Clinicopathologic characteristics and survival outcomes of five subtypes of adenocarcinoma

that has been associated with histological characteristics of EML4-ALK NSCLC

Sai-Hong Ignatius Ou, MD PhDAssociate Clinical Professor

Chao Family Comprehensive Cancer CenterDepartment of Medicine, Division of Hematology-Oncology

University of California Irvine Medical Center, Orange, CA 92868

Background• ALK translocation in NSCLC has recently been

discovered• At least 9 EML4-ALK fusion transcripts in NSCLC

described• Usually ALK +ve NSCLC are found in young, never-

smokers, with adenocarcinoma but only constitutes about 3-5% of all NSCLC

• Several adenocarcinoma histological subtypes have been associated with ALK +ve NSCLC including signet ring carcinoma (SRC), acinar carcinoma, papillary carcinoma, mixed adenocarcinoma, and even BAC

• An ALK inhibitor (Crizotinib-PF02341066) has significant clinical activity in ALK +ve NSCLC

Objective

• We investigated clinicopathologic characteristics and survival outcome of several rare adenocarcinoma subtypes to see if any one or more of the adenocarcinoma subtypes closely matches those described for ALK + ve NSCLC

Methods• Adenocarcinoma of the lung diagnosed from

1989 to 2006 were abstracted from the California Cancer Registry (CCR)

• Smoking status were abstracted from subgroup of patients within 3 regional CCR using a text mining algorithm

• Univariate analysis were performed by log-rank using Kaplan-Meier method

• Multivariate analysis were performed by Cox proportional hazards model

Results

• A total of 59501 cases were analyzed including– 50089 cases of adenocarcinoma– 7171 cases of BAC– 1241 cases of papillary carcinoma– 379 cases of acinar carcinoma– 359 cases of mixed adenocarcinoma– 262 cases of signet ring carcinoma

AdenoCA BAC Acinarcarcinoma

Papillary carcinoma

SRC Mixed adenoCA

p

N 50089 7171 379 1241 262 359

Median age (95% CI) 67 (46-83) 69 (49-83) 66 (47-83) 67 (46-82) 64 (40-80) 68 (48-85) < 0.0001

Median f/u time (95%CI) 9 (1-109) 28 (1-151) 31 (3-98) 17 (1-115) 5.5 (1-58) 21 (1-62) < 0.0001

Age category 0-39 40-49 50-59 60-69 70-79 80+

666 (1.3)3516 (7.0)

9852 (19.7)16198 (32.3)14822 (29.6)5035 (10.1)

66 (0.9)327 (4.6)

1095 (15.3)2197 (30.6)2569 (35.8)917 (12.8)

3 (0.8)24 (6.3)

61 (16.1)142 (37.5)111 (29.3)38 (10.0)

20 (1.6)86 (6.9)

253 (20.4)386 (31.1)386 (31.1)110 (8.9)

13 (5.0)24 (9.2)

64 (24.4)80 (30.5)65 (24.8)16 (6.1)

1 (0.3)21 (5.9)

65 (18.1)115 (32.0)101 (28.1)56 (15.6) < 0.0001

Gender Male Female

26062 (52.0)24027 (48.0)

2958 (41.3)4213 (58.8)

166 (43.8)213 (56.2)

592 (47.7)649 (52.3)

146 (55.7)116 (44.3)

149 (41.5)210 (58.5) < 0.0001

Ethnicity Caucasian African-American Hispanic Asian Other

37677 (75.2)3695 (7.4)4310 (8.6)4215 (8.4)192 (0.4)

5226 (72.9)481 (6.7)646 (9.0)

800 (11.2)18 (0.3)

290 (76.5)23 (6.1)30 (7.9)34 (9.0)2 (0.5)

875 (70.5)86 (6.9)

108 (8.7)169 (13.6)

3 (0.2)

190 (72.5)19 (7.3)

31 (11.8)21 (8.0)1 (0.4)

255 (71.0)20 (5.6)

37 (10.3)47 (13.1)

0 (0.0) 0.0001

Tumor differentiation Well Moderate Poor Undifferentiated Unknown

2635 (5.3)11484 (22.9)21743 (43.4)

794 (1.6)13433 (26.8)

2119 (29.6)1840 (25.7)

614 (8.6)55 (0.8)

2543 (35.5)

61 (16.1)208 (54.9)89 (23.5)

4 (1.1)17 (4.5)

204 (16.4)411 (33.1)189 (15.2)

16 (1.3)421 (33.9)

2 (0.8)24 99.2)

131 (50.0)3 (1.2)

102 (38.9)

86 (24.0)126 (35.1)86 (24.0)

6 (1.7)55 (15.3) < 0.0001

AJCC stage I II III IV Unknown

9174 (18.3)2610 (5.2)

8315 (16.6)18409 (36.8)11581 (23.1)

3139 (43.8)403 (5.6)658 (9.2)

1171 (16.3)1800 (25.1)

184 (48.6)47 (12.4)43 (11.4)26 (6.9)

79 (20.8)

319 (25.7)95 (7.7)

170 (13.7)375 (30.2)282 (22.7)

16 (6.1)13 (5.0)

54 (20.6)129 (49.2)50 (19.1)

152 (42.3)35 (9.8)

51 (14.2)39 (10.9)82 (22.8) < 0.0001

Smoking status according to adenoCA subtype

Kaplan-Meier survival curves by adenoCA subtypes

Cox analysisHazard Ratio 95% Confidence Interval p

Histology Adenocarcinoma Acinar carcinoma Mixed adenocarcinoma BAC Papillary carcinoma Signet-ring cell carcinoma

1.0000.7620.8150.8380.9031.215

(0.653-0.889)(0.688-0.966)(0.812-0.866)(0.848-0.963)(1.069-1.382)

0.00060.0182

< 0.00010.00190.0029

Age 1.012 (1.011-1.013) < 0.0001

Gender Male Female

1.0000.828 (0.813-0.843) < 0.0001

Ethnicity Caucasian African American Asian Hispanic

1.0001.0130.8100.988

(0.978-1.048)(0.784-0.838)(0.957-1.021)

0.4782< 0.00010.4714

Tumor differentiation* Well Moderate Poor Undifferentiated

1.0001.1731.3701.327

(1.126-1.221)(1.318-1.426)(1.226-1.437)

< 0.0001< 0.0001< 0.0001

AJCC stage* I II III IV

1.0001.8772.3053.588

(1.792-1.966)(2.220-2.392)(3.460-3.720)

< 0.0001< 0.0001< 0.0001

Conclusions• Acinar carcinoma subtype has the best OS• Signet ring carcinoma (SRC) subtype had the worst OS• Adenocarcinoma subtypes are heterogeneous• SRC had the highest proportion of never-smokers• All adenocarcinoma subtypes is a favorable prognostic

factor in OS when compared to adenocarcinoma• SRC is an independent unfavorable prognostic factor

after factoring in age, gender, ethnicity, stage, tumor differentiation, period of diagnosis and treatment (surgery, radiation, chemotherapy)