Differential p16/INK4A cyclin-dependent kinase inhibitor expression correlates with chemotherapy efficacy in a cohort of 88 malignant pleural mesothelioma patients

Our plain-English summary of Differential p16/INK4A cyclin-dependent kinase inhibitor expression correlates with chemotherapy efficacy in a cohort of 88 malignant pleural mesothelioma patients, by C.J. Jennings, B. Murer, A. O'Grady, et al (British Journal of Cancer, 2015).

The study

• Authors: C.J. Jennings, B. Murer, A. O'Grady, L.M. Hearn, B.J. Harvey, E.W. Kay, W. Thomas
• Journal: British Journal of Cancer
• Published: 2015;113(1):69-75
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare and essentially incurable malignancy most often linked with occupational exposure to asbestos fibres. In common with other malignancies, the development and progression of MPM is associated with extensive dysregulation of cell cycle checkpoint proteins that modulate cell proliferation, apoptosis, DNA repair and senescence.

Methods: The expression of cyclin-dependent kinase inhibitor p16/INK4A was evaluated by immunohistochemistry using tumour biopsy specimens from 88 MPM cases and a semi-quantitative score for p16/INK4A expression was obtained. Post-diagnosis survival and the survival benefit of chemotherapeutic intervention was correlated with p16/INK4A expression.

Results: A low, intermediate and high score for p16/INK4A expression was observed for 45 (51.1%), 28 (31.8%) and 15 (17.1%) of the MPM cases, respectively. Those cases with intermediate or high p16/INK4A tumour expression had a significantly better post-diagnosis survival than those cases whose tumours lost p16 expression (log-rank P<0.001). Those patients with sustained p16/INK4A expression who received chemotherapy also had a better survival than those treated patients whose tumours had lost p16/INK4A expression (log-rank P<0.001).

Conclusions: Sustained p16/INK4A expression predicts better post-diagnosis survival in MPM and also better survival following chemotherapeutic intervention.

In plain English

This study examined archived tumour samples from 88 people with confirmed malignant pleural mesothelioma from a hospital in Mestre-Venice, Italy. The researchers stained the samples for p16/INK4A, a protein that helps control cell division, scored the staining, and compared scores with survival after diagnosis and with cisplatin-based chemotherapy, which 64 patients had received. The article does not report the patients' asbestos exposure. Staining was low in 45 cases (51.1%), intermediate in 28 (31.8%) and high in 15 (17.1%). Median survival was 25 months for patients with intermediate or high staining versus 8 months for low staining, a statistically significant difference. Among patients who received chemotherapy, median survival was 29 months for the 34 p16-positive (intermediate or high staining) and 14 months for the 30 p16-negative, also significant. Among the 24 patients who did not receive chemotherapy, the difference (7 versus 4 months) was not statistically significant. The authors said this group was too small to determine significance. They noted that most epithelioid tumours also expressed p16. The authors concluded that sustained p16/INK4A expression predicts survival and correlates with chemotherapy efficacy.

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: Retrospective study of archived tumour biopsy specimens (immunohistochemistry scoring compared with survival and chemotherapy), plus laboratory experiments on mesothelioma cell lines
• Who was studied: 88 patients with confirmed malignant pleural mesothelioma (72 male, 16 female, aged 44 to 82 years) and three normal control subjects, from the Regional Hospital of Mestre-Venice, Italy. Histological types: 71 epithelioid, 9 biphasic, 8 sarcomatoid. Years of diagnosis are not given.
• Exposure: The study did not assess asbestos exposure. It compared tumour expression of the p16/INK4A protein (scored as low 0 to 3, intermediate 4 to 6, or high 7 to 8) and treatment with cisplatin-based chemotherapy, given to 64 of 88 patients.
• Main results:
  • Of the 88 tumours, p16/INK4A staining was high in 15 (17.1%), low in 45 (51.1%) and intermediate in 28 (31.8%).
  • Median post-diagnosis survival was 25 months for patients with high or intermediate p16 staining (n = 43) and 8 months for those with low or negative staining (n = 45). The difference was significant (log-rank P less than 0.001).
  • Median survival was 29 months in the high-expression group (n = 15) and 23 months in the intermediate group (n = 28). This difference was not significant (log-rank P = 0.413).
  • Among the 24 patients who did not receive chemotherapy, median survival was 4 months for the 15 p16-negative patients and 7 months for the 9 p16-positive patients. The difference was not significant (log-rank P = 0.069).
  • Among the 64 patients who received chemotherapy, median survival was 14 months for the 30 p16-negative patients and 29 months for the 34 p16-positive patients. The difference was significant (log-rank P less than 0.001).
  • In multivariate analysis (MANOVA), both p16/INK4A expression (P = 0.03) and chemotherapeutic treatment (P = 0.01) were significant for post-diagnosis survival. Age at diagnosis was a significant covariate (P = 0.049). Histological type and gender were not significant covariates in this data set.
  • In laboratory tests, p16/INK4A mRNA was detected in only 4 of 11 mesothelioma cell lines.
• The authors' conclusion: The authors concluded that sustained p16/INK4A expression predicts survival in malignant pleural mesothelioma and correlates with chemotherapeutic efficacy. They suggested that modification of the p16/INK4A protein may be a better predictor of survival and needs further investigation.
• Limitations the authors state:
  • The group of patients who did not receive chemotherapy was too small to determine statistical significance.
  • Histological type is itself an established predictor of survival and of chemotherapy effectiveness, and most epithelioid tumours in this study also expressed p16/INK4A.
  • In the cell line experiments, p16/INK4A mRNA levels did not always match the protein levels detected by western blotting.

Topics

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

Medical terms in this study, explained in our Lexicon: Chemotherapy, Pleural Mesothelioma, Occupational Exposure, Apoptosis, Immunohistochemistry, Biopsy.

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