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

270s Gastrointestinal (Noncolorectal) Cancer
4128 General Poster Session (Board #51G), Mon, 8:00 AM-12:00 PM
Prognostic relevance of circulating PIGF levels in patients with neuroendocrine
tumors. Presenting Author: Christian Fischer, Charité-Universitätsmedizin,
Berlin, Germany
Background: Placental growth factor (PlGF), a VEGF homolog implicated in
tumor angiogenesis and adaptation to antiangiogenic therapy, is emerging
as candidate target in malignancies. As antiangiogenic treatments are
introduced in the management of neuroendocrine tumors (NETs), we
addressed the expression and function of PlGF in NETs. Methods: Serum
levels of PlGF were determined in two independent cohorts of NET patients
collected retrospectively and prospectively (n�87 and n�84) using Roche
Elecsys and correlated with clinical data. Expression of PlGF in tumors was
evaluated by immunohistochemistry. PlGF effects on proliferation and
migration were examined in vitro using NET cell lines. Results: Circulating
and tumoral PlGF were found elevated in NET patients as compared to
control sera and pancreatic tissues in a retrospective analysis restricted to
patients with pancreatic NETs (pNETs). De novo expression of PlGF
occurred primarily in the tumor stroma, suggesting paracrine stimulatory
circuits. Indeed, PlGF enhanced proliferation and migration of NET cells,
and elevated circulating PlGF levels correlated with advanced tumor
grading, suggesting that PlGF supported a more aggressive phenotype. In
line with this notion, circulating PlGF levels above median predicted
reduced tumor related survival in pNET patients (p�0.012). Furthermore,
pathologic PlGF levels were associated with poor prognosis within the
subgroup of grade 2 tumors. Subsequent prospective PlGF determinations
confirmed and extended our observation of elevated PlGF levels for both,
pNETs (n�32, p�0.001) and midgut NETs (n�58, p�0.001). Since
median follow up was too short to determine survival, time to progression
(TTP) was analyzed instead. Most pNETs were progressive at the time of
sample collection, precluding an informative evaluation of TTP in this
subgroup. However, PlGF levels above median were correlated with shorter
TTP in midgut NETs (p�0.0091; TTP 27 months versus undefined, HR
3.802). Conclusions: These data assign to PlGF a novel function in the
pathobiology of NETs and propose PlGF as a prognostic parameter in
patients with NETs.
4130 General Poster Session (Board #52A), Mon, 8:00 AM-12:00 PM
Patients with carcinoma of unknown primary and “colon cancer profile”:
Clinicopathologic features and survival data. Presenting Author: Gauri R.
Varadhachary, University of Texas M. D. Anderson Cancer Center, Houston,
TX
Background: We have previously proposed a “colon cancer profile” (CCP-
CUP) favorable subset. CCP-CUP is ~ 8% of all CUP with features
resembling lower gastroinestional cancers. Distinguishing this entity from
other CUP pts is of significance given the progress in the treatment of
metastatic colorectal cancer (CRC). Additionally, emerging data suggests a
high level of agreement between histology�IHC and tissue of origin
profiling for CCP-CUP. Methods: The retrospective cohort includes 74 pts
from MD Anderson (50) and Sarah Cannon (24) Cancer Centers from 2004
-2010. Pts with CDX2� tumors and pathology suggesting a �GI profile�
were chosen. All pts met the definition of CUP and most had a negative
colonoscopy. Results: 2 cohorts were created - Cohort 1 (34 pts), labeled
“consistent with lower GI profile” [CDX2�, CK20�, CK7-] and Cohort 2
(40 pts), labeled “probable lower GI profile” [CDX2�, irrespective of
CK7/CK20 status]. Most pts had a good PS; 58% women, median age 59
yrs; 20 (27%) pts had ascites on presentation and the predominant sites of
metastases included liver (30%), carcinomatosis (50%), and nodes (51%).
53 pts received first line CRC regimens (FOLFOX or FOLFIRI based), 15 pts
received gemcitabine or taxane based and 3 ‘other’ regimens. OS was 37
mo (C.I 22- 52). 6 of these were �outliers� (Stage 4 NED or indolent
pathology). Excluding these, cohorts 1 and 2 had 32 and 36 pts - their OS
were 37 and 21 mo respectively. There was no difference in OS of pts with
or without ascites on presentation. Kras data was available for 17; 12 were
Kras mutant. On multivariate analysis, the factors found to negatively
influence survival were age, PS (of 2) and 3 or more sites of disease.
Conclusions: Survival of IHC defined CCP-CUP pts (which may include
colorectal, appendiceal and small bowel profile) exceeds historical control
and illustrates a new �favorable� subset. IHC is not without its limitations –
nonetheless, pts with CDX2 � tumors and CUP should undergo evaluation
for GI cancers and likely best served with an armamentarium of drugs used
for CRC. Since carcinomatosis and liver mets are predominant sites, all
patients with abdominal CUP should undergo optimal IHC (CDX-2, CK7,
and CK20) testing to rule out a CCP-CUP.
4129 General Poster Session (Board #51H), Mon, 8:00 AM-12:00 PM
Well-differentiated grade 3 digestive neuroendocrine tumors: Myth or
reality? The PRONET study group. Presenting Author: Jean-Yves Scoazec,
Hôpital Edouard Herriot, Lyon, France
Background: In contrast to the 2000 World Health Organization (WHO)
classification of digestive neuroendocrine tumors (NET) in which morphologic
differentiation was the first criterion, the 2010 WHO classification of
NET is based mostly on histologic grade. NET are now classified into three
main categories: NET G1 (mitotic count �2/10 HPF and/or �2% Ki67
index), NET G2 (2-20/10 HPF and/or 3-20%), and neuroendocrine
carcinoma (NEC) of small or large cell type. While NET G1 and G2 are
well-differentiated tumors, NEC are considered poorly differentiated G3
tumors. We looked at the agreement between grade and differentiation to
determine whether all NET can be readily classified according to the 2010
WHO classification. Methods: We designed a 1-year prospective, epidemiologic
study to assess the characteristics of newly diagnosed NET, including
diagnostic pathology. From August 2010 to July 2011, all pathology
laboratories in France were invited to register all incident cases of
gastroenteropancreatic (GEP) and thoracic NET, excluding small cell
carcinoma. For GEP-NET, investigators were asked to indicate morphologic
differentiation (according to WHO 2000) and elements of histologic grade
(mitotic index, Ki67 index), according to ENETS. Results: Of 500 invited
centers, 80 participated; 1417 incidental cases were included and 77
excluded (duplicates or exclusion criteria), totaling 1340 cases; 778
(58.1%) were GEP-NET; 660/778 (85%) were well differentiated, 72 (9%)
poorly differentiated, and 46 (6%) adenocarcinoid, nonclassified, or not
evaluable; 422 (54.2%) were G1, 220 (28%) G2, 104 (13.5%) G3, and
32 (4.1%) had missing grades. Of those deemed G3, 72 (69%) were
described as poorly differentiated, 21 (20%) as well differentiated (mean
Ki67 index 35%, range 25%-60%), and 11 (10.5%) as adenocarcinoid.
Conclusions: In this prospective, epidemiologic study, overall agreement
between grade and differentiation was good. However, a significant
proportion of G3 NET were classified as well differentiated and thus
unclassifiable by 2010 WHO classification. This group of tumor deserves to
be included in future classifications to help the clinician decide whether
they should be treated as NET G1/G2 or NEC G3.
4131 General Poster Session (Board #52B), Mon, 8:00 AM-12:00 PM
Mutation profling in patients with carcinoma of unknown primary using the
Sequenom MassARRAY system. Presenting Author: Katherine Stemke
Hale, University of Texas M. D. Anderson Cancer Center, Houston, TX
Background: CUP management may be viewed as an epitome of personalised
medicine as we apply our understanding of biological markers to this
heterogeneous disease. There is a significant interest in evaluating actionable
mutations in various signaling pathways, receptors and downstream
effectors in CUP that may help us understand its biology and serve as the
basis for unique targeted therapeutic approaches. Sequenom (SQM)
Massarray platform enables rapid mutation profiling in solid tumors which
we applied to CUP. Methods: 83 CUP samples were sent for DNA mass array
analysis. Sequenom was run on 60 samples; 23 samples lacked sufficient
quantity or quality of DNA. Data on clinicopathological features was
collected. Results: Of the 60 patient samples run on SQM, 16 patients had
changes including 11 mutations and 6 polymorphisms . The 6 polymorphisms
were in MET . The mutations reported were :RAS (7; 6 KRAS, 1
NRAS), IDH1 (2), PI3K (1) and MET (1). Atleast 50% of the tumors were
poorly differentiated. Interestingly, the 2 patients with IDH1 mutations
presented with osseous predominant metastatic disease. Of the 6 patients
with KRAS mutations, 4 presented with a gastrointestinal profile ( CDX2�
or CK20�) on IHC; in all 4, the DNA sequencing analysis results matched
the sequenom results. Conclusions: The (all-comers) overall mutation rate
in a heterogenous CUP population is low (11/60, 18%). No �new� low
frequency mutations were found using the current panel (Table). Rare and
potentially targetable mutations may be identified with a larger panel.
Focusing on CUP subsets using this approach may also provide a higher
mutational yield.
P13K/AKT pathway MEK pathway Receptors Downstream effectors
AKT1, 2, 3 BRAF EGFR CDK4
PIK3CA KRAS ALK CTNNB1
PHLPP2 MEK1,2 KIT IDH1,2
FRAP (mTOR) NRAS MET JAK2
RICTOR PRKAG1/2 PDGFRA RET
PDPK1 BRAF FLT3
PIK3R1 TNK2(ACK1)
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