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

10594 General Poster Session (Board #49C), Mon, 1:15 PM-5:15 PM
Prognostic value of “angiogenic” risk score in early-stage NSCLC. Presenting
Author: Elena Sanmartin, Fundación para la Investigación del Hospital
General Universitario de Valencia, Valencia, Spain
Background: Angiogenesis is a key mechanism in tumor growth and
dissemination mainly regulated by VEGF family members. We analyze the
expression of 11 angiogenic genes in a cohort of resectable NSCLC patients
and correlate them with clinico-pathological variables and prognosis.
Methods: RNA was obtained from tumor and normal lung specimens from
175 NSCLC patients. RT-PCR was performed to assess the expression of
HIF1-A, PIGF, VEGFA, VEGFB, VEGFC, VEGFD, VEGFR1, VEGFR2,
VEGFR3, NRP1 and NRP2. Relative expression was normalized by an
endogenous gene (GUS) using the Pfaffl formulae. Differences were
considered statistically significant at p�0.05. Results: We found that
tumor samples had a significant higher expression of PIGF and lower
expression of VEGFD, VEGFR2, and VEGFR3 compared with normal tissue
(2.76X, 0.035X, 0.417X and 0.426X, respectively). The group of patients
with higher expression levels of VEGFA or PlGF had a significantly reduced
TTP (p�0.024 and p�0.027, respectively) and OS (p�0.055 and
p�0.048, respectively) whereas those patients with values of VEGFB or
VEGFD below the median had reduced TTP (p�0.020 and p�0.135,
respectively) and OS (p�0.003 and p�0.089, respectively). The multivariate
Cox regression analysis revealed that VEGFA, VEGFB and PlGF were
independent prognostic markers for TTP and OS and based on these results
we generated an “angiogenic” risk score model. TTP and OS were
significantly different among the low, medium and high risk score patients
(Table). Conclusions: VEGF family members are master control genes of the
angiogenic process and have a crucial role in the prognostic of the disease.
We found differences in the expression of four genes between tumor and
normal lung samples. An “angiogenic” risk score (based on the expression
of PlGF, VEGF-A and VEGF-B) significantly predicts OS and TTP in our
cohort of early-stage NSCLC patients. Validation in an independent cohort
is needed. Supported by grants PS09-01149 and RD06/0020/1024 from
ISCIII.
TTP OS
Risk score N Median 95% CI p N Median 95% CI p
Low 45 NR - 0.001 47 NR - �0.0001
Intermediate 47 NR - 50 NR -
High 41 12.7 5.1-20.3 42 18.8 13.9-23.6
10596 General Poster Session (Board #49E), Mon, 1:15 PM-5:15 PM
Retrospective EGFR mutation testing of clinical specimens from the
EURTAC trial of erlotinib in non-small cell lung cancer (NSCLC) using a
novel allele-specific PCR (AS-PCR) assay. Presenting Author: Susana
Benlloch, Pangaea Biotech, USP Dexeus University Institute, Barcelona,
Spain
Background: Anti-EGFR inhibitors are superior to chemotherapy in first-line
therapy of advanced EGFR-mutant NSCLC. The EURTAC trial was a
randomized Phase III trial of erlotinib vs. chemotherapy in patients with
EGFR-mutant NSCLC. Interim results showed significant improvement in
progression-free survival (R. Rosell, ASCO 2011). An accurate rapid in vitro
diagnostic for EGFR mutations is needed to select patients for this therapy.
Methods: Prospective EGFR mutation testing for the trial was performed on
laser-capture microdissected tumor cells using a combination of 3 labdeveloped
tests (LDTs), including a Length Analysis of Fluorescentlylabeled
PCR (Genescan) method for exon 19 deletions, a Taqman-based
PCR assay for exon 21 mutation with laser-capture macrodissected tumor
cells, and secondary Sanger sequencing. A subset of samples from the trial
was retrospectively tested with an AS-PCR assay (cobas EGFR mutation
test) which detects L858R and � 29 exon 19 deletions. The test provides
automated results within 8 h; the DNA required can be isolated from one
5-micron tissue section. Four methods were compared: AS-PCR assay,
LDT, direct Sanger sequencing and massively parallel sequencing (MPS;
454, Branford, CT). Results: LDT results were obtained for 1044 screened
patients. Residual tumor blocks were available for 487 patients (47%),
including 303 wild-type, 172 mutant (135 enrolled on the trial) and 12
inconclusive cases by the LDT. Comparison of AS-PCR and LDT results
showed a positive percent agreement (PPA) – 93.7% (CI 88.8%, 96.5%),
and negative percent agreement (NPA) – 97.5% (94.9%, 98.8%). Comparison
of AS-PCR and Sanger results showed a PPA of 96.6% (91.7%,
98.7%) but an NPA of 88.3% (84.1%, 91.5%). Among 34 AS-PCR �
/
Sanger- case, MPS confirmed the presence of exon 19 deletions in 25 cases
and L858R mutations in 7. Direct comparison of AS-PCR and MPS results
showed a PPA of 93.1% (88.1%, 96.1%) and NPA of 97.7% (95.0%,
98.9%). Clinical outcomes for cases with mutations detected by the
AS-PCR test will be presented. Conclusions: The AS-PCR assay was highly
concordant with the LDT and MPS, and more sensitive than Sanger
sequencing.
Tumor Biology
679s
10595 General Poster Session (Board #49D), Mon, 1:15 PM-5:15 PM
Activation of angiogenic pathway in the prediction of pathologic response to
bevacizumab-based neoadjuvant therapy in breast cancer. Presenting
Author: Jose Manuel Lopez-Vega, Hospital Universitario Marques de
Valdecilla, Cantabria, Spain
Background: To evaluate potential biomarkers of pathological response to
bevacizumab-based neoadjuvant therapy in untreated breast cancers (BC)
patients recruited in a phase II, multicenter clinical trial. Methods: Patients
received a single infusion of bevacizumab (15 mg/ kg) (C1) 3 weeks prior to
the beginning of neoadjuvant chemotherapy (NAC) consisting in 4 cycles of
docetaxel (60 mg/mq), doxorubicin (50 mg/mq) and bevacizumab (15 mg/
kg) every 21 days (C2-C5) following by surgery. Biomarker expression was
assessed by immunohistochemistry (Ki67, CD31, CD31/Ki67, VEGFR2,
pVEGFR2 [Y951]) before and after bevacizumab infusion (C1). Gene
expression was analyzed using Affimetrix Human Gene ST 1.0. Results: This
analysis was performed on 73 patients (49 yr, range 29-70). Twenty (27%)
patients obtained best response (G4-G5) whether 50 (68%) were considered
as no responder (G1-G2-G3). Response was associated with negative
estrogen receptors expression (p�0.02) and high Ki67 basal and after C1
expression (p�0.009 and p�0.01). Six (54%) of the triple negative
tumors were responders (p�0.05). Interestingly, change in pVEGFR2
[Y951] staining induced by bevacizumab administration was found significantly
associated with response (p�0.0). Decrease in the phosphorilation
status of VEGFR2 (Y951) �70% yielded a receiver operating characteristic
(ROC) curve area of 0.681 (95% CI: 0.536 - 0.825) with 84% sensitivity
and 95% specificity. The positive and negative predictive values for this
marker were 60% and 64%, respectively. The change in phosphorilation
status of VEGFR2p remains a significant predictor biomarker of response in
multivariate analysis (OR�0.9, IC%95 0.96-0.99, p�0.04) after adjusting
for clinical-pathological characteristics. Conclusions: These findings
suggest the role of the phosphorilation status of VEGFR2 as predictive
biomarkers of pathological response to bevacizumab in neoadjuvant setting
in breast cancer.
10597 General Poster Session (Board #49F), Mon, 1:15 PM-5:15 PM
Response and long-term outcomes after neoadjuvant chemotherapy: Pooled
dataset of patients stratified by molecular subtyping by MammaPrint and
BluePrint. Presenting Author: Stefan Gluck, University of Miami/Sylvester
Comprehensive Cancer Center, Miami, FL
Background: Classification of breast cancers into molecular subtypes may
be important for the proper selection of therapy for patients with early
breast cancer. Previous analyses had shown that breast cancer subtypes
have distinct clinical outcome (Sorlie, PNAS, 2001; Esserman, BCRT,
2011). Herein, we analyze using MammaPrint together with an 80-gene
molecular subtyping profile (BluePrint) the response to neo-adjuvant
chemotherapy and long term outcomes. Methods: This study was carried out
on data from 144 patients from the I-SPY I trial; 232 patients from
biomarker discovery program at MD Anderson (133 and 99 respectively;
Hess, 2006, JCO; Iwamoto, 2011, BCRT); and 68 patients from City of
Hope (Somlo, ASCO, 2010). All patients were treated in the neo-adjuvant
setting with standard chemotherapy. MammaPrint and BluePrint were
determined on 44K Agilent arrays run at Agendia or available through the
I-SPY 1 data portal, or from Affymetrix U133A arrays. MammaPrint and
BluePrint resulted in 4 distinct molecular groups: Luminal A (MammaPrint
Low-risk/Luminal-type), Luminal B (MammaPrint High-risk/Luminal-type),
Basal-type and HER2-type. Results: The overall pCR of this patient cohort
was 22% but differed substantially among the subgroups. pCR was
observed in 5% of the Luminal-A samples and 10% of Luminal-B, in 39%
of the HER2-type samples and in 33% of the Basal-type samples. Patients
with Basal-type tumors had a 5-year DFS of 71%; HER2-type had a 5-year
DFS of 67%(n�71); 69% in HER2-type subgroup not treated with
HER2-targeted therapy (n�45); Luminal-B type had a 5-year DFS of 77%
and Luminal-A type showed 5-year DFS of 95%. Conclusions: We observed
marked differences in response and DFS to neo-adjuvant treatment in
groups stratified by MammaPrint and BluePrint. These findings confirm
differences in chemotherapy response among molecular subgroups and
indicate that the BluePrint and MP profile used for this analysis helps to
further establish a clinical correlation between molecular subtyping and
treatment outcomes.
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