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R.J. Young



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    O17 - Anatomical Pathology I (ID 128)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O17.07 - Prevalence, morphology and natural history of FGFR1-amplified lung cancer detected by FISH and SISH (ID 2776)

      10:30 - 12:00  |  Author(s): R.J. Young

      • Abstract
      • Presentation
      • Slides

      Background
      Fibroblast growth factor receptor 1 (FGFR1), which codes for a receptor tyrosine kinase, was recently reported to be amplified in 20% of lung squamous cell carcinoma (SqCC). In vitro and preclinical tests suggest that FGFR1 amplification is a therapeutic target. Our aims were to investigate the prevalence of FGFR1 amplification by fluorescence in situ hybridization (FISH) and determine correlation with outcome in an Australian cohort of resected lung cancer. We also correlated results of FGFR1 FISH with silver in situ hybridization (SISH).

      Methods
      A clinically-annotated tissue microarray was constructed from resected lung cancer tissue collected from 1996-2012. FGFR1 FISH and SISH were performed according to manufacturer’s protocols, with SISH performed on Ventana benchmark XT platform. FGFR1 FISH and SISH were scored by one pathologist, with high level amplification defined as ratio of FGFR1/centromere 8 ≥ 2, or tumor cell percentage with ≥ 15 signals ≥ 10%, or average number of FGFR1 signals/tumor cell nucleus ≥ 6, and low level amplification as tumor cell percentage with ≥ 5 signals ≥ 50%. Results of FGFR1 FISH and SISH were compared. Patient outcome related to FGFR1-amplified tumors was assessed and compared to patients with SqCC, or with a morphologic component of, or immunoprofile of SqCC, but normal FGFR1 copy number.

      Results
      Of 406 tumors tested, there were 191 pure SqCC, 28 carcinomas with a SqCC component, 24 large cell carcinomas with an immunoprofile of SqCC, 115 adenocarcinomas, 22 pulmonary neuroendocrine tumors, and 28 other carcinomas without a morphologic component or immunoprofile of SqCC. FGFR1 amplification was assessable in 368 tumors. FGFR1 amplification was identified with FISH in 50 tumors, 48 (48/225; 21.3%) of which were either pure SqCC or a carcinoma with morphologic component or immunoprofile of SqCC. Only two cases were completely of non-squamous origin (2/143; 1.4%, p<0.00001). FGFR1 SISH was performed in 385 tumors, with 347 tumors assessable. Of 46 FGFR1 FISH-amplified tumors assessed with FGFR1 SISH, all showed FGFR1 amplification with SISH, whilst all other tumors tested were negative. Survival from radically treated FGFR1-amplified tumors was similar to all others with a squamous component (73% versus 60% 5-yr survival, HR 0.68, p=0.25; Figure 1).Figure 1

      Conclusion
      FGFR1 amplification with FISH was identified in 21.3% of pure SqCC or carcinomas with a morphologic component or immunoprofile of SqCC, but only 1.4% of completely non-squamous tumors. All adenocarcinomas and neuroendocrine tumors were negative. FGFR1 SISH showed 1:1 correlation to FGFR1 FISH.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-002 - RLIP76 expression is prognostic and predictive of chemotherapy benefit in resected NSCLC (ID 247)

      09:30 - 16:30  |  Author(s): R.J. Young

      • Abstract

      Background
      Despite adjuvant chemotherapy improving overall survival of resected Stage II and III non-small cell lung cancer (NSCLC), acute and late toxicities of chemotherapy have highlighted the need to better predict which patients will benefit from treatment. RLIP76 is a ubiquitously expressed multi-functional transporter that is associated with cisplatin and vinorelbine resistance. Our aim was to analyse the prognostic and predictive value of RLIP76 expression in NSCLC.

      Methods
      We identified 367 NSCLC patients resected between 1996 and 2009. A tissue microarray was created and immunohistochemistry (IHC) performed with an anti-human RLIP76 rabbit polycloncal antibody (Millipore, Temecula, CA). The intensity (0-3) and proportion of tumour cells (0-100) with staining was scored. The product of RLIP76 intensity and proportion of tumour cells staining was calculated (range 0-300) and divided into high (>100) and no/low expression (≤100). RLIP76 expression was correlated with clinical features and patient outcome.

      Results
      IHC was available for 285 patients, 173(60.7%) of which were male. Number of patients according to stage I, II, III and IV was 150(52.6%), 83(29%), 44(15.4%) and 8(3%), respectively. RLIP76 was overexpressed in 117(41%) specimens. There was no relationship between RLIP76 expression and stage, histology, sex or age. High RLIP76 expression was associated with an improved prognosis on univariate (HR 0.62, CI 9.44-0.90, p=0.012,Figure 1) and multivariate analysis (HR 0.57, CI 0.39-0.83, p=0.003). Adjuvant chemotherapy was also associated with an improved survival on multivariate analysis (HR 0.52, CI 0.33-0.82, p=0.005). When stratifying by RLIP76 expression, the benefit of chemotherapy was limited to patients with no/low expression (HR =0.44, CI 0.24-0.8, p=0.008)(Figure 2). No benefit of chemotherapy was seen in patients with high RLIP76 expression (HR=0.75, CI 0.34-1.63, p=0.5). Figure 1 Figure 2

      Conclusion
      High RLIP76 expression is associated with an improved prognosis in resected NSCLC.Interestingly no/low RLIP76 expression may predict for benefit of adjuvant chemotherapy. Further studies are needed to confirm these results.