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Pooled analysis of prospective European studies assessing the impact of using the 21-gene Recurrence Score assay on clinical decision making in women with oestrogen receptor–positive, human epidermal growth factor receptor 2–negative early-stage breast cancer

Open AccessPublished:August 18, 2016DOI:https://doi.org/10.1016/j.ejca.2016.06.027

      Highlights

      • A pooled analysis of four European decision impact Recurrence Score studies is presented.
      • Recurrence Score testing impacted adjuvant treatment decision in 32% of patients.
      • Testing led to an overall reduction in adjuvant chemotherapy use (from 55% to 34%).
      • Testing led to a more homogenous treatment decision making (between the countries).
      • Testing led to increased physicians' confidence regarding treatment recommendations.

      Abstract

      Purpose

      The 21-gene Recurrence Score assay (Oncotype DX) provides prognostic/predictive information in oestrogen receptor positive (ER+) early breast cancer, but access/reimbursement has been limited in most European countries in the absence of prospective outcome data. Recently, two large prospective studies and a real-life 5-year outcome study have been reported. We performed a pooled analysis of prospective European impact studies to generate robust data on impact of use in different clinical subgroups.

      Methods

      The analysis included four studies (French, German, Spanish, and British) in ER+ human epidermal growth factor receptor 2–negative breast cancer patients (n = 527). Node-positive patients were excluded.

      Results

      The analysis demonstrated that treatment recommendations changed in 32% of patients post-testing; chemotherapy recommendation rate decreased from 55% to 34%. Change rates in the individual studies ranged from 30% to 37%. The highest change rates were in patients originally recommended chemotherapy and in grade II tumours; there was no subgroup without a treatment recommendation change. Notably, 31% of patients with an intermediate Recurrence Score result had a treatment recommendation change suggesting that testing provides actionable information in this group. With the exception of the German study (where chemotherapy rates remained high [41%] post-testing), between-study variability in treatment recommendations decreased post-testing (chemotherapy: from 36–52% to 26–29%; hormonal therapy: from 48–64% to 71–74%). Physicians' confidence regarding treatment recommendations improved in all the studies after testing.

      Conclusion

      Recurrence Score testing led to changes in adjuvant chemotherapy use in approximately a third of patients, to an overall reduced chemotherapy use, and to more homogeneous decision making.

      Keywords

      1. Introduction

      Only a modest proportion of patients with oestrogen receptor positive (ER+) human epidermal growth factor receptor 2 (HER2)–negative early breast cancer benefit from adjuvant chemotherapy [
      • Paik S.
      • Tang G.
      • Shak S.
      • Kim C.
      • Baker J.
      • Kim W.
      • et al.
      Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
      ]. Since currently used traditional markers are prognostic but not predictive of chemotherapy benefit, there is substantial overtreatment. The 21-gene Recurrence Score assay (the Oncotype DX® Breast Recurrence Score Assay; Genomic Health, Inc., Redwood City, CA) is a validated prognosticator (in ER+ node-negative and node-positive early breast cancer patients) that provides independent prognostic information to traditional measures and has been shown to predict adjuvant chemotherapy benefit when tested in patients previously included in phase III clinical trials that randomised patients to hormonal therapy (HT) alone versus chemohormonal therapy (CHT) [
      • Paik S.
      • Tang G.
      • Shak S.
      • Kim C.
      • Baker J.
      • Kim W.
      • et al.
      Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
      ,
      • Paik S.
      • Shak S.
      • Tang G.
      • Kim C.
      • Baker J.
      • Cronin M.
      • et al.
      A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
      ,
      • Habel L.A.
      • Shak S.
      • Jacobs M.K.
      • Capra A.
      • Alexander C.
      • Pho M.
      • et al.
      A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients.
      ,
      • Dowsett M.
      • Cuzick J.
      • Wale C.
      • Forbes J.
      • Mallon E.A.
      • Salter J.
      • et al.
      Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study.
      ,
      • Toi M.
      • Iwata H.
      • Yamanaka T.
      • Masuda N.
      • Ohno S.
      • Nakamura S.
      • et al.
      Clinical significance of the 21-gene signature (Oncotype DX) in hormone receptor-positive early stage primary breast cancer in the Japanese population.
      ,
      • Albain K.S.
      • Barlow W.E.
      • Shak S.
      • Hortobagyi G.N.
      • Livingston R.B.
      • Yeh I.T.
      • et al.
      Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial.
      ].
      Importantly, results from four recently published/presented studies now confirm the available prospective retrospective validation data. The prospective phase III TAILORx adjuvant trial demonstrated that in node-negative hormone receptor (HR)+ HER2-negative patients (n = 1626) with low (≤10) Recurrence Score results treated with HT alone, distant-recurrence risk at 5 years was very low (0.7%) [
      • Sparano J.A.
      • Gray R.J.
      • Makower D.F.
      • Pritchard K.I.
      • Albain K.S.
      • Hayes D.F.
      • et al.
      Prospective validation of a 21-gene expression assay in breast cancer.
      ]. The prospective phase III WSG Plan B trial in patients with node-positive or high-risk node-negative HR+ HER2-negative disease showed that in this patient population too, the distant-recurrence risk is very low in patients (n = 348) with Recurrence Score results ≤11 and HT alone (3-year event-free survival of 98.3%) [

      Gluz O, Nitz, U, Kreipe HH, Christgen M, Kates RE, Hofmann D, et al. Clinical impact of risk classification by central/local grade or luminal like subtype vs. Oncotype DX®: first prospective survival results from the WSG phase III planB trial. Presented at the European Cancer Congress 2015, Sep 25–29, 2015, Vienna, Austria.

      ]. The third study evaluated a large cohort (n = 2028) of patients for whom treatment decisions incorporated the assay in real-life clinical practice [

      Stemmer SM, Steiner M, Rizel S, Ben-Baruch N, Soussan-Gutman L, Geffen DB, et al. Real-life analysis evaluating 1594 N0/Nmic breast cancer patients for whom treatment decisions incorporated the 21-gene Recurrence Score result: 5-year KM estimate for breast cancer specific survival with Recurrence Score results ≤30 is >98%. Presented at San Antonio Breast Cancer Symposium (SABCS), Dec 8–12, 2015, San Antonio, TX.

      ]. It reported a 5-year rate of distant recurrence of 0.8% in patients with low Recurrence Score results (<18) treated with HT (2% chemotherapy use), a 3.2% rate in patients with intermediate scores (18–30) (25% chemotherapy use), and a 10.6% rate in patients with high scores (≥31) (88% chemotherapy use) [

      Stemmer SM, Steiner M, Rizel S, Ben-Baruch N, Soussan-Gutman L, Geffen DB, et al. Real-life analysis evaluating 1594 N0/Nmic breast cancer patients for whom treatment decisions incorporated the 21-gene Recurrence Score result: 5-year KM estimate for breast cancer specific survival with Recurrence Score results ≤30 is >98%. Presented at San Antonio Breast Cancer Symposium (SABCS), Dec 8–12, 2015, San Antonio, TX.

      ]. The fourth study was a prospectively defined analysis of the Surveillance, Epidemiology, and End Results registry which was electronically supplemented with Recurrence Score results. It reported survival data only and demonstrated excellent 5-year breast cancer-specific survival in >21,000 node-negative HR+ HER2-negative breast cancer patients with low Recurrence Score results (99.6%) [

      Shak S, Petkov VI, Miller DP, Howlader N, Gliner N, Howe W, et al. Breast cancer specific survival in 38,568 patients with node negative hormone receptor positive invasive breast cancer and Oncotype DX Recurrence Score results in the SEER database. Presented at San Antonio Breast Cancer Symposium (SABCS), Dec 8–12, 2015, San Antonio, TX.

      ].
      The Recurrence Score assay is incorporated in major international guidelines such as the American Society of Clinical Oncology (ASCO®), National Comprehensive Cancer Network® (NCCN®), European Society for Medical Oncology, and St Gallen as a tool to help estimate prognosis and the magnitude of chemotherapy benefit [
      • Senkus E.
      • Kyriakides S.
      • Penault-Llorca F.
      • Poortmans P.
      • Thompson A.
      • Zackrisson S.
      • et al.
      Primary breast cancer: ESMO clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ,
      • Goldhirsch A.
      • Winer E.P.
      • Coates A.S.
      • Gelber R.D.
      • Piccart-Gebhart M.
      • Thurlimann B.
      • et al.
      Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013.
      ,
      • NCCN Clinical Practice Guidelines in Oncology
      ,
      • Harris L.
      • Fritsche H.
      • Mennel R.
      • Norton L.
      • Ravdin P.
      • Taube S.
      • et al.
      American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer.
      ].
      Despite inclusion in all major international guidelines, less than 20% of patients in Europe have access to the Recurrence Score assay through national reimbursement. Absence of outcome data from prospective studies as well as from real-life studies in patient populations that are using the assay to guide treatment decisions has been stated as the main cause for lack of reimbursement in many countries. Treatment recommendations in ER+ early breast cancer in European countries vary owing to different therapeutic traditions/local guidelines. With prospective outcome data available, an increase in access and reimbursement is likely. Therefore, it is relevant to assess the impact of using the assay in different patient populations and countries. Here, we performed a pooled analysis in order to generate as robust data as possible regarding the impact of the assay on adjuvant treatment recommendations in node-negative ER+, HER2-negative breast cancer in available prospective European decision impact studies. We evaluated the association between traditional parameters and assay-driven treatment recommendation changes and also compared treatment recommendations between study countries pre- and post-assay.

      2. Methods

      2.1 Patient population

      The analysis included four European prospective studies finalised to date, according to the best knowledge of the authors. These similarly designed studies investigated the impact of Recurrence Score testing on clinical decisions in France, Germany, Spain, and the United Kingdom (UK) [
      • Gligorov J.
      • Pivot X.B.
      • Jacot W.
      • Naman H.L.
      • Spaeth D.
      • Misset J.L.
      • et al.
      Prospective clinical utility study of the use of the 21-gene assay in adjuvant clinical decision making in women with estrogen receptor-positive early invasive breast cancer: results from the SWITCH study.
      ,
      • Eiermann W.
      • Rezai M.
      • Kummel S.
      • Kuhn T.
      • Warm M.
      • Friedrichs K.
      • et al.
      The 21-gene recurrence score assay impacts adjuvant therapy recommendations for ER-positive, node-negative and node-positive early breast cancer resulting in a risk-adapted change in chemotherapy use.
      ,
      • Albanell J.
      • Gonzalez A.
      • Ruiz-Borrego M.
      • Alba E.
      • Garcia-Saenz J.A.
      • Corominas J.M.
      • et al.
      Prospective transGEICAM study of the impact of the 21-gene Recurrence Score assay and traditional clinicopathological factors on adjuvant clinical decision making in women with estrogen receptor-positive (ER+) node-negative breast cancer.
      ,
      • Holt S.
      • Bertelli G.
      • Humphreys I.
      • Valentine W.
      • Durrani S.
      • Pudney D.
      • et al.
      A decision impact, decision conflict and economic assessment of routine Oncotype DX testing of 146 women with node-negative or pNImi, ER-positive breast cancer in the UK.
      ]. In these studies, consecutive patients with no contraindications to chemotherapy were enrolled, adjuvant treatment recommendations of the treating physician pre- and post-Recurrence Score testing were recorded, and the treating physicians completed questionnaires regarding their confidence in their treatment recommendations before/after testing.
      All patients included in the final pooled analysis (n = 527) were node negative, ER+, HER2 negative and underwent Recurrence Score testing as per study protocols. Node-positive patients, patients with micrometastases, and those with no available Recurrence Score results were excluded (n = 151) to provide a more homogeneous study population.

      2.2 Statistical analysis

      Analysis of variance/chi-squared tests were used to assess continuous/categorical parameters across studies. McNemar's test was used to assess whether the change (from pre- to post-testing) in the proportion of patients with CHT and HT recommendations was significant. Wilcoxon signed-rank test was used to assess whether the change (from pre- to post-testing) in physicians' confidence was significant.
      Using logistic regression analysis, the probability of a treatment recommendation change was modelled as a function of the Recurrence Score category (as defined by Paik et al. [
      • Paik S.
      • Shak S.
      • Tang G.
      • Kim C.
      • Baker J.
      • Cronin M.
      • et al.
      A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
      ]), age (<55, ≥55 years; this cutoff value was chosen as a proxy for menopausal status), tumour size (≤2, >2 cm; i.e. T1 versus T2/T3), grade (I–III), progesterone receptor (PR) status, and Ki-67 levels (<20%, ≥20%). Patients with missing data were excluded from the analysis. Stepwise regression analysis was performed to determine whether interactions between the evaluated covariates and the Recurrence Score result should be included in the model.

      3. Results

      3.1 Study patients

      The analysis included 565 patients (French study, 83; Spanish study, 107; UK study, 131; and German study, 244). The patient populations were similar with respect to age and PR status and differed with respect to tumour size and grade (p < 0.0001, both variables) (Table 1).
      Table 1Patient and tumour characteristics.
      French study n = 83Spanish study n = 107UK study n = 131German study n = 244All studies N = 565
      Age, yearsa
       Mean (SD)55 (10)54 (11)56 (9)56 (11)56 (10)
       Median (range)55 (33–79)53 (29–78)55 (34–72)56 (25–85)55 (25–85)
      Age, n (%)b
       <55 years26 (31.3)39 (36.4)29 (22.1)77 (31.6)171 (30.3)
       ≥55 years57 (68.7)68 (63.6)102 (77.9)167 (68.4)394 (69.7)
      Tumour size, cmc
       Mean (SD)NANA2.0 (1.2)2.1 (1.2)2.1 (1.2)
       Median (range)NANA1.7 (0.5–6.0)1.8 (0.5–9.0)1.8 (0.5–9.0)
      Tumour size, n (%)d
       ≤2 cm67 (80.7)91 (85.0)85 (64.9)154 (63.1)397 (70.3)
       >2 cm15 (18.1)16 (15.0)46 (35.1)90 (36.9)167 (29.6)
       Unknown1 (1.2)1 (0.2)
      Tumour grade, n (%)e
       I6 (7.2)37 (34.6)23 (17.6)33 (13.5)99 (17.5)
       II67 (80.7)46 (43.0)86 (65.6)188 (77.0)387 (68.5)
       III10 (12.0)20 (18.7)22 (16.8)23 (9.4)75 (13.3)
       Unknown4 (3.7)4 (0.7)
      Progesterone receptor status, n (%)f
       Negative12 (14.5)16 (15.0)15 (11.5)28 (11.5)71 (12.6)
       Positive70 (84.3)90 (84.1)113 (86.3)216 (88.5)489 (86.5)
       Unknown1 (1.2)1 (0.9)3 (2.3)5 (0.9)
      Recurrence Score category, n (%)g
       Low (<18)47 (56.6)62 (57.9)72 (55.0)131 (53.7)312 (55.2)
       Intermediate (18–30)32 (38.6)35 (32.7)37 (28.2)95 (38.9)199 (35.2)
       High (≥31)4 (4.8)10 (9.3)22 (16.8)18 (7.4)54 (9.6)
      UK, United Kingdom; SD, standard deviation; ANOVA, analysis of variance.
      ap = 0.44 (ANOVA).
      bp = 0.099 (chi-squared test).
      cp = 0.66 (ANOVA). Detailed tumour size information was not available for the French and Spanish studies.
      dp < 0.0001 (chi-squared test).
      ep = 0.74 (chi-squared test).
      fp = 0.031 (chi-squared test).

      3.2 Recurrence Score distribution

      A wide range of Recurrence Score results was observed in the pooled cohort (Fig. 1) with a median (range) of 16 (0–81) and a mean (SD) of 18.1 (10.1) (p = 0.19 for comparison across studies). The distribution of Recurrence Score categories differed across the studies (p = 0.031) (Table 1).
      Fig. 1
      Fig. 1Distribution of Recurrence Score results for the entire cohort (N = 565). Recurrence Score groups were
      [
      • Paik S.
      • Shak S.
      • Tang G.
      • Kim C.
      • Baker J.
      • Cronin M.
      • et al.
      A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
      ]
      : blue, Recurrence Score results within the low range (<18); red, Recurrence Score results within the intermediate range (18–30); green, Recurrence Score results within the high range (≥31).
      The distribution of these Recurrence Score categories was similar in younger and older patients (<55, ≥55 years) and in patients with smaller and larger (≤2, >2 cm) tumours (p = 0.37 and p = 0.081, respectively); the distribution differed by grade (p < 0.0001) (Fig. 2).
      Fig. 2
      Fig. 2Distribution of Recurrence Score categories
      [
      • Paik S.
      • Shak S.
      • Tang G.
      • Kim C.
      • Baker J.
      • Cronin M.
      • et al.
      A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
      ]
      by patients' age, tumour size, and tumour grade; p = 0.37, p = 0.081, and p < 0.0001 for comparing Recurrence Score distribution across age groups, tumour size groups, and grade groups, respectively (chi-squared test).

      3.3 Changes in treatment recommendations

      Treatment recommendations before and after Recurrence Score testing were available for 527 patients. Pre-testing, 45.4% were recommended CHT and 54.6% HT (Table 2). Overall, 31.9% (95% confidence interval [CI], 27.9–35.9%) had a recommendation change post-testing. Of the CHT-recommended patients (pre-testing), 48.1% (95% CI, 41.8–54.5%) were recommended HT post-testing; of the HT-recommended patients (pre-testing), 18.4% (95% CI, 13.9–22.9%) were recommended CHT post-testing. After knowing the assay results, the proportion of CHT-recommended patients decreased to 33.6% (net reduction: 26%; relative reduction: 38%); the proportion of HT-recommended patients increased to 66.4% (Table 2; p < 0.0001). Knowing the assay result impacted treatment recommendations for patients in all Recurrence Score grade, age, and tumour size groups (Table 2). Significant changes in the proportion of CHT- and HT-recommended patients were also observed in the low Recurrence Score group as defined in the TAILORx study (<11) [
      • Sparano J.A.
      • Gray R.J.
      • Makower D.F.
      • Pritchard K.I.
      • Albain K.S.
      • Hayes D.F.
      • et al.
      Prospective validation of a 21-gene expression assay in breast cancer.
      ] (Table 2). These changes were aligned with the Recurrence Score results: a decrease in CHT recommendations was observed in low Recurrence Score patients and an increase in high Recurrence Score patients. Upon dividing the intermediate Recurrence Score group into two subgroups (18–25, 26–30), an increase in CHT recommendation was observed in both subgroups (statistically significant in the former [p = 0.0094] and trending in the latter [p = 0.058]) (Table 2).
      Table 2The impact of knowing the Recurrence Score result on treatment recommendation for the entire cohort, by Recurrence Score category, grades, age groups, and tumour size.
      HT (post-testing)CHT (post-testing)Total
      All patients (N = 527)a
       HT (pre-testing)235 (44.6%)53 (10.1%)288 (54.6%)
       CHT (pre-testing)115 (21.8%)124 (23.5%)239 (45.4%)
       Total350 (66.4%)177 (33.6%)527 (100%)
      Low
      • Paik S.
      • Shak S.
      • Tang G.
      • Kim C.
      • Baker J.
      • Cronin M.
      • et al.
      A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
      Recurrence Score (score values <18) (n=293)a
       HT (pre-testing)176 (60.1%)1 (0.3%)177 (60.4%)
       CHT (pre-testing)98 (33.4%)18 (6.1%)116 (39.6%)
       Total274 (93.5%)19 (6.5%)293 (100%)
      Intermediate
      • Paik S.
      • Shak S.
      • Tang G.
      • Kim C.
      • Baker J.
      • Cronin M.
      • et al.
      A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
      Recurrence Score (score values: 18–30) (n=185)b
       HT (pre-testing)57 (30.8%)41 (22.2%)98 (53.0%)
       CHT (pre-testing)17 (9.2%)70 (37.8%)87 (47.0%)
       Total74 (40.0%)111 (60.0%)185 (100%)
      High
      • Paik S.
      • Shak S.
      • Tang G.
      • Kim C.
      • Baker J.
      • Cronin M.
      • et al.
      A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
      Recurrence Score (score values ≥31) (n=49)c
       HT (pre-testing)2 (4.1%)11 (22.4%)13 (26.5%)
       CHT (pre-testing)0 (0%)36 (73.5%)36 (73.5%)
       Total2 (4.1%)47 (95.9%)49 (100%)
      TAILORx-based low Recurrence Score (score values <11) (n=99)a
       HT (pre-testing)65 (65.7%)0 (0%)65 (65.7%)
       CHT (pre-testing)32 (32.3%)2 (2.0%)34 (34.3%)
       Total97 (98.0%)2 (2.0%)99 (100%)
      Intermediate
      • Paik S.
      • Shak S.
      • Tang G.
      • Kim C.
      • Baker J.
      • Cronin M.
      • et al.
      A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
      group: Sub-analysis. Scores of 18–25 (n=155)d
       HT (pre-testing)51 (32.9%)33 (21.3%)84 (54.2%)
       CHT (pre-testing)15 (9.7%)56 (36.1%)71 (45.8%)
       Total66 (42.6%)89 (57.4%)155 (100%)
      Intermediate
      • Paik S.
      • Shak S.
      • Tang G.
      • Kim C.
      • Baker J.
      • Cronin M.
      • et al.
      A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
      group: sub-analysis. Scores of 26–30 (n=30)e
       HT (pre-testing)6 (20.0%)8 (26.7%)14 (46.7%)
       CHT (pre-testing)2 (6.7%)14 (46.7%)16 (53.3%)
       Total8 (26.7%)22 (73.3%)30 (100%)
      Grade I (n=91)f
       HT (pre-testing)67 (73.6%)2 (2.2%)69 (75.8%)
       CHT (pre-testing)12 (13.2%)10 (11.0%)22 (24.2%)
       Total79 (86.8%)12 (13.2%)91 (100%)
      Grade II (n = 362)a
       HT (pre-testing)155 (42.8%)43 (11.9%)198 (54.7%)
       CHT (pre-testing)92 (25.4%)72 (19.9%)164 (45.3%)
       Total247 (68.2%)115 (31.8%)362 (100%)
      Grade III (n=70)g
       HT (pre-testing)11 (15.7%)8 (11.4%)19 (27.1%)
       CHT (pre-testing)10 (14.3%)41 (58.6%)51 (72.9%)
       Total21 (30.0%)49 (70.0%)70 (100%)
      <55 years (n=164)a
       HT (pre-testing)59 (36.0%)16 (9.8%)75 (45.7%)
       CHT (pre-testing)50 (30.5%)39 (23.8%)89 (54.3%)
       Total109 (66.5%)55 (33.5%)164 (100%)
      ≥55 years (n=363)h
       HT (pre-testing)176 (48.5%)37 (10.2%)213 (58.7%)
       CHT (pre-testing)65 (17.9%)85 (23.4%)150 (41.3%)
       Total241 (66.4%)122 (33.6%)363 (100%)
      ≤2 cm (n=369)i
       HT (pre-testing)191 (51.8%)42 (11.4%)233 (63.1%)
       CHT (pre-testing)69 (18.7%)67 (18.2%)136 (36.9%)
       Total260 (70.5%)109 (29.5%)369 (100%)
      >2 cm (n=157)a
       HT (pre-testing)44 (28.0%)11 (7.0%)55 (35.0%)
       CHT (pre-testing)46 (29.3%)56 (35.7%)102 (65.0%)
       Total90 (57.3%)67 (42.7%)157 (100%)
      CHT, chemohormonal therapy; HT, hormonal therapy.
      ap < 0.0001; bp = 0.0016; cp = 0.0009; dp = 0.0094; ep = 0.058; fp = 0.0075; gp = 0.64; hp = 0.0056; ip = 0.010.
      All for change from CHT to HT and from HT to CHT; McNemar's test.
      The data from the individual studies were similar to those of the pooled analysis with the proportions of patients with a treatment recommendation change ranging from 29.9 to 36.6% (Table 3).
      Table 3The impact of knowing the Recurrence Score result on treatment recommendation by study.
      HT (post-testing)CHT (post-testing)Total
      German study (n = 244)a
      HT (pre-testing)99 (40.6%)28 (11.5%)127 (52.0%)
      CHT (pre-testing)45 (18.4%)72 (29.5%)117 (48.0%)
      Total144 (59.0%)100 (41.0%)244 (100%)
      French study (n=82)b
      HT (pre-testing)35 (42.7%)4 (4.9%)39 (47.6%)
      CHT (pre-testing)26 (31.7%)17 (20.7%)43 (52.4%)
      Total61 (74.4%)21 (25.6%)82 (100%)
      Spanish study (n=107)c
      HT (pre-testing)56 (52.3%)12 (11.2%)68 (63.6%)
      CHT (pre-testing)22 (20.6%)17 (15.9%)39 (36.4%)
      Total78 (72.9%)29 (27.1%)107 (100%)
      UK study (n=94)d
      HT (pre-testing)45 (47.9%)9 (9.6%)54 (57.4%)
      CHT (pre-testing)22 (23.4%)18 (19.1%)40 (42.6%)
      Total67 (71.3%)27 (28.7%)94 (100%)
      UK, United Kingdom; CHT, chemohormonal therapy; HT, hormonal therapy.
      ap = 0.047; bp < 0.0001; cp = 0.086; dp = 0.020.
      All for change from CHT to HT and from HT to CHT; McNemar's test.
      The changes in treatment recommendations (an overall decreased CHT and increased HT use) were statistically significant in the French, UK, and German studies (p < 0.0001, p = 0.020, and p = 0.047, respectively) and trending (p = 0.086) in the Spanish study. With the exception of the German study, which was characterised by a relatively high proportion of CHT-recommended patients post-testing (41%), the between-study variability in the proportions of CHT- and HT-recommended patients decreased post-testing (CHT: from 36.4–52.4% to 25.6–28.7%; HT: from 47.6–63.6% to 71.3–74.4%) (Fig. 3).
      Fig. 3
      Fig. 3The impact of knowing the Recurrence Score results on treatment recommendations by Recurrence Score category
      [
      • Paik S.
      • Shak S.
      • Tang G.
      • Kim C.
      • Baker J.
      • Cronin M.
      • et al.
      A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
      ]
      and study. CI, confidence interval; CHT, chemohormonal therapy.
      In a univariate analysis, the association between the Recurrence Score category and change in treatment recommendation was significant for both a change from HT to CHT (odds ratio [OR], 30.5 for high Recurrence Score versus intermediate and low categories combined; 95% Wald CI, 6.5–142.6; p < 0.0001) and from CHT to HT (OR, 34.0 for low Recurrence Score versus intermediate and high categories combined; 95% Wald CI, 16.6–69.6; p < 0.0001).
      A logistic regression analysis was used to model the probability of changing treatment recommendation as a function of the Recurrence Score category, age (<55, ≥55 years), tumour size (≤2, >2 cm), tumour grade (I–III), PR status (positive, negative), and the interactions thereof, for patients who were initially recommended HT as well as for patients who were initially recommended CHT. The probability could not be modelled using all Recurrence Score categories because of the prominent impact of the high and low Recurrence Score results in patients who were initially recommended CHT and HT, respectively. Therefore, we combined the intermediate and high categories for the analysis of CHT to HT change and the low and intermediate categories for the analysis of HT to CHT change. In a stepwise regression analysis, the interaction of the Recurrence Score category and the other covariates was determined to be non-significant. For patients who were initially recommended CHT, having a low (versus high/intermediate) Recurrence Score result was associated with significantly higher odds of CHT to HT change, as was having a grade I or II tumours, being PR-positive, and having smaller tumours. For patients who were initially recommended HT, having a high (versus low/intermediate) Recurrence Score result was associated with significantly higher odds of HT to CHT change, as was being younger, having grade III tumours, and being PR-negative (Table 4). In a logistic regression analysis using all the aforementioned covariates and Ki-67 levels (which were available only for 241 patients), only the Recurrence Score category was found to be a significant covariate in patients who were initially recommended CHT and none of the covariates were found to be significant in patients who were initially recommended HT.
      Table 4Odds ratios for changing treatment recommendations (logistic regression analysis).
      EffectOdds ratio95% Wald confidence limitsp-value
      Change from CHT to HT
       Recurrence Score group
      • Paik S.
      • Shak S.
      • Tang G.
      • Kim C.
      • Baker J.
      • Cronin M.
      • et al.
      A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
      : low versus int/high (combined)
      48.519.7–119.6< 0.0001
       Age: <55 years versus ≥55 years0.920.40–2.10.84
       Tumour size: ≤2 cm versus >2 cm2.71.1–6.70.029
       Tumour grade:
        Grade I versus II1.40.3–6.00.64
        Grade I versus III10.01.7–58.00.010
        Grade II versus III7.12.2–22.40.0008
       PR status: negative versus positive0.0780.017–0.360.001
      Change from HT to CHT
       Recurrence Score group
      • Paik S.
      • Shak S.
      • Tang G.
      • Kim C.
      • Baker J.
      • Cronin M.
      • et al.
      A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
      : high versus low/intermediate (combined)
      22.84.5–117.00.0002
       Age: <55 years versus ≥55 years2.31.0–5.00.042
       Tumour size: ≤2 cm versus >2 cm1.40.55–3.60.48
       Tumour grade:
        Grade I versus II0.120.026–0.510.004
        Grade I versus III0.0690.011–0.440.004
        Grade II versus III0.600.18–2.00.41
       PR status: negative versus positive5.62.2–14.40.0003
      CHT, chemohormonal therapy; HT, hormonal therapy; PR, progesterone receptor.
      Interactions between the Recurrence Score and the other covariates were found to be non-significant. The analysis included 236 patients for the CHT to HT analysis and 286 patients for the CHT to HT analysis (patients with missing data were excluded).
      In addition, we evaluated the correlation between Ki-67 and the Recurrence Score results in the 241 patients for whom both values were available and found a moderate Pearson correlation coefficient of 0.46.

      3.4 The impact of testing on physicians' confidence regarding treatment recommendations

      The four evaluated studies differed in the scale used to assess physicians' confidence regarding treatment recommendations. Therefore, these data were not pooled, and the analysis was performed for each study separately. Between 33.0% and 60.2% of physicians in the evaluated studies reported increased, 33.0–52.4% reported no change, and 6.8–14.9% reported decreased confidence regarding treatment recommendations (Fig. 4). In all studies, knowing the Recurrence Score result was associated with a significant improvement in physicians' confidence regarding treatment recommendations (p < 0.01, all studies). Knowing the Recurrence Score result increased the physicians' confidence in the final treatment recommendation, regardless of whether the treatment recommendation changed or not.
      Fig. 4
      Fig. 4The impact of knowing the Recurrence Score result on physicians' confidence regarding treatment recommendations.

      4. Discussion

      This pooled analysis of four prospective European studies demonstrated that despite differences in therapeutic traditions between countries, Recurrence Score testing significantly impacted adjuvant treatment recommendations and physicians' confidence about treatment recommendations in node-negative ER+, HER2-negative breast cancer, with an overall change rate of 32% and a relative reduction in chemotherapy use of 38%. These results are consistent with findings from studies performed worldwide [
      • Henry L.R.
      • Stojadinovic A.
      • Swain S.M.
      • Prindiville S.
      • Cordes R.
      • Soballe P.W.
      The influence of a gene expression profile on breast cancer decisions.
      ,
      • Klang S.H.
      • Hammerman A.
      • Liebermann N.
      • Efrat N.
      • Doberne J.
      • Hornberger J.
      Economic implications of 21-gene breast cancer risk assay from the perspective of an Israeli-managed health-care organization.
      ,
      • Lo S.S.
      • Mumby P.B.
      • Norton J.
      • Rychlik K.
      • Smerage J.
      • Kash J.
      • et al.
      Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologist and patient adjuvant breast cancer treatment selection.
      ,
      • Ademuyiwa F.O.
      • Miller A.
      • O'Connor T.
      • Edge S.B.
      • Thorat M.A.
      • Sledge G.W.
      • et al.
      The effects of oncotype DX recurrence scores on chemotherapy utilization in a multi-institutional breast cancer cohort.
      ,

      de Boer RH, Baker C, Speakman D, Mann B. Australian decision impact study: the impact of oncotype DX recurrence score (RS) on adjuvant treatment decisions in hormone receptor positive (HR+), node negative (N0) and node positive (N+) early stage breast cancer (ESBC) in the multidisciplinary clinic (MDC). Presented at the San Antonio Breast Cancer Symposium (SABCS), Dec 6–10, 2011, San Antonio, TX.

      ,
      • Kamal A.H.
      • Loprinzi C.L.
      • Reynolds C.
      • Dueck A.C.
      • Geiger X.J.
      • Ingle J.N.
      • et al.
      Breast medical oncologists' use of standard prognostic factors to predict a 21-gene recurrence score.
      ,
      • Yamauchi H.
      • Nakagawa C.
      • Yamashige S.
      • Takei H.
      • Yagata H.
      • Yoshida A.
      • et al.
      Decision impact and economic evaluation of the 21-gene recurrence score (RS) assay for physicians and patients in Japan.
      ,
      • Carlson J.J.
      • Roth J.A.
      The impact of the oncotype Dx breast cancer assay in clinical practice: a systematic review and meta-analysis.
      ], all showing a significant impact of testing on adjuvant treatment decisions with a change in approximately one third of patients.
      Treatment recommendations pre-testing were heterogeneous in the different studies with substantial differences in the proportion of patients with low, intermediate, and high Recurrence Score results being recommended chemotherapy. Post-testing, the between-study variability decreased and treatment recommendations became more homogeneous, suggesting that broad use of the assay may reduce heterogeneity in treatment decisions. Health-economic (HE) studies from all evaluated markets show that broad use of the assay is cost effective (reviewed by Zanotti et al. [
      • Zanotti L.
      • Bottini A.
      • Rossi C.
      • Generali D.
      • Cappelletti M.R.
      Diagnostic tests based on gene expression profile in breast cancer: from background to clinical use.
      ]). Nonetheless, from a medical as well as HE perspective, it is of interest to understand in which patients the assay has the highest utility. When assessing treatment recommendation change rates by subgroups, the highest change rate was seen in patients originally recommended chemotherapy (48.1%), grade II (37.3%), and younger patients (40.4%). Treatment recommendation changes were seen in a similar range of patients regardless of tumour size (≤2, >2 cm). Thus, it can be argued that from a HE perspective, the most important patient subgroups in which to use the assay include those originally recommended chemotherapy and those with grade II tumours. From a medical perspective, it is important to note that all the clinical categories listed above had a clinically relevant treatment recommendation change rate. Therefore, limiting the use of the assay to patients originally recommended chemotherapy means that some patients that could be identified by the assay as having a high likelihood of benefitting from chemotherapy will not receive a treatment that could reduce their distant-recurrence risk.
      It is sometimes argued that an intermediate Recurrence Score result is unhelpful. However, in our study, approximately a third (31.4%) of patients with intermediate results had a treatment recommendation change, demonstrating that intermediate results provide clinically actionable information. This is likely related to the fact that the Recurrence Score result is given on a continuous scale. Indeed, when the intermediate Recurrence Score group was divided into those with 18–25 and 26–30 Recurrence Score results, CHT recommendation rate increased more pronouncedly in the latter subgroup (relative increase of 37% versus 25%). The present data are consistent with studies from the United States and Israel showing that decisions in patients with intermediate results are determined primarily based on whether the result is low or high (within the intermediate range) with a strong increase in chemotherapy recommendations in patients with scores >25 and that other traditional factors such as grade, tumour size, and age also matter [

      Stemmer SM, Steiner M, Rizel S, Ben-Baruch N, Soussan-Gutman L, Geffen DB, et al. Real-life analysis evaluating 1594 N0/Nmic breast cancer patients for whom treatment decisions incorporated the 21-gene Recurrence Score result: 5-year KM estimate for breast cancer specific survival with Recurrence Score results ≤30 is >98%. Presented at San Antonio Breast Cancer Symposium (SABCS), Dec 8–12, 2015, San Antonio, TX.

      ,
      • Chen C.
      • Patt D.A.
      • Kazzaz D.R.
      • Shankleton J.
      • Forsyth M.T.
      • Ganesh R.
      Evaluating utilization characteristics for the oncotype DX recurrence score in early-stage breast cancer.
      ,
      • Fried G.
      • Moskovitz M.
      Treatment decisions in estrogen receptor-positive early breast cancer patients with intermediate oncotype DX recurrence score results.
      ]. Notably, results from the Clalit study [

      Stemmer SM, Steiner M, Rizel S, Ben-Baruch N, Soussan-Gutman L, Geffen DB, et al. Real-life analysis evaluating 1594 N0/Nmic breast cancer patients for whom treatment decisions incorporated the 21-gene Recurrence Score result: 5-year KM estimate for breast cancer specific survival with Recurrence Score results ≤30 is >98%. Presented at San Antonio Breast Cancer Symposium (SABCS), Dec 8–12, 2015, San Antonio, TX.

      ] where patients were not randomized to chemotherapy or no chemotherapy indicate that patients with Recurrence Score results of 25 or less without other high-risk features have little or no benefit from chemotherapy, although it should be noted that the results of TAILORx on the role of chemotherapy in intermediate Recurrence Score patients are pending. Ki-67 is used in many countries as a marker relevant for treatment decisions despite recent data highlighting substantial issues with reproducibility and data showing that the marker is not predictive of chemotherapy benefit [
      • Polley M.Y.
      • Leung S.C.
      • McShane L.M.
      • Gao D.
      • Hugh J.C.
      • Mastropasqua M.G.
      • et al.
      An international ki67 reproducibility study.
      ,
      • Viale G.
      • Regan M.M.
      • Mastropasqua M.G.
      • Maffini F.
      • Maiorano E.
      • Colleoni M.
      • et al.
      Predictive value of tumor Ki-67 expression in two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer.
      ]. In this pooled analysis, many but not all patients had Ki-67 assessments available. The correlation between Ki-67 and the Recurrence Score result was modest, consistent with data from the WSG Plan B study [

      Gluz O, Kreipe HH, Kates RE, Christgen M, Liedtke C, Shak S, et al. Prospective comparison of Recurrence Score and different definitions of luminal subtypes by central pathology assessment of single markers in early breast cancer: results from the phase III WSG-planB trial. Presented at the San Antonio Breast Cancer Symposium (SABCS), Dec 4–8, 2012, San Antonio, TX.

      ].
      In conclusion, our findings demonstrate that the Recurrence Score has a substantial impact on treatment recommendations with an overall significant reduction in chemotherapy use. The consistency of the results from different countries underlines the utility of the Recurrence Score. The highest change rates were seen in patients originally recommended chemotherapy, in younger patients, and in patients with grade II, but there was no subgroup of patients that did not have a clinically relevant rate of change in treatment recommendations. Limiting the use of the Recurrence Score assay to the subgroups of patients with the highest change rate may be of HE interest due to cost effectiveness and can even be associated with cost savings. From a medical perspective, a broad use of the assay has the advantage of both reducing chemotherapy in those with minimal if any benefit, as well as identifying a smaller proportion of patients that are likely to have a substantial benefit from chemotherapy. A broad use of the assay will also reduce the substantial heterogeneity of treatment recommendations currently seen when using traditional markers.

      Funding

      This work was supported by Genomic Health Inc. Medical writing support was provided by Avital Bareket-Samish, PhD (BioInsight Ltd), and was funded by Genomic Health Inc.

      Conflict of interest statement

      J. Albanell, J. Gligorov, S. Holt, J. Blohmer, R. Rouzier, and W. Eiermann declare advisory role for Genomic Health. S. Holt received honoraria from Genomic Health. C. Svedman is a Genomic Health employee. G. Bertelli and A. Lluch declare no conflict of interest.

      Acknowledgements

      J.A. acknowledges FIS PI12/00680 RD12/0036/0051, 2014SGR740 intensification grant ISCIII, and A Ll. PI12/01421 and RD12/0036/0070.
      The study sponsor, in collaboration with the investigators, designed the analyses and interpreted the data. The authors made the final decision to submit the manuscript for publication. All authors contributed to the writing and/or editing of the manuscript.

      References

        • Paik S.
        • Tang G.
        • Shak S.
        • Kim C.
        • Baker J.
        • Kim W.
        • et al.
        Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
        J Clin Oncol. 2006; 24: 3726-3734
        • Paik S.
        • Shak S.
        • Tang G.
        • Kim C.
        • Baker J.
        • Cronin M.
        • et al.
        A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
        N Engl J Med. 2004; 351: 2817-2826
        • Habel L.A.
        • Shak S.
        • Jacobs M.K.
        • Capra A.
        • Alexander C.
        • Pho M.
        • et al.
        A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients.
        Breast Cancer Res. 2006; 8: R25
        • Dowsett M.
        • Cuzick J.
        • Wale C.
        • Forbes J.
        • Mallon E.A.
        • Salter J.
        • et al.
        Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study.
        J Clin Oncol. 2010; 28: 1829-1834
        • Toi M.
        • Iwata H.
        • Yamanaka T.
        • Masuda N.
        • Ohno S.
        • Nakamura S.
        • et al.
        Clinical significance of the 21-gene signature (Oncotype DX) in hormone receptor-positive early stage primary breast cancer in the Japanese population.
        Cancer. 2010; 116: 3112-3118
        • Albain K.S.
        • Barlow W.E.
        • Shak S.
        • Hortobagyi G.N.
        • Livingston R.B.
        • Yeh I.T.
        • et al.
        Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial.
        Lancet Oncol. 2010; 11: 55-65
        • Sparano J.A.
        • Gray R.J.
        • Makower D.F.
        • Pritchard K.I.
        • Albain K.S.
        • Hayes D.F.
        • et al.
        Prospective validation of a 21-gene expression assay in breast cancer.
        N Engl J Med. 2015; 373: 2005-2014
      1. Gluz O, Nitz, U, Kreipe HH, Christgen M, Kates RE, Hofmann D, et al. Clinical impact of risk classification by central/local grade or luminal like subtype vs. Oncotype DX®: first prospective survival results from the WSG phase III planB trial. Presented at the European Cancer Congress 2015, Sep 25–29, 2015, Vienna, Austria.

      2. Stemmer SM, Steiner M, Rizel S, Ben-Baruch N, Soussan-Gutman L, Geffen DB, et al. Real-life analysis evaluating 1594 N0/Nmic breast cancer patients for whom treatment decisions incorporated the 21-gene Recurrence Score result: 5-year KM estimate for breast cancer specific survival with Recurrence Score results ≤30 is >98%. Presented at San Antonio Breast Cancer Symposium (SABCS), Dec 8–12, 2015, San Antonio, TX.

      3. Shak S, Petkov VI, Miller DP, Howlader N, Gliner N, Howe W, et al. Breast cancer specific survival in 38,568 patients with node negative hormone receptor positive invasive breast cancer and Oncotype DX Recurrence Score results in the SEER database. Presented at San Antonio Breast Cancer Symposium (SABCS), Dec 8–12, 2015, San Antonio, TX.

        • Senkus E.
        • Kyriakides S.
        • Penault-Llorca F.
        • Poortmans P.
        • Thompson A.
        • Zackrisson S.
        • et al.
        Primary breast cancer: ESMO clinical Practice Guidelines for diagnosis, treatment and follow-up.
        Ann Oncol. 2013; 24: vi7-vi23
        • Goldhirsch A.
        • Winer E.P.
        • Coates A.S.
        • Gelber R.D.
        • Piccart-Gebhart M.
        • Thurlimann B.
        • et al.
        Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013.
        Ann Oncol. 2013; 24: 2206-2223
        • NCCN Clinical Practice Guidelines in Oncology
        Breast cancer. Version 1.
        2016 (Available at:) ([accessed 31.01.16])
        • Harris L.
        • Fritsche H.
        • Mennel R.
        • Norton L.
        • Ravdin P.
        • Taube S.
        • et al.
        American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer.
        J Clin Oncol. 2007; 25: 5287-5312
        • Gligorov J.
        • Pivot X.B.
        • Jacot W.
        • Naman H.L.
        • Spaeth D.
        • Misset J.L.
        • et al.
        Prospective clinical utility study of the use of the 21-gene assay in adjuvant clinical decision making in women with estrogen receptor-positive early invasive breast cancer: results from the SWITCH study.
        Oncologist. 2015; 20: 873-879
        • Eiermann W.
        • Rezai M.
        • Kummel S.
        • Kuhn T.
        • Warm M.
        • Friedrichs K.
        • et al.
        The 21-gene recurrence score assay impacts adjuvant therapy recommendations for ER-positive, node-negative and node-positive early breast cancer resulting in a risk-adapted change in chemotherapy use.
        Ann Oncol. 2013; 24: 618-624
        • Albanell J.
        • Gonzalez A.
        • Ruiz-Borrego M.
        • Alba E.
        • Garcia-Saenz J.A.
        • Corominas J.M.
        • et al.
        Prospective transGEICAM study of the impact of the 21-gene Recurrence Score assay and traditional clinicopathological factors on adjuvant clinical decision making in women with estrogen receptor-positive (ER+) node-negative breast cancer.
        Ann Oncol. 2012; 23: 625-631
        • Holt S.
        • Bertelli G.
        • Humphreys I.
        • Valentine W.
        • Durrani S.
        • Pudney D.
        • et al.
        A decision impact, decision conflict and economic assessment of routine Oncotype DX testing of 146 women with node-negative or pNImi, ER-positive breast cancer in the UK.
        Br J Cancer. 2013; 108: 2250-2258
        • Henry L.R.
        • Stojadinovic A.
        • Swain S.M.
        • Prindiville S.
        • Cordes R.
        • Soballe P.W.
        The influence of a gene expression profile on breast cancer decisions.
        J Surg Oncol. 2009; 99: 319-323
        • Klang S.H.
        • Hammerman A.
        • Liebermann N.
        • Efrat N.
        • Doberne J.
        • Hornberger J.
        Economic implications of 21-gene breast cancer risk assay from the perspective of an Israeli-managed health-care organization.
        Value Health. 2010; 13: 381-387
        • Lo S.S.
        • Mumby P.B.
        • Norton J.
        • Rychlik K.
        • Smerage J.
        • Kash J.
        • et al.
        Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologist and patient adjuvant breast cancer treatment selection.
        J Clin Oncol. 2010; 28: 1671-1676
        • Ademuyiwa F.O.
        • Miller A.
        • O'Connor T.
        • Edge S.B.
        • Thorat M.A.
        • Sledge G.W.
        • et al.
        The effects of oncotype DX recurrence scores on chemotherapy utilization in a multi-institutional breast cancer cohort.
        Breast Cancer Res Treat. 2011; 126: 797-802
      4. de Boer RH, Baker C, Speakman D, Mann B. Australian decision impact study: the impact of oncotype DX recurrence score (RS) on adjuvant treatment decisions in hormone receptor positive (HR+), node negative (N0) and node positive (N+) early stage breast cancer (ESBC) in the multidisciplinary clinic (MDC). Presented at the San Antonio Breast Cancer Symposium (SABCS), Dec 6–10, 2011, San Antonio, TX.

        • Kamal A.H.
        • Loprinzi C.L.
        • Reynolds C.
        • Dueck A.C.
        • Geiger X.J.
        • Ingle J.N.
        • et al.
        Breast medical oncologists' use of standard prognostic factors to predict a 21-gene recurrence score.
        Oncologist. 2011; 16: 1359-1366
        • Yamauchi H.
        • Nakagawa C.
        • Yamashige S.
        • Takei H.
        • Yagata H.
        • Yoshida A.
        • et al.
        Decision impact and economic evaluation of the 21-gene recurrence score (RS) assay for physicians and patients in Japan.
        Eur J Cancer. 2011; 47
        • Carlson J.J.
        • Roth J.A.
        The impact of the oncotype Dx breast cancer assay in clinical practice: a systematic review and meta-analysis.
        Breast Cancer Res Treat. 2013; 141: 13-22
        • Zanotti L.
        • Bottini A.
        • Rossi C.
        • Generali D.
        • Cappelletti M.R.
        Diagnostic tests based on gene expression profile in breast cancer: from background to clinical use.
        Tumour Biol. 2014; 35: 8461-8470
        • Chen C.
        • Patt D.A.
        • Kazzaz D.R.
        • Shankleton J.
        • Forsyth M.T.
        • Ganesh R.
        Evaluating utilization characteristics for the oncotype DX recurrence score in early-stage breast cancer.
        J Clin Oncol. 2011; 15 (suppl: abstract 625)
        • Fried G.
        • Moskovitz M.
        Treatment decisions in estrogen receptor-positive early breast cancer patients with intermediate oncotype DX recurrence score results.
        Springerplus. 2014; 3: 71
        • Polley M.Y.
        • Leung S.C.
        • McShane L.M.
        • Gao D.
        • Hugh J.C.
        • Mastropasqua M.G.
        • et al.
        An international ki67 reproducibility study.
        J Natl Cancer Inst. 2013; 105: 1897-1906
        • Viale G.
        • Regan M.M.
        • Mastropasqua M.G.
        • Maffini F.
        • Maiorano E.
        • Colleoni M.
        • et al.
        Predictive value of tumor Ki-67 expression in two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer.
        J Natl Cancer Inst. 2008; 100: 207-212
      5. Gluz O, Kreipe HH, Kates RE, Christgen M, Liedtke C, Shak S, et al. Prospective comparison of Recurrence Score and different definitions of luminal subtypes by central pathology assessment of single markers in early breast cancer: results from the phase III WSG-planB trial. Presented at the San Antonio Breast Cancer Symposium (SABCS), Dec 4–8, 2012, San Antonio, TX.