- Email: [email protected]
Filling a gap in cervical cancer screening programmes
Comment
a phase 1 study to establish the maximum tolerated dose of the combination;8 this phase 2/3 trial measured progression-free survival as the primary endpoint. Since only 267 patients were recruited—of whom only 259 actually received the study drugs—the trial was underpowered and thus, perhaps unsurprisingly, there was no significant difference in progressionfree survival between groups. Median progressionfree survival was 9·7 months (95% CI 8·1–14·5) in the FOLFOX group, and 9·4 months (8·1–10·6) in the fluorouracil and cisplatin group (HR 0·93, 95% CI 0·70– 1·24; p=0·64). There were also no significant differences between groups in any of the secondary endpoints of overall survival, proportion of endoscopic complete responses, time to treatment failure, or occurrence of grade 3 or 4 toxicities. The authors conclude that the similar efficacy outcomes between the two treatment regimens have implications for the potential use of FOLFOX combination in cisplatin-intolerant patients. Previously, cisplatin-intolerant patients have been treated with radiotherapy alone, or with combinations of radiotherapy and non-platinum-containing regimens. However, most of these treatments have worse survival outcomes when compared with standard chemotherapy. Additionally, because of the high inpatient and outpatient admission rates associated with cisplatin as a result of patients requiring suitable hydration, there is a potential cost benefit to not including cisplatin in a treatment regimen. Thus, despite not improving progression-free survival, this study has potentially shown an improvement in the therapeutic ratio by increasing the treatment options for cisplatin-intolerant patients, and reducing the burden of treatment cost through a less time-consuming and easier to administer regimen—and thus, potentially, improving quality of life for patients. I commend the authors for completing this multicentre trial given its implications
for the future management strategies for oesophageal cancer. It sets the scene for further randomised trials designed to test similar endpoints with other treatment regimens that contain platinum, such as a regimen of carboplatin, paclitaxel, and radiotherapy, which has been effective in the neoadjuvant treatment of operable oesophageal carcinoma, and has low toxicty.9 Finally, I urge the authors of this trial to publish their quality-of-life data. A study of this type would be more complete with this additional data, which could enhance the argument for replacement of cisplatin with oxaliplatin. Bryan Burmeister Department of Radiation Oncology, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia [email protected] I declare that I have no competing interests. 1
2
3
4
5
6
7
8
9
Al-Sarraf M, Martz K, Herkovic A, et al. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol 1997; 1: 277–84. Wong R, Malthaner R. Combined chemotherapy and radiotherapy (without surgery) compared with radiotherapy alone in localized carcinoma of the esophagus. Cochrane Database Syst Rev 2006; 1: CD002092. Kohler RE, Sheets NC, Wheeler SB, et al. Two-year and lifetime cost-effectiveness of intensity modulated radiation therapy versus 3-dimensional conformal radiation therapy for head and neck cancer. Int J Radiat Oncol Biol Phys 2013; 87: 683–89. Crosby T, Hurt CN, Falk S, et al. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial. Lancet Oncol 2013; 14: 627–37. Conroy T, Galais M-P, Raoul J-L, et al. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol 2014; published online Feb 18. http://dx.doi. org/10.1016/S1470-2045(14)70028-2. Mauer AM, Kraut EH, Krauss SA, et al. Phase II trial of oxaliplatin, leucovorin and fluorouracil in patients with advanced carcinoma of the esophagus. Ann Oncol 2005; 16: 1320–25. Chiarion-Sileni V, Innocente R, Cavina R, et al. Multi-center phase II trial of chemo-radiotherapy with 5-fluorouracil, leucovorin and oxaliplatin in locally advanced esophageal cancer. Cancer Chemother Pharmacol 2009; 63: 1111–19. Conroy T, Viret F, Francois E, et al. Phase I trial of oxaliplatin with fluorouracil, folinic acid and concurrent radiotherapy for oesophageal cancer. Br J Cancer 2008; 99: 1395–401. van Hagen P, Hulschof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012; 366: 2074–84.
Filling a gap in cervical cancer screening programmes Cervical screening remains important, despite the longterm promise of human papillomavirus (HPV) vaccination. HPV testing is more sensitive than cytology for detection of cervical pre-cancer and cancer, providing increased reassurance and allowing extended screening intervals.1 www.thelancet.com/oncology Vol 15 March 2014
Nonetheless, the pace and manner of implementation of primary HPV testing has varied substantially. In the USA, HPV testing is recommended in conjunction with cytology, whereas in the Netherlands, it is recommended as one primary test.2,3 In many places, it is not used at all.
Published Online February 13, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70073-7 See Articles page 315
249
Comment
Cytology
HPV
Co-testing (cytology and HPV)
Technology
Pap smear or liquid based cytology; Clinician collected or self-collected manual or computer-assisted assessment
Co-collection or separate collection
Relative repeat interval for negative screen
Shortest (lowest negative predictive value)
Longest (greatest negative predictive value)
Longer (greater negative predictive value)
Triage test needed
For equivocal cytology results
For all positive results
For all HPV-positive, cytology-negative results
Triage test options
HPV or repeat cytology or p16/Ki-67
Cytology or HPV genotyping or p16/Ki-67 or methylation
Repeat co-test or HPV genotyping or p16/Ki-67 or methylation
Triage test sampling
Reflex triage or separate collection
Reflex triage or separate collection
Reflex triage or separate collection
Diagnostic test
Colposcopy and biopsy
Colposcopy and biopsy
Colposcopy and biopsy
The three major primary screening options are cytology, HPV testing, or a combination of the two (co-testing). Not considered here is visual inspection, a screening method under consideration for low-resource regions.
Table: Options for cervical cancer screening programmes
The successful introduction of HPV testing into cervical cancer screening needs more than a sensitive primary screening test (table). New programmes need to be built around HPV testing. The major goal of cervical screening programmes is to find pre-cancers that can be treated to prevent invasive cancers. A diagnosis of pre-cancer needs colposcopic assessment with cervical biopsies. Most HPV infections are transient; a HPV-positive woman has a low risk of progressing to pre-cancer and cancer. Thus, if HPV testing is used, secondary (triage) tests are needed to decide who in the HPV-positives needs to be referred to colposcopy. A common suggestion is to move cytology into the role of triage. New molecular assays such as p16/Ki-67 cytology have higher sensitivity at comparable specificity to cytology.4 Additional molecular markers such as host methylation and HPV methylation are also being investigated.5–7 Irrespective of which screening and triage tests are chosen, the crucial problem of non-participation remains. A substantial proportion of cervical cancers in developed countries arise in women who participate in screening irregularly, or not at all.8 Findings of previous trials from the Netherlands have shown that the offer of self-sampling for HPV testing to non-responders, instead of an office visit, can increase participation.9 As with all HPV testing, women found to be HPV positive by self-sampling need a triage test to decide who needs colposcopy. However, self-collected samples are not suitable for cell-based assays, such as cytology or p16/ Ki-67, so an additional collection is needed. In The Lancet Oncology, Verhoef and colleagues6 report the results of a randomised trial addressing this gap in their screening programme. Investigators 250
enrolled initially non-participating women, found to be HPV positive upon self-sampling, who were followed up with two different triage strategies: cytology from physician-collected samples or methylation testing of two genes, MAL and miR-124-2, from the selfcollected sample. The researchers found that the clinical performance of methylation testing from the self-collected specimen was equivalent to physiciancollected cytology. Because the assay was run from the same specimen collected at baseline in HPV-positive women, an additional office visit for most women was avoided. The Dutch team should be commended as pioneers in the creation of an integrated HPV-based cervical cancer screening programme. The approach described by Verhoef and colleagues further improves the safety net of their programme. As one possible caveat, the participants in the trial generally reported being screened before, and had a very high compliance after they were included in the study, suggesting that they were so-called soft refusers. The self-sampling strategy might not apply as well to the firm refusers who have never been screened before, putting them at highest risk. How do these results apply to cervical cancer screening in other places? Findings of a recent metaanalysis10 showed that self-sampling has slightly lower sensitivity compared with physician-collected samples;in most resource-rich settings, self-sampling is not approved as a first-line alternative. The offer of self-sampling for non-responders is especially attractive for organised screening settings, but is difficult to implement in countries with opportunistic screening like in the USA. Moreover, the methylation www.thelancet.com/oncology Vol 15 March 2014
Comment
assay used in the present study has not been approved for clinical use, is not available as a kit, and has not been assessed outside of the laboratory included in the Dutch screening trials. Our understanding of HPV and the natural history of cervical cancer has brought great methods for cervical cancer prevention, including vaccines for primary prevention, HPV testing for screening, and various molecular assays, including methylation markers, for detection of cervical pre-cancers. Presented with many HPV-related preventive options, high-resource countries are considering various combinations; no one winning strategy has emerged. However, low-resource countries cannot afford the complex programmes established or under development in industrialised countries. A triage test that can be done out of self-sampling material like the methylation assay described here could extend the options for cervical cancer screening in low-resource settings, where cytology programmes rarely exist and colposcopy capacity is very restricted. However, development of a robust, cheap methylation assay is paramount to achieve this goal.
MS has received HPV testing at no cost for NCI studies from Roche and Becton Dickinson. NW and MS were supported by the Intramural Research Program of the NIH, National Cancer Institute. The views expressed do not represent the views of the US National Cancer Institute, the National Institutes of Health, the Department of Health and Human Services, or the US Government. We declare that we have no competing interests.
*Nicolas Wentzensen, Mark Schiffman
10
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD 20892-9774, USA (NW, MS) [email protected]
1
2
3
4 5
6
7
8 9
Katki HA, Kinney WK, Fetterman B, et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol 2011; 12: 663–72. Health Council of the Netherlands. Population screening for cervical cancer. 2011. http://www.gezondheidsraad.nl/en/publications/prevention/ population-screening-cervical-cancer (accessed Feb 7, 2014). 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. Triage of HPV-positive women in cervical cancer screening. Lancet Oncol 2013; 14: 107–09. Mirabello L, Schiffman M, Ghosh A, et al. Elevated methylation of HPV16 DNA is associated with the development of high grade cervical intraepithelial neoplasia. Int J Cancer 2013; 132: 1412–22. Verhoef VMJ, Bosgraaf RP, van Kemenade FJ, et al. Triage by methylation-marker testing versus cytology in women who test HPV-positive on self-collected cervicovaginal specimens (PROHTECT-3): a randomised controlled non-inferiority trial. Lancet Oncol 2014; published online Feb 13. http://dx.doi.org/10.1016/S1470-2045(14)70019-1. Wentzensen N, Sun C, Ghosh A, et al. Methylation of HPV18, HPV31, and HPV45 genomes and cervical intraepithelial neoplasia grade 3. J Natl Cancer Inst 2012; 104: 1738–49. Spence AR, Goggin P, Franco EL. Process of care failures in invasive cervical cancer: systematic review and meta-analysis. Prev Med 2007; 45: 93–106. Gok M, Heideman DA, van Kemenade FJ, et al. HPV testing on self collected cervicovaginal lavage specimens as screening method for women who do not attend cervical screening: cohort study. BMJ 2010; 340: 1040. Arbyn M, Verdoodt F, Snijders PJ, et al. Accuracy of human papillomavirus testing on self-collected versus clinician-collected samples: a meta-analysis. Lancet Oncol 2014; 15: 172–83.
Advances in the understanding of the molecular profile of tumour cells and progress in systems biology and bioinformatics have led to the promise of precision medicine for treatment of human cancer. Melanoma has provided an opportunity for insights into both the potential benefit and limitations of precision medicine for cancer. In 2002, half of all human melanoma cells were shown to harbour mutations in the BRAF gene,1 the product of which has an important role in cell division, differentiation, and secretion through the MAPK or RAS-RAF-MEK-ERK pathways. Mutations in BRAF result in constitutive MAPK signalling and have been associated with a number of tumour types. The ability to detect mutations in BRAF from tumour biopsy www.thelancet.com/oncology Vol 15 March 2014
specimens and the availability of highly specific BRAF inhibitors have begun to change the notion of the clinical management of patients with melanoma. In 2011, the BRIM-3 phase 3 trial,2 comparing the oral BRAF inhibitor vemurafenib with dacarbazine in 675 patients with BRAF-mutated metastatic melanoma, was reported. Vemurafenib was associated with a significant reduction in the risk of death (hazard ratio [HR] 0·37, 95% CI 0·26–0·55; p<0·001).2 Common treatment-related adverse events included arthralgia, rash, fatigue, keratocanthoma, and squamous-cell carcinomas, with 38% of patients requiring dose modification. The results of this trial led to approval of vemurafenib by the US Food and Drug Administration (FDA) for patients with metastatic melanoma whose
Steve Gschmeissner/Science Photo Library
Melanoma as a model for precision medicine in oncology
Published Online February 7, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70059-2 See Articles page 323
251
a phase 1 study to establish the maximum tolerated dose of the combination;8 this phase 2/3 trial measured progression-free survival as the primary endpoint. Since only 267 patients were recruited—of whom only 259 actually received the study drugs—the trial was underpowered and thus, perhaps unsurprisingly, there was no significant difference in progressionfree survival between groups. Median progressionfree survival was 9·7 months (95% CI 8·1–14·5) in the FOLFOX group, and 9·4 months (8·1–10·6) in the fluorouracil and cisplatin group (HR 0·93, 95% CI 0·70– 1·24; p=0·64). There were also no significant differences between groups in any of the secondary endpoints of overall survival, proportion of endoscopic complete responses, time to treatment failure, or occurrence of grade 3 or 4 toxicities. The authors conclude that the similar efficacy outcomes between the two treatment regimens have implications for the potential use of FOLFOX combination in cisplatin-intolerant patients. Previously, cisplatin-intolerant patients have been treated with radiotherapy alone, or with combinations of radiotherapy and non-platinum-containing regimens. However, most of these treatments have worse survival outcomes when compared with standard chemotherapy. Additionally, because of the high inpatient and outpatient admission rates associated with cisplatin as a result of patients requiring suitable hydration, there is a potential cost benefit to not including cisplatin in a treatment regimen. Thus, despite not improving progression-free survival, this study has potentially shown an improvement in the therapeutic ratio by increasing the treatment options for cisplatin-intolerant patients, and reducing the burden of treatment cost through a less time-consuming and easier to administer regimen—and thus, potentially, improving quality of life for patients. I commend the authors for completing this multicentre trial given its implications
for the future management strategies for oesophageal cancer. It sets the scene for further randomised trials designed to test similar endpoints with other treatment regimens that contain platinum, such as a regimen of carboplatin, paclitaxel, and radiotherapy, which has been effective in the neoadjuvant treatment of operable oesophageal carcinoma, and has low toxicty.9 Finally, I urge the authors of this trial to publish their quality-of-life data. A study of this type would be more complete with this additional data, which could enhance the argument for replacement of cisplatin with oxaliplatin. Bryan Burmeister Department of Radiation Oncology, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia [email protected] I declare that I have no competing interests. 1
2
3
4
5
6
7
8
9
Al-Sarraf M, Martz K, Herkovic A, et al. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study. J Clin Oncol 1997; 1: 277–84. Wong R, Malthaner R. Combined chemotherapy and radiotherapy (without surgery) compared with radiotherapy alone in localized carcinoma of the esophagus. Cochrane Database Syst Rev 2006; 1: CD002092. Kohler RE, Sheets NC, Wheeler SB, et al. Two-year and lifetime cost-effectiveness of intensity modulated radiation therapy versus 3-dimensional conformal radiation therapy for head and neck cancer. Int J Radiat Oncol Biol Phys 2013; 87: 683–89. Crosby T, Hurt CN, Falk S, et al. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial. Lancet Oncol 2013; 14: 627–37. Conroy T, Galais M-P, Raoul J-L, et al. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol 2014; published online Feb 18. http://dx.doi. org/10.1016/S1470-2045(14)70028-2. Mauer AM, Kraut EH, Krauss SA, et al. Phase II trial of oxaliplatin, leucovorin and fluorouracil in patients with advanced carcinoma of the esophagus. Ann Oncol 2005; 16: 1320–25. Chiarion-Sileni V, Innocente R, Cavina R, et al. Multi-center phase II trial of chemo-radiotherapy with 5-fluorouracil, leucovorin and oxaliplatin in locally advanced esophageal cancer. Cancer Chemother Pharmacol 2009; 63: 1111–19. Conroy T, Viret F, Francois E, et al. Phase I trial of oxaliplatin with fluorouracil, folinic acid and concurrent radiotherapy for oesophageal cancer. Br J Cancer 2008; 99: 1395–401. van Hagen P, Hulschof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012; 366: 2074–84.
Filling a gap in cervical cancer screening programmes Cervical screening remains important, despite the longterm promise of human papillomavirus (HPV) vaccination. HPV testing is more sensitive than cytology for detection of cervical pre-cancer and cancer, providing increased reassurance and allowing extended screening intervals.1 www.thelancet.com/oncology Vol 15 March 2014
Nonetheless, the pace and manner of implementation of primary HPV testing has varied substantially. In the USA, HPV testing is recommended in conjunction with cytology, whereas in the Netherlands, it is recommended as one primary test.2,3 In many places, it is not used at all.
Published Online February 13, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70073-7 See Articles page 315
249
Comment
Cytology
HPV
Co-testing (cytology and HPV)
Technology
Pap smear or liquid based cytology; Clinician collected or self-collected manual or computer-assisted assessment
Co-collection or separate collection
Relative repeat interval for negative screen
Shortest (lowest negative predictive value)
Longest (greatest negative predictive value)
Longer (greater negative predictive value)
Triage test needed
For equivocal cytology results
For all positive results
For all HPV-positive, cytology-negative results
Triage test options
HPV or repeat cytology or p16/Ki-67
Cytology or HPV genotyping or p16/Ki-67 or methylation
Repeat co-test or HPV genotyping or p16/Ki-67 or methylation
Triage test sampling
Reflex triage or separate collection
Reflex triage or separate collection
Reflex triage or separate collection
Diagnostic test
Colposcopy and biopsy
Colposcopy and biopsy
Colposcopy and biopsy
The three major primary screening options are cytology, HPV testing, or a combination of the two (co-testing). Not considered here is visual inspection, a screening method under consideration for low-resource regions.
Table: Options for cervical cancer screening programmes
The successful introduction of HPV testing into cervical cancer screening needs more than a sensitive primary screening test (table). New programmes need to be built around HPV testing. The major goal of cervical screening programmes is to find pre-cancers that can be treated to prevent invasive cancers. A diagnosis of pre-cancer needs colposcopic assessment with cervical biopsies. Most HPV infections are transient; a HPV-positive woman has a low risk of progressing to pre-cancer and cancer. Thus, if HPV testing is used, secondary (triage) tests are needed to decide who in the HPV-positives needs to be referred to colposcopy. A common suggestion is to move cytology into the role of triage. New molecular assays such as p16/Ki-67 cytology have higher sensitivity at comparable specificity to cytology.4 Additional molecular markers such as host methylation and HPV methylation are also being investigated.5–7 Irrespective of which screening and triage tests are chosen, the crucial problem of non-participation remains. A substantial proportion of cervical cancers in developed countries arise in women who participate in screening irregularly, or not at all.8 Findings of previous trials from the Netherlands have shown that the offer of self-sampling for HPV testing to non-responders, instead of an office visit, can increase participation.9 As with all HPV testing, women found to be HPV positive by self-sampling need a triage test to decide who needs colposcopy. However, self-collected samples are not suitable for cell-based assays, such as cytology or p16/ Ki-67, so an additional collection is needed. In The Lancet Oncology, Verhoef and colleagues6 report the results of a randomised trial addressing this gap in their screening programme. Investigators 250
enrolled initially non-participating women, found to be HPV positive upon self-sampling, who were followed up with two different triage strategies: cytology from physician-collected samples or methylation testing of two genes, MAL and miR-124-2, from the selfcollected sample. The researchers found that the clinical performance of methylation testing from the self-collected specimen was equivalent to physiciancollected cytology. Because the assay was run from the same specimen collected at baseline in HPV-positive women, an additional office visit for most women was avoided. The Dutch team should be commended as pioneers in the creation of an integrated HPV-based cervical cancer screening programme. The approach described by Verhoef and colleagues further improves the safety net of their programme. As one possible caveat, the participants in the trial generally reported being screened before, and had a very high compliance after they were included in the study, suggesting that they were so-called soft refusers. The self-sampling strategy might not apply as well to the firm refusers who have never been screened before, putting them at highest risk. How do these results apply to cervical cancer screening in other places? Findings of a recent metaanalysis10 showed that self-sampling has slightly lower sensitivity compared with physician-collected samples;in most resource-rich settings, self-sampling is not approved as a first-line alternative. The offer of self-sampling for non-responders is especially attractive for organised screening settings, but is difficult to implement in countries with opportunistic screening like in the USA. Moreover, the methylation www.thelancet.com/oncology Vol 15 March 2014
Comment
assay used in the present study has not been approved for clinical use, is not available as a kit, and has not been assessed outside of the laboratory included in the Dutch screening trials. Our understanding of HPV and the natural history of cervical cancer has brought great methods for cervical cancer prevention, including vaccines for primary prevention, HPV testing for screening, and various molecular assays, including methylation markers, for detection of cervical pre-cancers. Presented with many HPV-related preventive options, high-resource countries are considering various combinations; no one winning strategy has emerged. However, low-resource countries cannot afford the complex programmes established or under development in industrialised countries. A triage test that can be done out of self-sampling material like the methylation assay described here could extend the options for cervical cancer screening in low-resource settings, where cytology programmes rarely exist and colposcopy capacity is very restricted. However, development of a robust, cheap methylation assay is paramount to achieve this goal.
MS has received HPV testing at no cost for NCI studies from Roche and Becton Dickinson. NW and MS were supported by the Intramural Research Program of the NIH, National Cancer Institute. The views expressed do not represent the views of the US National Cancer Institute, the National Institutes of Health, the Department of Health and Human Services, or the US Government. We declare that we have no competing interests.
*Nicolas Wentzensen, Mark Schiffman
10
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD 20892-9774, USA (NW, MS) [email protected]
1
2
3
4 5
6
7
8 9
Katki HA, Kinney WK, Fetterman B, et al. Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice. Lancet Oncol 2011; 12: 663–72. Health Council of the Netherlands. Population screening for cervical cancer. 2011. http://www.gezondheidsraad.nl/en/publications/prevention/ population-screening-cervical-cancer (accessed Feb 7, 2014). 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. Triage of HPV-positive women in cervical cancer screening. Lancet Oncol 2013; 14: 107–09. Mirabello L, Schiffman M, Ghosh A, et al. Elevated methylation of HPV16 DNA is associated with the development of high grade cervical intraepithelial neoplasia. Int J Cancer 2013; 132: 1412–22. Verhoef VMJ, Bosgraaf RP, van Kemenade FJ, et al. Triage by methylation-marker testing versus cytology in women who test HPV-positive on self-collected cervicovaginal specimens (PROHTECT-3): a randomised controlled non-inferiority trial. Lancet Oncol 2014; published online Feb 13. http://dx.doi.org/10.1016/S1470-2045(14)70019-1. Wentzensen N, Sun C, Ghosh A, et al. Methylation of HPV18, HPV31, and HPV45 genomes and cervical intraepithelial neoplasia grade 3. J Natl Cancer Inst 2012; 104: 1738–49. Spence AR, Goggin P, Franco EL. Process of care failures in invasive cervical cancer: systematic review and meta-analysis. Prev Med 2007; 45: 93–106. Gok M, Heideman DA, van Kemenade FJ, et al. HPV testing on self collected cervicovaginal lavage specimens as screening method for women who do not attend cervical screening: cohort study. BMJ 2010; 340: 1040. Arbyn M, Verdoodt F, Snijders PJ, et al. Accuracy of human papillomavirus testing on self-collected versus clinician-collected samples: a meta-analysis. Lancet Oncol 2014; 15: 172–83.
Advances in the understanding of the molecular profile of tumour cells and progress in systems biology and bioinformatics have led to the promise of precision medicine for treatment of human cancer. Melanoma has provided an opportunity for insights into both the potential benefit and limitations of precision medicine for cancer. In 2002, half of all human melanoma cells were shown to harbour mutations in the BRAF gene,1 the product of which has an important role in cell division, differentiation, and secretion through the MAPK or RAS-RAF-MEK-ERK pathways. Mutations in BRAF result in constitutive MAPK signalling and have been associated with a number of tumour types. The ability to detect mutations in BRAF from tumour biopsy www.thelancet.com/oncology Vol 15 March 2014
specimens and the availability of highly specific BRAF inhibitors have begun to change the notion of the clinical management of patients with melanoma. In 2011, the BRIM-3 phase 3 trial,2 comparing the oral BRAF inhibitor vemurafenib with dacarbazine in 675 patients with BRAF-mutated metastatic melanoma, was reported. Vemurafenib was associated with a significant reduction in the risk of death (hazard ratio [HR] 0·37, 95% CI 0·26–0·55; p<0·001).2 Common treatment-related adverse events included arthralgia, rash, fatigue, keratocanthoma, and squamous-cell carcinomas, with 38% of patients requiring dose modification. The results of this trial led to approval of vemurafenib by the US Food and Drug Administration (FDA) for patients with metastatic melanoma whose
Steve Gschmeissner/Science Photo Library
Melanoma as a model for precision medicine in oncology
Published Online February 7, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70059-2 See Articles page 323
251