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

8560 General Poster Session (Board #34B), Sun, 8:00 AM-12:00 PM
Adjuvant sunitinib in high-risk patients with uveal melanoma: A pilot study.
Presenting Author: Matias Emanuel Valsecchi, Department of Medical
Oncology, Jefferson Medical College of Thomas Jefferson University,
Philadelphia, PA
Background: Uveal melanoma is the most common primary intraocular
cancer in adults. Despite the successful treatments for primary tumors, up
to 50% of the patients later die of distant metastases. Currently no
effective adjuvant treatment is available for these patients. Our group
previously reported that sunitinib stabilized systemic metastases in 65% of
uveal melanoma patients who failed prior treatments. In this pilot study, we
tested sunitinib in an adjuvant setting in high-risk patients with primary
uveal melanoma. Methods: Patients with estimated metastatic death rate �
50% based on the following criteria were eligible: (1) monosomy 3 and 8q
amplification; (2) large tumor (� 15 mm in diameter and �7 mmin
thickness); (3) monosomy 3 and other risk factors (large tumor, epithelioid
dominant cell type, local recurrence, or extra-scleral extension). Sunitinib
was given at 25 mg PO daily for at least 6 months. Primary endpoint was
disease-free survival (DFS) and overall survival (OS), estimated with
Kaplan-Meier analysis (SPSS 17.0). Secondary endpoint was safety.
Results: A total of 23 Caucasian patients (median, 54 years; range: 25 –
77) were enrolled. All patients received sunitinib for at least 6 months
(range: 6 – 12). Eighteen patients had confirmed monosomy 3, from whom
13 (72%) also showed 8q amplification. The median follow-up was 24
months (range 12 – 54 months). Only one patient died of unknown cause
(OS: 30.4 months). A total of seven patients (30%) developed systemic
metastases, all of which were liver metastases. The DFS and OS rates at 2
years were 70% (95% CI: 47 – 86%) and 100%, respectively. The OS rate
at 2 years was better than historical control with monosomy 3 patients
(51%, 95% CI: 31 – 71%) (Invest Ophthalmol Vis Sci 2003; 44:1008). In
those patients who relapsed, the median time to progression after finishing
sunitinib was 2 months (range: 0 – 8). The most common adverse events
were: diarrhea (47%), fatigue (39%), dermatitis (30%), stomatitis (13%),
leucopenia (8%), and nausea (4%). Most were grade 1 or 2 (88%) and only
one was considered grade 4 (diarrhea). Conclusions: In high-risk uveal
melanoma patients with estimated metastatic death rate of � 50%,
adjuvant sunitinib showed promising results and deserves further investigation.
8562 General Poster Session (Board #34D), Sun, 8:00 AM-12:00 PM
mTOR pathway activation in KIT-mutated melanoma with acquired imatinib
resistance. Presenting Author: Lu Si, Peking University Cancer
Hospital and Institute, Beijing, China
Background: c-Kit mutation is a common genetic abnormality in certain
melanoma subtypes, and is a target for treatment. However, the mechanisms
of secondary (acquired) resistance and how to treat patients in the
second line are unknown. Methods: Tissuesamples were obtained from
c-Kit-mutated melanoma patients who failed of imatinib after having PR or
SD for at least 6 months pre- and post-imatinib therapy. Somatic mutations
in genes in MAP kinase (c-Kit, BRAF, NRAS, etc) and PI3K-AKT-mTOR
(AKT1, TSC1, PTEN, etc) pathways were detected by DNA sequencing. The
expression of pS6RP, p4E-BP1, pAKT and pERK1/2 were examined by
immunohistochemistry (IHC) assays. Results: Four paired samples (formalinfixed,
paraffin-embedded) were analyzed. 1) Laboratory results: No secondary
mutations in addition to the c-Kit mutations identified at baseline were
identified. However, IHC showed increased pS6RP and p4E-BP1 (two
targets of mTOR activation) as well as increased pAKT and pERK1/2 in
imatinib-resistant samples, suggested that mTOR signaling pathway was
selectively activated in these secondary imatinib-resistant melanomas. 2)
Treatment: Everolimus is an orally administered inhibitor of mTOR. The
four patients received everolimus (10 mg/day) by continuous daily dosing.
The tumor response revealed 1 PR and 3 SD (all �3 months) with grade 1-2
toxicities consisting of myelosupression, hyperglycemia, hypercholesterolemia
and hypertriglyceridemia, consistent with previously reported toxicities
for everolimus. Conclusions: The case series provides an important clue
that activation of the mTOR signal pathway may be one of the mechanisms
for secondary imatinib resistance in c-Kit-mutated melanomas. The results
also show that everolimus may be effective and safe for melanoma patients
who develop resistance to imatinib and could be investigated in combination
with c-Kit inhibitors in treatment-naive patients.
Melanoma/Skin Cancers
555s
8561 General Poster Session (Board #34C), Sun, 8:00 AM-12:00 PM
Association of the activation of the mTOR pathway with prognosis in
Chinese melanoma patients. Presenting Author: Yan Kong, Peking University
Cancer Hospital and Institute, Beijing, China
Background: mTOR is a ubiquitously expressed protein kinase and a
validated target in the treatment of cancer. However, the characterization
of mTOR pathway in Asian melanoma populations has not been reported.
Methods: This study involved primary tumor samples from 173 melanoma
patients (79 acral melanomas, 57 mucosal melanomas, 17 melanomas on
skin with chronic sun-induced damage, 20 melanomas on skin without
chronic sun-induced damage) in Peking University Cancer Hospital &
Institute. Clinical data were collected. Immunohistochemistry assays using
antibodies against pmTOR, pS6RP, p4E-BP1 and pAKT were performed on
formalin-fixed, paraffin-embedded specimens. Somatic mutations within
the hotspot regions of frequently mutated genes in mTOR pathway (AKT1,
TSC1, PI3K genes, etc) were analyzed by PCR amplification and Sanger
sequencing. Results: Among the 173 samples, 26% of the cases (45/173)
demonstrated positive staining with pmTOR. Expression of pS6RP was
observed in 37% (64/173) of cases. Expression of p4E-BP1 was observed
in 27% (46/173) of cases. pAKT was expressed by 22% (38/173) of cases.
Somatic mutations in examined genes were detected. The median survival
time for patients with expression of pmTOR was significantly shorter than
patients with absence of pmTOR expression (25.3 vs 62.9 months, P
�0.048). In addition, statistical differences were found for ulceration rates
between melanomas with or without pS6RP (64.1%vs 35.9%, P� 0.049).
Moreover, the median survival time for mucosal melanoma patients with
pAKT expression was significantly shorter than for patients with absence of
pAKT expression (20.4 vs 52.1 months, P �0.022). Conclusions: These
data demonstrate that activation of the mTOR signaling pathway carries
prognostic significance in Asia patients with melanoma. Targeted therapies
to mTOR pathway may offer a therapeutic benefit for these melanoma
patients.
8563 General Poster Session (Board #34E), Sun, 8:00 AM-12:00 PM
Analysis of KIT expression and mutations in sinonasal, genital, and
acrolentiginous melanomas. Presenting Author: Christian R. F. Bull,
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
Background: Melanoma is subdivided into molecular defined groups. One
major subtype is characterized by a mutation in the BRAF gene. BRAF is
less commonly mutated in acrolentiginous (ALM) and mucosal (MM)
melanomas, instead these subtypes predominantly show aberrations in the
KIT/CD117 gene. KIT aberrations predict the outcome of targeted therapies
in ALM and MM patients, however the particular role of KIT expression
in these melanoma subtypes remains controversial. To explore the relationship
between KIT expression, mutation, and tumor stages, we investigated
immunohistochemical KIT expression and mutation status in primary
ALM/MM lesions and their metastases. We also compared the frequency of
KIT mutations of MM in different anatomic locations. Methods: KIT
immunoreactivity and mutation status was assessed in 41 ALM and 25 MM
patients, using polyclonal rabbit anti-human KIT/CD117 antibody, and
PCR was performed for KIT gene exons 9,11,13,17 and 18. Of these, 19
ALM and 15 MM patients had matched primary and metastatic lesions.
Phosphorylated extracellular regulated kinase (P-ERK) was investigated in
a subset of 8 ALM and 8 MM matched primary/metastatic pairs by
immunohistochemistry. Results: Heterogeneous KIT immunoreactivity was
observed in both primary and metastatic lesions. Mutations were present in
four of 41 ALM (10%) and five of 25 MM (20%) patients. Only vulvar
mucosal samples carried KIT mutations in contrast to sinonasal lesions (p�
0.0109). In KIT-mutated tumors, the mutations were present in KIT
expressing as well as KIT negative cells, as shown by Laser Capture
Microdissection (LCM). P-ERK expression was preferentially found in
metastases. Conclusions: KIT expression is heterogeneous and shows no
relationship with disease progression and mutation status, therefore KIT
immunoreactivity is not a valuable marker for treatment decisions. In
mucosal melanoma patients, KIT mutation frequency is significantly
associated with anatomic location. Vulvar melanoma patients are prone to
carry activating KIT mutations and thus may be more likely to benefit from
KIT-targeted therapies than other subtypes. Therefore, especially vulvar
melanoma patients should be screened for activating KIT mutations.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.