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S. Visser
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MINI 08 - Prognostic/Predictive Biomarkers (ID 106)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:T.E. Stinchcombe, N. Pavlakis
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 4a-4f
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MINI08.02 - Prediction of Response to Pemetrexed in NSCLC by Immunohistochemical Phenotyping Based on Gene Expression Profiles (ID 2793)
16:50 - 16:55 | Author(s): S. Visser
- Abstract
- Presentation
Background:
A major challenge in the treatment of advanced non-small cell lung cancer (NSCLC) is to identify specific tumor properties that predict response to chemotherapy. Although thymidylate synthase (TS) immunohistochemical (IHC) staining has been extensively studied as a predictive marker for pemetrexed (PEM) sensitivity, its clinical value remains limited. We investigated IHC stainings of different molecular markers linked to the folate metabolic pathway (FMP) identified with gene expression profiling (Hou et al, JTO 2012;7:105-114). We used a population with advanced NSCLC treated with PEM for external validation.
Methods:
Resected tumor samples from PEM-naïve NSCLC patients were collected. Gene expression profiling with respect to predicted sensitivity to PEM was based on genes related to FMP. Based on differentially expressed genes, patients were divided into predicted responders (Rs) and non-responders (NRs). Genes showing a strong correlation with these FMP genes and for which IHC stainings were commercially available, were selected for measurement of corresponding protein expressions by IHC stainings. A semiquantitative scoring method was applied, which was used to construct a prediction model for response to PEM. Subsequently, a retrospective cohort of patients with advanced NSCLC was selected, who had received at least two cycles of PEM-based chemotherapy as first-line treatment. IHC staining scores for the same proteins were obtained from tumor tissue. The performance of the prediction model was tested in this population.
Results:
From 91 patients resected tumor samples were collected. The majority of patients had early or locally advanced NSCLC (96.3%). Gene expression profiling revealed five markers that showed mRNA levels strongly correlating to FMP genes mRNA levels: TPX2, CPA3, EZH2, MCM2 and TOPO2a. Of 63 patients IHC staining scores of these markers were obtained, which all correlated to their corresponding mRNA levels. The scores were significantly different between predicted NRs and Rs (p<0.05). Testing the IHC markers showed an optimized prediction model with CPA3 (OR=1.71, 95%CI (0.94-3.08)), EZH2 (OR=0.57, 95%CI (0.35-.093)) and TPX2 (OR=0.55, 95%CI (0.29-1.03)) included. With this model 86.5% of the predicted Rs and 72.7% of the predicted NRs were correctly classified. The ROC showed an AUC of 0.883 representing a good discriminatory performance. In the external study population (n=23) the majority of patients had metastatic NSCLC (95.7%). Partial response (PR) was established in 26.1%. Considering patients with PR as responders the prediction model classified 16.7% of the observed Rs and 88.2% of the observed NRs correctly. The ROC showed an AUC of 0.750.
Conclusion:
Using external validation this prediction model with IHC staining of FMP correlated markers shows a good specificity, but lacks sensitivity. Again this study shows the limited value of IHC markers as response predictors for PEM in clinical practice. This may be ascribed to the poor relation between IHC and protein activity but the biological significance of FMP genes may also be less important than other factors influencing PEM activity, like pharmacodynamics of PEM e.g. the formation of metabolites. Metabolomics may offer better understanding in cellular processing of PEM and could provide new insights for tailored chemotherapy. Supported by an unrestricted grant from Eli-Lilly, the Netherlands
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MINI 15 - Chemotherapy Developments for Lung Cancer (ID 128)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Crinò, C.P. Belani
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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MINI15.12 - Satisfaction with Therapy and the Relation with Quality of Life in Patients with Advanced NSCLC Receiving Chemotherapy (ID 2253)
17:50 - 17:55 | Author(s): S. Visser
- Abstract
- Presentation
Background:
In advanced non-small cell lung cancer (NSCLC) decisions regarding palliative treatment are based on tumor response, increasingly combined with patient reported outcomes, especially quality of life (QoL). However, considering treatment decisions in this manner ignores patients’ own opinion about (change in) QoL. A more patient-oriented view regarding therapy could offer valuable information in the process of shared decision-making about treatment initiation or continuation with chemotherapy. We assessed patients’ satisfaction with the received chemotherapy using the Cancer Therapy Satisfaction Questionnaire (CTSQ) in relation with QoL during treatment.
Methods:
In a prospective observational multi-center study, patients with stage IIIB or IV NSCLC receiving pemetrexed (PEM)-based chemotherapy as first or second line treatment were enrolled. Prior to and after four cycles of chemotherapy, patients completed the WHO Quality of Life-BREF (WHOQoL-BREF) and EORTC-Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30), which both contain one item measuring overall QoL on a 1-5 and 1-7 scale, respectively. After four cycles patients also completed the CTSQ, which consists of 16 items scored on a 1-5 scale and is divided in three domains, including the domain satisfaction with therapy (SWT). Linear transformation of the domain score results in a score range 0-100, with a higher score representing a better treatment satisfaction. Items of special interest were Question 7 (Q7) “Chemotherapy was worth taking even with side effects”, Question 16 (Q16) “If given the choice again, would you decide to take this chemotherapy treatment” and Question 2 (Q2) “Chemotherapy would cure the cancer”. From all patients tumor response measurements were obtained according to RECIST 1.1.
Results:
Of the 88 patients receiving four cycles of PEM-based chemotherapy, 65 patients completed the WHOQoL-BREF, EORTC-QLQ-30 and the CTSQ. The majority of these patients had stage IV NSCLC (87.7%) and received PEM-based therapy as first line treatment (92.3%). Treatment resulted in stable disease (53.8%), partial response (40.0%) and progressive disease (6.2%). Eighteen patients often (13.8%) or always (13.8%) expected chemotherapy would cure the cancer. During therapy, overall QoL measured by WHOQoL-BREF increased (1.3±0.6), remained stable (0±0) and decreased (-1.4±0.7) in respectively 15 (23.1%), 30 (46.2%) and 20 (30.8%) patients. The SWT domain score (77.5±12.3 vs. 83.8±13.1) and single item scores Q7 (4.1±0.9 vs. 4.4±0.8) and Q16 (4.4±0.7 vs. 4.5±0.6) in patients with decrease vs. increase of overall QoL did not differ significantly between the groups (p> 0.05). Change in overall QoL measured by the EORTC-QLQ-C30 related to SWT, Q7 and Q16 showed similar results.
Conclusion:
Despite a decrease of QoL during chemotherapy, patients still consider the treatment as worth taking and would decide to receive the chemotherapy again. Since the majority of patients understand that the treatment has no curative intentions, it is unlikely that the satisfaction with treatment only reflects false expectations of cancer cure. Our results represent a group of patients who mainly established disease stabilization, which could have influenced our findings. In shared decision-making on palliative treatment, patients’ QoL cannot be used as a single decision criterion because it does not reflect patients’ satisfaction with treatment. This study is funded by ZonMw, the Netherlands
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