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Differential Spatial Gene and Protein Expression Associated with Recurrence Following Chemoradiation for Localized Anal Squamous Cell Cancer.

ABSTRACT: The identification of transcriptomic and protein biomarkers prognosticating recurrence risk after chemoradiation of localized squamous cell carcinoma of the anus (SCCA) has been limited by a lack of available fresh tissue at initial presentation. We analyzed archival FFPE SCCA specimens from pretreatment biopsies prior to chemoradiation for protein and RNA biomarkers from patients with localized SCCA who recurred (N = 23) and who did not recur (N = 25). Tumor cells and the tumor microenvironment (TME) were analyzed separately to identify biomarkers with significantly different expression between the recurrent and non-recurrent groups. Recurrent patients had higher mean protein expression of FoxP3, MAPK-activation markers (BRAF, p38-MAPK) and PI3K/Akt activation (phospho-Akt) within the tumor regions. The TME was characterized by the higher protein expression of immune checkpoint biomarkers such as PD-1, OX40L and LAG3. For patients with recurrent SCCA, the higher mean protein expression of fibronectin was observed in the tumor and TME compartments. No significant differences in RNA expression were observed. The higher baseline expression of immune checkpoint biomarkers, together with markers of MAPK and PI3K/Akt signaling, are associated with recurrence following chemoradiation for patients with localized SCCA. These data provide a rationale towards the application of immune-based therapeutic strategies to improve curative-intent outcomes beyond conventional therapies for patients with SCCA.

SUBMITTER: Hernandez S

PROVIDER: S-EPMC10046657 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Differential Spatial Gene and Protein Expression Associated with Recurrence Following Chemoradiation for Localized Anal Squamous Cell Cancer.

Hernandez Sharia S Das Prajnan P Holliday Emma B EB Shen Li L Lu Wei W Johnson Benny B Messick Craig A CA Taniguchi Cullen M CM Skibber John J Ludmir Ethan B EB You Y Nancy YN Smith Grace Li GL Bednarski Brian B Kostousov Larisa L Koay Eugene J EJ Minsky Bruce D BD Tillman Matthew M Portier Shaelynn S Eng Cathy C Koong Albert C AC Chang George J GJ Foo Wai Chin WC Wang Jing J Soto Luisa Solis LS Morris Van K VK

Cancers 20230310 6

The identification of transcriptomic and protein biomarkers prognosticating recurrence risk after chemoradiation of localized squamous cell carcinoma of the anus (SCCA) has been limited by a lack of available fresh tissue at initial presentation. We analyzed archival FFPE SCCA specimens from pretreatment biopsies prior to chemoradiation for protein and RNA biomarkers from patients with localized SCCA who recurred (N = 23) and who did not recur (N = 25). Tumor cells and the tumor microenvironment ...[more]

PMID: 36980587

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Project description:ImportanceDefinitive chemoradiation for anal cancer is effective but may be associated with toxic effects, and some patients may not be able to complete the planned treatment. Identifying factors associated with treatment interruption and noncompletion is important to target quality improvement efforts.ObjectiveTo identify rates of chemoradiation treatment interruption or noncompletion and factors associated with this among patients with anal cancer treated in routine clinical practice.Design, setting, and participantsIn this population-based, retrospective cohort study, the Ontario Cancer Registry was used to identify all incident cases of squamous cell anal cancer treated with curative-intent radiation from 2007 to 2015 in Ontario, Canada. Final analysis of data was performed on August 9, 2019.ExposuresCurative-intent radiation therapy.Main outcomes and measuresTreatment interruption was defined as more than 7 days between fractions of radiation. Radiation completion was defined as receipt of 45 Gy or more and 25 fractions of radiation. Chemoradiation completion was defined as radiation completion and 2 doses of combination chemotherapy. Associations between patient factors and treatment interruption and noncompletion were estimated with log-binomial models. Cox proportional hazard models were used to estimate the association of treatment interruption or noncompletion with all-cause death, cancer-specific death, and the combined outcome of colostomy or death.ResultsOverall, 1125 patients with stage I-III anal cancer were treated with curative-intent radiation. Treatment interruptions occurred in 262 (23%). Radiation and chemoradiation noncompletion occurred in 199 (18%) and 280 (25%), respectively. No associations were found to correlate with an increased risk of treatment interruption. Patients older than 70 years were less likely to complete chemoradiation (risk ratio [RR], 0.60; 95% CI, 0.52-0.70), compared with those younger than 50 years. Patients with a higher number of comorbidities were also less likely to complete chemoradiation (RR, 0.70; 95% CI, 0.51-0.95). Patients who did not complete chemoradiation had a higher risk of requiring salvage abdominoperineal resection (RR, 1.54; 95% CI, 1.03, 2.31), overall death (hazard ratio [HR], 1.54; 95% CI, 1.23-1.92), cancer-specific death (HR, 1.59; 95% CI, 1.14-2.22), and colostomy or death (HR, 1.80; 95% CI: 1.10-2.93). Treatment interruptions longer than 7 days were not associated with death.Conclusions and relevanceMany patients undergoing curative-intent chemoradiation for anal cancer experienced treatment interruption or noncompletion. Quality improvement initiatives to optimize treatment continuity and completion are needed.

Project description:IntroductionThe incidence of metastatic squamous cell carcinoma of the anus (SCCA) is increasing. Even if systemic docetaxel, cisplatin, and 5-Fluorouracil (DCF) provide a high rate of long-term remission, the role of pelvic chemoradiation (CRT) is unknown in this setting. We reported the safety and efficacy of local CRT in patients with synchronous metastatic SCCA who achieved objective response after upfront DCF.MethodsPatients included in Epitopes HPV01 or Epitopes HPV02 or SCARCE trials and treated with DCF followed by pelvic CRT were included. Concurrent chemotherapy was based on mitomycin (MMC) (10 mg/m² for two cycles) and fluoropyrimidine (capecitabine 825 mg/m² twice a day at each RT treatment day or two cycles of intra-venous 5FU 1000 mg/m² from day 1 to day 4). Primary endpoints were safety, local complete response rate, and local progression-free survival (PFS). Secondary endpoints were PFS, overall survival (OS), and metastasis-free survival (MFS).ResultsFrom 2013 to 2018, 16 patients received DCF followed by a complementary pelvic CRT for advanced SCCA. Median follow-up was 42 months [range, 11-71]. All patients received the complete radiation dose. Compliance to concurrent CT was poor. Overall, 13/15 of the patients (87%) had at least one grade 1-2 acute toxicity and 11/15 of the patients (73%) had at least one grade 3-4 toxicity. There was no treatment-related death. The most frequent grade 3-4 adverse effects were neutropenia (36%), dermatitis (40%), and anitis (47%). Eleven patients (73%) had at least one chronic grade 1 or 2 toxicity. One patient had a grade 4 chronic rectitis (7%). Complete local response rate was 81% at first evaluation and 62.5% at the end of the follow-up. Median local PFS was not reached and the 3-year local PFS was 77% (95%CI 76.8-77).ConclusionsIn patients with metastatic SCCA who had a significant objective response after upfront DCF, local CRT was feasible with high complete local response rate. The good local control rate, despite interruptions due to toxicities and low CT compliance, underline the role of pelvic RT. The high rate of toxicity prompts the need to adapt CRT regimen in the metastatic setting.

Dataset Information

Differential Spatial Gene and Protein Expression Associated with Recurrence Following Chemoradiation for Localized Anal Squamous Cell Cancer.

Publications

Differential Spatial Gene and Protein Expression Associated with Recurrence Following Chemoradiation for Localized Anal Squamous Cell Cancer.

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