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Z. Lohinai
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OA19 - Translational Research in Early Stage NSCLC (ID 402)
- Event: WCLC 2016
- Type: Oral Session
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:G. Heller, G. Goss
- Coordinates: 12/07/2016, 11:00 - 12:30, Schubert 3
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OA19.05 - High Oncofetal Chondroitin Sulfate Expression is an Independent Prognostic Factor of Poor Survival in Early-Stage NSCLC (ID 5601)
11:45 - 11:55 | Author(s): Z. Lohinai
- Abstract
- Presentation
Background:
Most human cancers express proteoglycans modified with distinct oncofetal chondroitin sulfate (CS) chains that are normally restricted to placental tissue. Oncofetal CS chains can be conveniently detected and targeted by recombinant VAR2CSA (rVAR2) proteins derived from the malaria parasite Plasmodium falciparum. In the present study, we have analyzed the expression landscape of oncofetal CS modifications in early-stage non-small cell lung cancer (NSCLC).
Methods:
Tissue microarrays from four separate patient cohorts representing a total of 493 clinically annotated stage I-II NSCLC cases were stained for oncofetal CS using rVAR2. Data were analyzed for correlation between low and high oncofetal CS presentation by immunohistochemical (IHC) staining of tumor and stroma compartments in respect to EGFR and KRAS mutations, as well as to clinical characteristics including relapse-free survival (RFS) and overall survival (OS).
Results:
There were 351 patients with low (IHC score 0-1) and 142 with high (IHC score 2-3) expressing tumors. We identified 331 adenocarcinomas, 145 squamous cell carcinomas, and 12 cases with other NSCLC subtypes. There were 314 stage I and 179 stage II cases by AJCC 7[th] edition. High oncofetal CS expression was significantly associated with shorter RFS (vs. high expressiors; 58 vs. 39 months, respectively, p=0.034) and OS (vs. high expressors; 69 vs. 51 months, respectively, p=0.044). High oncofetal CS expression was significantly associated with shorter RFS vs. low expression in men (p=0.024), smokers (p=0.011), and in patients with squamous cell tumors (p=0.012). High oncofetal CS was also significantly associated with shorter OS in men (p=0.005) and smokers (p=0.028). There were no significant RFS or OS differences in oncofetal CS expressions when stratifying the patients according to their EGFR or KRAS statuses. In multivariate survival analyses, histology, stage, and high oncofetal CS expression was significantly associated with shorter RFS vs. high expression (HR, 1.8; 95% CI, 1.32–2.48; p < 0.001).
Conclusion:
This is the first study showing that high oncofetal CS expression is an independent prognostic factor of poor RFS in NSCLC and validates high oncofetal CS expression as a prognostic factor of poor OS. In contrast to non-smoker females, oncofetal CS appears to be a prognostic for OS in males and smokers. Our work promotes oncofetal CS as a candidate target for rVAR2-based therapeutic intervention in NSCLC patients with poor RFS/OS.
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P1.06 - Poster Session with Presenters Present (ID 458)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.06-012 - Central and Peripheral Lung Adenocarcinomas Exhibit Different Timing and Predilection for Distant Metastasis (ID 5649)
14:30 - 14:30 | Author(s): Z. Lohinai
- Abstract
Background:
Although distant metastases are major factors for unfavorable prognosis in lung adenocarcinoma (ADC), metastatic patterns have not been widely analyzed in this malignancy.
Methods:
Clinicopathological data of 1126 ADC patients (541 men, 585 women, mean age: 62.1 ± 9.4 years, 32-88 years) were studied retrospectively, focusing on the localization of primary tumor and distant metastases. Metastases diagnosed at the time of primary tumor diagnosis were defined as early metastases. For statistical analyses, Fisher's exact test and a chi-squared independence test were performed.
Results:
At time of diagnosis, 621 patients had stage IV disease. 435 of them had a solitary organ metastasis, mainly in the contralateral lung (n=187), in the brain (n=66), or in the bone (n=59). During the follow up period another 242 patients developed distant metastasis. 39% of all patients had central (i.e. endobronchially visible) tumor. In cases with early-, late-, and non-metastatic disease, the proportions of central tumors were 43%, 35% and 31%, respectively. Central primary tumors were significantly more likely to give rise to early metastases than peripheral ones (p=0.021). When comparing central and peripheral lung cancers according to their metastatic sites, in central tumors lung metastases appeared significantly earlier (p=0.017), while in peripheral ones bone metastases appeared significantly later (p=0.015). There were significant differences in the metastatic organ distributions of central vs. peripheral primary tumors for early (p=0.025) and late (p=0.009) metastases. There was no significant difference in the metastatic organ distributions of right vs. left lung primaries both for early and late metastases. In right lung tumors brain metastases appeared later (p=0.047). No significant difference was observed in the metastatic organ distributions of primary tumors of the upper vs. lower lobes for early (p=0.051), and late (p=0.528) metastases. Early appearance was characteristic for lung, pleural, and adrenal involvement (p<0.001 in all comparisons), while late development was typical for brain metastasis (p=0.002). Bone, liver, subcutaneous, and pericardial metastases showed no such tendencies.
Conclusion:
There are significant differences in metastatic organ distributions of central vs. peripheral lung cancers both for early and late metastases. Central primary tumors are more likely to give rise to early metastases than peripheral ones. Results of molecular subgroup analyses will be presented during the Conference.
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 2
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-023 - NGS May Discriminate Extreme Long-Term versus Short-Term Survival in Patients with Stage IV Small-Cell Lung Cancer (SCLC) (ID 5660)
14:30 - 14:30 | Author(s): Z. Lohinai
- Abstract
Background:
Molecular underpinnings that may prognosticate survival and could increase our understanding of tumor progression are far less understood processes in highly aggressive malignancies such as SCLC. We aimed to describe the clinocopathological characteristics and biomarker profiling of short versus long-term SCLC survivors using the latest, most clinically actionable genomic and immunohistochemical (IHC) alterations.
Methods:
Consecutive 876 metastatic SCLC patients receiving standard of care therapy were evaluated between 2000 and 2013 at the National Koranyi Institute of Pulmonology. Long-term (LT) (overall survival (OS) > 24 months) and short-term (ST) survivors (OS range 2-9 weeks) with histologically confirmed stage IV SCLC were included in this retrospective analysis. DNA and RNA were isolated from FFPE tissues. A comprehensive next-generation sequencing test (NGS) was performed to analyze gene mutations, copy number variations (CNV), mRNA expression, and protein expression by IHC (PCDx, Paradigm). Multiplex sequencing analysis had coverage >5,000x. We then evaluated the associations amongst these various biomarkers and clinicopathological characteristics.
Results:
Four LT and 11 ST were identified for NGS. There were five mutually exclusive gene mutations, previously not described in SCLC (EP300: c.650A>G p.N217S; c.4561G>A p.E152K; ERBB4: c.949G>A p.E317K; BRCA1: c.4981G>A p.E1661N; and EGFR (ERBB1): c.2225T>C p.V742A). Mismatch repair (MMR) deficiency, CNV and PD-L1 in tumor-infiltrating lymphocytes (TIL)/tumor cells were not found in any of the samples. TOP1 was highly elevated in both groups, supporting campothecins as effective drugs in SCLC. Certain mRNA genes appeared to be linked in a similar or overlapping pathway. HENT1 (SLC29A1) with 50-79% protein concordance and survivin (BIRC5) mRNAs were high in most of the ST vs. LT. All LT survivors, but none of the ST survivors, received consolidation thoracic radiation therapy (RT) along with standard of care chemotherapy. SSTR2 mRNA expressions were higher in LT survivors (vs. ST survivors) treated with first-line platinum-etoposide. Molecular testing revealed that ST survivors treated with cyclophosphamide, epirubicin, and vincristine were not predicted to be sensitive to doxorubicin or epirubicin. LT survivors proved to be sensitive to irinotecan/topotecan and lanreotide/octreotide but not to platinum (BRCA1 and/or survivin mRNA was not present).
Conclusion:
Consolidation RT and certain linked pathways may discriminate between LT and ST survivors in SCLC. NGS profiling of extreme survivors may improve classification of SCLC and possibly identify clinically-relevant new targets.
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P1.07-042 - Neutrophil-Lymphocyte and Platelet-Lymphocyte Ratios Predict Prognosis in Early-Stage Resected Small-Cell Lung Cancer Patients (ID 5657)
14:30 - 14:30 | Author(s): Z. Lohinai
- Abstract
Background:
Surgical resection is rarely possible in small-cell lung cancer (SCLC), a highly aggressive malignancy with limited treatment options. However, although in the past decades, for selected early-stage cases, a curative intent surgery is often performed, there is no biomarker to help the selection of patients eligible for surgery. Because previous studies - predominantly from East Asia - showed that high neutrophil to lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) correlate with poor prognosis in several types of tumors including SCLC, the aim of our study was to investigate the prognostic value of NLR and PLR in Caucasian patients with resected SCLC.
Methods:
Consecutive patients with histologically confirmed and surgically resected SCLC evaluated between 2000 and 2013 at the National Koranyi Institute of Pulmonology were analyzed in this retrospective analysis. Patients were divided into "high" and "low" groups according to their NLR and PLR at diagnosis. The cut-off NLR and PLR values were 3 and 110, respectively. Next, we evaluated the associations of preoperative NLR or PLR with vascular involvement, tumor necrosis, peritumoral inflammation, tumor grade, clinicopathological characteristics (including age, gender, stage) and overall survival (OS) in univariate and multivariate analyses.
Results:
There were a total of 65 patients (39 men and 26 women) with a median age of 57.7 years (range, 40-79). The pathological stages were 1, 2 and 3A in 23, 23 and 14 cases by AJCC 7[th] edition (in five patients no pTNM was available). PLR was high (HPLR) in 41 (63%) and low (LPNR) in 24 (37%) patients. NLR was high (HNLR) in 35 (66%) and low (LLNR) in 17 (33%) patients. PLR significantly correlated with pathologic lymph node status (p<0.001) and NLR (p=0.007). HPLR was associated with shorter OS (vs. LPLR, HR, 2.2; 95% CI, 1.13–4.29; p=0.02). There was a non-significant trend towards longer OS in patients with LNLR (vs. HNLR, p=0.078). There were no significant associations between NLR or PLR and age, gender, stage, vascular involvement, tumor necrosis, peritumoral inflammation and tumor grade.
Conclusion:
This is the first study in Caucasian patients with resected SCLC which shows that LPLR (<110) before surgical resection may be a favorable prognostic factor for longer OS. We also conclude that preoperative HPLR may predict lymph node involvement. PLR but not NLR may help in selecting patients for surgery in the future. Further prospective studies are needed to confirm these observations.
