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

234s Gastrointestinal (Colorectal) Cancer
3625 General Poster Session (Board #37F), Mon, 8:00 AM-12:00 PM
Impact of “poorly differentiated clusters” in primary lesion as a novel
prognostic indicator in colorectal liver metastasis. Presenting Author:
Tsuyoshi Konishi, Gastroenterology Center, Cancer Institute Hospital,
Tokyo, Japan
Background: Preoperative predictors for survival are needed in colorectal
liver metastasis in order to select poor-risk group that truly requires
perioperative chemotherapy. This study aimed to elucidate survival predictors
in patients undergoing curative hepatectomy for colorectal liver
metastasis, particularly focusing on the impact of poorly differentiated
clusters (PDC); a novel histologic grading system in primary lesion.
Methods: A total of 424 consecutive patients undergoing curative resection
of both primary colorectal cancers and metastatic liver lesions at two
referral centers were enrolled in the study. Determinants of overall survival
(OS) and recurrence free survival (RFS) after hepatectomy were investigated
by univariate and multivariate analysis, using detailed clinicopathological
parameters in primary and metastatic lesions. Cancer clusters of �5
cancer cells and lacking a gland-like structure were counted under a x20
objective lens in a field containing the highest number of clusters at
invasive front of primary lesions, and tumors with �5,5to9,and�10
clusters were classified as PDC grade (G)1, G2 and G3, respectively (n�65,
132, and 227 tumors, respectively). Results: OS and RFS at 3 years were
59% and 27%, respectively, with average follow up period of 43 months.
PDC grade in primary lesion was strongly associated with both 3-year-OS
(83%, 62%, and 51%, respectively, p�0.0001) and 3-year-RFS (55%,
30%, and 17%, respectively, p�0.0001). Multivariate analysis revealed
that PDC grade in primary lesion was the most potent prognostic factor after
hepatectomy independent of T and N of primary lesion and size of liver
metastasis. Conclusions: PDC grade in primary lesion is a novel potent
prognostic indicator in colorectal liver metastasis, which is independent of
T and N. It is noteworthy that PDC grade can bias the survival in clinical
studies targeting perioperative chemotherapy in colorectal liver metastasis.
3627 General Poster Session (Board #37H), Mon, 8:00 AM-12:00 PM
Effect of BSA dosing on 5-FU exposure among colorectal cancer patients
depending on their gender and age. Presenting Author: Abebe Haregewoin,
Myriad Genetics, Inc., Salt Lake City, UT
Background: 5-fluorouracil (5-FU) remains the cornerstone of colorectal
cancer (CRC) therapy and its dosing is based on body surface area (BSA).
Although convenient, BSA dosing disregards factors that impact 5-FU PK
such as genotype, age, gender, etc. Thus, patients receiving the same BSA
based dose show a wide range of 5-FU plasma levels (measured as AUC in
mg · h/L), resulting in ineffective or toxic doses affecting therapy outcome.
An optimal therapeutic AUC target range of 20-30 mg · h/L has been
proposed. Methods: Plasma samples from the initial treatment cycle of 927
CRC patients who received 2,400 mg/m2 continuous infusion of 5-FU over
44-48 hours, with or without bevacizumab, were tested for 5-FU exposure
using an immune-based assay (OnDose). AUC results were analyzed to
evaluate gender and age effects. Results: There are 391 (42.2%) female
and 536 (57.8%) male patients with age ranging from 17-93 years
(mean/SD: 58.5/11.8). See table. These analyses indicate that in comparison
to the proposed optimal AUC target range of 20-30 mg · h/L, females
receive supra-optimal doses compared to males (p�0.0083). Age also
affects the 5-FU AUC (p�0.0002), with younger patients more likely to
receive suboptimal doses than older patients. Conclusions: BSA dosing is
an unreliable indicator of exposure and may lead to under dosing in males
and younger patients, and overdosing in females and older patients,
potentially resulting in corresponding diminished efficacy or increased
toxicity. Data suggest that therapy could be optimizedby 5-FU dose
adjustment in subsequent cycles based on PK monitoring so that AUC
values will converge towards the target range irrespective of gender or age.
A large clinical trial is in progress to validate these findings.
Patient characteristic
Below
(8 - 19 mg · h/L)
AUC target range
Within
(20 - 30 mg · h/L)
Above
(31 - 60 mg · h/L)
Gender
Female 169 (43.2%) 165 (42.2%) 57 (14.6%)
Male 272 (50.7%) 210 (39.2%) 54 (10.1%)
Age (years)
< 45 68 (56.2%) 43 (35.5%) 10 (8.3%)
46-50 60 (55.1%) 37 (33.9%) 12 (11%)
51-55 79 (57.7%) 45 (32.8%) 13 (9.5%)
56-60 66 (46.8%) 58 (41.1%) 17 (12.1%)
61-65 74 (47.1%) 69 (44%) 14 (8.9%)
66-70 41 (35.6%) 53 (46.1%) 21 (18.3%)
> 70 53 (36.1%) 70 (47.6%) 24 (16.3%)
3626 General Poster Session (Board #37G), Mon, 8:00 AM-12:00 PM
Effect of the 12-gene colon cancer assay results on treatment recommendations
in patients with stage II colon cancer. Presenting Author: Thomas H.
Cartwright, Ocala Oncology, Ocala, FL
Background: The Oncotype DX Colon Cancer Recurrence Score (RS) has
been clinically validated as an independent predictor of individual recurrence
risk in stage II colon cancer patients following surgery. As a result,
physicians have been ordering the Oncotype DX assay for stage II colon
cancer patients since January 2010, yet no data exist on the assay’s impact
on adjuvant treatment planning in clinical practice. We performed a survey
to characterize the impact of the assay on adjuvant treatment recommendations
in stage II colon cancer. Methods: U.S. medical oncologists (n�346)
who ordered Oncotype DX for �3 patients with stage II colon cancer were
contacted and asked to complete a web-based survey regarding the single
most recent stage II colon cancer patient for whom the assay was ordered.
The survey was developed through cognitive interviews with four medical
oncologists, and the protocol was institutional review board approved.
Results: We analyzed survey results from 116 eligible physicians. Physicians
were more often in community (86%) than academic or other
practices, and had a median of 14.5 years (range, 2-40) of practice
experience. The median patient age was 62 years (range, 32–85). Most
patients (81%) had T3 disease. Patients had �8, 9-11 and �12 nodes
examined 3%, 13% and 84% of the time and 38% had comorbidities. Of
the 76 patients tested for MMR/MSI, 13 (17%) were MMR-D or MSI-H and
46 (61%) were MMR-P or MSI-L; 17 (22%) unknown. Median RS was 20
(range, 1-77). Before obtaining the RS, chemotherapy was planned in 52
(45%) patients, observation in 40 (34%), and there was no recommendation
in 24 (21%). For the 92 patients with pre-assay recommendations,
recommended treatment changed after obtaining the RS for 27 patients
(29%). Treatment intensity decreased for 18 (67%) and increased for 9
(33%) of 27 changed recommendations. A significant trend of decreasing
treatment intensity with lower RS values was observed (p�.0035).
Conclusions: These findings indicate that for stage II colon cancer patients,
treatment recommendations were changed by RS results in 29% of
patients. Use of the Oncotype DX assay may lead to reductions in treatment
intensity, contributing to the assay’s cost effectiveness.
3628 General Poster Session (Board #38A), Mon, 8:00 AM-12:00 PM
Use of gene set analysis (GSA) for molecular classification of responders
and nonresponders to FOLFOX therapy in colorectal cancer (CRC). Presenting
Author: Stephen Yip, British Columbia Cancer Agency, Vancouver, BC,
Canada
Background: Folinic acid (FOL) fluorouracil (F) and oxaliplatin (OX) chemotherapy
is a commonly used therapy for CRC. Lacking in current literature
are clinically relevant classifiers for potential responders. GSA technique is
statistical method that detects significance of sets of genes, instead of
examining a gene-by-gene basis. The objective of this study was to identify
differential functionally annotated gene expression profiles associated with
response to FOLFOX therapy in CRC tumors using gene-by-gene and GSA
approaches. Methods: Genome wide expression profile data were collected
on pre-treatment tumor tissues from patients with unresectable CRC
receiving FOLFOX therapy (n � 83, Affymetrix HG U133A, GSE28702,
Tsuji et al. BJC 2012). Gene expression was compared between responders
(n � 42) and Non-responders (n � 41). GSA was conducted on 3272
curated gene sets from the Molecular Signatures Database (Subramanian,
Tamayo et al. 2005, PNAS 102, 15545-15550) annotated by biological
pathway, biochemical function and clinical behavior. Significant analysis
of Microarray (SAM) and GSA (Tibshirani et al.) was done to identify gene
sets associated with FOLFOX response. Results: Differential expressions of
23 genes were significantly associated with response, based on a single
gene approach (p-value � 0.05). 13 of these were located on Chromosome
17 (p � 0.001). Among these, the top 5 ranked genes included NPEPPS,
MBTD1, CEP44, LTA4H and CPNE4 which are involved in metal ion
binding and aminopeptidase activity. GSA revealed only 44 out of 3272
gene sets were significantly associated with response, with a false discovery
rate less than 25%. Increased expression of B-lymphocyte differentiation
and Ras-signalling-related gene sets was associated with responders while
mTOR signaling and hematopoietic stem cell-related genes set were
associated with non-responders. Conclusions: Our data showed that differential
biological pathways could be identified to predict response to
FOLFOX therapy for CRC patients. Analysis may be useful to help define
clinically relevant biologic subtypes among patients with metastatic colorectal
cancer.
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