Annual Meeting Proceedings Part 1 - American Society of Clinical ...

18s Breast Cancer—HER2/ER
545 General Poster Session (Board #2C), Sat, 8:00 AM-12:00 PM
A dendritic metagene that predicts prognosis and endocrine resistance in
breast cancer. Presenting Author: Bianchini Giampaolo, Fondazione San
Raffaele del Monte Tabor, Milan, Italy
Background: High expression of dendritic-associated genes in estrogen
receptor-positive (ER�), highly proliferative breast cancer is associated
with good prognosis in untreated patients (pts) and poor response to
neoadjuvant endocrine therapy (Dunbier SABCS 2010). We examined the
prognostic and predictive value of a dendritic metagene (DM) signature in
subgroups defined by proliferation and estrogen-related genes (Bianchini
SABCS 2011). Methods: We evaluated Affymetrix HGU133A-based gene
expression profiles from ER� untreated (n�511) and adjuvant tamoxifen
(TAM)-treated pts (n�606). Three previously defined scores were assessed:
MKS for proliferation (Bianchini, Cancer Res 2010); estrogenrelated
score (ERS) adopted from Oncotype DX; and DM (Bianchini JCO
2010). Median cut-off points were used. Outcome was assessed according
to distant relapse. Results: DM was significantly predictive for early (within
5 years) relapse. In TAM-treated pts with low-MKS tumors, DM was not
significantly prognostic. The table shows hazard ratios (HRs) for low vs.
high-DM by ERS in untreated and TAM-treated pts with high-MKS. In
low-DM, the 5-yrs distant-event free survival was 92.3% and 60.6% (HR
6.58 (2.55-17.0); p�0.001) and in high-DM it was 80.7% and 79.8%
(HR 1.06 (0.48-2.32); p�0.88), respectively in high and low-ERS
respectively. The interaction between DM and ERS was significant only in
TAM-treated tumors (p�0.003). In high-MKS/low-ERS tumors, DM retained
significance over the 10-year period in multivariate analysis adjusting
for clinical variables (HR� 2.27 (1.13-4.58); p�0.02). Conclusions:
For high-MKS, untreated and TAM-treated tumors with low-ESR, high-DM
is associated with a low risk of relapse, and for untreated tumors with
high-ERS. These data suggest that high infiltration of tumor by dendritic
cells may be a novel mechanism of endocrine resistance. DM could refine
risk in poor prognosis ER� tumors and rationalize immuno-modulating
strategies.
Untreated/high MKS TAM-treated/high MKS
>High-ERS No.of pts/events HR (CI 95%) p No.of pts/events HR (CI 95%) p
Low
(vs high-DM)
116/21 2.9 (1.1-7.9) 0.039 127/15 0.4 (0.1-1.1) 0.067
Low-ERS Low
(vs high-DM)
169/64 3.0 (1.8-5.0) �0.0001 175/46 2.3 (1.3-4.2) 0.007
547 General Poster Session (Board #2E), Sat, 8:00 AM-12:00 PM
Adjuvant capecitabine for invasive lobular/mixed early breast cancer (EBC):
USON 01062 exploratory analyses. Presenting Author: Joyce
O’Shaughnessy, Baylor Sammons Cancer Center, Texas Oncology, US
Oncology, Dallas, TX
Background: Randomized phase III USON 01062 trial determining if
patients with EBC would benefit from addition of capecitabine to docetaxel
after AC (AC-T vs AC-XT). AC-T: docetaxel 100mg/M2 IV; AC-XT: docetaxel
75mg/M2 IV with capecitabine 825mg/M2 PO BID 14/7 days every 21days
for 4 cycles. The primary endpoint, improvement in disease-free survival
(DFS) at 5 years, was not met (HR�0.84, p�0.12) likely due to
lower-than-expected event rate. The secondary endpoint, overall survival
(OS), was improved with capecitabine (HR 0.68, p�0.01) (O’Shaughnessy,
J. ASCO, 2011). Methods: Molecular analyses demonstrate that pleomorphic
lobular (mixed lobular/ductal) carcinomas evolve from the same
precursor and/or through the same genetic pathway as classical lobular
cancers (Reis-Filho, J., J Path, 2005). We conducted exploratory analyses
to evaluate the addition of adjuvant capecitabine in ductal vs lobular or
lobular/ductal (mixed) EBC within USON 01062. Histology was classified
according to local pathology assessment on patients’ primary cancers.
Results: In ductal patients (n�2195), there was no difference in DFS
(HR�0.92, p�0.48) and OS (HR�0.75, p�0.07) with AC-T vs AC-XT. In
lobular/mixed patients (n�355), adding capecitabine improved DFS
(HR�0.55, p�0.055) and OS (HR�0.38, p�0.04). There was no difference
in DFS (HR�1.004, p�0.98) in the ER� ductal patients (n�1258)
with the addition of capecitabine. Conclusions: Ductal and lobular cancers
have distinct histologic and molecular characteristics; lobular cancers are
generally less sensitive to chemotherapy (Cristofanilli, M. JCO, 2005). This
exploratory analysis suggests that patients with lobular/mixed EBC may
benefit from adjuvant capecitabine. This hypothesis requires evaluation in
other adjuvant capecitabine trials.
Hazard ratio by disease histology in patients with different treatment.
End point Treatment
Events in ductal
n�2,195 (%)
Events in lobular/mixed
n�355 (%) HR P value
DFS All patients 254 (11.6) 43 (12.1) 1.003 0.98
AC-T 132 (12.0) 27 (15.3) 1.25 0.30
AC-XT 122 (11.1) 16 (8.9) 0.75 0.28
OS All patients 156 (7.1) 21 (5.9) 0.80 0.33
AC-T 89 (8.1) 15 (8.5) 1.02 0.95
AC-XT 67 (6.1) 6 (3.4) 0.52 0.13
546 General Poster Session (Board #2D), Sat, 8:00 AM-12:00 PM
A meta-analysis of receptor status discordance between primary breast
cancer and metastases. Presenting Author: Gaetano Aurilio, European
Institute of Oncology, Medical Oncology, Milan, Italy
Background: There is an increasing awareness that biology of breast cancer
may evolve over time. The discordance in estrogen (ER), progesterone
(PgR) and HER2 receptor status between primary breast cancer and
metastases is being intensively investigated and a large amount of data has
been produced. However, results from different studies seem to be
conflicting and heterogeneous. To highlight this issue, a meta-analysis of
published data was performed. Methods: A literature search was performed
with Medline. All studies published from 1983 to 2011 comparing
changes inER, PgR and/or HER2 status in patients with matched breast
primary and recurrent tumors were included. We used random-effects
models to estimate pooled discordance proportions. Results: We selected
42 articles, mostly reporting retrospective studies. Twenty-eight, 20 and
27 articles were focused on ER, PgR and HER2 changes, respectively. A
total of 2806 tumors were evaluated for ER discordance, 1809 for PgR
discordance and 2801 for HER2 discordance. The heterogeneity between
study-specific discordance proportions was high (I2 �75%, p�0.0001) for
ER, PgR and HER2. Pooled discordance proportions were 20% (95% CI:
16-25%) for ER, 33% (95% CI: 28-38%) for PgR and 9% (95% CI:
6-12%) for HER2. Pooled proportions of tumors shifting from positive to
negative and from negative to positive were 24% and 12% for ER
(p�0.0115), respectively. The same figures were 44% and 15% for PgR
(p�0.0001), and 14% and 6% for HER2 (p�0.04). Conclusions: To our
knowledge, this is the first meta-analysis addressing this topic. The findings
strengthen the concept that changes in receptor expression may occur
during the natural history of breast cancer and therefore clinical implications
with possible impact on treatment choice cannot be excluded.
However, the high heterogeneity observed in our analysis may explain the
disagreement among oncologists on performing a reassessment of the
biological features. In our opinion, only high-powered prospective and
randomized trials could clarify the controversies in this field.
548 General Poster Session (Board #2F), Sat, 8:00 AM-12:00 PM
Bisphosphonates in the adjuvant setting of breast cancer therapy: Effect on
survival—A systematic review and meta-analysis. Presenting Author: Liath
Vidal, Davidoff Center, Rabin Medical Center, Petach Tikva, Israel
Background: The role of bisphosphonates (BP) in the adjuvant setting in
breast cancer has been evaluated in several studies, yielding inconsistent
evidence. We performed a systematic review and meta-analysis of all
randomized controlled trials (RCTs) that evaluate the effects of BP
treatment on survival in patients with early breast cancer in the adjuvant
setting. Methods: RCTs that compared BP therapy in addition to the
standard adjuvant therapy (cytotoxic or hormonal) with standard adjuvant
therapy only were identified by searching the Cochrane Library, LILACS,
MEDLINE databases and conference proceedings (12.2011). Hazard
ratios (HRs) of overall survival (OS), disease-free survival (DFS) and relative
risks of adverse events were estimated and pooled. All statistical tests were
two-sided. Results: Thirteen trials met the inclusion criteria., among which
are the two recently published abstracts of large scale RCTs (NSABP-B34,
GAIN) evaluating a total of 15,762 patients. Ten trials reported the OS
outcome. Meta-analysis revealed no statistically significant benefit for BP
(HR 0.89, 95% CI � 0.79 to 1.01). Nine trials reported the DFS outcome.
Meta-analysis revealed no statistically significant better DFS for the
intervention (HR 0.95 (0.80-1.11)). Six trials reported DFS stratified upon
menopausal status. Postmenopausal patients who were treated with BP
therapy had statistically significant better DFS than the control group (HR
0.81(0.69-0.95)). In meta-regression, chemotherapy was negatively associated
with HR of OS (coefficient, -0.23; standard error, 0.144). BP
therapy resulted in less fractures in the intervention arm, but higher
incidence of osteonecrosis of the jaw and pyrexia. Conclusions: Our
meta-analysis indicates a positive effect for adjuvant BP on survival
outcomes only in postmenopausal patients with breast cancer. Metaregression
appraised the effect of confounders such as chemotherapy,
showed a negative association between chemotherapy use and the effect of
bisphosphonates on survival. Further large scale RCTs are warranted to
unravel the specific subgroups and adjuvant treatments that would benefit
from the addition of BP in the adjuvant setting.
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