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Imaging, Diagnosis, Prognosis

Breast Cancer Index Identifies Early-Stage Estrogen Receptor–Positive Breast Cancer Patients at Risk for Early- and Late-Distant Recurrence

Yi Zhang, Catherine A. Schnabel, Brock E. Schroeder, Piiha-Lotta Jerevall, Rachel C. Jankowitz, Tommy Fornander, Olle Stål, Adam M. Brufsky, Dennis Sgroi and Mark G. Erlander
Yi Zhang
1bioTheranostics, Inc., San Diego, California; 2Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; 3Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 4Department of Oncology, Karolinska University Hospital, Karolinska Institute, Stockholm; 5Department of Clinical and Experimental Medicine, Linköping University; and 6Department of Oncology, County Council of Östergötland, Linköping, Sweden
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Catherine A. Schnabel
1bioTheranostics, Inc., San Diego, California; 2Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; 3Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 4Department of Oncology, Karolinska University Hospital, Karolinska Institute, Stockholm; 5Department of Clinical and Experimental Medicine, Linköping University; and 6Department of Oncology, County Council of Östergötland, Linköping, Sweden
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Brock E. Schroeder
1bioTheranostics, Inc., San Diego, California; 2Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; 3Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 4Department of Oncology, Karolinska University Hospital, Karolinska Institute, Stockholm; 5Department of Clinical and Experimental Medicine, Linköping University; and 6Department of Oncology, County Council of Östergötland, Linköping, Sweden
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Piiha-Lotta Jerevall
1bioTheranostics, Inc., San Diego, California; 2Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; 3Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 4Department of Oncology, Karolinska University Hospital, Karolinska Institute, Stockholm; 5Department of Clinical and Experimental Medicine, Linköping University; and 6Department of Oncology, County Council of Östergötland, Linköping, Sweden
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Rachel C. Jankowitz
1bioTheranostics, Inc., San Diego, California; 2Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; 3Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 4Department of Oncology, Karolinska University Hospital, Karolinska Institute, Stockholm; 5Department of Clinical and Experimental Medicine, Linköping University; and 6Department of Oncology, County Council of Östergötland, Linköping, Sweden
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Tommy Fornander
1bioTheranostics, Inc., San Diego, California; 2Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; 3Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 4Department of Oncology, Karolinska University Hospital, Karolinska Institute, Stockholm; 5Department of Clinical and Experimental Medicine, Linköping University; and 6Department of Oncology, County Council of Östergötland, Linköping, Sweden
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Olle Stål
1bioTheranostics, Inc., San Diego, California; 2Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; 3Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 4Department of Oncology, Karolinska University Hospital, Karolinska Institute, Stockholm; 5Department of Clinical and Experimental Medicine, Linköping University; and 6Department of Oncology, County Council of Östergötland, Linköping, Sweden
1bioTheranostics, Inc., San Diego, California; 2Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; 3Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 4Department of Oncology, Karolinska University Hospital, Karolinska Institute, Stockholm; 5Department of Clinical and Experimental Medicine, Linköping University; and 6Department of Oncology, County Council of Östergötland, Linköping, Sweden
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Adam M. Brufsky
1bioTheranostics, Inc., San Diego, California; 2Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; 3Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 4Department of Oncology, Karolinska University Hospital, Karolinska Institute, Stockholm; 5Department of Clinical and Experimental Medicine, Linköping University; and 6Department of Oncology, County Council of Östergötland, Linköping, Sweden
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Dennis Sgroi
1bioTheranostics, Inc., San Diego, California; 2Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; 3Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 4Department of Oncology, Karolinska University Hospital, Karolinska Institute, Stockholm; 5Department of Clinical and Experimental Medicine, Linköping University; and 6Department of Oncology, County Council of Östergötland, Linköping, Sweden
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Mark G. Erlander
1bioTheranostics, Inc., San Diego, California; 2Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts; 3Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; 4Department of Oncology, Karolinska University Hospital, Karolinska Institute, Stockholm; 5Department of Clinical and Experimental Medicine, Linköping University; and 6Department of Oncology, County Council of Östergötland, Linköping, Sweden
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DOI: 10.1158/1078-0432.CCR-13-0804 Published August 2013
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  • Figure 1.
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    Figure 1.

    BCI risk groups for prediction of early- and late-distant recurrence in the Stockholm TAM cohort (ER+, LN−) and the multi-institutional cohort (ER+ LN−). A and C, early-distant recurrence (0–5 years). B and D, late-distant recurrence (>5 years) in patients recurrence-free at 5 years. HRs compare intermediate-risk (top) and high-risk (bottom) versus low-risk groups, respectively.

  • Figure 2.
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    Figure 2.

    Continuous BCI score for early (0–5 years) and late (>5 years) rate of distant recurrence in the Stockholm TAM cohort (ER+ LN−). A, rate of early-distant recurrence at 5 years. B, rate of late-distant recurrence at 10 years in patients recurrence-free at 5 years. Gray and black rugged bars indicate individual patient BCI scores for nonrecurrence and recurrence respectively.

Tables

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  • Table 1.

    Patient clinicopathologic characteristics in Stockholm and multi-institutional cohorts

    Stockholm untreated (n = 283)Stockholm TAM-treated (n = 317)Multi-institutional (n = 358)
    Age at surgery, y
     <504 (1%)2 (<1%)108 (30%)
     50–5992 (33%)89 (28%)113 (32%)
     60–69178 (63%)214 (68%)93 (26%)
     ≥709 (3%)12 (4%)44 (12%)
    Tumor size
     ≤20 mm230 (81%)259 (82%)237 (66%)
     >20 mm51 (18%)55 (17%)121 (34%)
     Unknown2 (1%)3 (1%)0
    Tumor grade
     Well69 (24%)67 (21%)82 (23%)
     Moderate175 (62%)211 (67%)219 (61%)
     Poor39 (14%)39 (12%)57 (16%)
    PR status
     Negative73 (26%)72 (23%)NA
     Positive182 (64%)220 (69%)
     Unknown28 (10%)25 (8%)
    HER2 status
     Negative257 (91%)295 (93%)316 (88%)
     Positive26 (9%)22 (7%)42 (12%)
    Adjuvant chemotherapy
     No283 (100%)317 (100%)243 (68%)
     Yes00115 (32%)
    Distant recurrence
     Overall56 (100%)33 (100%)57 (100%)
     Early (≤5 y)27 (48%)13 (39%)34 (60%)
     Late (>5 y)29 (52%)20 (61%)23 (40%)
    BCI groups
     Low156 (55%)202 (64%)196 (55%)
     Intermediate75 (27%)65 (20%)78 (22%)
     High52 (18%)50 (16%)84 (23%)

    Abbreviation: NA, not available.

    • Table 2.

      Kaplan–Meier estimates of early- and late-distant recurrence-free survival for 3 BCI risk groups in Stockholm TAM and multi-institutional cohorts

      Stockholm TAM-treatedMulti-institutional
      Patient subgroupsNo. of patients (%)No. DRDRFS (95% CI)No. of patients (%)No. DRDRFS (95% CI)
      Early-distant recurrence at 5 y
       BCI low risk202 (64%)498.0 (96.0–100)196 (55%)895.9 (93.1–98.7)
       BCI intermediate risk65 (20%)395.2 (90.1–100)78 (22%)692.3 (86.5–98.4)
       BCI high risk50 (16%)687.8 (79.0–97.4)84 (23%)2075.5 (66.7–85.4)
      Late-distant recurrence at 10 ya
       BCI low risk184 (65%)897.2 (94.8–99.7)181 (58%)497.5 (95.0–100.0)
       BCI intermediate risk58 (20%)592.8 (86.2–99.9)70 (22%)1083.1 (73.8–93.5)
       BCI high risk43 (15%)789.9 (80.9–99.8)61 (20%)985.0 (76.4–94.5)

      Abbreviations: DR, distant recurrence; DRFS, distant recurrence-free survival.

      • ↵aIn patients who were recurrence-free at 5 years.

    • Table 3.

      Early-distant recurrence: univariate and multivariate Cox model analysis after stepwise variable selection by AIC of likelihood of early-distant recurrence in Stockholm TAM and multi-institutional cohorts for all (ER+) and ER+/HER2− only patients

      All patients (ER+)ER+/HER2− only
      VariableaHR (95% CI)PHR (95% CI)P
      Stockholm TAMn = 317 (13 DR)n = 295 (11 DR)
       Univariate analysis
        Age at surgery0.76 (0.26–2.20)0.620.59 (0.19–1.86)0.37
        Tumor size1.68 (0.46–6.21)0.442.44 (0.63–9.45)0.20
        Tumor grade1.28 (0.28–5.84)0.751.08 (0.23–5.08)0.92
        PR status1.03 (0.28–3.79)0.970.69 (0.18–2.66)0.59
        HER2 status2.56 (0.56–11.68)0.23NANA
        BCI9.08 (1.86–44.4)0.00616.25 (2.59–102.0)0.003
       Multivariate analysis
        BCI9.08 (1.86–44.4)0.00616.25 (2.59–102.0)0.003
      Multi-institutionaln = 358 (34 DR)n = 316 (26 DR)
       Univariate analysis
        Age at surgery1.10 (0.80–1.50)0.571.16 (0.81–1.65)0.42
        Tumor size1.77 (0.90–3.47)0.101.49 (0.68–3.24)0.32
        Tumor grade3.21 (0.98–10.51)0.052.55 (0.77–8.49)0.13
        HER2 status2.44 (1.10–5.39)0.03NANA
        Chemo0.99 (0.48–2.04)0.981.08 (0.49–2.48)0.86
        BCI11.92 (4.53–31.33)<0.000113.71 (4.54–41.36)<0.0001
       Multivariate analysis
        Tumor grade2.32 (0.71–7.58)0.17NANA
        BCI11.50 (4.22–31.32)<0.000113.71 (4.54–41.36)<0.0001

      Abbreviations: AIC, Akaike's Information Criterion; DR, distant recurrences; NA, not applicable.

      • ↵aAge was by 10 years increment; tumor size was greater than 2 cm versus 2 cm or less; tumor grade was moderate/poorly differentiated versus well differentiated; PR and HER2 status was positive versus negative; chemo was no versus yes; BCI was continuous variable with 5 units increment (chosen to dichotomize BCI to facilitate the comparison of HRs with clinical covariates).

    • Table 4.

      Late-distant recurrence: univariate and multivariate Cox model analysis after stepwise variable selection by AIC of likelihood of late-distant recurrence in Stockholm TAM and multi-institutional cohorts for all (ER+) and ER+/HER2− patients

      All patients (ER+)ER+/HER2− Only
      VariableaHR (95% CI)PHR (95% CI)P
      Stockholm TAMn = 285 (20 DR)n = 266 (18 DR)
       Univariate analysis
        Age at surgery0.59 (0.26–1.34)0.210.54 (0.23–1.29)0.17
        Tumor size1.52 (0.50–4.57)0.461.43 (0.41–4.99)0.57
        Tumor grade0.69 (0.27–1.70)0.410.87 (0.32–2.35)0.78
        PR status0.45 (0.18–1.11)0.080.50 (0.18–1.34)0.17
        HER2 status1.38 (0.32–5.98)0.67NANA
        BCI4.07 (1.26–13.10)0.0194.92 (1.36–17.78)0.015
       Multivariate analysis
        PR status0.52 (0.21–1.32)0.170.54 (0.20–1.46)0.22
        BCI3.50 (1.09–11.21)0.0354.57 (1.28–16.37)0.020
      Multi-Institutionaln = 312 (23 DR)n = 281 (22 DR)
       Univariate analysis
        Age at surgery1.32 (0.90–1.95)0.161.48 (1.00–2.20)0.05
        Tumor size3.37 (1.46–7.79)0.013.17 (1.35–7.41)0.01
        Tumor grade2.37 (0.88–6.38)0.092.91 (0.98–8.58)0.05
        HER2 status0.40 (0.05–2.98)0.37NANA
        Chemo0.89 (0.38–2.11)0.801.04 (0.42–2.54)0.94
        BCI8.01 (2.61–24.56)0.000311.03 (3.36–36.21)<0.0001
       Multivariate analysis
        Tumor size2.66 (1.14–6.20)0.022.53 (1.07–5.97)0.03
        HER2 status0.17 (0.02–1.32)0.09NANA
        BCI9.24 (2.85–30.00)0.00029.33 (2.83–30.76)0.0002

      Abbreviations: DR, distant recurrences; NA, not applicable.

      • ↵aAge was by 10 years increment; tumor size was greater than 2 cm versus 2 cm or less; tumor grade was poorly differentiated versus moderate/well differentiated; PR and HER2 status was positive versus negative; chemo was no versus yes; BCI was continuous variable with 5 units increment (chosen to dichotomize BCI to facilitate the comparison of HRs with clinical covariates).

    Additional Files

    • Figures
    • Tables
    • Files in this Data Supplement:

      • Supplementary Figures 1-7 - Supplementary Figures 1-7 - PDF file 117K, Supplementary Figure 1. Cohorts used for BCI model training and validation Supplementary Figure 2. Performance of H:I and MGI for early (0-5 years) and late (> 5 years) distant recurrence in Stockholm ER+, LN- untreated patients. A, C: H:I, 0-5 years and > 5 years. B, D: MGI, 0-5 years and > 5 years. Supplementary Figure 3. BCI risk groups for prediction of overall distant recurrence in Stockholm TAM and Multi-institutional cohorts, ER+, LN- patients. Supplementary Figure 4. Continuous BCI score for overall (0 - 10 years) rate of distant recurrence in Stockholm TAM cohort. Supplementary Figure 5. BCI risk groups for prediction of early and late distant recurrence in the combined StockholmTAM and Multi-institutional cohort; ER+, LN-, tamoxifen-treated patients. Supplementary Figure 6. Continuous BCI score for early (0 - 5 years) and late (> 5 years) rate of distant recurrence in the combined Stockholm TAM and Multi-institutional cohort (ER+, LN-, tamoxifen-treated patients). Supplementary Figure 7. Prediction of tamoxifen benefit by H/I. A: no benefit of tamoxifen in H/I-low patients. B: benefit of tamoxifen in H/I-high patients
      • Supplementary Tables 1-2 - Supplementary Tables 1-2 - PDF file 101K, Supplementary Table 1. Kaplan-Meier estimates of overall distant recurrence free survival (DRFS) for 3 BCI risk groups in Stockholm TAM-treated and Multi-institutional cohorts. Supplementary Table 2. Overall distant recurrence: Univariate and multivariate Cox model analysis after stepwise variable selection by AIC of likelihood of overall distant recurrence in Stockholm TAM and Multi-institutional cohorts for all ER+ and ER+, HER2- patients
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    Clinical Cancer Research: 19 (15)
    August 2013
    Volume 19, Issue 15
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    Breast Cancer Index Identifies Early-Stage Estrogen Receptor–Positive Breast Cancer Patients at Risk for Early- and Late-Distant Recurrence
    Yi Zhang, Catherine A. Schnabel, Brock E. Schroeder, Piiha-Lotta Jerevall, Rachel C. Jankowitz, Tommy Fornander, Olle Stål, Adam M. Brufsky, Dennis Sgroi and Mark G. Erlander
    Clin Cancer Res August 1 2013 (19) (15) 4196-4205; DOI: 10.1158/1078-0432.CCR-13-0804

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    Breast Cancer Index Identifies Early-Stage Estrogen Receptor–Positive Breast Cancer Patients at Risk for Early- and Late-Distant Recurrence
    Yi Zhang, Catherine A. Schnabel, Brock E. Schroeder, Piiha-Lotta Jerevall, Rachel C. Jankowitz, Tommy Fornander, Olle Stål, Adam M. Brufsky, Dennis Sgroi and Mark G. Erlander
    Clin Cancer Res August 1 2013 (19) (15) 4196-4205; DOI: 10.1158/1078-0432.CCR-13-0804
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