Genomic Sequencing and Insight into Clinical Heterogeneity and Prognostic Pathway Genes in Patients with Metastatic Colorectal Cancer

Kawaguchi, Yoshikuni; Kopetz, Scott; Kwong, Lawrence N.; Xiao, Lianchun; Morris, Jeffrey S.; Cao, Hop S. Tran; Tzeng, Ching‐Wei D.; Chun, Yun Shin; Lee, Jeffrey E.; Vauthey, Jean Nicolas

doi:10.1016/j.jamcollsurg.2021.05.027

Cited by 23 publications

(13 citation statements)

References 36 publications

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“…These prognostic indicators include the histology of the peritoneal metastases as an assessment of aggressive versus indolent tumor biology, 4,5 the perioperative radiology with an assessment of concerning radiologic features, 6 the prior surgical score, 7 preoperative diagnostic laparoscopy, 8,9 the extent of disease as measured by the peritoneal cancer index (PCI), 10 complete or near complete response to preoperative chemotherapy, 11 and the completeness of cytoreduction score 7,10 . In the future, molecular assessments of the likelihood of complete cytoreduction will be possible, but progress to date is limited 12 …”

Section: Introductionmentioning

confidence: 99%

“…7,10 In the future, molecular assessments of the likelihood of complete cytoreduction will be possible, but progress to date is limited. 12 In the management of peritoneal metastases from mucinous appendiceal neoplasms and all other diseases that have peritoneal metastases as part of their natural history, a complete cytoreduction is the goal of treatment. Even though extensive surgery is performed, J Surg Oncol.…”

Section: Introductionmentioning

confidence: 99%

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Incomplete cytoreduction with peritoneal metastases from appendiceal mucinous neoplasms

Sugarbaker¹,

Chang

2022

Journal of Surgical Oncology

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Background Complete cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy is the standard of care for mucinous appendiceal neoplasms with peritoneal metastases. Despite many publications regarding selection factors favoring a complete CRS, incomplete CRS does occur. Patients with an incomplete CRS are the focus of this manuscript. Methods A retrospective analysis of prospective, histologic, and perioperative data was performed. Overall survival was the endpoint for the numerous assessments. Judgments regarding when to and when not to proceed with an incomplete CRS were sought. Results From a database of 949 patients who underwent an index CRS for appendiceal mucinous neoplasm, 264 patients (27.8%) had an incomplete CRS. The median overall survival was 1.8 years. Low‐grade histopathology and absence of tense ascites or bowel obstruction were significantly associated with increased overall survival. More extensive surgery suggested a more favorable outcome. Conclusions When a surgeon is confronted by a procedure that will inevitably end with an incomplete CRS, a current trend is to close quickly and always avoid complications. Patients with low‐grade neoplasms who present in the absence of tense ascites or bowel obstruction may gain years of survival by surgical reduction of tumor burden.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Incomplete cytoreduction with peritoneal metastases from appendiceal mucinous neoplasms

Sugarbaker¹,

Chang

2022

Journal of Surgical Oncology

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“…The Cancer Genome Atlas Pan-Cancer Analysis Project examined 123 patients with non-MSI, highly metastatic CRC, and found significant changes in the RTK-RAS, Notch, Wnt, p53, PI3K, TGF-β, and Myc pathways ( 24 ). These changes in the RTK-RAS and Notch pathway have been shown to be strongly related to poor OS in patients whose colorectal liver metastases were resected ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

DNAH7 mutations benefit colorectal cancer patients receiving immune checkpoint inhibitors

Yang¹,

Shen²,

Yang³

et al. 2022

Ann Transl Med

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Background: Colorectal cancer (CRC) is a malignant tumor associated with a high mortality rate. While the advent of immune checkpoint inhibitors (ICIs) has been a gamechanger, only a small percentage of CRC patients benefit from ICIs. The pathological mechanism of CRC is not well understood, but somatic mutations, especially missense mutations, are believed to play an important role. This study examined the relationship between ICIs in colorectal cancer and missense mutations in the axonemal dynein heavy chain gene 7 (DNAH7).Methods: A clinical cohort (n=690) and the CRC data from the publicly available Cancer Genome Atlas (TCGA) were examined. Gene Set Enrichment Analysis, ESTIMATE analysis, and clinical correlation analysis were performed to explore the effects and mechanisms of DNAH7 mutation on immunotherapy in colorectal cancer. Results:The results showed that CRC patients with DNAH7 mutations can benefit more from ICIs (P<0.05). Patients with DNAH7 mutation had higher ESTIMATE scores, immune scores, and matrix scores, compared to patients without the DNAH7 mutation (P<0.001). The transport of small molecules, keratinization, asthma, autoimmune thyroid disease, allograft rejection, and other pathways were significantly enriched in DNAH7 mutated tissues (P<0.05). The top key genes associated with the DNAH7 mutation included AQP8, MS4A12, GUCA2B, and ZG16 (P<0.01). Conclusions:The current study not only demonstrated the significance of DNAH7 as a risk factor and prognostic feature in CRC, but also revealed that DNAH7 mutations might affect the clinical efficacy of ICIs by impacting the tumor immune microenvironment.

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“…25 The Vauthey group also demonstrated that information about alterations in signaling pathways (eg, TP53, APC, RAS/BRAF, and SMAD4) improves prognostic stratification. 29 This pathway-centric approach was successful in stratifying patients into four groups with distinct prognoses. However, it cannot be used in isolation to deny surgery to patients, as the median OS of the highest risk group was as high as 48 months.…”

Section: Mutational Status Of Other Genes or Ras Variantsmentioning

confidence: 99%

“…For example, comutation of RAS and either TP53 or SMAD4 was associated with a median OS of 52 months after resection of CRLM, but while this was shorter than the survival of patients with RAS mutations alone, the survival period was too long to support the concept that patients with these comutations may not benefit from surgery 25 . The Vauthey group also demonstrated that information about alterations in signaling pathways (eg, TP53, APC, RAS/BRAF, and SMAD4 ) improves prognostic stratification 29 . This pathway‐centric approach was successful in stratifying patients into four groups with distinct prognoses.…”

Section: Patient Selection For Surgerymentioning

confidence: 99%

Precision surgery for colorectal liver metastases: Current knowledge and future perspectives

Margonis

Vauthey

2022

Annals of Gastroent Surgery

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Precision surgery for colorectal liver metastases (CRLM) includes optimal selection of both the patient and surgery. Initial attempts of using clinical risk scores to identify patients for whom technically feasible surgery is oncologically futile failed. Since then, patient selection for single-stage hepatectomy followed three distinct approaches, all of which incorporated biomarkers. The BRAF V600E mutation, the G12V KRAS variant, and the triple mutation of RAS, TP53, and SMAD4 appear to be the most promising, but none can be used in isolation to deny surgery in otherwise resectable cases. Combining biomarkers with clinicopathologic factors that predict poor prognosis may be used to select patients for surgery, but external validation and matched analyses with medically treated counterparts are needed. Patient selection for special surgical procedures (two-stage hepatectomy [TSH], Associating Liver Partition and Portal vein Ligation for staged hepatectomy [ALPPS], and liver transplant [LT]) has been recently refined. Specifically, BRAF mutations and right-sided laterality have been proposedas separate contraindications to LT. A similar association of right-sided laterality, particularly when combined with RAS mutations, with very poor outcomes has been observed for ALPPS and has been suggested as a biologic contraindication. Data are scarce for TSH but RAS mutations may portend very poor survival following TSH completion. The selection of the best single-stage hepatectomy (optimal margin and type of resection) based on biomarkers remains debated, although there is some evidence that RAS may play a significant role. Lastly, although there are currently no criteria to select among the three special techniques based on their efficacy or appropriateness in different settings, RAS mutational status may be used to select patients for TSH, while right-sided tumor in conjunction with a RAS mutation may be a contraindication to LT and ALPPS.

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Genomic Sequencing and Insight into Clinical Heterogeneity and Prognostic Pathway Genes in Patients with Metastatic Colorectal Cancer

Cited by 23 publications

References 36 publications

Incomplete cytoreduction with peritoneal metastases from appendiceal mucinous neoplasms

Incomplete cytoreduction with peritoneal metastases from appendiceal mucinous neoplasms

DNAH7 mutations benefit colorectal cancer patients receiving immune checkpoint inhibitors

Precision surgery for colorectal liver metastases: Current knowledge and future perspectives

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