Locally Advanced Rectal Cancer Research Articles

Prognostic value of neutrophil-to-lymphocyte ratio (NLR) and platelet-neutrophil (PN) index in locally advanced rectal cancer patients: a retrospective cohort study.

In locally advanced rectal cancers (LARC), tumour node metastasis (TNM) staging is far from optimal. The authors aimed to investigate the value of previously described circulating biomarkers as predictors of prognosis. Retrospective analysis of 245 LARC patients diagnosed between January 2010 and December 2022, who underwent neoadjuvant chemoradiotherapy and surgery at two centres. A Cox regression and Kaplan-Meier analysis were performed. Post-treatment platelet-to-lymphocyte ratio (PLR) predicted pathological complete response. The neutrophil-to-lymphocyte ratio (NLR) in two timepoints of the treatment significantly predicted overall survival, whereas the platelet-neutrophil (PN) index significantly predicted disease-free survival. In pathological stage II, the PN index predicted patients with a higher risk of disease-free survival. Blood parameters might allow the definition of subgroups of risk beyond TNM for the application of different therapeutic strategies.

Total neoadjuvant therapy in rectal cancer: a review across studies

Abstract The optimal management of locally advanced rectal cancer (LARC) often presents a therapeutic challenge. Balancing the benefits of treatment against toxicities and reducing the risk for local and distal recurrences are the mainstay of therapeutic approaches. Recently, several studies have compared a more aggressive approach of delivering several cycles of systemic chemotherapy to the established standard of combined chemoradiation. This approach is termed total neoadjuvant therapy and appears to be beneficial, at least for a subset of patients. The results of the main Phase III studies along with their variations in study design are hereby discussed with the goal of extracting useful clinical suggestions for treatment.

[Role of neoadjuvant rectal score in prognosis and adjuvant chemotherapy decision-making in locally advanced rectal cancer following neoadjuvant short-course radiotherapy and consolidation chemotherapy].

Objectives: To assess the prognostic impact of the neoadjuvant rectal (NAR) score following neoadjuvant short-course radiotherapy and consolidation chemotherapy in locally advanced rectal cancer (LARC), as well as its value in guiding decisions for adjuvant chemotherapy. Methods: Between August 2015 and August 2018, patients were eligible from the STELLAR phase III trial (NCT02533271) who received short-course radiotherapy plus consolidation chemotherapy and for whom the NAR score could be calculated. Based on the NAR score, patients were categorized into low (＜8), intermediate (8-16), and high (＞16) groups. The Kaplan-Meier method, log rank tests, and multivariate Cox proportional hazard regression models were used to evaluate the impact of the NAR score on disease-free survival (DFS). Results: Out of the 232 patients, 24.1%, 48.7%, and 27.2% had low (56 cases), intermediate (113 cases), and high NAR scores (63 cases), respectively. The median follow-up period was 37 months, with 3-year DFS rates of 87.3%, 68.3%, and 53.4% (P＜0.001) for the low, intermediate, and high NAR score groups. Multivariate analysis demonstrated that the NAR score (intermediate NAR score: HR, 3.10, 95% CI, 1.30-7.37, P=0.011; high NAR scores: HR=5.44, 95% CI, 2.26-13.09, P＜0.001), resection status (HR, 3.00, 95% CI, 1.64-5.52, P＜0.001), and adjuvant chemotherapy (HR, 3.25, 95% CI, 2.01-5.27, P＜0.001) were independent prognostic factors for DFS. In patients with R0 resection, the 3-year DFS rates were 97.8% and 78.0% for those with low and intermediate NAR scores who received adjuvant chemotherapy, significantly higher than the 43.2% and 50.6% for those who did not (P＜0.001, P=0.002). There was no significant difference in the 3-year DFS rate (54.2% vs 53.3%, P=0.214) among high NAR score patients, regardless of adjuvant chemotherapy. Conclusions: The NAR score is a robust prognostic indicator in LARC following neoadjuvant short-course radiotherapy and consolidation chemotherapy, with potential implications for subsequent decisions regarding adjuvant chemotherapy. These findings warrant further validation in studies with larger sample sizes.

Precision Identification of Locally Advanced Rectal Cancer in Denoised CT Scans Using EfficientNet and Voting System Algorithms.

Local advanced rectal cancer (LARC) poses significant treatment challenges due to its location and high recurrence rates. Accurate early detection is vital for treatment planning. With magnetic resonance imaging (MRI) being resource-intensive, this study explores using artificial intelligence (AI) to interpret computed tomography (CT) scans as an alternative, providing a quicker, more accessible diagnostic tool for LARC. In this retrospective study, CT images of 1070 T3-4 rectal cancer patients from 2010 to 2022 were analyzed. AI models, trained on 739 cases, were validated using two test sets of 134 and 197 cases. By utilizing techniques such as nonlocal mean filtering, dynamic histogram equalization, and the EfficientNetB0 algorithm, we identified images featuring characteristics of a positive circumferential resection margin (CRM) for the diagnosis of locally advanced rectal cancer (LARC). Importantly, this study employs an innovative approach by using both hard and soft voting systems in the second stage to ascertain the LARC status of cases, thus emphasizing the novelty of the soft voting system for improved case identification accuracy. The local recurrence rates and overall survival of the cases predicted by our model were assessed to underscore its clinical value. The AI model exhibited high accuracy in identifying CRM-positive images, achieving an area under the curve (AUC) of 0.89 in the first test set and 0.86 in the second. In a patient-based analysis, the model reached AUCs of 0.84 and 0.79 using a hard voting system. Employing a soft voting system, the model attained AUCs of 0.93 and 0.88, respectively. Notably, AI-identified LARC cases exhibited a significantly higher five-year local recurrence rate and displayed a trend towards increased mortality across various thresholds. Furthermore, the model's capability to predict adverse clinical outcomes was superior to those of traditional assessments. AI can precisely identify CRM-positive LARC cases from CT images, signaling an increased local recurrence and mortality rate. Our study presents a swifter and more reliable method for detecting LARC compared to traditional CT or MRI techniques.

A retrospective cohort study of neoadjuvant chemoradiotherapy combined with immune checkpoint inhibitors in locally advanced rectal cancer

IntroductionThis study aimed to investigate the safety and efficacy of neoadjuvant chemoradiotherapy combined with immune checkpoint inhibitors (ICIs) in patients with locally advanced rectal cancer (LARC). Patients diagnosed with LARC and treated with programmed cell death protein-1 (PD-1) inhibitors were recruited. MethodsFour different treatment strategies were employed in this study: plan A [long-course radiotherapy + PD-1 inhibitor/capecitabine + PD-1 inhibitor/XELOX+ total mesorectal excision (TME)], plan B (long-course radiotherapy + capecitabine + PD-1 inhibitor/XELOX + TME), plan C (short-course radiotherapy + PD-1 inhibitor/XELOX + TME), and plan D (PD-1 inhibitor/XELOX + short-course radiotherapy + TME). The basic information about patients, pathological indicators, adverse events, and efficacy indexes of treatment plans were analyzed. Results96.8% of patients were mismatch repair proficient (pMMR) and only 2 patients belonged to mismatch repair deficient (dMMR). The 2 patients with dMMR showed a pathological complete response (pCR) rate of 100%, while the pCR rate of pMMR patients was 43.3%. The overall tumor descending rate reached 79%, and the anus-retained rate was 88.7% in all LARC patients. Plan A exhibited the highest pCR rate of 60%, and plan C had the highest tumor descending rate and anal preservation rate. Radiation enteritis was the most common adverse event in LARC patients after neoadjuvant therapy, and its incidence was the highest in Plan A. ConclusionNeoadjuvant chemoradiotherapy combined with ICIs demonstrated favorable efficacy and safety in treating LARC patients.

Abstract CT130: Epacadostat with preoperative chemoradiation in locally advanced rectal cancer (LARC): Results of a translational phase I clinical trial

Abstract BACKGROUND: In preclinical studies, we found that the immuno-oncology target and tryptophan metabolizing enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) promotes resistance to radiation in rectal cancer regardless of MSI status. Furthermore, IDO1 inhibition with epacadostat improved tumor radiosensitivity, abrogated immunosuppression, limited distal recurrence, and was radioprotective of the normal intestine. This trial aimed to evaluate the safety of IDO1 inhibition when combined with neoadjuvant short-course radiation (SCRT) and chemotherapy with capecitabine and oxaliplatin (CAPOX) for LARC. METHODS: The primary objective was to determine the recommended phase II dose (RP2D) of epacadostat for combination with SCRT and CAPOX. Secondary objectives included determining antitumor activity as measured by neoadjuvant rectal (NAR) score and pathological or clinical complete responses. During the dose escalation phase, 3 doses of epacadostat (300mg, 400mg, & 600mg BID) were explored. Epacadostat was combined with SCRT (5Gy x 5 fractions) followed by 6 cycles of CAPOX chemotherapy, until the day of surgery (~24 wks). Tissues and blood were collected for correlative studies. A control cohort was generated from patients receiving the same treatment without epacadostat. NCT03516708 RESULTS: Seventeen patients were enrolled from 4/2019 to 8/2023. RP2D of epacadostat in combination with SCRT and CAPOX chemotherapy was determined to be 400mg BID. Two patients experienced dose-limiting toxicities (DLT) at 600mg dose level, one with G2 elevated ALT and another with G3 maculopapular rash. No DLT was reported at other dose levels. Of six patients who underwent surgery, the mean NAR score was 7.46 (SD 7.11; range 0 - 20.4), indicating potentially better response compared to the mean NAR of 17.8 in an institutional 2:1 matched control cohort (p=0.03). Tumor tissue revealed increased IDO1 expression and kynurenine levels in all patient tumors after radiation. After epacadostat, serum levels of kynurenine were reduced while TNFα, IFNγ, and MIP1a were all increased. Global metabolomics and RNAseq revealed a distinct pattern of serum biomarkers and immunophenotype respectively in patients after treatment. Tumoroids were evaluated as ex vivo models of treatment response. CONCLUSION: Epacadostat in combination with SCRT and CAPOX was well-tolerated. An NCI supported Phase 2 trial is ongoing to further evaluate the promising disease responses reported in dose escalation phase. Citation Format: Haeseong Park, Katrina Pedersen, Katherine Huang, Matthew Mutch, Hyun Kim, Nikolaos Trikalinos, Olivia Aranha, Benjamin Tan, Rama Suresh, Lee Ratner, Moh'd Khushman, John Visconti, Kian-Huat Lim, Lauren Henke, Maddie Swiecicki, Jingxia Liu, Parag Parikh, Matthew Ciorba. Epacadostat with preoperative chemoradiation in locally advanced rectal cancer (LARC): Results of a translational phase I clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT130.

Clinicopathological factors predict residual lymph node metastasis in locally advanced rectal cancer with ypT0-2 after neoadjuvant chemoradiotherapy

PurposeResidual lymph node metastases (RLNM) remained a great concern in the implementation of organ-preserving strategies and led to poor prognosis in locally advanced rectal cancer (LARC). In this study, we aimed to identify the clinicopathological factors correlated with RLNM in LARC patients with ypT0-2 after neoadjuvant chemoradiotherapy (NCRT).MethodsWe retrospectively analyzed 417 patients histologically diagnosed middle-low LARC after NCRT and total mesorectal excision (TME), whose pathological staging was ypT0-2. All patients received pelvic magnetic resonance imaging (MRI) before NCRT. The radiation doses were 50–50.6 Gy for the planning gross tumor volume and 41.8–45 Gy for the planning target volume, respectively. A nomogram for predicting RLNM was constructed using a binary logistic regression. Nomogram performance was assessed by receiver operating characteristic (ROC) curve, calibration curve, decision curve analysis (DCA) and clinical impact curve (CIC).ResultsAfter surgery, 191 patients (45.8%) were ypT0, 43 patients (10.3%) were ypT1 and 183 patients (43.9%) were ypT2, and a total of 49 patients (11.8%) were found the presence of RLNM. Multivariable analyses identified MRI-defined mesorectal fascia (MRF)-positive, high-grade histopathology at biopsy, advanced ypT-category, and the presence of perineural invasion (PNI) as the predictive factors. The nomogram, incorporating all these predictors, showed good discrimination and calibration efficacy, with the areas under the ROC curve of 0.690 (95% CI: 0.610–0.771). Both DCA and CIC demonstrated that this nomogram has good clinical usefulness.ConclusionThe nomogram model can predict RLNM in patients with ypT0-2 tumors. It can help select suitable patients for performing organ-preserving strategies after NCRT.

Therapy-induced senescent tumor cell-derived extracellular vesicles promote colorectal cancer progression through SERPINE1-mediated NF-κB p65 nuclear translocation

BackgroundCellular senescence frequently occurs during anti-cancer treatment, and persistent senescent tumor cells (STCs) unfavorably promote tumor progression through paracrine secretion of the senescence-associated secretory phenotype (SASP). Extracellular vesicles (EVs) have recently emerged as a novel component of the SASP and primarily mediate the tumor-promoting effect of the SASP. Of note, the potential effect of EVs released from STCs on tumor progression remains largely unknown.MethodsWe collected tumor tissues from two cohorts of colorectal cancer (CRC) patients to examine the expression of p16, p21, and SERPINE1 before and after anti-cancer treatment. Cohort 1 included 22 patients with locally advanced rectal cancer (LARC) who received neoadjuvant therapy before surgical resection. Cohort 2 included 30 patients with metastatic CRC (mCRC) who received first-line irinotecan-contained treatment. CCK-8, transwell, wound-healing assay, and tumor xenograft experiments were carried out to determine the impacts of EVs released from STCs on CRC progression in vitro and in vivo. Quantitative proteomic analysis was applied to identify protein cargo inside EVs secreted from STCs. Immunoprecipitation and mass spectrometer identification were utilized to explore the binding partners of SERPINE1. The interaction of SERPINE1 with p65 was verified by co-immunoprecipitation, and their co-localization was confirmed by immunofluorescence.ResultsChemotherapeutic agents and irradiation could potently induce senescence in CRC cells in vitro and in human CRC tissues. The more significant elevation of p16 and p21 expression in patients after anti-cancer treatment displayed shorter disease-free survival (DFS) for LARC or progression-free survival (PFS) for mCRC. We observed that compared to non-STCs, STCs released an increased number of EVs enriched in SERPINE1, which further promoted the progression of recipient cancer cells. Targeting SERPINE1 with a specific inhibitor, tiplaxtinin, markedly attenuated the tumor-promoting effect of STCs-derived EVs. Additionally, the patients with greater increment of SERPINE1 expression after anti-cancer treatment had shorter DFS for LARC or PFS for mCRC. Mechanistically, SERPINE1 bound to p65, promoting its nuclear translocation and subsequently activating the NF-κB signaling pathway.ConclusionsWe provide the in vivo evidence of the clinical prognostic implications of therapy-induced senescence. Our results revealed that STCs were responsible for CRC progression by producing large amounts of EVs enriched in SERPINE1. These findings further confirm the crucial role of therapy-induced senescence in tumor progression and offer a potential therapeutic strategy for CRC treatment.

Robotic surgery after total neoadjuvant therapy for rectal cancer: pitfalls of beyond total mesorectal excision for patients with sidewall invasion.

Total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC) is rapidly spreading. The robotic surgical techniques to approach lateral invasion, such as that of the pelvic plexus, have not yet been established. In this technical note, we present a video illustrating a surgical technique for lateral invasion using our novel technique and discuss its pitfalls. We present the case of a 65-year-old man with LARC. Robotic surgery was performed after TNT using the da Vinci Xi Surgical System (Intuitive Surgical Inc., Sunnyvale, CA, USA). The surgical procedure was as follows: (1) D3 lymph node dissection around the inferior mesenteric artery using a medial-to-lateral approach; (2) rectal mobilization; (3) dissection of the ureterohypogastric fascia and ureter; and (4) combined resection of the hypogastric nerve and pelvic plexus. The key surgical point for sidewall invasion is the resection extent. Dividing the resection extent into three areas is important: zone A, which contains the pelvic plexus and is closest to the tumour; zone B, which contains the iliac vessels; and zone C, the most lateral zone, which contains the obturator nerves. This allows organ and function preservation by resecting only the smallest organ that truly requires R0 resection. The operating time was 333 min, console time was 232 min, and blood loss was 0 mL. The circumferential resection margin was 10 mm, and an R0 resection was achieved. We introduced a novel approach for robotic surgery after TNT for LARC with sidewall invasion. This technique can be performed safely and may help standardize 'beyond total mesorectal excision'.

Assessing the OPRA trial for surgical oncologists: Safety and feasibility of a total neoadjuvant therapy approach in patients with rectal cancer

The Organ Preservation in patients with Rectal Adenocarcinoma (OPRA) trial is a randomized, non-blinded, phase II prospective study that investigated total neoadjuvant therapy (TNT) and a selective “watch-and-wait” (WW) approach in locally advanced rectal cancer (LARC). It compared two TNT regimens: induction chemotherapy-chemoradiotherapy (INCT-CRT) and chemoradiotherapy-consolidation chemotherapy (CRT-CNCT). Depending on tumor response, patients were offered WW or surgery. The primary endpoint was disease-free survival (DFS), hypothesizing that patients who underwent TNT with selective WW would have improved DFS compared to historical rates. Secondary endpoints included organ preservation (OP) and overall survival, hypothesizing that differences between INCT-CRT and CRT-CNCT could indicate a superior regimen. Results demonstrated treatment of LARC with TNT and selective WW allows for OP in approximately half of patients without negatively impacting oncologic outcomes such as DFS. The data show that a CRT-CNCT regimen had higher rates of OP, lower rates of tumor regrowth, and similar DFS compared to INCT-CRT. Lastly, DFS does not differ between patients who undergo immediate TME versus TME after regrowth. Thus, patients treated with TNT who achieve a clinical complete response (cCR) can safely undergo WW with the potential for OP. Current research to improve TNT and enhance cCR will expand the utility of the WW approach, including the intensification of neoadjuvant chemotherapy (Janus trial), comparing short-course and long-course CRT prior to CNCT (ENSEMBLE and German trials), utilizing fluoropyrimidine-chemotherapy with and without oxaliplatin in the context of WW (CHOW trial), and exploring less invasive operative approaches for early-stage tumors (NEO and NEO-RT trials). SynopsisThe OPRA trial demonstrates treatment of locally advanced rectal cancer using total neoadjuvant therapy with selective “watch-and-wait” allows organ preservation in approximately half of patients without negatively impacting oncologic outcomes. For widespread adoption of “watch-and-wait”, data from accruing prospective trials are needed to demonstrate its viability across diverse clinical settings.

Feasibility and safety of minimally invasive multivisceral resection for T4b rectal cancer: A 9-year review.

Colorectal cancer is the third most common cancer and the second highest cause of cancer-related mortality worldwide. About 5%-10% of patients are diagnosed with locally advanced rectal cancer (LARC) on presentation. For LARC invading into other structures (i.e. T4b), multivisceral resection (MVR) and/or pelvic exenteration (PE) remains the only potential curative surgical treatment. MVR and/or PE is a major and complex surgery with high post-operative morbidity. Minimally invasive surgery (MIS) has been shown to improve short-term post-operative outcomes in other gastrointestinal malignancies, but there is little evidence on its use in MVR, especially so for robotic MVR. To assess the feasibility and safety of minimally invasive MVR (miMVR), and compare post-operative outcomes between robotic and laparoscopic MVR. This is a single-center retrospective cohort study from 1st January 2015 to 31st March 2023. Inclusion criteria were patients diagnosed with cT4b rectal cancer and underwent MVR, or stage 4 disease with resectable systemic metastases. Patients who underwent curative MVR for locally recurrent rectal cancer, or metachronous rectal cancer were also included. Exclusion criteria were patients with systemic metastases with non-resectable disease. All patients planned for elective surgery were enrolled into the standard enhanced recovery after surgery pathway with standard peri-operative management for colorectal surgery. Complex surgery was defined based on technical difficulty of surgery (i.e. total PE, bladder-sparing prostatectomy, pelvic lymph node dissection or need for flap creation). Our primary outcomes were the margin status, and complication rates. Categorical values were described as percentages and analysed by the chi-square test. Continuous variables were expressed as median (range) and analysed by Mann-Whitney U test. Cumulative overall survival (OS) and recurrence-free survival (RFS) were analysed using Kaplan-Meier estimates with life table analysis. Log-rank test was performed to determine statistical significance between cumulative estimates. Statistical significance was defined as P < 0.05. A total of 46 patients were included in this study [open MVR (oMVR): 12 (26.1%), miMVR: 36 (73.9%)]. Patients' American Society of Anesthesiologists score, body mass index and co-morbidities were comparable between oMVR and miMVR. There is an increasing trend towards robotic MVR from 2015 to 2023. MiMVR was associated with lower estimated blood loss (EBL) (median 450 vs 1200 mL, P = 0.008), major morbidity (14.7% vs 50.0%, P = 0.014), post-operative intra-abdominal collections (11.8% vs 50.0%, P = 0.006), post-operative ileus (32.4% vs 66.7%, P = 0.04) and surgical site infection (11.8% vs 50.0%, P = 0.006) compared with oMVR. Length of stay was also shorter for miMVR compared with oMVR (median 10 vs 30 d, P = 0.001). Oncological outcomes-R0 resection, recurrence, OS and RFS were comparable between miMVR and oMVR. There was no 30-d mortality. More patients underwent robotic compared with laparoscopic MVR for complex cases (robotic 57.1% vs laparoscopic 7.7%, P = 0.004). The operating time was longer for robotic compared with laparoscopic MVR [robotic: 602 (400-900) min, laparoscopic: Median 455 (275-675) min, P < 0.001]. Incidence of R0 resection was similar (laparoscopic: 84.6% vs robotic: 76.2%, P = 0.555). Overall complication rates, major morbidity rates and 30-d readmission rates were similar between laparoscopic and robotic MVR. Interestingly, 3-year OS (robotic 83.1% vs 58.6%, P = 0.008) and RFS (robotic 72.9% vs 34.3%, P = 0.002) was superior for robotic compared with laparoscopic MVR. MiMVR had lower post-operative complications compared to oMVR. Robotic MVR was also safe, with acceptable post-operative complication rates. Prospective studies should be conducted to compare short-term and long-term outcomes between robotic vs laparoscopic MVR.

Value of perfusion parameters from golden-angle radial sparse parallel dynamic contrast-enhanced magnetic resonance imaging in predicting pathological complete response after neoadjuvant chemoradiotherapy for locally advanced rectal cancer.

Non-invasive methods for predicting pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) can provide distinct leverage in the management of patients with locally advanced rectal cancer (LARC). This study aimed to investigate whether including the golden-angle radial sparse parallel (GRASP) dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion parameter (Ktrans), in addition to tumor regression grading (TRG) and apparent diffusion coefficient (ADC) values, can improve the predictive ability for pCR. Patients with LARC who underwent nCRT and subsequent surgery were included. The imaging parameters were compared between patients with and without pCR. Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive ability of these parameters for pCR. A total of 111 patients were included in the study. A pCR was obtained in 32 patients (28.8%). MRI-based TRG (mrTRG) showed a negative correlation with pCR (r = -0.61, P < 0.001), and the average ADC value showed a positive correlation with pCR (r = 0.62, P < 0.001). Before nCRT, Ktrans in the pCR group was significantly higher than in the non-pCR group (1.30 ± 0.24 vs. 0.88 ± 0.34, P < 0.001), but no difference was identified after nCRT. Following ROC curve analysis, the area under the curve (AUC) of mrTRG (level 1-2), average ADC value, and Ktrans value for predicting pCR were 0.738 [95% confidence interval (CI): 0.65-0.82], 0.78 (95% CI: 0.69-0.86), and 0.84 (95% CI: 0.77-0.92), respectively. The model combining the three parameters had significantly higher predictive ability for pCR (AUC: 0.94, 95% CI: 0.88-0.98). The use of a combination of the GRASP DCE-MRI Ktrans with mrTRG and ADC can lead to a better pCR predictive performance.

Patient-Relevant Costs for Organ Preservation versus Radical Resection in Locally Advanced Rectal Cancer.

Total neoadjuvant therapy (TNT) is an evolving treatment schedule for locally advanced rectal cancer (LARC), allowing for organ preservation in a relevant number of patients in the case of complete response. Patients who undergo this so-called "watch and wait" approach are likely to benefit regarding their quality of life (QoL), especially if definitive ostomy could be avoided. In this work, we performed the first cost-effectiveness analysis from the patient perspective to compare costs for TNT with radical resection after neoadjuvant chemoradiation (CRT) in the German health care system. Individual costs for patients insured with a statutory health insurance were calculated with a Markov microsimulation. A subgroup analysis from the prospective "FinTox" trial was used to calibrate the model's parameters. We found that TNT was less expensive (-1540 EUR) and simultaneously resulted in a better QoL (+0.64 QALYs) during treatment and 5-year follow-up. The average cost for patients under TNT was 4711 EUR per year, which was equivalent to 3.2% of the net household income. CRT followed by resection resulted in higher overall costs for ostomy care, medication and greater loss of earnings. Overall, TNT appeared to be more efficacious and cost-effective from a patient's point of view in the German health care system.

The prognostic model and immune landscape based on cancer-associated fibroblast features for patients with locally advanced rectal cancer

BackgroundThis study aimed to construct a nomogram based on CAF features to predict the cancer-specific survival (CSS) rates of locally advanced rectal cancer (LARC) patients. MethodsThe EPIC algorithm was employed to calculate the proportion of CAFs. based on the differentially expressed genes between the high and low CAF proportion subgroups, prognostic genes were identified via LASSO and Cox regression analyses. They were then used to construct a prognostic risk signature. Moreover, the GSE39582 and GGSE38832 datasets were used for external validation. Lastly, the level of immune infiltration was evaluated using ssGSEA, ESTIMATE, CIBERSORTx, and TIMER. ResultsA higher level of CAF infiltration was associated with a worse prognosis. Additionally, the number of metastasized lymph nodes and distant metastases, as well as the level of immune infiltration were higher in the high CAF proportion subgroup. Five prognostic genes (SMOC2, TUBAL3, C2CD4A, MAP1B, BMP8A) were identified and subsequently incorporated into the prognostic risk signature to predict the 1-, 3-, and 5-year CSS rates in the training and validation sets. Differences in survival rates were also determined in the external validation cohort. Furthermore, independent prognostic factors, including TNM stage and risk score, were combined to established a nomogram. Notably, our results revealed that the proportions of macrophages and neutrophils and the levels of cytokines secreted by M2 macrophages were higher in the high-risk subgroup. Finally, the prognostic genes were significantly associated with the level of immune cell infiltration. ConclusionHerein, a nomogram based on CAF features was developed to predict the CSS rate of LARC patients. The risk model was capable of reflecting differences in the level of immune cell infiltration.

Abstract 5143: Molecular investigation of a polymorphic variant in JMJD1C that associates with chemoradiotherapy outcomes in locally advanced rectal and head and neck cancer

Abstract Background: Neoadjuvant chemoradiotherapy (nCRT) is standard therapy for locally advanced rectal cancer (LARC). While only a minority of patients are expected to have a complete response, all are at risk of toxicity. Currently no biomarkers reliably predict response to nCRT in LARC. Further, standard therapy in locally advanced head and neck squamous cell carcinoma (HNSCC) is adjuvant CRT. A major cause of poor outcomes in HNSCC is regional persistence or recurrence post-CRT. No biomarkers, apart from HPV, predict CRT response in HNSCC. CRT causes double-strand breaks (DSBs) and methylation of histones on lysine residues is known to affect chromatin, influencing DSB repair. We hypothesized that single nucleotide polymorphisms (SNP) in the histone 3 lysine 9 (H3K9) demethylase-encoding JMJD1C influenced CRT response. Methods: LARC patients (n=84) were divided into poor (PoR) and complete (CR) responders based on Neoadjuvant Rectal score. Lymphocyte DNA was sequenced, and LARC patient-derived cells were treated with DSB-inducing agents to assess viability. Sequencing was confirmed in an independent cohort of CRT-treated HNSCC patients (n=90) divided into: disease-free (n=30), recurrent disease (n=28), and never-disease-free (n=32). HNSCCs were in the larynx or oral cavity. Not all patients received HPV-testing; p16 expression was positive for 19/43 tumors. CRISPR/Cas9 editing of HPV-negative HNSCC lines (SCC9, Cal27) generated JMJD1C WT or SNP isogenic pairs. Bulk RNA-sequencing, colony survival, and immunofluorescence studies were performed. Results: In LARC patients, CRs were enriched for a coding, missense germline SNP in JMJD1C versus PoRs (discovery n=30, p&amp;lt;0.00001; validation n=54, p=0.001, Fisher’s Exact). When subjected to DSB, LARC patient-derived cells with the SNP displayed greater sensitivity than their WT counterparts (n=12, p&amp;lt;0.001, Mann-Whitney). In HNSCC, a correlation was identified between the same JMJD1C SNP and no recurrence (p=0.0003, Fisher’s Exact). HNSCC SNP cells showed changes in mRNA levels of DNA repair and immune response genes versus HNSCC WT cells (q-value&amp;lt;0.05). Upon irradiation, kinetics of foci resolution of the DNA damage response protein MDC1, specific to DSBs, were slower in SNP versus WT HNSCC cells (p&amp;lt;0.05, Mann Whitney). Further, there was reduced colocalization of BRCA1 with RAP80, a crucial factor for homology-directed DSB repair, in SNP versus WT HNSCC cells (p&amp;lt;0.01, Mann-Whitney).Targeted introduction of the SNP into HNSCC cell lines reduced viability and radiation response. Conclusion: Our study identifies a polymorphic coding variant in JMJD1C, as a predictive biomarker for CRT effectiveness in LARC and HNSCC, and defines a DNA repair mechanism by which JMJD1C influences response to irradiation. Citation Format: Adria Hasan, Elena V. Demidova, Philip Czyzewicz, Shreya M. Shah, Karthik Devarajan, Thomas J. Galloway, Margret B. Einarson, Barbara Burtness, Erica A. Golemis, Joshua E. Meyer, Sanjeevani Arora. Molecular investigation of a polymorphic variant in JMJD1C that associates with chemoradiotherapy outcomes in locally advanced rectal and head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5143.

Abstract 1304: Employing widening funds to address inequity in cancer research - example of the STEPUPIORS collaborative rectal cancer project

Abstract Introduction: Treatment of locally advanced rectal cancer (LARC) using neoadjuvant chemoradiotherapy (nCRT) improves local control and survival, but response varies. Patients treated at the Institute for Oncology and Radiology of Serbia (IORS) who undergo surgery upon complete response might be exposed to risks and poor quality of life. A consortium dedicated to redefining prognostic and predictive biomarkers in rectal cancer was formed within the framework of the STEPUPIORS Horizon Europe project. The current study evaluated whether employing collaborative widening funds might lead to sustainable strategies for cancer treatment, lowering inequity and steering societal impact, especially in countries with limited resources, using a pilot rectal cancer project. Patients and Methods: The analysis was performed in the period Oct 01, 2022, to Oct 01, 2023, with a Serbian coordinating institution and partners from Spain, Greece, and the Netherlands as expert twinning centers. RT was administered to 75 patients with LARC using volumetric modulated arc therapy-simultaneous integrated boost approach/concomitant chemotherapy (5FU/Leucovorin, week 1&amp;5) for the first time in Serbia. A comprehensive approach towards building human capacities on biobanking, multiomics analyses and project management was developed through intensive training and expert visits. Consensus consortium decisions were reached on regular partner meetings. Results: Patients with clinical complete response (16.0%) and initially distant-located tumors were enrolled in the watch and wait approach and are under follow up. Developed pipelines for multiomics analyses led to 4 high-quality papers on new predictive biomarkers to nCRT in LARC and the deposition of omics data in open-science repositories following FAIR data principles. A first Serbian cancer biobank was successfully installed. Fifteen IORS researchers (87% female), were certified in biobanking. A grant management office was established to provide and support the sustainability of future research projects. This led to 5 new grant applications and enrollment of 1 female project member in a Masters program for Management in the Health Care System. Conclusion: This study showed that even within the first 12 months, implementation of a 3-year collaborative grant dedicated to a specific research problem, might significantly change educational and treatment strategies enabling better patient care (OCEBM level of evidence 3). The results highlight that disparities in cancer outcomes and health equity might only be addressed by progressing beyond descriptions of said outcomes and taking specific action. Systematic, long-term strategic initiatives and collaborations among relevant stakeholders and ethical, legal and societal structures are needed in more countries. Acknowledgements: Horizon Europe Project STEPUPIORS (101079217). Citation Format: Milena Cavic, Ana Djuric, Mladen Marinkovic, Aleksandra Stanojevic, Miljana Tanic, Snezana Bjelogrlic, Jelena Spasic, Ana Damjanovic, Marija Djordjic Crnogorac, Ana Vuletic, Katarina Mirjacic Martinovic, Marko Radulovic, Suzana Stojanovic-Rundic, Ana Krivokuca, Radmila Jankovic, Sergi Castellvi-Bel, Jerome Zoidakis, Remond J. Fijneman. Employing widening funds to address inequity in cancer research - example of the STEPUPIORS collaborative rectal cancer project [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1304.

Abstract 2506: Novel biomarkers that predict response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer

Abstract Background: Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is standard of care for locally advanced rectal cancer (LARC). About 20% patients receiving nCRT alone experience a pathologic complete response (pCR), while up to 25% patients exhibit a poor response. Currently, there is no biomarker to predict response to nCRT. We hypothesized that inherited ability to recognize and repair DNA damage, especially lethal double-strand breaks (DSBs), manifest in lymphocytes, would yield a reproducible test predicting therapeutic response to nCRT. Methods: Expression of DNA damage response (DDR) proteins was studied using peripheral blood lymphocytes (PBLs) from LARC patients and healthy controls. PBLs from LARC patients collected either before nCRT or after a standard course of ~5.5 weeks of nCRT were assessed by immunofluorescence (IF) for phospho-γH2AXSer139 and by Luminex multi-analyte platform (xMAP) approaches. The xMAP assay was modified from a qualitative to a semi-quantitative assay that measures the following DDR-associated proteins- total ATR, phospho-γH2AXSer139, total MDM2, phospho-Chk1S345, phospho-Chk2T68, phospho-p53S15, total p21. The analytical performance of the assay was assessed with vendor-provided reference controls and banked PBLs from healthy controls (n=50). LARC patients were segregated by neoadjuvant rectal (NAR) score to determine if tested biomarkers correlated with nCRT response. We used two independent sets of LARC biospecimens for xMAP analysis (set 1, n=48; set 2, n=44). Results: IF-based assessment: Using PBLs from LARC patients, we found that poor responders (PoR; NAR score&amp;gt;14; n=21) had significantly lower γH2AX foci than complete responders (CR; NAR score&amp;lt;1; n=21) (P&amp;lt;0.0001, logistic regression). No significant difference was observed in positive γH2AX foci from PBLs drawn pre-nCRT versus post-nCRT from the same patient (p=0.4961, n=11, Wilcoxon test). xMAP assay performance: The performance assessment showed linear sample curves, precision with acceptable inter- and intra-assay coefficients of variability, and high reproducibility with ~1% outliers identified in replicates. Clinical associations using xMAP assay: levels of six proteins (ATR, p-γH2AXSer139, MDM2, p-Chk1S345, p-Chk2T68, p-p53S15) significantly differentiated CRs from PoRs (p-values and False Discovery Rate ⇐ 1e-5). The strongest associations with nCRT response were observed for: ATR, MDM2 and γH2AX. Conclusion: 1) we standardized an xMAP assay to assess DDRs in human PBLs, and 2) found novel biomarkers that predict response to nCRT in LARC patients using minimally invasive PBL biospecimen. In ongoing work, we are using a larger biospecimen set to establish clinical validity parameters. Citation Format: Adria Hasan, Elena V. Demidova, Philip Czyzewicz, Karthik Devarajan, Margret B. Einarson, Donald Baldwin, Erica A. Golemis, Joshua E. Meyer, Sanjeevani Arora. Novel biomarkers that predict response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2506.

Abstract 1172: Association between CD8+ PD-1+ T cell infiltration levels and improved response to total neoadjuvant therapy in mismatch-repair proficient locally advanced rectal cancer

Abstract Background: The tumor microenvironment plays a major role in colorectal cancer progression, dissemination, and response to therapy. As a mechanism of tumor immunity, CD8+ tumor infiltrating lymphocytes have been shown to express PD-1 in response to clonal neoantigens of tumors. We hypothesized that high levels of CD8+ PD-1+ T cell infiltration prior to treatment initiation may correlate with improved response to total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer (LARC). Methods: We analyzed untreated endoscopic biopsies from 159 patients diagnosed with stage II (n=25) or III (n=134), mismatch-repair proficient rectal adenocarcinoma. All patients were treated with TNT, consisting of either induction chemotherapy followed by chemoradiation (n=108) or chemoradiation followed by consolidative chemotherapy (n=51). FFPE blocks from each biopsy were sectioned into slides for H&amp;E and immunohistochemistry staining with antibodies for CD8 and PD-1 in a CLIA certified lab. CD8+ and PD-1+ cells were quantified using established protocols from the College of American Pathologists. We evaluated associations between response to TNT and tertiles of intratumoral CD8 and PD-1 expression (low/mid/high). Disease free survival (DFS) from the start of TNT and rate of sustained complete response (CR, either clinical or pathologic) were used as primary endpoints. Results: Median follow-up was 40.3 months. The overall CR rate was 42% and the 5-year DFS rate was 77%. Intratumoral CD8 levels were significantly correlated with improved response rates (56% in the top tertile vs. 27% in the bottom tertile, p=0.003, Fisher’s test) and improved 5-year DFS (92% vs. 67% for the top vs. bottom tertiles, respectively; p=0.006, log-rank test). Patients in the highest tertile of intratumoral PD-1 expression also had improved response (56% vs. 25%, p=0.002) and DFS (88% vs. 67%, p=0.034). CD8 and PD-1 levels were strongly correlated with each other (R=0.72, p&amp;lt;0.001, Spearman correlation). Finally, the 41 patients who met criteria for top tertiles of CD8 and PD-1 expression had higher CR rates (66% vs. 32%, p&amp;lt;0.001) and better 5-year DFS (97% vs. 70%, p=0.002) than the other patients. Conclusions: Higher levels of CD8+ and PD-1+ tumor infiltrating lymphocytes on pre-treatment biopsies are associated with improved response to TNT and disease free survival in LARC patients. Citation Format: Christina Lee, Chin-Tung Chen, Nil Urganci, Fan Wu, Canan Firat, Hannah Williams, Evan Seffar, Parisa Malekzadeh, Walid K. Chatila, Jinru Shia, Julio Garcia-Aguilar, Francisco Sanchez-Vega. Association between CD8+ PD-1+ T cell infiltration levels and improved response to total neoadjuvant therapy in mismatch-repair proficient locally advanced rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1172.

Radiomics-enhanced early regression index for predicting treatment response in rectal cancer: a multi-institutional 0.35T MRI-guided radiotherapy study.

The accurate prediction of treatment response in locally advanced rectal cancer (LARC) patients undergoing MRI-guided radiotherapy (MRIgRT) is essential for optimising treatment strategies. This multi-institutional study aimed to investigate the potential of radiomics in enhancing the predictive power of a known radiobiological parameter (Early Regression Index, ERITCP) to evaluate treatment response in LARC patients treated with MRIgRT. Patients from three international sites were included and divided into training and validation sets. 0.35T T2*/T1-weighted MR images were acquired during simulation and at each treatment fraction. The biologically effective dose (BED) conversion was used to account for different radiotherapy schemes: gross tumour volume was delineated on the MR images corresponding to specific BED levels and radiomic features were then extracted. Multiple logistic regression models were calculated, combining ERITCP with other radiomic features. The predictive performance of the different models was evaluated on both training and validation sets by calculating the receiver operating characteristic (ROC) curves. A total of 91 patients was enrolled: 58 were used as training, 33 as validation. Overall, pCR was observed in 25 cases. The model showing the highest performance was obtained combining ERITCP at BED = 26Gy with a radiomic feature (10th percentile of grey level histogram, 10GLH) calculated at BED = 40Gy. The area under ROC curve (AUC) of this combined model was 0.98 for training set and 0.92 for validation set, significantly higher (p = 0.04) than the AUC value obtained using ERITCP alone (0.94 in training and 0.89 in validation set). The integration of the radiomic analysis with ERITCP improves the pCR prediction in LARC patients, offering more precise predictive models to further personalise 0.35T MRIgRT treatments of LARC patients.

Development and validation of a multi-modal ultrasomics model to predict response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

To assess the performance of multi-modal ultrasomics model to predict efficacy to neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC) and compare with the clinical model. This study retrospectively included 106 patients with LARC who underwent total mesorectal excision after nCRT between April 2018 and April 2023 at our hospital, randomly divided into a training set of 74 and a validation set of 32 in a 7: 3 ratios. Ultrasomics features were extracted from the tumors' region of interest of B-mode ultrasound (BUS) and contrast-enhanced ultrasound (CEUS) images based on PyRadiomics. Mann-Whitney U test, spearman, and least absolute shrinkage and selection operator algorithms were utilized to reduce features dimension. Five models were built with ultrasomics and clinical analysis using multilayer perceptron neural network classifier based on python. Including BUS, CEUS, Combined_1, Combined_2 and Clinical models. The diagnostic performance of models was assessed with the area under the curve (AUC) of the receiver operating characteristic. The DeLong testing algorithm was utilized to compare the models' overall performance. The AUC (95% confidence interval [CI]) of the five models in the validation cohort were as follows: BUS 0.675 (95%CI: 0.481-0.868), CEUS 0.821 (95%CI: 0.660-0.983), Combined_1 0.829 (95%CI: 0.673-0.985), Combined_2 0.893 (95%CI: 0.780-1.000), and Clinical 0.690 (95%CI: 0.509-0.872). The Combined_2 model was the best in the overall prediction performance, showed significantly better compared to the Clinical model after DeLong testing (P < 0.01). Both univariate and multivariate logistic regression analyses showed that age (P < 0.01) and clinical stage (P < 0.01) could be an independent predictor of efficacy after nCRT in patients with LARC. The ultrasomics model had better diagnostic performance to predict efficacy to nCRT in patients with LARC than the Clinical model.