YEAR IN REVIEW CERVICAL CANCER IN 2013
Screening comes of age and treatment progress continues Chris J. L. M. Meijer and Peter J. F. Snijders
In 2013, studies confirmed that HPV infection of target cells predisposes to cervical (pre)cancer. In developed countries, HPV screening revealed superior protection than cytology screening. In India, visual inspection of the cervix after acetic acid application significantly reduced cervical cancer mortality after 12 years. Improved survival for women with advanced disease was observed after adjuvant bevacizumab. Meijer, C. J. L. M. & Snijders, P. J. F. Nat. Rev. Clin. Oncol. 11, 77–78 (2014); published online 21 January 2014; doi:10.1038/nrclinonc.2013.252
It has been known that infection with certain high-risk human papillomavirus (hrHPV) types is the main cause of cervical cancer. Despite this knowledge, it is still not clear what factors determine the malignant fate of an HPV infection, which occurs in only a small fraction (1–3%) of infected women. A discrete population of cuboidal epi thelial cells of embryonic origin localized in the squamocolumnar junction (SCJ) of the cervix may represent the cellular precursor of most cervical cancers.1 According to the current paradigm of cervical cancer development, most of the hrHPV infections that develop into lesions lead to new viral progeny (productive infections) and display no signs of cellular transformation. Such lesions are morphologically manifested as cervical intraepithelial neoplasia (CIN1 and part of CIN2), and arise from infection of basal cells of the squamous epithelium lining the transformation zone, or ectocervix. Conversely, in the case of transforming infections—as seen in the remaining part of CIN2, CIN3 and cervical cancers—the normal viral life cycle is aborted. Such infections are characterized by overexpression of the E6 and E7 oncogenes in the proliferating basal cells. It was not known what was responsible for this rather unnatural E6/E7 expression profile. The discovery by Herfs et al.1,2 of the cuboidal SCJ cells as a possible progenitor of cervical precancer and cancer is likely to pave the way for an explanation. They found that the cuboidal SCJ cells display a unique gene-expression profile and identified a SCJ-specific biomarker protein panel comprising KRT7, AGR2, MMP7, and GDA. Immunohistochemically, these SCJ bio markers were present in all cervical cancers analysed (squamous cell carcinomas (SCC)
and adenocarcinomas), most CIN2 and CIN3 lesions (91.8%), and a subset of CIN1 lesions (33.3%).1,2 Interestingly, 24.4% of the SCJ biomarker‑positive CIN1 lesions compared with 0% SCJ biomarker‑negative CIN1 lesions were diagnosed as CIN2/ CIN3 after 0.5 to 7 years of follow-up.1 The SCJ-specific markers could not be induced by HPV E6 or E7 in vitro in squamous epi thelial cells, and the biomarker panel was not expressed followi ng excision of the SCJ by cone biopsy or loop electrical excision.2 Thus, it was concluded that the SCJspecific expression profile in CIN lesions and cervical cancers was not acquired during the transformation process, but rather reflects the cell of origin. It is tempting to speculate that hrHPV infection of SCJ cells leads to deregulated E6 and E7 expression, triggeri ng a transforming infection. The high transformation susceptibility of cuboidal SCJ cells in relation to squamous cells is supported by the fact that HPV-related (pre)cancerous lesions are up to 20 times more common in the cervix (with a SCJ profile) than in other genital sites lacking a SCJ profile, such as the vagina and vulva.2 If confirmed, the potential implications of this discovery are manifold. Firstly, the absence of SCJ markers in CIN lesions likely reflects a negligible or low risk of malignant transformation and warrants a wait-and-see
management. Secondly, this finding might impact the assessment of the clinical value of novel molecular disease markers as candidate triage markers for the referral of hrHPV-positive women for colposcopy. Moreover, SCJ markers might provide interesting additive or alternative test-ofcure markers for monitoring women for the development of progressive post-treatment CIN2 or CIN3, as radical removal of SCJpositive cells is likely to be associated with a very low risk of recurrence. Another important publication in 2013 showed that hrHPV-based cervical screening provides 60–70% greater protection against invasive cervical carcinoma than cytology screening. 3 The authors had previously been involved in four earlier randomized controlled trials in which hrHPV-based screening was compared to cytology-based screening with CIN3 or worse (CIN3+) as the primary outcome measure. These trials comprised Swedescreen, POBASCAM, ARTISTIC and NTCC. To measure efficacy, the relative incidence rates of CIN3+ between hrHPV and cytology arms were compared.4 The researchers found that despite different screening protocols the relative incidence rate ratios (hrHPV versus cytology) of CIN3+ in the second screening round were similar in all trials (Swedescreen: 0.53 [95% CI 0.29–0.98]; POBASCAM: 0.39 [95% CI 0.27–0.53]; ARTISTIC: 0.52 [95% CI 0.28– 0.97]; NTCC: 0.34 [95%CI 0.15–0.75]), with no evidence of statistical heterogeneity between the results of the different studies.4 This indicates that hrHPV-based screening detects persistent high-grade CIN before cytology, thus increasing the probability of treatment before invasion. Although none of these studies was powered to detect invasive cervical cancer, two of them (NTCC and POBASCAM) showed better protection of a negative hrHPV test against invasive cancer.5,6
NPG
NATURE REVIEWS | CLINICAL ONCOLOGY
VOLUME 11 | FEBRUARY 2014 | 77 © 2014 Macmillan Publishers Limited. All rights reserved
YEAR IN REVIEW Key advances ■■ HPV infection of specific embryonal, cuboidal target cells in the squamocolumnar junction provides a likely explanation for the development of cervical precancer and cancer1,2 ■■ HPV-based cervical screening provides better protection against cervical cancer than Pap smear screening3 ■■ In low-income countries with poor infrastructure, screening with VIA by welltrained primary health workers shows good results in reducing cervical cancer mortality and should be further implemented7
In the pooled analysis by Ronco et al.,3 176,464 women were followed up for a median of 6.5 years to assess outcome according to screening type (hrHPV versus cytology). The cumulative detection of invasive cervical cancer 2 years after enrolment was similar in both arms. Thereafter, the relative incidence rate ratio dropped, and after 8 years the cumulative invasive cancer incidence was 46.7 per 100,000 in the hrHPV arm versus 93.6 per 100,000 in the cytology arm. The corresponding overall rate ratio was 0.61. This effect was not due to earlier detection of cancer in the first (prevalent) screen because the detection rate in the first 2.5 years was not significantly different between both arms. The rate ratio of invasive cervical cancer (hrHPV versus cytology) of 0.45 after 2.5 years provides the true gain in reducing the incidence of invasive cervical cancer. After a negative screen test at entry, the rate ratio of invasive cervical cancer was 0.30, indicating high efficacy of hrHPV screening. The relative incidence rate ratio was lower for adenocarcinomas than for SCC, in keeping with the observation that cytology is more efficient in detecting SCC than adenocarcinomas of the cervix. This is the first publication in the Western world to show a higher efficacy of hrHPV screening compared with cytology for detecting cervical cancer.3 The question of what age should HPV screening start has now been addressed. It is known that in young women cytology has low efficacy for high-grade lesions. In the NTCC study,4 overdiagnosis of regressive CIN lesions in the hrHPV arm had been suggested, which is explained partly by the more-intense follow-up of HPV positive women in the NTCC study and a relatively short screening interval of 3 years. No overdiagnosis was noted in the POBASCAM trial, which had a second screening round after 5 years. 5 Ronco et al. 3 showed the 78 | FEBRUARY 2014 | VOLUME 11
gain in efficacy with hrHPV screening at 30–34 years is at least as effective, if not better than in older women. They recommend starting hrHPV screening at the age of 30 with at least 5‑year intervals. The Dutch Minister of Health has decided that in 2016 population hrHPV-based screening should replace cytology, and should start at the age of 30, with screening rounds at 30, 35, 40, 50 and 60 years. Because HPV screening in India is diffi cult to implement, Shastri et al.7 explored visual inspection with acetic acid (VIA) in a cervical screening trial in India and compared the results with women who only obtained cancer education (control group). The quality of screening by primary health-care workers and expert gynaecologists was comparable. Using four rounds of cancer education in the control group and VIA screening every 24 months in the intervention group, after 12 years they showed a 31% reduction in mortality compared with the control group. Participation in screening (89% in VIA group and 79% in the control group), and compliance to treatment for invasive cancer in both groups was high (86% and 73%, respectively). These represent hopeful results with simple techniques in a country where cervical cancer incidence is high (27 per 100,000 women). Promising results have also been obtained regarding treatment in a study by Tewari et al.8 of a cluster randomized trial carried out in Mumbai. The authors showed that bevacizumab given as an adjuvant to standard chemot herapy in women with advanced cervical cancer increased overall survival by nearly 4 months compared with standard chemot herapy alone. The relevance of this finding has recently been highlighted in this journal.9 In summary, the paper of Ronco et al.3 has further strengthened the case for carrying out primary HPV screening instead of Pap smear testing. Future perspectives include the development of HPV self-s ampling, opening the way to molecular self-screening. For girls who have been vaccinated with prophylactic bivalent or quadrivalent HPV vaccine, the conversion to HPV screening will provide a joint approach to cancer prevention in the future. In underdeveloped countries, VIA screening with well- educated primary health-care workers also shows important results in reducing cervical cancer mortality. Although these positive results warrant implementation in the short run, long-term prevention strategies should focus on use of prophylactic HPV
vaccination at prepubertal age, and HPV testing with a cheap method at an older age (≥30 years). For women with advancedstage cancer, adjuvant treatment with bevacizumab shows hopeful results. Combined use of new therapies against specific targets involved in cervical carcinogenesis should be further explored. Department of Pathology, Vrije Universiteit Medical Centre Amsterdam, de Boelelaan 1117, 1084 HV Amsterdam, The Netherlands (C. J. L. M. Meijer, P. J. F. Snijders). Correspondence to: C. J. L. M. Meijer [email protected] Acknowledgements This work has been made possible by grants from the European Union: FP7 frame work programme agreement no242061 PREHDICT, and agreement no: 603019 COHEAHR. Competing interests C. J. L. M. Meijer has associations with the following companies: GlaxoSmithKline, Qiagen, Roche, Self‑Screen—a spin-off company at the Vrije Universiteit, Amsterdam. P. J. F. Snijders has associations with the following companies: GlaxoSmithKline, Gen‑probe, Roche, Self‑Screen. See the article online for full details of the relationships. 1.
2.
3.
4.
5.
6.
7.
8.
9.
Herfs, M. et al. Cervical squamocolumnar junction-specific markers define distinct, clinically relevant subsets of low-grade squamous intraepithelial lesions. Am. J. Surg. Pathol. 37, 1311–1318 (2013). Herfs, M. et al. A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer. Proc. Natl Acad. Sci. USA 109, 10516–10521 (2012). Ronco, G. et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet http:// dx.doi.org/10.1016/S0140-6736(13)62218-7 (2013). Arbyn, M. et al. Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer. Vaccine 30 (Suppl. 5), F88–F99 (2012). Rijkaart, D. C. et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncol. 13, 78–88 (2012). Ronco, G. et al. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol. 11, 249–257 (2010). Shastri, S. S. et al. Effect of visual inspection with acetic acid (VIA) screening by primary health workers on cervical cancer mortality: a cluster randomized controlled trial in Mumbai, India [abstract]. J. Clin. Oncol. 31 (Suppl.), a2 (2013). Tewari, K. S. et al. Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: a phase III randomized trial of the Gynecologic Oncology Group [abstract]. J. Clin. Oncol. 31 (Suppl.), a3 (2013). Kirk, R. From ASCO—Gynaecological cancer: advances in cervical cancer screening and treatment. Nat. Rev. Clin. Oncol. 10, 425 (2013).
www.nature.com/nrclinonc © 2014 Macmillan Publishers Limited. All rights reserved
Screening comes of age and treatment progress continues Chris J. L. M. Meijer and Peter J. F. Snijders
In 2013, studies confirmed that HPV infection of target cells predisposes to cervical (pre)cancer. In developed countries, HPV screening revealed superior protection than cytology screening. In India, visual inspection of the cervix after acetic acid application significantly reduced cervical cancer mortality after 12 years. Improved survival for women with advanced disease was observed after adjuvant bevacizumab. Meijer, C. J. L. M. & Snijders, P. J. F. Nat. Rev. Clin. Oncol. 11, 77–78 (2014); published online 21 January 2014; doi:10.1038/nrclinonc.2013.252
It has been known that infection with certain high-risk human papillomavirus (hrHPV) types is the main cause of cervical cancer. Despite this knowledge, it is still not clear what factors determine the malignant fate of an HPV infection, which occurs in only a small fraction (1–3%) of infected women. A discrete population of cuboidal epi thelial cells of embryonic origin localized in the squamocolumnar junction (SCJ) of the cervix may represent the cellular precursor of most cervical cancers.1 According to the current paradigm of cervical cancer development, most of the hrHPV infections that develop into lesions lead to new viral progeny (productive infections) and display no signs of cellular transformation. Such lesions are morphologically manifested as cervical intraepithelial neoplasia (CIN1 and part of CIN2), and arise from infection of basal cells of the squamous epithelium lining the transformation zone, or ectocervix. Conversely, in the case of transforming infections—as seen in the remaining part of CIN2, CIN3 and cervical cancers—the normal viral life cycle is aborted. Such infections are characterized by overexpression of the E6 and E7 oncogenes in the proliferating basal cells. It was not known what was responsible for this rather unnatural E6/E7 expression profile. The discovery by Herfs et al.1,2 of the cuboidal SCJ cells as a possible progenitor of cervical precancer and cancer is likely to pave the way for an explanation. They found that the cuboidal SCJ cells display a unique gene-expression profile and identified a SCJ-specific biomarker protein panel comprising KRT7, AGR2, MMP7, and GDA. Immunohistochemically, these SCJ bio markers were present in all cervical cancers analysed (squamous cell carcinomas (SCC)
and adenocarcinomas), most CIN2 and CIN3 lesions (91.8%), and a subset of CIN1 lesions (33.3%).1,2 Interestingly, 24.4% of the SCJ biomarker‑positive CIN1 lesions compared with 0% SCJ biomarker‑negative CIN1 lesions were diagnosed as CIN2/ CIN3 after 0.5 to 7 years of follow-up.1 The SCJ-specific markers could not be induced by HPV E6 or E7 in vitro in squamous epi thelial cells, and the biomarker panel was not expressed followi ng excision of the SCJ by cone biopsy or loop electrical excision.2 Thus, it was concluded that the SCJspecific expression profile in CIN lesions and cervical cancers was not acquired during the transformation process, but rather reflects the cell of origin. It is tempting to speculate that hrHPV infection of SCJ cells leads to deregulated E6 and E7 expression, triggeri ng a transforming infection. The high transformation susceptibility of cuboidal SCJ cells in relation to squamous cells is supported by the fact that HPV-related (pre)cancerous lesions are up to 20 times more common in the cervix (with a SCJ profile) than in other genital sites lacking a SCJ profile, such as the vagina and vulva.2 If confirmed, the potential implications of this discovery are manifold. Firstly, the absence of SCJ markers in CIN lesions likely reflects a negligible or low risk of malignant transformation and warrants a wait-and-see
management. Secondly, this finding might impact the assessment of the clinical value of novel molecular disease markers as candidate triage markers for the referral of hrHPV-positive women for colposcopy. Moreover, SCJ markers might provide interesting additive or alternative test-ofcure markers for monitoring women for the development of progressive post-treatment CIN2 or CIN3, as radical removal of SCJpositive cells is likely to be associated with a very low risk of recurrence. Another important publication in 2013 showed that hrHPV-based cervical screening provides 60–70% greater protection against invasive cervical carcinoma than cytology screening. 3 The authors had previously been involved in four earlier randomized controlled trials in which hrHPV-based screening was compared to cytology-based screening with CIN3 or worse (CIN3+) as the primary outcome measure. These trials comprised Swedescreen, POBASCAM, ARTISTIC and NTCC. To measure efficacy, the relative incidence rates of CIN3+ between hrHPV and cytology arms were compared.4 The researchers found that despite different screening protocols the relative incidence rate ratios (hrHPV versus cytology) of CIN3+ in the second screening round were similar in all trials (Swedescreen: 0.53 [95% CI 0.29–0.98]; POBASCAM: 0.39 [95% CI 0.27–0.53]; ARTISTIC: 0.52 [95% CI 0.28– 0.97]; NTCC: 0.34 [95%CI 0.15–0.75]), with no evidence of statistical heterogeneity between the results of the different studies.4 This indicates that hrHPV-based screening detects persistent high-grade CIN before cytology, thus increasing the probability of treatment before invasion. Although none of these studies was powered to detect invasive cervical cancer, two of them (NTCC and POBASCAM) showed better protection of a negative hrHPV test against invasive cancer.5,6
NPG
NATURE REVIEWS | CLINICAL ONCOLOGY
VOLUME 11 | FEBRUARY 2014 | 77 © 2014 Macmillan Publishers Limited. All rights reserved
YEAR IN REVIEW Key advances ■■ HPV infection of specific embryonal, cuboidal target cells in the squamocolumnar junction provides a likely explanation for the development of cervical precancer and cancer1,2 ■■ HPV-based cervical screening provides better protection against cervical cancer than Pap smear screening3 ■■ In low-income countries with poor infrastructure, screening with VIA by welltrained primary health workers shows good results in reducing cervical cancer mortality and should be further implemented7
In the pooled analysis by Ronco et al.,3 176,464 women were followed up for a median of 6.5 years to assess outcome according to screening type (hrHPV versus cytology). The cumulative detection of invasive cervical cancer 2 years after enrolment was similar in both arms. Thereafter, the relative incidence rate ratio dropped, and after 8 years the cumulative invasive cancer incidence was 46.7 per 100,000 in the hrHPV arm versus 93.6 per 100,000 in the cytology arm. The corresponding overall rate ratio was 0.61. This effect was not due to earlier detection of cancer in the first (prevalent) screen because the detection rate in the first 2.5 years was not significantly different between both arms. The rate ratio of invasive cervical cancer (hrHPV versus cytology) of 0.45 after 2.5 years provides the true gain in reducing the incidence of invasive cervical cancer. After a negative screen test at entry, the rate ratio of invasive cervical cancer was 0.30, indicating high efficacy of hrHPV screening. The relative incidence rate ratio was lower for adenocarcinomas than for SCC, in keeping with the observation that cytology is more efficient in detecting SCC than adenocarcinomas of the cervix. This is the first publication in the Western world to show a higher efficacy of hrHPV screening compared with cytology for detecting cervical cancer.3 The question of what age should HPV screening start has now been addressed. It is known that in young women cytology has low efficacy for high-grade lesions. In the NTCC study,4 overdiagnosis of regressive CIN lesions in the hrHPV arm had been suggested, which is explained partly by the more-intense follow-up of HPV positive women in the NTCC study and a relatively short screening interval of 3 years. No overdiagnosis was noted in the POBASCAM trial, which had a second screening round after 5 years. 5 Ronco et al. 3 showed the 78 | FEBRUARY 2014 | VOLUME 11
gain in efficacy with hrHPV screening at 30–34 years is at least as effective, if not better than in older women. They recommend starting hrHPV screening at the age of 30 with at least 5‑year intervals. The Dutch Minister of Health has decided that in 2016 population hrHPV-based screening should replace cytology, and should start at the age of 30, with screening rounds at 30, 35, 40, 50 and 60 years. Because HPV screening in India is diffi cult to implement, Shastri et al.7 explored visual inspection with acetic acid (VIA) in a cervical screening trial in India and compared the results with women who only obtained cancer education (control group). The quality of screening by primary health-care workers and expert gynaecologists was comparable. Using four rounds of cancer education in the control group and VIA screening every 24 months in the intervention group, after 12 years they showed a 31% reduction in mortality compared with the control group. Participation in screening (89% in VIA group and 79% in the control group), and compliance to treatment for invasive cancer in both groups was high (86% and 73%, respectively). These represent hopeful results with simple techniques in a country where cervical cancer incidence is high (27 per 100,000 women). Promising results have also been obtained regarding treatment in a study by Tewari et al.8 of a cluster randomized trial carried out in Mumbai. The authors showed that bevacizumab given as an adjuvant to standard chemot herapy in women with advanced cervical cancer increased overall survival by nearly 4 months compared with standard chemot herapy alone. The relevance of this finding has recently been highlighted in this journal.9 In summary, the paper of Ronco et al.3 has further strengthened the case for carrying out primary HPV screening instead of Pap smear testing. Future perspectives include the development of HPV self-s ampling, opening the way to molecular self-screening. For girls who have been vaccinated with prophylactic bivalent or quadrivalent HPV vaccine, the conversion to HPV screening will provide a joint approach to cancer prevention in the future. In underdeveloped countries, VIA screening with well- educated primary health-care workers also shows important results in reducing cervical cancer mortality. Although these positive results warrant implementation in the short run, long-term prevention strategies should focus on use of prophylactic HPV
vaccination at prepubertal age, and HPV testing with a cheap method at an older age (≥30 years). For women with advancedstage cancer, adjuvant treatment with bevacizumab shows hopeful results. Combined use of new therapies against specific targets involved in cervical carcinogenesis should be further explored. Department of Pathology, Vrije Universiteit Medical Centre Amsterdam, de Boelelaan 1117, 1084 HV Amsterdam, The Netherlands (C. J. L. M. Meijer, P. J. F. Snijders). Correspondence to: C. J. L. M. Meijer [email protected] Acknowledgements This work has been made possible by grants from the European Union: FP7 frame work programme agreement no242061 PREHDICT, and agreement no: 603019 COHEAHR. Competing interests C. J. L. M. Meijer has associations with the following companies: GlaxoSmithKline, Qiagen, Roche, Self‑Screen—a spin-off company at the Vrije Universiteit, Amsterdam. P. J. F. Snijders has associations with the following companies: GlaxoSmithKline, Gen‑probe, Roche, Self‑Screen. See the article online for full details of the relationships. 1.
2.
3.
4.
5.
6.
7.
8.
9.
Herfs, M. et al. Cervical squamocolumnar junction-specific markers define distinct, clinically relevant subsets of low-grade squamous intraepithelial lesions. Am. J. Surg. Pathol. 37, 1311–1318 (2013). Herfs, M. et al. A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer. Proc. Natl Acad. Sci. USA 109, 10516–10521 (2012). Ronco, G. et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet http:// dx.doi.org/10.1016/S0140-6736(13)62218-7 (2013). Arbyn, M. et al. Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer. Vaccine 30 (Suppl. 5), F88–F99 (2012). Rijkaart, D. C. et al. Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncol. 13, 78–88 (2012). Ronco, G. et al. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol. 11, 249–257 (2010). Shastri, S. S. et al. Effect of visual inspection with acetic acid (VIA) screening by primary health workers on cervical cancer mortality: a cluster randomized controlled trial in Mumbai, India [abstract]. J. Clin. Oncol. 31 (Suppl.), a2 (2013). Tewari, K. S. et al. Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: a phase III randomized trial of the Gynecologic Oncology Group [abstract]. J. Clin. Oncol. 31 (Suppl.), a3 (2013). Kirk, R. From ASCO—Gynaecological cancer: advances in cervical cancer screening and treatment. Nat. Rev. Clin. Oncol. 10, 425 (2013).
www.nature.com/nrclinonc © 2014 Macmillan Publishers Limited. All rights reserved
