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Impact of PD-L1 Scores and Changes on Clinical Outcome in Rectal Cancer Patients Undergoing Neoadjuvant Chemoradiotherapy.

ABSTRACT: Reports on the prognostic role of programmed death-ligand 1 (PD-L1) expression in rectal cancer are controversial. We investigated expression patterns and changes of PD-L1 in rectal cancer patients undergoing neoadjuvant chemoradiotherapy (CRT). Seventy-two patients diagnosed with rectal cancer and/or treated with fluorouracil-based neoadjuvant CRT at the Department of Internal Medicine III of the Paracelsus Medical University Salzburg (Austria) between January 2003 and October 2012 were included. PD-L1 scoring was performed according to the tumor proportion score (TPS), combined positive score (CPS), and immune cell score (IC). PD-L1 TPS prior to neoadjuvant CRT had a statistically significant impact on survival (median: ?1%: 95.4 months (95% CI: 51.8-not reached) vs. >1%: not reached, p = 0.03, log-rank). Patients with a PD-L1 TPS ?1% prior to and after CRT showed an inferior survival compared to all other patients (median: 56.7 months (95% CI: 51.4-not reached) vs. not reached, p = 0.005, log-rank). In multivariate analysis, PD-L1 TPS prior to neoadjuvant CRT (>1% vs. ?1%, hazard ratio: 0.29 (95% CI: 0.11-0.76), p = 0.01) remained independently associated with survival. In conclusion, low PD-L1 TPS was associated with inferior survival in rectal cancer patients undergoing neoadjuvant CRT. A prospective validation of the prognostic value of PD-L1 expression in rectal cancer patients within a clinical trial is necessitated.

SUBMITTER: Huemer F

PROVIDER: S-EPMC7563312 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Impact of PD-L1 Scores and Changes on Clinical Outcome in Rectal Cancer Patients Undergoing Neoadjuvant Chemoradiotherapy.

Huemer Florian F Klieser Eckhard E Neureiter Daniel D Schlintl Verena V Rinnerthaler Gabriel G Pagès Franck F Kirilovsky Amos A El Sissy Carine C Iglseder Wolfgang W Singhartinger Franz F Jäger Tarkan T Dinnewitzer Adam A Zaborsky Nadja N Steiner Markus M Greil Richard R Weiss Lukas L

Journal of clinical medicine 20200827 9

Reports on the prognostic role of programmed death-ligand 1 (PD-L1) expression in rectal cancer are controversial. We investigated expression patterns and changes of PD-L1 in rectal cancer patients undergoing neoadjuvant chemoradiotherapy (CRT). Seventy-two patients diagnosed with rectal cancer and/or treated with fluorouracil-based neoadjuvant CRT at the Department of Internal Medicine III of the Paracelsus Medical University Salzburg (Austria) between January 2003 and October 2012 were include ...[more]

PMID: 32867256

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Project description:Background: Neoadjuvant chemoradiotherapy (NCRT) is the treatment of choice in advanced rectal cancer, even though there are many patients who will not benefit from it. There are still no effective methods for predicting which patients will respond or not. The present study aimed to define the genomic profile of rectal tumors and to identify alterations that are predictive of response in order to optimize therapeutic strategies. Methods: Forty-eight candidates for NCRT were recruited and their pretherapy biopsies analyzed by array Comparative Genomic Hybridization (aCGH). Pathologic response was evaluated by tumor regression grade (TRG).Results: Both Smoothing and Hidden Markov Model (HMM) approaches identified similar alterations, with a prevalence of DNA gains. Non responsive patients had a different alteration profile from responsive ones, with a higher number of genome changes mainly located on 2q21, 7q21, 7q36, 13q12, 13q32-34, 16p13, 17p12 chromosomal regions. Conclusion: This exploratory study suggests that an in depth characterization of chromosomal alterations by aCGH would provide useful predictive information about response to NCRT and help to optimize therapy in rectal cancer patients. 48 samples included in the study were analyzed on whole genome BAC arrays with the aim to characterize genomic alterations and correlate them with the tumor response to therapy. The case series was composed by 15%,81% and 4% of uT2, uT3 and uT4 tumors, respectively. At the diagnosis 56% of patients had uN0 tumors and 44% uN+. 30%,13%, 23% and 34% of patients reached/mantained respectively ypT0, ypT1, ypT2 and ypT3. With regard to response to NCRT, according to TRG criteria proposed by Dworak, two group were defined: non responders (TRG0-2= 56%) and responders (TRG3-4=44%). Clinical and pathological parameters: uT: pre-therapy stage determined by ultrasounds techniques uN: pre-therapy lymph node status determined by ultrasounds techniques ypT: pathologic stage after a neoadjuvant treatment ypN: pathologic lymph node status after a neoadjuvant treatment

Project description:BackgroundThe aim of this paper is to share the methodological problems of an unsuccessful prospective single-arm feasibility trial conducted to evaluate the safety and feasibility of a 12-week progressive exercise intervention for adults undergoing neoadjuvant chemoradiotherapy for rectal cancer, as well as offer recommendations for future trials.MethodsThe initial plan was to recruit adults diagnosed with rectal cancer and scheduled for neoadjuvant chemoradiotherapy over a 12-month period. The exercise intervention was to consist of supervised exercise sessions delivered three times per week by a trained exercise specialist. Feasibility (i.e., recruitment, adherence, and compliance rates) and safety (i.e., adverse events) were to be assessed throughout the trial, and patient-reported and physical health outcomes were to be assessed pre- and post-intervention. After 8 months of open recruitment, we had been unable to successfully enroll patients into our trial. We therefore modified our eligibility criteria to increase the number of patients that could be recruited into our trial, and in turn increase our recruitment rate. We also amended our recruitment procedures to ensure we could reach patients who were either awaiting treatment, receiving treatment, or had completed treatments in the past 5 years. In doing so, we added a research objective, namely to determine the optimal timing of conducting an exercise intervention with adults diagnosed with rectal cancer (i.e., during neoadjuvant treatment, after surgery, during adjuvant treatment, or post-treatment).ResultsMany problems continued to hinder the progress of our trial, particularly the low recruitment rate and the failure to enroll the required sample size that would make our results reliable.ConclusionThis led us to conclude that our trial was not feasible and that it is advisable to consider some elements carefully (e.g., recruitment strategies, communication, and trial location) before designing and conducting future trials. If one or more of these elements still proves to be problematic, trial results risk being compromised and alternative approaches should be considered.Trial registrationClinicalTrials.gov NCT03049124 . Registered on 02 September 2017.

Project description:BackgroundWe aimed to investigate clinical implications of specific soluble immune checkpoint molecules (sICMs) in locally advanced rectal cancer (LARC) patients treated with neoadjuvant chemoradiotherapy (nCRT).MethodsWe prospectively enrolled 30 LARC patients treated with nCRT and collected blood samples from them before, during, and after nCRT for prospective studies. Immune checkpoints often refer to T cell surface molecules influencing the immune response. Immune checkpoints, in the form of a soluble monomeric form, is widely present in blood. In the study, eight immune checkpoint-related plasma proteins, including programmed death-ligand 1 (PD-L1), CD80, CD86, CD28, CD27, glucocorticoid-induced tumor necrosis factor receptor (GITR), GITR ligand (GITRL), and inducible T-cell costimulator (ICOS), were measured using the Luminex platform. Two independent pathologists categorized patients as the good responders and the poor responders according to Dworak tumor regression grade (TRG).ResultsOf the 30 patients, the levels of sPD-L1, sCD80, sCD86, sCD28, sGITR, sGITRL, sCD27, and sICOS decreased during nCRT (Pre-nCRT vs. During-nCRT, all p<0.05) but were restored after nCRT treatment (Pre-nCRT vs. Post-nCRT, all p>0.05). In the 14 good responders, the levels of sICMs, other than sGITR (p=0.081) and sGITRL (p=0.071), decreased significantly during nCRT (Pre-nCRT vs. During-nCRT, p<0.05), but they were all significantly increased after nCRT (During-nCRT vs. Post-nCRT, all p<0.05). In the 16 poor responders, only sCD80 was significantly reduced during nCRT (Pre-nCRT vs. During-nCRT, p<0.05), and none was significantly increased after nCRT (During-nCRT vs. Post-nCRT, all p<0.05). High levels of sICMs before nCRT were associated with poor response (all OR≥1). The Pre-model that incorporated the 8 sICMs before nCRT yielded a good predictive value (AUC, 0.848) and was identified as an independent predictor of treatment response (OR, 2.62; 95% CI, 1.11-6.18; p=0.027).ConclusionOur results suggest chemoradiotherapy could influence the change of sPD-L1, sCD80, sCD86, sCD28, sGITR, sGITRL, sCD27, and sICOS in patients with LARC. The levels of the majority of soluble immune checkpoint molecules were reduced during nCRT and then restored at the end of nCRT, particularly in patients who responded well to nCRT. Combined baseline sICMs can be developed to predict treatment response.

Dataset Information

Impact of PD-L1 Scores and Changes on Clinical Outcome in Rectal Cancer Patients Undergoing Neoadjuvant Chemoradiotherapy.

Publications

Impact of PD-L1 Scores and Changes on Clinical Outcome in Rectal Cancer Patients Undergoing Neoadjuvant Chemoradiotherapy.

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