA.
authors.forename: Brock
authors.initials: B
authors.lastname: Schroeder
authors.affiliation: bioTheranostics, San Diego, CA, USA.
authors.forename: Mark G
authors.initials: MG
authors.lastname: Erlander
authors.affiliation: Breakthrough Breast Cancer Centre, Royal Marsden Hospital, London, UK; Department of Biochemistry, University of Otago, Dunedin, New Zealand.
authors.forename: Anita
authors.initials: A
authors.lastname: Dunbier
authors.affiliation: Breakthrough Breast Cancer Centre, Royal Marsden Hospital, London, UK.
authors.forename: Kally
authors.initials: K
authors.lastname: Sidhu
authors.affiliation: Breakthrough Breast Cancer Centre, Royal Marsden Hospital, London, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Lopez-Knowles
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Charlestown, Boston, MA, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Goss
authors.affiliation: Breakthrough Breast Cancer Centre, Royal Marsden Hospital, London, UK; Institute of Cancer Research and Academic Department of Biochemistry, Royal Marsden Hospital, London, UK.
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism; D009367:Neoplasm Staging; D009570:Nitriles / Q000627:therapeutic use; D011379:Prognosis; D011446:Prospective Studies; D011960:Receptors, Estrogen / Q000378:metabolism*; D013629:Tamoxifen / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use
chemical_list: D018931:Antineoplastic Agents, Hormonal; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D013629:Tamoxifen; D000077384:Anastrozole
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