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

10076 General Poster Session (Board #51E), Sun, 8:00 AM-12:00 PM
Study of the expression of integrin pathway’s proteins as predictive markers
of response to neoadjuvant chemotherapy in pretreatment biopsies of
patients with high-grade osteosarcoma. Presenting Author: Elizabeth Laurence
Cohen-Jonathan Moyal, Institut Claudiusr Regaud-INSERM 1037,
Toulouse, France
Background: Up to now, chemosensitivity to neoadjuvant chemotherapy
performed for patients with osteosarcoma is evaluated on the surgical
resection by the evaluation of the percentage of necrotic cells. No
predictive profile of chemotherapy has been described yet. Because we
have previously shown that integrin pathway controls genotoxic-induced
cell death and hypoxia via ILK, FAK and RhoB, we hypothesized that the
expression of the proteins involved in this pathway in pre-treatment
biopsies could be associated with sensitivity to chemotherapy in osteosarcoma.
Methods: We studied by immunohistochemistry �1, �3, �5, integrins,
ILK, FAK, GSK-3�, RhoB and Ang-2 expression in 36 osteosarcomas
biopsies of patients obtained before treatment. All the patients were
treated by the SFOP OS94 chemotherapy protocol and underwent wide
conservative surgery. Response to preoperative chemotherapy was assessed
on the surgical resection by the Rosen’s protocol. An immunoreactive
score (IRS) was assessed, combining the percentage of positive tumour
cells and staining intensity. We evaluated the correlation of the selected
markers expression with response to preoperative chemotherapy and
clinical outcome. Results: FAK expression was statistically linked with ILK
expression (rho�0.43; p�0.020), �1integrin expression with FAK expression
(rho�0.51); p�0.003), RhoB with ILK expression (rho�0.55;
p�0.002), and �1 with �3integrin expression (rho�0.70; p�.001),
suggesting that a regulation of the integrin pathway that we studied might
exist in high grade osteosarcoma. Moreover, the combination of �5
integrin, FAK and GSK-3� discriminated good and poor responder to
chemotherapy (89.9%; 95% CI� [77.4;1.00], yielding a sensitivity of
94.1%, a specificity of 85.7% and a diagnostic accuracy of 90.3%.
Conclusions: We report for the first time a protein expression profile on
pre-treatment biopsies associating �5 integrin FAK and GSK-3� related
with a poor response to neoadjuvant chemotherapy. This profile could help
to select patients for clinical trials using inhibitors of this pathway in
association with chemotherapy.
10078 General Poster Session (Board #51G), Sun, 8:00 AM-12:00 PM
Primary localized gastrointestinal stromal tumors (GIST) of the duodenum:
Final results of a French Sarcoma Group (FSG) retrospective review of 110
patients (pts). Presenting Author: Thanh Khoa Huynh, University Hospital
La Timone, Marseille, France
Background: Duodenal GISTs represent 3-5% of all GISTs with limited
understanding of patient outcomes from small series. We conducted a
retrospective analysis of primary localized duodenal GISTs over the past 18
years. Methods: Pts were identified in two ways: a group of 101 pts reported
via survey from 20 FSG centers, and a group of 9 pts enrolled in the BFR14
trial. Results: Pts were:55 females, 55 males, with a median age of 57 years
(30-84), and median ECOG 0 (0-3). Abdominal pain, anemia, and GI
bleeding were the most common symptoms. Tumors (T) originated mainly
in D2 (41%), or D3 (27%), with a median size of 5 cm (1.5-30). All pts
except four had resection of the primary T. Surgical procedures were: local
resection (LR) [segmental duodenectomy (n�31), wedge local resection
(n�31), local excision (n�6)], and duodenopancreatectomy (DP, n�20).
Resections were R0 in 84 pts (79%), R1 in 6 pts (6%). T characteristics
included: KIT� (n�100), CD34 � (n� 54), mitoses/50 HPF � 5(n�70), or � 5(n�24), Miettinen low-risk (n�37), and high-risk (n�19), necrosis
(n�29), spindle cell (n�84). Genotype was evaluated in 36 cases: KIT
exon 11 mutant (n�30), no mutation (n�4), and KIT exon 9 mutant
(n�2). 12 pts received neoadjuvant imatinib (IM) therapy resulting in 6
PR, 3 SD, 1 PD. 17 pts received adjuvant IM therapy. With a median FU of
32 months (1-250), 95 pts (86%) are alive. Twenty-eight (26%) pts
relapsed: 6 LR, and 26 metastases. The 4-year OS and EFS rates were
89.5% and 68.2 %. The 6-year OS and EFS rates were 89.5% and 36.5%.
Univariate analysis showed that: age and ECOG PS have an impact on OS
(p� 0.008, p �0.001), necrosis, spindle-cell type, T size, mitoses/50
HPF, and Miettinen risk were predictive of relapse (p� 0.001). In
multivariate analysis tumor size and mitoses/ 50 HPF only were predictive
of relapse (p� 0.001). Conclusions: Pts with resected duodenal GIST have
a reasonably favourable prognosis. LR rather than DP should be pursued if
possible to preserve optimal pancreas function. Neoadjuvant IM may
potentially allow a proportion of patients requiring DP to undergo LR.
Adjuvant IM should be systematically discussed with a patient based on the
individual-risk of recurrence.
Sarcoma
649s
10077 General Poster Session (Board #51F), Sun, 8:00 AM-12:00 PM
Association of the genetic variants in the nucleotide excision repair genes
XPA and XPC with cisplatin-induced hearing loss in patients with osteosarcoma.
Presenting Author: Melanie M. Hagleitner, Radboud University
Medical Centre, Nijmegen, Netherlands
Background: Cisplatin is a widely used and effective chemotherapeutic
agent in the treatment of osteosarcoma. However, cisplatin-induced
ototoxicity is a serious problem, affecting more than 60% of patients and
compromising language and cognitive development. Unfortunately, individuals
at risk to develop ototoxicity cannot be identified upfront. Genetic
variants in genes involved in the metabolism of cisplatin may predispose to
cisplatin-induced hearing loss and help to identify patients at risk.
Methods: In a candidate gene pathway approach, we selected 224 SNPs in
30 candidate genes related to Platinum-DNA repair pathways and genotyped
for a discovery group of 105 patients with osteosarcoma for these
variants. Cisplatin-induced ototoxicity (n � 47), defined as the development
of grade 2–4 hearing impairment using Common Terminology Criteria
for Adverse Events (CTCAE version 3), showing a hearing loss of �25 dB at
frequencies of 4–8 kHz, was associated with genetic variation. A replication
study was performed in a independent cohort of 51 patients with
osteosarcoma. Genotyping was performed using the Illumina GoldenGate
assay. Association analysis and meta-analysis were performed using the
whole genome association analysis toolset PLINK. Results: In the discovery
cohort a total of 13 SNPs were significantly (p value � 0.05) associated
with ototoxicity. Upon meta-analysis, addition of the replication set
resulted in lower p-values for 2 SNPs. The two SNPs showing a strong
association with hearing loss in patients with osteosarcoma were rs2805835
in the gene XPA (p-value 0.01, OR�2.7 (95%CI: 1.20-6.15) and
rs2227999 in XPC (p-value 0.02; OR�3.2 (95% CI:1.19-8.80).
Conclusions: The Nucleotide Excision Repair (NER) genes XPA and XPC
form an important molecular mechanism by which cisplatin DNA adducts
can be repaired and it has recently been shown that these genes have a high
expression in the cochlea. Our data suggest that genetic variants in these
genes, may contribute to cisplatin ototoxicity. This study should be viewed
as the first step in the development of genetic markers to predict
cisplatin-induced ototoxicity in individual patients.
10079 General Poster Session (Board #51H), Sun, 8:00 AM-12:00 PM
Relationship of CUL4A gene underexpression and prognosis in localized
high-risk soft tissue sarcoma (STS) patients of limbs or trunk wall.
Presenting Author: Javier Martin Broto, Hospital Universitario Son Espases,
Palma de Mallorca, Spain
Background: Genes involved in cell cycle checkpoints and chromosome
stability seem to be relevant in distant metastases appearance in STS.
CUL4A is an E3 ubiquitin ligase that has been related to both p16
activation and maintenance of genomic stability. Expression of CUL4A has
been scarcely described in some tumors with divergent outcome and there
are no publications regarding its expression in STS patients. We previously
showed that protein underexpression of CUL4A in metastatic STS was
related to poor survival. Methods: The expression level of CUL4A was
determined by quantitative qPCR and was retrospectively performed in a
subset of 39 high-risk (grade 3, deep tumours and � than 5 cm) localized
STS of limbs or trunk wall patients for which histological material and
clinical data were available. Patients of this series were enrolled prospectively
into a randomized clinical trial conducted by the Italian and Spanish
sarcoma groups (ISG-GEIS 0101) comparing 3 vs 5 cycles of epirrubicin
and ifosfamide. Differences in PFS, RFS, and OS were calculated using
log-rank test Results: The median age was 51 years with a median follow-up
of 52 months. The pathologic subtypes were undifferentiated pleomorphic
sarcoma (35.3%), synovial sarcoma (23.5%) and mixed subtypes (41.2%).
Location was distributed as inferior limbs (66.6%), upper limbs (25.5%)
and trunk wall (7.9%). No relationship was seen between CUL4A expression
and clinical variables (histologic types, location, size or response to
neoadjuvant treatment). The expression level of CUL4A was significantly
associated with events of progression, 65% vs 32%, p �0.037, for
expression values under and over the median respectively. Regarding 4 y
actuarial survival, there was a significant worse PFS and RFS for patients
underexpressing CUL4A (p�0.041 and 0.009 respectively) and a trend
towards worse OS (p�0.056). Conclusions: Expression of CUL4A gene
shows a prognostic role in sarcomas within this high risk localized subset of
STS patients. The outcome of this exploratory analysis is aligned with our
hypothesis that genes implicated in cell cycle regulation and chromosome
stability could play a relevant prognostic role in STS.
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