Comment
survival matters to our patients and is something that physicians have long been waiting to see. In a population that usually presents with few or no disease-related symptoms, the clinical relevance of prolonged progression-free survival can only be claimed when toxic effects are acceptable. Here, this seems to be the case. Therefore, and with all due caution, based on sound preclinical evidence and these new clinical results, we believe that CDK4/6 inhibitors are here to stay.
4
5
6
7
8
*Michael Gnant, Guenther G Steger, Rupert Bartsch Departments of Surgery (MG) and Internal Medicine I (GGS, RB), Breast Health Center, Comprehensive Cancer Center, Medical University of Vienna, A-1090 Vienna, Austria [email protected] We declare no competing interests. 1
2
3
Bergh J, Jönsson PE, Lidbrink EK, et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptorpositive postmenopausal breast cancer. Clin Oncol 2012; 30: 1919–25. Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol 2008; 26: 1664–70. Howell A, Robertson JF, Quaresma Albano J, et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 2002; 20: 3396–403.
9 10
11
Osborne CK, Shou J, Massarweh S, Schiff R. Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clin Cancer Res 2005; 11 (suppl): 865–70s. Johnston S, Pippen J Jr, Pivot X, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 2009; 27: 5538–46. Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol 2009; 27: 5529–37. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012; 366: 520–29. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as firstline treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2014; published online Dec 16. http://dx.doi.org/10.1016/S14702045(14)71159-3. Caldon CE, Daly RJ, Sutherland RL, Musgrove EA. Cell cycle control in breast cancer cells. J Cell Biochem 2006; 97: 261–74. Dean JL, McClendon AK, Hickey TE, et al. Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors. Cell Cycle 2012; 11: 2756–61. Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 2009; 11: R77.
Estimates of associations between cancer risk and body-mass index (BMI) are robust and well replicated, but are largely based on studies in developed countries.1 Information about whether these associations are similar in developing countries is scarce, but understanding the burden of cancer risk due to high BMI is just as important in these populations. In The Lancet Oncology, Melina Arnold and colleagues2 use the available knowledge about associations of BMI with cancer incidence to estimate the proportions of cancers associated with high BMI in countries and regions worldwide. These population attributable fractions combine estimates of relative risks from meta-analyses of BMI and cancer incidence with worldwide cancer incidence data and models of country-specific BMI distributions by age and sex.3,4 The investigators estimate both the total proportion of cancers associated with BMI and the proportion www.thelancet.com/oncology Vol 16 January 2015
associated with trends in increasing BMI between 1982 and 2012, which might be more plausible as an estimate of the proportion of cancers that could be prevented in practice. Worldwide, Arnold and colleagues estimate that fairly few adult cancers were associated with high BMI in 2012: 481 000 or 3·6% of adult cancers overall (5·4% in women and 1·9% in men). Moreover, about 118 000 cancers—only 0·9% of adult cancers overall, although a quarter of the cancers associated with high BMI—could be attributed to the increase in BMI since 1982. These broad findings are likely to be robust and are supported by the results of a range of sensitivity analyses, although some country-specific estimates will be more uncertain because of the variable quality of cancer and BMI data for those populations.3,4 Arnold and colleagues’ results show at least two important dichotomies in the proportions of cancers
Jim Varney/Science Photo Library
Cancer and high body-mass index: global burden, global effort?
Published Online November 26, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70373-0 See Articles page 36
3
Comment
associated with high BMI. One is the roughly threetimes greater population attributable fraction in women than in men, largely due to endometrial and postmenopausal breast cancers. This difference is seen across geographical regions and levels of development, although it is unclear the extent to which this finding might be susceptible to data quality issues or heterogeneity of associations in some populations. Good reasons exist to believe that BMI has a causal association with risk of these cancers via hormonal pathways,5,6 and that this risk is therefore modifiable. This possibility is especially encouraging because these cancers also represent a substantial proportion of all adult cancers (ie, not only cancers in women) associated with high BMI. A second dichotomy is the difference between developed and developing countries (although differences are reported within these categories as well). In developed countries (ie, those with a high or very high human development index [HDI]), about 8% of cancers in women and 3% in men were associated with high BMI, and about 2% in women and 1% in men were associated with trends in increasing BMI since 1982. In developing countries (those with a lower HDI), only about 2% of cancers in women and 0·5% in men were associated with high BMI; less than 1% of cancers in women and essentially none in men were associated with trends in increasing BMI since 1982, since such trends were generally weaker or nonexistent in these countries. The differences between developed and developing countries suggest that different research and policy objectives might be appropriate in these different settings. In the well studied developed countries, more attention should now be given to the generation of data to directly support policy, particularly by quantifying the broader costs of overweight and obesity to individuals, health-care systems, economies, and societies. In developing countries, the past, present, and future might all be uncertain, but a wider view might be taken both across health outcomes and across risk factors, with the goal of making the best use of limited resources. Meanwhile, work should continue to improve crucial data for cancer incidence, the prevalence of overweight and obesity, and the association between the two. 4
Arnold and colleagues provide an important new context and baseline for understanding the global burden of cancer incidence in relation to high BMI.2 Although there are important differences between countries and regions, overall this burden is fairly small, so arguably these findings do not give much additional support for a global effort to address rising obesity. Such an effort is certainly needed, but mainly because of metabolic and vascular diseases, which dominate the burden of ill health associated with obesity.7 If 3·6% of all cancers are associated with high BMI, that is nearly half a million cancers, but this number is large mainly because the world population is large. Global health resources specifically for cancer prevention are not so large, and the resources targeted at obesity must be balanced against those for other important causes of cancer, particularly infections and tobacco use, which are each associated with much larger proportions of cases.8,9 Benjamin J Cairns Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK [email protected] I declare no competing interests. I acknowledge salary support from the British Heart Foundation Centre of Research Excellence (Oxford, UK). 1
2
3
4
5
6
7
8
9
Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008; 371: 569–78. Arnold M, Pandeya N, Byrnes G, et al. Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol 2014; published online Nov 24. http://dx.doi.org/10.1016/ S1470-2045(14)71123-4. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase No 11. Lyon: International Agency for Research on Cancer, 2013. Finucane MM, Stevens GA, Cowan MJ, et al, on behalf of the Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Body Mass Index). National, regional, and global trends in bodymass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9·1 million participants. Lancet 2011; 377: 557–67. Crosbie EJ, Zwahlen M, Kitchener HC, Egger M, Renehan AG. Body mass index, hormone replacement therapy, and endometrial cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2010; 19: 3119–30. Endogenous Hormones Breast Cancer Collaborative Group. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 2003; 95: 1218–26. Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2224–60. de Martel C, Ferlay J, Franceschi S, et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol 2012; 13: 607–15. Ezzati M, Henley SJ, Lopez AD, Thun MJ. Role of smoking in global and regional cancer epidemiology: current patterns and data needs. Int J Cancer 2005; 116: 963–71.
www.thelancet.com/oncology Vol 16 January 2015
survival matters to our patients and is something that physicians have long been waiting to see. In a population that usually presents with few or no disease-related symptoms, the clinical relevance of prolonged progression-free survival can only be claimed when toxic effects are acceptable. Here, this seems to be the case. Therefore, and with all due caution, based on sound preclinical evidence and these new clinical results, we believe that CDK4/6 inhibitors are here to stay.
4
5
6
7
8
*Michael Gnant, Guenther G Steger, Rupert Bartsch Departments of Surgery (MG) and Internal Medicine I (GGS, RB), Breast Health Center, Comprehensive Cancer Center, Medical University of Vienna, A-1090 Vienna, Austria [email protected] We declare no competing interests. 1
2
3
Bergh J, Jönsson PE, Lidbrink EK, et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptorpositive postmenopausal breast cancer. Clin Oncol 2012; 30: 1919–25. Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol 2008; 26: 1664–70. Howell A, Robertson JF, Quaresma Albano J, et al. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 2002; 20: 3396–403.
9 10
11
Osborne CK, Shou J, Massarweh S, Schiff R. Crosstalk between estrogen receptor and growth factor receptor pathways as a cause for endocrine therapy resistance in breast cancer. Clin Cancer Res 2005; 11 (suppl): 865–70s. Johnston S, Pippen J Jr, Pivot X, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 2009; 27: 5538–46. Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol 2009; 27: 5529–37. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012; 366: 520–29. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as firstline treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2014; published online Dec 16. http://dx.doi.org/10.1016/S14702045(14)71159-3. Caldon CE, Daly RJ, Sutherland RL, Musgrove EA. Cell cycle control in breast cancer cells. J Cell Biochem 2006; 97: 261–74. Dean JL, McClendon AK, Hickey TE, et al. Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors. Cell Cycle 2012; 11: 2756–61. Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 2009; 11: R77.
Estimates of associations between cancer risk and body-mass index (BMI) are robust and well replicated, but are largely based on studies in developed countries.1 Information about whether these associations are similar in developing countries is scarce, but understanding the burden of cancer risk due to high BMI is just as important in these populations. In The Lancet Oncology, Melina Arnold and colleagues2 use the available knowledge about associations of BMI with cancer incidence to estimate the proportions of cancers associated with high BMI in countries and regions worldwide. These population attributable fractions combine estimates of relative risks from meta-analyses of BMI and cancer incidence with worldwide cancer incidence data and models of country-specific BMI distributions by age and sex.3,4 The investigators estimate both the total proportion of cancers associated with BMI and the proportion www.thelancet.com/oncology Vol 16 January 2015
associated with trends in increasing BMI between 1982 and 2012, which might be more plausible as an estimate of the proportion of cancers that could be prevented in practice. Worldwide, Arnold and colleagues estimate that fairly few adult cancers were associated with high BMI in 2012: 481 000 or 3·6% of adult cancers overall (5·4% in women and 1·9% in men). Moreover, about 118 000 cancers—only 0·9% of adult cancers overall, although a quarter of the cancers associated with high BMI—could be attributed to the increase in BMI since 1982. These broad findings are likely to be robust and are supported by the results of a range of sensitivity analyses, although some country-specific estimates will be more uncertain because of the variable quality of cancer and BMI data for those populations.3,4 Arnold and colleagues’ results show at least two important dichotomies in the proportions of cancers
Jim Varney/Science Photo Library
Cancer and high body-mass index: global burden, global effort?
Published Online November 26, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70373-0 See Articles page 36
3
Comment
associated with high BMI. One is the roughly threetimes greater population attributable fraction in women than in men, largely due to endometrial and postmenopausal breast cancers. This difference is seen across geographical regions and levels of development, although it is unclear the extent to which this finding might be susceptible to data quality issues or heterogeneity of associations in some populations. Good reasons exist to believe that BMI has a causal association with risk of these cancers via hormonal pathways,5,6 and that this risk is therefore modifiable. This possibility is especially encouraging because these cancers also represent a substantial proportion of all adult cancers (ie, not only cancers in women) associated with high BMI. A second dichotomy is the difference between developed and developing countries (although differences are reported within these categories as well). In developed countries (ie, those with a high or very high human development index [HDI]), about 8% of cancers in women and 3% in men were associated with high BMI, and about 2% in women and 1% in men were associated with trends in increasing BMI since 1982. In developing countries (those with a lower HDI), only about 2% of cancers in women and 0·5% in men were associated with high BMI; less than 1% of cancers in women and essentially none in men were associated with trends in increasing BMI since 1982, since such trends were generally weaker or nonexistent in these countries. The differences between developed and developing countries suggest that different research and policy objectives might be appropriate in these different settings. In the well studied developed countries, more attention should now be given to the generation of data to directly support policy, particularly by quantifying the broader costs of overweight and obesity to individuals, health-care systems, economies, and societies. In developing countries, the past, present, and future might all be uncertain, but a wider view might be taken both across health outcomes and across risk factors, with the goal of making the best use of limited resources. Meanwhile, work should continue to improve crucial data for cancer incidence, the prevalence of overweight and obesity, and the association between the two. 4
Arnold and colleagues provide an important new context and baseline for understanding the global burden of cancer incidence in relation to high BMI.2 Although there are important differences between countries and regions, overall this burden is fairly small, so arguably these findings do not give much additional support for a global effort to address rising obesity. Such an effort is certainly needed, but mainly because of metabolic and vascular diseases, which dominate the burden of ill health associated with obesity.7 If 3·6% of all cancers are associated with high BMI, that is nearly half a million cancers, but this number is large mainly because the world population is large. Global health resources specifically for cancer prevention are not so large, and the resources targeted at obesity must be balanced against those for other important causes of cancer, particularly infections and tobacco use, which are each associated with much larger proportions of cases.8,9 Benjamin J Cairns Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK [email protected] I declare no competing interests. I acknowledge salary support from the British Heart Foundation Centre of Research Excellence (Oxford, UK). 1
2
3
4
5
6
7
8
9
Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008; 371: 569–78. Arnold M, Pandeya N, Byrnes G, et al. Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol 2014; published online Nov 24. http://dx.doi.org/10.1016/ S1470-2045(14)71123-4. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase No 11. Lyon: International Agency for Research on Cancer, 2013. Finucane MM, Stevens GA, Cowan MJ, et al, on behalf of the Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Body Mass Index). National, regional, and global trends in bodymass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9·1 million participants. Lancet 2011; 377: 557–67. Crosbie EJ, Zwahlen M, Kitchener HC, Egger M, Renehan AG. Body mass index, hormone replacement therapy, and endometrial cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2010; 19: 3119–30. Endogenous Hormones Breast Cancer Collaborative Group. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 2003; 95: 1218–26. Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2224–60. de Martel C, Ferlay J, Franceschi S, et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol 2012; 13: 607–15. Ezzati M, Henley SJ, Lopez AD, Thun MJ. Role of smoking in global and regional cancer epidemiology: current patterns and data needs. Int J Cancer 2005; 116: 963–71.
www.thelancet.com/oncology Vol 16 January 2015
