1. 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

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

4. 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: Azim HA et al, Breast Cancer Res 2014;16: Ravdin PM et al, J Clin Oncol 2001;19: Haybittle JL et al, Br J Cancer 1982;45: Engelhardt EG et al, J Clin Oncol 2014;32:

5. 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: Paik S et al, N Engl J Med 2004;351:
Sparano JA et al, N Engl J Med 2015;373: Cardoso F et al, N Engl J Med 2016;375:717-29

6. 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 years.

7. 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 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.

8. Study Procedure: Adjuvant! Online

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

10. Study Flow Chart

11. 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)

12. 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

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

14. Tool Calibration: Young Cohort
Results
Tool Calibration: Young Cohort

15. Tool Calibration: Older Cohort
Results
Tool Calibration: Older Cohort

16. 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

17. 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.

18. Conclusions

19. Don’t miss the opportunity to complete the BCY3/BCC 2017 survey on fertility and pregancy issues in breast cancer patients!

20. 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

21. BACK-UP SLIDES

22. 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.

23. 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.