Journal: Cancer
Study question
The investigators evaluated how different p16 (p16^INK4a) immunohistochemical staining patterns in gastric cancer relate to clinicopathologic features, survival, response to systemic therapy, and the tumor immune microenvironment.
Design and cohorts
- Retrospective analysis of two cohorts:
- Zhongshan Hospital (ZSHS): 443 patients
- Samsung Medical Center (SMC): 43 patients
- Tumor classification by p16 staining:
- Loss
- Wild-type (WT)
- Overexpression (OE)
Key findings
1. Frequency and clinicopathologic features
- Frequency of p16 overexpression:
- In the ZSHS cohort, 20.3% (90/443) of cases showed p16 overexpression.
- p16 OE tumors were associated with:
- More advanced pT stage (p = .011)
- Higher Ki-67 proliferation index (p < .001)
- Higher rates of Rb loss (p < .001)
- Higher CCNE1 overexpression (p < .001)
2. Survival
- p16 OE and overall survival:
- p16 OE was associated with worse overall survival compared with WT.
- ZSHS cohort: OE vs WT, p = .004
- The effect was particularly evident in MSI tumors (p = .019).
- p16 loss vs WT:
- p16 loss and WT tumors had similar overall survival (p = .424).
3. Response to adjuvant chemotherapy (ACT)
- p16 OE tumors:
- Patients with p16 OE tumors had inferior benefit from ACT compared with WT (p = .011).
- This was especially evident in MSI tumors (p = .024).
- p16 loss vs WT:
- p16 loss and WT tumors showed comparable response to ACT (p = .834).
4. Response to immune checkpoint inhibitors (ICI)
- p16 OE and ICI response:
- p16 OE was associated with poorer response to ICI compared with WT (p = .045).
- This negative association was particularly evident in:
- PD-L1 CPS ≥1 tumors (p = .027)
- Chromosomal instability (CIN) tumors (p = .032)
- p16 loss vs WT:
- p16 loss and WT tumors had similar outcomes with ICI (p = .223).
5. Immune microenvironment
p16 OE gastric cancers showed an “immune-evasive” profile, with:
- Lower infiltration of antitumor immune cells:
- M1 macrophages
- Neutrophils
- CD8 T cells
- Higher expression of immunosuppressive / pro-tumor factors:
- TGF-β
- CD73
- IDO
Conclusions and implications
- Three-tier p16 staining pattern: Loss, WT, and OE define biologically and clinically distinct subgroups in gastric cancer.
- p16 overexpression: Marks a subset with more aggressive disease, worse survival, reduced benefit from adjuvant chemotherapy and immune checkpoint blockade, and an immunosuppressive tumor microenvironment.
- p16 loss: Behaves similarly to WT in this dataset, suggesting that overexpression rather than loss is the adverse phenotype in gastric cancer.