Prognostic impact of thyroid transcription factor-1 expression and the efficacy of carboplatin plus (nab-) paclitaxel in non-squamous non-small cell lung cancer complicated with idiopathic interstitial pneumonias

Introduction

Lung cancer remains the leading cause of cancer-related mortality worldwide (1,2). Previous studies have established idiopathic interstitial pneumonias (IIPs) as independent risk factors for lung cancer, especially idiopathic pulmonary fibrosis (IPF), with the cumulative incidence of lung cancer reaching 15.4% at 5 years of follow-up (3). In patients with IIPs who develop lung cancer, lethal acute exacerbations (AEx) can occur following surgery, radiotherapy, or chemotherapy, with reported incidence rates ranging from 5.6% to 30.6% (4). Recent advances in molecular targeted therapies and immune checkpoint inhibitors (ICIs) have broadened therapeutic strategies for unresectable, advanced, or recurrent non-small cell lung cancer (NSCLC). However, in clinical practice, these agents are often avoided in patients with IIPs because of concerns regarding AEx. Therefore, platinum-based cytotoxic chemotherapy remains a commonly used treatment in patients with NSCLC with concomitant IIPs. Several prospective studies have reported favorable efficacy and acceptable safety profiles for carboplatin plus (nab-) paclitaxel in patients with advanced NSCLC complicated by IIPs (5-8).

Thyroid transcription factor 1 (TTF-1), which is expressed in approximately 60–80% of non-squamous non-small cell lung cancers (NS-NSCLCs) (9), is widely used as an immunohistochemical marker for histological classification and for distinguishing primary lung adenocarcinoma from metastatic adenocarcinomas (10-13). In adenocarcinoma coexisting with IIPs, TTF-1 expression is observed in approximately 40% of cases (14), whereas TTF-1 negativity has been linked to worse unfavorable prognosis in patients with advanced lung adenocarcinoma treated with cytotoxic chemotherapy (such as pemetrexed), immunotherapy, or chemoimmunotherapy (15-21). Furthermore, the extent of positive TTF-1 expression was associated with patient outcomes following chemoimmunotherapy (22). Previous retrospective data have indicated a potential association between TTF-1 positivity and improved immunotherapy outcomes in patients with NS-NSCLC complicated by interstitial lung disease (ILD) (23). However, the association between TTF-1 expression status (positive or negative) and the efficacy of platinum-based doublet chemotherapy among these patients has not been fully elucidated.

The objective of this retrospective study was to assess whether TTF-1 expression influences the prognosis of patients with NSCLC and coexisting IIPs receiving platinum-doublet chemotherapy. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1367/rc).

Methods

Patients

Between January 1, 2010, and December 31, 2024, 120 patients were diagnosed with unresectable, recurrent, or advanced NS-NSCLC complicated by IIPs at Nippon Medical School Hospital in Tokyo, Japan. Among them, 84 patients received first-line chemotherapy, and immunohistochemical (IHC) testing for TTF-1 was performed in 65 patients; it was not performed in 19 patients because IHC was not mandatory for diagnosis. Of these, 51 were treated with carboplatin plus (nab-) paclitaxel as first-line treatment for NS-NSCLC with IIPs (Figure S1). Clinical and pathological data, including age, sex, histological subtype, smoking history, Eastern Cooperative Oncology Group performance status (ECOG-PS), driver mutation status, programmed death-ligand 1 (PD-L1) expression, and clinical stage, were retrospectively extracted from medical records. Serum biomarkers, such as lactate dehydrogenase (LDH), Krebs von den Lungen-6 (KL-6), and surfactant protein D (SP-D), and pulmonary function parameters, including percent vital capacity (%VC) and percent diffusing capacity of the lungs for carbon monoxide (%DLco), were also assessed. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Graduate School of Medicine, Nippon Medical School Institutional Review Board (No. B-2023-768) and individual consent for this analysis was waived due to the retrospective nature.

Analysis of TTF-1 expression

TTF-1 expression was evaluated by immunohistochemistry using 4–5-µm-thick formalin-fixed, paraffin-embedded tissue sections obtained from lung cancer specimens collected at diagnosis by bronchoscopy, computed tomography (CT)-guided biopsy, or surgery. Antigen retrieval was performed by autoclaving the sections in citrate buffer (pH 8.5) at 95 ℃ for 36 minutes. The sections were subsequently incubated at room temperature for 16 minutes with a rabbit monoclonal anti-TTF-1 antibody (clone SP141; Roche, Basel, Switzerland). Immunoreactivity was detected using the VENTANA ultraView DAB universal kit (Roche), with visualization by diaminobenzidine chromogen and counterstaining with hematoxylin. TTF-1 expression was assessed by an experienced pathologist blinded to patients’ clinical information and was defined by nuclear staining in tumor cells. Consistent with previous reports using the SP141 clone, a cutoff value of ≥10% TTF-1-positive tumor cells were applied to classify tumors as TTF-1 positive in the present study (10). Patients were classified into two groups based on TTF-1 expression: TTF-1-positive (Figure 1A,1B) and TTF-1-negative (Figure 1C,1D).

Figure 1 Immunohistochemical staining for TTF-1 with the SP141 clone in tumor biopsy specimens of patients with NS-NSCLC. (A,B) NS-NSCLC with TTF-1 positive. (C,D) NS-NSCLC with TTF-1 negative. Scale bars: 100 µm (A-D). NS-NSCLC, non-squamous non-small cell lung cancer; TTF-1, thyroid transcription factor 1.

Analysis of IP

IIPs were clinically categorized into two patterns: usual interstitial pneumonia (UIP) and non-UIP. IPF was diagnosed in accordance with the criteria established by the American Thoracic Society and European Respiratory Society, as previously reported (24,25). When histopathological confirmation was unavailable, high-resolution computed tomography (HRCT) images were independently evaluated by at least two board-certified pulmonologists. The UIP pattern was defined by the presence of subpleural, basal-predominant reticular abnormalities accompanied by traction bronchiectasis and honeycombing, without radiological features atypical for IPF, such as peribronchovascular nodules, isolated cysts, or consolidation. In contrast, the non-UIP pattern was characterized by basal-predominant nonspecific fibrotic changes and/or ground-glass opacities, as well as other infiltrative findings inconsistent with a UIP pattern, as previously described (6). AEx of IIPs was diagnosed based on the following criteria: an acute worsening or new onset of dyspnea within one month; newly appearing bilateral ground-glass opacities or consolidation on chest CT; and hypoxemia, defined as a deterioration or severe impairment of gas exchange (26,27). Cases attributable to alternative causes, including heart failure, volume overload, pulmonary infection, or pulmonary embolism, were excluded.

Statistical analysis

Baseline patient characteristics are summarized as numbers and percentages. Categorical variables were analyzed using Fisher exact test, whereas continuous variables were compared using the Mann-Whitney U test. Differences in baseline characteristics and clinical responses to carboplatin plus (nab-) paclitaxel were compared between patients with TTF-1-positive tumors (TTF-1-positive group) and those with TTF-1-negative tumors (TTF-1-negative group). Progression-free survival (PFS) was defined as the interval from the start of chemotherapy to documented disease progression or death from any cause. Overall survival (OS) was defined as the time from chemotherapy initiation to death, irrespective of cause. Patients who had not experienced disease progression or who remained alive at the time of analysis were censored at their last follow-up. Kaplan-Meier methods were used to estimate PFS and OS, and between-group differences were evaluated using the log-rank test and Cox proportional hazards models. The overall response rate (ORR) was calculated as the proportion of patients achieving a complete or partial response as their best overall response, in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (28). Survival outcomes were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs), and a two-sided P value of less than 0.05 was considered statistically significant. All statistical computations were carried out using EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan) (29).

Results

Patient characteristics

The study cohort consisted of 51 patients with unresectable, advanced, or recurrent NS-NSCLC complicated by IIPs, all of whom received first-line carboplatin plus (nab-) paclitaxel therapy. Table 1 summarizes the patients’ pretreatment characteristics. The median age was 71 years (range, 48–86 years), and 40 patients (78.4%) were men. Most patients (86.3%) had a history of smoking, and 44 (86.3%) had an ECOG-PS score of 0 or 1. Adenocarcinoma was the predominant histology observed in 35 patients (68.6%), whereas 16 patients (31.4%) had non-adenocarcinoma, including not otherwise specified carcinomas. According to the 8th edition of the tumor-node-metastasis (TNM) classification for lung cancer, 28 patients (54.9%) had stage IV disease; 10 (19.6%), stage III; 2 (3.9%), stage II; and, 11 (21.6%), postoperative recurrent disease. Patients with stage II or III disease were treated with carboplatin plus (nab-) paclitaxel therapy due to poor surgical tolerance and a high risk of radiotherapy-related complications. The PD-L1 expression status was available in 26 patients (51.0%), and 15 of these (29.4%) had a tumor proportion score (TPS) of ≥1%. Three patients (5.9%) tested positive for actionable genetic alterations, and 17 (33.3%) had an unknown mutation status. The UIP pattern was observed in 25 (49.0%) patients. The median serum levels of LDH, KL-6, and SP-D were 228 IU/L, 824 U/mL, and 105.8 ng/mL, respectively. The median %VC and %DLco were 92.1% and 74.4%, respectively. Prior to chemotherapy, 12 patients (23.5%) received glucocorticosteroids, and 2 patients (3.9%) received antifibrotic agents. Regarding chemotherapy regimens, 40 patients (78.4%) received carboplatin plus (nab-) paclitaxel and 11 patients (21.6%) received carboplatin plus paclitaxel.

Association of the TTF-1 expression with carboplatin plus (nab-) paclitaxel efficacy

Patients were categorized into TTF-1-positive and TTF-1-negative groups [n=32 (62.7%); n=19 (37.3%), respectively]. The median PFS was significantly better in the TTF-1-positive group than that in the TTF-1-negative group [8.4 months (95% CI: 6.4–11.1) vs. 4.4 months (95% CI: 2.2–5.1); P<0.001; Figure 2A]. Similarly, patients in the TTF-1-positive group demonstrated a significantly longer median OS than those in the TTF-1-negative group {11.3 months [95% CI: 10.0–not attained (NA)] vs. 8.2 months (95% CI: 5.3–11.9); P=0.007; Figure 2B}.

Figure 2 Estimated Kaplan-Meier survival curves for PFS (A) and OS (B) comparing TTF-1-positive group (n=32) and TTF-1-negative group (n=19). CI, confidence interval; NA, not attained; OS, overall survival; PFS, progression-free survival; TTF-1, thyroid transcription factor 1.

Univariate analysis demonstrated a significant association between PFS and TTF-1 expression (negative vs. positive) (HR, 4.18; 95% CI: 2.07–8.46; P<0.001; Table 2). Multivariate analysis confirmed TTF-1 expression as an independent factor significantly associated with PFS (negative vs. positive) (HR, 4.27; 95% CI: 1.96–9.29; P<0.001; Table 2). Univariate analysis identified TTF-1 expression as a significant factor associated with OS (negative vs. positive) (HR, 2.76; 95% CI: 1.28–5.95; P=0.0096; Table 3). The multivariate analysis also revealed a significant association between OS and TTF-1 expression (negative vs. positive) (HR, 2.68; 95% CI: 1.09–6.58; P=0.03; Table 3).

The efficacies of chemotherapy in the TTF-1-positive and TTF-1-negative groups are shown (Table S1). A statistically significant difference in ORR was observed between the TTF-1-positive and TTF-1-negative groups [62.5% (95% CI: 43.7–78.9%) vs. 31.6% (95% CI: 12.6–56.6%), respectively; P=0.045; Figure 3].

Figure 3 Overall response rate comparing TTF-1-positive group (n=32) and TTF-1-negative group (n=19). TTF-1, thyroid transcription factor 1.

Finally, the incidence of AEx in IIPs did not differ significantly between the TTF-1-positive and negative groups [3.2% (95% CI: 0.1–16.7%) vs. 10.5% (95% CI: 1.3–33.1%); P=0.55; Table S2].

Association of the histological subtype with carboplatin plus (nab-) paclitaxel efficacy

Of the 51 patients, 35 (68.6%) had adenocarcinoma and 16 (31.4%) had non-adenocarcinoma. The median PFS was 7.0 months (95% CI: 4.8–8.2) and 6.4 months (95% CI: 3.1–8.4) in patients with adenocarcinoma and non-adenocarcinoma, respectively (Figure S2A). The median OS was 10.8 months (95% CI: 7.7–18.6) in patients with adenocarcinoma and 9.6 months (95% CI: 6.5–11.9) in those with non-adenocarcinoma (Figure S2B). No significant differences in OS and PFS were observed between patients with adenocarcinoma and those without adenocarcinoma (HR, 0.84; 95% CI: 0.42–1.66, P=0.61 and HR, 1.18; 95% CI: 0.53–2.63, P=0.68, respectively).

Association between TTF-1 expression and the presence of interstitial pneumonia (IP) in the background lung tissue of the primary tumor

In the TTF-1-positive group (n=32), 10 patients (31.3%) had IP in the background lung tissue on HRCT, characterized by tumor lesions located within fibrotic areas or UIP patterns (Figure 4A). By contrast, in the TTF-1-negative group (n=19), 17 patients (89.5%) showed IP in the background lung tissue of the primary tumor (defined as the IP-LK group; Figure 4B). CT images were independently and blindly evaluated by two pulmonologists. The proportion of patients classified as the IP-LK group was significantly higher in the TTF-1-negative group than in the TTF-1-positive group (P<0.001; Table 1). The median PFS was not significantly worse in the IP-LK group than in the group without IP-LK [5.0 months (95% CI: 2.9–7.7) vs. 7.4 months (95% CI: 5.1–10.5); P=0.08; Figure S3A]. In contrast, the median OS was significantly worse in the IP-LK group than in the group without IP-LK [8.2 months (95% CI: 5.6–13.0) vs. 11.3 months (95% CI: 8.3–NA); P=0.04; Figure S3B]. However, the incidence of AEx of IIPs did not differ significantly between the IP-LK group and the group without IP-LK [7.4% (95% CI: 0.9–24.3%) vs. 4.2% (95% CI: 0.1–21.1%); P>0.99; Table S3].

Figure 4 Association between TTF-1 expression and background lung tissue of the primary tumor. (A) In the TTF-1-positive group (n=32), 10 patients (31.3%) exhibited IP and 22 patients (68.7%) exhibited without IP in the background lung tissue of the primary tumor on HRCT. (B) In contrast, in the TTF-1-negative group (n=19), 17 patients (89.5%) exhibited IP and 2 patients (10.5%) exhibited without IP. HRCT, high-resolution computed tomography; IP, interstitial pneumonia; TTF-1, thyroid transcription factor 1.

Discussion

In this retrospective analysis of 51 patients with NS-NSCLC complicated by IIPs, multivariate analysis demonstrated that patients with TTF-1-positive tumors experienced significantly longer OS and PFS than those with TTF-1-negative tumors when treated with carboplatin plus (nab-) paclitaxel. To our knowledge, this study is the first to establish TTF-1 expression as a prognostic indicator in patients with NS-NSCLC and coexisting IIPs receiving cytotoxic chemotherapy. Consistent with our findings, previous studies have reported significantly prolonged PFS and OS in patients with TTF-1-positive tumors compared with those with TTF-1-negative tumors treated with cytotoxic chemotherapy, immunotherapy, or chemoimmunotherapy (15-21). One potential explanation for these findings involves differences in carcinogenesis. Lung adenocarcinomas are broadly categorized into terminal respiratory unit (TRU) and non-TRU subtypes. TRU-type tumors are generally well differentiated, express TTF-1, and arise from type II pneumocytes and Clara cells, whereas non-TRU-type tumors are frequently TTF-1 negative and may be associated with squamous cell carcinomas originating from type I pneumocytes (30). Thus, TTF-1-negative tumors may exhibit behavior similar to that of squamous cell carcinomas and are associated with a poorer prognosis. Furthermore, Kelch-like ECH-associated protein 1 (KEAP1) mutations, which have been linked to the response to cytotoxic chemotherapy, occur more frequently in TTF-1-negative tumors than in TTF-1-positive tumors (31,32). Although the KEAP1 status was not evaluated in this study, it may have contributed to the poorer outcomes observed in the TTF-1-negative group. In addition, no significant differences in OS and PFS were observed between patients with and without adenocarcinoma in this study. Therefore, TTF-1 expression, rather than the histological subtype, appears to be a significant prognostic factor in patients with NSCLC complicated by IIPs treated with carboplatin plus (nab-) paclitaxel.

Low TTF-1 expression is frequently observed in tumors arising within IP-affected lung tissue. Honeycomb lung, a hallmark lesion of IIPs, particularly IPF, reflects the destruction of TRU structures due to repetitive injury and aberrant repair, which are subsequently replaced by non-TRU components (14,30,33). Honeycomb lesions represent tissue remodeling in the advanced stages of chronic and severe lung disease and are characterized by collapsed fibrotic areas and dilated airspaces lined with metaplastic bronchial/bronchiolar epithelial cells. Chronic tissue injury increases the risk of cancer, as observed in conditions such as inflammatory bowel disease and chronic hepatitis (14). Lung cancers arising in the context of IIPs predominantly originate from non-TRU cells (14). Likewise, TTF-1-negative lung cancers are also known to arise mainly from non-TRU origins (30,34). Promoter methylation of the NKX2-1/TTF-1 gene has been implicated in the loss of TTF-1 expression and is associated with metaplastic transformation of bronchial epithelium and the development of mucin-producing columnar epithelial cells in honeycomb lung tissue (33,35,36). These epigenetic and histopathological mechanisms may explain the higher prevalence of IP-related changes, such as honeycombing, observed in the background lung tissue of primary tumors in the TTF-1-negative group in our study. These findings suggest that decreased TTF-1 expression involves in the pathogenesis of lung cancer arising from IIPs. However, further basic scientific research is required to confirm these hypotheses.

Serglycin (SRGN), a chondroitin sulfate proteoglycan, has been identified as a markedly overexpressed gene in TTF-1-negative lung adenocarcinoma (37). It has been shown to enhance cancer cell migration and invasion, while also promoting the expression of inflammatory cytokines such as CXCL1, IL-6, and IL-8 (37). Furthermore, SRGN contributes to the promotion of angiogenesis, activation of fibroblasts, and suppression of antitumor immunity (37). Through these mechanisms, TTF-1-negative lung cancer is known to be associated with a poor prognosis. These cytokines can stimulate angiogenesis through interactions with fibroblasts and endothelial cells, suggesting a potential mechanistic link between TTF-1 negativity and pulmonary inflammation (35). This inflammatory microenvironment may contribute to both the development and exacerbation of IIPs. Although our study did not demonstrate a statistically significant association between TTF-1-negative tumors and AEx, this may be attributed to the limited sample size. Given the biological plausibility of this association, further studies are warranted to clarify the association between TTF-1-negative tumors and AEx, particularly the role of inflammatory mediators.

Both PFS and OS were significantly prolonged in patients with TTF-1-positive tumors compared with those with TTF-1-negative tumors, and the ORR was likewise significantly higher in the TTF-1-positive group. Consistently, among patients with NS-NSCLC complicated by ILD who received immunotherapy, TTF-1 positivity was associated with significantly longer PFS and OS (23). However, patients with NSCLC coexisting with IIPs, particularly IPF, have been excluded from most clinical trials evaluating immunotherapy. In clinical practice, the use of ICIs in this population is challenging because of the risk of AEx. Consequently, platinum-based chemotherapy remains one of the most commonly administered treatments for patients with NSCLC complicated by IIPs (5-8). Current efforts are actively exploring potential prognostic factors to guide chemotherapy in this subset of patients. Although SPC25 and CADM1 gene mutations may be diagnostic biomarkers and therapeutic targets (38), few definitive biomarkers have been validated for predicting chemotherapy response in patients with coexisting IIPs. The present study suggests that TTF-1 expression may serve as a potential prognostic factor for predicting the efficacy of carboplatin plus (nab-) paclitaxel in patients with NS-NSCLC complicated by IIPs. From a clinical perspective, this study may suggest that, even with the potential risks, the addition of ICIs or anti-angiogenic agents to platinum-doublet chemotherapy could be considered in patients with TTF-1-negative NSCLC complicated by IIPs, a population with poor prognosis. Furthermore, our findings underscore the importance of early enhancement of supportive care in TTF-1-negative group.

This study has several limitations. First, TTF-1 expression was evaluated by a single experienced pathologist at a single institution, which may have introduced observer and institutional biases. In particular, decisions on whether to initiate treatment and the choice of regimen were made at the discretion of the treating physicians and may have been affected by institution-specific treatment practices. Second, TTF-1 immunohistochemistry was conducted using the SP141 clone, which has higher sensitivity but lower specificity compared with other commonly used clones, including 8G7G3/1 and SPT24 (10,39). Third, the study had a retrospective and non-randomized design, thereby limiting the ability to eliminate selection bias. Fourth, the relatively small sample size and the absence of external validation limit the generalizability of our findings. Given the small sample size, caution is warranted in interpreting the incidence of adverse events and subgroup analyses. Furthermore, recent reports recommend that, to assert a meaningful difference or association between two clinical measures, both a P value <0.05 and an effect size exceeding the minimal clinically important difference (MCID) should be considered (40). However, similar to many previous studies, the present study relies solely on the statistical significance of P values for interpretation. Finally, the follow-up period may have been too short to adequately evaluate long-term survival outcomes. Nevertheless, multivariate analyses were conducted to reduce the impact of potential confounding factors. Further prospective studies with larger patient cohorts are warranted to confirm these results. Moreover, the relationship between TTF-1 and other lung cancer subtypes, including small-cell lung cancer with concomitant IIPs, warrants further investigation in future studies.

Conclusions

In patients with NS-NSCLC complicated by IIPs, PFS and OS were significantly better in the TTF-1-positive group than those in the TTF-1-negative group, indicating that TTF-1 expression may be a prognostic factor for carboplatin plus (nab-) paclitaxel efficacy. Furthermore, there was a significantly higher incidence of lung cancer originating within the fibrotic lung tissue in the TTF-1-negative group, suggesting that decreased TTF-1 expression may be involved in the pathogenesis of lung cancer arising from IIPs.

Acknowledgments

We thank the patients, their families, and all the investigators who participated in this study. We also thank Editage (www.editage.jp) for English language editing.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1367/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1367/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1367/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-2025-1-1367/coif). Yuto Terashima reports honoraria from Taiho Pharmaceutical. Y.K. reports honoraria from Taiho Pharmaceutical. S.N. reports grants and honoraria from Taiho Pharmaceutical. S.T. reports honoraria from Taiho Pharmaceutical. M.S. reports honoraria from Taiho Pharmaceutical. The other authors have no conflicts of interest to declare.

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 conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Graduate School of Medicine, Nippon Medical School Institutional Review Board (No. B-2023-768) and individual consent for this analysis was waived due to the retrospective nature.

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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