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

558s Melanoma/Skin Cancers
8572 General Poster Session (Board #35F), Sun, 8:00 AM-12:00 PM
Use of Cobas 4800 BRAF mutation test for the analysis of BRAF V600
mutations in cytological samples (CS) from metastatic melanoma (MM).
Presenting Author: Salvador Martin-Algarra, Clínica Universidad de Navarra,
Pamplona, Spain
Background: Vemurafenib is currently the most active first-line treatment in
MM patients that harbor BRAF-V600E mutations. The Cobas 4800 BRAF
V600 Mutation Test is an FDA-approved, CE-marked test that identifies
formalin-fixed-paraffin-embedded samples (FFPE) carrying the BRAF V600E
mutation. Fine needle aspirates are frequently the only samples available in
MM patients, but the use of CS has not been validated in this platform. We
have evaluated the capability to identify BRAF-V600E mutations in CS of
MM with the Cobas 4800 BRAF Mutation Test, and results have been
compared to the conventional Sanger direct sequencing method. Methods:
BRAF mutations have been studied in 117 samples from 98 MM patients
with the conventional Sanger method: 37 (32%) FFPE and 80 (68%) CS.
DNA was extracted from 4-micron sections in FFPE and from stained
smears in CS. All CS contained �50% of tumor cells. In a second step, 57
out of the 117 samples have been studied using Cobas (25 CS and 32
FFPE). In CS, Nucleospin Tissue (Macherey-Nagel) DNA extraction was
used in 17 cases and the Cobas procedure in 8. FFPE and CS paired
samples were available in 9 patients. Results were compared using the
Kappa coefficient. Results: There was 93% (53/57) agreement between
Cobas and direct sequencing. All V600E� cases were detected with both
methods. Four V600R� cases were negative using Cobas. Mean DNA
concentrations using Nucleospin and Cobas procedures were 55.20 ng/�l
and 11.37 ng/�l respectively. Concordance using Cobas in FFPE and CS
paired samples was 100%. The table shows the results with Cobas and
direct sequencing in 25 CS. One V600R� case was not detected with
Cobas. Conclusions: The Cobas 4800 BRAF Mutation Test results using CS
containing �50% of tumor cells are identical to those obtained with FFPE.
In our experience, DNA concentrations from CS with the Cobas method are
lower than those obtained with Nucleospin procedure. These results
provide a strong rationale for a larger validation study.
Direct sequencing results
WT V600E V600K V600R Total
COBAS 4800 system results
MND 4 0 0 1 5
V600 0 16 4 0 20
Total 4 16 4 1 25
MND: Mutation not detected.
8574 General Poster Session (Board #35H), Sun, 8:00 AM-12:00 PM
Development of a melanoma risk prediction model incorporating MC1R
genotype and indoor tanning exposure. Presenting Author: Lauren A.
Smith, New York University Langone Medical Center, New York, NY
Background: Invasive melanoma is the second most common cancer in
young adults, yet they exhibit poor skin-protective behavior. We previously
demonstrated a significant association between melanoma risk, melanocortin
receptor (MC1R) polymorphisms, and indoor ultraviolet light (UV)
exposure. As existing melanoma risk models do not take these factors into
account, we investigated whether these variables would improve the
predictive ability of a clinical risk model, especially in a younger population.
Methods: We determined MC1R genotype and collected self-reported
phenotypic and UV (indoor and outdoor) exposure variables from 923
melanoma cases and 813 healthy controls between ages 25 – 59 from the
Minnesota Skin Health Study. These data were initially used to develop a
clinical melanoma risk model (Model A) with conventional risk factors (i.e.
age; gender; hair, skin, and eye color; mole count, freckling, and family
melanoma history). We then developed a second model (Model B) combining
outdoor UV, indoor UV, and MC1R genotype variables with those in
Model A to determine if the model’s predictive ability improved. Finally, we
assessed the predictive ability of both models when confined to younger
subjects (ages 25-35). Results: The clinical model, combining conventional
melanoma risk factors (Model A), yielded an area under the receiver
operating characteristic curve (AUC) of 0.72 (95% CI 0.70 – 0.75).
Incorporating outdoor UV, indoor UV, and MC1R genotype variables (Model
B) increased the AUC to 0.75 (p�0.001, 0.72 – 0.77). Confining the
analyses to younger subjects substantially increased the AUC of Model A to
0.78 (0.72 – 0.84) and Model B to 0.83 (p�0.007, 0.78-0.88).
Conclusions: This preliminary risk model is the first in melanoma to
demonstrate that the addition of genotypic data and indoor UV exposure
results in a measurable increase in predictive ability when compared to
models comprised only of clinical and outdoor UV exposure variables. The
enhanced predictive ability of the model (AUC�0.80) when limited to
younger individuals suggests the potential for developing tools to facilitate
targeted screening and prevention strategies in melanoma.
8573 General Poster Session (Board #35G), Sun, 8:00 AM-12:00 PM
Immunological and biological changes during ipilimumab (Ipi) treatment
and their correlation with clinical response and survival. Presenting Author:
Ester Simeone, Unit of Medical Oncology and Innovative Therapy, Istituto
Nazionale Tumori Fondazione Pascale, Napoli, Italy
Background: Ipilimumab (Ipi) is approved in the US as first and second line
therapy in patients with metastatic melanoma (MM) and in MM patients
with previous therapy in the EU, based on an overall survival benefit shown
in a phase III study (Hodi, NEJM 2010). To date, no clinical parameter has
been found to be predictive for response to treatment and only few
immunologic changes have been identified as potential candidates. Methods:
From June 2010 to November 2011 we treated in the Expanded Access
Program with Ipi at 3 mg/kg, 95 pre-treated metastatic melanoma patients.
The median age was 58 yrs (range 17-84); 10 pts (10,5%) were stage IIIc
inoperable, 2 pts (2,1%) stage M1a, 4 pts (4,2%) stage M1b, and 79 pts
(83,2%) stage M1c. 30/95 pts had brain metastases and 1/95 spinal cord
metastases. All 95 patients were evaluable for response (DCR �
CR�PR�SD according the irRC), overall survival, safety, including changes
in LDH, CRP (C-reactive protein) and lymphocyte populations
(CD4�,CD4CD25�,FOXP3/T-Reg cells). PBMC and sera were collected at
week 0, 4, 7, 10 and 12. Results: We found a statistical significant
decrease of LDH, CRP and FOXP3/T-Reg cells (p�0.0001; �2 and
Mann-Whitney), and an increase of lymphocyte count (p�.0001) in the
responders group. These differences were also correlated to survival
(log-rank test). No differences were observed for CD4� and CD4�CD25�
between responders and non-responders (p�0.39;p�0.83; Mann-Whitney).
An ORR of 22.1% (1CR�20PR; 95% CI 13.8-30.4) and a DCR at
week 24 of 37.9% (36/95; 28.1-47.6, 95% CI) were observed. Median
overall survival was estimated of 7.8 months (95%CI:5.0-10.6), with a p
value not evaluable at the moment of the analysis due to insufficient
follow-up because of long-term survival. Adverse events were registered in
40% (38/95) of patients and the most frequent were of grade 1 and 2
(pruritus 57.9%; rash 5.3%; thyroditis 5.3%). Conclusions: The decrease
of LDH, CRP and T-Reg cells during Ipi treatment suggest these parameters
should be further explored as potential predictive markers for response and
survival. Given the potential clinical utility of these findings, these data
warrants further prospective validation in a randomized trial.
8575 General Poster Session (Board #36A), Sun, 8:00 AM-12:00 PM
Evaluation of the absolute lymphocyte count as a biomarker for melanoma
patients treated with the commercially available dose of ipilimumab
(3mg/kg). Presenting Author: Michael Andrew Postow, Memorial Sloan-
Kettering Cancer Center, New York, NY
Background: Ipilimumab (ipi) has demonstrated an overall survival (OS)
benefit in 2 phase III trials. Only ~30% of patients (pts) achieve clinical
benefit, and factors that determine which pts benefit are unclear. For pts
treated with 10mg/kg of ipi, we previously reported that an absolute
lymphocyte count (ALC) �1000/�L prior to dose 3 [week (wk) 7] was
associated with improved OS. Since the mean increase in ALC during ipi
treatment correlates with dose, we investigated if ALC is also associated
with improved OS at 3mg/kg, the currently FDA approved, commercially
available dose. Methods: In an IRB-approved analysis, we evaluated
landmark survival data from 137 pts treated with 3mg/kg of ipi at Memorial
Sloan-Kettering Cancer Center. 67 pts were treated on an expanded access
protocol (CA 184-045). 70 pts were treated per FDA approval (commercial
ipi) with 4 standard induction doses. These 2 groups were analyzed
separately because some pts in CA 184-045 received re-induction ipi. ALC
was determined at first ipi dose (baseline, wk 1) and at subsequent doses
(wks 4, 7, and 10). Results: Pts treated with 3mg/kg on CA 184-045 with a
wk 7 (prior to dose 3) ALC �1000/�L had significantly improved OS
compared to pts with an ALC at wk 7 �1000/�L (Median OS: not reached
vs. 4.24 mos, p�0.001). This OS difference was also seen for pts treated
with commercial ipi (Median OS: not reached vs. 4.44 mos, p�0.01). This
difference remained significant in a multivariable model accounting for
Karnofsky performance score, LDH, M-stage, and number of prior therapies
for pts in the CA 184-045 group and commercial ipi group (p�0.01 and
p�0.05, respectively). Baseline ALC �1000/�L was associated with
improved OS (p�0.02) for pts in the commercial ipi group, though
follow-up is limited. Conclusions: At the FDA approved dose of ipi, 3mg/kg,
ALC at wk 7 remains significantly associated with improved OS. Our
preliminary finding of improved OS for pts treated with commercial ipi
whose pre-treatment baseline ALC �1000/�L deserves confirmation with
longer follow-up and prospective validation. Baseline or on treatment ALC
may be a marker of overall prognosis, regardless of therapy.
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