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

8584 General Poster Session (Board #37B), Sun, 8:00 AM-12:00 PM
Correlation of BRAF and NRAS mutation status with tumor characteristics
and treatment outcomes in melanoma patients with brain metastasis.
Presenting Author: Eugene J. Koay, University of Texas M. D. Anderson
Cancer Center, Houston, TX
Background: The management of melanoma has evolved rapidly with the
identification of activating mutations in the majority of patients (pts). We
reviewed characteristics and outcomes of molecularly characterized melanoma
pts with brain metastasis (BM) to help design and interpret future
clinical trials. Methods: We reviewed clinical and pathologic features of
melanoma pts with known BRAF and NRAS mutation status and BM. Pt
demographics, intra- (IC) and extra-cranial (EC) tumor characteristics, and
IC/EC disease treatments were correlated to BM treatment outcomes (local
and distant brain control [LC, DC]) and overall survival (OS). Univariate and
multivariate analyses were performed to identify significant associations
between mutation status and outcome. Results: We identified 296 pts with
melanoma BM and known BRAF/NRAS mutation status diagnosed from
2005 to 2011. Mutation prevalence was BRAF 57%, NRAS 17%, and
wild-type for both genes (WT) 26%. The initial treatments given for BM
were surgery/radiosurgery (SRS) 60%, surgery/SRS � whole brain radiation
(WBRT) 7%, WBRT alone 19%, systemic therapy alone 9%, and no
treatment 5%. Mutation status was not significantly associated with sex,
performance status, EC disease status, number of brain lesions, or BM
treatment. Pts with mutations were younger (p�0.0001) and more likely to
have symptomatic BM (p�0.0003) than WT pts. In univariate analysis, BM
treatment strategy (p�0.001) and mutation status predicted for poor LC,
with 6 month LC rates of 70% for any mutation and 88% for WT
(HR�1.86, p�0.048). Compared to systemic agents alone, use of radiation
(SRS or WBRT) improved LC for pts with a mutation (HR 0.23,
p�0.0006). Subsequent multivariate analysis identified mutation status
and radiation treatment as independent predictors of LC (HR 2.5 and 0.25,
respectively). Mutation status did not predict for DC or OS. Conclusions:
The presence of BRAF and NRAS mutations predicts worse LC following
conventional treatments for melanoma BM. Radiation may improve LC in
pts with a mutation. This data suggest a role for combining radiation with
targeted therapies in melanoma pts with activating BRAF or NRAS
mutations in the treatment of BM.
8586 General Poster Session (Board #37D), Sun, 8:00 AM-12:00 PM
Clinical experience with atypical spitzoid tumors in patients younger than
age 18: Does fluorescence in situ hybridization predict lymph node
metastasis? Presenting Author: Eric J. Stanelle, Memorial Sloan-Kettering
Cancer Center, New York, NY
Background: Determining the malignant potential of atypical spitzoid
melanocytic proliferations can be diagnostically challenging, and many
patients are therefore managed as if they had melanoma. However, few
studies focus specifically on atypical spitzoid tumors (AST). Further,
cytogenetic analysis using fluorescence in situ hybridization (FISH) has
been used to determine malignant potential. We reviewed our institutional
experience to determine staging and clinical outcomes, and the correlation
between FISH findings and regional nodal positivity in patients with AST.
Methods: With IRB approval, we retrospectively reviewed all patients aged
�18 years treated for AST from 1981-2011 to determine staging variables,
outcome, and the results of 4-probe FISH assay. A total of 44 patients with
a median age of 11.5 years were identified. All pathology was re-reviewed
by a single dermatopathologist. Staging was based on 2010 AJCC criteria.
Correlations were determined using either the Pearson or Spearman
correlation coefficient. Results: Median lesion thickness was 2.8 mm
(range: 0.55-12) and eight (18%) lesions met spitzoid melanoma criteria.
Median followup was 4.1 years for all patients (5.5 years for spitzoid
melanomas). Thirty-nine patients (89%) underwent sentinel lymph node
biopsies (SLNB) and 15 (38%) were positive. Lymph node (LN) positivity
correlated with tumor thickness (p�0.002), stage (p�0.001), and mitotic
rate (p�0.05). FISH was available for 17/39 patients who had SLNB;
sensitivity and specificity for LN metastases were 50% and 54%, respectively.
Of 15 patients with a positive SLNB, 12 underwent completion LN
dissection, three of which were positive for 1, 2, and 3 additional nodes,
respectively. There were no recurrences or disease-related deaths.
Conclusions: Traditional indicators of thickness and stage predicted nodal
involvement in pediatric patients with AST. However, FISH results did not
predict nodal status and should not be used to guide management. With
100% disease specific survival and no recurrences, AST should be
considered a separate entity from melanoma and complete excision may be
sufficient therapy.
Melanoma/Skin Cancers
561s
8585 General Poster Session (Board #37C), Sun, 8:00 AM-12:00 PM
Metastatic basal cell carcinoma: Differences in survival by site of spread.
Presenting Author: Margaret Elizabeth McCusker, Genentech, South San
Francisco, CA
Background: Basal cell carcinoma (BCC), the most common skin cancer,
rarely metastasizes. Consequently, the epidemiology of metastatic BCC
(mBCC) is poorly characterized. The largest published mBCC review
includes 170 cases reported from 1894–1980 (von Domarus H, Stevens P.
J Am Acad Dermatol 1984;10:1043-60). Targeted therapies with hedgehog
signaling pathway inhibitors, such as vismodegib, are currently being
developed to treat this rare disease. The objective of the current analysis
was to provide an updated description of the epidemiology and survival
outcomes for mBCC. Methods: A PubMed literature search was conducted
for mBCC case reports published in English during 1981–2011. mBCC
cases that met the following criteria were evaluated: primary BCC located
on skin; primary tumor and metastasis confirmed by pathology, and
metastasis was not the result of direct tumor spread. Only cases with
survival data giving dates (month and year) or durations were included in
the analysis. Differences between groups were assessed with t tests and �2 tests as appropriate. Survival was assessed with Kaplan–Meier (K-M)
methods. Results: We identified 101 mBCC cases that met the selection
criteria; 38 patients (38%) had lymph node-only disease (LD) and 63
(62%) had distant metastases (DM). In both groups, males predominated.
DM patients were younger at mBCC diagnosis (mean 59 vs 66 y for LD).
Among 96 cases with treatment data for metastatic disease, more DM
patients received chemotherapy (25% vs 9% for LD), but more LD patients
underwent surgery (85% vs 52% for DM). Survival duration ranged from 0
to 120� months in all patients. The overall 1-y probability of survival after
mBCC diagnosis was 75.7% (95% CI 67.2–84.2%), with lower survival in
DM patients (69.1%; 95% CI 57.5–80.7%) vs LD patients (86.5%; 95%
CI 75.5–97.5%). Conclusions: Patients with LD and DM mBCC may have
different clinical courses and outcomes. Based on published case reports,
DM patients were younger at mBCC diagnosis and had a lower 1-y survival
probability vs LD patients. To our knowledge, these are the first K-M
survival estimates reported for an mBCC case series of this size. These data
help to provide a historical context for novel mBCC therapies under
development, such as vismodegib.
8587 General Poster Session (Board #37E), Sun, 8:00 AM-12:00 PM
A phase II, multicenter, open-label study of YM155 plus docetaxel in
subjects with stage III (unresectable) or stage IV melanoma. Presenting
Author: Joyce Leta Steinberg, Astellas Pharma Global Development,
Deerfield, IL
Background: Survivin is a microtubule-associated protein implicated in
both preservation of cell viability and regulation of mitosis in tumor cells. It
is over-expressed in melanoma, breast, and non-Hodgkin’s lymphoma.
YM155 is a first in class survivin inhibitor. Methods: The study had 2 parts:
Part 1 established the dose of docetaxel that was tolerable in combination
withYM155 at 5 mg/m2 /day continuous infusion over 168 hours q 3 weeks.
Part 2 utilized the dose of docetaxel established in Part 1 to further
evaluate the tolerability and activity of the combination. The primary
endpoint was 6-month progression-free survival (PFS). Secondary endpoints
were overall response rate, 1-year overall survival (OS), time from
first response to progression, clinical benefit rate, time to response, and
safety. Results: 64 patients with metastatic melanoma were treated with
docetaxel followed by continuous infusion YM155. 7 patients were treated
with 100mg/m2 of docetaxel and 57 patients were treated with 75mg/m2 of
docetaxel. Median age was 59, with 44 men and 20 women treated.
6-month PFS per Independent Review Committee (IRC) was 34.8% (95%
CI 21.3 – 48.6%). Overall objective response rate per IRC was 12.5%, with
no complete responses (CR) and 8 patients with partial responses (PR). The
Stable disease (SD) rate was 51.6%, leading to a clinical benefit rate (CR �
PR � SD) of 64.1%. Estimated 1-year overall survival is 50.5%. 87.5% of
patients experienced a Grade 3 (G3) or Grade 4 (G4) event attributable to
either YM155 or docetaxel. The clinically pertinent G3 or 4 toxicities
occurring in greater than 5% of patients treated included neutropenia
(59.4%), febrile neutropenia (12.5%), mucositis (9.4%), fatigue (7.8%),
diarrhea (6.3%), and dehydration (6.3%). There were 3 deaths on study, all
attributable to disease progression. Conclusions: YM155 is a novel agent
that shows modest activity when combined with docetaxel in patients with
melanoma. YM155 was generally well tolerated, but the pre-determined
primary endpoint for efficacy was not achieved.
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