FAS and FASL genetic polymorphisms impact on clinical outcome of malignant pleural mesothelioma

Our plain-English summary of FAS and FASL genetic polymorphisms impact on clinical outcome of malignant pleural mesothelioma, by M. El-Hamamsy, R.R. Ghali, A.S. Saad, et al (OncoTargets and Therapy, 2016).

The study

• Authors: M. El-Hamamsy, R.R. Ghali, A.S. Saad, S.M. Shaheen, A.M. Salem
• Journal: OncoTargets and Therapy
• Published: 2016;9:6857-6863
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: FAS-670 A>G (rs1800682) and FASL-844 C>T (rs763110) polymorphisms have been previously correlated with clinical outcome of non-small cell lung cancer (NSCLC) and breast and bladder cancers. We investigated the influence of these polymorphisms on clinical outcome of malignant pleural mesothelioma (MPM) patients.

Patients And Methods: In this cohort study (NCT02269878), 68 epithelioid MPM Egyptian patients treated with first-line platinum-based chemotherapy were recruited in the period between April 2014 and May 2015. The genotype analysis was performed using TaqMan® single-nucleotide polymorphism genotyping assay. The association between the selected polymorphisms and response rate, progression-free survival (PFS) and overall survival (OS) at 18 months was evaluated.

Results: The median age of patients was 55 years and 45.6% of them received platinum in combination with pemetrexed, while 54.4% received platinum in combination with gemcitabine. FASL-844 CC genotype was more common than expected in early-stage tumor (P=0.042). It was found that there was no association between the investigated polymorphisms and response rate or 18-month OS. However, the PFS rate at 18 months for FASL-844 CC genotype carriers was 45% versus 10.6% for FASL-844 CT/TT genotypes carriers (log-rank: 6.2; P=0.013). Also, the number of platinum-based cycles and tumor stage were found to be significant variables for PFS by univariate analysis (P≤0.001 and P=0.006, respectively). Stratified Cox regression showed that the carriers of FASL-844 CT/TT genotypes were still more susceptible to disease progression than carriers of FASL-844 CC genotype (adjusted HR =3.77, 95% CI: 1.34-10.62, P=0.012).

Conclusion: The results of this study suggest that FASL-844 C/T polymorphism could predict PFS in MPM patients receiving platinum-based chemotherapy; therefore, this should be further evaluated as a potential marker for the prediction of clinical outcome in patients with MPM.

In plain English

This cohort study followed 68 Egyptian patients with epithelioid malignant pleural mesothelioma. They were recruited at two Cairo hospitals between April 2014 and May 2015 and treated with first-line platinum-based chemotherapy plus pemetrexed or gemcitabine. Using blood samples, the authors tested two gene variants, FAS-670 A>G and FASL-844 C>T, and tracked patients for 18 months. Fifty-six patients were recorded as having environmental or occupational asbestos exposure; fiber types were not reported. Neither variant showed a statistically significant association with tumor response or 18-month overall survival. Patients with the FASL-844 CC genotype had an 18-month progression-free survival rate of 45%, versus 10.6% for CT or TT carriers. Adjusted for tumor stage and stratified by number of chemotherapy cycles, CT/TT carriers had a hazard ratio of 3.77 (95% CI 1.34 to 10.62) for progression or death. FAS-670 A>G showed no significant association with progression-free survival. The authors concluded that the FASL-844 variant could predict progression-free survival in such patients. They noted a small sample, short follow-up, about 19% withdrawal and mixed treatments, and called for larger studies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Cohort study with patients followed prospectively for 18 months (registered as NCT02269878)
• Who was studied: 68 Egyptian patients with epithelioid malignant pleural mesothelioma receiving first-line platinum-based chemotherapy. They were recruited April 2014 to May 2015 at Ain Shams University and El-Nasr hospital in Helwan, both in Cairo. The median age was 55 years (range 28 to 75).
• Exposure: The studied factors were the patients' genotypes for two gene variants, FAS-670 A>G (rs1800682) and FASL-844 C>T (rs763110), measured in blood. All patients received platinum (cisplatin or carboplatin) combined with pemetrexed or gemcitabine. Asbestos exposure (environmental or occupational) was recorded only as exposed or unexposed; no fiber types were given.
• Main results:
  • 56 of the 68 patients (82.4%) were recorded as asbestos-exposed and 12 (17.6%) as unexposed.
  • The FASL-844 CC genotype was more common than expected in early-stage tumors, and the TT genotype was more common than expected in advanced tumors (P=0.042).
  • No patient had a complete response to chemotherapy. 20 patients (29.4%) had a partial response, 32 (47.1%) stable disease and 16 (23.5%) progressive disease.
  • Response did not differ between FASL-844 CC and CT/TT genotypes (P=0.98) or between FAS-670 AA and AG/GG genotypes (P=0.49).
  • For the whole cohort, the 18-month progression-free survival rate was 16.4%. Progression-free survival was measured to documented progression or death from any cause.
  • The 18-month progression-free survival rate was 45% for FASL-844 CC genotype carriers (12 patients) versus 10.6% for CT/TT carriers (56 patients) (log-rank 6.2; P=0.013).
  • In a stratified Cox regression adjusted for tumor stage and stratified by number of first-line chemotherapy cycles, FASL-844 CT/TT carriers had a hazard ratio for progression-free survival events (progression or death from any cause) of 3.77 compared with CC carriers (95% CI 1.34 to 10.62, P=0.012).
  • FAS-670 A>G genotypes showed no significant association with 18-month progression-free survival (log-rank 0.6; P=0.44).
  • Among clinical factors, tumor stage (P=0.006) and number of platinum cycles (P less than 0.001) were significantly associated with progression-free survival in univariate analysis.
  • The 18-month overall survival rate for the whole cohort was 47.7%. Overall survival was not significantly associated with FASL-844 C>T (log-rank 0.27; P=0.60) or FAS-670 A>G (log-rank 1.75; P=0.19).
  • In univariate analysis, 18-month progression-free survival was 18.5% in the asbestos-exposed group versus 8.3% in the unexposed group (P=0.25). Overall survival was 50.1% versus 38.9% (P=0.57). Neither difference was statistically significant.
• The authors' conclusion: The authors concluded that the FASL-844 C/T polymorphism could predict progression-free survival in mesothelioma patients receiving platinum-based chemotherapy. They said this should be validated in larger studies with uniformly treated patients.
• Limitations the authors state:
  • The sample size was relatively small, giving low statistical power.
  • The small sample may have hidden a real relationship between FAS-670 A>G and prognosis.
  • Follow-up was limited to 18 months.
  • About 19% of patients withdrew from the study, which the authors linked to lack of social support and low economic status.
  • Patients differed in clinical characteristics and treatment protocols.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Non-Small Cell Lung Cancer, Cohort Study, Epithelioid, Chemotherapy, Progression-Free Survival, Overall Survival, Pemetrexed (Alimta).

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