Clinical validation of a 90-gene expression test for tumor tissue of origin diagnosis: a large-scale multicenter study of 1417 patients

Our plain-English summary of Clinical validation of a 90-gene expression test for tumor tissue of origin diagnosis: a large-scale multicenter study of 1417 patients, by W. Sun, W. Wu, Q. Wang, et al (Journal of Translational Medicine, 2022).

The study

• Authors: W. Sun, W. Wu, Q. Wang, Q. Yao, Q. Feng, Y. Wang, Y. Sun, Y. Liu, Q. Lai, G. Zhang, P. Qi, Y. Sun, C. Qian, W. Ren, Z. Luo, J. Chen, H. Wang, Q. Xu, X. Zhou, W. Sun, D. Lin
• Journal: Journal of Translational Medicine
• Published: 2022;20(1):114
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Once malignancy tumors were diagnosed, the determination of tissue origin and tumor type is critical for clinical management. Although the significant advance in imaging techniques and histopathological approaches, the diagnosis remains challenging in patients with metastatic and poorly differentiated or undifferentiated tumors. Gene expression profiling has been demonstrated the ability to classify multiple tumor types. The present study aims to assess the performance of a 90-gene expression test for tumor classification (i.e. the determination of tumor tissue of origin) in real clinical settings.

Methods: Formalin-fixed paraffin-embedded samples and associated clinicopathologic information were collected from three cancer centers between January 2016 and January 2021. A total of 1417 specimens that met quality control criteria (RNA quality, tumor cell content ≥ 60% and so on) were analyzed by the 90-gene expression test to identify the tumor tissue of origin. The performance was evaluated by comparing the test results with histopathological diagnosis.

Results: The 1417 samples represent 21 main tumor types classified by common tissue origins and anatomic sites. Overall, the 90-gene expression test reached an accuracy of 94.4% (1338/1417, 95% CI: 0.93 to 0.96). Among different tumor types, sensitivities were ranged from 74.2% (head&neck tumor) to 100% (adrenal carcinoma, mesothelioma, and prostate cancer). Sensitivities for the most prevalent cancers of lung, breast, colorectum, and gastroesophagus are 95.0%, 98.4%, 93.9%, and 90.6%, respectively. Moreover, specificities for all 21 tumor types are greater than 99%.

Conclusions: These findings showed robust performance of the 90-gene expression test for identifying the tumor tissue of origin and support the use of molecular testing as an adjunct to tumor classification, especially to those poorly differentiated or undifferentiated tumors in clinical practice.

© 2022. The Author(s).

In plain English

The authors evaluated a laboratory test that measures the activity of 90 genes to identify where in the body a tumor started. Tumor samples came from 1540 patients at three cancer centers in China between January 2016 and January 2021, and 1417 passed quality checks. The test's result was compared with the pathologists' diagnosis. Overall, the two agreed for 94.4% of samples (1338 of 1417, 95% confidence interval 0.93 to 0.96). Across 21 tumor types, the share correctly identified ranged from 74.2% for head and neck tumors to 100% for adrenal, mesothelioma and prostate tumors. All 12 mesotheliomas were identified correctly, but only 54.5% of samples the test labeled mesothelioma were confirmed as mesothelioma. The article does not say where in the body the mesotheliomas arose and does not discuss asbestos. Accuracy was 92.1% in the prospective cohort and 95.7% in the retrospective cohort. The authors noted that biopsy and cytology samples were excluded and that performance for head and neck tumors was not optimal. They concluded that the findings support molecular testing as an aid to tumor classification.

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: Multicenter clinical validation study of a diagnostic test, with a retrospective cohort and a prospective cohort, comparing test results with the histopathological (reference) diagnosis
• Who was studied: 1540 patients' tumor specimens enrolled from three cancer centers in China (Beijing Cancer Hospital, Fudan University Shanghai Cancer Center, Zhejiang Cancer Hospital) between January 2016 and January 2021. 1417 met all criteria and were analyzed: 924 in the retrospective cohort and 493 in the prospective cohort. 1226 were primary tumors and 191 were metastatic tumors. Median age was 57 (range 9 to 88), and the specimens included 12 mesotheliomas.
• Exposure: Not studied: the article evaluates a 90-gene expression test and does not examine asbestos or any other exposure
• Main results:
  • Overall, the 90-gene test agreed with the pathological diagnosis in 94.4% of all 1417 samples (1338/1417, 95% CI: 0.93 to 0.96)
  • Sensitivity by tumor type ranged from 74.2% for head and neck tumors to 100% for adrenal, mesothelioma and prostate tumors
  • For mesothelioma (12 specimens), all 12 were correctly identified (sensitivity 100.0%). Specificity was 99.3% and positive prediction value was 54.5%, meaning just over half of the samples the test called mesothelioma were mesothelioma by reference diagnosis.
  • All 21 tumor types had specificities greater than 99%
  • Accuracy was lower in the prospective cohort than in the retrospective cohort (92.1% versus 95.7%, p-value = 0.007)
  • Accuracy was 95.5% (399 of 418) for well-moderately differentiated tumors and 94.5% (656 of 694) for poorly differentiated or undifferentiated tumors. The difference was not statistically significant (p-value = 0.59).
  • Eight head and neck tumors were misclassified, seven of them as gastroesophageal tumors
• The authors' conclusion: The authors concluded that the findings showed robust performance of the 90-gene test and support the use of molecular testing as an adjunct to tumor classification, especially for poorly differentiated or undifferentiated tumors
• Limitations the authors state:
  • Suboptimal specimens were excluded, such as biopsy samples, cytology samples, and samples with excess necrosis or few tumor cells. The authors noted that such samples are common in clinics.
  • Performance in identifying head and neck tumors was not optimal

Topics

Medical terms in this study, explained in our Lexicon: Carcinoma, Mesothelioma, Molecular Profiling.

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• Differential Diagnosis of Malignant Pleural Mesothelioma on Cytology: A Gene Expression Panel versus BRCA1-Associated Protein 1 and p16 Tests — R. Bruno, G. Alì, et al. (2020)
• Gene expression profiles reveal increased mClca3 (Gob5) expression and mucin production in a murine model of asbestos-induced fibrogenesis — T. Sabo-Attwood, M. Ramos-Nino, et al. (2005)

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