Download a prognostic factor index for overall survival in a her2

A prognostic fActor index for overAll survivAl in A Her2-negAtive endocrine-resistAnt
metAstAtic breAst cAncer populAtion: AnAlysis of tHe AtHenA triAl
#555
antonio llombart-Cussac,1 Xavier B Pivot,2 laura Biganzoli,3 Hernan Cortes-Funes,4 kathleen I Pritchard,5 Jean-Yves Pierga,6 Ian e Smith,7 Christoph thomssen,8 gemma Palacios,9 Stefanie Srock,10 Miguel Sampayo,11 Javier Cortes12
Hospital Arnau de Vilanova de Valencia, Valencia, Spain; 2Institut Regional du Cancer en Franche-Comté, Centre Hospitalier Universitaire de Besançon, Besançon, France; 3Sandro Pitigliani Medical Oncology Unit, Ospedale Misericordia e Dolce, Istituto Toscano Tumori, Prato, Italy; 4University Hospital 12 de Octubre, Madrid, Spain; 5Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada;
Institut Curie, Université Paris Descartes, Paris, France; 7Royal Marsden Hospital and the Institute of Cancer Research, London, UK; 8Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany; 9Roche Farma SA, Madrid, Spain; 10F Hoffmann-La Roche Ltd, Basel, Switzerland; 11Medica Scientia Innovation Research (MEDSIR ARO), Barcelona, Spain; 12Vall d’Hebron University Hospital, Barcelona, Spain
1
6
INtROduCtION
table 1. Baseline characteristics: HER2-negative analysis population (n=2203)
Parameter
l
l
l
l
l
For women with HER2-negative locally recurrent/metastatic
breast cancer (LR/mBC), there are no targeted therapies
and no gold-standard treatment.1
The impressive gains in progression-free survival
(PFS) achieved with the addition of bevacizumab to
chemotherapy regimens have been accompanied by
a lack of demonstrable overall survival (OS) benefit.2–4
OS varies considerably in this population and is
influenced by a wide range of biological and clinical
factors, some of which remain unclear.
Evidence-based definitions of ‘poor prognosis’ or
‘aggressive disease’ may help to guide treatment
decisions and improve clinical trial design.
In the multinational ATHENA study, 2264 patients with
HER2-negative LR/mBC were treated with first-line
bevacizumab in combination with non-anthracyclinecontaining chemotherapy in the context of routine
oncology practice.5
– The ATHENA population provides a rich dataset in
which to assess potential prognostic factors.
ECOG performance statusa
0
1
2
Disease-free interval, months
≤24
>24
Metastatic at diagnosis
Number of organs involvedb
1
2
≥3
Metastatic sitesc
Bone
Lung
Liver
Soft tissue
Pleural
Peritoneal
Stage at study entry
Locally recurrent
Metastatic
Hormone receptor status
ER and PgR positive
ER positive, PgR negative
ER negative, PgR positive
ER and PgR negative (triple negative)
Prior (neo)adjuvant chemotherapy
Anthracycline and/or taxane
Non-anthracycline and non-taxane
None
Prior endocrine therapy
(Neo)adjuvant setting
Metastatic setting
No. of patients (%)
1263 (57)
814 (37)
124 (6)
619 (28)
1172 (53)
412 (19)
1070 (49)
725 (33)
408 (19)
1093 (50)
791 (36)
790 (36)
676 (31)
119 (5)
39 (2)
163 (7)
2040 (93)
1096 (50)
334 (15)
87 (4)
585 (27)
1285 (58)
198 (9)
720 (33)
1069 (49)
533 (24)
Missing in one patient, ECOG performance status 3 in one patient. bSkin, lymph node, ipsi-/contralateral breast, or other
soft tissue involvement was scored as a single organ. cMore than one answer possible; sites reported in ≤1% of patients
not listed. ECOG = Eastern Cooperative Oncology Group; ER = estrogen receptor; PgR = progesterone receptor.
a
PatIeNtS aNd MetHOdS
l
l
l
We analyzed prognostic factors for OS in patients with HER2negative LR/mBC.
– Patients with disease reported as HER2-positive in the case
report form (n=61) were excluded from the present analysis.
Prognostic factors were selected from a univariate Cox regression
analysis.
Multivariate analysis was performed to explore the strongest
prognostic factors further.
table 2. Summary of efficacy: HER2-negative analysis population (n=2203)
Parameter
Response, n (%)
Objective response rate
Clinical benefit ratea
Time to disease progression
Events, n (%)
Median, months (95% CI)
Overall survival
Events, n (%)
Median, months (95% CI)
l
l
The analysis population included 2203 patients (Table 1) with a
median age of 53 years (range 22–93 years).
Bevacizumab was typically administered in combination with
single-agent taxane therapy (67% of patients). Approximately
one-fifth (22%) received bevacizumab with non-taxane therapy
and 11% received bevacizumab with a taxane combination
regimen.
After a median follow-up of 20.1 months, median OS for the entire
analysis population was 25.2 months (Table 2).
– OS was shorter with non-taxane than taxane-containing
regimens in combination with bevacizumab, although
interpretation is difficult as investigators chose chemotherapy
for each individual patient.
Figure 1. Cox regression univariate analysis of overall survival
Value
1191 (54)
1908 (87)
1592 (72)
9.7 (9.4–10.2)
table 3. Overall survival according to metastatic organ sites (HER2-negative
population, n=2203)
n (%)
Median OS,
months (95% CI)
790 (36)
1413 (64)
408 (19)
1795 (81)
941 (43)
1262 (57)
20.0 (18.6–22.0)
28.5 (26.4–30.0)
19.3 (17.2–21.8)
26.5 (25.5–28.5)
20.7 (19.5–22.5)
28.6 (26.4–30.1)
Metastatic sites
Liver metastases
≥3 sites
Liver metastases or
≥3 sites
Yes
No
Yes
No
Yes
No
Hazard ratio
(95% CI)
Figure 5. Overall survival in the hormone receptor-positive subgroup (n=1517)
according to number of prognostic factors present
p-value
1.5 (1.4–1.7)
<0.0001
1.5 (1.3–1.7)
<0.0001
1.5 (1.3–1.7)
<0.0001
Overall survival probability (%)
100
Prognostic factors
l
l
l
l
0/1
2
3
No. of patients
(%)
Median OS,
months (95% CI)
Hazard ratio
(95% CI)
942 (62)
453 (30)
122 (7)
32.9 (30.5–35.3)
22.1 (20.0–24.5)
15.9 (13.5–19.0)
Reference
1.7 (1.4–1.9)
2.4 (1.9–3.1)
p-value
<0.0001
60
40
Figure 3. Overall survival according to number of prognostic factors present
(HER2-negative population, n=2203)
0/1 prognostic factors
2 prognostic factors
20
n (%)
Hazard ratio
(95% CI)
p-value
<50
840 (38)
0.9 (0.8–1.0)
0.058
50–65
1033 (47)
1.1 (1.0–1.2)
0.263
>65
330 (15)
1.1 (0.9–1.3)
0.301
ECOG performance status 2
124 (6)
2.1 (1.7–2.6)
<0.001
Disease-free interval ≤24 months
619 (28)
2.0 (1.8–2.3)
<0.001
≥3
408 (19)
1.5 (1.3–1.7)
<0.001
Bone
1093 (50)
1.1 (1.0–1.2)
0.0822
Lung
791 (36)
1.2 (1.1–1.3)
0.004
Liver
790 (36)
1.5 (1.4–1.7)
<0.001
Soft tissue
676 (31)
1.0 (0.9–1.2)
0.455
Risk factor
Overall survival probability (%)
Risk of death
Higher
Lower
100
Age, years
3 prognostic factors
No. of prognostic
factors
No. of patients
(%)
Median OS,
months (95% CI)
Hazard ratio
(95% CI)
1118 (51)
659 (30)
426 (19)
32.9 (29.9–35.2)
22.6 (21.0–25.1)
14.2 (12.8–16.0)
Reference
1.5 (1.3–1.8)
2.8 (2.5–3.3)
0/1
2
3/4
p-value
0
<0.0001
60
40
l
2 prognostic factors
20
3/4 prognostic factors
1096 (50)
0.8 (0.7–0.9)
<0.001
334 (15)
0.9 (0.7–1.0)
0.092
ER negative, PgR positive
87 (4)
1.0 (0.8–1.3)
0.958
Triple negative
585 (27)
1.7 (1.5–1.9)
<0.001
0
14.2
0
10
Prior (neo)adjuvant chemotherapy
Anthracycline and/or taxane
1285 (58)
1.5 (1.4–1.7)
<0.001
Taxane without anthracycline
198 (9)
0.7 (0.6–0.9)
0.052
None
720 (33)
0.7 (0.6–0.8)
0.845
(Neo)adjuvant setting
1069 (49)
0.9 (0.8–1.0)
0.218
Metastatic setting
533 (24)
1.2 (1.1–1.4)
0.007
22.6
32.9
20
30
Time (months)
40
50
table 4. Multivariate analysis of overall survival according to prognostic factors
(HER2-negative population, n=2203)
Any medication at baseline
Cardiovascular
554 (25.2)
1.1 (0.99–1.3)
Bisphosphonates
420 (19.1)
1.2 (1.0–1.3)
0.028
Analgesics
603 (27.4)
1.6 (1.4–1.7)
<0.001
Corticosteroids
149 (6.8)
1.5 (1.2–1.9)
<0.001
Diabetes
108 (4.9)
1.2 (0.9–1.5)
0.158
Antidepressants
232 (10.5)
1.0 (0.9–1.3)
0.616
0.084
Prognostic factor
0
p<0.05 for highlighted factors.
0.25 0.5
1
1.5
2
2.5
Figure 2. Overall survival according to disease-free interval (HER2-negative
population, n=2203)
Hazard ratio (95% CI)
Disease-free interval ≤24 months
Liver metastases or ≥3 metastatic organ sites
Triple-negative disease
Prior (neo)adjuvant anthracycline and/or taxane therapy
Model adjustment
Concordance index
R2
Global p-value
l
1.74 (1.53–1.98)
1.64 (1.46–1.85)
1.56 (1.36–1.78)
1.27 (1.11–1.45)
0.631
0.099
p<0.0001
l
Figure 4. Overall survival in the TNBC subgroup (n=585) according to number
of additional prognostic factors present
Overall survival probability (%)
Overall survival probability (%)
100
<12 months
12–24 months
>24 months
Metastatic at diagnosis
80
100
No. of additional
prognostic factors
0
1
2/3
No. of patients
(%)
Median OS,
months (95% CI)
Hazard ratio
(95% CI)
102 (17)
179 (31)
304 (52)
34.1 (21.1–47.2)
24.8 (19.6–30.0)
13.7 (11.7–15.8)
Reference
1.3 (1.0–2.0)
2.8 (2.0–3.9)
60
40
40
20
20
10
40
50
20
30
Time (months)
40
50
0
In this analysis of the atHeNa dataset of >2000
patients with lR/mBC receiving bevacizumabcontaining therapy, we identified important
prognostic factors for OS (dFI ≤24 months, liver
metastases/≥3 metastatic organ sites, tNBC, prior
anthracycline/taxane therapy) that could be
considered in the design of new trials.
– the effectiveness of this prognostic index
requires validation before extrapolation to
nonbevacizumab-containing therapy.
Importantly, a well-defined population of patients
with hormone receptor-positive lR/mBC had a
prognosis as poor as that of the subset with highrisk tNBC, with similarly short OS expectancy.
In the absence of validated biomarkers,
application of these simple clinical criteria may
enable identification of patients with a poorer
prognosis in whom more aggressive systemic
regimens may be of interest.
ReFeReNCeS
1.
2.
3.
4.
5.
0 prognostic factors
0
20
30
Time (months)
p-value
<0.0001
80
60
0
10
32.9
0/1 prognostic factors
Hormone receptor status
ER positive, PgR negative
0
22.1
CONCluSIONS
Metastatic organ sites
ER and PgR positive
15.9
80
1171 (53)
25.2 (23.9–27.0)
In a univariate analysis, prognostic factors most closely and robustly
associated with worse OS (Figure 1) were:
– Liver metastases or ≥3 involved organs
– Disease-free interval (DFI) ≤24 months
– Prior adjuvant anthracycline and/or taxane therapy
– Triple-negative breast cancer (TNBC).
The small subgroup with ECOG performance status 2 also had poor
OS expectancy.
DFI and metastatic organ sites were analyzed further to explore the
definition providing the greatest prognostic value (Figure 2; Table 3).
The overall analysis population was categorized according to the
number of risk factors present and a multivariate analysis of OS was
performed (Figure 3; Table 4).
– Half of the population (51%) had one or no risk factors
– In 19%, three or four risk factors were present; these patients
had a significantly worse OS prognosis than patients with two or
fewer risk factors.
No. of prognostic
factors
80
Complete or partial response or stable disease. CI = confidence interval.
Patient population
l
Similar analyses in the subgroup of patients with TNBC and the
subgroup with hormone receptor-positive LR/mBC were performed
based on the three remaining risk factors (Figures 4 and 5).
– Within the TNBC population, a small subgroup with no additional
risk factors and a relatively good prognosis was identified.
– Conversely, within the hormone receptor-positive subgroup,
a small population of patients with all three remaining risk factors
was found to have a prognosis almost as poor as that of the
TNBC patients with two or three risk factors (median OS 15.9 vs
13.7 months, respectively).
Prior endocrine therapy
a
ReSultS
l
Cardoso F, et al. Ann Oncol 2012;23(Suppl. 7):vii11–9.
Miller KD, et al. N Engl J Med 2007;357:2666–76.
Miles DW, et al. J Clin Oncol 2010;28:3239–47.
Robert NJ, et al. J Clin Oncol 2011;29:1252–60.
Smith IE, et al. Breast Cancer Res Treat 2011;130:133–43.
1 prognostic factor
aCkNOwledgMeNtS
13.7
0
10
24.8
34.1
20
30
Time (months)
2/3 prognostic factors
40
50
l
l
F Hoffmann-La Roche Ltd sponsored the ATHENA trial.
Support for third-party writing assistance for this poster was provided by F Hoffmann-La Roche Ltd,
Basel, Switzerland.
Presented at the American Society of Clinical Oncology Annual Meeting; May 31 – June 4, 2013, Chicago, IL, USA.