Analysis of the differences in lung cancer research trends between China and the United States based using project funding data

Introduction

Lung cancer is the leading cause of cancer-related death. Approximately 1.8 million people are diagnosed with lung cancer and 1.6 million people die from lung cancer on average each year (1). The 5-year survival of lung cancer patients varies from 5% to 57% depending on the cancer stage and regional differences (2-5). Among the common subtypes of lung cancer, non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases (6).

In recent years, cancer immunotherapy has made significant progress with the support of a significant amount of funding (7-11). A study, funded by AstraZeneca reported that the clinical activity of durvalumab in patients with epidermal growth factor receptor (EGFR) + NSCLC with ≥25% of tumor cells expressing programmed death-ligand 1 (PD-L1) produced encouraging results (12,13). Results like the one above demonstrate how immunotherapy has fundamentally changed the treatment of patients with metastatic NSCLC (14). Research shows that PD-L1 is often highly expressed in NSCLC, which is a promising sign for patients with advanced lung cancer (15). The efficacy of immunotherapy alone, however, is considered to be limited, and many immunotherapy programs combined with targeted drug therapy have been included in clinical trials (16). The research goal for advanced NSCLC is to understand and solve the mechanism of drug resistance and refractory diseases and ultimately improve the cure rate.

All of the above-mentioned studies, and the issues they attempt to resolve, require considerable funding. The National Natural Science Foundation of China (NSFC) is the primary channel providing support for basic scientific research. The analysis of NSFC funding has become a valuable method for measuring the competitiveness in the basic research field, and can provide useful insights for researchers who wish to apply for scientific research funding. As the most advanced country in medical research, the United States, along with its primary medical agency, the National Institutes of Health (NIH), was also included in this analysis to enable a comparison of lung cancer research funding between China and the United States.

Methods

Study design

The information on the NSFC was retrieved from the network information system of the NSFC (https://isisn.nsfc.gov.cn/egrantindex/funcindex/prjsearch-list), the MedSci Natural Science Fund inquiry system (https://www.medsci.cn/sci/nsfc.do), and the inquiry system for scientific funding results in LetPub (https://www.letpub.com.cn/index.php?page=grant), with the keywords of “lung” and “lung cancer” for the period between 2008 and 2019. We wrote the corresponding web crawler code to integrate the search results into an excel table, and combined this with manual screening to obtain accurate project funding information. NIH funding information for the United States was downloaded from the NIH official website (https://report.nih.gov) with the keywords of “lung cancer” for the period between 2008 and 2020. We manually removed some items with incomplete information. The project name, person in charge, amount of funding, approval time, subject code, project approval number, application institution, and project type were included in our information table. Our study was conducted in accordance with the Declaration of Helsinki, and the Institutional Review Committee of Zhongshan Hospital (Fudan University, Shanghai, China) allowed this study to be exempt from ethical considerations because our study did not involve any patient’s information or animal experiment. The relationship between the frequency of corresponding keywords was analyzed by CiteSpace (5.3.R 8.12.30.2018).

Statistical analysis

The keywords of NSFC- and NIH-funded projects were obtained by using ROSTCM6 software to preprocess the data. They were successively imported into CiteSpace (5.3.R 8.12.30.2018) software for cluster analysis and word frequency analysis.

Results

A total of 1,745 and 5,939 search results were finally obtained from the NSFC and NIH respectively. First, we analyzed the trend in the annual total funds and the number of projects funded by the NSFC and NIH in the field of lung cancer from 2008 to 2020. It can be seen from Figure 1 that the funding including funding amount and funding number of lung cancer between China and the United States is significantly different. Figure 1A shows the NSFC funding situation in China. The amount of NSFC funding projects in the field of lung cancer increased steadily from 2008 to 2012, but did not change much after 2012. The proportion of the number of projects funded in lung cancer among the number of all medical science projects between 2008 to 2019 was 1.72%, 1.49%, 1.03%, 1.81%, 2.09%, 1.89%, 1.92%, 2.17%, 1.86%, 1.47%, 1.94%, and 2.01%, respectively. NIH funding for lung cancer was significantly higher in even years than in odd years in the period between 2008 to 2018. Generally speaking, NIH funding in the United States decreased each while the opposite trend was seen for the NSFC in China.

Figure 1 Founding situation of NSFC and NIH from 2008 to 2019. (A) Histogram of the total amount of the NSFC funding for lung cancer-related research between 2008 and 2019. (B) Histogram of the total amount of the NIH funding for lung cancer-related research between 2008 and 2020. NSFC, National Natural Science Foundation of China; NIH, National Institutes of Health.

As the respective scientific research institutions obtained the total amount of funding capital, the total number of projects could indirectly reflect the research level of institution in the field of lung cancer. We conducted a comparative analysis of the top 10 institutions that received the most funds between China and the United States, as shown in Tables 1 and 2, respectively. Shanghai Jiaotong University, Sun Yat-sen University, and Guangzhou Medical University were the top three research institutions in the field of lung cancer research in mainland China, receiving a total of 66.386, 57.140, and 43.195 millions CNY, respectively. The top three institutions that received the most number of funds were Shanghai Jiaotong University, Sun Yat-sen University, and Fudan University. Among the scientific research institutions in the United States, the top three scientific research institutions with the largest amount of funding received in the field of lung cancer were Leidos Biomedical Research, Inc., the University of Texas MD Anderson Cancer Center, and the University of Pennsylvania. The corresponding amount of funding was 71.484, 53.405, and 52.862 million USD, respectively. The top three institutions that received the most number of funded were the University of Texas MD Anderson Cancer Center, the University of Pennsylvania, and Stanford University.

Table 1 Research institution’s rank and bid amount for lung cancer projects funded by the NSFC between 2008 and 2019
Full table

Table 2 Research institution’s rank and bid amount for lung cancer projects funded by the NIH between 2008 and 2020
Full table

We also analyzed the trends in lung cancer research for the NSFC’s General Program and National Science Foundation for Young Scientists. As shown in Table 3 and Figure S1, both the General Program and the Foundation for Young Scientists have received an increasing amount of funding. Between 2008 and 2019, the year in which the General Program received the most funding was 2014, with the funding amount reaching 11.335 million CNY, while the Foundation for Young Scientists received the most funding in 2019, with the funding amount reaching 25.475 million CNY.

Table 3 NSFC’s funding for the General Program and NSFC for Young Scientists between 2008 and 2019
Full table

To explore the differences between China and the United States in the field of lung cancer research in the past 12 years, we analyzed the frequency of corresponding keywords and their relationship using the CiteSpace. We found that the basic experimental research of lung cancer in the past 12 years in the Chinese mainland included topics such as apoptosis, proliferation, invasion, metabolism, pathogenesis, cell signal transduction, epithelial-mesenchymal transformation (EMT), and immune-related research. In the clinical study of lung cancer, EGFR and KRAS gene mutations were the most frequently studied (Figure 2A, Table S1). Throughout the studied time period, the occurrence of lung cancer, EMT, and apoptosis were the main hotspots of research. Since 2011, the research on immunity-related to lung cancer, cancer cell metabolism, and EGFR inhibitors began to increase, while the research on long non-coding RNA (lncRNA), genomics, and KRAS gene mutations has started to grow in the past several years (Figure 2B).

Figure 2 Founding projects trends in non-small cell lung cancer between China and America. (A) Clustering analysis of word frequency of projects supported by the National Natural Science Foundation of China (NSFC) in lung cancer-related research over the years. (B) Trend chart of the critical projects supported by the NSFC in lung cancer-related research between 2008 and 2019. (C) Clustering analysis of the word frequency of projects supported by the NIH in lung cancer-related research over the years. (D) Trend chart of critical projects supported by the NIH in lung cancer-related research between 2008 and 2020.

Similarly, the basic experimental research of lung cancer founded by NIH in the United States has focused on the mechanism of lung cancer, biomarkers, targeted therapy, signal pathways, genomics, and immune-related research. In contrast, clinical research has focused on the diagnosis, treatment methods, and clinical risk factors of lung cancer, drug testing, and imaging (Figure 2C, Table S2). Recently, the United States has also begun to focus on funding immunotherapy-related research on lung cancer (Figure 2D).

Discussion

In recent years, significant progress has been made in lung cancer research, screening, and personalized treatment (precision medicine). Several diagnostic methods can be used to diagnose NSCLC, including X-ray, computed tomography (CT), and positron emission tomography (PET) imaging, and histological examination of tumor biopsy. Recent evidence suggests that low-dose CT screening can reduce lung cancer-specific mortality by 62 per 100,000 people per year (17). These methods have been improved through years of in-depth research on the clinical diagnosis and treatment of lung cancer. As our results show, in the past 12 years, both China and the United States have funded lung cancer imaging research, which is an essential support for the progress of the diagnostic imaging of lung cancer (18).

With the improvement and popularization of imaging examination, an increasing number of early-stage lung cancer patients are being identified. The predominant treatment of early-stage lung cancer is surgery. Many retrospective clinical studies funded by the NSFC and NIH have proven that the surgical treatment on early-stage lung cancer has an appreciable effect (19,20). Data show that patients diagnosed with early-stage lung cancer (T1a-cN0) have a high probability of remission (T1a =92%, T1b =86%, T1c =81%) (21). The support for clinical research has enabled us to see new viewpoints and experiences of lung cancer treatment in time, and has provided a platform through which clinicians can learn from one another.

Patients with advanced lung cancer are usually not suitable for surgical treatment, and so both the NSFC and NIH have given considerable funding support to the exploration of other treatment methods for lung cancer (22-24). Radiotherapy and chemotherapy can still improve the survival of patients with advanced lung cancer. However, according to our analysis, traditional treatment methods for advanced lung cancer, such as radiotherapy and chemotherapy, are still somewhat funded, but the relative proportion of the funding has declined. Abandoning chemotherapy and using molecular targeted therapy or immunotherapy is the standard first-line treatment for about 50% of patients with advanced NSCLC (25). A greater understanding of the pathogenic genomic changes of NSCLC and the development of new drugs represent the progress that has been made in NSCLC treatment. A variety of targeted drugs have been proven to be effective in improving the long-term survival of patients. Several driving gene mutations have been identified, including EGFR and anaplastic lymphoma kinase (ALK), and research has begun to tackle the problems of acquired drug resistance (26-28). Curiously, NIH funding for lung cancer was significantly higher in evenly numbered years, but we have no convincing explanation for this phenomenon. We speculate that it may represent a balancing adjustment across different fields or the product of the response to feedback from the preceding year.

In the past 2 years, one of the most popular research areas in cancer treatment has been immunotherapy. Our results indicate that both the NSFC and NIH have provided significant funding to immunotherapy research in recent years. Because of the remarkable curative effect of immunotherapy targeting programmed cell death protein 1 (PD1)/PD-L1, it has attracted the interest of relevant researchers, and studies related to tumor immunotherapy have exploded in number in recent years (29,30). However, immunotherapy has some limitations. For example, immunotherapy is only applicable to a portion of patients and may involve adverse reactions (31,32). To solve these issues, considerable funding is required.

Our analysis of NSFC and NIH lung cancer research funding may inform those researchers who wish to apply for scientific research funding through a better understanding of their research environment. However, there may be some limitations to this study. For one, some funded projects were excluded, which might have led to some deviation in the results. Also, we did not track the research results of these funded projects, as this would have required an intensive workload, but this is worth exploring further.

In conclusion, while some differences may exist in the funding trends in lung cancer research between China and the United States, both countries have increased their support for immune-related research in recent years.

Acknowledgments

We would like to thank International Science Editing (http://www.internationalscienceediting.com) for editing the language of the manuscript.

Funding: None.

Footnote

Peer Review File: Available at http://dx.doi.org/10.21037/atm-20-3957

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-3957). The 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. Our study was conducted in accordance with the Declaration of Helsinki, and the Institutional Review Committee of Zhongshan Hospital (Fudan University, Shanghai, China) allowed this study to be exempt from ethical considerations because our study did not involve any patient’s information or animal experiment.

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/.

References

1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-86. [Crossref] [PubMed]
2. Printz C. American Cancer Society's blueprint targets socioeconomic disparity. Cancer 2018;124:4275. [Crossref] [PubMed]
3. Henley SJ, Ward EM, Scott S, et al. Annual report to the nation on the status of cancer, part I: National cancer statistics. Cancer 2020;126:2225-49. [Crossref] [PubMed]
4. Mathur P, Sathishkumar K, Chaturvedi M, et al. Cancer Statistics, 2020: Report From National Cancer Registry Programme, India. JCO Glob Oncol 2020;6:1063-75. [Crossref] [PubMed]
5. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020;70:7-30. [Crossref] [PubMed]
6. Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol 2006;24:4539-44. [Crossref] [PubMed]
7. Quoix E, Lena H, Losonczy G, et al. TG4010 immunotherapy and first-line chemotherapy for advanced non-small-cell lung cancer (TIME): results from the phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial. Lancet Oncol 2016;17:212-23. [Crossref] [PubMed]
8. Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol 2016;17:299-308. [Crossref] [PubMed]
9. Barlesi F, Vansteenkiste J, Spigel D, et al. Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study. Lancet Oncol 2018;19:1468-79. [Crossref] [PubMed]
10. Wrangle JM, Velcheti V, Patel MR, et al. ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol 2018;19:694-704. [Crossref] [PubMed]
11. Vansteenkiste JF, Cho BC, Vanakesa T, et al. Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2016;17:822-35. [Crossref] [PubMed]
12. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 2019;394:1929-39. [Crossref] [PubMed]
13. Garassino MC, Cho BC, Kim JH, et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study. Lancet Oncol 2018;19:521-36. [Crossref] [PubMed]
14. Davar D, Kirkwood JM. PD-1 Immune Checkpoint Inhibitors and Immune-Related Adverse Events: Understanding the Upside of the Downside of Checkpoint Blockade. JAMA Oncol 2019;5:942-3. [Crossref] [PubMed]
15. Brahmer JR, Pardoll DM. Immune checkpoint inhibitors: making immunotherapy a reality for the treatment of lung cancer. Cancer Immunol Res 2013;1:85-91. [Crossref] [PubMed]
16. Pollack SM, Ingham M, Spraker MB, et al. Emerging Targeted and Immune-Based Therapies in Sarcoma. J Clin Oncol 2018;36:125-35. [Crossref] [PubMed]
17. Fucito LM, Czabafy S, Hendricks PS, et al. Pairing smoking-cessation services with lung cancer screening: A clinical guideline from the Association for the Treatment of Tobacco Use and Dependence and the Society for Research on Nicotine and Tobacco. Cancer 2016;122:1150-9. [Crossref] [PubMed]
18. Han J, Zhao Y, Zhao X, et al. Therapeutic efficacy and imaging assessment of the HER2-targeting chemotherapy drug Z HER2:V2-pemetrexed in lung adenocarcinoma Xenografts. Invest New Drugs 2020;38:1031-43. [Crossref] [PubMed]
19. Tuminello S, Schwartz RM, Liu B, et al. Opioid Use After Open Resection or Video-Assisted Thoracoscopic Surgery for Early-Stage Lung Cancer. JAMA Oncol 2018;4:1611-3. [Crossref] [PubMed]
20. Howington JA, Blum MG, Chang AC, et al. Treatment of stage I and II non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e278S-e313S.
21. Coonar A, Aresu G, Peryt A, et al. Thoracic surgery for lung cancer: current practice and future directions. J R Soc Med 2019;112:136-9. [Crossref] [PubMed]
22. Lian S, Xie R, Ye Y, et al. Simultaneous blocking of CD47 and PD-L1 increases innate and adaptive cancer immune responses and cytokine release. EBioMedicine 2019;42:281-95. [Crossref] [PubMed]
23. Drilon A, Cappuzzo F, Ou SI, et al. Targeting MET in Lung Cancer: Will Expectations Finally Be MET? J Thorac Oncol 2017;12:15-26. [Crossref] [PubMed]
24. Osmani L, Askin F, Gabrielson E, et al. Current WHO guidelines and the critical role of immunohistochemical markers in the subclassification of non-small cell lung carcinoma (NSCLC): Moving from targeted therapy to immunotherapy. Semin Cancer Biol 2018;52:103-9. [Crossref] [PubMed]
25. Jordan EJ, Kim HR, Arcila ME, et al. Prospective Comprehensive Molecular Characterization of Lung Adenocarcinomas for Efficient Patient Matching to Approved and Emerging Therapies. Cancer Discov 2017;7:596-609. [Crossref] [PubMed]
26. Recondo G, Facchinetti F, Olaussen KA, et al. Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI? Nat Rev Clin Oncol 2018;15:694-708. [Crossref] [PubMed]
27. Martínez P, Mak RH, Oxnard GR. Targeted Therapy as an Alternative to Whole-Brain Radiotherapy in EGFR-Mutant or ALK-Positive Non-Small-Cell Lung Cancer With Brain Metastases. JAMA Oncol 2017;3:1274-5. [Crossref] [PubMed]
28. Chapman AM, Sun KY, Ruestow P, et al. Lung cancer mutation profile of EGFR, ALK, and KRAS: Meta-analysis and comparison of never and ever smokers. Lung Cancer 2016;102:122-34. [Crossref] [PubMed]
29. Forde PM, Chaft JE, Smith KN, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med 2018;378:1976-86. [Crossref] [PubMed]
30. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33. [Crossref] [PubMed]
31. Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 2019;16:563-80. [Crossref] [PubMed]
32. Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol 2016;27:559-74. [Crossref] [PubMed]

(English Language Editor: J. Gray)