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

562s Melanoma/Skin Cancers
8588 General Poster Session (Board #37F), Sun, 8:00 AM-12:00 PM
KIT, NRAS, BRAF, and PTEN alterations in acral lentiginous melanomas.
Presenting Author: Abdlsattar Zebary, Department of Oncology-Pathology,
Karolinska Institute, Stockholm, Sweden
Background: Acral lentiginous melanoma (ALM) accounts for ~5% of all
melanomas. ALMs are often located on palms, soles and under nails.
Patients with ALM are significantly older at diagnosis and have a poorer
prognosis than patients with other types of cutaneous melanoma. We
analyzed a large series of ALMs from Swedish patients to better define the
frequency of KIT, BRAF, NRAS, and PTEN mutations in ALM. The effect of
mutation status on tumor and patients characteristics was also studied.
Methods: A total of 77 primary ALMs and 8 paired metastases were
analyzed. Laser capture microdissection was used to dissect tumor cells
from formalin-fixed paraffin-embedded tissue. Tumors were screened for
mutations in the KIT (exons 11, 13, 17 and 18), NRAS (exons 1 and 2),
BRAF (exons 11 and 15) and PTEN (exons 1, 3-6, 10, 11 and 12) genes by
direct sequencing. Results: There were 42 females and 35 males with a
median age at diagnosis of 71 years. The most common location was the
feet (60.5%), followed by subungual sites (34.2%). Overall, mutations in
KIT, NRAS and BRAF were detected in 11.8%, 14.5% and 16.0% of the
ALMs, respectively. In no case were KIT, NRAS and BRAF mutations
detected in the same tumor. For 8 primary ALMs the corresponding
metastases were available for analysis. In five metastases the same KIT
(n�3) or BRAF (n�2) mutation was detected as in the primary ALMs,
suggesting that the KIT and BRAF mutations had occurred before metastasis.
BRAF and NRAS mutations were significantly more common in females
(P�0.044). ALMs with NRAS and BRAF mutations were more commonly
located on the feet compared with KIT mutated ALMs which were more
frequent on subungual sites (P�0.041). Other clinicopathological features
such as age at diagnosis, thickness, ulceration, histological subtype and
Clark’s level showed no significant correlation with the mutation status. A
subset of 25 tumors was evaluated for mutations in the PTEN tumor
suppressor gene. One tumor was found to carry a nonsense mutation
(W111X). To our knowledge, this is the first description of a PTEN mutation
in ALM. Conclusions: Our results confirm the presence of KIT, NRAS and
BRAF mutations in ALM. KIT, NRAS and BRAF mutation status associated
significantly with anatomical site. PTEN mutations seem to be rare in
ALMs.
8590 General Poster Session (Board #37H), Sun, 8:00 AM-12:00 PM
The impact of immune status on clinical outcomes in patients with Merkel
cell carcinoma. Presenting Author: Sean Donovan, Mayo Clinic, Jacksonville,
FL
Background: Merkel Cell Carcinoma (MCC) is an aggressive cutaneous
malignancy of neuroendocrine origin associated with immunosuppression
presumably through infection with Merkel Cell Polyomavirus present in
�80% of patients (pts). The impact of immune status on clinical outcomes
in pts with MCC is unknown. The primary objective of this study was to
compare clinical characteristics and outcomes of pts with MCC who are
immunosuppressed (ISP) versus non-immunosuppressed (non-ISP).
Methods: We performed a retrospective chart review on pts with MCC
diagnosed at the Mayo Clinic between 1981 and 2009. A dermatopathologist
confirmed all cases. ISP was defined as pts diagnosed with chronic
lymphocytic leukemia, HIV, solid organ transplant recipients, or chronic
immunosuppressive medication. The association between ISP status and
overall survival was summarized using the hazard ratio (HR) and 95%
confidence interval (CI) estimated from a Cox regression model. Results: Of
the 268 pts identified and included in the study, 38 (14%) were ISP. We
found no differences in age, tumor size, tumor location, stage of disease, or
recurrence rate in ISP vs Non-ISP. Among pts who had Stage 3-4 disease,
there was no difference in the size of the primary between groups. Among
pts with Stage 1-2 disease, ISP status was not significantly associated with
poorer survival (HR 1.5, 95% CI 0.7-3.3). However, among pts with Stage
3-4 disease, ISP pts had significantly poorer survival compared to non-ISP
pts (HR 2.7, 95% CI 1.2 - 6.2). Conclusions: Baseline clinical characteristics
of pts with MCC do not differ based on immunosuppression, and
outcomes do not differ in pts in regards to immunosuppression in early
stage MCC (Stage 1-2). However, in pts with Stage III-IV MCC, ISP pts have
a worse clinical outcome suggesting that metastatic MCC either behaves
more aggressively in ISP pts either through intrinsic differences in the
biology of the tumor or improved immune evasion in ISP pts. These results
should be cautiously interpreted given the small number (n�12) of
immunosuppressed pts with advanced stage MCC. The authors will update
their data with an additional 58 patients by the date of presentation.
8589 General Poster Session (Board #37G), Sun, 8:00 AM-12:00 PM
TILs in metastatic melanoma tumors: A biomarker for immunotherapy?
Presenting Author: Sunandana Chandra, New York University School of
Medicine, New York, NY
Background: Increased tumor infiltrating lymphocytes (TILs) in primary (P)
and locoregional melanoma tissue correlate with improved clinical outcome.
Our recent data have suggested that matrix metalloproteinase 23
(MMP 23) expression (exp) in P result in lower prevalence of TILs and
correlate with poor clinical outcome. On this basis, we examined P and
metastatic (M) melanoma tissues to assess for concordance between the
presence of TILs, MMP 23 protein levels and clinical response(resp) to
anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) therapy (tx). Methods: 21
melanoma patients (pts) with M specimens were analyzed. 17 matched P
specimens were also evaluated. Immunohistochemical (IHC) staining for
TILs of the pre-anti-CTLA4 specimens were conducted and confirmed by 2
pathologists. IHC TILs were graded- 2�: �10% TILs present in multiple
foci in both peri- and through the tumor; 1�: 1-10% TILs present in one or
more foci in the tumor and predominantly peri-tumor; 0: no TILs were
present or if the lymphocytes did not infiltrate the tumor. TILs in P and M
were analyzed for concordance and potential for predictability of resp to
anti-CTLA4 tx. Staining to identify lymphocyte subtypes and MMP 23 exp
in M is being completed. Results: 20 pts received anti-CTLA4 tx. M
analysis- 6 pts with 0 TILs in M (5 no response [NR], 1 partial response[PR]);
8 pts with 1-2� TILs in M (1 complete response [CR], 5 PR, 2
progressive disease [PD]); 6 pts with 2� TILs inM(3CR,2PR,1PD). 1 pt
with 2� TILs in M resected, no tx and 4 years disease free. TILs present in
13 P, absent in 4 P and not evaluable in 4 pts with unknown P melanoma.
MMP 23 protein scores in P (range 2-4) correlated with melanoma
recurrence. MMP 23 exp in M will be reported. Conclusions: TILs in P do not
appear to correlate with TILs in M or predict for resp to anti-CTLA4 tx. TILs
in M may be an indicator of responsiveness to anti-CTLA4 tx. Identification
of the type of M TIL subsets may further refine tx recommendations.
8591 General Poster Session (Board #38A), Sun, 8:00 AM-12:00 PM
Vemurafenib (V) in BRAF V600E metastatic melanoma (mM): Analysis of 507
patients (pts) enrolled in the French temporary authorization for use (ATU).
Presenting Author: Celeste Lebbe, Saint-Louis Hospital, Paris, France
Background: V, a selective BRAF inhibitor, significantly improves OS in BRAF
mutated mM. ATU is an exceptional measure making available drugs that have
not yet been granted a Marketing Authorisation. We provide demographic data of
pts treated by V in the ATU. Methods: V 960 mg BID was given to pts with
unresectable stage IIIC or IV BRAF V600E mM. Genotyping was done on the
national network of molecular genetics platforms funded by the Institut National
du Cancer. Data were prospectively collected. Results: From Apr 2011 to Jan
2012, 83 sites enrolled 507 pts. 80% were treated by oncodermatologists. Pts
characteristics at baseline are summarized below. Safety and efficacy data are
being evaluated. Conclusions: Around 2 out of 3 patients with a BRAF mutated
mM were enrolled in France in the ATU highlighting a large access to BRAF
genotyping and to V. Demographic data differs from literature and clinical trials
for: site of primary melanoma (reverse trunk/extremity ratio) and inclusion of pts
with brain metastasis or PS�2 (excluded in CT). A high number of pts had risk
factors for NMSC emphasizing the importance of the communication between
oncologists and dermatologists for managing V therapy.
n� 507
Males (%) 54.8
Median age (years), range 57 (22-92)
ECOG PS (%)
0-1
2-3
4
Site on primary melanoma (%)
Extremity
Trunk
Head /neck
Occult
Others
Mucosal
86.4
9.7
4
44
34.7
11.5
8.5
1
0.2
Current AJCC stage IV (%) 97
Mean time from diagnosis of stage IV or unresectable stage III C (months) (range) 4 (0-261)
Median number of metastatic sites, (range) 3 (1-7)
Brain metastasis (%) 31.9
Number of previous therapies for mM ( %)
0
1
>2
Main previous therapies (%)
Dacarbazine
Fotemustine
Ipilimumab
Temozolamide
Previous tyrosine kinase inhibitors (n)
BRAF inh
MEK inh
Epithelial proliferations at baseline (%)
Actinic keratosis
Basal cell carcinoma
Squamous cell carcinoma
Risk factors for nonmelanoma skin cancer (NMSC) (%)
Previous radiation
Past history of NMSC
BRAF V600E identification method (%)
Sanger sequencing
Pyrosequencing
Allele-specific oligonucleotide PCR
High-resolution melt
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31.7
61.8
6.5
45.1
17.9
10.6
6.7
4
7
13.8
3.1
1.5
12.4
14.4
43.4
14.8
12.8
12.4