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

374s Head and Neck Cancer
5572 General Poster Session (Board #27B), Sat, 1:15 PM-5:15 PM
Correlation between PI3K/PTEN/AKT/mTOR pathway genetic variations
and clinical outcome in patients with squamous cell carcinoma of the head
and neck receiving cetuximab-docetaxel treatment. Presenting Author:
Alberto Fusi, Department of Hematology and Medical Oncology, Charité,
CBF, Berlin, Germany
Background: The PI3K/PTEN/AKT/mTOR pathway is one of the most
targeted in human cancers and alterations in the axis are frequent events in
squamous cell carcinoma of the head and neck (HNSCC). Specific genetic
variations in this pathway have been associated with variation in recurrence,
survival and response in lung cancer and esophageal cancer. The
aim of this study was to determine whether single nucleotide nucleotide
polymorphisms (SNPs) in AKT1, AKT2, FRAP1, PI3KCA and PTEN
identified in other cancers were associated with treatment response and
clinical outcome in patients with HNSCC. Methods: Genomic DNA was
extracted from FFPE tissue specimens of 45 patients with recurrent or
initially metastatic HNSCC who received a combined treatment with
docetaxel and cetuximab in a phase II study. Eleven single SNPs in the
genes AKT1, AKT2, FRAP1 (mTOR), PIK3CA and PTEN were genotyped by
means of Real Time PCR system or by direct sequencing and analysed for
association with response to therapy and survival. Results: None of the
SNPs was related to treatment response. Two SNPs (AKT2:rs8100018 and
PTEN:rs12569998) were associated with variation in progression risk. The
AKT2:rs8100018 homozygous variant resulted in increased risk, with a HR
of 4.83 (95% CI, 1.11-21.03) and the PTEN:rs12569998 homozygous
variant in an increased risk, with a HR of 2.36 (95% CI, 1.24-4.50).
AKT2:rs8100018 and PTEN:rs12569998 genetic variation had an additive
effect on risk of tumor progression. The AKT2:rs8100018 homozygous
variant was significantly associated with overall survival (OS) with HR of
3.57 (95% CI, 1.06-12.00) while presence of one of the two variant alleles
of AKT1:rs3803304 with a lower risk of death (HR: 0.51; 95% CI,
0.27-0.97). Conclusions: We found significant associations between common
genetic variants in the PI3K/PTEN/AKT/mTOR pathway and outcome
in patients with HNSCC. Despite the small sample size, patient cohort and
treatment were homogeneous. As a consequence, evaluation of SNPs as a
host factor may be considered in addition to tumor-specific mutations for
personalized treatment development.
5574 General Poster Session (Board #28A), Sat, 1:15 PM-5:15 PM
Genetic alterations in HRAS gene in relation to outcome and response to
cetuximab in head and neck squamous cell carcinoma. Presenting Author:
Theodoros Rampias, Yale University School of Medicine, New Haven, CT
Background: Aberrant signaling through RAS/MAPK pathway is implicated
in resistance to EGFR-targeted agents in cancer. Genetic alterations in
Hras gene such as mutations and specific polymorphisms are associated
with aggressive phenotype in several smoking-related malignancies. We
sought to determine the impact of Hras genetic alterations on response to
cetuximab and prognosis in HNSCC. Methods: Clinical outcome according
to Hras status was investigated in a retrospective cohort of 140 HNSCC
specimens. Primary endpoints were overall survival (OS) and disease-free
survival (DFS) and secondary endpoint was treatment response. For
statistical analysis, T-test was used for continuous data and x2 –test for
categorical data. Cetuximab-resistant cell lines harboring mutant Hras
(BB49, T24) were infected with lentivirus expressing shRNA targeting the
Hras or a scrambled- shRNA. MTT assay was used to determine the effect of
cetuximab on growth of lentivirus infected cells. Biochemical analysis
involved immunoblotting for pERK1/2. Results: Mutationanalysis of tumor
samples showed that 5.7% participants harbored Hras mutations and
16.42% harbored Hras polymorphisms (rs12628, rs41258054) that are
associated with tumorigenesis. Patients bearing tumors with mutated Hras
had inferior mean OS ( 22.13vs 35.20, p�0.02) and a non-significant
trend for inferior mean DFS. Patients with tumors containing Hras genetic
alterations (mutation or polymorphism) had significantly inferior mean OS
(p�0.02) compared to those harboring wt Hras and trended towards
inferior DFS (p�0.07). Patients had received various treatments such as
surgery plus/minus RT and various chemotherapy regimens. A subgroup
analysis of 38 patients treated with cetuximab-based regimens showed that
wt Hras was associated with higher likelihood of attaining CR or PR to
treatment of borderline significance (p�0.06) due to small sample size.
Silencing of Hras in Hras-mutant cell lines restored sensitivity to cetuximab
and caused a direct downregulation of pERK1/2 levels. Conclusions: Hras
genetic alterations are associated with aggressive clinical course and may
affect response to cetuximab in HNSCC.
5573 General Poster Session (Board #27C), Sat, 1:15 PM-5:15 PM
Correlation of microbiomic profiles with disease status and MDR1 methylation
in head and neck squamous cell carcinoma (HNSCC). Presenting
Author: Pauline Funchain, Cleveland Clinic, Cleveland, OH
Background: Recent studies of the aerodigestive tract have uncovered the
functional importance of the microbiome, the total collection of microorganisms
that reside within the human host. Furthermore, specific bacterial
species have been shown to be etiologic agents or show potential as a
screening biomarker in cancers including gastric, colon and pancreas.
Here, we hypothesize that specific microbial populations may contribute to
HNSCC pathogenesis via epigenetic modifications in inflammatory- and
HNSCC-associated genes. Methods: Matched tumor and adjacent normal
fresh frozen tissue specimens were collected from 55 prospectively
enrolled HNSCC patients. Microbiomic profiles were obtained using Sanger
sequencing of 16S rDNA PCR products. Methylation status of four genes
previously linked to HNSCC or inflammation (MDR1, IL8, RARB, TGFBR2)
was assessed in 49 samples by combined bisulfite restriction analysis and
by Illumina HumanMethylation27 chip. Principle component analysis and
multivariate analysis of covariance (MANCOVA) were used to identify
bacterial subpopulations significantly associated with HNSCC and relevant
clinical variables. Results: In this cohort, median age is 62, male:female
ratio is 3:2, 16% are HPV�. Specific bacterial subpopulations associate
with HNSCC over normal tissue and correlate with larger tumor size and
higher nodal stage (p�0.05). Furthermore, microbial populations can
separate tumors by tobacco (p�0.005) but not alcohol (p�0.7) status.
Bacterial profiles are independent of HPV status. MDR1 promoter methylation
is seen in tumor samples but not in normal oral mucosa (22/49 vs
0/49), and associates with specific microbiomic subpopulations in the
order Enterobacteriales and phylum Tenericutes (p�0.001). Additionally,
MDR1 methylation correlates with regional nodal metastases. Conclusions:
Specific bacterial subpopulations differ between normal and tumor tissue
and show association to specific clinicopathologic features, suggesting a
role for microbial profiling in HNSCC as a novel area of investigation for
diagnosis, prognostication, and therapeutic targeting.
5575 General Poster Session (Board #28B), Sat, 1:15 PM-5:15 PM
Identification of head and neck cancers (SCCHN) that may respond to dual
inhibition of EGFR and HER3 signaling. Presenting Author: David S.
Shames, Genentech, South San Francisco, CA
Background: Oncogenic signaling through the epidermal growth factor
receptor family is one of the most frequent alterations found in human
epithelial cancers. These receptor tyrosine kinases mediate their effects via
high-level co-expression and homo- and heterodimerization events that
drive tumor growth, metastasis, and survival. Extensive preclinical studies
suggested that some cell lines depend on oncogenic autocrine signaling
through HER3 (Wilson et al.). This phenotype was particularly prominent in
cell lines derived from SCCHN and was strongly correlated with high HRG
expression. Interestingly, two patients with SCCHN tumors that expressed
high levels of HRG in our phase Ia trial (abstract #95245) of MEHD7954A,
a dual-action human IgG1 antibody that blocks ligand binding to EGFR and
HER3 (Schaefer et al.) had partial responses. To further explore the
hypothesis that high-level HRG expression defines a sub-population of
SCCHN that may be sensitive to agents targeting HER3, and to identify
other potential target indications for the development of MEHD7954A, we
evaluated the expression of HRG in large cohorts of multiple solid tumor
indications. Methods: HER3 and HRG expression was analyzed by qRT-PCR
in 648 formalin-fixed paraffin embedded primary tumor samples from
patients with NSCLC, SCCHN, melanoma, CRC and triple-negative breast
cancer. Results: SCCHN-derived tumor samples had the highest levels of
HRG expression, exhibiting a bimodal distribution in SCCHN – a pattern
that is clearly distinct when compared to other tumor types. These data
suggest that high HRG levels and potentially HER3-dependent autocrine
signaling occur more frequently in SCCHN than in other tumors. Further we
investigated whether overexpression of HRG in SCCHN correlated with
stage and disease outcome. Updated results from these extended studies
will be presented. Conclusions: SCCHN tumors exhibit bimodal expression
of HRG, suggesting that HRG expression levels may be useful in identifying
a subset of patients most likely to benefit from inhibition of HER3 activity.
Antitumor activity in such patients has been observed in a phase I study of
MEHD7954A (abstract #95245).
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