The impact of APC mutation on the efficacy of anti-EGFR therapy in metastatic colorectal cancer with RAS wild type: a retrospective analysis

Abstract

Background:

Anti-epidermal growth factor receptor (EGFR) therapies including cetuximab are a key component of treatment for metastatic colorectal cancer (CRC) with Rat Sarcoma viral oncogene homolog (RAS) wild-type status. However, predictive biomarkers for anti-EGFR therapy beyond RAS status remain controversial. The Wnt signaling pathway, which is essential for embryonic development, becomes frequently dysregulated in the presence of APC mutations.

Objectives:

To evaluate the impact of APC mutation status on survival outcomes in patients with RAS wild-type CRC treated with cetuximab-containing chemotherapy

Design:

Single-center retrospective analysis

Methods:

We retrospectively analyzed patients with RAS wild-type metastatic CRC who received first-line cetuximab plus chemotherapy at Samsung Medical Center between February 2021 and June 2024. The status of the APC mutation was determined by next-generation sequencing (NGS). We evaluated the impact of APC mutation on the treatment of cetuximab-containing chemotherapy.

Results:

Among 104 RAS wild metastatic CRC patients with cetuximab-containing chemotherapy as first-line therapy, 75 (72%) had APC-mutant tumors and 29 (28%) had APC wild. The presence of liver metastases and primary tumor locations was significantly different between patients with APC mutation and wild type. No complete responses were observed, and partial response was achieved in 64 patients with APC-mutated tumors (85%) and 17 patients with APC wild type tumors (59%). There was a significant difference in the objective response rate (ORR) between patients with APC mutation and wild type (p-value of 0.003). The disease control rate (DCR) was 89.7% for patients with APC wild type and 97.3% for the APC-mutant group. The median OS was not reached (95% CI, 31.5–NA) in patients with the APC mutation, whereas it was 37.3 months (95% CI, 23.4–NA) in those with APC-wild type tumors (p = 0.024).

Conclusion:

This study showed that the status of APC mutation may be associated with clinical outcomes in patients receiving cetuximab-containing chemotherapy in RAS wild metastatic CRC. Further prospective studies are warranted to validate and incorporate APC mutation into clinical decision-making algorithms.

Plain language summary

How APC gene status influences response to cetuximab in RAS wild-type metastatic colorectal cancer

This study looked at whether a specific gene change (called an APC mutation) affects how well a common cancer drug works in patients with advanced colorectal cancer that has spread to other parts of the body. Cetuximab is a targeted therapy used as a first-line treatment for metastatic colorectal cancer in patients whose tumors do not have RAS gene mutations. While cetuximab helps many patients, not everyone responds equally, and researchers are working to find markers that can predict who will benefit most. The researchers reviewed records of 104 patients treated at Samsung Medical Center in Seoul, Korea, between 2021 and 2024. All patients had RAS wild-type metastatic colorectal cancer and received cetuximab-based chemotherapy as their first treatment. Using genetic testing, they found that 75 patients (72%) had APC-mutated tumors and 29 (28%) had APC wild-type tumors. Key findings showed that patients with APC mutations had a significantly higher tumor response rate (85% vs. 59%) and longer overall survival compared to those without APC mutations. When looking at subgroups, the survival benefit of APC mutation was especially striking in patients without liver metastasis, where APC-mutated tumors showed significantly better progression-free and overall survival. The study suggests that APC mutation status could serve as a useful marker to help predict which patients will respond better to cetuximab-based treatment. However, since this was a single-center retrospective study with a relatively small number of patients, larger prospective studies are needed to confirm these findings.

Keywords

adenomatous polyposis coli anti-EGFR therapy cetuximab chemotherapy colorectal cancer

Introduction

Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer and the second leading cause of cancer-related deaths.¹ Approximately 20%–25% of patients with CRC present with metastatic disease at diagnosis,² and 20%–30% of those initially diagnosed with localized disease eventually experienced a recurrence, necessitating palliative systemic therapy.³ Cetuximab, an immunoglobulin G1 monoclonal antibody against Epidermal Growth Factor Receptor (EGFR), is one of the targeted agents used in the treatment of metastatic CRC.⁴ Cetuximab binds to EGFR and acts by suppressing cancer cell proliferation, promoting cell apoptosis, and reducing matrix metalloproteinases production.⁵ The clinical efficacy of cetuximab has been established through pivotal clinical trials, supporting its incorporation into first-line treatment regimens in combination with 5-Fluorouracil with oxaliplatin (FOLFOX) or 5-fluorouracil with irinotecan (FOLFIRI), specifically in patients with left-sided colorectal tumors and confirmed RAS wild-type status.^6–8

Extensive efforts have been made to identify patient subgroups that derive maximal benefit from cetuximab. Since its initial clinical application, reduced efficacy has been observed in tumors harboring activating mutations in the RAS pathway and in those originating from the right side of the colon.^4,6,8 EGFR functions as a membrane-bound receptor tyrosine kinase, initiating downstream signaling pathways such as the RAS-RAF-MEK-ERK cascade. Activating mutations in RAS, particularly in KRAS or NRAS, lead to constitutive activation of this pathway independent of EGFR, rendering anti-EGFR monoclonal antibodies ineffective.⁹ Similarly, tumors harboring BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutations, a downstream effector of the MAPK signaling pathway, also show limited responsiveness to anti-EGFR therapy.¹⁰ As a result, cetuximab is generally not recommended in these settings, with anti-vascular endothelial growth factor (VEGF) antibodies preferentially combined with 5-fluorouracil (5-FU) based chemotherapy. Beyond these established factors, ongoing research has focused on identifying additional biomarkers predictive of optimal response to anti-EGFR antibody therapy.¹¹ However, predictive biomarkers for anti-EGFR therapy remain limited.

Mutations in the APC gene play a pivotal role in the early stages of colorectal tumorigenesis and are detected in approximately 80% of sporadic CRC cases.¹² Also, germline pathogenic mutations in APC are also responsible for familial adenomatous polyposis (FAP). The Wnt signaling pathway, which is essential for embryonic development, becomes dysregulated in the presence of APC mutations. These mutations typically result in premature truncation of the APC protein, leading to impaired regulation of β-catenin. This dysregulation promotes nuclear accumulation of β-catenin and alters T-cell factor 4 (TCF-4) mediated transcriptional activity, ultimately driving the proliferation of intestinal crypt epithelial cells and contributing to tumorigenesis.¹³ Previous studies in vitro have shown that cetuximab suppresses the Wnt/β-catenin pathway by reducing β-catenin nuclear localization and modulating downstream effectors like Phospholipase C Beta3 (PLCB3). PLCB3 is involved in intracellular phosphoinositide signaling and has been implicated in the regulation of Wnt signaling activity. These findings raise the possibility that APC mutation may potentially influence the response to anti-EGFR therapy.¹⁴

Herein, we intended to evaluate the impact of APC mutation on the treatment of cetuximab-containing chemotherapy in CRC patients with RAS wild type.

Methods

Study participants

This retrospective study included patients aged 18 years or older with histologically confirmed metastatic CRC and RAS wild-type status. The study population consisted of patients who received cetuximab plus FOLFIRI or FOLFOX as first-line therapy at Samsung Medical Center from February 2021 to June 2024. A key inclusion criteria was the availability of comprehensive genomic profiling via next-generation Sequencing (NGS) to evaluate APC and other relevant molecular alterations. NGS testing was performed as part of routine clinical practice, and results were used to guide treatment decisions. Patients were excluded if they had insufficient electronic medical record (EMR) data to assess treatment response or survival outcomes or had hereditary polyposis syndrome. Demographic information was extracted from EMR when the first-line treatment was initiated, and patient age, sex, Eastern Cooperative Oncology Group performance status (ECOG PS), tumor location, initial metastasis site and other mutation status of KRAS, BRAF and HER2 IHC were reviewed. The aberration of APC, KRAS, BRAF, tumor mutational burden (TMB) and MSI status were evaluated using an NGS with the TruSight Oncology 500 assay (Illumina, San Diego, CA, USA).

The reporting of this study conforms to the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement¹⁵ (Supplemental Material).

Next-generation sequencing

Tumor samples were obtained at the time of initial diagnosis or progression, and formalin-fixed paraffin-embedded (FFPE) material was used. The Qubit dsDNA HS Assay (Thermo Fisher Scientific) on the Qubit 2.0 Fluorometer (Thermo Fisher Scientific) was used to quantify the 40 ng of DNA. The Covaris E220 Focused-ultrasonicator (Woburn, MA, USA) and the eight microTUBE–50 Strip AFA Fiber V2 were used for shearing. The treatment time was optimized for FFPE material, and the treatment settings were as follows: peak incident power (W): 75; duty factor: 15%; cycles per burst: 500; treatment time (s): 360; temperature (°C): 7; water level: 6. We used the TruSight™ Oncology 500 Kit (Illumina) for DNA library preparation and enrichment, following the manufacturer’s instructions. The post-enriched libraries were quantified, pooled, and sequenced on a NextSeq 500 (Illumina Inc., San Diego, CA, USA). The quality of the NextSeq 500 (Illumina) sequencing runs was assessed with the Illumina sequencing Analysis Viewer (Illumina). TruSight Oncology 500 Local App Version 1.3.0.39 (Illumina) was used to analyze the sequencing data. The TruSight™ Oncology 500 is a comprehensive tumor profiling assay designed to identify various tumor biomarkers, including small variants, splice variants, and fusions.

Statistical analysis

Categorical and continuous variables were summarized using descriptive statistics. Response rate (RR) was calculated as the percentage of patients experiencing a confirmed complete response (CR) or partial response (PR), and disease control rate (DCR) was calculated as RR or stable disease (SD), as per the RECIST 1.1 guidelines. The progression-free survival (PFS) was defined as the time from cetuximab plus chemotherapy to documentation of either disease progression or death. Overall survival was defined as the time from initiation of cetuximab plus chemotherapy to death from any cause. Patients with no event at the data cutoff date were censored on the last date of follow-up. Survival curves were calculated using the Kaplan–Meier method and compared using the log-rank test and Cox proportional hazards regression model. Additionally, subgroup analyses were performed according to the presence of liver metastasis to evaluate potential differences in PFS and overall survival between groups.

All p values were two-sided, and p < 0.05 was statistically significant. All statistical analyses were performed using IBM SPSS Statistics 27 and R version 4.4.1.

Results

Patient characteristics

Between February 2021 and June 2024, a total of 168 patients received cetuximab plus chemotherapy as first-line therapy. Among them, NGS data were available for 104 patients to assess APC mutation status. In 104 patients, 75 (72%) had APC-mutant tumors and 29 (28%) had APC wild type. Table 1 summarizes the baseline characteristics of the patients. All patients had a tumor with a microsatellite stable (MSS) type. TMB-high tumors were observed in 6 patients (17%) in the APC wild-type group and 10 patients (13%) in the APC-mutant group. 58 patients (77%) and 22 patients (76%) were male in patients with APC-mutant and APC-wild-type tumors, respectively. There was no difference in most clinical characteristics between patients with APC mutants and wild-type tumors. However, the presence of liver metastases and primary tumor locations is significantly different between patients with APC mutation and wild type. Liver metastases were observed in 58 patients (77.3%) with the APC mutation, compared to 14 (48.3%) with the APC wild type. Also, the right-sided tumor was more prevalent in patients with the APC wild-type, with eight patients (28%). Patients who underwent local therapies for oligometastatic disease, including surgical resection of metastatic lesions, were not excluded from the analysis. All patients were negative for the BRAF V600E mutation. During the course of treatment, 54 patients underwent local treatment including surgical resection or radiofrequency ablation (RFA). The proportion of patients who received local treatment was not significantly different between the APC mutated and APC wild-type group (56% vs 41%, p = 0.18)

Table 1.

Baseline patient characteristics.

Characteristics	APC wild (N = 29)	APC mutated (N = 75)	p-Value
Mean age (range)	56 (25–77)	59 (25–88)	0.30
Sex			1.00
Male	22 (76%)	58 (77%)
Female	7 (24%)	17 (23%)
ECOG performance status			0.46
0	14 (48%)	44 (59%)
1	15 (52%)	31 (41%)
Tumor location			0.001
Rt. Colon	8 (28%)	4 (5%)
Lt. Colon	11 (38%)	31 (41%)
Rectum	8 (28%)	40 (53%)
Unknown	2 (7%)	0 (0%)
Histology			0.02
Adenocarcinoma	26 (90%)	75 (100%)
Others	3 (10%)
Initial metastasis			0.15
Post-operative recurrence	9 (31%)	12 (16%)
Initially advanced	20 (69%)	63 (84%)
Local treatment			0.18
Operation & RFA	12 (41%)	42 (56%)
Baseline metastasis site
Distant lymph node	15 (52%)	34 (45%)	0.71
Liver	14 (48%)	58 (77%)	0.008
Peritoneum	11 (38%)	14 (19%)	0.07
Lung	4 (14%)	11 (15%)	1.00
Bone	2 (7%)	3 (4%)	0.61
Others	9 (31%)	12 (16%)	0.10
Tumor mutation burden
TMB-high	6 (21%)	10 (13%)	0.37

Independent t-test for continuous variables and Chi-square test or †Fisher’s exact test for categorical variables.

ECOG, eastern cooperative oncology group; RFA, radiofrequency ablation; SD, standard deviation; TMB, tumor mutational burden.

Treatment outcomes according to the status of APC mutation

There was no CR in patients with APC mutation and wild type, and PR was achieved in 64 patients with APC mutation (85.3%) and 17 in APC wild type (58.6%). There was a significant difference in the objective response rate (ORR) between patients with APC mutation and wild type (85% vs 59%, p-value of 0.003; Table 2). The median PFS was 20.9 months (95% CI, 14.5–NA) in patients with APC mutation and 11.0 months (95% CI, 8.7–NA) with APC wild type (Figure 1). Patients with APC mutation showed a favorable trend in PFS as compared to those with APC wild-type (HR 0.72, 95% CI, 0.40–1.30). The median OS was not reached (95% CI, 31.5–NA) in patients with the APC mutation, whereas it was 37.3 months (95% CI, 23.4–NA) in those with APC-wild type tumors (Table 3), showing a significant difference between the groups (HR 0.41, 95% CI 0.19–0.91, p = 0.024; Figure 2). The median follow-up duration was 22.2 months (95% CI, 20.6–27.9) in the APC mutated group and 21.1 months (95% CI, 19.6–36.7) in the APC wild type group.

Table 2.

Tumor response.

Treatment response	APC wild	APC mutated
Complete response	0	0
Partial response	17 (58.6%)	64 (85.3%)
Stable disease	9 (31.0%)	9 (12%)
Progressive disease	3 (10.3%)	2 (2.7%)
Objective response rate (95% CI)	58.6% (40.7–74.9)	85.3% (75.6–92.2)
Disease control rate (95% CI)	89.7% (73.0–97.9)	97.3% (90.5–99.7)

Figure 1.

Kaplan–Meier curve of progression-free survival according to APC mutation status.

Table 3.

Survival outcomes according to APC mutation status.

Outcomes	APC wild (N = 29)	APC mutated (N = 75)
Median progression-free survival	11.0 (95% CI, 8.7–NA)	20.9 (95% CI, 14.5–NA)
	0.72 (95% CI, 0.40–1.30, p = 0.27
Median overall survival	37.3 (95% CI, 23.4–NA)	NR (95% CI, 31.5–NA)
	0.41 (95% CI, 0.19–0.91, p = 0.024)

Figure 2.

Kaplan–Meier curve of overall survival according to APC mutation status.

Subsequent treatment after progression on cetuximab plus chemotherapy

Among 29 patients with APC wild-type, 16 (55%) patients experienced disease progression. Of these patients, nine received subsequent treatment with FOLFOX plus bevacizumab, while three patients did not receive further therapy due to deterioration of performance status. In patients with the APC mutation, disease progression was observed in 36 (48%) patients. Consistent with patients with APC wild type, most patients (n = 29) were treated with FOLFOX plus bevacizumab (Table 4).

Table 4.

Subsequent treatment pattern after progression.

Treatment pattern	APC wild (N = 29)	APC mutated (N = 75)
Disease progression	16 (55%)	36 (48%)
Subsequent treatment
FOLFOX + Bevacizumab	9 (31%)	29 (39%)
Other chemotherapy	4 (14%)	4 (5%)
No further treatment	3 (10%)	3 (4%)

Subgroup analysis according to liver metastasis and left side CRC

In the subgroup analysis according to the presence of liver metastasis, no significant difference in PFS was observed between APC-mutant and APC wild-type tumors among patients with liver metastasis (72 patients; HR 2.14, 95% CI 0.75–6.07, p = 0.14). Similarly, there was no significant difference in overall survival between the two groups in this subgroup (HR 0.91, 95% CI 0.26–3.19, p = 0.88; Figure 3).

Figure 3.

Kaplan–Meier curves of progression-free survival and overall survival in patients with hepatic metastasis.

In contrast, among patients without liver metastasis (32 patients), APC-mutant tumors demonstrated significantly improved PFS compared with APC wild-type tumors (HR 0.20, 95% CI 0.06–0.64, p = 0.0027). For overall survival, no deaths were observed in the APC-mutant group, consequently showing significant difference between the groups (p = 0.00088; Figure 4).

Figure 4.

Kaplan–Meier curves of progression-free survival and overall survival in patients without hepatic metastasis.

Further analysis was performed according to primary tumor location. Due to the limited number of patients with right-sided tumors (n = 12), the analysis focused exclusively on patients with left side tumors.

Among patients with left side tumors, no significant difference in PFS was observed between the APC-mutant group and the APC wild-type group. The median PFS showed no statistically significant correlation with APC mutation status (HR 0.95, 95% CI 0.47–1.93, p = 0.89). Similarly, for overall survival, although the APC-mutated group showed a numerically lower hazard ratio, it did not reach statistical significance in this subgroup (HR 0.59, 95% CI 0.23–1.56, p = 0.28; Figure 5).

Figure 5.

Kaplan–Meier curves of progression-free survival and overall survival of patients with left side colorectal cancer.

Discussion

This study evaluated the treatment outcome of cetuximab plus chemotherapy as the first line according to the status of APC mutation, to assess the potential of APC mutation status as a prognostic factor for cetuximab-containing therapies. There was a significant difference in the ORR between patients with APC mutation and wild type (85% vs 59%, p-value of 0.003). Patients with APC wild type exhibited a median PFS of 11.0 months (95% CI 8.7–NA) and a median OS of 37.3 months (95% CI 23.4–NA). While the difference in PFS between patients with APC mutation and wild type did not reach statistical significance, a favorable trend was observed in the APC-mutant tumors. The median OS was not reached (95% CI, 31.5–NA) in patients with the APC mutation, compared to those with APC wild type, 37.3 months (95% CI, 23.4–NA), with a statistically significant difference (p = 0.024)

These findings suggested that APC mutation may be associated with clinical outcomes in patients receiving cetuximab-containing chemotherapy. Furthermore, APC-mutant tumors frequently harbor distinct co-occurring genomic alterations that may influence signaling networks relevant to therapeutic response.^16,17 Recent studies have suggested that specific mutation combinations, particularly involving APC and TP53 may be associated with sensitivity to EGFR inhibitor therapy which may provide a potential biological basis for the improved response observed in APC-mutant tumors in our cohort.¹⁸

In prior pivotal trials, such as the CRYSTAL study, the combination of FOLFIRI and cetuximab yielded a median PFS of 8.9 months and a median OS of 19.9 months. Similarly, the FIRE-3 study reported a median PFS of 10.0 months and a median OS of 28.7 months in patients treated with the same regimen.^8,19 The favorable survival outcomes observed in our study may be attributable to a more proactive and precision-based approach at our institution, including a greater emphasis on surgical resection where feasible and molecularly hyper-selection using NGS result. Molecular hyper-selection is a strategy to refine patient candidate by excluding rare genomic alterations, that trigger bypass signaling pathways and cause primary resistance to anti-EGFR therapy. The clinical utility of this approach was shown in PRESSING study, showing superior median PFS of 6.3 months compared to 2.7 months in patient with any such alterations.²⁰

The cetuximab plus chemotherapy is considered as standard first-line treatment for patients with RAS wild-type, left-sided CRC.⁴ While extensive research has been conducted to identify other predictive biomarkers for cetuximab efficacy, a clinically effective biomarker beyond RAS wild-type status remains elusive.²¹ The findings of our study suggested that anti EGFR therapy such as cetuximab may be better option in patients with RAS wild type and APC mutation as combinational partner with cytotoxic chemotherapy. Alternatively, incorporation of APC mutation status and other genomic profiles into clinical decision-making may facilitate the selection of the most optimal first-line treatment strategy tailored to individual patients.

This study has several limitations. First, it was retrospective in nature with a clinically heterogeneous population subject to potential bias. In addition, this was a single-center study, which may limit the generalizability of the findings. Second, the study included a relatively small number of patients, making it difficult to draw definite conclusions regarding genomic biomarkers. Moreover, differences in baseline characteristics of patients between the APC wild-type and APC mutation may have introduced additional confounding factors. Finally, while this study focused exclusively on the association between APC mutation status and survival outcomes, previous research has indicated that other genomic alterations, such as TP53 and SMAD4 mutations, may also influence the therapeutic efficacy of cetuximab.^22,23 These factors were not included in the present analysis of treatment outcomes with cetuximab plus chemotherapy. However, due to a too small sample size, the effect of other genomic alterations could not be concluded. Lastly, although multivariable Cox analysis was considered to adjust for potential confounders, it was not included in the report due to numerical instability. Therefore, our results should be interpreted with caution, and further validation in larger, prospective cohorts is required.

Nevertheless, this study showed that the status of APC mutation may serve as a novel biomarker for the treatment of cetuximab-containing chemotherapy in RAS wild metastatic CRC. Further prospective studies are warranted to validate and incorporate the APC mutation into clinical decision-making algorithms.

Conclusion

In this retrospective analysis of patients with RAS wild-type advanced CRC, APC mutation was associated with improved ORR and overall survival in patients treated with first-line cetuximab with cytotoxic chemotherapy. These results suggest that APC mutation status may represent a prognostic marker for anti-EGFR therapy, warranting further prospective trials.

Supplemental Material

sj-docx-1-tam-10.1177_17588359261446799 – Supplemental material for The impact of APC mutation on the efficacy of anti-EGFR therapy in metastatic colorectal cancer with RAS wild type: a retrospective analysis

Supplemental material, sj-docx-1-tam-10.1177_17588359261446799 for The impact of APC mutation on the efficacy of anti-EGFR therapy in metastatic colorectal cancer with RAS wild type: a retrospective analysis by Junkyu Kim, Changgon Kim, Ji Eun Shin, Sung Hee Lim and Seung Tae Kim in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Junkyu Kim

Changgon Kim

Supplemental material

Supplemental material for this article is available online.

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