Precision medicine for metastatic colorectal cancer in clinical practice

Riedesser, Julian E.; Ebert, Matthias; Betge, Johannes

doi:10.1177/17588359211072703

Cited by 38 publications

(45 citation statements)

References 239 publications

(319 reference statements)

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“…The prognosis of patients who have metastatic CRC (mCRC) has significantly improved in the past 20 years with the introduction of more effective therapeutic approaches, including surgery of liver and lung metastases and novel anticancer drugs. 6 However, mCRC in most cases remains a noncurable disease.…”

Section: Introductionmentioning

confidence: 99%

Clinical management of metastatic colorectal cancer in the era of precision medicine

Ciardiello

Martini

et al. 2022

CA A Cancer J Clinicians

296

161

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Colorectal cancer (CRC) represents approximately 10% of all cancers and is the second most common cause of cancer deaths. Initial clinical presentation as metastatic CRC (mCRC) occurs in approximately 20% of patients. Moreover, up to 50% of patients with localized disease eventually develop metastases. Appropriate clinical management of these patients is still a challenging medical issue. Major efforts have been made to unveil the molecular landscape of mCRC. This has resulted in the identification of several druggable tumor molecular targets with the aim of developing personalized treatments for each patient. This review summarizes the improvements in the clinical management of patients with mCRC in the emerging era of precision medicine. In fact, molecular stratification, on which the current treatment algorithm for mCRC is based, although it does not completely represent the complexity of this disease, has been the first significant step toward clinically informative genetic profiling for implementing more effective therapeutic approaches. This has resulted in a clinically relevant increase in mCRC disease control and patient survival. The next steps in the clinical management of mCRC will be to integrate the comprehensive knowledge of tumor gene alterations, of tumor and microenvironment gene and protein expression profiling, of host immune competence as well as the application of the resulting dynamic changes to a precision medicine-based continuum of care for each patient. This approach could result in the identification of individual prognostic and predictive parameters, which could help the clinician in choosing the most appropriate therapeutic program(s) throughout the entire disease journey for each patient with mCRC.

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Section: Introductionmentioning

confidence: 99%

Clinical management of metastatic colorectal cancer in the era of precision medicine

Ciardiello

Martini

et al. 2022

CA A Cancer J Clinicians

296

161

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“…It is involved in signaling pathways, such as tumor proliferation, angiogenesis, and migration. Cetuximab and panitumumab are EGFR inhibitors and were found to have a significant survival advantage over supportive care in patients with chemotherapy-refractory tumors, and when combined with chemotherapy as first-line therapy, it significantly improved PFS and OS ( Riedesser et al, 2022 ). Currently, anti-EGFR therapy is mainly used for treating metastatic colorectal cancer patients with wild-type RAS/BRAF, since RAS/BRAF mutant patients do not respond well to anti-EGFR therapy.…”

Section: Discussionmentioning

confidence: 99%

Survival for patients with metastatic colon cancer underwent cytoreductive colectomy in the era of rapid development of anticancer drugs: A real-world analysis based on updated population dataset of 2004–2018

2022

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Objective: Metastatic colon cancer (mCC) poses a great threat to the survival of patients suffering from it. In the past decade, many clinical trials have been carried out to improve the prognosis of patients with mCC. Numerous treatments have emerged, and satisfactory efficacy has been demonstrated in randomized phase III trials in highly selective patients with mCC. Our present study aims to investigate whether these therapeutic advances can be reflected to the broader mCC patients who performed cytoreductive colectomy.Method: General and prognostic data for patients diagnosed with mCC who underwent cytoreductive colectomy between 2004–2018 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazards model. The hazard ratio (HR) and its 95% confidence interval (CI) were used to evaluate the influence of risk factors on prognosis.Results: A total of 26,301 patients diagnosed with mCC treated with cytoreductive colectomy were included in this study. The median overall survival was 19 months (range, 17–23). The good prognosis was associated with patients diagnosed at the most recent year, younger age, non-black race, female, married, without previous history of malignancy, no second malignancy onset, descending/sigmoid/splenic flexure colon tumor, normal CEA levels at diagnosis, low primary tumor burden, T1/T2 stage, N0 stage, single organ metastasis, underwent surgical resection of synchronous distant metastatic lymph nodes or organs, a high number of lymph-node examinations, low positive lymph-node ratio and received adjuvant chemotherapy. The proportion of patients surviving for ≥24 months increased from 37% in 2004 to 44.2% in 2016 (p < 0.001), especially in ≤49 years patients [46.8% in 2004 to 57.8% in 2016 (p < 0.001)]. The percentage of patients who died within 3 months decreased between 2004 and 2018 (from 19.6% to 15.7%; p < 0.001).Conclusion: Over a span of 15 years, the long-term survival has improved in real-world mCC patients who were treated with cytoreductive colectomy, especially among younger patients. However, the median overall survival remains not substantial.

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“…About 20% of cases are diagnosed in a metastatic stage and a significant percentage of initially stage II and stage III patients will have a metastatic relapse [ 2 ]. Metastatic colorectal cancer remains most often an incurable disease, despite progress in systemic and local therapies that have improved outcomes [ 3 ]. The elucidation of the molecular pathogenesis of colorectal cancer has resulted in introduction of targeted therapies that have improved survival of selected patients [ 4 , 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Sensitivities and Dependencies of BRAF Mutant Colorectal Cancer Cell Lines with or without PIK3CA Mutations for Discovery of Vulnerabilities with Therapeutic Potential

Voutsadakis

2022

Medicina

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Background: Colorectal cancer represents a common malignancy and remains incurable in the metastatic stage. Identification of molecular alterations that are present in colorectal cancer has led to the introduction of targeted therapies that improve outcomes. BRAF and PIK3CA mutations are observed in a subset of colorectal cancers. Colorectal cancers bearing BRAF mutations may be treated with specific BRAF inhibitors. These drugs benefit patients with BRAF mutant colorectal cancers but responses are rather brief, and progression is the rule. In contrast, no PI3K inhibitors have proven successful yet in the disease. Thus, new treatments to supplement the currently available drugs would be welcome to further improve survival. Methods: Profiled colorectal cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE) were examined for BRAF and PIK3CA mutations and were interrogated for molecular characteristics and concomitant alterations that mirror clinical sample alterations. The Genomics of Drug Sensitivity in Cancer (GDSC) project was used for determination of drug sensitivities of BRAF mutated colorectal cell lines with or without concomitant PIK3CA mutations. The Cancer Dependency Map project served as the basis for identification of molecular dependencies and vulnerabilities in these cell lines. Results: CCLE includes 84 colorectal cancer cell lines, which recapitulate the molecular landscape of colorectal cancer. Of these, 23 and 24 cell lines possess BRAF and PIK3CA mutations, respectively. Seven BRAF mutant cell lines have V600E mutations and 14 PIK3CA mutant cell lines have hotspot helical or kinase domain mutations. V600E BRAF mutant cell lines with or without hotspot PIK3CA mutations are heterogeneous in their MSI status and mimic colorectal cancer tissues in other prevalent abnormalities including APC and TP53 mutations. Essential genes for survival include CTNNB1, WRN, and pyrimidine metabolism enzyme CAD. Besides BRAF mutations, BRAF inhibitor sensitivity in colorectal cancer cell lines is conferred by SACS mutations and PRKN locus loss. Conclusions: Colorectal cancer cell lines bearing the frequent BRAF and PIK3CA mutations present many alterations of the parental cancer tissue. Described vulnerabilities represent leads for therapeutic exploration in colorectal cancers with the corresponding alterations.

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Precision medicine for metastatic colorectal cancer in clinical practice

Cited by 38 publications

References 239 publications

Clinical management of metastatic colorectal cancer in the era of precision medicine

Clinical management of metastatic colorectal cancer in the era of precision medicine

Survival for patients with metastatic colon cancer underwent cytoreductive colectomy in the era of rapid development of anticancer drugs: A real-world analysis based on updated population dataset of 2004–2018

Sensitivities and Dependencies of BRAF Mutant Colorectal Cancer Cell Lines with or without PIK3CA Mutations for Discovery of Vulnerabilities with Therapeutic Potential

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