Simple Summary Colorectal cancer is one of the leading causes of cancer-associated deaths worldwide. From the 1960s to 2002, the standard systemic treatment consisted of cytotoxic chemotherapy. However, in the past 20 years, the development of targeted therapies has revolutionized care for CRC. Dozens of new drugs have been developed specifically targeting actionable and identifiable molecular biomarkers expressed by these tumors. This growing field, precision oncology, has been responsible for a dramatic drop of more than 50% in the CRC mortality rate in the United States. As research into this field exponentially expands, new targets are being uncovered, and new drugs are being developed. This review aims to summarize the recent advances in biomarkers, landmark trials, and future perspectives for colorectal cancer. Abstract In 2022, approximately 600,000 cancer deaths were expected; more than 50,000 of those deaths would be from colorectal cancer (CRC). The CRC mortality rate in the US has decreased in recent decades, with a 51% drop between 1976 and 2014. This drop is attributed, in part, to the tremendous therapeutic improvements, especially after the 2000s, in addition to increased social awareness regarding risk factors and diagnostic improvement. Five-fluorouracil, irinotecan, capecitabine, and later oxaliplatin were the mainstays of mCRC treatment from the 1960s to 2002. Since then, more than a dozen drugs have been approved for the disease, betting on a new chapter in medicine, precision oncology, which uses patient and tumor characteristics to guide the therapeutic choice. Thus, this review will summarize the current literature on targeted therapies, highlighting the molecular biomarkers involved and their pathways.

/pdf/targeted-therapies-in-colorectal-cancer-recent-advances-in-3at9vd0v.pdf

Targeted Therapies in Colorectal Cancer: Recent Advances in Biomarkers, Landmark Trials, and Future Perspectives

Epigenetic modifiers of the histone deacetylase (HDAC) family are often dysregulated in cancer cells. Experiments with small molecule HDAC inhibitors (HDACi) have proven that HDACs are a vulnerability of transformed cells. We evaluated a novel hydroxamic acid-based HDACi (KH16; termed yanostat) in human pancreatic ductal adenocarcinoma (PDAC) cells, short- and long-term cultured colorectal cancer (CRC) cells, and retinal pigment epithelial cells. We show that KH16 induces cell cycle arrest and apoptosis, both time and dose dependently in PDAC and CRC cells. This is associated with altered expression of BCL2 family members controlling intrinsic apoptosis. Recent data illustrate that PDAC cells frequently have an altered expression of the pro-apoptotic BH3-only protein NOXA and that HDACi induce an accumulation of NOXA. Using PDAC cells with a deletion of NOXA by CRISPR-Cas9, we found that a lack of NOXA delayed apoptosis induction by KH16. These results suggest that KH16 is a new chemotype of hydroxamic acid HDACi with superior activity against solid tumor-derived cells. Thus, KH16 is a scaffold for future research on compounds with nanomolar activity against HDACs.

NOXA Accentuates Apoptosis Induction by a Novel Histone Deacetylase Inhibitor

BRAF mutation occurs in 5%–10% of metastatic colorectal cancers (mCRCs). Patients with BRAF mutant mCRC exhibit a specific metastatic pattern and poor prognosis. Survival outcomes are heterogeneous in cases of mCRC with a BRAF mutation. The optimal first‐line therapy is still controversial.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cam4.5783

Real‐world treatment and outcomes of patients with metastatic BRAF mutant colorectal cancer

BRAF non-V600 mutations are a distinct molecular subset of colorectal cancer (CRC) that has little to no clinical similarity to the BRAF V600 mutations. It is generally considered that the BRAF non-V600 mutations correlate with better survival of CRC patients. In this report, we present an unusual case of that a midlife female patient who was initially diagnosed with stage IIIC colon cancer, and multiple metastases were found 25 months after radical surgery. Next-generation sequencing (NGS) revealed the BRAF p.N581I (c.1742A>T) mutation. She received chemotherapy, targeted therapy, and immunotherapy. However, the disease progressed rapidly with rare metastasis of the bone and cerebellum. This case highlights that the BRAF non-V600 mutations, such as BRAF p.N581I mutant, may lead to resistance to epidermal growth factor receptor (EGFR) inhibitors and result in a rapid course in colorectal cancer. The role of BRAF p.N581I mutation in colorectal cancer demands more attention.

Multidrug resistance in the standardized treatment of colon cancer harboring a rare fibrosarcoma B-type (BRAF) p.N581I mutation: a case report

Background and Objectives: We aimed to investigate the role of Wnt2 expression in colorectal cancer (CRC) prognosis and evaluate its potential as a therapeutic target in BRAF-mutated CRC. Materials and Methods: Exactly 136 samples of formalin-fixed paraffin-embedded CRC tissue specimens were obtained from patients who underwent surgical resection for CRC. The gene mutation status of the samples was detected using fluorescence PCR. Wnt2 expression was detected using immunohistochemistry. Survival curves with high Wnt2 expression and BRAF mutations were compared using the Kaplan–Meier method. A nomogram was constructed to determine the estimated overall survival probability. We also predicted the 3-year and 5-year survival rates for patients with high Wnt2 expression and BRAF mutations. In total, 50 samples of BRAF-mutated CRC were collected and detected Wnt2 expression by immunohistochemistry. The Chi-squared test was used to analyze the association between Wnt2 expression and BRAF-mutated CRC. Results: High Wnt2 expression and BRAF mutations are associated with poor prognosis of CRC. Multivariate survival analyses indicated that high Wnt2 expression and BRAF mutations are significant independent predictors of CRC prognosis. Furthermore, high Wnt2 expression was significantly associated with BRAF-mutated CRC, and Wnt2 may be a potential therapeutic target for BRAF-mutated CRC. Conclusions: High Wnt2 expression confers poor prognosis in colorectal cancer and represents a novel therapeutic target in BRAF-mutated CRC.

/pdf/high-wnt2-expression-confers-poor-prognosis-in-colorectal-2oic0ng0.pdf

High Wnt2 Expression Confers Poor Prognosis in Colorectal Cancer, and Represents a Novel Therapeutic Target in BRAF-Mutated Colorectal Cancer

Simple Summary In this literature review, we investigated the relationship between BRAF mutation and prognosis in patients with colorectal cancer liver metastases. We also investigated factors affecting the prognosis of patients with BRAF mutations and summarized the latest research on targeted therapies. Abstract Surgery combined with chemotherapy and precision medicine is the only potential treatment for patients with colorectal cancer liver metastases (CRLM). The use of modern molecular biotechnology to identify suitable biomarkers is of great significance for predicting prognosis and formulating individualized treatment plans for these patients. BRAF mutations, particularly V600E, are widely believed to be associated with poor prognosis in patients with metastatic CRC (mCRC). However, it is unclear which specific factors affect the prognosis of CRLM patients with BRAF mutations. It is also unknown whether patients with resectable CRLM and BRAF mutations should undergo surgical treatment since there is an increased recurrence rate after surgery in these patients. In this review, we combined the molecular mechanism and clinical characteristics of BRAF mutations to explore the prognostic significance and potential targeted therapy strategies for patients with BRAF-mutated CRLM.

/pdf/braf-mutations-in-colorectal-liver-metastases-prognostic-7wcc29rj.pdf

BRAF Mutations in Colorectal Liver Metastases: Prognostic Implications and Potential Therapeutic Strategies

https://doi.org/10.1016/j.wnsx.2022.100150

Laparoscopic Resection of Pelvic Schwannomas: A 9-Year Experience at a Single Center

Anal Sparing Surgery: Pushing the Limits of Patient Autonomy

Although primary tumor sidedness (PTS) has a known prognostic role in sporadic colorectal cancer (CRC), its role in Inflammatory Bowel Disease related CRC (IBD-CRC) is largely unknown. Thus, we aimed to evaluate the prognostic role of PTS in patients with IBD-CRC. All eligible patients with surgically treated, non-metastatic IBD-CRC were retrospectively identified from institutional databases at ten European and Asian academic centers. Long term endpoints included recurrence–free (RFS) and overall survival (OS). Multivariable Cox proportional hazard regression as well as propensity score analyses were performed to evaluate whether PTS was significantly associated with RFS and OS. A total of 213 patients were included in the analysis, of which 32.4% had right-sided (RS) tumors and 67.6% had left-sided (LS) tumors. PTS was not associated with OS and RFS even on univariable analysis (5-year OS for RS vs LS tumors was 68.0% vs 77.3%, respectively, p = 0.31; 5-year RFS for RS vs LS tumors was 62.8% vs 65.4%, respectively, p = 0.51). Similarly, PTS was not associated with OS and RFS on propensity score matched analysis (5-year OS for RS vs LS tumors was 82.9% vs 91.3%, p = 0.79; 5-year RFS for RS vs LS tumors was 85.1% vs 81.5%, p = 0.69). These results were maintained when OS and RFS were calculated in patients with RS vs LS tumors after excluding patients with rectal tumors (5-year OS for RS vs LS tumors was 68.0% vs 77.2%, respectively, p = 0.38; 5-year RFS for RS vs LS tumors was 62.8% vs 59.2%, respectively, p = 0.98). In contrast to sporadic CRC, PTS does not appear to have a prognostic role in IBD-CRC. 

Prognostic value of primary tumor sidedness in patients with non-metastatic IBD related CRC - Is it the exception to the rule?

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Papers

BRAF Mutations in Colorectal Liver Metastases: Prognostic Implications and Potential Therapeutic Strategies

Laparoscopic Resection of Pelvic Schwannomas: A 9-Year Experience at a Single Center

Anal Sparing Surgery: Pushing the Limits of Patient Autonomy

Prognostic value of primary tumor sidedness in patients with non-metastatic IBD related CRC - Is it the exception to the rule?