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

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7579 General Poster Session (Board #49E), Sat, 1:15 PM-5:15 PM<br />

Family history <strong>of</strong> lung cancer in never smokers with non-small cell lung<br />

cancer (NSCLC) and its association with tumors harboring epidermal<br />

growth factor receptor (EGFR) mutations. Presenting Author: Elizabeth<br />

Mary Gaughan, Beth Israel Deaconess Medical Center/Harvard Medical<br />

School, Boston, MA<br />

Background: Inherited susceptibility to lung cancer is an understudied<br />

subject, however it has been described among never smokers (�100<br />

cigarettes/lifetime). Never smokers with NSCLC comprise an important<br />

subgroup <strong>of</strong> patients enriched for tumors harboring oncogene aberrations in<br />

the EGFR and ALK genes. We aimed to better characterize the incidence <strong>of</strong><br />

family history <strong>of</strong> lung cancer in the setting <strong>of</strong> routine tumor genotyping<br />

among never smokers with NSCLC. Methods: Clinicopathologic data plus<br />

tumor genotype (EGFR, KRAS, ALK) from 230 consecutive never smokers<br />

seen at Beth Israel Deaconess Medical Center and Dana-Farber Cancer<br />

Institute was compiled. We retrospectively analyzed the incidence <strong>of</strong> a<br />

family history <strong>of</strong> any cancer and lung cancer in these patients. Results: In<br />

our cohort, the average age was 56 years, 67% <strong>of</strong> the patients were women,<br />

75% were white, 41% had advanced NSCLC and 87% had adenocarcinoma<br />

histology. In these tumors, 98/230 (43%) had an EGFR mutation,<br />

16/155 (10%) had KRAS mutations and 27/127 (17%) had an ALK<br />

translocation. Family history <strong>of</strong> any cancer was common (57%) and specific<br />

family history <strong>of</strong> lung cancer was present in 42/230 cases (18%). Out <strong>of</strong><br />

thecases with a family history <strong>of</strong> any cancer, 22/53 (41.5%) EGFRmutated,<br />

1/6 (17%) KRAS-mutated and 3/20 (15%) ALK-translocated<br />

cohorts had a family history <strong>of</strong> lung cancer. The rate <strong>of</strong> family history <strong>of</strong> lung<br />

cancer to family history <strong>of</strong> cancer was significantly higher in the EGFRmutated<br />

cohort when compared to the ALK translocated plus KRASmutated<br />

cohorts (p�0.023). Conclusions: Family history <strong>of</strong> lung cancer is<br />

common in never smokers with NSCLC, and there seems to be a particular<br />

link in families in which the proband has an EGFR-mutated tumor. Further<br />

study <strong>of</strong> families with EGFR-mutated NSCLC may yield insights into the<br />

pathogenesis <strong>of</strong> this tumor type.<br />

7581 General Poster Session (Board #49G), Sat, 1:15 PM-5:15 PM<br />

NGR-hTNF plus chemotherapy as first-line therapy <strong>of</strong> non-small cell lung<br />

cancer (NSCLC). Presenting Author: Vanesa Gregorc, Department <strong>of</strong><br />

Oncology, Istituto Scientifico San Raffaele, Milan, Italy<br />

Background: NGR-hTNF (asparagine-glycine-arginine human tumor necrosis<br />

factor) is a selective vascular targeting agent able to improve intratumoral<br />

chemotherapy uptake. Methods: Chemo-naive, stage IIIb-IV NSCLC<br />

patients (pts), stratified by histology (nonsquamous or squamous) and PS<br />

(0 or 1), were randomized to cisplatin 80 mg/m2 /day(d)1 plus either<br />

pemetrexed 500 mg/m2 /d1 (nonsquamous) or gemcitabine 1,250 mg/m2 /<br />

d1�8 (squamous) every 3 weeks (q3w) up to 6 cycles with (arm A) or<br />

without (arm B) NGR-hTNF 0.8 �g/m2 /d1 q3w until progression. Progression<br />

free survival (PFS) was primary end point <strong>of</strong> this phase 2 trial<br />

(��20%, ��20%, HR�0.62, and n�102). Secondary end points included<br />

adverse events (AEs), response rate (RR) and overall survival (OS).<br />

Results: 59 pts were assigned to arm A and 57 to arm B. Baseline<br />

characteristics in arm A/B were: median age 62/63; male 34/37; PS 1<br />

21/21; squamous 15/15; nonsmokers 14/12; EGFR mutations 5/5. For the<br />

nonsquamous group, 281 cycles (mean 6.5; range 1-18) were given in arm<br />

A and 190 (mean 4.7; range 1-6) in arm B, while for the squamous group,<br />

88 (mean 6.3; range 1-19) in arm A and 48 (mean 3.7; range 1-6) in arm<br />

B. Most common grade 3/4 AEs were neutropenia 14% vs 17% and fatigue<br />

7% vs 11% in arm A and B, respectively. No grade 3/4 AEs related to<br />

NGR-hTNF or bleeding in pts with squamous histology were noted. Median<br />

follow-up was 12.4 months. In the whole study population, median (m)PFS<br />

was 5.8 vs 5.7 months (HR�0.95), RR was 23% vs 19%, and 1-year OS<br />

was 62% vs 62% in arm A and B, respectively. In the nonsquamous subset,<br />

a trend toward longer mPFS in arm A compared to arm B was noted in pts<br />

with a PS <strong>of</strong> 1 (6.7 vs 4.6 months, respectively), nonsmoking history (6.2 vs<br />

3.4), younger age (6.5 vs 3.4), and EGFR mutations (7.2 vs 3.3). In the<br />

squamous subset, mPFS was 5.1 vs 3.9 months (HR�0.71) and mOS was<br />

14.2 vs 10.8 months (HR�0.73) in arm A and B, respectively. In these pts,<br />

ORR was 36% in arm A and 23% in arm B, while median changes from<br />

baseline in target tumor size after 2, 4, and 6 cycles were -29%, -45%, and<br />

-41%, respectively in arm A, and -18%, -22%, and -14%, respectively in<br />

arm B. Conclusions: Regardless <strong>of</strong> histology, NGR-hTNF can be safely given<br />

with standard chemotherapy, showing tolerability and hint <strong>of</strong> activity in<br />

squamous NSCLC.<br />

Lung Cancer—Non-small Cell Metastatic<br />

499s<br />

7580 General Poster Session (Board #49F), Sat, 1:15 PM-5:15 PM<br />

Comparison <strong>of</strong> the KRAS/EGFR mutation pr<strong>of</strong>ile and survival <strong>of</strong> “collegiate<br />

smokers” and never smokers with advanced lung cancers. Presenting<br />

Author: Anna M. Varghese, Memorial Sloan-Kettering Cancer Center, New<br />

York, NY<br />

Background: In practice, we encounter patients (pts) with lung cancers who<br />

state they smoked only while in college. The impact <strong>of</strong> this degree <strong>of</strong><br />

tobacco use on cancer biology is unknown. We have shown that EGFR<br />

mutations are less common in pts who smoked � 15 pack years (PY). We<br />

hypothesize that among pts with lung cancer the KRAS / EGFR mutation<br />

pr<strong>of</strong>ile and overall survival (OS) <strong>of</strong> “collegiate smokers” (former smokers<br />

who smoked between 101 lifetime cigarettes and 5 PY) will be distinct<br />

from never smokers and former smokers with � 15 PY. Methods: We<br />

collected age, sex, stage, and survival for pts evaluated from 2004 - 2009<br />

with stage IIIB/IV lung cancer with known KRAS and EGFR status. ALK<br />

testing was not available routinely during this time. Smoking history was<br />

obtained using a patient completed survey. The Fisher exact test was used<br />

to compare mutation pr<strong>of</strong>iles. The log rank test was used to compare OS.<br />

Results: Smoking history and clinical data were available for 852 pts with<br />

Stage IIIB/IV lung cancer with known KRAS and EGFR status: 307 never<br />

smokers, 178 current smokers, and 367 former smokers. Of the former<br />

smokers, 55 were “collegiate smokers”, 61 had smoked 5-15 PY, and 251<br />

had smoked � 15 PY. The KRAS / EGFR mutation pr<strong>of</strong>iles by smoking<br />

history are shown below (Table). The KRAS / EGFR mutation pr<strong>of</strong>ile <strong>of</strong><br />

“collegiate smokers” is distinct from those <strong>of</strong> pts who were never smokers<br />

(p � .001) and former smokers with � 15 PY (p � .001) but similar to that<br />

<strong>of</strong> pts who were former smokers with 5-15 PY (p � 0.9). Median OS after<br />

diagnosis <strong>of</strong> stage IIIB/IV lung cancer for “collegiate smokers” was 25<br />

months (mos), compared to 32 mos for never smokers (p � 0.4) and 21<br />

mos for former smokers with � 15 PY (p � 0.63). Conclusions: “Collegiate<br />

smokers” are a distinct group <strong>of</strong> pts with a higher incidence <strong>of</strong> KRAS<br />

mutations and lower incidence <strong>of</strong> EGFR mutations compared to never<br />

smokers. These data suggest that even a small amount <strong>of</strong> cigarette smoking<br />

influences the biology <strong>of</strong> lung cancer. These findings reinforce the<br />

importance <strong>of</strong> doing mutation testing routinely for all pts with lung cancer<br />

to guide clinical care.<br />

Total EGFR KRAS<br />

N N % N %<br />

Never smokers 307 149 49 13 4<br />

�Collegiate smokers� 55 15 27 8 15<br />

Former smokers with > 15 pack years 251 27 11 100 40<br />

7582 General Poster Session (Board #49H), Sat, 1:15 PM-5:15 PM<br />

Thymidylate synthase (TS) gene expression in patients with ALK positive<br />

(�) non-small cell lung cancer (NSCLC): Implications for therapy. Presenting<br />

Author: David R. Gandara, University <strong>of</strong> California Davis Cancer Center,<br />

Sacramento, CA<br />

Background: ALK� NSCLC represents a molecular target-defined patient<br />

population highly responsive to the ALK inhibitor crizotinib. Previous<br />

reports have also suggested increased sensitivity <strong>of</strong> ALK� NSCLC to the<br />

chemotherapeutic agent pemetrexed. Thymidylate synthase (TS) is a<br />

candidate predictive biomarker for pemetrexed activity. Here we report<br />

analysis <strong>of</strong> the Response Genetics Inc. (RGI) database for this association<br />

and implications for therapy. Methods: ALK fusion was identified by a novel<br />

RT-PCR assay (Danenberg et al: ASCO 2010). For TS, RNA from microdissected<br />

formalin-fixed paraffin-embedded tumors was analyzed as previously<br />

described, reported as the ratio <strong>of</strong> gene expression to �-actin. For<br />

reference, a TS level �2.33 is the cutpoint for sensitivity. Results: TS levels<br />

were available from 63 ALK� patients and 1,698 ALK- control lung<br />

adenocarcinoma patients. All ALK� patients had adenocarcinomas without<br />

EGFR or KRAS mutations. Median age: 59.0 (range 33-88), gender<br />

(male/female) 32/31 (51%/49%). Median TS RNA level in ALK� patients<br />

was 2.02, range (0.55-19.44), and in ALK- patients was 3.32 (0.36-<br />

53.51), p�0.0001 (Mann-Whitney test). The majority <strong>of</strong> ALK� patients<br />

(N�43, 68%) had a TS level �2.33 cutpoint, compared to only 32% <strong>of</strong><br />

ALK- patients (N�551, p�0.0001). Conclusions: This analysis demonstrates<br />

relatively low TS gene expression in ALK� patient tumors as<br />

determined by RT-PCR. These data provide a mechanism <strong>of</strong> action<br />

supportive <strong>of</strong> pemetrexed sensitivity for ALK� NSCLC.<br />

TS expression N Median 95% CI Range Mean 95% CI p value<br />

ALK� patients 63 2.02 1.60-2.11 0.55-19.44 2.53 1.89-3.16 �0.0001<br />

ALK- patients 1698 3.32 3.15-3.45 0.36-53.51 7.87 1.68-14.05<br />

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