HER2 Expression Is Predictive of Survival in Cetuximab Treated Patients with RAS Wild Type Metastatic Colorectal Cancer

Khelwatty, Said Abdullah; Puvanenthiran, Soozana; Essapen, Sharadah; Bagwan, Izhar; Seddon, Alan M.; Modjtahedi, Helmout

doi:10.3390/cancers13040638

Cited by 10 publications

(10 citation statements)

References 52 publications

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“…Moreover, KRAS is the most common form of mutated oncogene in cancer, and the frequency of KRAS mutations is particularly high in colorectal, pancreatic, and lung cancers [ 24 – 26 ]. Cetuximab, an EGFR-targeting agent, is a standard treatment for KRAS wild-type mCRC [ 27 ]. KRAS mutant CRC cells have been reported that it could promote tumour progression and induce resistance to cetuximab therapy [ 28 ]; however, there is no effective treatment to specifically treat cancers expressing KRAS mutations [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer

et al. 2021

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Cetuximab is approved for the treatment of metastatic colorectal cancer (mCRC) with RAS wild-type. Nevertheless, the prognosis remains poor and the effectiveness of cetuximab is limited in KRAS mutant mCRC. Recently, emerging evidence has shown that ferroptosis, a newly discovered form of nonapoptotic cell death, is closely related to KRAS mutant cells. Here, we further investigated whether cetuximab-mediated regulation of p38/Nrf2/HO-1 promotes RSL3-induced ferroptosis and plays a pivotal role in overcoming drug resistance in KRAS mutant colorectal cancer (CRC). In our research, we used two KRAS mutant CRC cell lines, HCT116 and DLD-1, as models of intrinsic resistance to cetuximab. The viability of cells treated with the combination of RSL3 and cetuximab was assessed by the CCK-8 and colony formation assays. The effective of cetuximab to promote RSL3-induced ferroptosis was investigated by evaluating lipid reactive oxygen species accumulation and the expression of the malondialdehyde and the intracellular iron assay. Cetuximab therapy contributed to regulating the p38/Nrf2/HO-1 axis, as determined by western blotting and transfection with small interfering RNAs. Cetuximab promoted RSL3-induced ferroptosis by inhibiting the Nrf2/HO-1 in KRAS mutant CRC cells, and this was further demonstrated in a xenograft nude mouse model. Our work reveals that cetuximab enhances the cytotoxic effect of RSL3 on KRAS mutant CRC cells and that cetuximab enhances RSL3-induced ferroptosis by inhibiting the Nrf2/HO-1 axis through the activation of p38 MAPK.

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Section: Discussionmentioning

confidence: 99%

Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer

et al. 2021

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“… d Assumed from KM curve follow-up. e The HR for OS in Khelwatty et al 29 was inconsistent, the lower CI was higher than HR value (HR, 0.21 [95% CI, 0.62-0.73]), and it was excluded from the OS analysis. Study authors were contacted to clarify the data but no response was received.…”

Section: Resultsmentioning

confidence: 99%

“…Some heterogeneity in the HER2 detection method and HER2-positivity criteria utilized in each study was identified. All patients received anti-EGFR treatment, either as monotherapy or in combination with standard chemotherapy, and with the exception of Khelwatty et al, 29 across different lines of therapy ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Impact of Anti-EGFR Therapies on HER2-Positive Metastatic Colorectal Cancer: A Systematic Literature Review and Meta-Analysis of Clinical Outcomes

Bekaii‐Saab

Lach²,

Hsu

et al. 2023

The Oncologist

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Background HER2 overexpression/amplification in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) may be associated with resistance to standard-of-care anti-EGFR therapies. Given the lack of comprehensive investigations into this association, we assessed the prognostic or predictive effect of HER2 amplification/overexpression on anti-EGFR treatment outcomes. Methods A systematic review of MEDLINE, Embase, and Cochrane Library (2001-2021) identified studies evaluating progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) in HER2-positive vs. HER2-negative patients with RAS WT mCRC who received anti-EGFR treatments and whose HER2 status was known. Meta-analyses of proportions (ORR) and hazard ratios (PFS, OS) were performed using random-effect models with pre-specified sensitivity analyses. Results Five high-quality retrospective cohort studies were included in the meta-analyses representing 594 patients with mCRC. All patients received anti-EGFR treatment, either as monotherapy or in combination with chemotherapy. Meta-analysis of PFS demonstrated a 2.84-fold higher risk of death or progression (95% CI, 1.44-5.60) in patients with HER2-positive (vs. HER2-negative) RAS WT mCRC treated with anti-EGFR regimens. The odds of response to anti-EGFR treatment were 2-fold higher in HER2-negative vs. HER2-positive (odds ratio, 1.96 [95% CI, 1.10-3.48]). Differences in OS were not statistically significant. Sensitivity analyses confirmed the robustness of the base-case estimates. Conclusions While this study could not account for all confounding factors, in patients with RAS WT mCRC who received anti-EGFR therapy, HER2 overexpression/amplification was associated with worse PFS and ORR and may therefore predict poorer outcomes. HER2 testing is important to inform treatment decisions and could optimize outcomes for patients.

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“…This result might be the consequence of biological characteristics not measured in the clinical practice in RAS/BRAF wild-type patients, such as APC mutations, which confer worse prognoses more frequently found in EOCRC [27]. Other alterations are known to be bad prognostic factors in the RAS/BRAF wild type, but to our knowledge, they have not been described as being more prevalent in EOCRC patients, such as PIK3CA mutations (a known negative predictor of response to EGFR inhibitors in RAS wild-type tumors [28]) and HER2 status (its expression in the membrane of the tumor cells is associated with a shorter progression-free survival (PFS) to EGFR inhibitors) [29]. Whether ultraselection of RAS/BRAF wild-type patients is the key to improving prognosis in this population is yet to be determined [30,31].…”

Section: Discussionmentioning

confidence: 99%

Clinico-Pathological Features, Outcomes and Impacts of COVID-19 Pandemic on Patients with Early-Onset Colorectal Cancer: A Single-Institution Experience

Martinez-Perez,

Viñal,

Peña-Lopez

et al. 2023

Cancers

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Background: The rising incidence of colorectal cancer (CRC) among young patients is alarming. We aim to characterize the clinico-pathological features and outcomes of patients with early-onset CRC (EOCRC), as well as the impacts of COVID-19 pandemic. Methods: We included all patients with pathologically confirmed diagnoses of CRC at Hospital Universitario La Paz from October 2016 to December 2021. The EOCRC cut-off age was 50 years old. Results: A total of 1475 patients diagnosed with CRC were included, eighty (5.4%) of whom had EOCRC. Significant differences were found between EOCRC and later-onset patients regarding T, N stage and metastatic presentation at diagnosis; perineural invasion; tumor budding; high-grade tumors; and signet ring cell histology, with all issues having higher prevalence in the early-onset group. More EOCRC patients had the RAS/ BRAF wild type. Chemotherapy was administered more frequently to patients with EOCRC. In the metastatic setting, the EOCRC group presented a significantly longer median OS. Regarding the COVID-19 pandemic, more patients with COVID-19 were diagnosed with metastatic disease (61%) in the year after the lockdown (14 March 2020) than in the pre-pandemic EOCRC group (29%). Conclusions: EOCRC is diagnosed at a more advanced stage and with worse survival features in localized patients. More patients with EOCRC were diagnosed with metastatic disease in the year after the COVID-19 pandemic lockdown. The long-term consequences of COVID-19 are yet to be determined.

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HER2 Expression Is Predictive of Survival in Cetuximab Treated Patients with RAS Wild Type Metastatic Colorectal Cancer

Cited by 10 publications

References 52 publications

Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer

Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer

Impact of Anti-EGFR Therapies on HER2-Positive Metastatic Colorectal Cancer: A Systematic Literature Review and Meta-Analysis of Clinical Outcomes

Clinico-Pathological Features, Outcomes and Impacts of COVID-19 Pandemic on Patients with Early-Onset Colorectal Cancer: A Single-Institution Experience

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