The therapeutic landscape in locally advanced rectal cancer (LARC) has undergone a significant paradigm shift in recent years with the rising adoption of total neoadjuvant treatment (TNT). This comprehensive approach entails administering chemotherapy and radiation therapy before surgery, followed by optional adjuvant chemotherapy. To establish and deliver the optimal tailored treatment regimen to the patient, it is crucial to foster collaboration among a multidisciplinary team comprising healthcare professionals from various specialties, including medical oncology, radiation oncology, surgical oncology, radiology, and pathology. This review aims to provide insights into the current state of TNT for LARC and new emerging strategies to identify potential directions for future research and clinical practice, such as circulating tumor-DNA, immunotherapy in mismatch-repair-deficient tumors, and nonoperative management.

PURPOSE: Patients with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) resectable gastroesophageal adenocarcinoma (GEA) have better survival after surgery and scant/no benefit from chemotherapy. Preoperative immune checkpoint inhibitors (ICIs) demonstrated a high proportion of major complete pathologic response, possibly allowing chemotherapy/surgery-free approaches. METHODS: Individual patient data pooled analysis was performed to determine an optimal strategy for resectable dMMR/MSI-H GEA. Patients were stratified across four groups: neoadjuvant dual CTLA-4/PD-(L)1 ICIs with or without surgery, perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) and surgery, and surgery alone or with older perioperative/adjuvant chemotherapy regimens. Primary end points were pathologic complete and major complete pathologic response proportion (pathologic complete response [pCR], tumor regression grade [TRG]1a, major pathologic response [MPR], TRG1a/b Becker criteria) in resected patients. Secondary end points were event-free survival (EFS) and overall survival (OS) in the overall population. RESULTS: Among 197 patients, 49 received ICIs, 27 FLOT, 33 surgery alone, and 88 older chemotherapy regimens. Among 69 patients who underwent surgery after ICIs or FLOT, ICIs demonstrated significantly higher pathologic response versus FLOT (pCR, 61.9% v 3.7%; odds ratio [OR], 54.8; P = .002; MPR, 78.6% v 10%; OR, 39.3; P < .001) and lower ypN+ (14.3% v 37%; OR, 4.2; P = .015) and ypT (OR, 16.4; P < .001) stage. No significant differences in EFS/OS were observed (the 36-month EFS and OS were 70.4% v 80.6% and 72.7% v 90.4% with ICI v surgery alone). Residual nodal disease (ypN+) or ypT4 status after neoadjuvant ICIs or FLOT and nonpathologic response status were associated with inferior progression-free survival/OS. CONCLUSION: In resectable dMMR/MSI-H GEA, neoadjuvant ICIs significantly increase pathologic response and downstaging versus FLOT, with comparable EFS/OS with surgery with or without chemotherapy. The higher proportion of ypN0 and lack of ypT4 after neoadjuvant ICIs versus FLOT should drive preoperative treatment choices in clinical high-risk disease. The high proportion of pCR/MPR with ICIs provides rationale for exploring organ-sparing surgery or nonoperative management.

Thymic epithelial tumors (TETs) comprise a rare group of thoracic cancers, classified as thymomas and thymic carcinomas (TC). To date, chemotherapy is still the standard treatment for advanced disease. Unfortunately, few therapeutic options are available for relapsed/refractory tumors. Unlike other solid cancers, the development of targeted biologic and/or immunologic therapies in TETs remains in its nascent stages. Moreover, since the thymus plays a key role in the development of immune tolerance, thymic tumors have a unique biology, which can confer susceptibility to autoimmune diseases and ultimately influence the risk–benefit balance of immunotherapy, especially for patients with thymoma. Indeed, early results from single-arm studies have shown interesting clinical activity, albeit at a cost of a higher incidence of immune-related side effects. The lack of knowledge of the immune mechanisms associated with TETs and the absence of biomarkers predictive of response or toxicity to immunotherapy risk limiting the evolution of immunotherapeutic strategies for managing these rare tumors. The aim of this review is to summarize the existing literature about the thymus’s immune biology and its association with autoimmune paraneoplastic diseases, as well as the results of the available studies with immune checkpoint inhibitors and cancer vaccines.

We report 5-year results of the phase III randomized TRIPLETE study. Eligible patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC) received first-line modified fluorouracil, leucovorin, oxaliplatin (mFOLFOX)/panitumumab (control group, n = 217) versus modified fluorouracil, leucovorin, oxaliplatin, irinotecan (mFOLFOXIRI)/panitumumab (experimental group, n = 218). We present overall survival (OS) and updated outcomes in the intention-to-treat population. The median follow-up was 60.2 months (IQR, 49.3-70.0). The median OS was 41.1 and 33.3 months for experimental and control groups, respectively (hazard ratio [HR], 0.79 [95% CI, 0.63 to 0.99]; P = .049). OS outcomes favored the experimental group regardless of clinical features. No differences in objective response rate (primary end point; 75%/78%, odds ratio, 0.84 [95% CI, 0.54 to 1.31]; P = .442), early tumor shrinkage rate ( P = .954), depth of response ( P = .573), no residual tumor resection rate ( P = .329), and progression-free survival (HR, 0.95 [95% CI, 0.78 to 1.16]; P = .606) were confirmed. Among patients alive at the time of disease progression, the median postprogression survival was 24.6 and 17.7 months for experimental and control groups, respectively (HR, 0.79 [95% CI, 0.62 to 1.01]; P = .062). Similar proportions of patients in both groups received subsequent lines of therapy (control/experimental: second line 73%/71%, third line 51%/49%, fourth line 31%/32%), as well as nonpalliative locoregional treatments (control/experimental: 16%/16%). Upfront mFOLFOXIRI/panitumumab significantly improves OS compared with mFOLFOX/panitumumab in patients with RAS/BRAF wild-type mCRC.

Immune checkpoint inhibitors and immune-related biomarkers are increasingly investigated in rectal cancer (RC). We retrospectively analysed PD-L1 expression in diagnostic biopsy and resection samples from RC patients treated at our centre between 2000 and 2020. PD-L1 immunostaining (22C3 clone) was evaluated according to tumour proportion (TPS), immune cell (ICS), and the combined positive score (CPS). Eighty-three patients were included. At diagnosis, PD-L1 expression ≥1%/≥5% was observed in 15.4%/0%, 80.7%/37.4%, and 69.2%/25.6% of patients based on TPS, ICS, and CPS, respectively. At surgery, the respective figures were 4.6%/1.5%, 60.2%/32.5%, and 50.7%/26.2%. Using the 1% cut-off and regardless of the scoring system, PD-L1 was less expressed in surgery than biopsy samples (p ≤ 0.04). In paired specimens, PD-L1-ICS reduction was especially observed following neoadjuvant long-course (chemo)radiotherapy (p = 0.03). PD-L1-ICS of ≥5% in surgical samples (HR: 0.17; p = 0.02), and a biopsy-to-surgery increase in PD-L1-ICS (HR: 0.19; p = 0.04) was predictive for longer disease-free survival, while the PD-L1-ICS of either ≥1% (HR 0.28; p = 0.04) or ≥5% (HR 0.19; p = 0.03) in surgical samples and the biopsy-to-surgery increase in PD-L1-ICS (HR: 0.20; p = 0.04) were associated with better overall survival. Our study suggests that PD-L1 expression in RC is largely reflective of immune cell infiltration, and its presence/increase in surgical samples predicts better outcomes.

Purpose: Longitudinal measuring of circulating tumor DNA (ctDNA) during systemic treatment of metastatic colorectal cancer (mCRC) is promising for disease monitoring, but it is hampered by high costs and lacks formal demonstration of clinical usefulness. Experimental Design: We leveraged METER, a novel, highly reproducible, computational workflow that infers ctDNA presence and fraction from low-pass whole-genome bisulfite sequencing to investigate baseline and 8-week ctDNA dynamics in patients with RAS wild-type mCRC undergoing first-line treatment with panitumumab/FOLFOX in the VALENTINO randomized phase II trial. IchorCNA was used to provide a benchmark for METER. Results: A total of 154 patients were evaluable. Baseline ctDNA was detected in 72.7% of patients and was associated with significantly higher risk of progression [1.65, 95% confidence interval (CI), 1.13–2.42; P = 0.010] and death (HR: 2.24; 95% CI, 1.37–3.66; P < 0.001). CtDNA clearance at 8 weeks was observed in 80.2% of patients with baseline detectable ctDNA; persistence of ctDNA was associated with significantly higher risk of progression (2.70, 95% CI, 1.63–4.49; P < 0.001) and death (HR: 3.37; 95% CI, 2–5.69; P < 0.001). CtDNA clearance was associated with a more profound depth of response (median −48.4% vs. −41.2%; P = 0.023) but not with a higher frequency of early tumor shrinkage (72% vs. 73.7%; P = 1). METER expanded the number of ctDNA-positive patients relative to copy-number alteration– and variant allele frequency–based methods. Conclusions: CtDNA detection and quantification with METER is a promising tool for cost-effective treatment monitoring in mCRC and can complement radiologic assessment of response dynamics.