Chemotherapy re-challenge response rate in metastatic colorectal cancer

Chambers, Alexandra E; Frick, Jacob; Tanner, Natalee; Gerkin, Richard; Kundranda, Madappa N.; Dragovich, Tomislav

doi:10.21037/jgo.2018.04.08

Cited by 15 publications

(12 citation statements)

References 22 publications

(49 reference statements)

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“…Unfortunately, mCRC patients treated with these antibodies progress and develop resistance in most cases [18]. If the disease progresses, one should administer different cytotoxic drugs in order to avoid chemotherapy resistance [19,20].…”

Section: Introductionmentioning

confidence: 99%

KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study

Garcia-Carbonero

Martínez‐Useros

et al. 2020

Cells

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KRAS mutation is a confirmed predictive biomarker for anti-EGFR monoclonal antibody therapy response for metastatic colorectal cancer. However, its prognosis impact and the predictive potential for first-line standard chemotherapy remains unclear. On the other hand, V600E mutation is the most frequent and studied mutation in the BRAF gene, and it has been associated with a poor outcome of patients and a low response to anti-EGFR treatment. Thus, the aim of this study is to evaluate the role of KRAS and BRAF mutations as prognosis factors and predictive biomarkers for 1st line standard chemotherapy in metastatic colorectal cancer. KRAS mutations and BRAF V600E mutations exhibited a poor outcome (p = 0.021 and p < 0.0001, respectively). Cox multivariate analysis showed that the presence of liver metastasis (HR = 1.595; 95% CI: 1.086–2.343; p = 0.017), KRAS mutation (HR = 1.643; 95% CI: 1.110–2.431; p = 0.013) and BRAF V600E mutation (HR = 5.861; 95% CI: 2.531–13.570; p < 0.0001) were statistically significant co-variables for progression-free survival. Interestingly, patients with KRAS mutations were associated with a poor response to first line standard chemotherapy (p = 0.008). In contrast, the BRAF V600E mutation did not have any impact on the first line standard chemotherapy response (p = 0.540). Therefore, in the present study, we provide new insight on the role of KRAS and BRAF, not only as prognosis biomarkers, but also as first line standard chemotherapy response biomarkers in metastatic colorectal cancer.

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Section: Introductionmentioning

confidence: 99%

KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study

Garcia-Carbonero

Martínez‐Useros

et al. 2020

Cells

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“…Recently, molecular-targeted agents [17], such as cetuximab and panizumab [18], bevacizumab [19,20], regofenib [21] , remoluzumab [22,23] and RTKs [24,25] have been used clinically in the treatment of CRC. However, little research has been done on multidrug-resistant cells in colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

Anlotinib overcomes multiple drug resistant of the colorectal cancer cells via inactivating PI3K/AKT pathway

Lan

Zhao

Shang

et al. 2019

Preprint

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Background: Anlotinib is a multi-tyrosine kinase inhibitor that has been reported to have activity against colorectal cancer. However, the functional mechanisms whereby anlotinib mediates against deadly drug-resistant colorectal cancer (CRC) has not been fully describedspecifically, the potential mechanisms that inhibit proliferation and induce apoptosis remain largely unknown. Methods:MTT assays were used to detect cell viability and calculate the resistance index. Colony formation was used to evaluate the proliferation of resistant cells. DAPI staining was used to detect cell apoptosis morphologically. Annexin V-FITC with PI staining was used to detect early and late-stage apoptosis of cells. Cell cycle distribution was determined by Flow cytometry. Transwell assays were performed to examine the ability of migration and invasion. Cyclin D1 Survivin, CDK4, Bcl-2, Bax and changes of PI3K/AKT pathway were detected by Western blotting. Compared as a single agent or combined with anlotinib or LY294002, PI3K inhibitor (LY294002) was used to verify whether it inhibited drug-resistant CRC cells by lowering PI3K/AKT. Results: HCT-8/5-FU cells showed multiple drug resistance. Drug resistance index of 5-FU, ADM and DDP were 390.27, 2.55 and 4.57, respectively. Anlotinib was shown to inhibit cell viability on HCT-8/5-FU and HCT-8 cells for 24 h and 48 h in a dosage-and time-dependent pattern. Compared with 48 h, intervened with anlotinib (0 μM, 10 μM, 20 μM and 40 μM) for 24 h, the HCT-8/5-FU cells were sensitive to anlotinib, and their sensitivity was greater than that of the parent cell line (HCT-8) at 24 h. Further, anlotinib inhibited the number of cloned cells significantly and had a significant inhibitory effect on cell cycle, mainly by blocking G1 transferring to S phase. Moreover, anlotinib could down-regulate the expression of survivin, cyclin D1, CDK4, caspase-3, Bcl-2, MMP-2, vimentin, MMP-9, and N-cadherin, while up-regulating cleaved-caspase-3, Bax and E-cadherin. Anlotinib inhibited the activity of the PI3K/AKT pathway and induced apoptosis in HCT-8/5-FU cells. Using LY294002, a specific PI3K inhibitor, our experiment found anlotinib can inhibit drug-resistant CRC cells by reducing PI3K and p-AKT activity-induce apoptosis.Conclusions: Anlotinib inhibited the proliferation , metastasis and induced apoptosis of HCT-8 / 5-FU cells ; and the mechanism could be that anlotinib overcomes multiple drug resistant of the colorectal cancer cells via inactivating PI3K/AKT pathway .

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“…Re-challenge chemotherapy is defined as the re-introduction of previously used chemotherapy with oxaliplatin or irinotecan-based regimens at least 9 months after the end of the initial exposure. Re-challenge chemotherapy constitutes an important option in patients who still present with good performance status and organ function reserve, especially in those in whom the initial chemotherapy was discontinued before progression of the disease (e.g., due to cumulative toxicities) [63][64][65]. Such approach did not shorten the period of the best supportive care and, more importantly, might prolong OS [65].…”

Section: Re-challenge Chemotherapymentioning

confidence: 99%

“…Such approach did not shorten the period of the best supportive care and, more importantly, might prolong OS [65]. According to Chambers et al, clinical benefit rate (defined as the proportion of patients with partial response or stable disease) after re-challenge chemotherapy was 75.5% and time to progression equaled 6.5 months [63]. Moreover, re-challenge chemotherapy after regorafenib treatment seems to be a good strategy in heavily pretreated patients with metastatic colorectal cancer.…”

Section: Re-challenge Chemotherapymentioning

confidence: 99%

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Further Therapeutic Options in Heavily Pretreated Colorectal Cancer Patients

Zygulska¹

2019

Multidisciplinary Approach for Colorectal Cancer

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In this paper, currently available systemic treatment options (regorafenib, trifluridine/tipiracil, re-challenge chemotherapy, mitomycin C plus capecitabine) for pretreated patients with metastatic colorectal cancer are discussed and compared in terms of their efficacy and safety profiles. Treatment of these patients has remained a challenge for oncologists. The evidence from clinical trials is encouraging. Knowledge of response biomarkers and/or prognostic factors may be helpful in the identification of patients who could benefit most from the treatment. Adequate medication compliance can be achieved due to awareness of toxicity risk among both physicians and cancer patients and appropriate prevention and management of adverse events.

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Chemotherapy re-challenge response rate in metastatic colorectal cancer

Abstract: Oxaliplatin or irinotecan-based re-challenge should be considered as a third or fourth line treatment option in select patients with mCRC. CBR and especially TTP compare favorably to approved third line therapies such as regorafenib or trifluridine-tipiracil.

Cited by 15 publications

References 22 publications

KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study

KRAS and BRAF Mutations as Prognostic and Predictive Biomarkers for Standard Chemotherapy Response in Metastatic Colorectal Cancer: A Single Institutional Study

Anlotinib overcomes multiple drug resistant of the colorectal cancer cells via inactivating PI3K/AKT pathway

Further Therapeutic Options in Heavily Pretreated Colorectal Cancer Patients

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