Download the ESMO 2012 Abstract Book - Oxford Journals

Annals of Oncology
629 DIFFERENT CLINICAL OUTCOME OF METASTATIC
COLORECTAL CANCER (MCRC) PATIENTS TREATED WITH
INTENSIVE TRIPLET CHEMOTHERAPY PLUS BEVACIZUMAB
(FIR-B/FOX) ACCORDING TO KRAS GENOTYPE AND DISEASE
EXTENSION
G. Bruera 1 , K. Cannita 1 , D. Di Giacomo 2 , A. Lamy 3 , A. Dal Mas 4 , T. Frebourg 5 ,J.
C. Sabourin 6 , M. Tosi 5 , C. Ficorella 1 , E. Ricevuto 1
1 Medical Oncology, S. Salvatore Hospital, University of L’Aquila, L’Aquila, ITALY,
2 Department of Experimental Medicine, University of L’Aquila, L’Aquila, ITALY,
3 Laboratory of Tumor Genetics, University Hospital, Rouen, Rouen, FRANCE,
4 Pathology, S. Salvatore Hospital, L’Aquila, ITALY, 5 INSERM U614, University of
Rouen, Rouen, FRANCE, 6 Department of Pathology, INSERM U614, Rouen
University Hospital, Rouen, FRANCE
Background: Bevacizumab (BEV) plus triplet chemotherapy can increase efficacy of
first-line treatment of MCRC (Bruera G et al, BMC Cancer 2010, 10:567),
particularly if integrated with secondary liver surgery in liver-limited (L-L) patients
(pts) (Bruera G et al, Clin Colorectal Cancer 2012). Clinical outcome of FIr-B/FOx
regimen was evaluated according to KRAS genotype in L-L and other MCRC pts.
Methods: Tumoral and metastatic samples were screened for KRAS codon 12 and
13, and BRAF mutations by SNaPshot and/or direct sequencing. MCRC pts were
classified as L-L and other or multiple metastatic (O/MM). Activity and efficacy were
evaluated and compared using log-rank test.
Results: Fifty-nine pts were evaluated: 31 KRAS wild-type, 53%; 28 KRAS mutant,
47%. At 21.5 months median follow-up, objective response rate (ORR),
progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS
wild-type 90%, 14 months, 38 months; KRAS mutant 67%, 11 months, 20 months.
PFS and OS were, respectively: overall in 25 L-L compared to 32 O/MM evaluable
pts, 17 and 12 months, 47 and 21 months, significantly different; in KRAS wild-type,
12 L-L compared to 18 O/MM, 21 and 12 months, 47 and 28 months, significantly
different; in KRAS mutant, 13 L-L compared to 14 O/MMS, 11 months equivalently,
39 and 19 months, not significantly different.
Conclusion: First line FIr-B/FOx regimen can increase activity and efficacy of KRAS
wild-type and mutant MCRC pts; integration with secondary liver surgery
significantly discriminates increased clinical outcome in KRAS wild-type L-L
compared to O/MM pts while not in KRAS mutant pts.
Disclosure: All authors have declared no conflicts of interest.
630 POTENTIAL BIOMARKERS FOR RESPONSE TO CETUXIMAB IN
PATIENTS WITH METASTATIC COLORECTAL CANCER (MCRC).
A HELLENIC COOPERATIVE ONCOLOGY GROUP STUDY
E. Razis 1 , M. Bobos 1 , W. De Roock 2 , M. Bai 1 , A. Gousia 1 , I. Xanthakis 1 ,
E. Tsolaki 1 , P. Papakostas 1 , S. Tejpar 3 , G. Fountzilas 1
1 Data Office, Hellenic Cooperative Oncology Group (HeCOG), Athens, GREECE,
2 Human Genetics, Katholieke Universiteit Leuven, Leuven, BELGIUM, 3 Digestive
Oncology Unit, University Hospital Gasthuisberg, Leuven, BELGIUM
Background: Cetuximab has improved outcome of patients (pts) with mCRC. KRAS
has emerged as a marker of resistance to monoclonal antibodies against EGFR,
including cetuximab. Further biomarkers for response to cetuximab are being explored.
Methods: In a heterogeneous cetuximab-treated population we retrospectively
evaluated formalin-fixed paraffin-embedded tissue for EGFR and PTEN by
Fluorescence In Situ Hybridization (FISH) and for PIK3CA and KRAS mutations by
PCR and examined the association of these markers with patient outcome.
Results: Two hundred twenty-three cetuximab-treated mCRC pts were identified,
of which 38 were treated in first line, 107 in second and 78 in ≥ 3 rd line.
Cetuximab was used with irinotecan-based therapy in 54.3% and with oxaliplatin
in 26.9% of the cases. Two pts achieved a complete response, 53 a partial
response and 65 stable disease for a clinical benefit rate of 63.2%. EGFR
amplification was noted in 5 cases, PTEN deletion in 58 and PTEN gain in
2. Finally, KRAS was mutated in 72 cases, and PIK3CA in 37. The mutations
detected for KRAS were G12 (45 pts, 62.5%), G13 (16 pts, 22.2%), G61 (4 pts,
5.6%) and A146 (7 pts, 9.7%) and for PIK3CA Exon9 (20 pts, 54.1%), Exon20
(5 pts, 13.5%) and other (12 pts, 32.4%). No associations were found between
these markers. PTEN deletion was associated with a higher overall response rate
(ORR) (p = 0.031), while the other markers were not. Progression-free survival
(PFS) and survival were calculated from initiation of cetuximab. PFS was
numerically associated with EGFR gain but the numbers (5 gain vs. 138 normal)
do not allow for a sound result. Additionally, given the different impact of
diverse KRAS mutations on outcome, we evaluated the outcome in relation to
the G12 mutations. The latter exhibited a trend for decreased survival (p =
0.057).
Conclusions: After a median follow up of 55.3 months (5.8-88.4 months), PTEN
deletion was associated with improved ORR to cetuximab. Further examination of
EGFR and PTEN by immunohistochemistry is in progress.
Disclosure: E. Razis: Dr E. Razis received research grant from Merck S.A. and Roche
(Hellas) S.A. All other authors have declared no conflicts of interest.
631 BRAFV600E MUTATION ANALYSIS IN PATIENTS WITH
METASTATIC COLORECTAL CANCER (MCRC) IN DAILY
CLINICAL PRACTICE: CORRELATIONS WITH CLINICAL
CHARACTERISTICS, PROGNOSTIC AND PREDICTIVE VALUES
Z. Saridaki 1 , M. Tzardi 2 , M. Sfakianaki 3 , C. Papadaki 3 , K. Mpananis 3 ,
E. Tsakalaki 3 , M. Trypaki 3 , I. Messaritakis 3 , V. Georgoulias 4 , J. Souglakos 4
1 Laboratory of Tumor Cell Biology, University of Crete, School of Medicine,
Heraklion, GREECE, 2 Laboratory of Pathology, University of Crete, School of
Medicine, Heraklion, GREECE, 3 Laboratory of Tumor Cell Biology, School of
Medicine, University of Crete, Heraklion, GREECE, 4 Medical Oncology, University
Hospital of Heraklion, Heraklion, GREECE
Aim: To evaluate the usefulness of the BRAFV600E detection in the daily clinical
practice, it’s clinical correlations and prognostic/predictive values in a prospective
database of patients with mCRC.
Patients and methods: 442 mCRC patients treated with systemic chemotherapy ±
biologics at the Medical Oncology Department of the University Hospital of Heraklion
from 1-07-07 were prospectively analyzed. The BRAF mutation was assessed by
RT-qPCR using the allelic discrimination method. The laboratory findings were
correlated with patients’ clinical-pathologic characteristics and the treatment outcome.
Results: The median age was 68 years of age (21-89) while 37% of them were > 65 old;
61% were male, in 71% of them the primary tumor was located in the colon and in
29% in the rectum 48% of the tumors were low grade and 21% presented mucinous
features. Salvage cetuximab or panitumumab therapy was administered to 228 patients
with KRASwt tumors. The BRAF mutation was detected in 32 (7.5%) patients.
Statistically significant higher incidence of the BRAF mutation was observed in patients
with ECOG-PS 2 (p = 0.0001), > 65 years old (p = 0.001), primaries located in the right
colon (p = 0.004), lowgrade tumors (p = 0.001) and in those with mucinous features
(p = 0.021). Patients whose tumors harbored the BRAF mutation had a reduced
progression-free survival (PFS) (4.1 months) compared with the wild-type (wt) (11.4
months, p < 0.0001). The overall survival (OS) of the patients with BRAF mutation was
statistically significantly shorter (13.5 months) compared with the wt ones (33.3
months, p < 0.0001). In the multivariate analysis the BRAF mutation detection
emerged as independent factor associated with reduced PFS (HR: 4.1, 95% CI 2.7-6.2,
p < 0.0001) and OS (HR: 5.9, 95% CI 3.7-9.5, p < 0.0001). Among the patients treated
with anti-EGFR moAbs salvage therapy, the BRAF mutation was correlated with
reduced PFS (2.2 vs 6.0 months, p < 0.0001) and OS (4.3 vs 17.4 months, p < 0.0001).
Conclusion: Our results document the unfavorable prognostic value of the
BRAFV600E mutation and advocate in favor of its predictive value towards
anti-EGFR moAbs therapy.
Disclosure: All authors have declared no conflicts of interest.
632 EPIDEMIOLOGY PROJECTION TRENDS FOR METASTATIC
COLORECTAL CANCER (MCRC) PATIENTS RECEIVING
SECOND LINE (2L) THERAPY IN EU AND US
O. Moulard 1 , J. Mehta 2 , S. Naoshy 2 , R. Olivares 1 , S.U. Iqbal 2 , I. Chau 3
1 Evidence and Value Development, Sanofi, Chilly Mazarin, FRANCE, 2 Evidence
and Value Development, Sanofi, Cambridge, MA, UNITED STATES OF
AMERICA, 3 Medicine, Royal Marsden Hospital, Sutton, UNITED KINGDOM
Background: Worldwide, CRC is the third most common cancer in men (663,000
cases, 10% of the total) and second in women (571,000 cases, 9.4% of the total)
(IARC 2008). Due to demographic expansion and an ageing population, the annual
number of newly diagnosed and treated CRC cases is expected to increase in Western
countries. Hence, epidemiology projection estimates by line of therapy are needed to
support clinical, economic and resource planning.
Methods: Epidemiological data was obtained using the CancerMPact® database
(accessed Oct 2011), which includes line of therapy estimations through the US
National Oncology Data Alliance and survey of a representative physician sample.
Data was grouped by stage at diagnosis and stage IV refers to metastatic patients.
Results: From 2010-2020, the distribution of mCRC patients receiving 2L differs by
country in EU. The highest number of treated patients is in Germany, followed by
Italy and UK. Among all treated mCRC patients, about 42% of patients in EU and
45% of patients in US will go on to 2L. By 2020, the percentage of patients receiving
1L and 2L will increase by about 15% across US and EU. Over a 10 year period, the
number of treated patients for each line of therapy will increase by 19%, 11%, 15%,
20%, and 14% for France, Germany, Italy, Spain and UK, respectively. The table
below refers to the number of metastatic patients by line of therapy.
Conclusions: Despite improvement in survival rates, approximately half of patients
in US and EU who receive 1L go on to 2L. In addition to survey data, real world
data and disease based registries can help validate these projection estimates. The
projected increase in mCRC patients by 10-20% across the EU has implications for
disease management and health resource planning in oncology.
Disclosure: O. Moulard: I am an employee of Sanofi. J. Mehta: I am an employee of
Sanofi. S. Naoshy: I am an employee of Sanofi. R. Olivares: I am an employee of
Sanofi. S.U. Iqbal: I am an employee of Sanofi. All other authors have declared no
conflicts of interest.
Volume 23 | Supplement 9 | September 2012 doi:10.1093/annonc/mds397 | ix213