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

552s Melanoma/Skin Cancers
8548 General Poster Session (Board #32F), Sun, 8:00 AM-12:00 PM
Correlations of molecular alterations in clinical stage III cutaneous melanoma
with clinical-pathological features and patients outcome. Presenting
Author: Piotr Rutkowski, Maria Sklodowska-Curie Memorial Cancer Center
and Institute of Oncology, Warsaw, Poland
Background: To evaluate frequency and type of oncogenic BRAF/NRAS
mutations in cutaneous melanoma with clinically detected nodal metastases
(stage IIIB,C) in relation to clinicopathologic features and outcome.
Methods: We analyzed 221 patients after therapeutic lymphadenectomy-
LND (1995-2010) not treated with tyrosine kinase inhibitors and performed
molecular characterization of nodal metastases in terms of BRAF/
NRAS genes (analyzed by sequencing of respective coding sequences).
Median follow-up time was 53 months. Results: BRAF mutations were
detected in 139 (63%) cases (127–V600E, 8–V600K, 4-others), mutually
exclusive NRAS mutations in 35(15.8%) cases (mainly Q61R and Q61K).
BRAF mutation presence correlated with patients’ younger age(median 52
vs 60 years for BRAF� vs. BRAF-, p�0.05), metastases in axillary basin
(p�0.05) and less involved nodes (median 3 vs. 4; p�0.05). 5-year overall
survival (OS) was 35% and 45% (calculated from date of LND and primary
tumor excision, respectively); 5-year recurrence-free survival RFS (from
LND) – 29%. We have not found correlation between mutational status and
RFS or OS (calculated from date of LND and primary tumor excision) – for
BRAF mutated-melanomas prognosis was the same as wild-type melanoma
patients(p�0.26) with even trend for better OS for non-V600E mutants.
Negative prognostic factors (in univariate and multivariate analysis) for OS
and RFS were: male gender (p�0.01), metastatic lymph nodes�1
(p�0.001), nodal metastases extracapsular extension (p�0.001). The
interval from diagnosis of first-ever melanoma to regional nodal metastasis
(median-10 months) was not significantly different between BRAF-mutant
and BRAF wild-type patients (p�0.29). Conclusions: BRAF/NRAS mutational
status is not prognostic marker in stage III melanoma patients with
macroscopic nodal involvement, what may have implication for potential
adjuvant therapy. BRAF status had no impact on disease-free interval from
diagnosis of primary melanoma to nodal metastases. Our first-ever comprehensive
molecular analysis of clinical stage III melanomas revealed that
BRAF-mutants show characteristic clinicopathologic features.
8550 General Poster Session (Board #32H), Sun, 8:00 AM-12:00 PM
Early alterations of microRNA expression to predict and modulate melanoma
metastasis. Presenting Author: Eva Hernando, New York University
School of Medicine, New York, NY
Background: Melanoma is curable for most patients whose tumors are
surgically removed early in disease progression; however, many primary
melanomas recur and progress to metastasis. Clinical staging is insufficient
to robustly classify patients at highest risk of recurrence, and prognostic
molecular biomarkers have not yet been identified. Methods: We performed
miRNA profiling of 92 FFPE primary melanomas to discover metastasis
relevant miRNAs and develop predictive models of recurrence, which were
then validated in an independent cohort. We identified miRNAs differentially
expressed between primary tumors that did and did not recur (3-year
minimum follow-up) and between thick and thin lesions. We selected
candidate miRs for screening in a fluorescence-based in vitro invasion
assay, and prioritized a subset for in vivo testing. Potential downstream
mediators of these miRNAs were selected by mRNA array analysis and
tested in a secondary invasion screen. mRNA candidates that mimicked the
miR’s invasion-suppressive effect were tested in 3’UTR reporter assays to
confirm them as direct targets. Results: Using the discovery cohort we
identified a 20 miRNA signature that can distinguish Stage I/II primary
tumors (n�70) that did from those did not recur with 3-year minimum
follow-up with an AUC�94%, 95% CI: (0.88, 0.99). Applying this model
to predict risk for recurrence in the independent validation cohort yielded
an AUC � 96%, 95% CI: (0.90, 1) in discriminating recurrent versus
non-recurrent stages I/ II patients (n�45). From the discovery cohort, 40
candidates were selected for invasion assay screening, of which 5 miRNAs
robustly inhibit in vitro invasion in 5 melanoma cell lines. Three miRs
(miR-382, miR-516b, and miR-7) strongly suppressed metastasis in a
mouse model. Moreover, multiple mRNAs tested as potential mediators
mimicked the invasion-suppressive effects of candidate miRs. Of those,
NCAPG2 and CDC42 were identified as miR-516b targets, CTTN as a
miR-382 target, and PIK3CD as a miR-7 target. These genes have been
linked to metastasis in melanoma or other tumors. Conclusions: Our data
demonstrate that aberrant expression of specific miRNAs at diagnosis is
predictive of and functionally impacts melanoma progression.
8549 General Poster Session (Board #32G), Sun, 8:00 AM-12:00 PM
Ipilimumab in the treatment of uveal melanoma: The Memorial Sloan-
Kettering Cancer Center experience. Presenting Author: Shaheer A. Khan,
Memorial Sloan-Kettering Cancer Center, New York, NY
Background: Ipilimumab (ipi) is an antibody that blocks cytotoxic Tlymphocyte
antigen-4 (CTLA-4) and improves overall survival in patients
(pts) with metastatic melanoma. Uveal melanoma (UM) is a rare and
biologically unique disease subtype with no known effective systemic
therapy. Ipi has proven efficacy in cutaneous melanoma (CM), but limited
data exists regarding its activity in UM. We reviewed our single-institutional
experience with ipi in advanced UM. Methods: After IRB approval, the
MSKCC melanoma database was queried for patients with metastatic UM
treated with ipi between 03/08-01/12. Radiographic response by RECIST
and immune-related response criteria (irRC) was assessed by a single
radiologist blinded to clinical outcomes. Immune-related adverse events
(irAEs), survival and absolute lymphocyte count (ALC) were also evaluated.
Results: 20 pts were identified: the median age was 61yrs (range 46-83),
55% were male, 85% had liver metastases, 60% had elevated LDH, and
pts reported a median of 1 prior therapies (range 0-5). Pts received a
median of 4 doses (range 1-16) of ipi. Response rates (RR) by irRC at 12
and 24 wks are listed below. Among pts with stable disease (SD) at 12 wks,
the median time to progression was 30.6 wks (range 19.6-83), with one
partial response (PR) occurring after 24 wks (overall RR 10%). Responses
were observed in lung, liver and peritoneal metastases. Pts with an ALC �
1.0 at 7 wks had a trend toward a higher clinical benefit (CB� CR � PR �
SD) than pts with ALC � 1.0 (5/12 [42%] vs 0/5 [0%]; p� .09), consistent
with prior studies in CM. To date, median survival for the group is 8.6 mos
(95% CI, 3.5-NR), with two ongoing PRs (3� yrs and 24� wks). Reported
irAEs include rash/pruritis (10/20), hepatitis (1/20), colitis (1/20), pancreatitis
(1/20) and uveitis (1/20). Conclusions: Ipi has potential for benefit in
pts with advanced UM; RR and irAE rates are similar to those observed in
pts with advanced CM. Further evaluation of ipi in the treatment of UM,
including identification of potential biomarkers of CB, is warranted.
Immune-related response criteria 12 wks 24 wks
Stable disease 7/20 (35%) 4/20 (20%)
Partial response 1/20 (5%) 1/20 (5%)
Complete response 0/20 0/20
Clinical benefit 8/20 (40%) 5/20 (25%)
8551 General Poster Session (Board #33A), Sun, 8:00 AM-12:00 PM
Targeted agents matched with tumor molecular aberrations: Review of 160
patients with advanced melanoma treated in a phase I clinic. Presenting
Author: Haby Adel Henary, University of Texas M. D. Anderson Cancer
Center, and Department of Investigational Cancer Therapeutics, Houston,
TX
Background: Identification of activating mutations in melanoma has increased
the number of novel targeted agents for this disease. Methods:
Weretrospectively reviewed clinical outcomes of 160 consecutive metastatic
melanoma patients (pts) treated in the Dept of Investigational Cancer
Therapeutics (Phase I program) at M. D. Anderson since 2008, and
compared their median progression free survival (PFS) to their first and last
standard systemic therapy PFS. In addition, we compared those pts’
outcomes tested for tumor molecular aberrations on a phase I trial with a
matched targeted agent with those of pts who were treated without regard
for their molecular profiles. Results: Of 160 pts treated on 35 different
phase 1 clinical trials, 110 pts (69%) had � 1 molecular aberration. Of
those pts who had adequate tissue for molecular analysis, 63% (85/134)
pts had BRAF mutation, 20% (22/109) NRAS mutation, 20% (1/5) GNAQ
mutation, 11% (1/9) P53 mutation, 2.5% (1/39) PIK3CA and 1.3% (1/76)
had KIT mutation. 77 (48%) pts were treated on a phase I trial with a
matched targeted agent and 83 (52%) pts were treated on a non-matched
phase 1 trial. The overall response rate was 39% (complete response [CR],
9%; partial response [PR], 30%) in the 77 pts treated with matched
therapy and 9% (all PRs) in the 83 pts treated without matched therapy (P
� 0.0018). 139 (87%) pts received at least one systemic therapy before
referral to phase I, median PFS was longer on phase 1 therapy than on last
line standard therapy prior to referral to phase 1 (4.2 vs. 2.8 months, P �
0.002). Median PFS was greater for pts on matched vs. non-matched
therapy (5.3 vs. 3.7 months, log rank P � 0.004). Also, median PFS was
longer on phase 1 matched trial than on first standard treatment (5.3 vs.
3.9 months, log rank P � 0.045).PFS did not differ between first standard
and non-matched phase 1 study. Univariate analyses with the log rank test
revealed that matched therapy (P � 0.004) was positively associated with
longer PFS on phase I clinical trials. Conclusions: Matching melanoma pts
with targeted drugsbased on specific molecular aberrations in the phase I
setting can be associated with superior outcomes compared to prior
standard systemic therapies.
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