Download Rebecca Suk Heist, MD, MPH: LCS Study Update: Survival Outcomes

LCS Study Update: Survival Outcomes
Rebecca Suk Heist, MD MPH
April 14, 2007
Lung Cancer Susceptibility (LCS) Study
• Case-control study of lung cancer susceptibility at
Massachusetts General Hospital (MGH)
• Enrolling patients and controls since 1992
• MGH thoracic oncology and thoracic surgery units
• Blood samples and tumor tissue collected at time of
recruitment
• Questionnaires for smoking, environmental exposures, diet
• Informed consent obtained, including for follow-up data
collection and contact
Lung Cancer Survival by Clinical Stage
Chest 1997; 111: 1710-7
Survival Study: Case Ascertainment in LCS
• Early Stage (I – II)
– 12/92 – 12/01
– Treated with surgical resection at MGH
• Late Stage (IIIA – IV)
– 12/92 – 7/04
– Received treatment at MGH
– Initially focused on platinum-treated -> expanded to all
• No other malignancy (other than non-melanoma skin cancer)
in the previous five years prior to lung cancer diagnosis
Clinical Outcomes in LCS
• Clinical data extraction
– TNM Stage
– Treatment
• Type of surgery
• Radiation
• Chemotherapy
• Survival outcomes
– Date of death or last known date alive
• MGH tumor registry, SSDI, NDI, patient’s physician or family
– Date of progression or last known date without progression
• Toxicity outcomes
Patient Characteristics
n = 1015
Age
66 (31-89)
Male
Female
519 (51%)
496 (49%)
Never Smoker
Former Smoker
Current Smoker
84 (8%)
507 (50%)
424 (42%)
Pack-years
49 (0-204)
Stage Characteristics
n = 1015
Stage IA
Stage IB
285 (28%)
163 (16%)
Stage IIA
Stage IIB
23 (2%)
87 (9%)
Stage IIIA
Stage IIIB
85 (8%)
78 (8%)
Stage IV
294 (29%)
Histologic Subtype
n = 1015
Adenocarcinoma
Squamous Cell
Large Cell
BAC
NSCLC NOS
514 (51%)
240 (23%)
94 (9%)
87 (9%)
80 (8%)
Treatment Characteristics (Stage I – II)
n = 558
Type of Surgery
Lobectomy
Wedge/Segmentectomy
Pneumonectomy
Bilobectomy
Sleeve Lobectomy
Other
342 (61%)
144 (26%)
29 (5%)
16 (3%)
22 (4%)
5 (1%)
Adjuvant radiation
43 (8%)
Adjuvant chemotherapy
5 (1%)
Chemotherapy included in First Regimen
(Stage III – IV)
n = 457
Carboplatin
Cisplatin
Paclitaxel
Gemcitabine
Navelbine
Docetaxel
Vinblastine
5FU
Etoposide
Gefitinib
Erlotinib
284
105
236
53
16
13
48
56
45
12
11
Survival by Stage (I – II)
1. 00
0. 75
IA
IB
0. 50
IIA
IIB
0. 25
0. 00
0
2
4
6
Ov e r a l l
S T RA T A :
S T A GE = 1 A
Su r v i v a l
S T A GE = 1 B
8
t i me
10
( year s)
S T A GE = 2 A
S T A GE = 2 B
12
Survival by Stage (IIIA - IV)
1. 00
0. 75
0. 50
IIIA
IIIB
0. 25
IV
0. 00
0
2
4
6
Ov e r a l l
S T RA T A :
S T A GE = 3 A
8
Su r v i v a l
t i me
10
( year s)
S T A GE = 3 B
S T A GE = 4
12
14
Survival by Gender (Stage I - II)
1. 00
0. 75
F
0. 50
M
0. 25
0. 00
0
2
4
6
Ov e r a l l
S T RA T A :
Su r v i v a l
SEX= 1
8
t i me
( year s)
SEX= 2
10
12
Survival by Gender (Stage IIIA – IV)
1. 00
0. 75
0. 50
F
0. 25
M
0. 00
0
2
4
6
Ov e r a l l
S T RA T A :
8
Su r v i v a l
SEX= 1
t i me
10
( year s)
SEX= 2
12
14
Investigating Prognostic and Predictive Factors
• Stage I and II surgically resected
– Currently no adjuvant treatment, but will include with
more current updates
• Stage III and IV
– Chemotherapy
– +/- Radiation
– +/- Surgery
Potential Prognostic and Predictive Factors
• Genetic polymorphisms
– DNA repair
– MMP
– MDM2
• Environmental and Dietary Exposures
– Smoking
– Vitamin D
Role of DNA repair in lung cancer outcomes?
Defective DNA Repair
Genetic mutations
accumulate
DNA damage from
platinum cannot be
repaired as efficently
More aggressive tumor
Better response
Worse survival
Better survival
DNA repair expression and survival
• Platinum-treated advanced stage:
– Increased DNA repair expression has been associated
with resistance to platinum chemotherapy and worse
survival in multiple cancers
• Early stage:
– Increased DNA repair expression in tumor associated
with better survival
DNA Repair Polymorphisms and Survival
• Stage IIIA, IIIB, IV
• Platinum-treated, histologically defined NSCLC
– carboplatin/taxane
– cisplatin/vinca
– cisplatin/etoposide
– other combinations
• 60% also received radiation
Median Survival
Genotype
Median survival time
(months)
p
ERCC2 Asp312Asn
Asp/Asp
Asp/Asn
Asn/Asn
16.3 mo
15.2 mo
6.6 mo
p = 0.003
XRCC1 Arg399Gln
Arg/Arg
Arg/Gln
Gln/Gln
17.3 mo
11.4 mo
7.7 mo
p = 0.07
ERCC1 C8092A
C/C
C/A + A/A
22.3 mo
13.4 mo
p = 0.006
Gurubhagavatula et al, JCO 2004; 22: 2594-601
Zhou et al, Clin Cancer Res 2004; 10: 4939-43
Median survival by # variant alleles
XPD and XRCC1 # pts
Median
survival
(months)
Adjusted HR
(95% CI)
0 variant alleles
1
2
3
20.4
16.6
11.0
6.8
p = 0.009
Reference
0.75 (0.41 – 1.38)
1.38 (0.73 - 2.63)
2.72 (1.31 – 5.67)
26
40
24
13
Gurubhagavatula et al, JCO 2004; 22: 2594-601
Survival by DNA repair polymorphisms
Gurubhagavatula et al, JCO 2004; 22: 2594-60
DNA Repair in Early Stage Lung Cancer
• Patient Population
– Stage I – II
– Surgically resected NSCLC
– No adjuvant chemotherapy or radiation
• Prognostic evaluation
• Individual and combined effect of DNA repair pathway
gene polymorphisms
– XRCC1 Arg399Gln, hOGG1 Ser326Cys, APE1 Asp148Glu,
ERCC2 Asp312Asn, ERCC2 Lys751Gln, ERCC1 8092C/A
DNA Repair in Early Stage Lung Cancer
Genotype
5-yr Overall Survival (95% CI)
XRCC1 Arg/Arg
XRCC1 Arg/Gln
XRCC1 Gln/Gln
57% (48-64)
57% (49-65)
62% (48-72)
hOGG1 C/C
hOGG1 C/G + G/G
53% (46-60)
65% (57-72)
APE1 T/T
APE1 T/G
APE1 G/G
54% (45-63)
58% (50-65)
64% (51-74)
ERCC2 Lys/Lys
ERCC2 Lys/Gln
ERCC2 Gln/Gln
52% (44-60)
63% (55-70)
58% (51-76)
ERCC2 Asp/Asp
ERCC2 Asp/Asn
ERCC2 Asn/Asn
54% (46-62)
59% (51-66)
63% (48-75)
ERCC1 C/C
ERCC1 C/A + A/A
55% (48-62)
62% (54-69)
Survival by DNA repair variant alleles
1. 00
0. 75
>5
0. 50
3-4
0. 25
0-2
0. 00
0
2
4
6
Ov e r a l l
S T RA T A :
v ar y 4=1
8
Su r v i v a l
t i me
v ar y 4=2
10
12
( year s)
v ar y 4=3
Heist et al, AACR 2007
DNA Repair and Clinical Outcomes
•
Looked separately at
– early stage – no chemotherapy or radiation
– late stage – treated with chemotherapy and/or radiation
• Direction of effect of DNA repair polymorphisms opposite
in early and late stages
• DNA repair polymorphisms may have different roles in
tumor behavior and response to chemotherapy
• Consistent with findings from mRNA and IHC analysis
Matrix Metalloproteinases (MMPs)
• Proteolytic enzymes that degrade extracellular matrix and
facilitate invasion through the basement membrane
– Remodeling and degrading extracellular matrix
– Angiogenesis
– Mediating cell-cell adhesions
• Elevated levels of MMPs have been associated with worse
survival in NSCLC
Polymorphisms in MMP-1,-3,-12 with potential function
MMP-1 -1607 1G/2G (rs1799750)
2G higher transcriptional activity
MMP-3 -1612 5A/6A (rs3025058)
5A higher transcriptional activity
MMP-12 -82 A/G (rs2276109)
A allele higher transcriptional activity
MMP-12 1082A/G (357Asn/Ser, rs652438)
location in hemopexin domain
MMP Polymorphisms and Survival
Genotype
MMP-12 1082A/G
A/A
A/G + G/G
Events/
Total
Adjusted HR
(95% CI)
157/336 Reference
30/46
1.94 (1.28 – 2.97)
p = 0.002
Heist et al, Clin Cancer Res 2006; 12: 5448-53
MMP-12 1082 A/G Polymorphism and Survival
5-yr OS 62%
5-yr OS 47%
Heist et al, Clin Cancer Res 2006; 12: 5448-53
MDM2
Alarcan-Vargas & Ronai, Carcinogenesis 2002; 23: 541-7
Polymorphism in MDM2
• T->G at position 309 in promoter area
• Increase binding affinity of Sp1 transcription factor
• G/G associated with higher MDM2 mRNA and protein
levels, and inactivation of p53 pathway
• Hypothesis: G/G genotype worse survival
Bond et al, Cell 2004; 119: 591-602
MDM2 and Survival for Stage I – II NSCLC
MDM2
5-yr OS (95% CI)
Adjusted HR
(95% CI)
T/T
T/G
G/G
61% (53-69)
58% (50-66)
44% (31-57)
Reference
1.10 (0.79-1.54)
1.57 (1.03-2.40)
Heist et al, JCO in press
MDM2 and Survival among Squamous Cell
1.00
Log rank p = 0.0001
0.75
T/T
0.50
T/G
0.25
G/G
0.00
0
T/T
T/G
G/G
59%
STRATA:
52%
7%
2
4
6
8
10
12
Overall Survival time (years)
MDM2=1
MDM2=2
MDM2=3
Heist et al, JCO in press
Vitamin D Metabolism
Vitamin D and Cancer
• Epidemiologic studies have linked season and geographic
latitude with incidence and mortality from a variety of
cancers
• Anti-proliferative effects
– Induction of G0/G1 cell cycle arrest
• VDR knock-out mice develop more tumors when exposed
to carcinogens
• In a mouse model, metastatic spread of Lewis lung
carcinoma cells inhibited by higher serum 1,25(OH)2D
Bouillon et al, J Steroid Biochem Mol Bio 2006; 102: 156-62
Nakagawa et al, Carcinogenesis 2005; 26: 429-40
Surgery Season and Dietary Vitamin D
Zhou et al, CEBP 2005; 14: 2303-9
Serum Vitamin D Levels and Survival
Quartiles of
serum Vit D
Events/Total
Adjusted HR
< 10.2 ng/mL
66/111
Reference
10.2 – 15.7
64/114
1.07 (0.74 – 1.53)
15.7 – 21.8
57/111
0.80 (0.55 – 1.18)
> 21.8
47/111
0.74 (0.50 – 1.10)
ptrend = 0.07
Zhou et al, JCO 2007; 25: 479-85
Summary
• Detailed dataset of clinical information and survival
outcomes in NSCLC patients
• Platform for investigating prognostic/predictive markers
• Candidate SNPs
• Dietary/environmental factors
Future Directions
• Pathway based approach rather than one candidate gene
–
–
–
–
–
DNA repair
Inflammation
Angiogenesis
Hormonal
Cell cycle/apoptosis
• Haplotype tagging SNPs
• Correlation with tumor tissue levels
• Tumor genomics
Acknowledgements
CHRISTIANI LAB – LCS GROUP
David Christiani, MD
Kofi Asomaning, MD
Emilie Bruzelius
Daisy Chiu
Thea Cogan-Drew
Sarada Gurubhagavatula, MD
Sohee Park, PhD
Xihong Lin, PhD
Geoffrey Liu, MD
Ariela Marshall
Sal Mucci
Donna Neuberg, ScD
Vanessa Salas
Andrea Shafer
Li Su
Lily Wong
Wei Zhou MD, PhD
MGH
Tom Lynch, MD
Bruce Chabner, MD
John Wain, MD
MGH Thoracic Oncology
MGH Thoracic Surgery
All the patients, physicians, surgeons,
of the MGH Cancer Center
ERCC1 mRNA in resected NSCLC
Simon et al. Chest 2005; 127: 978-83
ERCC1 mRNA in advanced NSCLC
Lord et al. Clin Cancer Res 2002; ;2286-91
ERCC1 IHC as a Predictive Marker
Olaussen et al, NEJM 2006; 355: 983-91
ERCC1 IHC as Prognostic/Predictive Marker
Chemotherapy
n=389
5-year survival
rate,
Median survival
Control group
n=372
5-year survival
rate,
Median survival
Hazard ratio
for death
CT vs. no CT
ERCC1 negative
tumors n=426
47% [40%-55%]
39% [32%-47%]
0.65
56 months
42 months
[0.50-0.86]
p = 0.002
ERCC1 positive
tumors n=335
40% [32%-49%]
46% [37%-55%]
1.14
50 months
55 months
[0.84-1.55]
p = 0.40
Soria et al, ASCO 2006
ERCC1 and RRM1 in Stage I resected NSCLC
Zheng et al, NEJM 2007; 356: 800-8