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Prospective Validation Obtained in a Similar Group of Patients and with Similar High Throughput Biological Tests Failed to Confirm Signatures for Prediction of Response to Chemotherapy and Survival in Advanced NSCLC: A Prospective Study from the European Lung Cancer Working Party.

Berghmans T, Ameye L, Lafitte JJ, Colinet B, Cortot A, CsToth I, Holbrechts S, Lecomte J, Mascaux C, Meert AP, Paesmans M, Richez M, Scherpereel A, Tulippe C, Willems L, Dernies T, Leclercq N, Sculier JP, European Lung Cancer Working Par - Front Oncol (2015)

Bottom Line: No statistically significant differences were observed according to the main clinical characteristics, response rate (43 vs. 41%) or survival (median 25 vs. 29 months) between derivation and validation sets.However, these results could not be reproduced in an independent validation set.The role of miRNA and mRNA as predictive or prognostic factors remains a research topic and the use of high throughput technology in that context questionable.

View Article: PubMed Central - PubMed

Affiliation: Department of Intensive Care and Oncological Emergencies and Thoracic Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles , Brussels , Belgium.

ABSTRACT

Aim: Cisplatin doublets are standard 1st line treatment for advanced non-small cell lung cancer (NSCLC), without accurate predictor for response and survival, but important toxicity. Our aims were to identify predictive (for response) and prognostic (for survival) biological signatures in patients with NSCLC using messenger RNAs (mRNA) and miRNA expression.

Methods: Patients with pathologically proven untreated NSCLC, receiving 1st line cisplatin-vinorelbine and with an assessable lesion were eligible. A bronchial biopsy was lysed into Tripure Isolation Reagent on ice, snap frozen, and stored at -80°C. mRNA expression was analyzed using microarrays Agilent Technologies. miRNA expression was assessed using TaqMan Low Density Arrays (756 human miR panel, Applied Biosystems). Validation was performed by RT-PCR on the selected genes. Survival was measured from the registration date and response assessed by WHO criteria.

Results: Biopsies for transcriptomic analyses were obtained from 60 consecutive patients. No statistically significant differences were observed according to the main clinical characteristics, response rate (43 vs. 41%) or survival (median 25 vs. 29 months) between derivation and validation sets. In the derivation set (n = 38 patients), two mRNA and one miRNA predictive signatures for response were obtained. One mRNA and one miRNA prognostic signatures were derived from the first set, allowing an adequate distinction of patients with good and poor overall and progression-free survivals. None of these signatures could be validated in the validation set (n = 22 patients).

Conclusion: In this prospective study with advanced NSCLC treated with cisplatin-vinorelbine, we were able to derive with high throughput techniques predictive and prognostic signatures based on transcriptomic analyses. However, these results could not be reproduced in an independent validation set. The role of miRNA and mRNA as predictive or prognostic factors remains a research topic and the use of high throughput technology in that context questionable. The ClinicalTrials.gov study identifier is NCT00864266 (www.clinicaltrials.gov).

No MeSH data available.


Related in: MedlinePlus

Overall survival curves according to the mRNA prognostic signature in the derivation group. MST, median survival time. Patients from the derivation group could be dichotomized according to the mRNA prognostic signature (−3*KRT16 + 2*ULBP2). A value >1 is predicting a poor overall survival while a value <1 is associated with a good overall survival.
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Figure 3: Overall survival curves according to the mRNA prognostic signature in the derivation group. MST, median survival time. Patients from the derivation group could be dichotomized according to the mRNA prognostic signature (−3*KRT16 + 2*ULBP2). A value >1 is predicting a poor overall survival while a value <1 is associated with a good overall survival.

Mentions: Using the same statistical methodology, we constructed a signature specifically predicting overall survival using the mRNAs with a FC >3. The signature included two mRNAs (KRT16 and ULBP2) and was designed as −3*KRT16 + 2*ULBP2. At the best cut-off of 1, it allowed distinguishing patients with poor and good overall survival (HR 22.2, 95% CI 4.6–107.7; log-rank and Wilcoxon test p < 0.001) (Figure 3, Table 7). Respective median survival times were for the “good overall survival group” of 40 months (95% CI 25–52 months) and for the “poor overall survival group” of 15 months (95% CI 7–19 months). The same signature was statistically significantly predicting progression-free survival (HR 3.8, 95% CI 1.5–9.3; p < 0.001). Respective median progression-free survival times were for the “good overall survival group” of 18.6 months (95% CI, 12.3–27.3 months) and for the “poor overall survival group” of 8.1 months (95% CI, 5.8–15.5 months).


Prospective Validation Obtained in a Similar Group of Patients and with Similar High Throughput Biological Tests Failed to Confirm Signatures for Prediction of Response to Chemotherapy and Survival in Advanced NSCLC: A Prospective Study from the European Lung Cancer Working Party.

Berghmans T, Ameye L, Lafitte JJ, Colinet B, Cortot A, CsToth I, Holbrechts S, Lecomte J, Mascaux C, Meert AP, Paesmans M, Richez M, Scherpereel A, Tulippe C, Willems L, Dernies T, Leclercq N, Sculier JP, European Lung Cancer Working Par - Front Oncol (2015)

Overall survival curves according to the mRNA prognostic signature in the derivation group. MST, median survival time. Patients from the derivation group could be dichotomized according to the mRNA prognostic signature (−3*KRT16 + 2*ULBP2). A value >1 is predicting a poor overall survival while a value <1 is associated with a good overall survival.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4309174&req=5

Figure 3: Overall survival curves according to the mRNA prognostic signature in the derivation group. MST, median survival time. Patients from the derivation group could be dichotomized according to the mRNA prognostic signature (−3*KRT16 + 2*ULBP2). A value >1 is predicting a poor overall survival while a value <1 is associated with a good overall survival.
Mentions: Using the same statistical methodology, we constructed a signature specifically predicting overall survival using the mRNAs with a FC >3. The signature included two mRNAs (KRT16 and ULBP2) and was designed as −3*KRT16 + 2*ULBP2. At the best cut-off of 1, it allowed distinguishing patients with poor and good overall survival (HR 22.2, 95% CI 4.6–107.7; log-rank and Wilcoxon test p < 0.001) (Figure 3, Table 7). Respective median survival times were for the “good overall survival group” of 40 months (95% CI 25–52 months) and for the “poor overall survival group” of 15 months (95% CI 7–19 months). The same signature was statistically significantly predicting progression-free survival (HR 3.8, 95% CI 1.5–9.3; p < 0.001). Respective median progression-free survival times were for the “good overall survival group” of 18.6 months (95% CI, 12.3–27.3 months) and for the “poor overall survival group” of 8.1 months (95% CI, 5.8–15.5 months).

Bottom Line: No statistically significant differences were observed according to the main clinical characteristics, response rate (43 vs. 41%) or survival (median 25 vs. 29 months) between derivation and validation sets.However, these results could not be reproduced in an independent validation set.The role of miRNA and mRNA as predictive or prognostic factors remains a research topic and the use of high throughput technology in that context questionable.

View Article: PubMed Central - PubMed

Affiliation: Department of Intensive Care and Oncological Emergencies and Thoracic Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles , Brussels , Belgium.

ABSTRACT

Aim: Cisplatin doublets are standard 1st line treatment for advanced non-small cell lung cancer (NSCLC), without accurate predictor for response and survival, but important toxicity. Our aims were to identify predictive (for response) and prognostic (for survival) biological signatures in patients with NSCLC using messenger RNAs (mRNA) and miRNA expression.

Methods: Patients with pathologically proven untreated NSCLC, receiving 1st line cisplatin-vinorelbine and with an assessable lesion were eligible. A bronchial biopsy was lysed into Tripure Isolation Reagent on ice, snap frozen, and stored at -80°C. mRNA expression was analyzed using microarrays Agilent Technologies. miRNA expression was assessed using TaqMan Low Density Arrays (756 human miR panel, Applied Biosystems). Validation was performed by RT-PCR on the selected genes. Survival was measured from the registration date and response assessed by WHO criteria.

Results: Biopsies for transcriptomic analyses were obtained from 60 consecutive patients. No statistically significant differences were observed according to the main clinical characteristics, response rate (43 vs. 41%) or survival (median 25 vs. 29 months) between derivation and validation sets. In the derivation set (n = 38 patients), two mRNA and one miRNA predictive signatures for response were obtained. One mRNA and one miRNA prognostic signatures were derived from the first set, allowing an adequate distinction of patients with good and poor overall and progression-free survivals. None of these signatures could be validated in the validation set (n = 22 patients).

Conclusion: In this prospective study with advanced NSCLC treated with cisplatin-vinorelbine, we were able to derive with high throughput techniques predictive and prognostic signatures based on transcriptomic analyses. However, these results could not be reproduced in an independent validation set. The role of miRNA and mRNA as predictive or prognostic factors remains a research topic and the use of high throughput technology in that context questionable. The ClinicalTrials.gov study identifier is NCT00864266 (www.clinicaltrials.gov).

No MeSH data available.


Related in: MedlinePlus