D5-03: Prognostic implications of cell cycle-related proteins in primary resectable pn2 non-small cell lung cancer

12th World Conference on Lung Cancer

Journal of Thoracic Oncology • Volume 2, Number 8, Supplement 4, August 2007

Session D5: Prognostic Factors

D5-02

Increased BRCA1 mRNA: an independent prognostic variable in completely resected chemonaive non-small-cell lung cancer (NSCLC) patients (p)

Thursday, September 6

D5-01

Prognostic Factors, Thu, 12:30 - 14:15

Prognostic significance of molecular markers and clinical factors in stage ib non-small cell lung cancer (NSCLC): a laboratory companion study to CALGB 9633

Graziano, Stephen L.1 Gu, Lin2 Wang, Xiaofei F.2 Tatum, Arthur H.1 Vollmer, Robin T.2 Strauss, Gary M.3 Kratzke, Robert A.4 Green, Mark R.5 Vokes, Everett E.6 1 SUNY Upstate Medical University, Syracuse, NY, USA 2 Duke University Medical Center, Durham, NC, USA 3 Tufts New England Medical Center, Boston, MA, USA 4 University of Minnesota, Minneapolis, MN, USA 5 Care Alliance Roper Hospital, Charleston, SC, USA 6 University of Chicago, Chicago, IL, USA Background: CALGB 9633 is a randomized trial that randomized patients to observation (O) or 4 cycles of adjuvant chemotherapy with carboplatin and paclitaxel (C). A statistically significant effect in favor of adjuvant chemotherapy was seen for failure-free survival and overall survival for tumors ≥ 4 cm. A laboratory companion study was conducted to see if additional prognostic information could be obtained from molecular and clinical factors. Methods: Paraffin blocks were obtained for 249 of the 344 patients randomized. Immunohistochemical (IHC) staining was successfully performed on 241 cases for bcl-2, p53, blood group antigen A and mucin and correlated with failure-free survival. Results: The prevalence of the markers was a follows: bcl-2 17% (O/C 15%/19%), p53 47% (42%/51%), blood group antigen A 25% (28%/23%) and mucin 46% (48%/42%). There are no statistically significant associations between marker positivity and treatment arm (p>0.15). Analysis of failure-free survival (FFS) survival is shown below: Marker bcl-2

Median FFS

in months (95%CI)

Log-rank

negative

positive

p-value

66(54,98)

70(34,NR)

0.65

p53

98(57,NR)

63(37,88)

0.11

antigen A

88(52,NR)

67(54,NR)

0.88

NR

51(28,NR)

0.0016

mucin

Prognostic Factors, Thu, 12:30 - 14:15

*NR=not reached

In multivariate analysis using a model with all 4 variables, a statistically significant association between shorter FFS and mucin positive (p-value=0.0024; hazard ration (HR) 2.14) and p53 positive (p-value 0.0057; HR 1.95) patients was seen. Gender and estimated tumor volume were also prognostic (p-value <0.05). Conclusions: Preliminary analysis of the biological markers bcl-2, p53, blood group antigen A and mucin expression showed a statistically significant association between shorter FFS and p53 and mucin IHC expression. Additional analysis including tumor size and lymph node sampling as well as effects on survival will be presented.

Rosell, Rafael1 Jassem, Ewa2 Skrzypski, Marcin2 Taron, Miguel3 Mendez, Pedro3 Roca, Laia P.3 Szymanowska, Amelia2 Rzyman, Witold4 Gulida, Grazyna K.5 Jassem, Jacek6 1 Institut Catala d’Oncologia-Hospital Germans Trias i Pujol, Badalona, Spain 2 Medical University of Gdansk, Allergology Service, Gdansk, Poland 3 Institut Catala d’Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain 4 Medical University of Gdansk, Thoracic Surgery Service, Gdansk, Poland 5 Medical University of Gdansk, Pathology Servcice, Gdansk, Poland 6 Medical University of Gdansk, Oncology and Radiotherapy Servcice, Gdansk, Poland Background: Following surgical resection in operable NSCLC, 5-year survival is 60% in stage I, 39% in stage IIB and 23% in stage IIIA, with relapse commonly as distant metastases. The average benefit of adjuvant chemotherapy is 5%, ranging from nil in stage I to 15% in stage II-IIIA. Caretaker genes involved in keeping genetic alterations to a minimum include the nucleotide excision repair genes ERCC1 and myeloid zinc finger 1 (MZF1), which mediates ERCC1 expression, and other stability genes, such as BRCA1, which control processes involving large portions of chromosomes. Thioredoxin-1 (TRX1) is a redox protein overexpressed in NSCLC that is correlated with poor prognosis, and TWIST contributes to metastasis by promoting epithelial-mesenchymal transition. Methods: In order to identify p with a high risk of relapse, we investigated the expression of these 5 transcripts in frozen resected tumors from 126 resected NSCLC p by real-time quantitative PCR. Gene expression was normalized using a-actin and 18SrRNA expression as internal references. Results: Adenocarcinoma (adeno), 33 p; squamous cell carcinoma (SCC), 93 p. Stage: IA, 18 p; IB, 53 p; IIB, 33 p; IIIA, 22 p. Tumoral transcript expression with a-actin: ERCC1, 1.23; MZF1, 0.53; BRCA1, 3.65; TRX1, 1.82; TWIST, 7.75. A strong correlation was observed between the expression of ERCC1, MZF1 and BRCA1 (P<0.001). Expression of each of the 5 transcripts was higher in SCC than in adeno (P<0.001). Median survival (MS): low ERCC1 (<1.5) = not reached (NR), high ERCC1 = 33 months (m) (P=0.21); low MZF1 (<0.5) = NR, high MZF1 = 33 m (P=0.04); low BRCA1 (<5) = NR, high BRCA1 = 22 months (m) (P=0.01); low TRX1 (<0.8) = NR, high TRX1 = 39.5 m (P=0.02); no differences in MS according to levels of TWIST. In a multivariate Cox model for survival, BRCA1 and stage emerged as independent prognostic variables (Table). Conclusion: Increased BRCA1 is associated with shorter survival, and BRCA1 assessment could be useful for customizing adjuvant chemotherapy. HR

p

1.02-3.06

0.04

Stage IA

1

IIA- IIIA

1.75

BRCA Level <5 <5

Copyright © 2007 by the International Association for the Study of Lung Cancer

95% CI

1 1.77

1.02-3.06

0.04

S403