- Email: [email protected]
Chromoplexy and hypoxic microenvironment drives prostate cancer
Comment
TSC on the endocrine system are not yet understood,9 and TSC might cause amenorrhea independently. This relationship needs to be assessed. Finally, the authors mention the benefits of oral mTOR inhibitors for patients with TSC that are not addressed by this analysis. mTOR inhibitors are efficacious for renal angiomyolipomas and lymphangioleimyomatosis,10,11 and there are continuing and completed studies in patients with TSC to assess oral mTOR inhibitors for intractable epilepsy (EXIST-3; NCT01713946) and cognition (TRON; NCT01954693) and topical mTOR inhibitors for disfiguring facial angiofibromas (TREATMENT; NCT01526356). Surgical interventions for SEGAs do not offer these positive sideeffects in the rest of the body. With the recent promise shown by mTOR inhibitors to help neural connectivity and the fairly minor negative side-effect profile, the drugs might soon be prescribed to patients with TSC for indications other than tumour shrinkage. The mTOR inhibitor revolution rolls on… Hope Northrup Division of Medical Genetics, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX 77030, USA [email protected]
I declare honoraria and payment of travel expenses from Novartis for speaking at the TSC Days Conference in Dublin, Ireland; Sept 12–13, 2014. 1
2
3
4
5
6
7
8
9
10
11
Franz DN, Belousova E, Sparagana S, et al. Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol 2014; published online Nov 10. http://dx.doi.org/10.1016/S14702045(14)70489-9. Northrup H, Koenig MK, Au KS. Tuberous sclerosis complex. In: Pagon RA, Bird TD, Dolan CR, et al, eds. GeneReviews. Medical Genetics Information Resource. Seattle: University of Washington, 2011. van Slegtenhorst M, de Hoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997; 277: 805–08. The European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993; 75: 1305–15. Potter CJ, Huang H, Xu T. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 2001; 105: 357–68. Tapon N, Ito N, Dickson BJ, Treisman JE, Hariharan IK. The drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 2001; 105: 345–55. Franz DN, Leonard J, Tudor C, et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 2006; 59: 490–98. Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicenter, randomized, placebo-controlled phase 3 trial. Lancet 2013; 381: 125–32. Gabitzsch EK, Hashmi SS, Koenig MK, et al. Self-reported reproductive health in women with tuberous sclerosis complex. Genet Med 2013; 15: 966–71. Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008; 358: 140–51. McCormack FX, Inoue Y, Moss J, et al, for the National Institutes of Health Rare Lung Diseases Consortium and the MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011; 364: 1595–606.
In The Lancet Oncology, Emilie Lalonde and colleagues’ retrospective cohort analysis1 assesses genomics, genomic instability, and hypoxia as predictors of recurrence in men with localised prostate cancer. Recurrence was measured mainly on the basis of recurrence and progression of prostate-specific antigen by standard definitions after either radiotherapy or surgery. The investigators controlled for pretreatment prostate-specific antigen, Gleason score, and T stage. Their results suggest that genomic signatures or measures of genomic instability have independent value in prediction of biochemical (prostate-specific antigen) relapse and clinical metastasis in patients with localised prostate cancer. The addition of tumour hypoxia measures to genomic data refined prediction of www.thelancet.com/oncology Vol 15 December 2014
recurrence when the investigators controlled for clinical covariates. Hypoxia was not associated with a specific genomic signature, suggesting that it is caused by epigenetic factors that determine the microenvironment of a tumour. Although the mechanisms by which hypoxia leads to radiation resistance can be reasonably assumed, the mechanism for an association between hypoxia in tumour tissue and biochemical recurrence after surgery is far less clear. Genetic aberrations driving both hypoxia and cancer progression could be an explanation, but in this study there was no association between genomic alterations and hypoxia. As such, the work in Lalonde and colleagues’ study is novel in that it shows that cancer aggression is driven not only by genome instability and mutations, but also by tissue hypoxia.
GJLP/Science Photo Library
Chromoplexy and hypoxic microenvironment drives prostate cancer
Published Online November 13, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)71114-3 See Articles page 1521
1419
Comment
The effectiveness of radiation is very dependent on the oxygen status of the tissue being treated, with tumour sensitivity increased by a factor of about 3 in normoxic compared with hypoxic tumours. A rapid increase in radiosensitivity happens as the oxygen concentration reaches 30 mm Hg or 0·5% oxygen.2 Studies of patients with cervical cancer and soft-tissue sarcoma treated with radiation have shown that hypoxic tumours are more likely to recur and metastasize than are normoxic tumours.3,4 A series of interventions to improve tumour oxygenation have been attempted in order to improve radiotherapy efficacy. These interventions are divided into three categories: first, increased oxygen delivery by the blood (hyperbaric oxygen, breathing carbogen [a mixture of oxygen and carbon dioxide], nicotinamide, blood transfusions, and erythropoietin), second, oxygen mimetics used in the radiochemical process (nitroimidazoles), and, third, destruction of hypoxic cells (hypoxic cytotoxins and hyperthermia).5 In a meta-analysis5 of more than 10 000 patients with solid tumors (including bladder, uterine cervix, head and neck, brain, lung, oesophagus, and pancreas) from 86 clinical trials using hyperbaric oxygen, chemical sensitizers, carbogen breathing, and blood transfusions, the investigators reported a significant improvement in locoregional control (odds ratio [OR] 0·77, 95% CI 0·71–0·86) and a significant survival benefit (0·87, 0·81–0·95) with hypoxic modifiers. Use of hyperbaric oxygen was more beneficial than other hypoxic modifications. Despite these findings, hypoxia modification is not used on a routine basis clinically and should be further explored. In terms of genomic signatures, Lalonde and colleagues provide strong evidence that links differences in the prostate cancer genome with clinical outcomes. Identification of a DNA signature that robustly predicts biochemical recurrence represents a great stride in the molecular characterisation of prostate cancer. Not only was the 100-loci signature independently prognostic, but it also outperformed all published RNA signatures. DNA signatures are likely to be more consistent than are those generated from RNA expression, because of transcriptional heterogeneity and epigenetic effects. Notably, Lalonde and colleagues’ findings show that the combination of percentage of genome alteration and hypoxia selects a group of about 25% of low-risk men with prostate cancer who are likely to have biochemical 1420
failure before 18 months. In the context of management of clinical prostate cancer, this DNA–hypoxia signature for pretreatment stratification might become especially useful for enabling of active surveillance strategies. With validation in an active surveillance population, a socalled quiet genomic or hypoxic subtype could be added to criteria, thus enabling patients who are classified as high risk on the basis of genomic categorisation to receive upfront treatment while allowing the quiet group to avoid intervention. The potential of the specific methodology described by Lalonde and coleagues will need to be compared with other gene signatures in development and use.6 Genomic instability is an evolving concept in clinical cancer. Chromoplexy, or chromosomal change, in which the prostate cancer tumour genome advances through mutation, translocation, and other interdependent DNA rearrangements mediated by post-translational modifications such as ubiquitination and sumoylation, might be key to a series of essential cancer processes including avoidance of apoptosis, invasion, and metastasis, and therapeutic resistance.7 Hence, measures of genomic heterogeneity, instability or change might better characterise the notion of chromoplexy as a measure of cancer cells or clusters to achieve key biological functions needed for tumour progression compared with individual genetic aberrations or disordered pathway signaling. Findings in Lalonde and colleagues’ study related to risk strata need prospective validation in other cohorts. Although still strictly hypothesis-generating, risk strata are not only an important biological accomplishment, but might also have therapeutic implications. Actionable mutations can be targeted while hypoxia might be modulated in various ways, each with the goal of improving response and outcome. Much work still needs to be done to formulate the best combination of targeted therapy for the cancer cell and modification of the microenvironment to optimise some of our oldest therapies, including radiation. Leslie K Ballas, Brian R Hu, *David I Quinn Department of Radiation Oncology, Institute of Urology and Division of Oncology, Department of Medicine, Keck School of University of Southern California and USC Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA [email protected]
www.thelancet.com/oncology Vol 15 December 2014
Comment
We have no competing interests.
4
Brizel DM, Scully SP, Harrelson JM, et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 1996; 56: 941–43. Overgaard J. Hypoxic radiosensitization: adored and ignored. J Clin Oncol 2007; 25: 4066–74. Klein EA, Cooperberg MR, Magi-Galluzzi C, et al. A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason Grade heterogeneity, tumor multifocality, and biopsy undersampling. Eur Urol 2014; 66: 550–60. Baca SC, Prandi D, Lawrence MS, et al. Punctuated evolution of prostate cancer genomes. Cell 2013; 153: 666–77.
Copyright © Ballas et al. Open Access article distributed under the terms of CC BY. 1
2 3
Lalonde L, Ishkanian AS, Sykes J, et al. Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet Oncol 2014; published online Nov 13. http://dx.doi.org/10.1016/ S1470-2045(14)71021-6. Hall EJ, Giaccia AJ. Radiobiology for the radiologist, 6th edN. Philadelphia: Lippincott Williams & Wilkins, 2006. Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 1996; 56: 4509–15.
5 6
7
Global uptake of BHGI guidelines for breast cancer
www.thelancet.com/oncology Vol 15 December 2014
authors and were not included in our analysis. The final sample consisted of 552 articles. The BHGI guidelines have been increasingly referenced in global health literature (figure). Of the 552 unique articles citing the BHGI guidelines, 359 (65%) referenced either the guidelines’ overviews (200 [36%]) or the early detection guidelines (159 [29%]). The remaining guideline topics were cited less frequently: breast cancer diagnosis (52 [9%]), treatment (84 [15%]), and the changes needed to the health-care systems (48 [9%]). Health-care system guidelines were increasingly referenced over time, and by 2011, exceeded the articles referencing diagnostic guidelines. Of the 552 documents, 283 (51%) focused on LMICs in sub-Saharan Africa (77 [14%]), Asia (71 [13%]), Latin America (71 [13%]), and the Middle East (50 [9%]). Another 181 (33%) articles were non-country specific, and the remainder came from HICs. On the basis of the citation analysis, 375 (68%) cited BHGI guidelines as a
120 100 Number of articles
Breast cancer is the most common cause of cancer deaths for women worldwide.1 The number of women with breast cancer in low-income and middleincome regions is increasing over time.2 Important advances for effective breast cancer management have mainly benefited high-income countries. In such countries, evidence-based guidelines outlining optimum approaches for early detection, diagnosis, and treatment of breast cancer have been implemented in national cancer control programmes.3 Poor healthcare resources and poorly organised health-care systems, however, represent a substantial barrier to the implementation of such practices in low-to-middle income countries (LMICs).4 The Breast Health Global Initiative (BHGI) developed practical guidelines for breast cancer control that are evidence-based, resource stratified, and culturally appropriate, with the aim of integrating practices in early detection, diagnosis, and treatment for breast cancer into existing health-care systems in LMICs. Since 2002, the BHGI has held a series of international summits that have brought together experts from around the world to develop consensus panels to devise appropriate resource-stratified guidelines for breast cancer care and management. We examined the literature systematically to assess implementation of BHGI guidelines from the creation of knowledge in guideline development, through guideline dissemination in the global health published work, and organisational adoption and implementation of the guidelines. The search identified 2097 articles, of which 1033 were duplicates, and 288 documents were not relevant to BHGI. Of the 776 remaining articles, 224 (29%) were direct products of the BHGI group and
80 60 40 20 0
2003
2004
2005
2006
2008 2007 Year
2009
2010
2011
2012
Figure: Frequency of articles referencing the Breast Health Global Initiative guidelines, by year of publication (n=552)
1421
TSC on the endocrine system are not yet understood,9 and TSC might cause amenorrhea independently. This relationship needs to be assessed. Finally, the authors mention the benefits of oral mTOR inhibitors for patients with TSC that are not addressed by this analysis. mTOR inhibitors are efficacious for renal angiomyolipomas and lymphangioleimyomatosis,10,11 and there are continuing and completed studies in patients with TSC to assess oral mTOR inhibitors for intractable epilepsy (EXIST-3; NCT01713946) and cognition (TRON; NCT01954693) and topical mTOR inhibitors for disfiguring facial angiofibromas (TREATMENT; NCT01526356). Surgical interventions for SEGAs do not offer these positive sideeffects in the rest of the body. With the recent promise shown by mTOR inhibitors to help neural connectivity and the fairly minor negative side-effect profile, the drugs might soon be prescribed to patients with TSC for indications other than tumour shrinkage. The mTOR inhibitor revolution rolls on… Hope Northrup Division of Medical Genetics, Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX 77030, USA [email protected]
I declare honoraria and payment of travel expenses from Novartis for speaking at the TSC Days Conference in Dublin, Ireland; Sept 12–13, 2014. 1
2
3
4
5
6
7
8
9
10
11
Franz DN, Belousova E, Sparagana S, et al. Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol 2014; published online Nov 10. http://dx.doi.org/10.1016/S14702045(14)70489-9. Northrup H, Koenig MK, Au KS. Tuberous sclerosis complex. In: Pagon RA, Bird TD, Dolan CR, et al, eds. GeneReviews. Medical Genetics Information Resource. Seattle: University of Washington, 2011. van Slegtenhorst M, de Hoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997; 277: 805–08. The European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993; 75: 1305–15. Potter CJ, Huang H, Xu T. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 2001; 105: 357–68. Tapon N, Ito N, Dickson BJ, Treisman JE, Hariharan IK. The drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 2001; 105: 345–55. Franz DN, Leonard J, Tudor C, et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 2006; 59: 490–98. Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicenter, randomized, placebo-controlled phase 3 trial. Lancet 2013; 381: 125–32. Gabitzsch EK, Hashmi SS, Koenig MK, et al. Self-reported reproductive health in women with tuberous sclerosis complex. Genet Med 2013; 15: 966–71. Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008; 358: 140–51. McCormack FX, Inoue Y, Moss J, et al, for the National Institutes of Health Rare Lung Diseases Consortium and the MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011; 364: 1595–606.
In The Lancet Oncology, Emilie Lalonde and colleagues’ retrospective cohort analysis1 assesses genomics, genomic instability, and hypoxia as predictors of recurrence in men with localised prostate cancer. Recurrence was measured mainly on the basis of recurrence and progression of prostate-specific antigen by standard definitions after either radiotherapy or surgery. The investigators controlled for pretreatment prostate-specific antigen, Gleason score, and T stage. Their results suggest that genomic signatures or measures of genomic instability have independent value in prediction of biochemical (prostate-specific antigen) relapse and clinical metastasis in patients with localised prostate cancer. The addition of tumour hypoxia measures to genomic data refined prediction of www.thelancet.com/oncology Vol 15 December 2014
recurrence when the investigators controlled for clinical covariates. Hypoxia was not associated with a specific genomic signature, suggesting that it is caused by epigenetic factors that determine the microenvironment of a tumour. Although the mechanisms by which hypoxia leads to radiation resistance can be reasonably assumed, the mechanism for an association between hypoxia in tumour tissue and biochemical recurrence after surgery is far less clear. Genetic aberrations driving both hypoxia and cancer progression could be an explanation, but in this study there was no association between genomic alterations and hypoxia. As such, the work in Lalonde and colleagues’ study is novel in that it shows that cancer aggression is driven not only by genome instability and mutations, but also by tissue hypoxia.
GJLP/Science Photo Library
Chromoplexy and hypoxic microenvironment drives prostate cancer
Published Online November 13, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)71114-3 See Articles page 1521
1419
Comment
The effectiveness of radiation is very dependent on the oxygen status of the tissue being treated, with tumour sensitivity increased by a factor of about 3 in normoxic compared with hypoxic tumours. A rapid increase in radiosensitivity happens as the oxygen concentration reaches 30 mm Hg or 0·5% oxygen.2 Studies of patients with cervical cancer and soft-tissue sarcoma treated with radiation have shown that hypoxic tumours are more likely to recur and metastasize than are normoxic tumours.3,4 A series of interventions to improve tumour oxygenation have been attempted in order to improve radiotherapy efficacy. These interventions are divided into three categories: first, increased oxygen delivery by the blood (hyperbaric oxygen, breathing carbogen [a mixture of oxygen and carbon dioxide], nicotinamide, blood transfusions, and erythropoietin), second, oxygen mimetics used in the radiochemical process (nitroimidazoles), and, third, destruction of hypoxic cells (hypoxic cytotoxins and hyperthermia).5 In a meta-analysis5 of more than 10 000 patients with solid tumors (including bladder, uterine cervix, head and neck, brain, lung, oesophagus, and pancreas) from 86 clinical trials using hyperbaric oxygen, chemical sensitizers, carbogen breathing, and blood transfusions, the investigators reported a significant improvement in locoregional control (odds ratio [OR] 0·77, 95% CI 0·71–0·86) and a significant survival benefit (0·87, 0·81–0·95) with hypoxic modifiers. Use of hyperbaric oxygen was more beneficial than other hypoxic modifications. Despite these findings, hypoxia modification is not used on a routine basis clinically and should be further explored. In terms of genomic signatures, Lalonde and colleagues provide strong evidence that links differences in the prostate cancer genome with clinical outcomes. Identification of a DNA signature that robustly predicts biochemical recurrence represents a great stride in the molecular characterisation of prostate cancer. Not only was the 100-loci signature independently prognostic, but it also outperformed all published RNA signatures. DNA signatures are likely to be more consistent than are those generated from RNA expression, because of transcriptional heterogeneity and epigenetic effects. Notably, Lalonde and colleagues’ findings show that the combination of percentage of genome alteration and hypoxia selects a group of about 25% of low-risk men with prostate cancer who are likely to have biochemical 1420
failure before 18 months. In the context of management of clinical prostate cancer, this DNA–hypoxia signature for pretreatment stratification might become especially useful for enabling of active surveillance strategies. With validation in an active surveillance population, a socalled quiet genomic or hypoxic subtype could be added to criteria, thus enabling patients who are classified as high risk on the basis of genomic categorisation to receive upfront treatment while allowing the quiet group to avoid intervention. The potential of the specific methodology described by Lalonde and coleagues will need to be compared with other gene signatures in development and use.6 Genomic instability is an evolving concept in clinical cancer. Chromoplexy, or chromosomal change, in which the prostate cancer tumour genome advances through mutation, translocation, and other interdependent DNA rearrangements mediated by post-translational modifications such as ubiquitination and sumoylation, might be key to a series of essential cancer processes including avoidance of apoptosis, invasion, and metastasis, and therapeutic resistance.7 Hence, measures of genomic heterogeneity, instability or change might better characterise the notion of chromoplexy as a measure of cancer cells or clusters to achieve key biological functions needed for tumour progression compared with individual genetic aberrations or disordered pathway signaling. Findings in Lalonde and colleagues’ study related to risk strata need prospective validation in other cohorts. Although still strictly hypothesis-generating, risk strata are not only an important biological accomplishment, but might also have therapeutic implications. Actionable mutations can be targeted while hypoxia might be modulated in various ways, each with the goal of improving response and outcome. Much work still needs to be done to formulate the best combination of targeted therapy for the cancer cell and modification of the microenvironment to optimise some of our oldest therapies, including radiation. Leslie K Ballas, Brian R Hu, *David I Quinn Department of Radiation Oncology, Institute of Urology and Division of Oncology, Department of Medicine, Keck School of University of Southern California and USC Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA [email protected]
www.thelancet.com/oncology Vol 15 December 2014
Comment
We have no competing interests.
4
Brizel DM, Scully SP, Harrelson JM, et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res 1996; 56: 941–43. Overgaard J. Hypoxic radiosensitization: adored and ignored. J Clin Oncol 2007; 25: 4066–74. Klein EA, Cooperberg MR, Magi-Galluzzi C, et al. A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason Grade heterogeneity, tumor multifocality, and biopsy undersampling. Eur Urol 2014; 66: 550–60. Baca SC, Prandi D, Lawrence MS, et al. Punctuated evolution of prostate cancer genomes. Cell 2013; 153: 666–77.
Copyright © Ballas et al. Open Access article distributed under the terms of CC BY. 1
2 3
Lalonde L, Ishkanian AS, Sykes J, et al. Tumour genomic and microenvironmental heterogeneity for integrated prediction of 5-year biochemical recurrence of prostate cancer: a retrospective cohort study. Lancet Oncol 2014; published online Nov 13. http://dx.doi.org/10.1016/ S1470-2045(14)71021-6. Hall EJ, Giaccia AJ. Radiobiology for the radiologist, 6th edN. Philadelphia: Lippincott Williams & Wilkins, 2006. Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 1996; 56: 4509–15.
5 6
7
Global uptake of BHGI guidelines for breast cancer
www.thelancet.com/oncology Vol 15 December 2014
authors and were not included in our analysis. The final sample consisted of 552 articles. The BHGI guidelines have been increasingly referenced in global health literature (figure). Of the 552 unique articles citing the BHGI guidelines, 359 (65%) referenced either the guidelines’ overviews (200 [36%]) or the early detection guidelines (159 [29%]). The remaining guideline topics were cited less frequently: breast cancer diagnosis (52 [9%]), treatment (84 [15%]), and the changes needed to the health-care systems (48 [9%]). Health-care system guidelines were increasingly referenced over time, and by 2011, exceeded the articles referencing diagnostic guidelines. Of the 552 documents, 283 (51%) focused on LMICs in sub-Saharan Africa (77 [14%]), Asia (71 [13%]), Latin America (71 [13%]), and the Middle East (50 [9%]). Another 181 (33%) articles were non-country specific, and the remainder came from HICs. On the basis of the citation analysis, 375 (68%) cited BHGI guidelines as a
120 100 Number of articles
Breast cancer is the most common cause of cancer deaths for women worldwide.1 The number of women with breast cancer in low-income and middleincome regions is increasing over time.2 Important advances for effective breast cancer management have mainly benefited high-income countries. In such countries, evidence-based guidelines outlining optimum approaches for early detection, diagnosis, and treatment of breast cancer have been implemented in national cancer control programmes.3 Poor healthcare resources and poorly organised health-care systems, however, represent a substantial barrier to the implementation of such practices in low-to-middle income countries (LMICs).4 The Breast Health Global Initiative (BHGI) developed practical guidelines for breast cancer control that are evidence-based, resource stratified, and culturally appropriate, with the aim of integrating practices in early detection, diagnosis, and treatment for breast cancer into existing health-care systems in LMICs. Since 2002, the BHGI has held a series of international summits that have brought together experts from around the world to develop consensus panels to devise appropriate resource-stratified guidelines for breast cancer care and management. We examined the literature systematically to assess implementation of BHGI guidelines from the creation of knowledge in guideline development, through guideline dissemination in the global health published work, and organisational adoption and implementation of the guidelines. The search identified 2097 articles, of which 1033 were duplicates, and 288 documents were not relevant to BHGI. Of the 776 remaining articles, 224 (29%) were direct products of the BHGI group and
80 60 40 20 0
2003
2004
2005
2006
2008 2007 Year
2009
2010
2011
2012
Figure: Frequency of articles referencing the Breast Health Global Initiative guidelines, by year of publication (n=552)
1421