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

268s Gastrointestinal (Noncolorectal) Cancer
4120 General Poster Session (Board #50G), Mon, 8:00 AM-12:00 PM
Merkel cell polyomavirus in gastrointestinal neuroendocrine tumors. Presenting
Author: Salvatore Lorenzo Renne, European Institute of Oncology,
Milan, Italy
Background: Cutaneous Merkel cell carcinoma (MCC) is a high grade
neuroendocrine carcinoma potentially induced by Merkel Cell Polyomavirus
(MCPyV), a clonally integrated host in the tumor cell genome.
Integration of viral DNA and truncating mutations in the helicase domain of
the large T (LT) antigen, a protein implicated in the viral life cycle, have
been detected in all MCPyV associated MCCs. These results suggest a role
of the virus in tumor pathogenesis according to a two step model: a
necessary but not sufficient integration of viral DNA followed by LT antigen
premature truncations. Gastrointestinal neuroendocrine tumors (GI-NETs)
share common phenotypical features with MCCs, therefore we evaluated
whether MCPyVs may be present in GI-NET. Methods: Formalin–fixed and
paraffin-embedded samples from 14 cases of liver metastases of G2
GI-NETs, 9 small cell lung cancer (SCLCs) and 4 MCCs of the skin were
screened for MCPyV-DNA positivity using two PCR primer sets mapping the
LT antigen gene. Then to confirm the putative pathogenetic role of the
virus, we seeked for premature truncation of LT antigen by sequencing the
helicase portion using seven amplicons mapping 1356-2210 region of the
MCPyV complete genome (RefSeq: NC_010277.1). Results: Viral DNA was
detected in 7/14 GI-NETs, in 0/9 SCLCs and in 4/4 MCCs. We found a
premature stop codon truncating the helicase domain in two GI-NETs. Both
the patients had a rapid disease progression. We also found previously not
reported alterations in MCCs: a single aminoacid deletion in 3 cases and a
point mutation causing a single aminoacid substitution in another case.
Conclusions: For the first time the potential tumorigenic signature of MCPyV
has been detected in GI-NETs, suggesting a possible role in pathogenesis.
The study is ongoing to confirm these observations that could support new
diagnostic and therapeutical perspectives of a subset of GI NETs. Moreover
we have shown that the clonal integration of MCPyV in MCCs produces
different genetic alterations with unknown effects on cell biology.
4122 General Poster Session (Board #51A), Mon, 8:00 AM-12:00 PM
RAMSETE: A single-arm, multicenter, single-stage phase II trial of RAD001
(everolimus) in advanced and metastatic silent neuro-endocrine tumours in
Europe. Presenting Author: Marianne E. Pavel, Charite Universitatsmedizin,
Berlin, Germany
Background: The mammalian target of rapamycin (mTOR) signaling pathway
is involved in the pathogenesis of neuroendocrine tumors (NET).
Everolimus (RAD001), an oral mTOR inhibitor, has antitumor activity in
patients (pts) with advanced NET. In this open-label, multicenter, phase II
study (RAMSETE), the safety and efficacy of everolimus monotherapy was
evaluated in pts with advanced nonsyndromic, nonpancreatic NET. Methods:
Pts with advanced (unresectable or metastatic), progressive, nonsyndromic,
nonpancreatic NET received everolimus (10 mg/day) as monotherapy.
The primary endpoint was objective response rate (proportion of
pts with best overall complete response [CR] or partial response [PR] per
RECIST v1.0) by central radiologic review. A secondary endpoint included
progression-free survival (PFS). Results: By database soft lock (December
1, 2011), 73 pts from 16 European clinics received everolimus (median
duration of treatment: 193 days). Fifty-five (75%) pts discontinued;
reasons included disease progression (n�23), adverse events (AEs [n�23]),
withdrawal of consent (n�4), death (n�3), and protocol deviation (n�2).
In the per protocol population (N�60), 32 (53%) pts received prior
antineoplastic therapy. The best response by central review was stable
disease in 55%. By local review, 3 (5%) pts had a PR, with SD in 39 (65%)
pts. Median PFS by central review was 185 days (95% CI: 158-255).
Median PFS by local investigator review was 285 days (95% CI: 231-not
estimable). 69 (95%) pts reported treatment-related AEs of any grade,
including rash (n�28; 38%), diarrhea (n�20; 27%), mucosal inflammation
(n�18; 25%), and decreased appetite (n�17; 23%). Treatmentrelated
grades 3 and 4 AEs and serious AEs were reported by 27 (37%) and
18 (25%) pts, respectively.Conclusions: In this open-label trial of everolimus
in pts with advanced, nonsyndromic, extrapancreatic NET, a high rate
of disease stabilization was achieved after prior tumor progression with
favorable median PFS. This study further supports efficacy of everolimus in
types of NET other than those studied in RADIANT-3 (pancreatic NET) and
RADIANT-2 (NET associated with carcinoid syndrome).
4121 General Poster Session (Board #50H), Mon, 8:00 AM-12:00 PM
Treatment of advanced neuroendocrine tumors: Results of the UKINETS
and NCRI randomized phase II NET01 trial. Presenting Author: Philippa
Corrie, Oncology Centre, Cambridge University Hospitals NHS Foundation
Trust (Addenbrooke’s Hospital), Cambridge , United Kingdom
Background: Chemotherapy is widely used for advanced, unresectable
neuroendocine tumours (NETs) but only four randomised trials are published.
The first combined streptozocin (strep) and 5fluorouracil (5FU),
reporting 63% response rate (RR), but subsequent retrospective studies
had lower RRs (6-45%). Cisplatin has been combined with strep�5FU in a
retrospective study with promising activity in NETs and capecitabine (cap)
has been effectively substituted for 5FU in many tumours. The NET01 trial
was designed to investigate whether cap�strep � cisplatin warrant further
evaluation. Methods: Patients (pts) with histologically confirmed, unresectable,
advanced and/or metastatic NETs of foregut, pancreatic or unknown
primary site were randomised (ratio 1:1) to 6 cycles of 3-weekly cap 625
mg/m2 po bd daily (D1-21), strep 1.0g/m2 IV (D1), with cisplatin 70mg/m2 IV(D1) (Cap-cist) or without (Cap-strep). The primary outcome measure was
RR using RECIST criteria (v 1.0). 84 pts were required to test a RR of
�40% vs �60% with a significance level of 5% and 80% power in each
arm. Central pathology review was performed; retrospective central radiology
review was undertaken on 10% of randomly selected cases. Results: 86
pts (58% male, median age 59 years) were randomised (44 Cap-strep, 42
Cap-cist) with primary site – foregut 20%, pancreatic 48% and unknown
33%. The grade was low 8 (11%), intermediate 47 (67%) and high 15
(21%). Baseline characteristics were balanced between the 2 arms. 60%
Cap-strep pts received �6 cycles compared with 33% Cap-cist pts. 17
Cap-strep and 26 Cap-cist pts experienced grade �3 toxicities. Outcome
results are summarised in the table. Ki67, mitotic index or primary site of
origin did not appear to predict for response. Conclusions: The novel
Cap-strep � cisplatin regimens were associated with overall disease control
and survival durations consistent with published studies. Cap-strep was
better tolerated than Cap-cist. Further prospective randomised studies are
required to determine optimal NET chemotherapy.
Cap-cist Cap-strep
Response
14%
8%
PR
64%
74%
SD
22%
18%
PD
PFS 33 (79)
30 (68)
No. progressions/deaths, n (%)
9.7
10.2
Median (mo)
OS 34 (40)
No. deaths, n (%)
34.7
Median (mo)
4123 General Poster Session (Board #51B), Mon, 8:00 AM-12:00 PM
Circulating tumor cells as prognostic and predictive markers in neuroendocrine
tumors. Presenting Author: Mohid Shakil Khan, University College
London, London, United Kingdom
Background: Neuroendocrine tumors (NETs) are a heterogeneous group of
tumors with variable survival. While Ki67 in tumour tissue is prognostic,
there have been no prospectively validated circulating prognostic or
predictive markers. Here we present results from a large prospective study
of circulating tumor cells (CTCs) in patients with NETs. Methods: Patients
about to commence therapy had a 7.5 ml blood sample taken at baseline
with additional samples taken at 3-5 weeks after commencing treatment.
CTCs were enumerated using the CellSearch system and counted independently
by two observers. Radiological response was classified according to
RECIST 1.1. PFS and OS were measured from start date of therapy, to date
of progression and date of death, respectively. In order to define a
prognostic cut off value for CTCs, 90 patients were enrolled in a training set
and 85 patients in a validation set. The optimal cut-off level validated was
CTC�1. Prognostic factors including Ki67 were evaluated using Cox
regression. Changes in CTCs after treatment were divided into tertiles.
Results: 138 patients with metastatic NET (31 pancreatic, 81 midgut, 12
bronchopulmonary, 11 unknown primary, 3 hindgut) were recruited who
were about to undergo treatment with somatostatin analogues(34), chemotherapy(28),
PRRT(40), TAE(18), RFA(3), Sunitinib(4), interferon(4) and
surgery(7). Median follow-up was 9.7 months (range 5-29). Patients with
baseline CTC�1 had significantly worse PFS (HR 4.3 95%CI 1.8-10.3),
and OS (HR 6.1 95%CI 1.8-20.3) than those without CTCs. In multivariate
analysis CTC presence was associated with worse PFS (HR 3.7 95%CI
1.5-8.9) and OS (HR 5.1 95%CI1.5-7.3). Changes in CTCs predicted
response to therapy (Fisher’s exact p�0.001) and those with increase in
CTCs by �33% post-therapy had significantly worse PFS (HR 23.1 95%CI
5.37-99.0) and OS (HR18.9 95%CI 2.4-146) than a fall or �33%
increase. Conclusions: In metastatic NETs, CTCs are a promising prognostic
marker and may be an early marker of response to therapy. Further
evaluation of CTCs in the context of therapeutic trials is required.
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