April 14, 2007

LCS Study Update: Survival OutcomesRebecca Suk Heist, MD MPH

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

BACNSCLC 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)

0. 00

0. 25

0. 50

0. 75

1. 00

Over al l Sur vi val t i me ( year s )

0 2 4 6 8 10 12

STRATA: STAGE=1A STAGE=1B STAGE=2A STAGE=2B

IA

IB

IIA

IIB

Survival by Stage (IIIA - IV)

0. 00

0. 25

0. 50

0. 75

1. 00

Over al l Sur vi val t i me ( year s )

0 2 4 6 8 10 12 14

STRATA: STAGE=3A STAGE=3B STAGE=4

IIIA

IIIB

IV

Survival by Gender (Stage I - II)

0. 00

0. 25

0. 50

0. 75

1. 00

Over al l Sur vi val t i me ( year s )

0 2 4 6 8 10 12

STRATA: SEX=1 SEX=2

M

F

Survival by Gender (Stage IIIA – IV)

0. 00

0. 25

0. 50

0. 75

1. 00

Over al l Sur vi val t i me ( year s )

0 2 4 6 8 10 12 14

STRATA: SEX=1 SEX=2

F

M

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

More aggressive tumor

Worse survival

DNA damage from platinum cannot be

repaired as efficently

Better response

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: 2594-601Zhou et al, Clin Cancer Res 2004; 10: 4939-43

Median survival by # variant alleles

Gurubhagavatula et al, JCO 2004; 22: 2594-601

XPD and XRCC1 # pts Median survival (months)

Adjusted HR

(95% CI)

0 variant alleles

1

2

3

26

40

24

13

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)

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

0. 00

0. 25

0. 50

0. 75

1. 00

Over al l Sur vi val t i me ( year s )

0 2 4 6 8 10 12

STRATA: var y4=1 var y4=2 var y4=3 Heist et al, AACR 2007

0-2

3-4

>5

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

Heist et al, Clin Cancer Res 2006; 12: 5448-53

Genotype Events/

Total

Adjusted HR

(95% CI)

MMP-12 1082A/G

A/A

A/G + G/G

157/336

30/46

Reference

1.94 (1.28 – 2.97)

p = 0.002

MMP-12 1082 A/G Polymorphism and Survival

Heist et al, Clin Cancer Res 2006; 12: 5448-53

5-yr OS 62%

5-yr OS 47%

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

Heist et al, JCO in press

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)

MDM2 and Survival among Squamous Cell

Heist et al, JCO in press

Log rank p = 0.0001

T/T

T/G

G/G

T/T 59%T/G 52%G/G 7%

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: 156-62Nakagawa 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

Zhou et al, JCO 2007; 25: 479-85

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

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 GROUPDavid Christiani, MDKofi Asomaning, MDEmilie BruzeliusDaisy ChiuThea Cogan-DrewSarada Gurubhagavatula, MDSohee Park, PhDXihong Lin, PhDGeoffrey Liu, MDAriela MarshallSal MucciDonna Neuberg, ScDVanessa SalasAndrea ShaferLi SuLily WongWei 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%]

56 months

39% [32%-47%]

42 months

0.65[0.50-0.86]

p = 0.002

ERCC1 positive tumors n=335

40% [32%-49%]

50 months

46% [37%-55%]

55 months

1.14[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