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translational research
1644PD ANTIBODY-DEPENDENT CELL-MEDIATED CYTOTOXICITY
(ADCC) EVOLUTION UNDER TREATMENT BY CETUXIMAB
AND LINKS WITH TREATMENT OUTCOME IN LOCALLY
ADVANCED HEAD AND NECK (LAHNSCC) AND IN
METASTATIC COLORECTAL CANCER (MCRC) PATIENTS
C. Lo Nigro 1 , M. Monteverde 1 , G. Strola 2 ,M.Maffi 1 , E. Miraglio 1 , L. Lattanzio 1 ,
D. Vivenza 1 , F. Messa 1 , G. Milano 3 , M. Merlano 1
1 Oncology, S. Croce General Hospital, Cuneo, ITALY, 2 Laboratory, S. Croce
General Hospital, Cuneo, ITALY, 3 Oncopharmacology Unit, Lacassagne, Nice,
FRANCE
Background: ADCC may play a role in antitumor activity of IgG1 mAb by inducing
immune cell-mediated tumor lysis. We evaluated ADCC ability before and under
cetuximab treatment and impact on survival in locally advanced Head and Neck
(LAHNSCC) or metastatic colorectal cancer (mCRC).
Methods: 82 patients (60 men, 22 women; median age 64, range 39-87), 39
LAHNSCC and 43 mCRC, treated with chemotherapy (irinotecan or folfiri) plus
cetuximab, were prospectively enrolled. ADCC ex-vivo was measured before
treatment and every 2 months (1 to 7 measurements/patient, 44 patients with
≥2 measurements). 400 000 purified Natural Killer cells (CD3- CD56+) from
patients were incubated with 10 000 target cells (CAL166 cell line expressing
EGFR) and 10 µg/ml cetuximab. Cytotoxicity was measured by LDH-release
assay. ADCC was expressed as % of lysed target cells. Polymorphisms of Fcg
receptors FcgR2a (131Arg > His) and FcgR3a (158Phe > Val) were analyzed by
Allelic Discrimination assay.
Results: The feasibility rate of ADCC measurements was 85-90%. Basal ADCC
ranged between 30% and 100% (mean 62%, median 66%) and was not
influenced by gender. A trend for an increased basal ADCC was observed in
younger patients: median was 66% in the 22 patients < 65 vs 56% in the 22
patients ≥ 65 years (p = 0.084), with a marked difference by tumour site (H&N
p = 0.056; colon p= 0.16). FcgR2a and FcgR3a gene polymorphisms were not
linked to basal ADCC. The evolution of individual ADCC ability before
treatment and 2 months later revealed a significant drop in ADCC (intra-patient
comparison, N = 44, p = 0.003, absolute median drop of 20%). 82 patients were
assessable for survival (43 deaths; median follow up = 10.3 month). Cutaneous
rash, but not basal ADCC, was related to survival (p = 0.043). There were no
correlation between ADCC evolution (decrease/increase during the two months)
vs EGFR status nor vs cutaneous rash.
Conclusions: A new generation of mAb is currently being developed with the aim to
amplify ADCC. Present data illustrate the feasibility of ADCC measurement in
mAb-treated patients and reveal an initial drop in ADCC under treatment that may
reflect the variable chemotherapy-induced impact on host immunity.
Disclosure: All authors have declared no conflicts of interest.
1645PD MICRORNA-9 AND -224 IN TRASTUZUMAB RESISTANT
HER2 POSITIVE BREAST CANCER CELLS
K. Howe, A. Eustace, S. Souahli, B.C. Browne, S. Aherne, N. Barron, N. Walsh,
J.P. Crown, N. O’Donovan
National Institute for Cellular Biotechnology, Molecular Therapeutics for Cancer
Ireland, Dublin City University, Dublin, IRELAND
HER2 positive breast cancer accounts for approximately 25 % of all breast
cancer cases. Trastuzumab, a humanised monoclonal antibody, is an approved
established treatment for HER2 positive breast cancer; however, patients that
initially respond frequently develop resistance. The aim of this study is to
investigate microRNAs in cell line models of acquired and innate trastuzumab
resistance. MicroRNA was extracted from the HER2 positive cells; SKBR3,
BT474, and the acquired trastuzumab resistant variants SKBR3-T and BT474-T,
and from a panel of innate trastuzumab sensitive (BT474, EFM-192A, SKBR3
and MDA-MB-361) or resistant cell lines (UACC-732, JIMT-1, HCC-202,
HCC-1954, HCC1569 and MDA-MB-453), in triplicate. MicroRNA profiling was
performed on SKBR3 and SKBR3-T using Taqman Low Density Arrays (TLDA).
Annals of Oncology 23 (Supplement 9): ix528–ix540, 2012
doi:10.1093/annonc/mds417
Differentially regulated miRNAs were selected using > 2-fold change and a
P-value of < 0.05. Individual quantitative RT-PCR (qRT-PCR) was performed to
confirm alterations in miRNAs. Functional studies were carried out using
Ambion® Pre-miR miRNA Precursors and Anti-miR miRNA Inhibitors for
miR-224 in SKBR3 cells. TLDA analysis identified nine differentially regulated
microRNAs in the SKBR3-T cells. Individual qRT-PCR assays confirmed that 5
miRNAs were up-regulated and 4 were down-regulated. MiR-9 was 2.2-fold
up-regulated (p = 0.04), while miR-224 was 1.6-fold down-regulated (p = 0.01) in
SKBR3-T compared to the SKBR3 cells. Further validation of these targets in the
BT474 model showed that miR-224 expression is lost in the resistant cells
compared to the parental BT474 cells. MiR-9 is not significantly altered in the
BT474-T cells. In the innate resistant models, miR-224 expression is reduced or
lost in 4/6 resistant cell lines. Expression of miR-9 does not significantly differ
between the innately sensitive and resistant cell lines. Transfection of SKBR3
cells with pre-miR-224 significantly decreases cell proliferation by 23.5% (p =
0.04).
Conclusions: This is the first report of the involvement of miR-9 and miR-224 in
trastuzumab resistance in HER2 positive breast cancer. Preliminary functional studies
suggest that miR-224 may play a role in regulating cell growth in HER2 positive
breast cancer cells.
Disclosure: All authors have declared no conflicts of interest.
1646PD CUSTOMIZED FIRST LINE CHEMOTHERAPY ACCORDING
TO ERCC1 AND RRM1 SNPS IN ADVANCED
NON-SMALL-CELL LUNG CANCER (NSCLC) PATIENTS: A
PHASE II STUDY
F. Mazzoni 1 , G. Meoni 1 , F.L. Cecere 1 , C. Giuliani 2 , A. Camerini 3 , G. Allegrini 4 ,
F. Martella 5 , L. Boni 6 , F. Torricelli 2 , F. Di Costanzo 1
1 Medical Oncology Unit, Azienda Ospedaliero Universitaria Careggi, Firenze,
ITALY, 2 Genetic Diagnosis Laboratory, AOU Careggi, Firenze, ITALY, 3 Medical
Oncology Unit, Versilia Hospital, Viareggio, ITALY, 4 Medical Oncology Unit,
Pontedera Hospital, Pontedera, ITALY, 5 Oncology Unit, Ospedale di S. Maria
Annunziata, Bagno a Ripoli, ITALY, 6 Centro Coordinamento Sperimentazioni
Cliniche, ITT-AOU Careggi, Firenze, ITALY
Introduction: Excision repair cross complementation group 1 (ERCC1) and
ribonucleotide reductase 1 (RRM1) expression levels are predictive of chemotherapy
(CT) efficacy in some malignancies. Customized CT has several advantages: patients
(pts) are more likely to be treated with agents that they will respond to, pts can be
spared the toxicity of agents that they are resistant to.
Methods: We planned a phase II multicentric trial in two steps based on Simon
design. Pts affected by advanced NSCLC are treated with first line CT according
to Single Nucleotide Polymorphisms (SNPs) of ERCC1 (T118C and C8092A)
and RRM1 (-37C > A and -524T > C), which are supposed to be correlated with
specific expression levels. CT is delivered as follow: treatment A (low ERCC1
and RRM1) Cisplatin plus Gemcitabine; treatment B (low ERCC1, high RRM1)
Cisplatin plus Docetaxel; treatment C (high ERCC1, low RRM1) Gemcitabine
plus Docetaxel; treatment D (high ERCC1 and RRM1) Docetaxel plus
Vinorelbine.
Results: Here we report the first step analysis for futility: 42 pts were enrolled from
January 2010 to November 2011; 40 pts received at least 1 cycle of CT; median age
was 66 years (range 47-72); 30(75%) pts were males; 21(52%) pts showed ECOG PS
0, 19(48%) PS 1; 36(90%) pts had stage IV and 4(10%) IIIB; 23(58%) pts had
adenocarcinoma, 14(35%) squamous, 3(7%) other types; 25(62%) pts received
treatment A, 3(8%) treatment B, 11(27%) treatment C, 1(3%) treatment D. As
primary end-point we assessed the overall best response and found a 55% response
rate (RR) [38.7 – 70.4, 95% CI] in the intention to treat population. Subgroups
analysis showed 46.2% RR in non squamous pts and 71.4% RR in squamous pts.
Secondary end-points were progression free survival (PFS), overall survival (OS) and
safety. The median follow-up time is 7.1 months, 12 pts did not show progression
disease and 23 pts are still alive, then data for PFS and OS are not mature. CT was
well tolerated: only 17(42%) pts showed grade 3-4 toxicity and there were no
treatment related deaths.
Conclusions: We observed an increase of RR in advanced NSCLC pts treated with
CT according to ERCC1 and RRM1 SNPs status, the treatment strategy overcomes
the first step of the study.
Disclosure: All authors have declared no conflicts of interest.
© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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