Impact of Results of TTF-1 Immunostaining on Efficacy of Platinum-Doublet Chemotherapy in Japanese Patients with Nonsquamous Non-Small-Cell Lung Cancer

Abstract

Background: Pemetrexed is a key drug in chemotherapy for nonsquamous non-small-cell lung cancer (nonsq NSCLC). Several studies have reported thyroid transcription factor-1 (TTF-1) as a biomarker of the efficacy in chemotherapy regimens, including pemetrexed in non-Asian people. Objective: We aimed to examine the impact of the results of the TTF-1 immunostaining of tumor cells on the therapeutic effect of chemotherapy in Japanese patients with nonsq NSCLC. Methods: We examined the results of TTF-1 immunostaining and the clinical background of Japanese patients with nonsq NSCLC who received platinum-doublet chemotherapy at our hospital, from April 2009 to April 2021, and the correlation between regimens with or without pemetrexed in progression-free survival (PFS) and overall survival (OS). The efficacy of each regimen was then compared between TTF-1-positive and TTF-1-negative tumors. Results: TTF-1 immunostaining was performed in 145 patients during the study period: 92 were positive, and 53 were negative. A total of 24 patients presented with EGFR/ALK gene abnormality (16.6%). The PFS and OS of patients who were TTF-1-positive tended to be longer than those of the patients who were TTF-1-negative under either regimen. In other words, patients who were TTF-1-negative were frequently resistant to numerous chemotherapy drugs and experienced a poor prognosis under both regimens. The OS of patients who were TTF-1-positive and treated with the pemetrexed regimen was significantly longer than those on regimens without pemetrexed (963 vs. 412 days, HR = 0.73; 95% CI 0.55–0.96, p = 0.022), whereas there was no difference in PFS. Conclusions: The positivity of TTF-1 immunostaining in tumors could be a predominant prognostic marker for patients who have advanced nonsq NSCLC. Our analysis examined the possibility of a pemetrexed regimen leading to a longer prognosis in Asian patients who were TTF-1-positive for nonsq NSCLC, as shown in previous studies.

Predictive Impact of Diffuse Positivity for TTF-1 Expression in Patients Treated With Platinum-Doublet Chemotherapy Plus Immune Checkpoint Inhibitors for Advanced Nonsquamous NSCLC

“…Previous reports have suggested that pemetrexed is less effective in patients with smoking history and TTF-1 negativity. 20 , 21 , 22 , 23 Thus, considering the possibility of similarities between TTF-1–negative and focally TTF-1–positive tumors, which have been seemed to be less effective toward pemetrexed, the results of our study indicated that survival response to chemoimmunotherapy including pemetrexed was significantly better in patients with diffusely TTF-1–positive tumors.…”

“…Several studies exploring TTF-1 expression status as a treatment response marker reported that the PFS and OS were significantly better in patients with TTF-1–positive tumors than in those with TTF-1–negative tumors. 13 , 14 , 18 , 19 , 20 , 32 , 33 , 34 Low thymidylate synthase, which is the main target of pemetrexed, was also associated with significantly better clinical response in patients with advanced nonsquamous NSCLC receiving pemetrexed-based chemotherapy. 18 , 35 Nevertheless, some patients with TTF-1–positive tumors exhibited minimal response to chemoimmunotherapy.…”

“…In addition, survival response to chemoimmunotherapy including pemetrexed was significantly better in patients with TTF-1–positive tumors than those with TTF-1–negative tumors. 13 , 18 , 19 , 20 , 21 , 22 , 23 , 24 It has been reported that KEAP1 mutations, interleukin 35, and A2A adenosine receptor, which are associated with the efficacy of immunotherapy, were more expressive in TTF-1–positive tumors than TTF-1–negative tumors. 25 , 26 , 27 , 28 In light of these previous studies, although these factors were not assessed in this study, the present study findings indicate that the behavior of tumors with focal TTF-1 positivity might be more similar to the behavior of TTF-1–negative tumors than that of tumors with diffuse TTF-1 positivity, and chemoimmunotherapy was less effective in patients with focally TTF-1–positive tumors.…”

“… 9 , 10 , 11 , 12 Among the commercially available TTF-1 clones for immunohistochemical staining, such as mouse (e.g., 8G7G3/1, SPT24, BGX-397A, SMP150, and 5S143) and rabbit (e.g., SP141, EP15844, C12-I, and G21-G) monoclonal antibodies, 36 the 8G7G3/1, SPT24, and the newly introduced SP141 clones are routinely used in clinical practice. Although 8G7G3/1 is the most frequently used clone in studies investigating the relationship between lung carcinoma and TTF-1 expression, 13 , 14 , 18 , 20 , 33 the SP141 clone was used to assess TTF-1 expression because of new technology in the present study. The SP141 clone is more sensitive but less specific than the 8G7G3/1 and SPT24 clones.…”

Prognostic and predictive value ofTTF-1 expression in patients with recurrent or advanced lung adenocarcinoma without sensitizing EGFR mutations or ALK translocation treated with platinum-based chemotherapy

“…Another study showed that the PFS and OS of TTF-1-negative patients improved after administration of PEM-free platinum regimens, whereas OS was the same regardless of the regimen in TTF-1-positive patients [18]. Two studies from Asian countries reported that TTF-1 status is a prognostic factor rather than a predictive factor of the response to platinum-based chemotherapy including PEM [24,25]. However, those studies included patients with EGFR/ALK mutations.…”