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Prospective Clinical Study of Postoperative Individualized Adjuvant Chemotherapy for Patients with Non-Small-Cell Lung Cancer Based on mRNA Expression of the Molecular Markers RRM1, TUBB3, and ERCC1

Prospective Clinical Study of Postoperative Individualized Adjuvant Chemotherapy for Patients... Hindawi Journal of Oncology Volume 2021, Article ID 8820691, 8 pages https://doi.org/10.1155/2021/8820691 Research Article Prospective Clinical Study of Postoperative Individualized Adjuvant Chemotherapy for Patients with Non-Small-Cell Lung Cancer Based on mRNA Expression of the Molecular Markers RRM1, TUBB3, and ERCC1 1 1 2 1 1 1 3 1 Jingyao Li, Yang Qiu, Junxiu Yi, Xi Liu, Shixin Zhang, Deli Tan, Tao Jing, Yi Liao, 1 1 1 Meng Tang, Jie Liu, and Haidong Wang Department of oracic Surgery, Southwest Hospital, Army Medical University, Chongqing 400038, China Department of Ultrasonic Diagnosis, Southwest Hospital, Army Medical University, Chongqing 400038, China Department of Vasculocardiology, Southwest Hospital, Army Medical University, Chongqing 400038, China Correspondence should be addressed to Haidong Wang; haidongwang1970@163.com Received 1 September 2020; Revised 12 August 2021; Accepted 11 September 2021; Published 24 September 2021 Academic Editor: Nicola Silvestris Copyright © 2021 Jingyao Li et al. +is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. To investigate the clinical significance of the mRNA expression of RRM1, TUBB3, and ERCC1 in non-small-cell lung cancer (NSCLC) tissues for the selection of adjuvant/postoperative chemotherapy regimens. Methods. Patients diagnosed with stage Ib-IIIa NSCLC were enrolled and randomly divided into a control group (undetected group) and an experimental group (detected group) after radical operation. +e control group randomly received chemotherapy with gemcitabine plus cisplatin or paclitaxel plus cisplatin. +e mRNA expression of RRM1, TUBB3, and ERCC1 was detected in the experimental group before chemotherapy, and based on the detected expression, the chemotherapy regimen of cisplatin plus gemcitabine or cisplatin plus paclitaxel was chosen. +e disease-free survival (DFS) of the control group and experimental group was compared. Results. Pathological type, stage, gene expression detection, and treatment method were not significantly correlated with DFS (P> 0.05). In the subgroups treated with gemcitabine, the median DFS was 17 months in the detected group and 10.5 months in the undetected group (hazard ratio � 0.2147, 95% confidence interval: 0.07909–0.5827, P � 0.0025). Multivariate regression analysis was per- formed to analyse whether gene expression detection was independently correlated with DFS in the subgroups treated with gemcitabine (P � 0.025). In the detected group, the prognosis of patients with low expression of RRM1 was better than that of patients with high expression of RRM1 after paclitaxel treatment (P � 0.0039). Conclusions. +e selection of chemotherapy regimen based on mRNA expression of the RRM1, TUBB3, and ERCC1 genes may improve selection of candidate patients to receive clinical chemotherapy. However, large-scale prospective clinical studies are needed for in-depth investigation. in stages Ib, IIa, IIb, and IIIa require postoperative adjuvant 1. Introduction chemotherapy to improve long-term survival [2]. Lung cancer is currently the leading cause of cancer-related In the 21st century, adjuvant chemotherapy is recom- death in humans, and its morbidity and mortality are mended for the postoperative management of stage Ib, II, constantly increasing [1]. Non-small-cell lung cancer and IIIa lung cancer patients as it improved the 5-year (NSCLC) accounts for 80–85% of all lung cancer cases. +e survival rate in several phase III clinical trials (ANITA and JBR10) and in a meta-analyses [3, 4]. +e meta-analysis by National Comprehensive Cancer Network (NCCN) guide- lines state that patients with stage Ia NSCLC do not require the LACE Collaborative Group showed that surgery com- postoperative chemotherapy, while the patients with NSCLC bined with cisplatin-based adjuvant chemotherapy 2 Journal of Oncology (mRNA expression of ERCC1, RRM1, and TUBB3) in tu- significantly improved the overall survival compared with surgical treatment alone, and the 5-year absolute benefit in mour tissue specimens from patients who needed adjuvant chemotherapy after surgery. Based on the detected gene patients who underwent the chemotherapy was 5.4%. +erefore, the recommended standard adjuvant chemo- expression levels, the appropriate first-line chemotherapy therapy regimen for patients with NSCLC after complete regimen was selected for chemotherapy and the efficacy of surgical resection is the combined use of a platinum-based gene expression-based chemotherapy was evaluated. drug and a third-generation antitumour drug (gemcitabine, paclitaxel, and vinorelbine) [5]. 2. Data and Methods Sensitivity to chemotherapy, both in the metastatic and 2.1. Source of the Specimen. All NSCLC tissue specimens in the adjuvant setting, differs by the clinicopathologic characteristics of patients [6–8]. Besides that, also molecular were obtained during surgery, and their locations were all in the central tumour area (nonnecrotic area), as confirmed by differences might be involved. As our understanding of the mechanism of chemotherapy sensitivity has advanced, it has histopathological examination. +e specimens were fixed in 10% formalin solution and sent to Yishan Medical Labo- been found that the changes in some molecular tumour markers may be related to the chemotherapy sensitivity. ratory (Guangzhou, China), an independent third party, for +erefore, in recent years, the concept of individualized gene expression detection. All patients signed an informed consent form. +is study was approved by the Ethics Review therapy has taken hold. +e selection of high-efficiency, less- toxic individualized chemotherapy regimens based on the Board of the First Affiliated Hospital of the Army Medical University. expression levels of molecular markers in lung cancer tissues will be valuable in improving survival and quality of life in patients with NSCLC [9, 10]. 2.2. Clinical Data. Patients who were diagnosed with Ribonucleotide reductase regulatory subunit 1 (RRM1) NSCLC at the Ib-IIIa stage in the Department of +oracic is often used as a predictive marker of gemcitabine efficacy Surgery in the First Affiliated Hospital of the Army Medical [11, 12]. Clinical studies showed that gemcitabine had better University from July 2014 to June 2017 were enrolled in this efficacy in lung cancer patients with low RRM1 mRNA study, and all patients voluntarily participated and signed an expression levels and prolonged their median survival time informed consent form. +e subjects were diagnosed with [13]. Tubulin beta 3 (TUBB3) is closely related to the effects NSCLC by clinical manifestations, medical history, and of antimicrotubule agents. +e close relationship between pathological result and had no history of other malignancies the TUBB3 mRNA expression level and the resistance to or relevant antitumour treatments before enrolment. +e antimicrotubule agents in chemotherapy, especially pacli- histopathological classification was based on the standard taxel, has been confirmed in many tumour cell lines and formulated by World Health Organization in 1999, and clinical studies [14]. +erefore, TUBB3 may be used as a staging was based on the criteria developed by the Inter- prognostic indicator. High expression of TUBB3 in NSCLC national Union Against Cancer in 2009. +is study enrolled patients was associated with poor prognosis. NSCLC pa- a total of 150 patients. However, more than 50% of them quit tients with low TUBB3 expression had a better response to the study, so only 67 patients successfully completed the paclitaxel and had longer median survival times. In contrast, follow-up. According to the follow-up results, they were patients with high TUBB3 expression had poor efficacy of randomly assigned into an experimental group (gene de- chemotherapy with antimicrotubule agents [15]. +e gene tected group, 39 cases) and a control group (undetected expression level of excision repair cross-complementation group, 28 cases). +e experimental group had 28 males and group 1 (ERCC1) directly affects the overall process of DNA 11 females, with an average age of 54.74 years, including 20 repair. ERCC1 is involved in the development of resistance cases of squamous cell carcinoma and 19 cases of adeno- to platinum-based chemotherapeutic agents, and its ex- carcinoma. +e control group had 23 males and five females, pression level is negatively correlated with the efficacy of with an average age of 51.78 years. +ere were nine cases of platinum-based chemotherapy agents and survival time [16]. squamous-cell carcinoma, 17 cases of adenocarcinoma, and Detection of ERCC1 mRNA expression level before plati- two cases of other malignancies. num-based chemotherapy can improve the treatment effi- cacy and the survival rate of patients. +erefore, ERCC1 gene expression can be used as a marker for monitoring cisplatin 2.3. Treatment Method efficacy. Individualized treatment is the ultimate direction of 2.3.1. Random Grouping. Subjects who met the inclusion chemotherapy for NSCLC. Chemotherapy regimens based criteria and signed the informed consent form were ran- on the information of molecular markers in patients have domly assigned to the experimental group or the control better efficacy, a better safety profile, and lower costs and group at a 1 : 1 ratio according to the minimization method result in better quality of life [17]. As different races carry (a dynamic randomized algorithm) by a central random- different genetic information, their treatment regimens and ization system (which was supervised by Chengdu Mingke efficacy should be different, as has been recognized in Hongneng Clinical Research Co., Ltd., an independent molecular-targeted therapy for patients with EGFR muta- third party). +e control group was then randomly divided tions [18]. In this study, a prospective randomized controlled into a gemcitabine group and a paclitaxel group (2 : 1 : 1 trial was conducted to measure the molecular markers randomization). After randomization of the subjects, the Journal of Oncology 3 Screening cases Sign informed consent form and before operation randomly enrolled cases Screening cases Operation and during operation specimen collection Control group Experimental group Gemcitabine Paclitaxel plus ERCC1, RRM1 and TUBB3 plus carboplatin carboplatin mRNAs were detected Gemcitabine Paclitaxel plus plus carboplatin carboplatin 4 Cycles 4 Cycles Follow-up Follow-up Figure 1: Experimental flowchart. central randomization system immediately assigned each 2.3.3. Control Group. Patients randomized to the control subject a unique number (i.e., a random number) via SMS group underwent four cycles (21 to 28 days per cycle) of or Internet. chemotherapy with gemcitabine (1250 mg/m , d1, 8) plus carboplatin (AUC � 5, d1) or four cycles (21 to 28 days per cycle) of chemotherapy with paclitaxel (1250 mg/m , d1) plus carboplatin (AUC � 5, d1). 2.3.2. Experimental Group. +e platinum-based dual-agent chemotherapy regimen recommended by the NCCN guidelines was used for chemotherapy in NSCLC patients. 2.3.4. Follow-Up. After the chemotherapy, patients were Before chemotherapy, ERCC1, RRM1, and TUBB3 mRNAs followed up once every 3 months in the first year and the were detected in patients in the experimental group to second year and once every 6 months in the third year until further divide them into a gemcitabine plus carboplatin the disease progressed or the 36-month follow-up was group (ERCC1 <75%, RRM1< TUBB3, and RRM1< 75%) completed. and a paclitaxel plus carboplatin group (ERCC1< 75%, TUBB3< RRM1, and TUBB3< 75%) (Figure 1). +e gemcitabine plus carboplatin group received four cycles (21 2.4. Method of Gene Expression Detection. +e mRNA ex- to 28 days per cycle) of chemotherapy with gemcitabine pression levels of RRM1, TUBB3, and ERCC1 were detected (1250 mg/m , d1, 8) plus carboplatin (area under the curve using the branched-DNA liquid chip technique. +e specific (AUC) � 5, d1). +e paclitaxel plus carboplatin group re- steps were as follows. (1) An appropriate amount of the lysis ceived four cycles (21 to 28 days per cycle) of chemotherapy buffer was added to formalin-fixed, paraffin-embedded with paclitaxel (1250 mg/m , d1) plus carboplatin samples, they were lysed at 56 C for 2 h, and the total mRNA (AUC � 5, d1). purity in the lysis buffer was analysed. (2) +e lysis buffer 4 Journal of Oncology Table 1: Univariate analysis of the prognosis of the enrolled patients. Clinicopathologic variable N � 67 Median DFS (months) HR 95% CI P value Tumour type Patient group Squamous cell carcinoma 29 16.00 0.6841 0.3754–1.247 0.2151 Adenocarcinoma 36 14.00 Others (not included in statistical analysis) 2 Stage I 28 20.00 II 20 16.00 0.5412 III 19 14.00 Age, years >52 32 16.50 0.8897 0.4925–1.607 0.6984 ≤52 35 16.00 Sex Male 51 16.00 1.096 0.5540–2.169 0.7918 Female 16 20.00 Whether to detect the expression of three genes Yes 39 16.00 0.6693 0.3616–1.239 0.2011 No 28 12.50 Treatment Gemcitabine 31 16.00 1.540 0.8447–2.806 0.1588 Paclitaxel 36 22.5 was transferred to the incubation plate, and the supportive treatment in which tumour is not detectable in patient’s probe-microspheres, supportive extension probes, and body) of the control group and experimental group. buffer were added and incubated at 55 C with shaking. (3) Univariate analysis for prognosis and the calculation of On the next day, the mixture was placed on a magnetic stand hazard ratios (HR) with corresponding 95% confidence for 1 min. +e supernatant was discarded. +e wash solution intervals (CI) and logrank-P value were conducted using was added, and the mixture was shaken for 1 min. After the GraphPad Prism 7.0 to compare the efficacy and survival mixture rested on the magnetic stand for 1 min, the su- between the two groups of patients. Multivariate Cox pernatant was discarded. (4) +e amplification and exten- regression analysis and Fisher’s exact test were performed sion probes and the labelled probes were added to the wash using the SPSS statistical software, version 19.0. P< 0.05 solution at the same time, and the solution was shaken at was considered significant. 50 C for 1 h and placed on a magnetic stand for 1 min. +e supernatant was discarded, and the mixture was rinsed with 3. Results wash solution twice. (5) Streptavidin-phycoerythrin was added to the wash solution, followed by shaking at 50 C for Univariate analysis of the prognosis of the enrolled patients 30 min. After the mixture rested on the magnetic stand for showed that, between the two groups, there was no significant 1 min, the supernatant was discarded and the mixture was difference in the correlations between disease-free survival washed twice. Finally, the wash solution was added, with and age, sex, pathological type, stage, and gene expression shaking for 5 min. (6) Data from a Luminex array reader detection (P> 0.05) (Table 1). Moreover, we compared the were analysed to obtain the detected gene expression levels. baseline characteristics of all patients. Fisher’s exact test in- dicated that there was no significant difference in all clini- copathologic variable or treatment method (Table S1). 2.5. Patient Follow-Up. We conducted telephone or out- +e patients were divided into subgroups according to patient follow-up of patients with NSCLC enrolled in this the tumour type, stage, age, years, sex, whether to detect the study. +e follow-up examinations included chest computed expression of three genes, and the treatment. +e impact of tomography, abdominal ultrasonography, cranial magnetic gene expression detection on prognosis was analysed. +e resonance imaging, whole-body bone scan, and positron- results suggested that, in the subgroups treated with gem- emission tomography-computed tomography if necessary. citabine, the median DFS was 17 months in the detected We defined postoperative recurrence and metastasis in lung group and 10.5 months in the undetected group (hazard cancer patients as the presence of extrapulmonary and ratio (HR) � 0.2147, 95% confidence interval (CI): intrapulmonary space-occupying lesions and typical lung 0.07909–0.5827). +at is, the risk of recurrence after gem- cancer manifestations on imaging examinations. +e follow- citabine treatment in the detected group was 0.2147 times up lasted 3 years and ended on December 31, 2018. that in the undetected group (Table 2). +e survival curve is shown in Figure 2. +e prognosis-related multivariate re- 2.6. Statistical Methods. Kaplan–Meier survival curves gression analysis showed no correlation between patho- were drawn by R version 3.6.2 software to compare the logical type, stage, age, and sex in gemcitabine-treated disease-free survival (DFS: the length of time after patients (P> 0.05), but gene expression detection was Journal of Oncology 5 Table 2: +e patients were divided into subgroups according to their clinical characteristics, and the impact of gene expression detection on prognosis was analysed. Patient group Median DFS (months) Variable Experimental group vs. control Experimental group vs. control HR 95% CI P value group group Tumour type Squamous cell n � 19 vs. n � 17 16.00 vs. 14.00 0.7601 0.3518–1.642 0.4851 carcinoma Adenocarcinoma n � 20 vs. n � 9 21.00 vs. 10.00 0.5940 0.1951–1.808 0.3591 Stage I n � 16 vs. n � 12 36.00 vs. 12.00 0.4111 0.1468–1.151 0.0905 II n � 12 vs. n � 8 16.00 vs. 16.50 1.404 0.4515–4.366 0.5577 III n � 11 vs. n � 8 16.00 vs. 11.00 0.5853 0.1939–1.767 0.3419 Age, years ≤52 n � 19 vs. n � 16 16.00 vs. 10.5 0.5402 0.2313–1.262 0.1547 >52 n � 20 vs. n � 12 18.50 vs. 14.00 0.9117 0.3695–2.249 0.8409 Sex Male n � 28 vs. n � 23 16.00 vs. 11.00 0.5825 0.2882–1.177 0.1323 Female n � 11 vs. n � 5 20.00 vs. 22.00 1.127 0.2981–4.258 0.8605 Treatment Gemcitabine n � 19 vs. n � 12 17.00 vs. 10.50 0.2147 0.07909–0.5827 0.0025 Paclitaxel n � 20 vs. n � 16 16.00 vs. 22.50 1.041 0.4371–2.479 0.9279 1.00 overall prognosis of NSCLC patients is poor due to the frequent occurrence of chemoresistance [21]. +e expression of DNA repair-related genes in lung cancer cells is closely 0.75 related to their chemotherapy resistance [22, 23]. Among these genes, ERCC1 is the most studied. Its low expression is 0.50 often accompanied by an increase in the incidence of lung cancer, while its high expression can cause the rapid repair of 0.25 p = 0.0025 damaged DNA in cells arrested at G2/M phase, resulting in cisplatin resistance [24]. RRM1 is a rate-limiting enzyme in 0.00 the DNA synthesis pathway, and its high expression is as- 0 10 20 30 40 sociated with gemcitabine resistance [10]. TUBB3 protein, Months encoded by the TUBB3 gene, has the closest relationship Number at risk with the sensitivity of cancer cells to antimicrotubule che- Gemcitabine-detected 19 16 960 Gemcitabine-not detected 12 8000 motherapeutic agents. Tumour patients with low expression of TUBB3 have a better response to paclitaxel and have 0 10 20 30 40 longer median survival times, while the efficacy of anti- Months microtubule agents is poor for patients with high TUBB3 + Gemcitabine-detected expression [25, 26]. Different individualized chemotherapy + Gemcitabine-not detected regimens targeting different molecular markers have had Figure 2: Survival analysis of patients’ gene expression detected or success in improving the survival time of NSCLC patients. not in the gemcitabine treatment subgroup. Predicting the efficacy of chemotherapy by detecting certain molecular markers may be a way to improve the effectiveness independently correlated with DFS (P � 0.025, 95% CI: of chemotherapy and the long-term survival rate of NSCLC 0.121–0.870) (Table 3). patients in the future [27]. Patients were dichotomized based on the median mRNA On the basis of experimental research, this study de- expression of RRM1, TUBB3, and ERCC1 genes. Patients tected molecular markers (ERCC1, RRM1, and TUBB3 with low RRM1 expression had a better prognosis after mRNAs) in tumour tissue specimens from patients who paclitaxel treatment than those with high RRM1 expression. needed adjuvant chemotherapy after surgery. Based on the +e χ value of the logrank test was 8.350 (P � 0.0039, detected gene expression levels, the appropriate first-line HR � 0.1638, 95% CI: 0.04801–0.5588). +e survival curve is chemotherapy regimen was selected. After four cycles of shown in Figure 3. chemotherapy, patients were strictly followed up, and the DFS of each group of patients was statistically analysed. +e relationship between the gene expression levels of ERCC1, 4. Discussion RRM1, and TUBB3 and the sensitivity to first-line chemo- NSCLC is the most common lung cancer, accounting for therapy after surgery for NSCLC was prospectively inves- approximately 80% of all lung cancer cases [19, 20]. +e tigated to find out whether ERCC1, RRM1, and TUBB3 genes Disease−free survival (%) 6 Journal of Oncology Table 3: Multivariable Cox regression analysis of the prognosis of the patients treated with gemcitabine. Clinicopathologic variable N � 31 Median DFS (months) HR 95% CI P value Tumour type Adenocarcinoma 21 14.00 0.895 0.344–2.327 0.819 Squamous cell carcinoma 10 16.00 Stage I 12 16.00 0.281 II 7 16.00 0.508 0.188–1.377 0.183 III 12 11.00 0.459 0.149–1.420 0.177 Age, years >52 14 14.00 0.861 0.359–2.065 0.738 ≤52 17 16.00 Sex Female 5 20.00 1.518 0.364–6.340 0.567 Male 26 14.00 Whether to detect the expression of three genes Yes 19 17.00 0.324 0.121–0.870 0.025 No 12 10.00 1.00 recurrence (P � 0.0025, HR � 0.2147, 95% CI: 0.07909–0.5827), mainly because the gene expression results 0.75 let patients with high RRM1 expression avoid gemcitabine treatment. +e detection of RRM1 expression can help 0.50 determine whether gemcitabine should be included in chemotherapy. Patients with high RRM1 expression were 0.25 not suitable for gemcitabine chemotherapy, in line with a p = 0.0039 previous report [10]. Among the patients who underwent gene expression detection, patients with low expression of 0.00 TUBB3 and RRM1 benefited most from paclitaxel treatment 0 10 20 30 (P � 0.0039, HR � 0.1638, 95% CI: 0.04801–0.5588). De- Months Number at risk tection of TUBB3 and RRM1 expression can help determine Paclitaxel-RRM1 High 632222 whether paclitaxel should be included in chemotherapy, and Paclitaxel-RRM1 Low 10 97777 patients with low expression of TUBB3 and RRM1 are 10 15 20 25 30 35 suitable for paclitaxel treatment [24]. Because of the high Months percentage of patients who quit this study, the targeted + Paclitaxel-RRM1 High overall survival could not be reached. +erefore, more cases + Paclitaxel-RRM1 Low are needed and the follow-up mechanism needs to be Figure 3: Survival analysis of patients with low RRM1 expression improved. and patients with high RRM1 expression in the paclitaxel-treated In summary, the intratumoural expression levels of the subgroup. three genes, ERCC1, TUBB3, and RRM1, were detected. Basing the chemotherapy regimens on the detected gene expression levels played a positive role in the control of could be used as markers for sensitivity to first-line che- disease progression. +is study provides a basis for the motherapy. +is study provides a theoretical and practical clinical application of discoveries on chemotherapy resis- basis for postoperative individualized adjuvant chemotherapy tance and new ideas for chemotherapy regimens in lung for Chinese NSCLC patients and has important implications cancer. However, the occurrence and development of lung for both scientific research and clinical treatment. cancer are a long-term process with changes in multiple A total of 67 patients who were enrolled in this study and genes, and it is impossible for a single mechanism to completely explain chemotherapy resistance in lung cancer. had complete follow-up data were randomly divided into the experimental group (detected group) and the control group To translate the discoveries on chemotherapy resistance into clinical practice, more prospective randomized clinical (undetected group) using the central randomization system. Since the small number of cases may have affected the studies are needed to confirm the feasibility of the selection correlation between gene expression detection and DFS, the of chemotherapy regimens to ultimately improve the number of cases needs to be expanded to verify our con- therapeutic efficacy and patient survival. clusions. In the subgroups treated with gemcitabine, gene expression detection was independently correlated with DFS Data Availability after postoperative chemotherapy (P � 0.025, 95% CI: 0.121–0.870), and the detection of expression of the RRM1, All data generated or analysed during this study are included TUBB3, and ERCC1 genes reduced the risk of postoperative in this published article. Disease−free survival (%) Journal of Oncology 7 with advanced NSCLC and a PD-L1 expression of ≥50%,” Ethical Approval Cancer Immunology Immunotherapy, vol. 69, no. 11, pp. 2209–2221, 2020. +e study has been approved by the Ethics Review Board of [7] A. Brunelli, C. Pompili, M. 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Prospective Clinical Study of Postoperative Individualized Adjuvant Chemotherapy for Patients with Non-Small-Cell Lung Cancer Based on mRNA Expression of the Molecular Markers RRM1, TUBB3, and ERCC1

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Hindawi Journal of Oncology Volume 2021, Article ID 8820691, 8 pages https://doi.org/10.1155/2021/8820691 Research Article Prospective Clinical Study of Postoperative Individualized Adjuvant Chemotherapy for Patients with Non-Small-Cell Lung Cancer Based on mRNA Expression of the Molecular Markers RRM1, TUBB3, and ERCC1 1 1 2 1 1 1 3 1 Jingyao Li, Yang Qiu, Junxiu Yi, Xi Liu, Shixin Zhang, Deli Tan, Tao Jing, Yi Liao, 1 1 1 Meng Tang, Jie Liu, and Haidong Wang Department of oracic Surgery, Southwest Hospital, Army Medical University, Chongqing 400038, China Department of Ultrasonic Diagnosis, Southwest Hospital, Army Medical University, Chongqing 400038, China Department of Vasculocardiology, Southwest Hospital, Army Medical University, Chongqing 400038, China Correspondence should be addressed to Haidong Wang; haidongwang1970@163.com Received 1 September 2020; Revised 12 August 2021; Accepted 11 September 2021; Published 24 September 2021 Academic Editor: Nicola Silvestris Copyright © 2021 Jingyao Li et al. +is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. To investigate the clinical significance of the mRNA expression of RRM1, TUBB3, and ERCC1 in non-small-cell lung cancer (NSCLC) tissues for the selection of adjuvant/postoperative chemotherapy regimens. Methods. Patients diagnosed with stage Ib-IIIa NSCLC were enrolled and randomly divided into a control group (undetected group) and an experimental group (detected group) after radical operation. +e control group randomly received chemotherapy with gemcitabine plus cisplatin or paclitaxel plus cisplatin. +e mRNA expression of RRM1, TUBB3, and ERCC1 was detected in the experimental group before chemotherapy, and based on the detected expression, the chemotherapy regimen of cisplatin plus gemcitabine or cisplatin plus paclitaxel was chosen. +e disease-free survival (DFS) of the control group and experimental group was compared. Results. Pathological type, stage, gene expression detection, and treatment method were not significantly correlated with DFS (P> 0.05). In the subgroups treated with gemcitabine, the median DFS was 17 months in the detected group and 10.5 months in the undetected group (hazard ratio � 0.2147, 95% confidence interval: 0.07909–0.5827, P � 0.0025). Multivariate regression analysis was per- formed to analyse whether gene expression detection was independently correlated with DFS in the subgroups treated with gemcitabine (P � 0.025). In the detected group, the prognosis of patients with low expression of RRM1 was better than that of patients with high expression of RRM1 after paclitaxel treatment (P � 0.0039). Conclusions. +e selection of chemotherapy regimen based on mRNA expression of the RRM1, TUBB3, and ERCC1 genes may improve selection of candidate patients to receive clinical chemotherapy. However, large-scale prospective clinical studies are needed for in-depth investigation. in stages Ib, IIa, IIb, and IIIa require postoperative adjuvant 1. Introduction chemotherapy to improve long-term survival [2]. Lung cancer is currently the leading cause of cancer-related In the 21st century, adjuvant chemotherapy is recom- death in humans, and its morbidity and mortality are mended for the postoperative management of stage Ib, II, constantly increasing [1]. Non-small-cell lung cancer and IIIa lung cancer patients as it improved the 5-year (NSCLC) accounts for 80–85% of all lung cancer cases. +e survival rate in several phase III clinical trials (ANITA and JBR10) and in a meta-analyses [3, 4]. +e meta-analysis by National Comprehensive Cancer Network (NCCN) guide- lines state that patients with stage Ia NSCLC do not require the LACE Collaborative Group showed that surgery com- postoperative chemotherapy, while the patients with NSCLC bined with cisplatin-based adjuvant chemotherapy 2 Journal of Oncology (mRNA expression of ERCC1, RRM1, and TUBB3) in tu- significantly improved the overall survival compared with surgical treatment alone, and the 5-year absolute benefit in mour tissue specimens from patients who needed adjuvant chemotherapy after surgery. Based on the detected gene patients who underwent the chemotherapy was 5.4%. +erefore, the recommended standard adjuvant chemo- expression levels, the appropriate first-line chemotherapy therapy regimen for patients with NSCLC after complete regimen was selected for chemotherapy and the efficacy of surgical resection is the combined use of a platinum-based gene expression-based chemotherapy was evaluated. drug and a third-generation antitumour drug (gemcitabine, paclitaxel, and vinorelbine) [5]. 2. Data and Methods Sensitivity to chemotherapy, both in the metastatic and 2.1. Source of the Specimen. All NSCLC tissue specimens in the adjuvant setting, differs by the clinicopathologic characteristics of patients [6–8]. Besides that, also molecular were obtained during surgery, and their locations were all in the central tumour area (nonnecrotic area), as confirmed by differences might be involved. As our understanding of the mechanism of chemotherapy sensitivity has advanced, it has histopathological examination. +e specimens were fixed in 10% formalin solution and sent to Yishan Medical Labo- been found that the changes in some molecular tumour markers may be related to the chemotherapy sensitivity. ratory (Guangzhou, China), an independent third party, for +erefore, in recent years, the concept of individualized gene expression detection. All patients signed an informed consent form. +is study was approved by the Ethics Review therapy has taken hold. +e selection of high-efficiency, less- toxic individualized chemotherapy regimens based on the Board of the First Affiliated Hospital of the Army Medical University. expression levels of molecular markers in lung cancer tissues will be valuable in improving survival and quality of life in patients with NSCLC [9, 10]. 2.2. Clinical Data. Patients who were diagnosed with Ribonucleotide reductase regulatory subunit 1 (RRM1) NSCLC at the Ib-IIIa stage in the Department of +oracic is often used as a predictive marker of gemcitabine efficacy Surgery in the First Affiliated Hospital of the Army Medical [11, 12]. Clinical studies showed that gemcitabine had better University from July 2014 to June 2017 were enrolled in this efficacy in lung cancer patients with low RRM1 mRNA study, and all patients voluntarily participated and signed an expression levels and prolonged their median survival time informed consent form. +e subjects were diagnosed with [13]. Tubulin beta 3 (TUBB3) is closely related to the effects NSCLC by clinical manifestations, medical history, and of antimicrotubule agents. +e close relationship between pathological result and had no history of other malignancies the TUBB3 mRNA expression level and the resistance to or relevant antitumour treatments before enrolment. +e antimicrotubule agents in chemotherapy, especially pacli- histopathological classification was based on the standard taxel, has been confirmed in many tumour cell lines and formulated by World Health Organization in 1999, and clinical studies [14]. +erefore, TUBB3 may be used as a staging was based on the criteria developed by the Inter- prognostic indicator. High expression of TUBB3 in NSCLC national Union Against Cancer in 2009. +is study enrolled patients was associated with poor prognosis. NSCLC pa- a total of 150 patients. However, more than 50% of them quit tients with low TUBB3 expression had a better response to the study, so only 67 patients successfully completed the paclitaxel and had longer median survival times. In contrast, follow-up. According to the follow-up results, they were patients with high TUBB3 expression had poor efficacy of randomly assigned into an experimental group (gene de- chemotherapy with antimicrotubule agents [15]. +e gene tected group, 39 cases) and a control group (undetected expression level of excision repair cross-complementation group, 28 cases). +e experimental group had 28 males and group 1 (ERCC1) directly affects the overall process of DNA 11 females, with an average age of 54.74 years, including 20 repair. ERCC1 is involved in the development of resistance cases of squamous cell carcinoma and 19 cases of adeno- to platinum-based chemotherapeutic agents, and its ex- carcinoma. +e control group had 23 males and five females, pression level is negatively correlated with the efficacy of with an average age of 51.78 years. +ere were nine cases of platinum-based chemotherapy agents and survival time [16]. squamous-cell carcinoma, 17 cases of adenocarcinoma, and Detection of ERCC1 mRNA expression level before plati- two cases of other malignancies. num-based chemotherapy can improve the treatment effi- cacy and the survival rate of patients. +erefore, ERCC1 gene expression can be used as a marker for monitoring cisplatin 2.3. Treatment Method efficacy. Individualized treatment is the ultimate direction of 2.3.1. Random Grouping. Subjects who met the inclusion chemotherapy for NSCLC. Chemotherapy regimens based criteria and signed the informed consent form were ran- on the information of molecular markers in patients have domly assigned to the experimental group or the control better efficacy, a better safety profile, and lower costs and group at a 1 : 1 ratio according to the minimization method result in better quality of life [17]. As different races carry (a dynamic randomized algorithm) by a central random- different genetic information, their treatment regimens and ization system (which was supervised by Chengdu Mingke efficacy should be different, as has been recognized in Hongneng Clinical Research Co., Ltd., an independent molecular-targeted therapy for patients with EGFR muta- third party). +e control group was then randomly divided tions [18]. In this study, a prospective randomized controlled into a gemcitabine group and a paclitaxel group (2 : 1 : 1 trial was conducted to measure the molecular markers randomization). After randomization of the subjects, the Journal of Oncology 3 Screening cases Sign informed consent form and before operation randomly enrolled cases Screening cases Operation and during operation specimen collection Control group Experimental group Gemcitabine Paclitaxel plus ERCC1, RRM1 and TUBB3 plus carboplatin carboplatin mRNAs were detected Gemcitabine Paclitaxel plus plus carboplatin carboplatin 4 Cycles 4 Cycles Follow-up Follow-up Figure 1: Experimental flowchart. central randomization system immediately assigned each 2.3.3. Control Group. Patients randomized to the control subject a unique number (i.e., a random number) via SMS group underwent four cycles (21 to 28 days per cycle) of or Internet. chemotherapy with gemcitabine (1250 mg/m , d1, 8) plus carboplatin (AUC � 5, d1) or four cycles (21 to 28 days per cycle) of chemotherapy with paclitaxel (1250 mg/m , d1) plus carboplatin (AUC � 5, d1). 2.3.2. Experimental Group. +e platinum-based dual-agent chemotherapy regimen recommended by the NCCN guidelines was used for chemotherapy in NSCLC patients. 2.3.4. Follow-Up. After the chemotherapy, patients were Before chemotherapy, ERCC1, RRM1, and TUBB3 mRNAs followed up once every 3 months in the first year and the were detected in patients in the experimental group to second year and once every 6 months in the third year until further divide them into a gemcitabine plus carboplatin the disease progressed or the 36-month follow-up was group (ERCC1 <75%, RRM1< TUBB3, and RRM1< 75%) completed. and a paclitaxel plus carboplatin group (ERCC1< 75%, TUBB3< RRM1, and TUBB3< 75%) (Figure 1). +e gemcitabine plus carboplatin group received four cycles (21 2.4. Method of Gene Expression Detection. +e mRNA ex- to 28 days per cycle) of chemotherapy with gemcitabine pression levels of RRM1, TUBB3, and ERCC1 were detected (1250 mg/m , d1, 8) plus carboplatin (area under the curve using the branched-DNA liquid chip technique. +e specific (AUC) � 5, d1). +e paclitaxel plus carboplatin group re- steps were as follows. (1) An appropriate amount of the lysis ceived four cycles (21 to 28 days per cycle) of chemotherapy buffer was added to formalin-fixed, paraffin-embedded with paclitaxel (1250 mg/m , d1) plus carboplatin samples, they were lysed at 56 C for 2 h, and the total mRNA (AUC � 5, d1). purity in the lysis buffer was analysed. (2) +e lysis buffer 4 Journal of Oncology Table 1: Univariate analysis of the prognosis of the enrolled patients. Clinicopathologic variable N � 67 Median DFS (months) HR 95% CI P value Tumour type Patient group Squamous cell carcinoma 29 16.00 0.6841 0.3754–1.247 0.2151 Adenocarcinoma 36 14.00 Others (not included in statistical analysis) 2 Stage I 28 20.00 II 20 16.00 0.5412 III 19 14.00 Age, years >52 32 16.50 0.8897 0.4925–1.607 0.6984 ≤52 35 16.00 Sex Male 51 16.00 1.096 0.5540–2.169 0.7918 Female 16 20.00 Whether to detect the expression of three genes Yes 39 16.00 0.6693 0.3616–1.239 0.2011 No 28 12.50 Treatment Gemcitabine 31 16.00 1.540 0.8447–2.806 0.1588 Paclitaxel 36 22.5 was transferred to the incubation plate, and the supportive treatment in which tumour is not detectable in patient’s probe-microspheres, supportive extension probes, and body) of the control group and experimental group. buffer were added and incubated at 55 C with shaking. (3) Univariate analysis for prognosis and the calculation of On the next day, the mixture was placed on a magnetic stand hazard ratios (HR) with corresponding 95% confidence for 1 min. +e supernatant was discarded. +e wash solution intervals (CI) and logrank-P value were conducted using was added, and the mixture was shaken for 1 min. After the GraphPad Prism 7.0 to compare the efficacy and survival mixture rested on the magnetic stand for 1 min, the su- between the two groups of patients. Multivariate Cox pernatant was discarded. (4) +e amplification and exten- regression analysis and Fisher’s exact test were performed sion probes and the labelled probes were added to the wash using the SPSS statistical software, version 19.0. P< 0.05 solution at the same time, and the solution was shaken at was considered significant. 50 C for 1 h and placed on a magnetic stand for 1 min. +e supernatant was discarded, and the mixture was rinsed with 3. Results wash solution twice. (5) Streptavidin-phycoerythrin was added to the wash solution, followed by shaking at 50 C for Univariate analysis of the prognosis of the enrolled patients 30 min. After the mixture rested on the magnetic stand for showed that, between the two groups, there was no significant 1 min, the supernatant was discarded and the mixture was difference in the correlations between disease-free survival washed twice. Finally, the wash solution was added, with and age, sex, pathological type, stage, and gene expression shaking for 5 min. (6) Data from a Luminex array reader detection (P> 0.05) (Table 1). Moreover, we compared the were analysed to obtain the detected gene expression levels. baseline characteristics of all patients. Fisher’s exact test in- dicated that there was no significant difference in all clini- copathologic variable or treatment method (Table S1). 2.5. Patient Follow-Up. We conducted telephone or out- +e patients were divided into subgroups according to patient follow-up of patients with NSCLC enrolled in this the tumour type, stage, age, years, sex, whether to detect the study. +e follow-up examinations included chest computed expression of three genes, and the treatment. +e impact of tomography, abdominal ultrasonography, cranial magnetic gene expression detection on prognosis was analysed. +e resonance imaging, whole-body bone scan, and positron- results suggested that, in the subgroups treated with gem- emission tomography-computed tomography if necessary. citabine, the median DFS was 17 months in the detected We defined postoperative recurrence and metastasis in lung group and 10.5 months in the undetected group (hazard cancer patients as the presence of extrapulmonary and ratio (HR) � 0.2147, 95% confidence interval (CI): intrapulmonary space-occupying lesions and typical lung 0.07909–0.5827). +at is, the risk of recurrence after gem- cancer manifestations on imaging examinations. +e follow- citabine treatment in the detected group was 0.2147 times up lasted 3 years and ended on December 31, 2018. that in the undetected group (Table 2). +e survival curve is shown in Figure 2. +e prognosis-related multivariate re- 2.6. Statistical Methods. Kaplan–Meier survival curves gression analysis showed no correlation between patho- were drawn by R version 3.6.2 software to compare the logical type, stage, age, and sex in gemcitabine-treated disease-free survival (DFS: the length of time after patients (P> 0.05), but gene expression detection was Journal of Oncology 5 Table 2: +e patients were divided into subgroups according to their clinical characteristics, and the impact of gene expression detection on prognosis was analysed. Patient group Median DFS (months) Variable Experimental group vs. control Experimental group vs. control HR 95% CI P value group group Tumour type Squamous cell n � 19 vs. n � 17 16.00 vs. 14.00 0.7601 0.3518–1.642 0.4851 carcinoma Adenocarcinoma n � 20 vs. n � 9 21.00 vs. 10.00 0.5940 0.1951–1.808 0.3591 Stage I n � 16 vs. n � 12 36.00 vs. 12.00 0.4111 0.1468–1.151 0.0905 II n � 12 vs. n � 8 16.00 vs. 16.50 1.404 0.4515–4.366 0.5577 III n � 11 vs. n � 8 16.00 vs. 11.00 0.5853 0.1939–1.767 0.3419 Age, years ≤52 n � 19 vs. n � 16 16.00 vs. 10.5 0.5402 0.2313–1.262 0.1547 >52 n � 20 vs. n � 12 18.50 vs. 14.00 0.9117 0.3695–2.249 0.8409 Sex Male n � 28 vs. n � 23 16.00 vs. 11.00 0.5825 0.2882–1.177 0.1323 Female n � 11 vs. n � 5 20.00 vs. 22.00 1.127 0.2981–4.258 0.8605 Treatment Gemcitabine n � 19 vs. n � 12 17.00 vs. 10.50 0.2147 0.07909–0.5827 0.0025 Paclitaxel n � 20 vs. n � 16 16.00 vs. 22.50 1.041 0.4371–2.479 0.9279 1.00 overall prognosis of NSCLC patients is poor due to the frequent occurrence of chemoresistance [21]. +e expression of DNA repair-related genes in lung cancer cells is closely 0.75 related to their chemotherapy resistance [22, 23]. Among these genes, ERCC1 is the most studied. Its low expression is 0.50 often accompanied by an increase in the incidence of lung cancer, while its high expression can cause the rapid repair of 0.25 p = 0.0025 damaged DNA in cells arrested at G2/M phase, resulting in cisplatin resistance [24]. RRM1 is a rate-limiting enzyme in 0.00 the DNA synthesis pathway, and its high expression is as- 0 10 20 30 40 sociated with gemcitabine resistance [10]. TUBB3 protein, Months encoded by the TUBB3 gene, has the closest relationship Number at risk with the sensitivity of cancer cells to antimicrotubule che- Gemcitabine-detected 19 16 960 Gemcitabine-not detected 12 8000 motherapeutic agents. Tumour patients with low expression of TUBB3 have a better response to paclitaxel and have 0 10 20 30 40 longer median survival times, while the efficacy of anti- Months microtubule agents is poor for patients with high TUBB3 + Gemcitabine-detected expression [25, 26]. Different individualized chemotherapy + Gemcitabine-not detected regimens targeting different molecular markers have had Figure 2: Survival analysis of patients’ gene expression detected or success in improving the survival time of NSCLC patients. not in the gemcitabine treatment subgroup. Predicting the efficacy of chemotherapy by detecting certain molecular markers may be a way to improve the effectiveness independently correlated with DFS (P � 0.025, 95% CI: of chemotherapy and the long-term survival rate of NSCLC 0.121–0.870) (Table 3). patients in the future [27]. Patients were dichotomized based on the median mRNA On the basis of experimental research, this study de- expression of RRM1, TUBB3, and ERCC1 genes. Patients tected molecular markers (ERCC1, RRM1, and TUBB3 with low RRM1 expression had a better prognosis after mRNAs) in tumour tissue specimens from patients who paclitaxel treatment than those with high RRM1 expression. needed adjuvant chemotherapy after surgery. Based on the +e χ value of the logrank test was 8.350 (P � 0.0039, detected gene expression levels, the appropriate first-line HR � 0.1638, 95% CI: 0.04801–0.5588). +e survival curve is chemotherapy regimen was selected. After four cycles of shown in Figure 3. chemotherapy, patients were strictly followed up, and the DFS of each group of patients was statistically analysed. +e relationship between the gene expression levels of ERCC1, 4. Discussion RRM1, and TUBB3 and the sensitivity to first-line chemo- NSCLC is the most common lung cancer, accounting for therapy after surgery for NSCLC was prospectively inves- approximately 80% of all lung cancer cases [19, 20]. +e tigated to find out whether ERCC1, RRM1, and TUBB3 genes Disease−free survival (%) 6 Journal of Oncology Table 3: Multivariable Cox regression analysis of the prognosis of the patients treated with gemcitabine. Clinicopathologic variable N � 31 Median DFS (months) HR 95% CI P value Tumour type Adenocarcinoma 21 14.00 0.895 0.344–2.327 0.819 Squamous cell carcinoma 10 16.00 Stage I 12 16.00 0.281 II 7 16.00 0.508 0.188–1.377 0.183 III 12 11.00 0.459 0.149–1.420 0.177 Age, years >52 14 14.00 0.861 0.359–2.065 0.738 ≤52 17 16.00 Sex Female 5 20.00 1.518 0.364–6.340 0.567 Male 26 14.00 Whether to detect the expression of three genes Yes 19 17.00 0.324 0.121–0.870 0.025 No 12 10.00 1.00 recurrence (P � 0.0025, HR � 0.2147, 95% CI: 0.07909–0.5827), mainly because the gene expression results 0.75 let patients with high RRM1 expression avoid gemcitabine treatment. +e detection of RRM1 expression can help 0.50 determine whether gemcitabine should be included in chemotherapy. Patients with high RRM1 expression were 0.25 not suitable for gemcitabine chemotherapy, in line with a p = 0.0039 previous report [10]. Among the patients who underwent gene expression detection, patients with low expression of 0.00 TUBB3 and RRM1 benefited most from paclitaxel treatment 0 10 20 30 (P � 0.0039, HR � 0.1638, 95% CI: 0.04801–0.5588). De- Months Number at risk tection of TUBB3 and RRM1 expression can help determine Paclitaxel-RRM1 High 632222 whether paclitaxel should be included in chemotherapy, and Paclitaxel-RRM1 Low 10 97777 patients with low expression of TUBB3 and RRM1 are 10 15 20 25 30 35 suitable for paclitaxel treatment [24]. Because of the high Months percentage of patients who quit this study, the targeted + Paclitaxel-RRM1 High overall survival could not be reached. +erefore, more cases + Paclitaxel-RRM1 Low are needed and the follow-up mechanism needs to be Figure 3: Survival analysis of patients with low RRM1 expression improved. and patients with high RRM1 expression in the paclitaxel-treated In summary, the intratumoural expression levels of the subgroup. three genes, ERCC1, TUBB3, and RRM1, were detected. Basing the chemotherapy regimens on the detected gene expression levels played a positive role in the control of could be used as markers for sensitivity to first-line che- disease progression. +is study provides a basis for the motherapy. +is study provides a theoretical and practical clinical application of discoveries on chemotherapy resis- basis for postoperative individualized adjuvant chemotherapy tance and new ideas for chemotherapy regimens in lung for Chinese NSCLC patients and has important implications cancer. However, the occurrence and development of lung for both scientific research and clinical treatment. cancer are a long-term process with changes in multiple A total of 67 patients who were enrolled in this study and genes, and it is impossible for a single mechanism to completely explain chemotherapy resistance in lung cancer. had complete follow-up data were randomly divided into the experimental group (detected group) and the control group To translate the discoveries on chemotherapy resistance into clinical practice, more prospective randomized clinical (undetected group) using the central randomization system. Since the small number of cases may have affected the studies are needed to confirm the feasibility of the selection correlation between gene expression detection and DFS, the of chemotherapy regimens to ultimately improve the number of cases needs to be expanded to verify our con- therapeutic efficacy and patient survival. clusions. In the subgroups treated with gemcitabine, gene expression detection was independently correlated with DFS Data Availability after postoperative chemotherapy (P � 0.025, 95% CI: 0.121–0.870), and the detection of expression of the RRM1, All data generated or analysed during this study are included TUBB3, and ERCC1 genes reduced the risk of postoperative in this published article. Disease−free survival (%) Journal of Oncology 7 with advanced NSCLC and a PD-L1 expression of ≥50%,” Ethical Approval Cancer Immunology Immunotherapy, vol. 69, no. 11, pp. 2209–2221, 2020. +e study has been approved by the Ethics Review Board of [7] A. Brunelli, C. Pompili, M. Salati et al., “Preoperative max- the First Affiliated Hospital of the Army Medical University. imum oxygen consumption is associated with prognosis after pulmonary resection in stage I non-small cell lung cancer,” Consent e Annals of oracic Surgery, vol. 98, no. 1, pp. 238–242, All patients signed an informed consent form and vol- [8] R. Berardi, S. Rinaldi, M. Santoni et al., “Prognostic models to unteered to participate in this study. predict survival in patients with advanced non-small cell lung cancer treated with first-line chemo-or targeted therapy,” Conflicts of Interest Oncotarget, vol. 7, no. 18, pp. 26916–26924, 2016. [9] M. Wang, W. Li, X. Xing, D. Zhang, J. Lei, and G. Li, “BRCA1 +e authors declare that they have no conflicts of interest. and STMN1 as prognostic markers in NSCLCs who received cisplatin-based adjuvant chemotherapy,” Oncotarget, vol. 8, Authors’ Contributions no. 46, pp. 80869–80877, 2017. [10] J. G. Liang, Z. Y. Jin, X. D. Gao, M. R. Te, L. H. Ge, and Jingyao Li and Yang Qiu performed the follow-up and C. L. Wang, “Predictive role of RRM1 and BRCA1 mRNA analysis of the data. Junxiu Yi, Xi Liu, Shixin Zhang, Deli expression on the clinical outcome of advanced non-small cell Tan, Meng Tang, and Jie Liu helped collect the samples. Yi lung cancer,” Genetics and Molecular Research, vol. 13, no. 3, pp. 5292–5298, 2014. Liao and Tao Jing prepared the first draft of the manuscript. [11] B. Besse, K. A. Olaussen, and J.-C. Soria, “ERCC1 and RRM1: Haidong Wang finalized the manuscript and instructed the ready for prime time?” Journal of Clinical Oncology, vol. 31, study. Jingyao Li and Yang Qiu contributed equally to this no. 8, pp. 1050–1060, 2013. study. [12] G. R. Simon, M. J. Schell, M. 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Published: Sep 24, 2021

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