Jun Huang

Neoadjuvant PD-1 blockade produces substantial tumor regression in mismatch repair-deficient or microsatellite instability-high (dMMR/MSI-H) locally advanced lower rectal cancer (LRC), but response assessment and the safety of watch-and-wait (W&W) remain uncertain. BASKET was an open-label, multicenter, single-arm, phase 2 study conducted at two Chinese centers (ClinicalTrials.gov, NCT04643041). Patients with non-metastatic dMMR/MSI-H LRC received six cycles of neoadjuvant sintilimab (200 mg every 3 weeks), followed by multimodal assessment including endoscopy, digital rectal examination, CEA, MRI, CT, and transrectal ultrasound-guided biopsy. Patients meeting protocol-defined clinical complete response (cCR) criteria entered W&W surveillance. Of 15 treated patients, 13 completed treatment and response assessment. All 13 per-protocol patients achieved cCR and entered W&W (13/13, 100%), corresponding to 13/15 (86.7%) in the intention-to-treat (ITT) population. Only 1 of 13 per-protocol patients (7.7%) achieved radiologic complete response on MRI; persistent radiographic abnormalities were adjudicated using the other response modalities. At a median follow-up of 37.7 months (range, 0.7–56.2) in the ITT population, one death occurred 0.7 months after treatment initiation, and no local recurrence or distant metastasis. The estimated 1-year disease-free and overall survival rates were both 93.3% (95% CI, 68.1%–99.8%). Among the 13 per-protocol patients no local recurrence, distant metastasis, or death was observed. No grade 3 or higher immune-related adverse events or biopsy-related complications occurred. These findings suggest that W&W may be feasible in carefully selected patients following rigorous multimodal response assessment and with close surveillance; however, the incremental value of biopsy and the oncologic equivalence of W&W to surgery remain unproven.

Background: Neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME) is currently the standard of care for locally advanced rectal cancer (LARC), as recommended by existing guidelines. This study aimed to evaluate the efficacy and safety of short-course radiotherapy (SCRT) combined with cadonilimab and chemotherapy in patients with LARC. Methods: This was a prospective, open-label, single-arm, multi-center phase 2 study. We enrolled patients aged 18-79 years with untreated mismatch repair proficient (pMMR) or microsatellite stability (MSS) LARC (cT3-T4 and/or N+) and an Eastern Cooperative Oncology Group performance score of 0–1. They received radiation of 25 Gy /5 fraction for 5 days, followed by cadonilimab 6 mg/kg combined with mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 on day 1, and 5-fluorouracil infusion 2400 mg/m2 for 48 h) every 2 weeks for 6 cycles preoperatively. Pathological complete response (pCR) was the primary endpoint. This study was registered at ClinicalTrials.gov (NCT05792735). Findings: Among the 27 patients, 24 (88.9%) underwent surgery. The rates of pCR and major pathological response (MPR) for the entire cohort were 37.0% (95% CI: 19.4-57.6%) and 59.3% (95% CI: 32.5-82.5%), respectively. The median follow-up of time is 22.7 months (IQR, 18.4-31.8) , during which 2-year event free survival（EFS) is 81.3%(95% CI: 67.8%-97.5%), 2-year overall survival (OS) is 92.6% (95% CI: 83.2%-99.9%). The most common treatment-related adverse events were diarrhea (37.0%), nausea (37.0%), fatigue (37.0%), and neutropenia (25.9%). Additionally, grade 3-5 adverse events occurred in 6 (22.2%) patients. Furthermore, T-CD8-TRGC2 cells were significantly enriched in MPR cases (p=0.015). Differential expression analysis revealed MPR-associated metabolic and immune pathway alterations in this subset, which were closely correlated with the composition of specific macrophage populations. Interpretation: The combination of neoadjuvant SCRT, cadonilimab, and mFOLFOX6 shows promising antitumor efficacy along with a manageable safety profile in patients with pMMR/MSS LARC. Moreover, T-CD8-TRGC2 cells emerge as a potential predictor of treatment response, likely through involvement in a broader immune remodeling process that also engages myeloid compartments in patients who achieve a MPR.

Laparoscopic radical resection has become the most important treatment for resectable colorectal cancer (CRC). However, there is still a lack of researches on the efficacy and safety of reduced-port laparoscopic surgery (RPLS) versus conventional laparoscopic surgery (CLS) in the treatment of CRC. From January 2019 to July 2022, 698 patients with CRC received surgical treatment in the Sixth Affiliated Hospital of Sun Yat-sen University were enrolled in this retrospective cohort study. Patients were divided into RPLS group (n = 220) and CLS group (n = 478) according to their surgical procedures. Propensity score matching (PSM) was used to adjust the differences in baseline characteristics. The incidence of perioperative outcomes and survival rates related results were analyzed after PSM. Four hundred twenty-two patients were equally divided into RPLS group (n = 211) and CLS group (n = 211) after PSM. There were no statistically significant differences in overall survival (OS) and progression-free survival (PFS) between the two groups (P value was 0.773 and 0.579 respectively). The perioperative outcomes of patients between the two groups were comparable, except that patients in the RPLS group had a shorter postoperative hospital stay (P value < 0.001). For patients with CRC, both RPLS and CLS might be acceptable surgical options. No significant differences in perioperative outcomes, PFS rates and OS rates were observed between the two groups. For certain cases, RPLS was superior to CLS in terms of postoperative recovery.

Original Article PD-1 blockade combined with chemotherapy and bevacizumab in DNA mismatch repair-proficient/microsatellite stable colorectal liver metastases Qianqian Men, Yinghua Duan, Fengyun Pei, Qijun Yao, Wan He, Yandong Zhao, Lishuo Shi, Guangjian Liu, Jun Huang

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

Background: Patients with DNA mismatch repair‐proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to immune checkpoint inhibitors (i.e., anti‐PD‐1 antibodies). pMMR/MSS CRC patients with locally advanced cancers need effective combined therapies. Methods: In this pilot study, we administered six preoperative doses of each 2‐week cycle of the anti‐PD‐1 antibody sintilimab (at a fixed dose of 200 mg), oxaliplatin, and 5‐FU/CF (mFOLFOX6) combined with five doses of bevacizumab (the number of doses was reduced to prevent surgical delays) to patients with cT4NxM0 colon or upper rectal cancers. And radical surgery was performed approximately 2 weeks after the last dose of neoadjuvant therapy. The primary endpoint was a pathologic complete response (pCR). We also evaluated major pathologic response (MPR, ≤10% residual viable tumor), radiological and pathological regression, safety, and tumor mutation burden (TMB), and tumor microenvironment (TME) characteristics. Results: By the cutoff date (September 2023), 22 patients with cT4NxM0 pMMR/MSS colon or upper rectal cancers were enrolled and the median follow‐up was 24.7 months (IQR: 21.1–26.1). All patients underwent R0 surgical resection without treatment‐related surgical delays. pCR occurred in 12 of 22 resected tumors (54.5%) and MPR occurred in 18 of 22 (81.8%) patients. At the cutoff date, all patients were alive, and 21/22 were recurrence‐free. Treatment‐related adverse events of grade 3 or higher occurred in of 2/22 (9.1%) patients. Among the pCR tumors, two were found to harbor POLE mutations. The degree of pathological regression was significantly greater than that of radiological regression ( p = 1.35 × 10 ⁻⁸ ). The number of CD3+/CD4+ cells in the tumor and stroma in pretreated biopsied tissues was markedly lower in pCR tumors than in non‐pCR tumors ( p = 0.038 and p = 0.015, respectively). Conclusions: Neoadjuvant sintilimab combined with bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery, and led to pCR and non‐pCR in 54.5% and 81.8% of the cases, respectively. Downregulation of CD3/CD4 expression in the tumor and stroma is related to pCR. However, the molecular mechanisms underlying PD‐1 blockade‐enhanced targeted chemotherapy require further investigation.

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.