Breast Journal Club – L’Importanza della Ricerca in Oncologia The Prognostic Performance of Adjuvant Online and Nottingham Prognostic Index in Young Breast Cancer Patients Matteo Lambertini, MD ESMO Fellow Institut Jules Bordet, Brussels Napoli, 11 Marzo 2017

Disclosure Information Relationship Relevant to this Conference Lambertini, Matteo: No relevant relationship to disclose.

Study Background Treatment recommendations in early-stage breast cancer are based on both patient’s prognosis and expected benefit of adjuvant therapies1. In young breast cancer patients, an adequate estimation of their prognosis in order to optimize adjuvant management strategies is of particular importance2. Adjuvant! Online3 and Nottingham Prognostic Index4 are two widely used tools based on traditional clinico-pathological factors5. Although performing globally well, some concerns have been raised regarding their applicability in specific subgroups such as women ≤ 40 years5. 1. Coates AS et al, Ann Oncol 2015;26:1533-46. 2. Azim HA et al, Breast Cancer Res 2014;16:427. 3. Ravdin PM et al, J Clin Oncol 2001;19:980-91. 4. Haybittle JL et al, Br J Cancer 1982;45:361-6. 5. Engelhardt EG et al, J Clin Oncol 2014;32:238-50.

Study Background The clinical utility of genomic tests Can prognostic genomic signatures be used in young breast cancer patients? Type of genomic test Definition of young age No. young patients No. high genomic risk Van de Vijver et al. (2002) MammaPrint < 40 years 63/295 (21.4%) 52/63 (82.5%) Paik et al. (2004) Oncotype Dx 59/668 (8.8%) 33/59 (55.9%) Sparano et al. (2015) ≤ 40 years 377/8523* (4.4%) ?? Cardoso et al. (2016) < 35 years 112/6693 (1.8%) 78/112 (69.6%) The clinical utility of genomic tests in young patients remains unanswered The clinical utility of genomic tests in HER2-positive and TNBC is limited *Recurrence score 0 – 10 and 11 – 25 only Van de Vijver et al, N Engl J Med 2002;347:1999-2009. Paik S et al, N Engl J Med 2004;351:2817-26 Sparano JA et al, N Engl J Med 2015;373:2005-14. Cardoso F et al, N Engl J Med 2016;375:717-29

Study Design and Objectives Multicenter hospital-based retrospective cohort study conducted in 4 Belgian and Italian institutions. Eligibility criteria: diagnosis of invasive breast cancer treated with upfront surgery between January 1, 2000 and December 31, 2004: Young cohort: age at diagnosis ≤ 40 years; Older cohort: age at diagnosis 55-60 years.

Study Design and Objectives Multicenter hospital-based retrospective cohort study conducted in 4 Belgian and Italian institutions. Eligibility criteria: diagnosis of invasive breast cancer treated with upfront surgery between January 1, 2000 and December 31, 2004: Young cohort: age at diagnosis ≤ 40 years; Older cohort: age at diagnosis 55-60 years. Primary objective: To evaluate the prognostic performance of Adjuvant! Online and Nottingham Prognostic Index in terms of calibration and discriminatory accuracy. Secondary objective: To describe the differences in prognostic accuracy of both tools according to breast cancer pathologic subtypes. To describe the characteristics of tumors, the type of treatments administered and survival outcomes in the two cohorts.

Study Procedure: Adjuvant! Online www.adjuvantonline.com

Study Procedure: Nottingham Prognostic Index NPI score = maximum tumor size (cm) x 0.2 + nodal status + tumor grade Quintyne KI et al, Clin Breast Cancer 2013;13:233-8

Study Flow Chart

Patients Characteristics Young cohort (n = 376) n (%) Older cohort (n = 907) P value Tumor size 1-10 11-20 24-50 > 50   55 (15) 150 (40) 151 (40) 20 (5) 243 (27) 377 (42) 251 (28) 36 (4) < 0.001 Nodal status 1-3 > 3 206 (55) 116 (31) 54 (14) 585 (65) 226 (25) 96 (11) 0.002 Tumor grade G1 G2 G3 27 (7) 152 (40) 197 (52) 210 (23) 447 (49) 250 (28) ER status ER-negative ER-positive Unknown 120 (32) 255 (68) 1 (0.3) 130 (14) 772 (86) 5 (0.6) HER2 status HER2-negative HER2-positive 267 (78) 74 (22) 35 (9) 668 (87) 102 (13) 137 (15) Tumor subtype ER-positive HER2-negative ER-negative HER2-negative 181 (53) 86 (25) 591 (77) 76 (10) 138 (15) Systemic treatment None Chemotherapy only Endocrine therapy only Chemotherapy and endocrine therapy 14 (4) 104 (28) 44 (12) 214 (57) 42 (5) 119 (13) 437 (48) 309 (34)

Results Patient Outcome in the Four Participating Centers Overall survival: young cohort Overall survival: older cohort 10-year OS: 84.6% 10-year OS: 88.4% Survival outcomes were homogeneous among centers

Results Nottingham Prognostic Index Overall survival: young cohort Overall survival: older cohort NPI identified 6 classes of patients with distinct outcomes

Tool Calibration: Young Cohort Results Tool Calibration: Young Cohort

Tool Calibration: Older Cohort Results Tool Calibration: Older Cohort

Tool Discriminatory Accuracy: Both Cohorts Disease-free survival Results Tool Discriminatory Accuracy: Both Cohorts Young cohort Older cohort Overall survival AUC AoL: 73.1 AUC NPI: 71.9 AUC AoL: 74.0 AUC NPI: 74.1 p=0.45 p=0.94 Disease-free survival AUC AoL: 66.0 AUC NPI: 64.6 AUC AoL: 63.5 AUC NPI: 64.9 p=0.51 p=0.35

Conclusions As compared with those in the older cohort, patients in the young cohort were diagnosed with more advanced and biologically aggressive tumors and received more often chemotherapy. Ten-year survival outcomes in both the young (84.6%) and older (88.4%) cohorts were quite impressive. Adjuvant! Online is a reliable tool in predicting overall survival at 10 years in young breast cancer patients but not disease-free survival. The performance of Nottingham Prognostic Index in young breast cancer patients is suboptimal. Due to the relative underestimation of long-term outcomes in the older cohort, the role of Adjuvant! Online and Nottingham Prognostic Index deserves further investigations.

Conclusions

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Breast International Group Institut Jules Bordet Erasme Hospital Martine Piccart Christos Sotiriou Ahmad Awada Christine Desmedt Florian Clatot Françoise Rothé Marion Maetens Bastien Nguyen Yacine Bareche Evandro de Azambuja Michail Ignatiadis Frederic Henot Noam F. Pondé Samuel Martel Christian Maurer Cinzia Solinas Giulia Viglietti Isabelle Demeestere Oranite Goldrat Breast International Group Debora Fumagalli Innate Pharma Hatem A. Azim Jr. IRCCS AOU San Martino - IST Lucia Del Mastro Francesca Poggio Alessia Levaggi Paola Anserini Maria Carolina Pescio Chiara Dellepiane Istituto Europeo di Oncologia Fedro A. Peccatori matteo.lambertini85@gmail.com matteo.lambertini@bordet.be

BACK-UP SLIDES

Statistical Considerations Disease-free survival and overall survival curves for the two cohorts of patients were calculated with the Kaplan-Meier method. Long-rank test was used for comparing the curves between the six classes of Nottingham Prognostic Index. For assessing calibration, the trimmed mean of predicted 10-year survival probabilities (by Adjuvant! Online and Nottingham Prognostic Index) was compared with the observed 10-year survival rates (Kaplan-Meier curves). For assessing discriminatory accuracy, the area under the receiver-operator characteristic curve (AUC under the ROC) and corresponding 95% confidence intervals for 10-year predicted survival outcomes were calculated.

Results Nottingham Prognostic Index NPI groupings NPI score Estimated 10-year OS (Quintyne et al, 2013) Observed 10-year OS in the young cohort Observed 10-year OS in the older cohort Excellent prognostic group ≤2.40 96% 100% 97% Good prognostic group 2.42 to 3.40 93% 94% Moderate 1 prognostic group 3.42 to 4.40 81% 91% Moderate 2 prognostic group 4.42 to 5.40 74% 83% Poor prognostic group 5.42 to 6.40 50% 76% 66% Very poor prognostic group ≥6.40 38% 57% 63% Higher survival rates in our study than Quintyne et al.