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Cancers
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Metastatic Colorectal Cancer: Biological Features, Old and New Treatments
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Metastatic Colorectal Cancer: Biological Features, Old and New Treatments

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (20 July 2022) | Viewed by 28550

Special Issue Editors

Dr. Anna Maria Chiaravalli

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Guest Editor
Department of Pathology, ASST Sette Laghi, 21100 Varese, Italy
Interests: Gastrointestinal cancer; Breast cancer; immunohistochemistry; prognostic and predictive markers
Dr. Elena Magni

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Guest Editor
Department of Oncology, ASST Sette Laghi, 21100 Varese, Italy
Interests: colorectal cancer; immunotherapy; target therapy

Special Issue Information

Colorectal cancer (CRC) is the fourth most common cause of death from cancer in the world, the third most common cancer in men, and the second most common cancer in women. About 25% of patients present with metastatic disease at initial diagnosis and 50% of patients at an early disease stage will develop metastases.

The outcome and the success of therapy for metastatic CRC is related to the resectability of the metastases, the patient’s clinical status, the tumor’s location, and the biomarker profile, which determines the systemic approach to be taken. In an oligometastatic setting, resection or local treatment of metastases using a multimodal approach is a reasonable option.

At present, RAS/BRAF mutational status and tumor location are the gold standards for treatment choice. Emerging data regarding new pathways implicated in resistance to anti-EGFR therapy and the role of immunocheckpoint inhibitors in subsets of tumors need to be further investigated.

Recently, four consensus molecular subtypes of CRC (MSI-immune, Canonical, Metabolic, and Mesenchymal) were identified, each of which is characterized by different biological and clinical features, including metastatic potential, relapse-free survival, and overall survival, and different therapeutic chances of success.

This Special Issue will highlight existing and future potential therapeutic approaches on the basis of our current and emerging knowledge of the biology of metastatic CRC.

Dr. Anna Maria Chiaravalli
Dr. Elena Magni
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • metastatic colorectal cancer
  • molecular profile
  • target therapy
  • local treatment
  • immunotherapy

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Published Papers (7 papers)

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16 pages, 3329 KiB  
Article
Tumor Antigenicity and a Pre-Existing Adaptive Immune Response in Advanced BRAF Mutant Colorectal Cancers
by Elena Bolzacchini, Laura Libera, Sarah E. Church, Nora Sahnane, Raffaella Bombelli, Nunzio Digiacomo, Monica Giordano, Guido Petracco, Fausto Sessa, Carlo Capella and Daniela Furlan
Cancers 2022, 14(16), 3951; https://doi.org/10.3390/cancers14163951 - 16 Aug 2022
Cited by 6 | Viewed by 2592
Abstract
The main hypothesis of this study is that gene expression profiles (GEPs) integrating both tumor antigenicity and a pre-existing adaptive immune response can be used to generate distinct immune-related signatures of BRAF mutant colorectal cancers (BRAF-CRCs) to identify actionable biomarkers predicting response to [...] Read more.
The main hypothesis of this study is that gene expression profiles (GEPs) integrating both tumor antigenicity and a pre-existing adaptive immune response can be used to generate distinct immune-related signatures of BRAF mutant colorectal cancers (BRAF-CRCs) to identify actionable biomarkers predicting response to immunotherapy. GEPs of 89 immunotherapy-naïve BRAF-CRCs were generated using the Pan-Cancer IO 360 gene expression panel and the NanoString nCounter platform and were correlated with microsatellite instability (MSI) status and with CD8+ tumor-infiltrating lymphocyte (TIL) content. Hot/inflamed profiles were found in 52% of all cases, and high scores of Tumor Inflammation Signature were observed in 42% of the metastatic BRAF-CRCs. A subset of MSI tumors showed a cold profile. Antigen Processing Machinery (APM) signature was not differentially expressed in MSI tumors compared with MSS cases. By contrast, the APM signature was significantly upregulated in CD8+ BRAF-CRCs versus CD8− tumors. Our study demonstrates that a significant fraction of BRAF-CRCs may be a candidate for immunotherapy and that the simultaneous analysis of MSI status and CD8+ TIL content increases accuracy in identifying patients who can potentially benefit from immune checkpoint inhibitors. GEPs may be very useful in expanding the spectrum of patients with BRAF-CRCs who can benefit from immune checkpoint blockade. Full article
(This article belongs to the Special Issue Metastatic Colorectal Cancer: Biological Features, Old and New Treatments)
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13 pages, 1614 KiB  
Article
Anti-EGFR Reintroduction and Rechallenge in Metastatic Colorectal Cancer (mCRC): A Real-World Analysis
by Martin S. Schulz, Sebastian Wolf, Vera Struck, Niklas Thomas, Gabriele Husman, Stefan Zeuzem, Christine Koch, Jörg Trojan, Andreas Anton Schnitzbauer, Wolf Otto Bechstein and Oliver Waidmann
Cancers 2022, 14(7), 1641; https://doi.org/10.3390/cancers14071641 - 24 Mar 2022
Cited by 9 | Viewed by 3593
Abstract
Background and Aims: In patients with Rat sarcoma proto-oncogene (RAS) wild-type metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor (EGFR) antibodies have been established in first- and further therapy lines. Due to limited treatment options upon disease progression, anti-EGFR re-exposure is [...] Read more.
Background and Aims: In patients with Rat sarcoma proto-oncogene (RAS) wild-type metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor (EGFR) antibodies have been established in first- and further therapy lines. Due to limited treatment options upon disease progression, anti-EGFR re-exposure is increasingly employed in real-world oncology. The aim of this study was to assess clinical implementation and utility of anti-EGFR retreatment strategies in real-world mCRC patients. Methods: In this monocentric retrospective study, we included 524 patients with CRC and identified patients who received an anti-EGFR-based treatment as well as anti-EGFR rechallenge (progression on first-line anti-EGFR therapy) or reintroduction (discontinuation due to intolerance/toxicity/other). Results: In total, 143 patients received an anti-EGFR-based first- or second-line treatment, showing a similar overall survival (OS) compared to the non-anti-EGFR treatment group (38.3 vs. 39.6 months, p = 0.88). Thirty-three patients met the inclusion criteria for anti-EGFR re-exposure and were either assigned to rechallenge (n = 21) or reintroduction (n = 12) subgroups. The median FU after re-exposure was 45.8 months. Cetuximab and Panitumumab were used in 21 and 12 patients, respectively, and the main chemotherapy at re-exposure was FOLFIRI in 39.4%. Anti-EGFR re-exposure was associated with a distinct trend towards a better outcome (median OS 56.0 vs. 35.4 months, p = 0.06). In a subgroup comparison, reintroduction was associated with a higher OS and PFS in trend compared to the rechallenge (mOS 66 vs. 52.4, n.s., mPFS 7.33 vs. 3.68 months, n.s.). Conclusions: This retrospective study provides real-world evidence underscoring that anti-EGFR re-exposure strategies might benefit patients independently of the reason for prior discontinuation. Full article
(This article belongs to the Special Issue Metastatic Colorectal Cancer: Biological Features, Old and New Treatments)
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12 pages, 427 KiB  
Article
The Characteristics of 206 Long-Term Survivors with Peritoneal Metastases from Colorectal Cancer Treated with Curative Intent Surgery: A Multi-Center Cohort from PSOGI
by Yasuyuki Kamada, Koya Hida, Yutaka Yonemura, Paul H. Sugarbaker, Shadin Ghabra, Soichiro Ishihara, Hiroshi Nagata, Koji Murono, Takanori Goi, Kanji Katayama, Mitsuhiro Morikawa, Beate Rau, Pompiliu Piso, Miklos Acs, Federico Coccolini, Emel Canbay, Mao-Chih Hsieh, Aditi Bhatt, Pierre-Emmanuel Bonnot and Olivier Glehen
Cancers 2021, 13(12), 2964; https://doi.org/10.3390/cancers13122964 - 13 Jun 2021
Cited by 7 | Viewed by 3600
Abstract
Background: We conducted this study to review the patient characteristics associated with long-term survival in patients with peritoneal metastases from colorectal cancer who underwent cytoreductive surgery (CRS). Methods: We retrospectively investigated patients with peritoneal metastases from CRC treated with curative intent surgery with [...] Read more.
Background: We conducted this study to review the patient characteristics associated with long-term survival in patients with peritoneal metastases from colorectal cancer who underwent cytoreductive surgery (CRS). Methods: We retrospectively investigated patients with peritoneal metastases from CRC treated with curative intent surgery with or without hyperthermic intraperitoneal chemotherapy at 13 institutions worldwide between January 1985 and April 2015 and survived longer than five years after the first CRS for peritoneal metastases. Clinical and oncological features and therapeutic parameters were described and analyzed. Results: Two hundred six long-term survivors were available for study. The median peritoneal cancer index (PCI) of this cohort was 4 (interquartile range (IQR), 2–7), and the median score of the small bowel regions of the PCI (SB-PCI) was 0 (IQR, 0–2). Complete cytoreduction (CC-0) was achieved in 180 (87.4%) patients. Recurrence was observed in 122 (59.2%) patients at a median of 1.8 (IQR, 1.2–2.6) years. Conclusions: While most long-term survivors showed low PCI/SB-PCI and CCR-0, some had characteristics considered associated with poor prognosis. Curative intent treatments may be considered in well-informed and fit patients showing negative factors affecting survival outcome. Full article
(This article belongs to the Special Issue Metastatic Colorectal Cancer: Biological Features, Old and New Treatments)
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13 pages, 813 KiB  
Article
Clinical, Pathological and Prognostic Features of Rare BRAF Mutations in Metastatic Colorectal Cancer (mCRC): A Bi-Institutional Retrospective Analysis (REBUS Study)
by Maria Alessandra Calegari, Lisa Salvatore, Brunella Di Stefano, Michele Basso, Armando Orlandi, Alessandra Boccaccino, Fiorella Lombardo, Alessandra Auriemma, Ina Valeria Zurlo, Maria Bensi, Floriana Camarda, Marta Ribelli, Raffaella Vivolo, Alessandra Cocomazzi, Carmelo Pozzo, Michele Milella, Maurizio Martini, Emilio Bria and Giampaolo Tortora
Cancers 2021, 13(9), 2098; https://doi.org/10.3390/cancers13092098 - 27 Apr 2021
Cited by 5 | Viewed by 2673
Abstract
Recently, retrospective analysis began to shed light on metastatic colorectal cancers (mCRCs) harboring rare BRAF non-V600 mutations, documenting a distinct phenotype and a favorable prognosis. This study aimed to confirm features and prognosis of rare BRAF non-V600 mCRCs compared to BRAF V600E and [...] Read more.
Recently, retrospective analysis began to shed light on metastatic colorectal cancers (mCRCs) harboring rare BRAF non-V600 mutations, documenting a distinct phenotype and a favorable prognosis. This study aimed to confirm features and prognosis of rare BRAF non-V600 mCRCs compared to BRAF V600E and BRAF wild-type mCRCs treated at two Italian Institutions. Overall, 537 cases were retrospectively evaluated: 221 RAS/BRAF wild-type, 261 RAS mutated, 46 BRAF V600E and 9 BRAF non-V600. Compared to BRAF V600E mCRC, BRAF non-V600 mCRC were more frequently left-sided, had a lower tumor burden and displayed a lower grade and an MMR proficient/MSS status. In addition, non-V600 mCRC patients underwent more frequently to resection of metastases with radical intent. Median overall survival (mOS) was significantly longer in the non-V600 compared to the V600E group. At multivariate analysis, only age < 65 years and ECOG PS 0 were identified as independent predictors of better OS. BRAF V600E mCRCs showed a statistically significant worse mOS when compared to BRAF wild-type mCRCs, whereas no significant difference was observed between BRAF non-V600 and BRAF wild-type mCRCs. Our study corroborates available evidence concerning incidence, clinicopathologic characteristics and prognosis of BRAF-mutated mCRCs. Full article
(This article belongs to the Special Issue Metastatic Colorectal Cancer: Biological Features, Old and New Treatments)
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17 pages, 5627 KiB  
Article
IL15RA and SMAD3 Genetic Variants Predict Overall Survival in Metastatic Colorectal Cancer Patients Treated with FOLFIRI Therapy: A New Paradigm
by Elena De Mattia, Jerry Polesel, Rossana Roncato, Adrien Labriet, Alessia Bignucolo, Sara Gagno, Angela Buonadonna, Mario D’Andrea, Eric Lévesque, Derek Jonker, Félix Couture, Chantal Guillemette, Erika Cecchin and Giuseppe Toffoli
Cancers 2021, 13(7), 1705; https://doi.org/10.3390/cancers13071705 - 3 Apr 2021
Cited by 8 | Viewed by 2771
Abstract
A new paradigm in cancer chemotherapy derives from the interaction between chemotherapeutics, including irinotecan and 5-fluorouracil (5-FU), and the immune system. The patient’s immune response can modulate chemotherapy effectiveness, and, on the other hand, chemotherapeutic agents can foster tumor cell immunogenicity. On these [...] Read more.
A new paradigm in cancer chemotherapy derives from the interaction between chemotherapeutics, including irinotecan and 5-fluorouracil (5-FU), and the immune system. The patient’s immune response can modulate chemotherapy effectiveness, and, on the other hand, chemotherapeutic agents can foster tumor cell immunogenicity. On these grounds, the analysis of the cancer patients’ immunogenetic characteristics and their effect on survival after chemotherapy represent a new frontier. This study aims to identify genetic determinants in the immuno-related pathways predictive of overall survival (OS) after FOLFIRI (irinotecan, 5-FU, leucovorin) therapy. Two independent cohorts comprising a total of 335 patients with metastatic colorectal cancer (mCRC) homogeneously treated with first-line FOLFIRI were included in the study. The prognostic effect of 192 tagging genetic polymorphisms in 34 immune-related genes was evaluated using the bead array technology. The IL15RA rs7910212-C allele was associated with worse OS in both discovery (HR: 1.57, p = 0.0327, Bootstrap p-value = 0.0280) and replication (HR: 1.71, p = 0.0411) cohorts. Conversely, SMAD3 rs7179840-C allele was associated with better OS in both discovery (HR: 0.65, p = 0.0202, Bootstrap p-value = 0.0203) and replication (HR: 0.61, p = 0.0216) cohorts. A genetic prognostic score was generated integrating IL15RA-rs7910212 and SMAD3-rs7179840 markers with inflammation-related prognostic polymorphisms we previously identified in the same study population (i.e., PXR [NR1I2]-rs1054190, VDR-rs7299460). The calculated genetic score successfully discriminated patients with different survival probabilities (p < 0.0001 log-rank test). These findings provide new insight on the prognostic value of genetic determinants, such as IL15RA and SMAD3 markers, and could offer a new decision tool to improve the clinical management of patients with mCRC receiving FOLFIRI. Full article
(This article belongs to the Special Issue Metastatic Colorectal Cancer: Biological Features, Old and New Treatments)
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Review

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14 pages, 1216 KiB  
Review
Bacteriocins as Potential Therapeutic Approaches in the Treatment of Various Cancers: A Review of In Vitro Studies
by Arnold Marshall Molujin, Sahar Abbasiliasi, Armania Nurdin, Ping-Chin Lee, Jualang Azlan Gansau and Roslina Jawan
Cancers 2022, 14(19), 4758; https://doi.org/10.3390/cancers14194758 - 29 Sep 2022
Cited by 26 | Viewed by 3827
Abstract
Cancer is regarded as one of the most common and leading causes of death. Despite the availability of conventional treatments against cancer cells, current treatments are not the optimal treatment for cancer as they possess the possibility of causing various unwanted side effects [...] Read more.
Cancer is regarded as one of the most common and leading causes of death. Despite the availability of conventional treatments against cancer cells, current treatments are not the optimal treatment for cancer as they possess the possibility of causing various unwanted side effects to the body. As a result, this prompts a search for an alternative treatment without exhibiting any additional side effects. One of the promising novel therapeutic candidates against cancer is an antimicrobial peptide produced by bacteria called bacteriocin. It is a non-toxic peptide that is reported to exhibit potency against cancer cell lines. Experimental studies have outlined the therapeutic potential of bacteriocin against various cancer cell lines. In this review article, the paper focuses on the various bacteriocins and their cytotoxic effects, mode of action and efficacies as therapeutic agents against various cancer cell lines. Full article
(This article belongs to the Special Issue Metastatic Colorectal Cancer: Biological Features, Old and New Treatments)
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15 pages, 1701 KiB  
Review
The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer
by Gianluca Mauri, Erica Bonazzina, Alessio Amatu, Federica Tosi, Katia Bencardino, Viviana Gori, Daniela Massihnia, Tiziana Cipani, Francesco Spina, Silvia Ghezzi, Salvatore Siena and Andrea Sartore-Bianchi
Cancers 2021, 13(1), 137; https://doi.org/10.3390/cancers13010137 - 4 Jan 2021
Cited by 55 | Viewed by 7971
Abstract
The BRAFV600E mutation is found in 8–10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with [...] Read more.
The BRAFV600E mutation is found in 8–10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAFV600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients. Full article
(This article belongs to the Special Issue Metastatic Colorectal Cancer: Biological Features, Old and New Treatments)
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