The effect of clinical covariates on the diagnostic and prognostic value of soluble mesothelin and megakaryocyte potentiating factor

Our plain-English summary of The effect of clinical covariates on the diagnostic and prognostic value of soluble mesothelin and megakaryocyte potentiating factor, by K. Hollevoet, K. Nackaerts, O. Thas, et al (Chest, 2012).

The study

• Authors: K. Hollevoet, K. Nackaerts, O. Thas, J. Thimpont, P. Germonpré, P. De Vuyst, L. Bosquée, C. Legrand, E. Kellen, Y. Kishi, J.R. Delanghe, J.P. van Meerbeeck
• Journal: Chest
• Published: 2012;141(2):477-484
• Cited by: 44 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Soluble mesothelin (SM) and megakaryocyte potentiating factor (MPF) are serum biomarkers of mesothelioma. This study examined the effect of clinical covariates on biomarkers levels and their diagnostic and prognostic value.

Methods: Five hundred ninety-four participants were enrolled in a multicenter study, including 106 patients with mesothelioma and 488 control subjects. Multiple linear regression analyses were used to identify which covariates were independently associated with SM and MPF levels. The effect of these covariates on the diagnostic accuracy was evaluated with receiver operating characteristics curve analysis. In patients with mesothelioma, survival analysis was performed with Cox regression.

Results: SM and MPF levels were independently associated with age, glomerular filtration rate (GFR), and BMI in control subjects and with GFR and tumor stage in patients with mesothelioma. The diagnostic accuracy of SM and MPF was significantly affected by the distribution of these covariates in the study population. The patients with mesothelioma were best discriminated from the control subjects with either the youngest age, the highest GFR, or the largest BMI. Furthermore, the control subjects were significantly better differentiated from stage II to IV than from stage I mesothelioma. MPF, not SM, was an independent negative prognostic factor, but only if adjusted for the biomarker-associated covariates.

Conclusions: SM and MPF levels were affected by the same clinical covariates, which also had a significant impact on their diagnostic and prognostic value. To improve the interpretation of biomarker results, age, GFR, and BMI should be routinely recorded. Approaches to account for these covariates require further validation, as does the prognostic value of SM and MPF.

In plain English

This prospective multicenter Belgian study examined two blood markers of mesothelioma, soluble mesothelin (SM) and megakaryocyte potentiating factor (MPF). It included 106 patients with malignant pleural mesothelioma and 488 controls, 215 with documented asbestos exposure. Every control group had lower marker levels than patients. In controls, both markers were independently associated with age, kidney function (glomerular filtration rate, GFR) and body mass index (BMI). In patients, they were associated with GFR and tumor stage. Test accuracy varied with these factors, being highest against the youngest controls and those with the highest GFR or largest BMI. Among epithelioid cases, accuracy was lower for stage I (22 patients) than stage II to IV (69). In 78 chemotherapy-treated patients, higher MPF was linked to poorer survival but was an independent predictor only when adjusted for age, GFR and BMI. SM was not a significant prognostic factor; the authors said this needs cautious interpretation given few patients and deaths. The authors concluded that age, GFR and BMI should be recorded routinely, and that ways to account for them, and the markers' prognostic value, need validation.

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: Prospective multicenter diagnostic and prognostic biomarker study with consecutive recruitment
• Who was studied: 594 participants recruited at Belgian hospitals between June 2004 and 2010: 106 patients with histologically proven malignant pleural mesothelioma and 488 control subjects. The controls were 101 healthy people, 215 asbestos-exposed people, 78 patients with a benign non-asbestos-related respiratory disease, 69 with lung cancer and 25 with a nonrespiratory epithelial cancer.
• Exposure: The study measured serum SM and MPF and the clinical factors that affect them (age, GFR, BMI, tumor stage); it did not study asbestos exposure itself. No fiber types, jobs or doses were reported. Within the asbestos-exposed control cohort, 71 had pleural plaques, 39 diffuse pleural thickening, 16 other lesions (mainly asbestosis) and 89 no radiologically obvious asbestos-related lesions.
• Main results:
  • Each control cohort had significantly lower SM and MPF levels than the mesothelioma patients. Median SM was 2.31 nmol/L in mesothelioma patients versus 0.95 to 1.07 nmol/L in the control groups. Median MPF was 18.20 ng/mL in mesothelioma patients versus 6.16 to 7.80 ng/mL in the control groups.
  • In control subjects, age, GFR and BMI were each independently associated with SM and MPF levels in multiple linear regression (adjusted R squared 12.7% for SM and 10.0% for MPF). Sex and smoking history were not significantly associated.
  • In mesothelioma patients, only GFR and tumor stage (I vs II to IV) were independently associated with SM and MPF (adjusted R squared 14.2% and 13.0%). Age, BMI, sex, smoking, histology, CRP and blood counts were not.
  • Stage I mesothelioma patients had lower marker levels than stage II to IV patients. Medians for stage I were SM 1.52 nmol/L and MPF 10.90 ng/mL; for stage II to IV they were SM 2.83 nmol/L and MPF 60.75 ng/mL.
  • When the 488 controls were split into quarters by age, GFR or BMI and compared with all 106 mesothelioma patients, accuracy (area under the curve) ranged from 0.79 to 0.92 for SM and from 0.79 to 0.88 for MPF. Accuracy improved as control age decreased or as GFR or BMI increased.
  • The MPF threshold of 11.16 ng/mL gave 95% specificity in the quarter of controls with the highest GFR, but only 21% specificity in the quarter with the lowest GFR.
  • Compared with all 488 controls, both markers had significantly higher accuracy for 69 patients with epithelioid stage II to IV mesothelioma than for 22 patients with epithelioid stage I mesothelioma. For epithelioid stage I, SM sensitivity was 23% and MPF sensitivity was 46%, although their AUCs were very similar.
  • Among 78 patients treated with cisplatin and/or pemetrexed-based chemotherapy (50 died), continuous MPF was significantly associated with survival in the univariate analysis (hazard ratio 1.0023, 95% CI, 1.0003-1.0044, P = .03).
  • In the multivariate analysis that included age, GFR and BMI, continuous MPF was an independent predictor of survival. Its hazard ratio was 1.0024 (95% CI, 1.0001-1.0047) per 1 ng/mL; the authors stated that a 50 ng/mL increase corresponded to a 10.5% increase in risk of death. Tumor stage II to IV vs I had a hazard ratio of 3.0652 (95% CI, 1.0631-8.8344).
  • MPF was an independent prognostic factor in the multivariate analysis only when that analysis was adjusted for age, GFR and BMI; without that adjustment it was not significant (P = .11).
  • SM was not a significant prognostic factor, even when corrected for age, GFR and BMI, and no prognostic threshold was found for SM or MPF. The authors cautioned that, because of low power, the absence of prognostic significance for SM should be interpreted with caution.
  • The authors noted that age, GFR and BMI explained only a small part of the differences in marker levels between individuals.
• The authors' conclusion: The authors concluded that SM and MPF levels were affected by the same clinical covariates, which also affected their diagnostic and prognostic value. They said age, GFR and BMI should be recorded routinely. They added that approaches to account for these covariates, and the prognostic value of SM and MPF, require further validation.
• Limitations the authors state:
  • The finding that MPF was twice as sensitive as SM for stage I mesothelioma rested on few patients, and the two AUCs were virtually identical.
  • Controls were grouped by covariate quarters regardless of medical condition, although some had cancers that could also overexpress mesothelin.
  • Mesothelioma patients were not split by covariate quarters because of the small number of cases and unbalanced tumor stages.
  • The relatively low number of patients and deaths limited the survival analysis. No prognostic MPF threshold was found, and the absence of prognostic significance for SM should be interpreted with caution.
  • The study's series was not suitable, in number or covariate distribution, for developing covariate-specific reference intervals.
  • There were few patients with nonepithelioid mesothelioma, which likely explains why marker levels did not differ by histology.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelin, Biomarker, Mesothelioma.

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