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

7579 General Poster Session (Board #49E), Sat, 1:15 PM-5:15 PM
Family history of lung cancer in never smokers with non-small cell lung
cancer (NSCLC) and its association with tumors harboring epidermal
growth factor receptor (EGFR) mutations. Presenting Author: Elizabeth
Mary Gaughan, Beth Israel Deaconess Medical Center/Harvard Medical
School, Boston, MA
Background: Inherited susceptibility to lung cancer is an understudied
subject, however it has been described among never smokers (�100
cigarettes/lifetime). Never smokers with NSCLC comprise an important
subgroup of patients enriched for tumors harboring oncogene aberrations in
the EGFR and ALK genes. We aimed to better characterize the incidence of
family history of lung cancer in the setting of routine tumor genotyping
among never smokers with NSCLC. Methods: Clinicopathologic data plus
tumor genotype (EGFR, KRAS, ALK) from 230 consecutive never smokers
seen at Beth Israel Deaconess Medical Center and Dana-Farber Cancer
Institute was compiled. We retrospectively analyzed the incidence of a
family history of any cancer and lung cancer in these patients. Results: In
our cohort, the average age was 56 years, 67% of the patients were women,
75% were white, 41% had advanced NSCLC and 87% had adenocarcinoma
histology. In these tumors, 98/230 (43%) had an EGFR mutation,
16/155 (10%) had KRAS mutations and 27/127 (17%) had an ALK
translocation. Family history of any cancer was common (57%) and specific
family history of lung cancer was present in 42/230 cases (18%). Out of
thecases with a family history of any cancer, 22/53 (41.5%) EGFRmutated,
1/6 (17%) KRAS-mutated and 3/20 (15%) ALK-translocated
cohorts had a family history of lung cancer. The rate of family history of lung
cancer to family history of cancer was significantly higher in the EGFRmutated
cohort when compared to the ALK translocated plus KRASmutated
cohorts (p�0.023). Conclusions: Family history of lung cancer is
common in never smokers with NSCLC, and there seems to be a particular
link in families in which the proband has an EGFR-mutated tumor. Further
study of families with EGFR-mutated NSCLC may yield insights into the
pathogenesis of this tumor type.
7581 General Poster Session (Board #49G), Sat, 1:15 PM-5:15 PM
NGR-hTNF plus chemotherapy as first-line therapy of non-small cell lung
cancer (NSCLC). Presenting Author: Vanesa Gregorc, Department of
Oncology, Istituto Scientifico San Raffaele, Milan, Italy
Background: NGR-hTNF (asparagine-glycine-arginine human tumor necrosis
factor) is a selective vascular targeting agent able to improve intratumoral
chemotherapy uptake. Methods: Chemo-naive, stage IIIb-IV NSCLC
patients (pts), stratified by histology (nonsquamous or squamous) and PS
(0 or 1), were randomized to cisplatin 80 mg/m2 /day(d)1 plus either
pemetrexed 500 mg/m2 /d1 (nonsquamous) or gemcitabine 1,250 mg/m2 /
d1�8 (squamous) every 3 weeks (q3w) up to 6 cycles with (arm A) or
without (arm B) NGR-hTNF 0.8 �g/m2 /d1 q3w until progression. Progression
free survival (PFS) was primary end point of this phase 2 trial
(��20%, ��20%, HR�0.62, and n�102). Secondary end points included
adverse events (AEs), response rate (RR) and overall survival (OS).
Results: 59 pts were assigned to arm A and 57 to arm B. Baseline
characteristics in arm A/B were: median age 62/63; male 34/37; PS 1
21/21; squamous 15/15; nonsmokers 14/12; EGFR mutations 5/5. For the
nonsquamous group, 281 cycles (mean 6.5; range 1-18) were given in arm
A and 190 (mean 4.7; range 1-6) in arm B, while for the squamous group,
88 (mean 6.3; range 1-19) in arm A and 48 (mean 3.7; range 1-6) in arm
B. Most common grade 3/4 AEs were neutropenia 14% vs 17% and fatigue
7% vs 11% in arm A and B, respectively. No grade 3/4 AEs related to
NGR-hTNF or bleeding in pts with squamous histology were noted. Median
follow-up was 12.4 months. In the whole study population, median (m)PFS
was 5.8 vs 5.7 months (HR�0.95), RR was 23% vs 19%, and 1-year OS
was 62% vs 62% in arm A and B, respectively. In the nonsquamous subset,
a trend toward longer mPFS in arm A compared to arm B was noted in pts
with a PS of 1 (6.7 vs 4.6 months, respectively), nonsmoking history (6.2 vs
3.4), younger age (6.5 vs 3.4), and EGFR mutations (7.2 vs 3.3). In the
squamous subset, mPFS was 5.1 vs 3.9 months (HR�0.71) and mOS was
14.2 vs 10.8 months (HR�0.73) in arm A and B, respectively. In these pts,
ORR was 36% in arm A and 23% in arm B, while median changes from
baseline in target tumor size after 2, 4, and 6 cycles were -29%, -45%, and
-41%, respectively in arm A, and -18%, -22%, and -14%, respectively in
arm B. Conclusions: Regardless of histology, NGR-hTNF can be safely given
with standard chemotherapy, showing tolerability and hint of activity in
squamous NSCLC.
Lung Cancer—Non-small Cell Metastatic
499s
7580 General Poster Session (Board #49F), Sat, 1:15 PM-5:15 PM
Comparison of the KRAS/EGFR mutation profile and survival of “collegiate
smokers” and never smokers with advanced lung cancers. Presenting
Author: Anna M. Varghese, Memorial Sloan-Kettering Cancer Center, New
York, NY
Background: In practice, we encounter patients (pts) with lung cancers who
state they smoked only while in college. The impact of this degree of
tobacco use on cancer biology is unknown. We have shown that EGFR
mutations are less common in pts who smoked � 15 pack years (PY). We
hypothesize that among pts with lung cancer the KRAS / EGFR mutation
profile and overall survival (OS) of “collegiate smokers” (former smokers
who smoked between 101 lifetime cigarettes and 5 PY) will be distinct
from never smokers and former smokers with � 15 PY. Methods: We
collected age, sex, stage, and survival for pts evaluated from 2004 - 2009
with stage IIIB/IV lung cancer with known KRAS and EGFR status. ALK
testing was not available routinely during this time. Smoking history was
obtained using a patient completed survey. The Fisher exact test was used
to compare mutation profiles. The log rank test was used to compare OS.
Results: Smoking history and clinical data were available for 852 pts with
Stage IIIB/IV lung cancer with known KRAS and EGFR status: 307 never
smokers, 178 current smokers, and 367 former smokers. Of the former
smokers, 55 were “collegiate smokers”, 61 had smoked 5-15 PY, and 251
had smoked � 15 PY. The KRAS / EGFR mutation profiles by smoking
history are shown below (Table). The KRAS / EGFR mutation profile of
“collegiate smokers” is distinct from those of pts who were never smokers
(p � .001) and former smokers with � 15 PY (p � .001) but similar to that
of pts who were former smokers with 5-15 PY (p � 0.9). Median OS after
diagnosis of stage IIIB/IV lung cancer for “collegiate smokers” was 25
months (mos), compared to 32 mos for never smokers (p � 0.4) and 21
mos for former smokers with � 15 PY (p � 0.63). Conclusions: “Collegiate
smokers” are a distinct group of pts with a higher incidence of KRAS
mutations and lower incidence of EGFR mutations compared to never
smokers. These data suggest that even a small amount of cigarette smoking
influences the biology of lung cancer. These findings reinforce the
importance of doing mutation testing routinely for all pts with lung cancer
to guide clinical care.
Total EGFR KRAS
N N % N %
Never smokers 307 149 49 13 4
�Collegiate smokers� 55 15 27 8 15
Former smokers with > 15 pack years 251 27 11 100 40
7582 General Poster Session (Board #49H), Sat, 1:15 PM-5:15 PM
Thymidylate synthase (TS) gene expression in patients with ALK positive
(�) non-small cell lung cancer (NSCLC): Implications for therapy. Presenting
Author: David R. Gandara, University of California Davis Cancer Center,
Sacramento, CA
Background: ALK� NSCLC represents a molecular target-defined patient
population highly responsive to the ALK inhibitor crizotinib. Previous
reports have also suggested increased sensitivity of ALK� NSCLC to the
chemotherapeutic agent pemetrexed. Thymidylate synthase (TS) is a
candidate predictive biomarker for pemetrexed activity. Here we report
analysis of the Response Genetics Inc. (RGI) database for this association
and implications for therapy. Methods: ALK fusion was identified by a novel
RT-PCR assay (Danenberg et al: ASCO 2010). For TS, RNA from microdissected
formalin-fixed paraffin-embedded tumors was analyzed as previously
described, reported as the ratio of gene expression to �-actin. For
reference, a TS level �2.33 is the cutpoint for sensitivity. Results: TS levels
were available from 63 ALK� patients and 1,698 ALK- control lung
adenocarcinoma patients. All ALK� patients had adenocarcinomas without
EGFR or KRAS mutations. Median age: 59.0 (range 33-88), gender
(male/female) 32/31 (51%/49%). Median TS RNA level in ALK� patients
was 2.02, range (0.55-19.44), and in ALK- patients was 3.32 (0.36-
53.51), p�0.0001 (Mann-Whitney test). The majority of ALK� patients
(N�43, 68%) had a TS level �2.33 cutpoint, compared to only 32% of
ALK- patients (N�551, p�0.0001). Conclusions: This analysis demonstrates
relatively low TS gene expression in ALK� patient tumors as
determined by RT-PCR. These data provide a mechanism of action
supportive of pemetrexed sensitivity for ALK� NSCLC.
TS expression N Median 95% CI Range Mean 95% CI p value
ALK� patients 63 2.02 1.60-2.11 0.55-19.44 2.53 1.89-3.16 �0.0001
ALK- patients 1698 3.32 3.15-3.45 0.36-53.51 7.87 1.68-14.05
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