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18 pages, 2309 KiB

Open AccessArticle

Cyclophilin A: An Independent Prognostic Factor for Survival in Patients with Metastatic Colorectal Cancer Treated with Bevacizumab and Chemotherapy

by Diana Cornelia Moisuc, Daniela Constantinescu, Mihai Vasile Marinca, Bogdan Gafton, Mariana Pavel-Tanasa and Petru Cianga

Cancers 2024, 16(2), 385; https://doi.org/10.3390/cancers16020385 - 16 Jan 2024

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Abstract

Colorectal cancer (CRC) ranks as second most common cause of cancer-related deaths. The CRC management considerably improved in recent years, especially due to biological therapies such as bevacizumab. The lack of predictive or prognostic biomarkers remains one of the major disadvantages of using [...] Read more.

Colorectal cancer (CRC) ranks as second most common cause of cancer-related deaths. The CRC management considerably improved in recent years, especially due to biological therapies such as bevacizumab. The lack of predictive or prognostic biomarkers remains one of the major disadvantages of using bevacizumab in the CRC management. We performed a prospective study to analyze the prognostic and predictive roles of three potential serum biomarkers (Cyclophilin A (CypA), copeptin and Tie2) investigated by ELISA in 56 patients with metastatic CRC undergoing bevacizumab and chemotherapy between May 2019 and September 2021 at baseline and after one and six months of therapy. We showed that low levels of CypA at baseline and after one month of treatment were associated with better overall survival (OS) (42 versus 24 months, p = 0.029 at baseline; 42 versus 25 months, p = 0.039 after one month). For copeptin and Tie2, Kaplan–Meier curves showed no correlation between these biomarkers and OS or progression-free survival. When adjusting for baseline and post-treatment factors, a multivariate Cox analysis showed that low values of CypA at baseline and after one month of treatment were independent prognostic factors for OS and correlated with a better prognosis in metastatic CRC patients. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer 2.0)

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11 pages, 1576 KiB

Open AccessEditor’s ChoiceArticle

Primary Tumor Resection in Synchronous Metastatic Colorectal Cancer Patients Treated with Upfront Chemotherapy plus Bevacizumab: A Pooled Analysis of TRIBE and TRIBE2 Studies

by Valentina Fanotto, Daniele Rossini, Mariaelena Casagrande, Francesca Bergamo, Andrea Spagnoletti, Daniele Santini, Carlotta Antoniotti, Samanta Cupini, Francesca Daniel, Vincenzo Nasca, Guglielmo Vetere, Alberto Zaniboni, Beatrice Borelli, Martina Carullo, Veronica Conca, Alessandro Passardi, Emiliano Tamburini, Gianluca Masi, Nicoletta Pella and Chiara Cremolini

Cancers 2023, 15(22), 5451; https://doi.org/10.3390/cancers15225451 - 16 Nov 2023

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Abstract

Background: The decision to resect or not the primary tumor in asymptomatic patients with synchronous metastatic colorectal cancer (mCRC) is a complex and challenging issue for oncologists, especially when an antiangiogenic-based therapy is planned. Methods: Patients enrolled in the phase III TRIBE and [...] Read more.

Background: The decision to resect or not the primary tumor in asymptomatic patients with synchronous metastatic colorectal cancer (mCRC) is a complex and challenging issue for oncologists, especially when an antiangiogenic-based therapy is planned. Methods: Patients enrolled in the phase III TRIBE and TRIBE2 studies that compared upfront FOLFOXIRI + bevacizumab to FOLFIRI or FOLFOX + bevacizumab, respectively, were included. We assessed the association of primary tumor resection (PTR) with progression-free survival (PFS), overall survival (OS), response rate (ORR), rate of grade > 2 adverse events (AEs), and serious gastrointestinal and surgical AEs in the overall population and according to the treatment arm. Results: Of the 999 patients included, 513 (51%) underwent PTR at baseline. Longer PFS and OS were observed in resected patients compared to those with unresected primary tumors: 11.2 vs. 10.0 months (p < 0.001) and 26.6 vs. 22.5 (p < 0.001), respectively. In multivariate models, PTR was confirmed as an independent prognostic factor for better PFS (p = 0.032) and OS (p = 0.018). Patients with PTR experienced a higher incidence of grade 3 or 4 diarrhea (p = 0.055) and lower incidence of anemia (p = 0.053), perforation (p = 0.015), and serious gastrointestinal and surgical AEs (p < 0.001). No statistically significant differences were noted in incidence of bleeding (p = 0.39). The benefit of FOLFOXIRI + bevacizumab in terms of PFS (p for interaction: 0.46), OS (p for interaction: 0.80), ORR (p for interaction: 0.36), and incidence of grade 3 or 4 AEs was independent of PTR. Conclusions: PTR at baseline was independently associated with good prognosis in synchronous mCRC patients and with lower incidence of serious gastrointestinal and surgical AEs during upfront chemotherapy plus bevacizumab. The benefit and toxicity profile of FOLFOXIRI plus bevacizumab was independent of PTR. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer 2.0)

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13 pages, 1362 KiB

Open AccessArticle

Survival Evidence of Local Control for Colorectal Cancer Liver Metastases by Hepatectomy and/or Radiofrequency Ablation

by Lariza Marie Canseco, Yueh-Wei Liu, Chien-Chang Lu, Ko-Chao Lee, Hong-Hwa Chen, Wan-Hsiang Hu, Kai-Lung Tsai, Yao-Hsu Yang, Chih-Chi Wang and Chao-Hung Hung

Cancers 2023, 15(18), 4434; https://doi.org/10.3390/cancers15184434 - 06 Sep 2023

Viewed by 959

Abstract

Hepatectomy and/or local ablation therapy have been recommended for colorectal cancer liver metastases (CRLM). However, they still lack strong evidence for their survival benefits, in addition to systemic therapy. This study aims to evaluate the survival evidence of hepatectomy and/or radiofrequency ablation (RFA) [...] Read more.

Hepatectomy and/or local ablation therapy have been recommended for colorectal cancer liver metastases (CRLM). However, they still lack strong evidence for their survival benefits, in addition to systemic therapy. This study aims to evaluate the survival evidence of hepatectomy and/or radiofrequency ablation (RFA) therapy in CRLM patients from a large multi-institutional database. A total of 20,251 patients with colorectal cancer, 4521 of whom were with CRLM, were screened for eligibility. Finally, 2612 patients (637 hepatectomy, 93 RFA, 92 combined hepatectomy and RFA, and 1790 non-aggressive treatment) were enrolled. Frequency matching analysis was used to adjust for baseline differences. The 5-year overall survival (OS) was as follows: hepatectomy alone was 47.8%, combined hepatectomy plus RFA was 35.9%, RFA alone was 29.2%, and the non-aggressive treatment group was 7.4%. Kaplan–Meier curves showed that hepatectomy, RFA, and combination were significantly associated with a better OS compared to those without aggressive local therapy (p < 0.001). Multivariate Cox regression analysis showed that male gender (hazard ratio (HR) 0.89; 95% confidence interval (CI), 0.81–0.97; p = 0.011), old age (≥60 years) (HR 1.20; 95% CI, 1.09–1.32; p < 0.001), high CEA level (>5 ng/mL) (HR 2.14; 95% CI, 1.89–2.42; p < 0.001), primary right-sided cancer (HR 1.35; 95% CI, 1.22–1.51; p < 0.001), extrahepatic metastasis (HR 1.46; 95% CI, 1.33–1.60; p < 0.001), systemic therapy (HR 0.7; 95% CI, 0.62–0.79; p < 0.001), and aggressive local therapy (hepatectomy vs. non-local therapy HR 0.22; 95% CI, 0.20–0.26; p < 0.001; RFA vs. non-local therapy HR 0.29; 95% CI, 0.29–0.41; p < 0.001) were independent factors associated with OS. In the frequency matching analysis, patients receiving hepatectomy and/or RFA resulted in a better OS than those without (p < 0.001). In conclusion, aggressive local treatment provides survival advantages over systemic therapy alone among CRLM patients. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer 2.0)

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10 pages, 401 KiB

Open AccessArticle

Completion of Genetic Testing and Incidence of Pathogenic Germline Mutation among Patients with Early-Onset Colorectal Cancer: A Single Institution Analysis

by Michael H. Storandt, Kara R. Rogen, Anushka Iyyangar, Rylie R. Schnell, Jessica L. Mitchell, Joleen M. Hubbard, Frank A. Sinicrope, Aminah Jatoi, Amit Mahipal, Qian Shi and Zhaohui Jin

Cancers 2023, 15(14), 3570; https://doi.org/10.3390/cancers15143570 - 11 Jul 2023

Viewed by 1050

Abstract

Over the past 20 years, rates of early-onset colorectal cancer (eoCRC), defined as <50 years of age at diagnosis, have increased, with 16–25% associated with a pathogenic germline variant (PGV) resulting in a hereditary cancer syndrome. In the present study, we sought to [...] Read more.

Over the past 20 years, rates of early-onset colorectal cancer (eoCRC), defined as <50 years of age at diagnosis, have increased, with 16–25% associated with a pathogenic germline variant (PGV) resulting in a hereditary cancer syndrome. In the present study, we sought to further characterize PGVs observed in patients with eoCRC. We conducted a retrospective analysis of patients with a history of CRC referred for genetic counseling at Mayo Clinic Rochester between April 2019 and April 2022. Three hundred and three CRC patients were referred to medical genetics, including 124 with a history of eoCRC. Only 84 patients (68%) with eoCRC referred for genetic counseling completed genetic testing, with an average of 48 genes evaluated. PGVs were identified in 27.4% with eoCRC, including 8.3% with Lynch syndrome (LS). Other detected PGVs known to increase the risk of CRC included MUTYH (4.8%), CHEK2 (3.6%), APC, BMPR1A, and TP53 (1.3% each). Among those with aoCRC, 109 patients (61%) completed genetic testing, among which 88% had either a dMMR tumor, personal history of an additional LS malignancy, or family history of LS malignancy, with PGVs detected in 23% of patients. This study reinforces the importance for all patients with CRC, especially those with eoCRC, to undergo germline testing. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer 2.0)

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12 pages, 2078 KiB

Open AccessArticle

Exploring the Outcome of Disappearance or Small Remnants of Colorectal Liver Metastases during First-Line Chemotherapy on Hepatobiliary Contrast-Enhanced and Diffusion-Weighted MR Imaging

by Piero Boraschi, Roberto Moretto, Francescamaria Donati, Beatrice Borelli, Giuseppe Mercogliano, Luigi Giugliano, Alessandra Boccaccino, Maria Clotilde Della Pina, Piero Colombatto, Stefano Signori, Gianluca Masi, Chiara Cremolini and Lucio Urbani

Cancers 2023, 15(8), 2200; https://doi.org/10.3390/cancers15082200 - 08 Apr 2023

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Abstract

We aimed to evaluate the outcome of the disappearance or small remnants of colorectal liver metastases during first-line chemotherapy assessed by hepatobiliary contrast-enhanced and diffusion-weighted MR imaging (DW-MRI). Consecutive patients with at least one disappearing liver metastasis (DLM) or small residual liver metastases [...] Read more.

We aimed to evaluate the outcome of the disappearance or small remnants of colorectal liver metastases during first-line chemotherapy assessed by hepatobiliary contrast-enhanced and diffusion-weighted MR imaging (DW-MRI). Consecutive patients with at least one disappearing liver metastasis (DLM) or small residual liver metastases (≤10 mm) assessed by hepatobiliary contrast-enhanced and DW-MRI during first-line chemotherapy were included. Liver lesions were categorized into three groups: DLM; residual tiny liver metastases (RTLM) when ≤5 mm; small residual liver metastases (SRLM) when >5mm and ≤10 mm. The outcome of resected liver metastases was assessed in terms of pathological response, whereas lesions left in situ were evaluated in terms of local relapse or progression. Fifty-two outpatients with 265 liver lesions were radiologically reviewed; 185 metastases fulfilled the inclusion criteria: 40 DLM, 82 RTLM and 60 SRLM. We observed a pCR rate of 75% (3/4) in resected DLM and 33% (12/36) of local relapse for DLM left in situ. We observed a risk of relapse of 29% and 57% for RTLM and SRLM left in situ, respectively, and a pCR rate of about 40% overall for resected lesions. DLM assessed via hepatobiliary contrast-enhanced and DW-MRI very probably indicates a complete response. The surgical removal of small remnants of liver metastases should always be advocated whenever technically possible. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer 2.0)

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Review

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30 pages, 1126 KiB

Open AccessReview

Immunocheckpoint Inhibitors in Microsatellite-Stable or Proficient Mismatch Repair Metastatic Colorectal Cancer: Are We Entering a New Era?

by Laura Matteucci, Alessandro Bittoni, Graziana Gallo, Laura Ridolfi and Alessandro Passardi

Cancers 2023, 15(21), 5189; https://doi.org/10.3390/cancers15215189 - 28 Oct 2023

Cited by 1 | Viewed by 1691

Abstract

Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related deaths in Europe. About 5% of metastatic CRC (mCRC) are characterized by high microsatellite instability (MSI) due to a deficient DNA mismatch repair (dMMR), and this condition [...] Read more.

Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related deaths in Europe. About 5% of metastatic CRC (mCRC) are characterized by high microsatellite instability (MSI) due to a deficient DNA mismatch repair (dMMR), and this condition has been related to a high sensitivity to immunotherapy, in particular to the Immune Checkpoint Inhibitors (ICIs). In fact, in MSI-H or dMMR mCRC, treatment with ICIs induced remarkable response rates and prolonged survival. However, the majority of mCRC cases are mismatch-repair-proficient (pMMR) and microsatellite-stable (MSS), and unfortunately these conditions involve resistance to ICIs. This review aims to provide an overview of the strategies implemented to overcome ICI resistance and/or define subgroups of patients with MSS or dMMR mCRC who may benefit from immunotherapy. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer 2.0)

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19 pages, 1009 KiB

Open AccessReview

Unravelling the Complexity of Colorectal Cancer: Heterogeneity, Clonal Evolution, and Clinical Implications

by Nadia Saoudi González, Francesc Salvà, Javier Ros, Iosune Baraibar, Marta Rodríguez-Castells, Ariadna García, Adriana Alcaráz, Sharela Vega, Sergio Bueno, Josep Tabernero and Elena Elez

Cancers 2023, 15(16), 4020; https://doi.org/10.3390/cancers15164020 - 08 Aug 2023

Cited by 4 | Viewed by 1737

Abstract

Colorectal cancer (CRC) is a global health concern and a leading cause of death worldwide. The disease’s course and response to treatment are significantly influenced by its heterogeneity, both within a single lesion and between primary and metastatic sites. Biomarkers, such as mutations [...] Read more.

Colorectal cancer (CRC) is a global health concern and a leading cause of death worldwide. The disease’s course and response to treatment are significantly influenced by its heterogeneity, both within a single lesion and between primary and metastatic sites. Biomarkers, such as mutations in KRAS, NRAS, and BRAF, provide valuable guidance for treatment decisions in patients with metastatic CRC. While high concordance exists between mutational status in primary and metastatic lesions, some heterogeneity may be present. Circulating tumor DNA (ctDNA) analysis has proven invaluable in identifying genetic heterogeneity and predicting prognosis in RAS-mutated metastatic CRC patients. Tumor heterogeneity can arise from genetic and non-genetic factors, affecting tumor development and response to therapy. To comprehend and address clonal evolution and intratumoral heterogeneity, comprehensive genomic studies employing techniques such as next-generation sequencing and computational analysis are essential. Liquid biopsy, notably through analysis of ctDNA, enables real-time clonal evolution and treatment response monitoring. However, challenges remain in standardizing procedures and accurately characterizing tumor subpopulations. Various models elucidate the origin of CRC heterogeneity, highlighting the intricate molecular pathways involved. This review focuses on intrapatient cancer heterogeneity and genetic clonal evolution in metastatic CRC, with an emphasis on clinical applications. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer 2.0)

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23 pages, 1350 KiB

Open AccessReview

Early Onset Metastatic Colorectal Cancer: Current Insights and Clinical Management of a Rising Condition

by Bianca Medici, Beatrice Riccò, Eugenia Caffari, Silvia Zaniboni, Massimiliano Salati, Andrea Spallanzani, Ingrid Garajovà, Stefania Benatti, Chiara Chiavelli, Massimo Dominici and Fabio Gelsomino

Cancers 2023, 15(13), 3509; https://doi.org/10.3390/cancers15133509 - 05 Jul 2023

Cited by 3 | Viewed by 2589

Abstract

Despite a recent overall decrease in colorectal cancer (CRC) incidence and mortality, there has been a significant rise in CRC diagnoses in young adults. Early onset colorectal cancer (EOCRC) is defined as CRC diagnosed before the age of 50. Possible predisposing conditions include [...] Read more.

Despite a recent overall decrease in colorectal cancer (CRC) incidence and mortality, there has been a significant rise in CRC diagnoses in young adults. Early onset colorectal cancer (EOCRC) is defined as CRC diagnosed before the age of 50. Possible predisposing conditions include not only genetic syndromes but also other risk factors, such as microbiome alteration, antibiotic exposure, obesity, diabetes mellitus, and inflammatory bowel disease. EOCRC tends to be diagnosed later than in the older counterpart because of a lack of awareness and the fact that screening for CRC usually starts at the age of 50. Furthermore, CRC in young adults seems to be related to unique molecular features and more aggressive clinical behavior. This paper aims to provide an in-depth review of this poorly understood subject, with a comprehensive review of the state of the art and considerations for future perspectives. Full article

(This article belongs to the Special Issue Metastatic Colorectal Cancer 2.0)

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