Skip to main content
Top
Published in: BMC Cancer 1/2010

Open Access 01-12-2010 | Research article

Comparison of prevalence, viral load, physical status and expression of human papillomavirus-16, -18 and -58 in esophageal and cervical cancer: a case-control study

Authors: Donghong Zhang, Qingying Zhang, Li Zhou, Leijun Huo, Yi Zhang, Zhongying Shen, Yi Zhu

Published in: BMC Cancer | Issue 1/2010

Login to get access

Abstract

Background

Human papillomavirus (HPV) infection is a major risk factor for the development of nearly all cases of cervical cancer worldwide. The presence of HPV DNA in cases of esophageal squamous-cell carcinoma (ESCC) has been reported repeatedly from Shantou, China, and other regions with a high incidence of esophageal carcinoma (EC). However, unlike in cervical squamous-cell carcinoma (CSCC), in ESCC, the characteristics of HPV are unclear. Thus, the role of high-risk HPV types in the carcinogenesis of ESCC remains uncertain.

Methods

Seventy cases of ESCC with 60 controls and 39 cases of CSCC with 54 controls collected from patients in Shantou region in China were compared for the distributions of HPV-16, -18 and -58; viral load; and viral integration using real-time PCR assay and HPV-16 expression using immunostaining.

Results

The detection rates and viral loads of HR-HPV infection were significantly lower in ESCC than in CSCC (50.0% vs. 79.48%, P = 0.005; 2.55 ± 3.19 vs. 361.29 ± 441.75, P = 0.002, respectively). The combined integration level of HPV-16, -18 and -58 was slightly lower in ESCC than in CSCC (P = 0.022). HPV-16 expression was detected in 59.26% of ESCC tissue and significantly associated with tumour grade (P = 0.027).

Conclusions

High levels of HR-HPV expression and integration may be an indicator of the risk of ESCC, at least for patients in the Shantou region of China. However, a relatively low HPV copy number and infection rate in ESCC is unlikely to play an essential a role in the carcinogenesis of ESCC as in cervical cancer. Factors other than HR-HPV infection may contribute to the carcinogenesis of ESCC.
Appendix
Available only for authorised users
Literature
1.
go back to reference Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 2005, 55 (2): 74-108. 10.3322/canjclin.55.2.74.CrossRefPubMed Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 2005, 55 (2): 74-108. 10.3322/canjclin.55.2.74.CrossRefPubMed
2.
go back to reference Su M, Liu M, Tian DP, Li XY, Zhang GH, Yang HL, Fan X, Huang HH, Gao YX: Temporal trends of esophageal cancer during 1995-2004 in Nanao Island, an extremely high-risk area in China. Eur J Epidemiol. 2007, 22 (1): 43-48. 10.1007/s10654-006-9086-x.CrossRefPubMed Su M, Liu M, Tian DP, Li XY, Zhang GH, Yang HL, Fan X, Huang HH, Gao YX: Temporal trends of esophageal cancer during 1995-2004 in Nanao Island, an extremely high-risk area in China. Eur J Epidemiol. 2007, 22 (1): 43-48. 10.1007/s10654-006-9086-x.CrossRefPubMed
3.
go back to reference Ke L, Yu P, Zhang ZX: Novel epidemiologic evidence for the association between fermented fish sauce and esophageal cancer in South China. Int J Cancer. 2002, 99 (3): 424-426. 10.1002/ijc.10293.CrossRefPubMed Ke L, Yu P, Zhang ZX: Novel epidemiologic evidence for the association between fermented fish sauce and esophageal cancer in South China. Int J Cancer. 2002, 99 (3): 424-426. 10.1002/ijc.10293.CrossRefPubMed
4.
go back to reference Ke L, Yu P, Zhang ZX, Huang SS, Huang G, Ma XH: Congou tea drinking and oesophageal cancer in South China. Br J Cancer. 2002, 86 (3): 346-347. 10.1038/sj.bjc.6600054.CrossRefPubMedPubMedCentral Ke L, Yu P, Zhang ZX, Huang SS, Huang G, Ma XH: Congou tea drinking and oesophageal cancer in South China. Br J Cancer. 2002, 86 (3): 346-347. 10.1038/sj.bjc.6600054.CrossRefPubMedPubMedCentral
6.
go back to reference Shen ZY, Hu SP, Lu LC, Tang CZ, Kuang ZS, Zhong SP, Zeng Y: Detection of human papillomavirus in esophageal carcinoma. J Med Virol. 2002, 68 (3): 412-416. 10.1002/jmv.10219.CrossRefPubMed Shen ZY, Hu SP, Lu LC, Tang CZ, Kuang ZS, Zhong SP, Zeng Y: Detection of human papillomavirus in esophageal carcinoma. J Med Virol. 2002, 68 (3): 412-416. 10.1002/jmv.10219.CrossRefPubMed
7.
go back to reference Shen ZY, Cen S, Xu LY, Cai WJ, Chen MH, Shen J, Zeng Y: E6/E7 genes of human papilloma virus type 18 induced immortalization of human fetal esophageal epithelium. Oncol Rep. 2003, 10 (5): 1431-1436.PubMed Shen ZY, Cen S, Xu LY, Cai WJ, Chen MH, Shen J, Zeng Y: E6/E7 genes of human papilloma virus type 18 induced immortalization of human fetal esophageal epithelium. Oncol Rep. 2003, 10 (5): 1431-1436.PubMed
8.
go back to reference Bao YP, Li N, Smith JS, Qiao YL: Human papillomavirus type-distribution in the cervix of Chinese women: a meta-analysis. Int J Std Aids. 2008, 19 (2): 106-111. 10.1258/ijsa.2007.007113.CrossRefPubMed Bao YP, Li N, Smith JS, Qiao YL: Human papillomavirus type-distribution in the cervix of Chinese women: a meta-analysis. Int J Std Aids. 2008, 19 (2): 106-111. 10.1258/ijsa.2007.007113.CrossRefPubMed
9.
go back to reference Tabora N, Ferrera A, Bakkers JM, Massuger LF, Melchers WJ: High HPV 16 viral load is associated with increased cervical dysplasia in Honduran women. Am J Trop Med Hyg. 2008, 78 (5): 843-846.PubMed Tabora N, Ferrera A, Bakkers JM, Massuger LF, Melchers WJ: High HPV 16 viral load is associated with increased cervical dysplasia in Honduran women. Am J Trop Med Hyg. 2008, 78 (5): 843-846.PubMed
10.
go back to reference Briolat J, Dalstein V, Saunier M, Joseph K, Caudroy S, Pretet JL, Birembaut P, Clavel C: HPV prevalence, viral load and physical state of HPV-16 in cervical smears of patients with different grades of CIN. Int J Cancer. 2007, 121 (10): 2198-2204. 10.1002/ijc.22959.CrossRefPubMed Briolat J, Dalstein V, Saunier M, Joseph K, Caudroy S, Pretet JL, Birembaut P, Clavel C: HPV prevalence, viral load and physical state of HPV-16 in cervical smears of patients with different grades of CIN. Int J Cancer. 2007, 121 (10): 2198-2204. 10.1002/ijc.22959.CrossRefPubMed
11.
go back to reference Jeon S, Lambert PF: Integration of human papillomavirus type 16 DNA into the human genome leads to increased stability of E6 and E7 mRNAs: implications for cervical carcinogenesis. Proc Natl Acad Sci USA. 1995, 92 (5): 1654-1658. 10.1073/pnas.92.5.1654.CrossRefPubMedPubMedCentral Jeon S, Lambert PF: Integration of human papillomavirus type 16 DNA into the human genome leads to increased stability of E6 and E7 mRNAs: implications for cervical carcinogenesis. Proc Natl Acad Sci USA. 1995, 92 (5): 1654-1658. 10.1073/pnas.92.5.1654.CrossRefPubMedPubMedCentral
12.
go back to reference Liu SS, Tsang PC, Chan KY, Cheung AN, Chan KK, Leung RC, Ngan HY: Distribution of six oncogenic types of human papillomavirus and type 16 integration analysis in Chinese women with cervical precancerous lesions and carcinomas. Tumour Biol. 2008, 29 (2): 105-113. 10.1159/000135690.CrossRefPubMed Liu SS, Tsang PC, Chan KY, Cheung AN, Chan KK, Leung RC, Ngan HY: Distribution of six oncogenic types of human papillomavirus and type 16 integration analysis in Chinese women with cervical precancerous lesions and carcinomas. Tumour Biol. 2008, 29 (2): 105-113. 10.1159/000135690.CrossRefPubMed
13.
go back to reference Si HX, Tsao SW, Poon CS, Wong YC, Cheung AL: Physical status of HPV-16 in esophageal squamous cell carcinoma. J Clin Virol. 2005, 32 (1): 19-23. 10.1016/j.jcv.2004.04.004.CrossRefPubMed Si HX, Tsao SW, Poon CS, Wong YC, Cheung AL: Physical status of HPV-16 in esophageal squamous cell carcinoma. J Clin Virol. 2005, 32 (1): 19-23. 10.1016/j.jcv.2004.04.004.CrossRefPubMed
14.
go back to reference Ruutu MP, Kulmala SM, Peitsaro P, Syrjanen SM: The performance of the HPV16 real-time PCR integration assay. Clin Biochem. 2008, 41 (6): 423-428. 10.1016/j.clinbiochem.2007.12.014.CrossRefPubMed Ruutu MP, Kulmala SM, Peitsaro P, Syrjanen SM: The performance of the HPV16 real-time PCR integration assay. Clin Biochem. 2008, 41 (6): 423-428. 10.1016/j.clinbiochem.2007.12.014.CrossRefPubMed
15.
go back to reference Szostek S, Zawilinska B, Kopec J, Kosz-Vnenchak M: Herpesviruses as possible cofactors in HPV-16-related oncogenesis. Acta Biochim Pol. 2009, 56 (2): 337-342.PubMed Szostek S, Zawilinska B, Kopec J, Kosz-Vnenchak M: Herpesviruses as possible cofactors in HPV-16-related oncogenesis. Acta Biochim Pol. 2009, 56 (2): 337-342.PubMed
16.
go back to reference Arias-Pulido H, Peyton CL, Joste NE, Vargas H, Wheeler CM: Human papillomavirus type 16 integration in cervical carcinoma in situ and in invasive cervical cancer. J Clin Microbiol. 2006, 44 (5): 1755-1762. 10.1128/JCM.44.5.1755-1762.2006.CrossRefPubMedPubMedCentral Arias-Pulido H, Peyton CL, Joste NE, Vargas H, Wheeler CM: Human papillomavirus type 16 integration in cervical carcinoma in situ and in invasive cervical cancer. J Clin Microbiol. 2006, 44 (5): 1755-1762. 10.1128/JCM.44.5.1755-1762.2006.CrossRefPubMedPubMedCentral
17.
go back to reference Guo M, Sneige N, Silva EG, Jan YJ, Cogdell DE, Lin E, Luthra R, Zhang W: Distribution and viral load of eight oncogenic types of human papillomavirus (HPV) and HPV 16 integration status in cervical intraepithelial neoplasia and carcinoma. Modern Pathology. 2007, 20 (2): 256-266. 10.1038/modpathol.3800737.CrossRefPubMed Guo M, Sneige N, Silva EG, Jan YJ, Cogdell DE, Lin E, Luthra R, Zhang W: Distribution and viral load of eight oncogenic types of human papillomavirus (HPV) and HPV 16 integration status in cervical intraepithelial neoplasia and carcinoma. Modern Pathology. 2007, 20 (2): 256-266. 10.1038/modpathol.3800737.CrossRefPubMed
18.
go back to reference Cui L, Xu LY, Shen ZY, Tao Q, Gao SY, Lv Z, Du ZP, Fang WK, Li EM: NGALR is overexpressed and regulated by hypomethylation in esophageal squamous cell carcinoma. Clin Cancer Res. 2008, 14 (23): 7674-7681. 10.1158/1078-0432.CCR-08-0420.CrossRefPubMed Cui L, Xu LY, Shen ZY, Tao Q, Gao SY, Lv Z, Du ZP, Fang WK, Li EM: NGALR is overexpressed and regulated by hypomethylation in esophageal squamous cell carcinoma. Clin Cancer Res. 2008, 14 (23): 7674-7681. 10.1158/1078-0432.CCR-08-0420.CrossRefPubMed
19.
go back to reference Qi ZL, Huo X, Xu XJ, Zhang B, Du MG, Yang HW, Zheng LK, Li J, Shen ZY: Relationship between HPV16/18 E6 and 53, 21WAF1, MDM2, Ki67 and cyclin D1 expression in esophageal squamous cell carcinoma: comparative study by using tissue microarray technology. Exp Oncol. 2006, 28 (3): 235-240.PubMed Qi ZL, Huo X, Xu XJ, Zhang B, Du MG, Yang HW, Zheng LK, Li J, Shen ZY: Relationship between HPV16/18 E6 and 53, 21WAF1, MDM2, Ki67 and cyclin D1 expression in esophageal squamous cell carcinoma: comparative study by using tissue microarray technology. Exp Oncol. 2006, 28 (3): 235-240.PubMed
20.
go back to reference Smith JS, Lindsay L, Hoots B, Keys J, Franceschi S, Winer R, Clifford GM: Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer. 2007, 121 (3): 621-632. 10.1002/ijc.22527.CrossRefPubMed Smith JS, Lindsay L, Hoots B, Keys J, Franceschi S, Winer R, Clifford GM: Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer. 2007, 121 (3): 621-632. 10.1002/ijc.22527.CrossRefPubMed
21.
go back to reference Wang X, Tian X, Liu F, Zhao Y, Sun M, Chen D, Lu C, Wang Z, Shi X, Zhang Q, Zhang D, Shen Z, Li F, Harris CC, Cai H, Ke Y: Detection of HPV DNA in esophageal cancer specimens from different regions and ethnic groups: a descriptive study. Bmc Cancer. 2010, 10 (1): 19-10.1186/1471-2407-10-19.CrossRefPubMedPubMedCentral Wang X, Tian X, Liu F, Zhao Y, Sun M, Chen D, Lu C, Wang Z, Shi X, Zhang Q, Zhang D, Shen Z, Li F, Harris CC, Cai H, Ke Y: Detection of HPV DNA in esophageal cancer specimens from different regions and ethnic groups: a descriptive study. Bmc Cancer. 2010, 10 (1): 19-10.1186/1471-2407-10-19.CrossRefPubMedPubMedCentral
22.
go back to reference Dreilich M, Bergqvist M, Moberg M, Brattstrom D, Gustavsson I, Bergstrom S, Wanders A, Hesselius P, Wagenius G, Gyllensten U: High-risk human papilloma virus (HPV) and survival in patients with esophageal carcinoma: a pilot study. Bmc Cancer. 2006, 6: 94-10.1186/1471-2407-6-94.CrossRefPubMedPubMedCentral Dreilich M, Bergqvist M, Moberg M, Brattstrom D, Gustavsson I, Bergstrom S, Wanders A, Hesselius P, Wagenius G, Gyllensten U: High-risk human papilloma virus (HPV) and survival in patients with esophageal carcinoma: a pilot study. Bmc Cancer. 2006, 6: 94-10.1186/1471-2407-6-94.CrossRefPubMedPubMedCentral
23.
go back to reference Si HX, Tsao SW, Poon CS, Wang LD, Wong YC, Cheung AL: Viral load of HPV in esophageal squamous cell carcinoma. Int J Cancer. 2003, 103 (4): 496-500. 10.1002/ijc.10865.CrossRefPubMed Si HX, Tsao SW, Poon CS, Wang LD, Wong YC, Cheung AL: Viral load of HPV in esophageal squamous cell carcinoma. Int J Cancer. 2003, 103 (4): 496-500. 10.1002/ijc.10865.CrossRefPubMed
24.
go back to reference Beby-Defaux A, Bourgoin A, Ragot S, Battandier D, Lemasson JM, Renaud O, Bouguermouh S, Vienne MML, Agius G: Human papillomavirus infection of the cervix uteri in women attending a Health Examination Center of the French social security. J Med Virol. 2004, 73 (2): 262-268. 10.1002/jmv.20085.CrossRefPubMed Beby-Defaux A, Bourgoin A, Ragot S, Battandier D, Lemasson JM, Renaud O, Bouguermouh S, Vienne MML, Agius G: Human papillomavirus infection of the cervix uteri in women attending a Health Examination Center of the French social security. J Med Virol. 2004, 73 (2): 262-268. 10.1002/jmv.20085.CrossRefPubMed
25.
go back to reference Hildesheim A, Wang SS: H ost and viral genetics and risk of cervical cancer: a review. Virus Res. 2002, 89 (2): 229-240. 10.1016/S0168-1702(02)00191-0.CrossRefPubMed Hildesheim A, Wang SS: H ost and viral genetics and risk of cervical cancer: a review. Virus Res. 2002, 89 (2): 229-240. 10.1016/S0168-1702(02)00191-0.CrossRefPubMed
26.
go back to reference Shuyama K, Castillo A, Aguayo F, Sun Q, Khan N, Koriyama C, Akiba S: Human papillomavirus in high- and low-risk areas of oesophageal squamous cell carcinoma in China. Br J Cancer. 2007, 96 (10): 1554-1559. 10.1038/sj.bjc.6603765.CrossRefPubMedPubMedCentral Shuyama K, Castillo A, Aguayo F, Sun Q, Khan N, Koriyama C, Akiba S: Human papillomavirus in high- and low-risk areas of oesophageal squamous cell carcinoma in China. Br J Cancer. 2007, 96 (10): 1554-1559. 10.1038/sj.bjc.6603765.CrossRefPubMedPubMedCentral
27.
go back to reference Koskinen WJ, Chen RW, Leivo I, Mäkitie A, Bäck L, Kontio R, Suuronen R, Lindqvist C, Auvinen E, Molijn A, Quint WG, Vaheri A, Aaltonen LM: Prevalence and physical status of human papillomavirus in squamous cell carcinomas of the head and neck. Int J Cancer. 2003, 107 (3): 401-406. 10.1002/ijc.11381.CrossRefPubMed Koskinen WJ, Chen RW, Leivo I, Mäkitie A, Bäck L, Kontio R, Suuronen R, Lindqvist C, Auvinen E, Molijn A, Quint WG, Vaheri A, Aaltonen LM: Prevalence and physical status of human papillomavirus in squamous cell carcinomas of the head and neck. Int J Cancer. 2003, 107 (3): 401-406. 10.1002/ijc.11381.CrossRefPubMed
28.
go back to reference Zehbe I, Rylander E, Edlund K, Wadell G, Wilander E: Detection of human papillomavirus in cervical intra-epithelial neoplasia, using in situ hybridization and various polymerase chain reaction techniques. Virchows Arch. 1996, 428 (3): 151-157. 10.1007/BF00200657.CrossRefPubMed Zehbe I, Rylander E, Edlund K, Wadell G, Wilander E: Detection of human papillomavirus in cervical intra-epithelial neoplasia, using in situ hybridization and various polymerase chain reaction techniques. Virchows Arch. 1996, 428 (3): 151-157. 10.1007/BF00200657.CrossRefPubMed
29.
go back to reference Begum S, Cao D, Gillison M, Zahurak M, Westra WH: Tissue distribution of human papillomavirus 16 DNA integration in patients with tonsillar carcinoma. Clin Cancer Res. 2005, 11 (16): 5694-5699. 10.1158/1078-0432.CCR-05-0587.CrossRefPubMed Begum S, Cao D, Gillison M, Zahurak M, Westra WH: Tissue distribution of human papillomavirus 16 DNA integration in patients with tonsillar carcinoma. Clin Cancer Res. 2005, 11 (16): 5694-5699. 10.1158/1078-0432.CCR-05-0587.CrossRefPubMed
30.
go back to reference Bodaghi S, Yamanegi K, Xiao SY, Da CM, Palefsky JM, Zheng ZM: Colorectal papillomavirus infection in patients with colorectal cancer. Clin Cancer Res. 2005, 11 (8): 2862-2867. 10.1158/1078-0432.CCR-04-1680.CrossRefPubMedPubMedCentral Bodaghi S, Yamanegi K, Xiao SY, Da CM, Palefsky JM, Zheng ZM: Colorectal papillomavirus infection in patients with colorectal cancer. Clin Cancer Res. 2005, 11 (8): 2862-2867. 10.1158/1078-0432.CCR-04-1680.CrossRefPubMedPubMedCentral
31.
go back to reference Lorincz AT, Castle PE, Sherman ME, Scott DR, Glass AG, Wacholder S, Rush BB, Gravitt PE, Schussler JE, Schiffman M: Viral load of human papillomavirus and risk of CIN3 or cervical cancer. Lancet. 2002, 360 (9328): 228-229. 10.1016/S0140-6736(02)09463-1.CrossRefPubMed Lorincz AT, Castle PE, Sherman ME, Scott DR, Glass AG, Wacholder S, Rush BB, Gravitt PE, Schussler JE, Schiffman M: Viral load of human papillomavirus and risk of CIN3 or cervical cancer. Lancet. 2002, 360 (9328): 228-229. 10.1016/S0140-6736(02)09463-1.CrossRefPubMed
32.
go back to reference Vinokurova S, Wentzensen N, Kraus I, Klaes R, Driesch C, Melsheimer P, Kisseljov F, Durst M, Schneider A, von Knebel DM: Type-dependent integration frequency of human papillomavirus genomes in cervical lesions. Cancer Res. 2008, 68 (1): 307-313. 10.1158/0008-5472.CAN-07-2754.CrossRefPubMed Vinokurova S, Wentzensen N, Kraus I, Klaes R, Driesch C, Melsheimer P, Kisseljov F, Durst M, Schneider A, von Knebel DM: Type-dependent integration frequency of human papillomavirus genomes in cervical lesions. Cancer Res. 2008, 68 (1): 307-313. 10.1158/0008-5472.CAN-07-2754.CrossRefPubMed
33.
go back to reference Alazawi W, Pett M, Arch B, Scott L, Freeman T, Stanley MA, Coleman N: Changes in cervical keratinocyte gene expression associated with integration of human papillomavirus 16. Cancer Res. 2002, 62 (23): 6959-6965.PubMed Alazawi W, Pett M, Arch B, Scott L, Freeman T, Stanley MA, Coleman N: Changes in cervical keratinocyte gene expression associated with integration of human papillomavirus 16. Cancer Res. 2002, 62 (23): 6959-6965.PubMed
34.
go back to reference Ragin CC, Reshmi SC, Gollin SM: Mapping and analysis of HPV16 integration sites in a head and neck cancer cell line. Int J Cancer. 2004, 110 (5): 701-709. 10.1002/ijc.20193.CrossRefPubMed Ragin CC, Reshmi SC, Gollin SM: Mapping and analysis of HPV16 integration sites in a head and neck cancer cell line. Int J Cancer. 2004, 110 (5): 701-709. 10.1002/ijc.20193.CrossRefPubMed
35.
go back to reference Ziegert C, Wentzensen N, Vinokurova S, Kisseljov F, Einenkel J, Hoeckel M, von Knebel DM: A comprehensive analysis of HPV integration loci in anogenital lesions combining transcript and genome-based amplification techniques. Oncogene. 2003, 22 (25): 3977-3984. 10.1038/sj.onc.1206629.CrossRefPubMed Ziegert C, Wentzensen N, Vinokurova S, Kisseljov F, Einenkel J, Hoeckel M, von Knebel DM: A comprehensive analysis of HPV integration loci in anogenital lesions combining transcript and genome-based amplification techniques. Oncogene. 2003, 22 (25): 3977-3984. 10.1038/sj.onc.1206629.CrossRefPubMed
Metadata
Title
Comparison of prevalence, viral load, physical status and expression of human papillomavirus-16, -18 and -58 in esophageal and cervical cancer: a case-control study
Authors
Donghong Zhang
Qingying Zhang
Li Zhou
Leijun Huo
Yi Zhang
Zhongying Shen
Yi Zhu
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2010
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-10-650

Other articles of this Issue 1/2010

BMC Cancer 1/2010 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine