Keywords
1. Colorectal Cancer Survival
2. Adjuvant Chemotherapy
3. Recurrence Molecular Biomarkers
4. TGF-β Pathway in CRC
5. Fluoropyrimidine
6. Oxaliplatin Treatment
Colorectal cancer (CRC) is the third most common cancer diagnosis and the second leading cause of cancer death worldwide. After undergoing potentially curative surgery followed by chemotherapy, the risk of recurrence remains a major concern for patients with stage III or high-risk stage II CRC. The survival after recurrence (SAR) is a crucial parameter, and the discovery of associated molecular characteristics could have significant implications for prognosis and personalized treatment strategies. In a groundbreaking study published in BMC Cancer, researchers from Seoul National University Hospital have unveiled an association between mutations in the TGF-β pathway and SAR in patients with CRC who had received adjuvant fluoropyrimidine and oxaliplatin chemotherapy (DOI: 10.1186/s12885-019-5650-0).
This research provides insight into the critical role of the Transforming Growth Factor-beta (TGF-β) pathway in determining SAR and identifies it as a potential negative prognostic factor for CRC patients who experience a recurrence, emphasizing the complexity of cancer biology and the need for personalized medicine approaches in oncology.
Study Overview
The study analyzed 516 patients with stage III or high-risk stage II CRC who were treated with surgery and adjuvant chemotherapy. Of these, 87 patients who experienced distant recurrence were included in the analysis. Researchers focused on the association between SAR and mutations across 40 genes that are part of five critical pathways involved in CRC: WNT, P53, RTK-RAS, TGF-β, and PI3K.
The results demonstrated mutations in the WNT (79.3%), P53 (69.0%), RTK-RAS (65.5%), TGF-β (24.1%), and PI3K (21.8%) pathways respectively. Notably, TGF-β pathway mutations were found in younger patients, who also had a higher incidence of mucinous adenocarcinoma (MAC) histology and microsatellite instability-high (MSI-H).
Key Findings and Implications
The study findings are particularly compelling, with TGF-β pathway mutations being associated with poor SAR (median SAR of 21.6 vs. 44.4 months, p = 0.021). Additionally, the presence of MAC was tied to unfavorable SAR outcomes (20.0 vs. 44.4 months, p = 0.003). Conversely, patients receiving curative resection after recurrence saw a much more favorable SAR (Not reached vs. 23.6 months, p < 0.001).
The significance of TGF-β Pathway Mutations
When excluding MAC as a covariate, multivariate analysis revealed TGF-β pathway mutations as an independent prognostic factor for SAR. The use of bioinformatics tools such as PROVEAN, SIFT, and PolyPhen-2 predicted that the majority of the TGF-β mutations examined were likely to be damaging.
This discovery highlights the TGF-β pathway as carrying significant weight in the prognosis of CRC, as its mutation may specifically contribute to poorer outcomes after recurrence. Moreover, these findings support utilizing the TGF-β pathway as a biomarker to identify high-risk individuals for whom more aggressive treatment or monitoring post-surgery may be beneficial.
A Step Towards Personalized Medicine
The identification of pathway-specific mutations arms clinicians with valuable prognostic information which could be instrumental in refining therapeutic approaches. The ability to predict SAR based on genetic profiling may allow for more tailored treatment strategies that could improve patient outcomes and potentially transform the management of CRC.
Limitations and Future Research
While this study represents an advance in CRC research, it also acknowledges limitations inherent to its design. The retrospective nature of the study and the relatively small cohort size necessitate further research to validate these findings. Prospective studies with larger populations are required to consolidate the role of TGF-β pathway mutations in CRC recurrence and survival outcomes.
Conclusion
In conclusion, the study performed by Lee Dae-Won and colleagues sheds new light on the intricate mechanisms underpinning CRC recurrence and SAR. The association of TGF-β pathway mutation with poorer SAR outcomes provides a pivotal piece of the puzzle in understanding CRC biology. Moving forward, these insights forge a path towards enhanced patient stratification and the advent of precision medicine in the fight against colorectal cancer.
References
1. Jemal A, et al. (2011). Global cancer statistics. CA Cancer J Clin. DOI: 10.3322/caac.20107.
2. Guinney J, et al. (2015). The consensus molecular subtypes of colorectal cancer. Nat Med. DOI: 10.1038/nm.3967.
3. Cancer Genome Atlas N. (2012). Comprehensive molecular characterization of human colon and rectal cancer. Nature. DOI: 10.1038/nature11252.
4. Fearon ER. (2011). Molecular genetics of colorectal cancer. Annu Rev Pathol. DOI: 10.1146/annurev-pathol-011110-130235.
5. Andre T, et al. (2009). Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. DOI: 10.1200/JCO.2008.20.6771.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The ethical approval and consent to participate were secured according to the institutional review board of SNUH [H-1210-016-430]. This study was carried out following the recommendations of the Declaration of Helsinki. Because the study was retrospective, the informed consent was not obtained from each patient.