Chemotherapy is commonly used as a translational therapy strategy for patients with locally advanced unresectable PSCC. However, despite the meaningful response to systemic chemotherapy, long-term survival rates were disappointing, with 2-year progression-free survival (PFS) and disease-specific survival (DSS) probabilities of 12% and 28%, respectively. Moreover, patient resistance to chemotherapy have a worse prognosis. Therefore, there is a urgent need to find new translational therapeutic strategies with higher efficacy and low toxicity profile. Referring to the experience with advanced non-small cell lung cancer and melanoma, PD-(L)1 blockade plus chemotherapy may be a promising option.
Theoretically, in the primary tumor, PD-(L)1 blockade relieves the suppressive immune microenvironment, restores the activity of exhausted cytotoxic T cells, and mediates tumor regression. Simultaneously, chemotherapy causes tumor cell necrosis and releases more tumor antigens. In the presence of ICIs, dendritic cells can present antigens to T cells more efficiently, initiating tumor-specific T cell proliferation and activation. Activated T cells leave the tumor-draining lymph nodes into the bloodstream and migrate to tumor sites and distant micro-metastases, shrinking the primary lesion and reducing postoperative distant recurrence. In addition, the preoperatively induced systemic immune response generates long-term immune memory and prevents tumor recurrence.These suggest that immunotherapy combined with chemotherapy is a promising translational treatment strategy.
Numerous factors are involved in the effectiveness of immunotherapy. To explore the treatment options, we performed immunohistochemistry and next generation sequencing (NGS) analysis on our patient. PD-L1 expression in tumor tissues is validated companion diagnostic test for predicting efficacy of treatment with ICIs. Several studies have shown that 40–60% of PSCC patients express PD-L1 (PD-L1 positivity defined by > 5% tumor expression), and high PD-L1 expression positive associated with worse staging and prognosis . It is also associated with lower numbers of Tumor-infiltrating lymphocytes (TILs) in tumor tissue. The PD-L1 expression of our patient was 40%(Tumor Proportion Score, TPS), and these findings provide a rationale for the use of ICIs as a treatment option for patients with PSCC. Tumor mutation burden (TMB) is also a promising immunotherapeutic marker in many cancer types. However, the TMB cut-off values are not the same in different cancers. In our case, the patient had a TMB of 5.0 mutations per mega base (Muts/Mb), slightly higher than the median value (4.5 Muts/Mb) in PSCC, and a recent report suggests that mutations in select genes may be a better predictor than TMB. Microsatellite instability high (MSI-H) is another valid marker of sensitivity to ICIs. Our case was microsatellite stable (MSS), the literature reports a low incidence of MSI-H in PSCC.
More interesting, patient’s laboratory testing got human papillomavirus (HPV) 16 DNA. Patients with HPV+ PSCC have a better prognosis than those with HPV−. The possible mechanism is that the virus increases the production of neo-antigens, while increasing the number of infiltrating CD8+T cells in the tumor microenvironment. Does this mean that the HPV virus could be a meaningful biomarker for immunotherapy? Considering the impact of HPV on the tumor, several clinical trials of combinatorial immunotherapy augmented with HPV-targeted vaccines have been conducted in HPV-associated malignancies. Current results regarding the association between the status of HPV and the expression of PD-L1 are conflicting and need to be confirmed by more studies. However, the differences in TMB between HPV− and HPV+ PSCC patients are minimal.
In addition, patient in current case had high expression of epidermal growth factor receptor (EGFR) by immunohistochemistry and was treated experimentally with EGFR monoclonal antibody. Several studies have shown that high EGFR expression detected by IHC is frequently seen in PSCC . High expression of EGFR may be associated with poor prognosis, implying better effects by targeting EGFR. Retrospective studies have shown that the use of Cetuximab or dacomitinib (a pan-HER tyrosine kinase inhibitor) provide benefit to only a small number of patients. Our patient had disease progression after attempting EGFR monoclonal antibodies. NGS of this case showed a mutation in PIK3CA p.E453K. In colon cancer, PIK3CA mutations are significantly associated with clinical resistance to EGFR monoclonal antibodies.
In conclusion, current case present with HPV+ locally advanced inoperable PSCC that responded well to ICI plus chemotherapy, converted to operable, and underwent inguinal lymph node dissection, which was pathologically confirmed to achieve a complete response. Postoperative disease-free survival (DFS) exceeded 12 months and continued the trend of prolongation. For this group, immunotherapy combined with chemotherapy is a promising translational treatment option. However, more clinical trials are needed to validate this notion and effective biomarkers need to be further explored.