- Email: [email protected]
Triage of HPV-positive women in cervical cancer screening
Comment
6
7
Kapur P, Peña-Llopis S, Christie A, et al. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol 2013; published online Jan 16. http://dx.doi.org/10.1016/S14702045(12)70584-3. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366: 883–92.
8
9
Guo G, Gui Y, Gao S, et al. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat Genet 2011; 44: 17–19. Sonpavde G, Choueiri TK. Biomarkers: the next therapeutic hurdle in metastatic renal cell carcinoma. Br J Cancer 2012; 107: 1009–16.
Almost all cases of cervical cancer are caused by human papillomavirus (HPV) infection, which is the first step in a carcinogenic process that can take decades.1 A negative result from a sensitive HPV test provides sufficient reassurance that cervical cancer will not develop in the next decade; screening intervals can be extended to at least 3–5 years for women with a negative HPV result. Therefore, HPV testing has been incorporated into cervical-cancer screening programmes in several countries. However, how best to manage HPV-positive women is unclear, because most HPV infections resolve in a few months or years. Identification of women with cervical precancer who need treatment is important, but unnecessary referral of women who have transient infections should be avoided. In The Lancet Oncology, Francesca Carozzi and colleagues present the first longitudinal data
of p16-INK4A (henceforth p16) cytology as a triage test in HPV-positive women from the New Technologies for Cervical Cancer screening (NTCC) trial.2 Of 1170 HPV-positive women with available p16 samples, 493 (42%) overexpressed p16 (ie, were p16 positive) at baseline. Women were followed up for up to 3 years and screened for cervical lesions. Cervical intraepithelial neoplasia of grade 3 (CIN3) or worse was detected at baseline in the first round of screening or during follow-up in 55 of the 493 (9·7% [95% CI 7·2–12·2]; weighted for inverse of tested fraction) HPV-positive, p16-positive women and ten of 644 (1·7% [0·7–2·8]) HPV-positive, p16-negative women (relative risk 5·57 [2·88–10·76]; longitudinal sensitivity of p16 82·4% [67·8–97·0]). Carozzi and colleagues2 concluded that p16 testing could be used as a triage method for HPV-positive women and that
Baseline Proportion of patients with a positive result (%) Sensitivity for CIN3 or worse (%)
David Mack/Science Photo Library
Triage of HPV-positive women in cervical cancer screening
Published Online December 21, 2012 http://dx.doi.org/10.1016/ S1470-2045(12)70568-5 See Articles page 168
3-year follow-up
Risk of CIN3 or worse in individuals who tested positive (%)
Risk of CIN3 or worse in individuals who tested negative (%)
Sensitivity for CIN3 or worse (%)
Risk of CIN3 or worse in individuals who tested positive (%)
Risk of CIN3 or worse in individuals who tested negative (%)
ATHENA trial6 Immediate colposcopy
100%
ASCUS
27%
·· 53·3%
7·2% 14·1%
··
··
··
··
NR
··
··
··
HPV16 or HPV18
28%
59·5%
15·5%
NR
··
··
··
HPV16, HPV18, or low-grade squamous intraepithelial lesions
38%
72·2%
13·9%
NR
··
··
··
HPV16, HPV18, or ASCUS
45%
78·2%
12·6%
NR
··
··
··
NTCC trial2,7 Immediate (and 3-year follow-up) colposcopy p16-INK4A
100% 42%
··
3·7%*
··
··
5·2%†
··
90·5%
7·7%*
1·0%*
82·4%
9·7%†
1·7%†
3-year follow-up data for ATHENA trial not reported yet. CIN3=cervical intraepithelial neoplasia of grade 3. ATHENA=Addressing THE Need for Advanced HPV Diagnostics. ASCUS=atypical cells of undetermined significance. NR=not reported. HPV=human papillomavirus. NTCC=New Technologies for Cervical Cancer screening. *Unweighted estimates. †Weighted for inverse of tested fraction.2
Table: Comparison of different triage options for HPV-positive women in cervical-cancer screening
www.thelancet.com/oncology Vol 14 February 2013
107
Comment
p16-negative women could be safely retested after 2–3 years. A comparison of p16 cytology with HPV16 or HPV18 genotyping—another approach proposed to triage HPV-positive women—is instructive. Infection with HPV16 and HPV18 predicts a much higher risk of precancer than with other carcinogenic HPV types.3 HPV16 and HPV18 genotyping is objective and is provided as part of some HPV assays. By contrast, p16 is a marker of HPV oncogene activity that is independent of carcinogenic virus type and indicates early stages of precancer.4 However, the p16 assay necessitates preparation of a cytological slide and microscopic assessment for p16 staining. Several factors have to be considered when deciding which strategies to use for triage of HPV-positive women. First, triage-test positivity indicates the percentage of the HPV-positive population that will be referred to colposcopy. Second, absolute risk and the difference between risk in individuals with positive and negative results show whether different management is warranted on the basis of the result of the triage test. Finally, the longitudinal risk in individuals with negative results indicates how long test intervals can safely be.5 The table shows several of these key measures for triage of HPVpositive women in the ATHENA trial, which assessed various combinations of HPV16 genotyping, HPV18 genotyping, and cytology,6 and in the NTCC trial, which assessed p16.2,7 The baseline prevalence (or pretest risk) of CIN3 or worse in all HPV-positive women was higher in the ATHENA trial than in the NTCC study (table). The relative increase in risk of CIN3 or worse in individuals who had positive results for triage tests was similar for the various strategies in the ATHENA trial6 and for p16 cytology in the NTCC study2,7 (about twice the risk in all individuals who had not undergone the triage test). Of all strategies, p16 had the highest sensitivity at baseline, and the proportion of patients with a positive result (ie, were referred for further tests) was the second highest of all strategies (table). Although comparisons between the two trials2,6,7 have to be made with caution, sensitivity of p16 was higher but referral lower than for the combination of testing for HPV16 or HPV18 and for atypical cells of undetermined significance—one of the presently 108
recommended triage strategies for HPV-positive women.8 Longitudinal data from the ATHENA trial will be important to establish screening intervals in triage based on testing for HPV16 or HPV18. Notably, a new assay based on dual staining for p16 and Ki-67 has been introduced that obviates the need for morphological assessment of p16-stained cells as was done by Carozzi and coworkers.2 However, a crosssectional study with the new assay9 suggested that the p16 and Ki-67 assay successfully detects cervical precancer at the same frequency as the older assay. Carozzi and colleagues’ findings2 need to be replicated in other populations with the new dual stain assay, and assessment of p16 and HPV genotyping in the same population will be important to formally compare these options. Different health-care settings will probably need different triage strategies—eg, an organised invitation-based screening programme is more likely to adopt extended screening intervals than a clinical setting that relies on opportunistic screening and has large loss to follow-up. Because of the inherent complexity of assessment of management strategies of HPV-positive women, cost-effectiveness modelling will be important to provide guidance for implementation for various triage options. Nicolas Wentzensen Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892–7234, USA [email protected] NW is supported by the Intramural Research Program of the National Cancer Institute. The views expressed do not represent those of the National Cancer Institute, the National Institutes of Health, the Department of Health and Human Services, or the US Government. He declares that he has no conflicts of interest. 1
2
3
4
5
Schiffman M, Wentzensen N, Wacholder S, Kinney W, Gage JC, Castle PE. Human papillomavirus testing in the prevention of cervical cancer. J Natl Cancer Inst 2011; 103: 368–83. Carozzi F, Gillio-Tos A, Confortini M, et al. Risk of high grade cervical intraepithelial neoplasia during follow-up in HPV-positive women according to baseline p16-INK4A results: a prospective analysis of a nested substudy of the NTCC randomised controlled trial. Lancet Oncol 2012; published online Dec 21. http://dx.doi.org/10.1016/S14702045(12)70529-6. Schiffman M, Glass AG, Wentzensen N, et al. A long-term prospective study of type-specific human papillomavirus infection and risk of cervical neoplasia among 20,000 women in the Portland Kaiser Cohort Study. Cancer Epidemiol Biomarkers Prev 2011; 20: 1398–409. Cuschieri K, Wentzensen N. Human papillomavirus mRNA and p16 detection as biomarkers for the improved diagnosis of cervical neoplasia. Cancer Epidemiol Biomarkers Prev 2008; 17: 2536–45. Wentzensen N, Wacholder S. From differences in means between cases and controls to risk stratification: a business plan for biomarker development. Cancer Discovery (in press).
www.thelancet.com/oncology Vol 14 February 2013
Comment
6
7
Castle PE, Stoler MH, Wright TC Jr, Sharma A, Wright TL, Behrens CM. Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study. Lancet Oncol 2011; 12: 880–90. Carozzi F, Confortini M, Dalla PP, et al. Use of p16-INK4A overexpression to increase the specificity of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial. Lancet Oncol 2008; 9: 937–45.
8
9
Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin 2012; 62: 147–72. Wentzensen N, Schwartz L, Zuna RE, et al. Performance of p16/Ki-67 immunostaining to detect cervical cancer precursors in a colposcopy referral population. Clin Cancer Res 2012; 18: 4154–62.
International Rare Cancers Initiative The definition of a rare cancer has not been agreed internationally. In Europe, rare diseases are often defined as those with a prevalence of less than 50 per 100 000.1 In the USA, a published definition of a rare cancer is less than 15 per 100 000 per year.2 The estimated yearly incidence of all rare cancers in Europe, (based on the RARECARE definition of an incidence of
and the coordination of operations between organisations. These challenges might be overcome through careful planning, frequent communication, and cooperative collaboration.4 International trials in rare diseases are practicable with appropriate funding, planning, and support; in an attempt to encourage the development of international trials for rare cancers, the International Rare Cancers Initiative (IRCI) was established early in 2011. IRCI is a joint initiative between the National Institute for Health Research Cancer Research Network, Cancer Research UK, the National Cancer Institute, and the European Organisation for Research and Treatment of Cancer (EORTC). The objective of this initiative is to facilitate the development of international clinical trials for patients with rare cancers to boost the progress of new treatments for these patients. For the purpose of this initiative, rare has been broadly defined as an incidence of less than two per 100 000. Occasionally, rare clinical scenarios have also been considered. So far, IRCI has excluded rare molecular subtypes of common cancers. However, a rare molecular subtype could be considered if it is a distinct, prospectively identifiable rare subgroup with a strong rationale for separate research, rather than inclusion as a molecular stratum in a mainline trial. Priority has been given to cancers with potential for an interventional trial (usually randomised) rather than an audit, registry, or non-trial tissue collection. The IRCI hopes to encourage the use of innovative trial designs to maximise the potential for research questions to be answered, and to identify and overcome barriers to international trials to allow agreed IRCI trials to run smoothly. At the outset of the initiative, clinical communities associated with each partner organisation were asked to identify rare cancers when there was enthusiasm for international collaborations and the potential 109
6
7
Kapur P, Peña-Llopis S, Christie A, et al. Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol 2013; published online Jan 16. http://dx.doi.org/10.1016/S14702045(12)70584-3. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366: 883–92.
8
9
Guo G, Gui Y, Gao S, et al. Frequent mutations of genes encoding ubiquitin-mediated proteolysis pathway components in clear cell renal cell carcinoma. Nat Genet 2011; 44: 17–19. Sonpavde G, Choueiri TK. Biomarkers: the next therapeutic hurdle in metastatic renal cell carcinoma. Br J Cancer 2012; 107: 1009–16.
Almost all cases of cervical cancer are caused by human papillomavirus (HPV) infection, which is the first step in a carcinogenic process that can take decades.1 A negative result from a sensitive HPV test provides sufficient reassurance that cervical cancer will not develop in the next decade; screening intervals can be extended to at least 3–5 years for women with a negative HPV result. Therefore, HPV testing has been incorporated into cervical-cancer screening programmes in several countries. However, how best to manage HPV-positive women is unclear, because most HPV infections resolve in a few months or years. Identification of women with cervical precancer who need treatment is important, but unnecessary referral of women who have transient infections should be avoided. In The Lancet Oncology, Francesca Carozzi and colleagues present the first longitudinal data
of p16-INK4A (henceforth p16) cytology as a triage test in HPV-positive women from the New Technologies for Cervical Cancer screening (NTCC) trial.2 Of 1170 HPV-positive women with available p16 samples, 493 (42%) overexpressed p16 (ie, were p16 positive) at baseline. Women were followed up for up to 3 years and screened for cervical lesions. Cervical intraepithelial neoplasia of grade 3 (CIN3) or worse was detected at baseline in the first round of screening or during follow-up in 55 of the 493 (9·7% [95% CI 7·2–12·2]; weighted for inverse of tested fraction) HPV-positive, p16-positive women and ten of 644 (1·7% [0·7–2·8]) HPV-positive, p16-negative women (relative risk 5·57 [2·88–10·76]; longitudinal sensitivity of p16 82·4% [67·8–97·0]). Carozzi and colleagues2 concluded that p16 testing could be used as a triage method for HPV-positive women and that
Baseline Proportion of patients with a positive result (%) Sensitivity for CIN3 or worse (%)
David Mack/Science Photo Library
Triage of HPV-positive women in cervical cancer screening
Published Online December 21, 2012 http://dx.doi.org/10.1016/ S1470-2045(12)70568-5 See Articles page 168
3-year follow-up
Risk of CIN3 or worse in individuals who tested positive (%)
Risk of CIN3 or worse in individuals who tested negative (%)
Sensitivity for CIN3 or worse (%)
Risk of CIN3 or worse in individuals who tested positive (%)
Risk of CIN3 or worse in individuals who tested negative (%)
ATHENA trial6 Immediate colposcopy
100%
ASCUS
27%
·· 53·3%
7·2% 14·1%
··
··
··
··
NR
··
··
··
HPV16 or HPV18
28%
59·5%
15·5%
NR
··
··
··
HPV16, HPV18, or low-grade squamous intraepithelial lesions
38%
72·2%
13·9%
NR
··
··
··
HPV16, HPV18, or ASCUS
45%
78·2%
12·6%
NR
··
··
··
NTCC trial2,7 Immediate (and 3-year follow-up) colposcopy p16-INK4A
100% 42%
··
3·7%*
··
··
5·2%†
··
90·5%
7·7%*
1·0%*
82·4%
9·7%†
1·7%†
3-year follow-up data for ATHENA trial not reported yet. CIN3=cervical intraepithelial neoplasia of grade 3. ATHENA=Addressing THE Need for Advanced HPV Diagnostics. ASCUS=atypical cells of undetermined significance. NR=not reported. HPV=human papillomavirus. NTCC=New Technologies for Cervical Cancer screening. *Unweighted estimates. †Weighted for inverse of tested fraction.2
Table: Comparison of different triage options for HPV-positive women in cervical-cancer screening
www.thelancet.com/oncology Vol 14 February 2013
107
Comment
p16-negative women could be safely retested after 2–3 years. A comparison of p16 cytology with HPV16 or HPV18 genotyping—another approach proposed to triage HPV-positive women—is instructive. Infection with HPV16 and HPV18 predicts a much higher risk of precancer than with other carcinogenic HPV types.3 HPV16 and HPV18 genotyping is objective and is provided as part of some HPV assays. By contrast, p16 is a marker of HPV oncogene activity that is independent of carcinogenic virus type and indicates early stages of precancer.4 However, the p16 assay necessitates preparation of a cytological slide and microscopic assessment for p16 staining. Several factors have to be considered when deciding which strategies to use for triage of HPV-positive women. First, triage-test positivity indicates the percentage of the HPV-positive population that will be referred to colposcopy. Second, absolute risk and the difference between risk in individuals with positive and negative results show whether different management is warranted on the basis of the result of the triage test. Finally, the longitudinal risk in individuals with negative results indicates how long test intervals can safely be.5 The table shows several of these key measures for triage of HPVpositive women in the ATHENA trial, which assessed various combinations of HPV16 genotyping, HPV18 genotyping, and cytology,6 and in the NTCC trial, which assessed p16.2,7 The baseline prevalence (or pretest risk) of CIN3 or worse in all HPV-positive women was higher in the ATHENA trial than in the NTCC study (table). The relative increase in risk of CIN3 or worse in individuals who had positive results for triage tests was similar for the various strategies in the ATHENA trial6 and for p16 cytology in the NTCC study2,7 (about twice the risk in all individuals who had not undergone the triage test). Of all strategies, p16 had the highest sensitivity at baseline, and the proportion of patients with a positive result (ie, were referred for further tests) was the second highest of all strategies (table). Although comparisons between the two trials2,6,7 have to be made with caution, sensitivity of p16 was higher but referral lower than for the combination of testing for HPV16 or HPV18 and for atypical cells of undetermined significance—one of the presently 108
recommended triage strategies for HPV-positive women.8 Longitudinal data from the ATHENA trial will be important to establish screening intervals in triage based on testing for HPV16 or HPV18. Notably, a new assay based on dual staining for p16 and Ki-67 has been introduced that obviates the need for morphological assessment of p16-stained cells as was done by Carozzi and coworkers.2 However, a crosssectional study with the new assay9 suggested that the p16 and Ki-67 assay successfully detects cervical precancer at the same frequency as the older assay. Carozzi and colleagues’ findings2 need to be replicated in other populations with the new dual stain assay, and assessment of p16 and HPV genotyping in the same population will be important to formally compare these options. Different health-care settings will probably need different triage strategies—eg, an organised invitation-based screening programme is more likely to adopt extended screening intervals than a clinical setting that relies on opportunistic screening and has large loss to follow-up. Because of the inherent complexity of assessment of management strategies of HPV-positive women, cost-effectiveness modelling will be important to provide guidance for implementation for various triage options. Nicolas Wentzensen Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892–7234, USA [email protected] NW is supported by the Intramural Research Program of the National Cancer Institute. The views expressed do not represent those of the National Cancer Institute, the National Institutes of Health, the Department of Health and Human Services, or the US Government. He declares that he has no conflicts of interest. 1
2
3
4
5
Schiffman M, Wentzensen N, Wacholder S, Kinney W, Gage JC, Castle PE. Human papillomavirus testing in the prevention of cervical cancer. J Natl Cancer Inst 2011; 103: 368–83. Carozzi F, Gillio-Tos A, Confortini M, et al. Risk of high grade cervical intraepithelial neoplasia during follow-up in HPV-positive women according to baseline p16-INK4A results: a prospective analysis of a nested substudy of the NTCC randomised controlled trial. Lancet Oncol 2012; published online Dec 21. http://dx.doi.org/10.1016/S14702045(12)70529-6. Schiffman M, Glass AG, Wentzensen N, et al. A long-term prospective study of type-specific human papillomavirus infection and risk of cervical neoplasia among 20,000 women in the Portland Kaiser Cohort Study. Cancer Epidemiol Biomarkers Prev 2011; 20: 1398–409. Cuschieri K, Wentzensen N. Human papillomavirus mRNA and p16 detection as biomarkers for the improved diagnosis of cervical neoplasia. Cancer Epidemiol Biomarkers Prev 2008; 17: 2536–45. Wentzensen N, Wacholder S. From differences in means between cases and controls to risk stratification: a business plan for biomarker development. Cancer Discovery (in press).
www.thelancet.com/oncology Vol 14 February 2013
Comment
6
7
Castle PE, Stoler MH, Wright TC Jr, Sharma A, Wright TL, Behrens CM. Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study. Lancet Oncol 2011; 12: 880–90. Carozzi F, Confortini M, Dalla PP, et al. Use of p16-INK4A overexpression to increase the specificity of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial. Lancet Oncol 2008; 9: 937–45.
8
9
Saslow D, Solomon D, Lawson HW, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin 2012; 62: 147–72. Wentzensen N, Schwartz L, Zuna RE, et al. Performance of p16/Ki-67 immunostaining to detect cervical cancer precursors in a colposcopy referral population. Clin Cancer Res 2012; 18: 4154–62.
International Rare Cancers Initiative The definition of a rare cancer has not been agreed internationally. In Europe, rare diseases are often defined as those with a prevalence of less than 50 per 100 000.1 In the USA, a published definition of a rare cancer is less than 15 per 100 000 per year.2 The estimated yearly incidence of all rare cancers in Europe, (based on the RARECARE definition of an incidence of
and the coordination of operations between organisations. These challenges might be overcome through careful planning, frequent communication, and cooperative collaboration.4 International trials in rare diseases are practicable with appropriate funding, planning, and support; in an attempt to encourage the development of international trials for rare cancers, the International Rare Cancers Initiative (IRCI) was established early in 2011. IRCI is a joint initiative between the National Institute for Health Research Cancer Research Network, Cancer Research UK, the National Cancer Institute, and the European Organisation for Research and Treatment of Cancer (EORTC). The objective of this initiative is to facilitate the development of international clinical trials for patients with rare cancers to boost the progress of new treatments for these patients. For the purpose of this initiative, rare has been broadly defined as an incidence of less than two per 100 000. Occasionally, rare clinical scenarios have also been considered. So far, IRCI has excluded rare molecular subtypes of common cancers. However, a rare molecular subtype could be considered if it is a distinct, prospectively identifiable rare subgroup with a strong rationale for separate research, rather than inclusion as a molecular stratum in a mainline trial. Priority has been given to cancers with potential for an interventional trial (usually randomised) rather than an audit, registry, or non-trial tissue collection. The IRCI hopes to encourage the use of innovative trial designs to maximise the potential for research questions to be answered, and to identify and overcome barriers to international trials to allow agreed IRCI trials to run smoothly. At the outset of the initiative, clinical communities associated with each partner organisation were asked to identify rare cancers when there was enthusiasm for international collaborations and the potential 109