Abstract
Introduction
Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is a target of antibody-drug conjugate therapy for NSCLC. High expression of CEACAM5 has been reported in approximately 25% of patients with lung adenocarcinoma. However, CEACAM5 expression has not been systematically examined in a real-world and large patient population with NSCLC. There are also limited data on the prognostic impact of CEACAM5 protein expression.
Methods
We assessed CEACAM5 protein expression by immunohistochemistry in two separate cohorts of patients with NSCLC to include both routine clinical biopsy and resection specimens, using the anti-CEACAM5 clone 769 antibody assay protocol and scoring scheme for the tusamitamab ravtansine clinical trials. Expression levels were categorized as high (≥50% tumor cells at ≥2+ intensity), moderate (1%–49% tumor cells at ≥2+ intensity), and negative (0/1+ intensity) and scored independently by three thoracic pathologists. Interrater reliability was determined by Kendall’s coefficient of concordance and Fleiss’ kappa. Association with PD-L1 and driver mutation was calculated by Fisher exact or chi-square test. Correlation with recurrence-free survival and overall survival was determined by log-rank tests.
Results
The interrater reliability of CEACAM5 assessment was moderate among three pathologists. The overall prevalence of high CEACAM5 expression was 18%. CEACAM5 expression did not significantly correlate with tumor stage, PD-L1 expression, tumor mutation burden, and EGFR or KRAS mutations. There was no prognostic effect of CEACAM5 expression on recurrence-free survival or overall survival.
Conclusions
Our data revealed that 18% of routinely diagnosed clinical NSCLC samples had high CEACAM5 expression by immunohistochemistry, and its expression was not associated with oncogenic driver mutations or patient prognosis in a predominantly early stage NSCLC cohort.
Keywords: CEACAM5, Biomarker, Antibody-drug conjugate, Lung cancer, Prognostic marker
Introduction
There are limited therapeutic options for patients with NSCLC that lack targetable oncogenic drivers or refractory to first-line immune checkpoint inhibitors with or without chemotherapies. However, novel systemic therapies are emerging. The development of antibody-drug conjugate (ADC) is revolutionizing the delivery of systemic chemotherapies with favorable safety profile.1,2 ADC consists of an antibody to the target antigen and an attached cytotoxic payload, resulting in antitumor activity and bystander effect.
Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) has been selected as a potential target of ADC therapies for various cancers, including NSCLC.3 Interest in this antigen has resulted in recent and ongoing clinical trials.4,5 In addition, the efficacies of bispecific immunotherapy and chimeric antigen receptor T-cell therapy targeting CEACAM5-expressing NSCLC are under investigation.6, 7, 8, 9, 10
The oncogenic properties of CEACAM5 have been investigated for decades, as CEACAM5 overexpression is observed in various cancers, including NSCLC.11,12 CEACAM5 has been implicated in tumorigenesis, invasiveness, and metastasis.13, 14, 15, 16, 17, 18 CEACAM5 expression has also been associated with tumor stage or survival.19, 20, 21 Yet, the pathways associated with its expression are incompletely understood. High CEACAM5 expression has been reported in approximately 25% of lung adenocarcinoma.3 However, there have been few studies evaluating CEACAM5 protein expression systematically by immunohistochemistry (IHC) in a large patient population with NSCLC including both adenocarcinoma and squamous cell carcinoma. Furthermore, the reliability of a CEACAM5 scoring scheme as a predictive biomarker has not been assessed.
In this study, we have assessed the CEACAM5 protein expression by IHC in routinely diagnosed clinical biopsy and resection samples of NSCLC. We determined the interrater agreement of CEACAM5 expression scoring scheme and highlighted challenging areas of discordant classification. We further explored the association of CEACAM5 with routinely assessed lung cancer biomarkers and its prognostic effect in a large cohort of patients with resected NSCLC.
Materials and Methods
Patient Cohorts
The study included two non-overlapping patient cohorts. Cohort 1 consisted of patients who underwent diagnostic clinical biopsy or resection of consecutively diagnosed NSCLC from September 2022 to March 2024. Patients with samples insufficient for routine clinical biomarker testing (PD-L1 and targeted next-generation sequencing) were excluded. Clinical and biomarker testing data were obtained from chart review. Cohort 2 comprised a retrospective cohort of patients with NSCLC resection specimens from 2005 to 2012. Clinical data were obtained from chart review. The tumor stage was based on the eighth edition of TNM classification. This study has received approval by the University Health Network Research Ethics Board (CAPCR 22-5155).
Immunohistochemical Assays and CEACAM5 Scoring Scheme
We assessed the expression of CEACAM5 by IHC, using the anti-CEACAM5 clone 769 antibody assay protocol and scoring scheme developed for the tusamitamab ravtansine clinical trials.3 Expression levels were categorized as high (≥50% tumor cells at ≥2+ intensity), moderate (1%–49% tumor cells at ≥2+ intensity), and negative/weak (0 or 1+ intensity). Staining intensity scale was assessed as follows: 0 (no staining at any magnification), 1+ (faint staining at 20–40×), 2+ (moderate staining visible at 10–20×), and 3+ (strong staining visible at 2–5×). Positive membranous staining included both complete and incomplete or polarized membranous expression. CEACAM5 expression was scored independently by three thoracic pathologists (AAl, YRH, and MST). Discordant classification was reviewed at multiheaded microscope with the final classification achieved by consensus.
PD-L1 expression results in cohort 1 were obtained as a part of reflex lung cancer clinical biomarker testing using the PD-L1 22C3 pharmDx assay on the Dako Autostainer Link 48 platform (Agilent Dako, Santa Clara, CA). PD-L1 expression in cohort 2 was assessed (by AAz and LH) using a staining protocol with the Ventana SP263 rabbit monoclonal antibody (catalogue number 790-4905) on a BenchMark Discovery stainer (Roche Diagnostics, Tucson, AZ).22 PD-L1 expression is scored using the tumor proportion score (TPS).
Tumor Genomic Sequencing Data and Analysis
Targeted NGS was performed on formalin-fixed paraffin-embedded (FFPE) tumor samples of cohort 1. DNA and RNA were extracted from FFPE tumor tissue blocks and analyzed using the Oncomine Comprehensive Assay v3 (Thermo Fisher Scientific, Waltham, MA). The NGS results were obtained as a part of reflex lung cancer clinical biomarker testing.
For cohort 2, whole-exome sequencing was performed on available biobanked snap-frozen tumor samples. The raw paired-end sequence reads were aligned to the human reference genome (hg19) using Burrows-Wheeler Aligner (v.0.7.12).23 Further processing of the mapped reads was performed using the standard Genome Analysis Toolkit (GATK) pipeline (v.3.4).24 The single-nucleotide variant (SNV) calling was done using MuTect (v.1.0),25 and insertions/deletions (indels) were called using VarScan (v.2.3.8).26 The public cohorts such as dbSNP27 were used as filters for samples without matched normal tissue. ANNOVAR28 and Variant Effect Predictor (v.87)29 were used to annotate final mutation calls. The tumor mutation burden (TMB), defined as the number of exonic mutations per megabase, was calculated.
Whole transcriptome RNA sequencing was also performed on these tumor samples. STAR package was used to align the RNA reads in raw FASTQ files using human hg19 genome as reference and then STAR-Fusion was used to identify fusion transcripts.30
Statistical Analysis
We assessed the interrater reliability by Kendall’s coefficient of concordance (W) for the three categorical classifications of CEACAM5 and by Fleiss’ kappa (k) for the negative/weak/moderate versus high categorization. For both W and k, values of −1, 0, and 1 indicate perfect disagreement, no agreement, and perfect agreement, respectively. The level of agreement between 0 and 1 was categorized as substantial (0.80–1), moderate (0.60–0.79), weak (0.40–0.59), and minimal (<0.40).31
The association with PD-L1 TPS, TMB, and oncogenic driver mutations was determined by Fisher exact or chi-square test. Correlation with recurrence-free survival (RFS) and overall survival (OS) was determined by log-rank tests.
Results
Patient Characteristics
The entire study cohort (n = 600) enrolled two separate patient cohorts and consisted of cohort 1 (n = 206) and cohort 2 (n = 394). The patient demographics and tumor histologic types of the two cohorts are summarized in Table 1. The distributions of age and sex were similar between the two cohorts. In both cohorts, adenocarcinoma was the most common histology. In the overall cohort, 584 samples were derived from the primary and 16 samples were derived from metastatic sites. In cohort 2, most of the tumor represented resected stage I (54%) and stage 2 (26%) NSCLC.
Table 1.
Patient and Tumor Characteristics
| Factor | Overall (n = 600) | Cohort 1 (n = 206) | Cohort 2 (n = 394) |
|---|---|---|---|
| Age (y) | |||
| Mean (SD) | 68.4 (10.0) | 70.4 (9.3) | 67.3 (10.1) |
| Sex, n (%) | |||
| Female | 321 (54) | 111 (54) | 210 (53) |
| Male | 279 (47) | 95 (46) | 184 (47) |
| Specimen type, n (%) | |||
| Biopsy | 151 (25) | 151 (73) | 0 (0) |
| Resection | 449 (75) | 55 (27) | 394 (100) |
| Histology, n (%) | |||
| Adenocarcinoma | 475 (79) | 184 (89) | 291 (74) |
| Adenosquamous carcinoma | 2 (0) | 1 (0) | 1 (0) |
| Pleomorphic carcinoma | 9 (1) | 1 (0) | 8 (2) |
| Squamous cell carcinoma | 114 (19) | 20 (10) | 94 (24) |
| Tumor sample site, n (%) | |||
| Lung | 584 (97) | 190 (92) | 394 (100) |
| Metastasis | 16 (3) | 16 (8) | 0 (0) |
| Lymph node | 3 | 3 | 0 |
| Pleura | 4 | 4 | 0 |
| Liver | 2 | 2 | 0 |
| Bone and soft tissue | 3 | 3 | 0 |
| Brain | 4 | 4 | 0 |
| Stage group | |||
| 1 | n/a | n/a | 212 (54) |
| 2 | n/a | n/a | 103 (26) |
| 3 | n/a | n/a | 69 (18) |
| 4 | n/a | n/a | 10 (3) |
NA, not assessable.
CEACAM5 Immunohistochemistry
CEACAM5 expression was assessed by IHC in a total of 589 cases (Table 2). In cohort 2, 11 cases were excluded due to suboptimal tumor sections for evaluation. Both membranous and cytoplasmic CEACAM5 expression was observed in the neoplastic cells but was consistently absent in the nonneoplastic cells (Fig. 1A). Challenging features included the determination of staining intensity, mixed membranous and cytoplasmic staining pattern, and cases near the cutoffs of the defined categories (Fig. 1B–D). Among cases with any staining, only a small proportion of cases had pure cytoplasmic (5%) or pure membranous (7%) staining, and those were often observed in small areas of the tumors. The interrater reliability of CEACAM5 was assessed in both cohort 1 (n = 206) and cohort 2 (n = 322). The level of interrater agreement across all categories was moderate in both cohort 1 (W = 0.77) and cohort 2 (W = 0.67). Interrater agreement between high CEACAM5 expression versus moderate/weak/negative categories combined was also moderate in cohort 1 (k = 0.60) and weak in cohort 2 (k = 0.56). In general, interrater agreement was better in biopsy specimens than in resection specimens (Fig. 2).
Table 2.
Prevalence of Tumor Biomarker Expressions and EGFR and KRAS Mutations
| Factor | Overall (n = 600) | Cohort 1 (n = 206) | Cohort 2 (n = 394) |
|---|---|---|---|
| CEACAM5 | n (%) | n (%) | n (%) |
| Weak/negative | 227 (39) | 90 (44) | 137 (36) |
| Moderate | 255 (43) | 71 (34) | 184 (48) |
| High | 107 (18) | 45 (22) | 62 (16) |
| NA | 11 | 0 | 11 |
| PD-L1 TPS | |||
| <1% | 357 (60) | 87 (42) | 270 (69) |
| 1%–49% | 150 (25) | 70 (34) | 80 (20) |
| ≥50% | 91 (15) | 49 (24) | 42 (11) |
| NA | 2 | 0 | 2 |
| EGFR | |||
| Yes | 122 (20) | 74 (36) | 48 (12) |
| No | 298 (50) | 132 (64) | 166 (42) |
| Unknown | 180 (30) | 0 (0) | 180 (46) |
| KRAS | |||
| Yes | 127 (21) | 49 (24) | 78 (20) |
| No | 293 (49) | 157 (76) | 136 (35) |
| Unknown | 180 (30) | 0 (0) | 180 (46) |
Weak = 0 or 1+ intensity.
Moderate = 1% to 49% tumor cells at ≥ 2+ intensity.
High = ≥50% tumor cells at ≥2+ intensity.
NA, not assessable.
Figure 1.
CEACAM5 protein expression by immunohistochemistry. (A) A case of adenocarcinoma with moderate (2+) membranous and cytoplasmic expressions exhibiting clear membranous accentuation. (B) Weak (1+) to moderate (2+) staining of tumor cells with difficult to interpret membranous accentuation. (C, D) Moderate (2+) to strong (3+) staining of tumor cells with difficult to quantitate incomplete membranous accentuation.
Figure 2.
Proportion of the assigned CEACAM5 classification by individual rater (1, 2, 3) in cohort 1 (left) and cohort 2 (right).
The distribution of CEACAM5 expression following consensus classification revealed that the prevalence of high CEACAM5 membranous expression was 22% (n = 45) in cohort 1 and 16% (n = 62) in cohort 2 (Table 2). The overall prevalence of high CEACAM5 expression was 18% with 25% (four of 16) in the metastatic sites. The overall prevalence of weak/negative and moderate CEACAM5 expressions was 39% and 43%, respectively. The overall prevalence of high CEACAM5 expression was much lower in squamous cell carcinoma (2.8%) than adenocarcinoma (22%) (Supplementary Fig. 1).
In addition, we assessed the cytoplasmic expression in a similar scoring scheme as the membranous expression. The agreement between membranous and cytoplasmic staining was substantial in both cohort 1 (W = 0.858) and cohort 2 (W = 0.818). The level of interrater agreement across all categories was substantial in cohort 1 (W = 0.83) and moderate in cohort 2 (W = 0.64) (Supplementary Fig. 2). However, interrater agreement between high cytoplasmic expression versus moderate/weak/negative categories combined was weak in cohort 1 (k = 0.49) and minimal in cohort 2 (k = 0.38).
Sex differences in CEACAM5 expression were observed only in cohort 2; strong CEACAM5 expression was observed in 23% of female patients and 9% of male patients (p < 0.001). No statistically significant differences by sex were observed in cohort 1.
Association of CEACAM5 Expression With Other Biomarkers
The association of high CEACAM5 expression with oncogenic driver mutations was assessed in both cohorts, and there was no statistically significant association with either EGFR or KRAS mutation (p > 0.1), although a trend toward KRAS mutation was noted in moderate and high CEACAM5 expressors (Fig. 3A and B). Neither PD-L1 TPS nor TMB was associated with CEACAM5 expression in either cohort (p > 0.1) (Fig. 3C and D).
Figure 3.
CEACAM5 protein expression is not associated with (A) KRAS, (B) EGFR, (C) PD-L1 TPS, or (D) tumor mutation burden.
Prognostic Effect of CEACAM5 in Resected NSCLC
The prognostic significance of CEACAM5 protein expression was determined in cohort 2, which consisted of resected NSCLC with long-term follow-up data. CEACAM5 expression was not significantly associated with tumor stage (p = 0.4), RFS (p = 0.8), or OS (p = 0.7) (Fig. 4). This observation was consistent by either membranous or cytoplasmic expression (Supplementary Fig. 3).
Figure 4.
CEACAM5 protein expression is not associated with overall survival (left) or recurrence-free survival (right).
Discussion
We have evaluated CEACAM5 protein expression by IHC in a large cohort of 589 NSCLC cases. By using two separate cohorts, we were able to assess CEACAM5 IHC in both real-world biopsy and archival resection specimens. Our study provided the first systematic evaluation of CEACAM5 expression patterns and interrater agreement in a real-world patient population with NSCLC. We found moderate interrater agreement in both cohorts and highlighted challenging aspects in the routine clinical assessment of CEACAM5 as an immunohistochemical predictive biomarker. We observed no significant association between CEACAM5 protein expression and frequently assessed lung cancer biomarkers, including oncogenic drivers, PD-L1, and TMB. Moreover, we did not identify a prognostic effect of CEACAM5 protein expression in our cohort of predominantly resected early stage NSCLC.
The level of interrater agreement of CEACAM5 across various expression levels is generally similar to other IHC-based predictive biomarkers using either percentage cutoff or tiered score system.32,33 In particular, the separation of granular membranous expression and cytoplasmic expression could be very challenging. We found the kappa value tended to be higher with biopsy than resection specimens. As expected, the larger area and frequently observed intratumoral heterogeneous expression pattern likely contributed to the interobserver variability. Moreover, the agreement in the very high expressors (≥80% tumor cells at ≥2+ intensity) was only slightly improved in cohort 2 (W = 0.72 versus 0.67). The interobserver variability in the selection of high CEACAM5 expressor may play a role in the determination of efficacy. Consistent with previous findings, CEACAM5 protein was not expressed in normal lung parenchyma, indicating high specificity of the antibody, and squamous cell carcinoma tends to have low prevalence of high CEACAM5 expression.34
In the CARMEN-LC03 trial, tusamitamab ravtansine versus docetaxel did not meet primary endpoints of PFS and OS.35 In subgroup analyses, there was a trend to improved relative PFS and interim OS with very high CEACAM5 expression (≥80% tumor cells at ≥2+ intensity).36 We also evaluated our data for the very high CEACAM5 category; however, the number was too small (n = 26) for statistical analysis.
The data on prognostic effect of CEACAM5 expression have been inconsistent. Previous study based on CEACAM5 mRNA expression level reported association with worse prognosis in female patients with early stage lung adenocarcinoma.37 Association of high CEACAM5 with T stage, lymph node metastasis, and histologic grade in NSCLC has also been reported.19 Our data based on membranous CEACAM5 protein expression may explain the difference and a lack of prognostic effect, as the correlation between CEACAM5 mRNA and protein expressions may be imperfect. Similar to prior study, the prevalence of high CEACAM5 expression appears to be higher in metastatic tumors3; however, the number was small and not statistically significant.
A higher prevalence of high CEACAM5 expression with KRAS alterations has been observed in recent studies.3,38 In our cohorts, we observed a trend toward higher CEACAM5 expression in KRAS alterations, although the association was not statistically significant (p = 0.15) and may be explained by the difference in demographics. An inverse association between CEACAM5 and PD-L1 expressions was noted by Lefebvre et al.,3 but this was not observed in our cohorts.
Our study has several limitations. Our data based on a retrospective cohort of resected NSCLC may introduce bias to our analysis. Our cohort may potentially be underpowered to detect association of high CEACAM5 expression in more advanced NSCLC, due to primarily early stage diseases. The role of secreted or exosome-bound CEACAM5 is unclear based solely on the assessment of FFPE tissue due to the focus on membranous expression of CEACAM5. Moreover, the assessments of both membranous and cytoplasmic expression patterns and the use of machine-learning algorithm such as that of TROP2 normalized membrane ratio may become important in future IHC-based biomarker evaluations of ADC.39
In conclusion, we presented our experiences in evaluating CEACAM5 IHC in a real-world patient population with NSCLC. The interrater agreement of CEACAM5 across various categories of expression was moderate, which may pose challenges in patient selection. With ongoing trials targeting CEACAM5 molecule, a refined and standardized interpretation of CEACAM5 expression may be necessary.
CRediT Authorship Contribution Statement
Ying-Han R. Hsu: Conceptualization, Methodology, Investigation, Data acquisition, Data curation and analysis, Writing - original draft, Writing - review & editing.
Amna Almutrafi: Methodology, Investigation, Data acquisition, Data curation and analysis, Writing - review.
Katrina Hueniken: Methodology, Data curation and analysis, Writing - review & editing.
Alhareth Azaizeh: Methodology, Investigation, Data acquisition, Writing - review & editing.
Likun Hou: Methodology, Investigation, Data acquisition, Writing - review & editing.
Quan Li: Methodology, Investigation, Data curation and analysis, Writing - original draft, Writing - review.
Mackenzie Bates: Methodology, Investigation, Data acquisition, Writing - review.
Nhu-An Pham: Methodology, Investigation, Data curation, Writing - review & editing.
Ming-Sound Tsao: Conceptualization, Methodology, Investigation, Data acquisition, Data curation and analysis, Writing - original draft, Writing - review & editing, Administrative support.
Disclosure
Dr. Tsao received personal fee/support from Sanofi, AstraZeneca, Daiichi Sankyo, Boehringer-Ingelheim, and Amgen and research grant from AstraZeneca and Sanofi. The remaining authors declare no conflict of interest.
Acknowledgments
This project is supported by Sanofi-Aventis Canada.
Footnotes
Cite this article as: Hsu YHR, Almutrafi A, Hueniken K, et al. The landscape of CEACAM5 expression by immunohistochemistry in NSCLC. JTO Clin Res Rep 2025;7:100943
Note: To access the supplementary material accompanying this article, visit the online version of the JTO Clinical and Research Reports at www.jtocrr.org and at https://doi.org/10.1016/j.jtocrr.2025.100943.
Supplementary Data
References
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