TROP2 expression as a prognostic predictor for osimertinib in patients with EGFR-mutant non-small cell lung cancer

Introduction

Epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) accounts for approximately 50% of lung adenocarcinoma cases in Japanese patients, representing one of the most common molecular NSCLC subsets (1). In this population, EGFR-tyrosine kinase inhibitors (TKIs) are the mainstay of first-line therapy. Based on the FLAURA trial, osimertinib is a standard treatment for EGFR-mutated NSCLC, achieving a median progression-free survival (PFS) of 18.9 months and a median overall survival (OS) of 38.6 months (2,3). Despite these efficacy, acquired resistance to osimertinib almost inevitably develops during treatment (4). Following disease progression, therapeutic options are limited and the prognosis remains poor (4). Clinically validated baseline markers beyond EGFR genotype are scarce in the first-line settings, limiting risk stratification at treatment initiation. Although prognostic differences between exon 19 deletions (del 19) and the exon 21 codon p.Leu858Arg (L858R) mutation have been described, the clinical course varies widely among individuals, indicating a need for additional prognostic markers.

Trophoblast cell- surface antigen 2 (TROP2; TACSTD2) is a transmembrane glycoprotein involved in tumor proliferation, invasion, and metastasis (5). Although TROP2 is expressed at low levels in normal epithelial tissues, it is frequently overexpressed in epithelial malignancies, including lung cancer (6). While its prognostic value remains under investigation, several studies have reported that TROP2 overexpression is associated with poor clinical outcomes (7,8). In a cohort of 110 patients treated with nivolumab plus ipilimumab, TROP2 overexpression was associated with shorter PFS and OS (9). Given this context, TROP2 has recently gained attention as a therapeutic target for antibody-drug conjugates (ADCs). The Phase III TROPION-Lung01 trial, which evaluated the TROP2-directed ADC datopotamab deruxtecan (Dato-DXd) versus docetaxel in patients previously treated with systemic therapy with advanced or metastatic NSCLC, demonstrating improved efficacy and a manageable safety profile (10). Similarly, the TROPION-Lung15 trial is an ongoing Phase III clinical study assessing the efficacy of Dato-DXd in patients previously treated with osimertinib (11). Collectively, these findings establish TROP2 as a promising therapeutic target.

The prognostic significance of TROP2 expression in EGFR-mutated lung adenocarcinoma remains unclear, with limited subgroup analyses for major mutations such as del 19 or L858R (8,12). Preclinical studies have suggested a potential interaction between EGFR signaling and TROP2 expression, and exploratory clinical data indicated that TROP2 is expressed in a substantial proportion of these tumors (8,12,13). This suggests that TROP2 may influence tumor biology and resistance in this subgroup, warranting investigation of its prognostic relevance in osimertinib-treated patients. However, no established data exist for patients receiving osimertinib as a first-line treatment. Most prior studies involved heterogeneous regimens, including combined chemotherapy or first or second-generation EGFR-TKIs. To address this gap, we evaluated a cohort receiving osimertinib as initial treatment for recurrent or metastatic disease. Prognostic outcomes, such as PFS and OS, vary widely in this subgroup, making the discovery of baseline prognostic biomarkers clinically important. Therefore, we investigated the relationship between TROP2 expression and clinicopathological features and outcomes in patients with EGFR-mutated lung adenocarcinoma initially treated with osimertinib for recurrent or metastatic disease. We present this article in accordance with the REMARK reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1494/rc).

Methods

Patients

Between August 2018 and December 2023, 189 patients with EGFR-mutant NSCLC received first-line osimertinib monotherapy at Saitama Medical University International Medical Center. Eligible patients required a history of first-line osimertinib, a major EGFR mutation (del 19 or L858R), and sufficient pre-treatment tumor specimens for immunohistochemistry (IHC). Of the initial cohort, 34 patients lacked sufficient specimens for IHC before osimertinib therapy, leaving 155 patients eligible for analysis. Clinical data, including age, sex, performance status (PS), smoking history, radiological examination, and survival information, were extracted from medical records. This study was approved by the Institutional Review Board (IRB) of Saitama Medical University International Medical Center (approval number: 2025-126). Given the retrospective design of the study, the requirement for written informed consent was waived; and an opt-out method was implemented in accordance with the IRB-approved protocol. All procedures complied with the institutional ethical standards and the principles of the Declaration of Helsinki and its later amendments.

Treatment and evaluation

All patients received first-line oral osimertinib (80 mg/day). Dose adjustments (reduction or discontinuation) were made at the discretion of the treating physician. Physical examination, laboratory tests (complete blood counts, biochemical tests for liver/renal function, and electrolytes), and adverse events (AEs) assessments were performed by the physician. Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 (14). Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (15). The objective response rate (ORR) assessed. The ORR was defined as the percentage achieving a complete response (CR), partial response (PR).

Immunohistochemistry for TROP2 expression

Immunohistochemical staining was performed as described previously (9,16-18). To detection TROP2, tumor sections were incubated overnight at 4 °C with a rabbit monoclonal antibody against TROP2 (clone EPR20043; ab214488; Abcam, Cambridge, UK) diluted 1:2,000 in antibody diluent (Dako, Glostrup, Denmark; S2022), using pH6 retrieval. This was followed by a 30-minute incubation at room temperature. Staining of the plasma membrane and cytoplasm was interpreted as positive for TROP2.

TROP2 expression was scored by combining staining intensity and the proportion of positive tumor cells, as previously described (16-18). Intensity was graded as 0 (negative), 1 (weak), 2 (moderate), or 3 (strong). The proportion score reflected the percentage of positive tumor cells: 1 (<10%), 2 (10–50%), 3 (50–80%), or 4 (80–100%). The final immunostaining score (range, 0–12) was obtained by multiplying the intensity and proportion scores. TROP2 overexpression was defined as a score of 12.

All slides were independently examined by two observers (N.H. and K.K.) at ×200 and ×400 magnifications using a light microscope. Any discrepant assessments were resolved by joint re-evaluation until a consensus was reached. The observers were blinded to patient outcomes.

Statistical analysis

Continuous variables were dichotomized as described, and categorical variables were compared using the χ² test. Statistical significance was set at a P value <0.05. PFS was defined as the time from treatment initiation to disease progression or death from any cause. OS was defined as the time from treatment initiation to death from any cause. For analysis based on TROP2 expression, the cohort was stratified into high expression (overexpression, score =12) and low expression (non-overexpression, score <12) groups. Survival curves were generated using the Kaplan-Meier method and compared with the log-rank test. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using univariate Cox proportional hazards models. Variables with P value <0.05 in univariate Cox analyses were subsequently included in multivariate Cox models. All statistical analyses were performed using GraphPad Prism (version 10.0; GraphPad Software, San Diego, CA, USA) and JMP (version 16.0; SAS Institute Inc., Cary, NC, USA).

Results

Patient demographics

Patient characteristics are summarized in Table 1. The median age was 71 years (range, 42–88 years). The cohort details were as follow: 63 patients were male and 92 were female; 49, 76, 17, and 3 patients had a PS of 0, 1, 2, and 4, respectively; 61 and 83 patients, had a programmed death-ligand 1 (PD-L1) expression if PD-L1 expression of <1% and ≥1%, respectively; 76 and 74 patients had EGFR exon 19 and L858R, respectively. Stage IV disease at baseline was present in 117 patients, 38 patients had recurrence after curative surgery. ORR was 91 of 155 patients, comprising 3 CR, 88 PR. stable disease (SD), progressive disease (PD), not evaluable (NE) responses were observed in 30, 10, and 24 patients, respectively. Grade 3 or 4 AEs occurred in 30 patients, including 17 patients who experienced interstitial lung disease (ILD).

Immunohistochemical evaluation

IHC for TROP2 was performed on tumor specimens from 155 patients, and detectable TROP2 expression was observed in all cases (Figure 1). Overexpression was observed in 72 patients (46.5%). A TROP2 intensity score of 3 (indicative of cytoplastic staining) was seen in 81 patients (52.3%), and a proportion score of 4 was seen in 119 (76.8%) patients. TROP2 overexpression was significantly associated with stage IV disease at diagnosis and in the specimens used for diagnosis; however, driver mutation type was not associated with the frequency of TROP2 overexpression (Table 2).

Figure 1 Evaluation method of TROP2 expression. Staining intensity is scored as 0–3 (A), reflecting the strength of immunostaining. Proportion of positive cells are classified as 1–4 (B), based on the percentage of TROP2-positive tumor cells. Images shown are representative microscopic fields. The image corresponding to an intensity score of 0 represents a negative staining area within a tumor specimen and does not indicate a completely negative case. Scale bars, 50 µm. TROP2, trophoblast cell-surface antigen 2.

Survival analysis

The median PFS and OS were 433 and 769 days, respectively. Recurrence occurred in 117 patients, and 91 died due to disease progression. The Kaplan-Meier curves for all patients are shown in Figure 2. In univariate Kaplan-Meier analyses, both TROP2 overexpression and a high TROP2 intensity score were associated with shorter PFS and OS, whereas the TROP2 proportion score showed no significant association with either endpoint. Because univariate analyses do not account for confounding factors, the independent prognostic relevance of these variables was subsequently evaluated using multivariate Cox models.

Figure 2 Kaplan-Meier survival curve in all patients is shown according to three TROP2 metrics: TROP2 expression [for PFS (A) and OS (B)], TROP2 intensity score [PFS (C) and OS (D)], TROP2 proportion score [PFS (E) and OS (F)]. The median PFS and OS values, along with HRs, 95% CIs, and log-rank P values derived from univariate Kaplan-Meier analyses, were as follows: TROP2 expression: PFS 742 vs. 339 days (HR =1.21, 95% CI: 1.01–1.46) (A); OS 1,346 vs. 769 days (HR =1.40, 95% CI: 1.14–1.73) (B). TROP2 intensity score: PFS 757 vs. 337 days (HR =1.32, 95% CI: 1.09–1.59) (C); OS 1,346 vs. 769 days (HR =1.45, 95% CI: 1.17–1.79) (D). TROP2 proportion score: PFS 701 vs. 443 days (HR =0.95, 95% CI: 0.76–1.18) (E); OS 1,138 vs. 963 days (HR =1.07, 95% CI: 0.84–1.38) (F). CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; TROP2, trophoblast cell-surface antigen 2.

Univariate and multivariate analyses were performed to identify prognostic factors associated with PFS and OS (Table 3). In this univariate analysis, PS, clinical stage at diagnosis, driver mutation type, TROP2 IHC findings, and liver metastasis were significant predictors of PFS. Significant predictors of OS were PS, age, clinical stage at diagnosis, TROP2 IHC findings, and liver metastasis. Variables with P value <0.05 in the univariate log-rank test were selected for multivariate analysis. The multivariate analysis identified PS, clinical stage at diagnosis, driver mutation type, and liver metastasis were independent prognostic factors for worse PFS. For OS, independent prognostic factors were age, PS, clinical stage at diagnosis, TROP2 IHC finding, and liver metastasis. Overall, TROP2 IHC findings remained an independent prognostic factor for OS but not for PFS in the multivariate analysis.

The Kaplan-Meier curves stratified by EGFR mutation status and biopsy type are shown in Figure 3. In the subgroup analyses, in patients with an EGFR del 19, a high TROP2 intensity score and TROP2 overexpression were significantly associated with worse OS, but not with PFS. In patients with EGFR L858R mutation, only TROP2 intensity score was significantly associated with a worse OS. In patients with a definite diagnosis from biopsy specimens, TROP2 overexpression was significantly associated with OS, while a high TROP2 intensity score was significantly associated with both OS and PFS. The relationship between TROP2 expression and prognostic outcomes in each subgroup are summarized in Table S1. These subgroup analyses were exploratory, and the results should be interpreted with caution.

Figure 3 Kaplan-Meier survival curves for PFS and OS are presented for the following subgroup analysis: Exon 19 deletion (del 19) subgroup, stratified by TROP2 expression [PFS (A), OS (B)], TROP2 intensity score [PFS (C), OS (D)] and TROP2 proportion score [PFS (E), OS (F)]; L858R subgroup, stratified by TROP2 expression [PFS (G), OS (H)], TROP2 intensity score [PFS (I), OS (J)] and proportion score [PFS (K), OS (L)]; biopsy subgroup, stratified by TROP2 expression [PFS (M), OS (N)], TROP2 intensity score [PFS (O), OS (P)] and proportion score [PFS (Q), OS (R)]. The median PFS and OS, HRs, 95% CIs, and log-rank P values were as follows: del 19 subgroup, by TROP2 expression (total): PFS 762 vs. 431 days (HR =1.11, 95% CI: 0.84–1.47) (A); OS 1,458 vs. 880 days (HR =1.38, 95% CI: 1.00–1.90) (B). By TROP2 intensity score: PFS 790 vs. 431 days (HR =1.27, 95% CI: 0.96–1.67) (C); OS 1,477 vs. 934 days (HR =1.40, 95% CI: 1.02–1.93) (D). By TROP2 proportion score: PFS 790 vs. 643 days (HR =0.96, 95% CI: 0.69–1.25) (E); OS 1,149 vs. 1,186 days (HR =1.06, 95% CI: 0.75–1.49) (F). L858R subgroup, by TROP2 expression (total): PFS 717 vs. 337 days (HR =1.18, 95% CI: 0.91–1.54) (G); OS 1,346 vs. 723 days (HR =1.33, 95% CI: 0.99–1.80) (H). By TROP2 intensity score: PFS 757 vs. 304 days (HR =1.28, 95% CI: 0.98–1.67) (I); OS 1,116 vs. 718 days (HR =1.43, 95% CI: 1.05–1.96) (J). By TROP2 proportion score: PFS 300 vs. 373 days (HR =0.78, 95% CI: 0.54–1.13) (K); OS 644 vs. 835 days (HR =0.91, 95% CI: 0.61–1.36) (L). Biopsy subgroup, by TROP expression (total): PFS 717 vs. 323 days (HR =1.20, 95% CI: 0.97–1.48) (M); OS 1,193 vs. 723 days (HR =1.50, 95% CI: 1.17–1.92) (N). By TROP2 intensity score: PFS 733 vs. 323 days (HR =1.25, 95% CI: 1.00–1.56) (O); OS 1,193 vs. 723 days (HR =1.49, 95% CI: 1.14–1.95) (P). By TROP2 proportion score: PFS 757 vs. 385 days (HR =1.13, 95% CI: 0.87–1.46) (Q); OS 1,138 vs. 844 days (HR =1.17, 95% CI: 0.88–1.55) (R). CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; TROP2, trophoblast cell-surface antigen 2.

Discussion

No previous studies have established the prognostic significance of TROP2 expression in patients with EGFR-mutated NSCLC (8,12). To the best of our knowledge, no study has performed a detailed subgroup analysis focusing specifically on EGFR-mutated populations. In our study, we assessed the clinicopathological features of EGFR-mutated NSCLC and identified TROP2 overexpression as an independent prognostic factor for OS; no significant association was observed for PFS. When stratified by driver mutation type, TROP2 overexpression was significantly associated with worse OS in patients with EGFR del 19, while no significant association was observed in patients with EGFR L858R mutation. We also found that TROP2 intensity was a more important determinant of survival assessment than the proportion of positive cells in TROP2 IHC. Because our study used a retrospective approach, the observed outcomes after osimertinib treatment was shorter than that reported in the FLAURA trial (2). Furthermore, patient demographics in our study different from those in the FLAURA trial, including the frequency of EGFR del 19 (49% versus 63%) (2). Although EGFR exon 19 deletion has been reported to be associated with a more favorable prognosis than the EGFR L858R mutation, this difference was not observed in the univariate analysis of OS in our cohort. Because OS incorporates the post-progression clinical course and subsequent treatment decisions, differences related to EGFR mutation subtype may not be apparent. In addition, the limited sample size of each mutation subgroup may have reduced the statistical power to detect modest survival differences.

TROP2 overexpression has been widely observed in various tumors, including pancreatic, ovarian, prostate, and breast cancer (19-23). Similar findings have been reported in lung cancer, even in tumors harboring EGFR mutations (8,24). Consistent with these reports, all patients with EGFR-mutated in our study showed TROP2 expression within the tumor membrane, and 72 (46.5%) patients demonstrated its overexpression. While previous studies on EGFR-mutated NSCLC reported no significant relationship between TROP2 expression and prognosis, our study found that TROP2 overexpression was significantly associated with shorter OS (8,24). One plausible explanation for this discrepancy is that osimertinib exposure may induce TROP2 expression in EGFR-mutated tumors, as recently demonstrated by Baldacci et al. (13). The TROP2 upregulation has been implicated in the persistence of drug-tolerant clones and may reduce the efficacy of subsequent treatment regimens. Therefore, even if PFS remains comparable during first-line osimertinib therapy, the diminished response to later lines of therapy could ultimately translate into inferior OS. Furthermore, 71% of the specimens in our study were diagnosed by biopsy, therefore, the potential influence of selection bias could not be excluded. Biopsy specimens are frequently used for EGFR mutation testing in routine clinical practice, while many previous studies have predominantly used surgically resected tissues (8,25,26). Consequently, our findings may more reflect real-world clinical settings.

Analysis stratified by EGFR mutation subtype showed that TROP2 total score and intensity score were significantly associated with OS in the del 19 subgroup, while only TROP2 intensity score remained significant in L858R subgroup. Although the prognostic significance of TROP2 parameters differed between subtypes, both groups exhibited a comparable overall pattern, in which higher TROP2 intensity was associated with poorer survival. This finding suggests that the TROP2 intensity score may serve as a more sensitive prognostic indicator than the TROP2 total score. As a standardized method for evaluating TROP2 expression remains undefined, whether using the H-score or other scoring systems, our findings support assessing TROP2 intensity and proportion as separate parameters, consistent with previous reports (9).

In our study, TROP2 overexpression did not influence PFS in patients treated with first-line osimertinib. Osimertinib provides strong on-target inhibition of the EGFR-PI3K/Akt signaling pathway in EGFR-addicted tumors, which may reduce the early influence of alternative growth pathways on the treatment response (4,27,28). Previous studies using gefitinib have shown that TROP2 enhances IGF2-IGF1R-Akt signaling as an off-target bypass mechanism, promoting drug resistance (29). However, osimertinib suppresses the EGFR-Akt pathway stronger than first-generation EGFR-TKIs. Therefore, an IGF-mediated bypass may not be sufficient to overcome this inhibition in the early phase of treatment (27). This biological context may explain why differences in TROP2 expression did not translate into differences in PFS in our cohort. Although these findings suggest a potential interaction between EGFR-related signaling and TROP2-mediated pathways, the functional relationship between EGFR signaling and TROP2 expression was not directly evaluated in this study. In this context, ongoing trials such as TROPION-Lung15 are evaluating TROP2-directed antibody-drug conjugates after EGFR-TKI resistance, supporting the clinical development of TROP2-targeted therapies (11).

This study had several limitations. First, the sample size was limited because the analysis was conducted at a single institution, which may have introduced selection bias. Second, detailed information on second-line and subsequent therapies after disease progression was not systematically incorporated into the analyses. OS can be influenced by post-progression treatments, including chemotherapy, immune checkpoint inhibitors, and participation in clinical trials. Differences in subsequent treatment strategies may therefore have affected OS outcomes in this cohort. Third, we were unable to compare our results with the outcomes of other EGFR-TKI-based treatment strategies, particularly chemotherapy-TKI combination regimens. Fourth, no standardized method for assessing TROP2 expression has been established; therefore, the results may vary depending on the scoring technique used. In this study, we selected an evaluation method based on previously published reports (9,16-18). Recently, alternative immunohistochemical scoring approaches for TROP2 that take subcellular localization into account have been reported (30), such as methods evaluating the relative distribution of membranous and intracellular expression. These approaches have been described mainly in exploratory analyses and have not yet been widely standardized. In addition, because this was a retrospective study using archival tumor specimens, functional molecular analyses such as Western blotting or quantitative polymerase chain reaction to explore the mechanistic relationship between EGFR signaling and TROP2 expression could not be performed.

Conclusions

TROP2 expression was associated with poor survival outcomes in patients with EGFR-mutated NSCLC receiving osimertinib monotherapy. TROP2 overexpression remained an independent prognostic factor for OS. These findings highlight the prognostic relevance of TROP2 expression and support further investigation of TROP2-directed therapeutic strategies in this population.

Acknowledgments

The authors would like to thank Ms. Kozue Watanabe, Joji Shiotani, and Koko Kodaira for their assistance in preparing the manuscript. The authors also thank Editage (www.editage.jp) for the English language editing.

Footnote

Reporting Checklist: The authors have completed the REMARK reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1494/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1494/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1494/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1494/coif). K.K. has received speaker honoraria from Ono Pharmaceutical Company, Chugai Pharmaceutical, and AstraZeneca, and research grants from AstraZeneca. A.M. and O.Y. received speaker honoraria from Chugai Pharmaceutical and AstraZeneca, respectively. H.K. received research grants from Ono Pharmaceutical Company, Boehringer Ingelheim, and Chugai Pharmaceutical; and speaker honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Bristol-Myers Company, and MSD

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Institutional Review Board (IRB) of Saitama Medical University International Medical Center (approval number: 2025-126). Due to the retrospective study design, the requirement for written informed consent was waived by the IRB. In accordance with the IRB-approved protocol, an opt-out method was employed, whereby study details were publicly disclosed and patients were given the opportunity to decline participation. All procedures were conducted in accordance with the ethical standards of the Institutional Review Board and the Declaration of Helsinki and its later amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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