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

3621 General Poster Session (Board #37B), Mon, 8:00 AM-12:00 PM
Colorectal cancer characteristics and outcomes in patients less than age
50: A comparison of an urban university hospital with the NCI SEER
database. Presenting Author: Edith P. Mitchell, Kimmel Cancer Center at
Thomas Jefferson University, Philadelphia, PA
Background: Cancer of the colon and rectum is the third most commonly
occurring cancer, as well as the third leading cause of cancer deaths in
American men and women. Colorectal cancer in younger patients is
believed to have worse pathological features and prognosis than in older
patients. The objective of this study was to assess pathological features and
outcomes of CRC in patients less than age 50 using an institutional sample
and comparing to the Surveillance, Epidemiology and End Results (SEER)
database. Methods: Included in the study were a total of 4595 cases from
the Tumor Registry at Thomas Jefferson University Hospital (TJUH) over a
twenty year period from 1988 through 2007 and 290,338 cases from the
Surveillance, Epidemiology and End Results (SEER) database from 1988
through 2004. Patients less than age 50 were compared to those age 50
and older. Results: Patients under age 50 with CRC presented with more
advanced stage tumors in both data sets (�0.0001) , and had more poorly
differentiated tumors than older patients (PTJUH�0.02754; PSEER�0.0001). Patients under 50 also had more mucinous/signet ring
cell tumors with 12 percent to 8.1 percent in the TJUH data (p�0.002916)
and 13.2 percent to 10.3 percent in the SEER data (p�0.0001), with
younger males having the highest prevalence in both data sets. Younger
patients had fewer proximal tumors than patients 50 and over, and a higher
proportion of rectal tumors (p�0.001). Patients under age 50 were more
likely to have positive nodes at all stages (PSEER �0.0001) relative to 50
and over, as well as more likely to develop peritoneal metastases
(PTJUH�0.3507),, but less likely to have lung metastases PTJUH�0.05249) than older pts. Despite their poor pathologic features, patients under age
50 had better than or equal survival to those 50 and older. Conclusions:
Colorectal cancer patients under age 50 presented with worse histological
characteristics and metastasized much sooner, yet the younger patients
had better than or equal survival to those ages 50 and older. Ongoing
studies will assess differences in treatment and molecular features between
younger and older colorectal cancer patients.
3623 General Poster Session (Board #37D), Mon, 8:00 AM-12:00 PM
Clinicopathologic and molecular associations of PIK3CA and PTEN mutation
in colorectal cancer. Presenting Author: Fiona Lee Day, Ludwig
Institute for Cancer Research, Parkville, Melbourne, Australia
Background: The phosphatidylinositol 3-kinase (PI3K) signaling pathway
has been implicated in the development of colorectal cancer (CRC),
however a systematic analysis of pathway members and their association
with clinical, pathological and other molecular features has been lacking.
Methods: We determined the prevalence of PIK3CA (exons 9, 20) mutations
in a large cohort (n�1092) of community-based patients (pts) with stage
I-IV CRCs. A subset (n�744, 68%) were also tested for mutation in PTEN
(exons 3,4,5,6,7,8), PTEN LOH and CIMP. All tumors were characterised
for MSI, KRAS and BRAF mutations, and annotated for clinico-pathologic
features and patient outcomes in a prospectively-recorded database.
Detected novel PIK3CA exon-specific correlates were further explored in a
combined analysis integrating the data of other published cohorts (total
n�3677). Results: PIK3CA mutations occurred in 11.6% of primary
tumors and were associated with older pt age (p�0.009), proximal site
(p�0.001), lower lymphovascular invasion (p�0.018) and KRAS mutation
(p�0.001), but not with gender, tumor stage or differentiation. Direct
comparison of PIK3CA exon 9 and 20 mutations in the combined analysis
(mixed effect logistic regression) finds both at increased frequency in
KRAS-mutant tumors (p�0.098 for difference); however PIK3CA exon 20
mutations uniquely correlated with BRAF mutation (p�0.002 for difference),
MSI (p�0.001) and CIMP-high status (p�0.031). PTEN mutations
were present in 5.8% of tumors and associated with proximal site
(p�0.013), mucinous histology (p�0.013), MSI (p�0.001), CIMP-high
(p�0.001), and BRAF mutation (p�0.001). There was a trend toward
mutation of both PIK3CA and PTEN and strong selection for two hits to
PTEN (mut/mut or mut/LOH, p�0.001). In our cohort neither PIK3CA or
PTEN mutation were associated with pt survival outcomes. Conclusions: In
CRC, common mutations in the PI3K signaling pathway are universally
associated with proximal site, however display unique gene- and exonspecific
associations with tumor histology, MSI, CIMP, KRAS and BRAF
mutation. These need to be considered when exploring targeted therapeutic
options for pts with CRC.
Gastrointestinal (Colorectal) Cancer
233s
3622 General Poster Session (Board #37C), Mon, 8:00 AM-12:00 PM
Novel colon cancer tumor suppressor gene, �-defensin 1, to predict
recurrence in patients with stage II and III colon cancer. Presenting Author:
Melissa Janae Labonte, University of Southern California Norris Comprehensive
Cancer Center, Los Angeles, CA
Background: Human �-defensin 1 (hBD-1) encoded by the DEFB1 gene is
an antimicrobial peptide involved in the innate immune response and is
expressed in epithelial cells, including the colon. hBD-1 has been shown to
have tumor suppressor functions in urothelial cancer models. We tested
whether 4 germline single nucleotide polymorphisms (SNPs) in DEFB1
could predict time to tumor recurrence (TTR) in stage II and III colon
cancer (CC) patients. We then sought to demonstrate if hBD-1 has tumor
suppressor functions in CC models. Methods: A total of 234 patients, 105
stage II and 129 stage III, treated with 5-FU-based chemotherapy at the
University of Southern California were included. The median follow-up time
was 4.4 yrs. SNPs were analyzed from whole blood samples using direct
DNA-sequencing. To gain insight into hBD-1’s function, hBD-1 expression
in CC cell lines was determined by qRT-PCR and Western blotting. hBD-1
expression was induced ectopically and CC cells and viability, membrane
permeability, cell-cycle and apoptosis analyzed. Results: Stage III patients
with rs1800972 DEFB1 -44G containing genotypes had longer TTR than
patients with C/C genotype (11.3 mo vs 2.7 mo; p�.008). In contrast in
stage II, patients with rs1799946 DEFB1 -52A containing genotypes, had
significantly longer TTR than patients with G/G genotype (16.8 mo vs 5.9
mo; p�.017). In the multivariate analysis, both DEFB1 -44C/G and DEFB1
-52G/A SNPs remained significant, respectively in stage III (HR�.419;
95%CI .201-.87; p�.020) and in stage II (HR�.360; 95%CI .152-.853;
p�.020). Haplotype of all four SNPs was significantly associated with
stage-specific TTR (to be presented at the meeting). In CC cell line models,
there was a loss of hBD-1 expression, and induction of hBD-1 expression
resulted in a loss of cell viability, membrane permeability and the induction
of apoptosis. Conclusions: The results demonstrate for the first time
evidence of hBD-1’s potential influence on the microenvironment and its
role as a tumor suppressor in CC. Further studies need to be conducted to
better understand the role of hBD-1 in CC development and progression
and evaluate the potential utility of hBD-1 as a therapeutic strategy.
3624 General Poster Session (Board #37E), Mon, 8:00 AM-12:00 PM
Methylations of NEUROG1, p16, and MLH1 and recurrence following
adjuvant FOLFOX in colorectal cancer. Presenting Author: Hyun-Jung Lee,
Department of Internal Medicine, Seoul National University Hospital,
Seoul, South Korea
Background: CpG island methylator phenotype (CIMP) is characterized by
concurrent methylation of multiple CpG islands in tumor DNA, which can
inactivate tumor suppressor genes or promote carcinogenesis. The prognostic
impact of CIMP on treatment outcome of colon cancer patients receiving
adjuvant 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) is unclear. We
investigated CIMP markers in colorectal cancer patients treated with
adjuvant FOLFOX. Methods: Sporadic colorectal cancer patients treated
with curative resection followed by adjuvant FOLFOX were included. DNA
was extracted from formalin-fixed paraffin-embedded surgical specimen. 8
CpG island loci (CACNA1G, CRABP1, IGF2, MLH1, NEUROG1, P16,
RUNX3 and SOCS1) were examined using MethyLight analysis. Diseasefree
survival (DFS) was evaluated according to each methylation loci.
Results: A total of 322 patients were included. Methylation at 1 or more loci
was observed in 150 patients (46.6%) and 6 or more loci in 15 (4.7%).
During a median follow-up duration of 39.7 months, 55 recurrences were
observed. Three year DFS in the patient cohort was 84%. CRABP1 (23.9%)
was the most frequently methylated loci, followed by p16 (22.7%) and
NEUROG1 (20.8%). Patients having methylation at NEUROG1 (3 year
DFS 78% in (�) vs. 86% in (-), p � 0.014) and p16 (3 year DFS 78% in
(�) vs. 86% in (-), p � 0.12) had worse DFS, whereas methylation at MLH1
had better DFS (3 year DFS 100% in (�) vs. 86% in (-), p � 0.19). In a
combined analysis, patients with MLH1(-)/NEUROG1(�)/p16(�) had
worst treatment outcome compared to MLH1(-)/NEUROG1(�) or p16(�),
MLH1(-)/ NEUROG1(-) /p16(-), and MLH1(�) (3 year DFS 62%, 82%,
87%, and 100%, respectively; p � 0.002). In multivariate analysis,
NEUROG1(�)/p16(�) was associated with significantly higher recurrence
compared with other patients (adjusted hazard ratio (HR) 2.15 (95%
confidence interval (CI) 1.08 - 4.27, p � 0.029). Conclusions: Methylation
status of NEUROG1, p16, and MLH1 is associated with recurrence
following adjuvant FOLFOX in stage II/III colorectal cancer. Further
validation and translational studies to improve treatment outcome in the
subset of patients are warranted in the future.
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