Impact of Primary Tumor Location and Genomic Alterations on Survival Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion for Colorectal Peritoneal Metastases

Hamed, Ahmed B.; Shuai, Yongli; Derby, Joshua; Holtzman, Matthew P.; Ongchin, Melanie; Bartlett, David L.; Pingpank, James F.; Pai, Reetesh K.; Singhi, Aatur D.; Choudry, Haroon A.

doi:10.1245/s10434-023-13463-x

Cited by 7 publications

(2 citation statements)

References 49 publications

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“…Two exclusive CRS ± HIPEC studies included 15–44 patients with dMMR, both showing superior RFS and OS compared to pMMR. 15 , 20 , 21 These results align with our study and show that local therapy of metastases in patients with dMMR mCRC that are not pretreated with immunotherapy can lead to durable RFS and reasonable OS. On the other hand, immunotherapy also shows durable responses and long-term survival benefit in patients with dMMR mCRC.…”

Section: Discussionsupporting

confidence: 88%

Survival of Patients with Deficient Mismatch Repair Versus Proficient Mismatch Repair Metastatic Colorectal Cancer Receiving Curative-Intent Local Treatment of Metastases in a Nationwide Cohort

Zwart,

van der Baan,

Punt

et al. 2023

Ann Surg Oncol

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Background It is unclear whether curative-intent local therapy of metastases is of similar benefit for the biological distinct subgroup of patients with deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC) compared with proficient mismatch repair (pMMR) mCRC. Patients and Methods In this nationwide study, recurrence-free (RFS) and overall survival (OS) were analyzed in patients with dMMR versus pMMR mCRC who underwent curative-intent local treatment of metastases between 2015 and 2018. Subgroup analyses were performed for resection of colorectal liver metastases (CRLM) and cytoreductive surgery ± hyperthermic intraperitoneal chemotherapy (CRS ± HIPEC). Multivariable regression was conducted. Results Median RFS was 11.1 months [95% confidence interval (CI) 8.5–41.1 months] for patients with dMMR tumors compared with 8.9 months (95% CI 8.1–9.8 months) for pMMR tumors. Two-year RFS was higher in patients with dMMR versus pMMR (43% vs. 21%). Results were similar within subgroups of local treatment (CRLM and CRS ± HIPEC). Characteristics differed significantly between patients with dMMR and pMMR mCRC; however, multivariable analysis continued to demonstrate dMMR as independent factor for improved RFS [hazard ratio (HR): 0.57, 95% CI 0.38–0.87]. Median OS was 33.3 months for dMMR mCRC compared with 43.5 months for pMMR mCRC, mainly due to poor survival of patients with dMMR in cases of recurrence in the preimmunotherapy era. Conclusion Patients with dMMR eligible for curative-intent local treatment of metastases showed a comparable to more favorable RFS compared with patients with pMMR, with a clinically relevant proportion of patients remaining free of recurrence. This supports local treatment as a valuable treatment option in patients with dMMR mCRC and can aid in shared decision-making regarding upfront local therapy versus immunotherapy.

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Section: Discussionsupporting

confidence: 88%

Survival of Patients with Deficient Mismatch Repair Versus Proficient Mismatch Repair Metastatic Colorectal Cancer Receiving Curative-Intent Local Treatment of Metastases in a Nationwide Cohort

Zwart,

van der Baan,

Punt

et al. 2023

Ann Surg Oncol

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“…At the DNA level, mutations have typically been reported either as multi-gene profiling of small cohorts or as single-gene analysis of larger cohorts, generally, with limited statistical power and varying quality and detail regarding clinical information [ 3 ]. More recently, two comprehensive mutational studies of larger cohorts (250–350 cases) have been published [ 4 , 5 ], but still, interpretation is hampered by lack of clinical data or limited gene analysis. In spite of shortcomings in existing studies, and in agreement with findings in mCRC in general, PM-CRC patients with tumors that have mutations in the BRAF oncogene have been identified as a subgroup with less favorable prognosis than BRAF wild-type cases.…”

Section: Introductionmentioning

confidence: 99%

Novel drug resistance mechanisms and drug targets in BRAF-mutated peritoneal metastasis from colorectal cancer

Lund-Andersen,

Torgunrud,

Kanduri

et al. 2024

J Transl Med

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Background Patients with peritoneal metastasis from colorectal cancer (PM-CRC) have inferior prognosis and respond particularly poorly to chemotherapy. This study aims to identify the molecular explanation for the observed clinical behavior and suggest novel treatment strategies in PM-CRC. Methods Tumor samples (230) from a Norwegian national cohort undergoing surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC) for PM-CRC were subjected to targeted DNA sequencing, and associations with clinical data were analyzed. mRNA sequencing was conducted on a subset of 30 samples to compare gene expression in tumors harboring BRAF or KRAS mutations and wild-type tumors. Results BRAF mutations were detected in 27% of the patients, and the BRAF-mutated subgroup had inferior overall survival compared to wild-type cases (median 16 vs 36 months, respectively, p < 0.001). BRAF mutations were associated with RNF43/RSPO aberrations and low expression of negative Wnt regulators (ligand-dependent Wnt activation). Furthermore, BRAF mutations were associated with gene expression changes in transport solute carrier proteins (specifically SLC7A6) and drug metabolism enzymes (CES1 and CYP3A4) that could influence the efficacy of MMC and irinotecan, respectively. BRAF-mutated tumors additionally exhibited increased expression of members of the novel butyrophilin subfamily of immune checkpoint molecules (BTN1A1 and BTNL9). Conclusions BRAF mutations were frequently detected and were associated with particularly poor survival in this cohort, possibly related to ligand-dependent Wnt activation and altered drug transport and metabolism that could confer resistance to MMC and irinotecan. Drugs that target ligand-dependent Wnt activation or the BTN immune checkpoints could represent two novel therapy approaches.

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Effect of RAS and BRAF mutations on peritoneal metastasis risk and cytoreductive surgery/hyperthermic intraperitoneal chemotherapy efficacy in colorectal cancer: A systematic review and meta-analysis

Gao,

Qi,

Wang

et al. 2024

European Journal of Surgical Oncology

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Impact of Primary Tumor Location and Genomic Alterations on Survival Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion for Colorectal Peritoneal Metastases

Cited by 7 publications

References 49 publications

Survival of Patients with Deficient Mismatch Repair Versus Proficient Mismatch Repair Metastatic Colorectal Cancer Receiving Curative-Intent Local Treatment of Metastases in a Nationwide Cohort

Survival of Patients with Deficient Mismatch Repair Versus Proficient Mismatch Repair Metastatic Colorectal Cancer Receiving Curative-Intent Local Treatment of Metastases in a Nationwide Cohort

Novel drug resistance mechanisms and drug targets in BRAF-mutated peritoneal metastasis from colorectal cancer

Effect of RAS and BRAF mutations on peritoneal metastasis risk and cytoreductive surgery/hyperthermic intraperitoneal chemotherapy efficacy in colorectal cancer: A systematic review and meta-analysis

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