- Email: [email protected]
Menarche, menopause, and breast cancer risk
Comment
this largely chemotherapy-resistant disease. However, response assessment is challenging in these tumours and a single-arm study cannot confirm whether the duration of stable disease is longer than the underlying biology of this particular subtype. What has become clear over the past decade is that the application of dimensional criteria alone is insufficient to assess the benefit of novel drugs and that functional imaging should have a central role in the design and undertaking of clinical trials. RG7112 was reasonably well tolerated, although seven patients experienced treatment-related serious adverse events, which were all haematological (thrombocytopenia, neutropenia, and neutropenic fever). This proportion of serious adverse events suggests that future trials with this drug will need careful monitoring, particularly with the prospect of combining this drug with other compounds such as CDK4 inhibitors. Collaborative trials must be undertaken in sarcoma with the incorporation of molecular markers and also functional imaging to define the subgroups most likely to benefit from a particular treatment. With this in mind, the trial by Ray-Coquard and colleagues7 is a step toward better systemic treatment for patients with largely chemotherapy-resistant sarcoma subtypes but
also shows that clinical trial design should routinely incorporate biomarker assessment. Anastasia Constantinidou, Seth M Pollack, *Robin L Jones Royal Marsden Hospital, London, UK (AC); University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, USA (SMP, RLJ) [email protected] We declare that we have no conflicts of interest. 1
2
3 4 5 6 7
8
9
Wunder JS, Nielsen TO, Maki RG, O’Sullivan B, Alman BA. Opportunities for improving the therapeutic ratio for patients with sarcoma. Lancet Oncol 2007; 8: 513–24. Fabre-Guillevin E, Coindre JM, Somerhausen Nde S, Bonichon F, Stoeckle E, Bui NB. Retroperitoneal liposarcomas: follow-up analysis of dedifferentiation after clinicopathologic reexamination of 86 liposarcomas and malignant fibrous histiocytomas. Cancer 2006; 106: 2725–33. Jones RL, Fisher C, Al-Muderis O, Judson IR. Differential sensitivity of liposarcoma subtypes to chemotherapy. Eur J Cancer 2005; 41: 2853–60. Rubin BP, Fletcher CD. The cytogenetics of lipomatous tumours. Histopathology 1997; 30: 507–11. Coindre JM, Pedeutour F, Aurias A. Well-differentiated and dedifferentiated liposarcomas. Virchows Arch 2010; 456: 167–79. Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004; 303: 844–48. Ray-Coquard I, Blay J-Y, Italiano A, et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol 2012; published online October 16. http://dx.doi.org/10.1016/S1470-2045(12)70474-6. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783–92. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947–57.
The longer a woman is exposed to cycling reproductive hormones the higher her risk of breast cancer. If she has an early menarche or a late menopause, or both, her risk of breast cancer is increased. Additionally, women who bear children (parous) have a decreased risk of breast cancer compared those without children (nulliparous),1,2 purportedly because of the break in reproductive cycling. An understanding of how these reproductive behaviours mediate breast cancer risk will help to establish whether the cumulative length of cycling itself increases breast cancer risk, or whether exposure to the mitogenic effects of oestrogen is more important. This is timely research because women in the 21st century are undergoing menarche earlier, going through menopause later, bearing fewer children, and beginning their families later than ever before.3 In The Lancet Oncology, the Collaborative Group on Hormonal Factors in Breast Cancer report the www.thelancet.com/oncology Vol 13 November 2012
results of their meta-analysis assessing the ability of early menarche and late menopause to increase a woman’s risk of breast cancer.4 They have calculated the adjusted relative risks (RRs) of breast cancer in women across 117 epidemiological studies, spanning 35 countries, including 118 964 women with invasive breast cancer and 306 091 women without breast cancer. The group confirmed that longer reproductive cycling is associated with an increased risk of breast cancer. The novel finding was that lengthening of the reproductive years at menarche conferred a higher RR of breast cancer than did lengthening at menopause. An early menarche was associated with an increased RR of 1·05 (95% CI 1·044–1.057, 5% increase) for each year of younger onset of menarche, while for each year of older onset of menopause, RR was 1·029 (1·025–1·032, 2·9% increase). To put this finding into context with known modifiers of risk, the RR
Coneyl Jay/Science Photo Library
Menarche, menopause, and breast cancer risk
Published Online October 17, 2012 http://dx.doi.org/10.1016/ S1470-2045(12)70456-4 See Articles page 1141
1071
Comment
of contralateral breast cancer occurring in BRCA1 or BRCA2 carriers who have a history of breast cancer is about 5% per year.5 By comparison, the risk associated with later age at menopause is much the same as the increase in RR for each year of delay in childbearing, which is 3%.6 Thus, lengthening of reproductive cycling at menarche increases breast cancer risk more than a later menopause. The higher risk associated with early menarche than with delayed menopause might be attributable to the higher oestrogen concentrations present in adolescents who experience early menarche, when assessed before onset. Urinary oestrogens are significantly higher in girls who have early menarche than in those with normal menarche,7 thereby exposing these girls to higher concentrations of oestrogen during the initial stages of breast development, a time when oestrogen responsiveness is heightened.8 For ethical reasons, the dosedependent effects of oestrogen on the immature breast have not been assessed in women, but should be addressed in studies in rodents to confirm whether such changes in oestrogen at this stage can have longlasting effects on breast cancer risk. Complicating the matter, women who have early menarche are also known to maintain high oestrogen concentrations throughout their reproductive years and indeed, serum oestrogen concentrations can be used in menopausal women to predict those who underwent early menarche.9 Therefore, increased oestrogens during development and adulthood might mediate increased risk. The collaborative group looked at the association between early menarche and late menopause and different subtypes of breast cancer. This aspect is particularly important because parity only protects against development of oestrogen receptor-positive tumours.10 The investigators showed that the trend for increasing breast cancer risk with increasing age at menopause was significantly greater for oestrogenreceptor positive disease than for oestrogen-receptor negative cancers, and for lobular rather than ductal tumours. This finding is consistent with established risk of oestrogen receptor-positive cancers in postmenopausal women who use hormone therapy. The increased risk of breast cancer associated with early menarche was also stronger in lobular tumours, but was 1072
not specific to oestrogen receptor-positive tumours. The association with reproductive events in lobular rather than ductal tumours is not surprising since they are slower growing tumours and commonly oestrogen receptor-positive and progesterone receptor-positive. The observation that early menarche affects risk equally in oestrogen receptor-positive and oestrogen receptornegative cancers adds further support to the researchers’ hypothesis that the effects of menarche and menopause timing on breast cancer risk are not only attributable to increased time of reproductive exposure but also occur via distinct mechanisms. In view of the importance of menarche and menopause in definition of breast cancer risk, researchers need to use these important findings to drive investigations into the cause of these different effects of menarche and menopause. We should now establish the role of oestrogen in mediation of the increased risk at each end of the reproductive years and also work out the changes that occur in the breast tissue of women who undergo early versus late menarche or menopause. Kara Britt Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC 3002, Australia [email protected] I declare that I have no conflicts of interest. 1 2 3
4
5
6
7
8 9
10
Brinton LA, Schairer C, Hoover RN, Fraumeni JF Jr. Menstrual factors and risk of breast cancer. Cancer Invest 1988; 6: 245–54. MacMahon B, Cole P, Lin TM, et al. Age at first birth and breast cancer risk. Bull World Health Organ 1970; 43: 209–21. Australian Bureau of Statistics. Australian Social Trends December 2010. http://www.ausstats.abs.gov.au/Ausstats/subscriber.nsf/0/DE5DE30C9CF6 E5E3CA25748E00126A25/$File/41020_2008.pdf (accessed Sept 30, 2012). Collaborative Group on Hormonal Factors in Breast Cancer. Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol 2012; published online Oct 17. http://dx.doi.org/10.1016/S1470-2045(12)70425-4. Frank TS, Manley SA, Olopade OI, et al. Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol 1998; 16: 2417–25. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50 302 women with breast cancer and 96 973 women without the disease. Lancet 2002; 360: 187–95. Shi L, Remer T, Buyken AE, Hartmann MF, Hoffmann P, Wudy SA. Prepubertal urinary estrogen excretion and its relationship with pubertal timing. Am J Physiol Endocrinol Metab 2010; 299: E990–97. Haslam SZ. The ontogeny of mouse mammary gland responsiveness to ovarian steroid hormones. Endocrinology 1989; 125: 2766–72. Madigan MP, Troisi R, Potischman N, Dorgan JF, Brinton LA, Hoover RN. Serum hormone levels in relation to reproductive and lifestyle factors in Cancer Causes Control 1998; 9: 199–207. Ma H, Bernstein L, Pike MC, Ursin G. Reproductive factors and breast cancer risk according to joint estrogen and progesterone receptor status: a meta-analysis of epidemiological studies. Breast Cancer Res 2006; 8: R43
www.thelancet.com/oncology Vol 13 November 2012
this largely chemotherapy-resistant disease. However, response assessment is challenging in these tumours and a single-arm study cannot confirm whether the duration of stable disease is longer than the underlying biology of this particular subtype. What has become clear over the past decade is that the application of dimensional criteria alone is insufficient to assess the benefit of novel drugs and that functional imaging should have a central role in the design and undertaking of clinical trials. RG7112 was reasonably well tolerated, although seven patients experienced treatment-related serious adverse events, which were all haematological (thrombocytopenia, neutropenia, and neutropenic fever). This proportion of serious adverse events suggests that future trials with this drug will need careful monitoring, particularly with the prospect of combining this drug with other compounds such as CDK4 inhibitors. Collaborative trials must be undertaken in sarcoma with the incorporation of molecular markers and also functional imaging to define the subgroups most likely to benefit from a particular treatment. With this in mind, the trial by Ray-Coquard and colleagues7 is a step toward better systemic treatment for patients with largely chemotherapy-resistant sarcoma subtypes but
also shows that clinical trial design should routinely incorporate biomarker assessment. Anastasia Constantinidou, Seth M Pollack, *Robin L Jones Royal Marsden Hospital, London, UK (AC); University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, USA (SMP, RLJ) [email protected] We declare that we have no conflicts of interest. 1
2
3 4 5 6 7
8
9
Wunder JS, Nielsen TO, Maki RG, O’Sullivan B, Alman BA. Opportunities for improving the therapeutic ratio for patients with sarcoma. Lancet Oncol 2007; 8: 513–24. Fabre-Guillevin E, Coindre JM, Somerhausen Nde S, Bonichon F, Stoeckle E, Bui NB. Retroperitoneal liposarcomas: follow-up analysis of dedifferentiation after clinicopathologic reexamination of 86 liposarcomas and malignant fibrous histiocytomas. Cancer 2006; 106: 2725–33. Jones RL, Fisher C, Al-Muderis O, Judson IR. Differential sensitivity of liposarcoma subtypes to chemotherapy. Eur J Cancer 2005; 41: 2853–60. Rubin BP, Fletcher CD. The cytogenetics of lipomatous tumours. Histopathology 1997; 30: 507–11. Coindre JM, Pedeutour F, Aurias A. Well-differentiated and dedifferentiated liposarcomas. Virchows Arch 2010; 456: 167–79. Vassilev LT, Vu BT, Graves B, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 2004; 303: 844–48. Ray-Coquard I, Blay J-Y, Italiano A, et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol 2012; published online October 16. http://dx.doi.org/10.1016/S1470-2045(12)70474-6. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783–92. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947–57.
The longer a woman is exposed to cycling reproductive hormones the higher her risk of breast cancer. If she has an early menarche or a late menopause, or both, her risk of breast cancer is increased. Additionally, women who bear children (parous) have a decreased risk of breast cancer compared those without children (nulliparous),1,2 purportedly because of the break in reproductive cycling. An understanding of how these reproductive behaviours mediate breast cancer risk will help to establish whether the cumulative length of cycling itself increases breast cancer risk, or whether exposure to the mitogenic effects of oestrogen is more important. This is timely research because women in the 21st century are undergoing menarche earlier, going through menopause later, bearing fewer children, and beginning their families later than ever before.3 In The Lancet Oncology, the Collaborative Group on Hormonal Factors in Breast Cancer report the www.thelancet.com/oncology Vol 13 November 2012
results of their meta-analysis assessing the ability of early menarche and late menopause to increase a woman’s risk of breast cancer.4 They have calculated the adjusted relative risks (RRs) of breast cancer in women across 117 epidemiological studies, spanning 35 countries, including 118 964 women with invasive breast cancer and 306 091 women without breast cancer. The group confirmed that longer reproductive cycling is associated with an increased risk of breast cancer. The novel finding was that lengthening of the reproductive years at menarche conferred a higher RR of breast cancer than did lengthening at menopause. An early menarche was associated with an increased RR of 1·05 (95% CI 1·044–1.057, 5% increase) for each year of younger onset of menarche, while for each year of older onset of menopause, RR was 1·029 (1·025–1·032, 2·9% increase). To put this finding into context with known modifiers of risk, the RR
Coneyl Jay/Science Photo Library
Menarche, menopause, and breast cancer risk
Published Online October 17, 2012 http://dx.doi.org/10.1016/ S1470-2045(12)70456-4 See Articles page 1141
1071
Comment
of contralateral breast cancer occurring in BRCA1 or BRCA2 carriers who have a history of breast cancer is about 5% per year.5 By comparison, the risk associated with later age at menopause is much the same as the increase in RR for each year of delay in childbearing, which is 3%.6 Thus, lengthening of reproductive cycling at menarche increases breast cancer risk more than a later menopause. The higher risk associated with early menarche than with delayed menopause might be attributable to the higher oestrogen concentrations present in adolescents who experience early menarche, when assessed before onset. Urinary oestrogens are significantly higher in girls who have early menarche than in those with normal menarche,7 thereby exposing these girls to higher concentrations of oestrogen during the initial stages of breast development, a time when oestrogen responsiveness is heightened.8 For ethical reasons, the dosedependent effects of oestrogen on the immature breast have not been assessed in women, but should be addressed in studies in rodents to confirm whether such changes in oestrogen at this stage can have longlasting effects on breast cancer risk. Complicating the matter, women who have early menarche are also known to maintain high oestrogen concentrations throughout their reproductive years and indeed, serum oestrogen concentrations can be used in menopausal women to predict those who underwent early menarche.9 Therefore, increased oestrogens during development and adulthood might mediate increased risk. The collaborative group looked at the association between early menarche and late menopause and different subtypes of breast cancer. This aspect is particularly important because parity only protects against development of oestrogen receptor-positive tumours.10 The investigators showed that the trend for increasing breast cancer risk with increasing age at menopause was significantly greater for oestrogenreceptor positive disease than for oestrogen-receptor negative cancers, and for lobular rather than ductal tumours. This finding is consistent with established risk of oestrogen receptor-positive cancers in postmenopausal women who use hormone therapy. The increased risk of breast cancer associated with early menarche was also stronger in lobular tumours, but was 1072
not specific to oestrogen receptor-positive tumours. The association with reproductive events in lobular rather than ductal tumours is not surprising since they are slower growing tumours and commonly oestrogen receptor-positive and progesterone receptor-positive. The observation that early menarche affects risk equally in oestrogen receptor-positive and oestrogen receptornegative cancers adds further support to the researchers’ hypothesis that the effects of menarche and menopause timing on breast cancer risk are not only attributable to increased time of reproductive exposure but also occur via distinct mechanisms. In view of the importance of menarche and menopause in definition of breast cancer risk, researchers need to use these important findings to drive investigations into the cause of these different effects of menarche and menopause. We should now establish the role of oestrogen in mediation of the increased risk at each end of the reproductive years and also work out the changes that occur in the breast tissue of women who undergo early versus late menarche or menopause. Kara Britt Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, VIC 3002, Australia [email protected] I declare that I have no conflicts of interest. 1 2 3
4
5
6
7
8 9
10
Brinton LA, Schairer C, Hoover RN, Fraumeni JF Jr. Menstrual factors and risk of breast cancer. Cancer Invest 1988; 6: 245–54. MacMahon B, Cole P, Lin TM, et al. Age at first birth and breast cancer risk. Bull World Health Organ 1970; 43: 209–21. Australian Bureau of Statistics. Australian Social Trends December 2010. http://www.ausstats.abs.gov.au/Ausstats/subscriber.nsf/0/DE5DE30C9CF6 E5E3CA25748E00126A25/$File/41020_2008.pdf (accessed Sept 30, 2012). Collaborative Group on Hormonal Factors in Breast Cancer. Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol 2012; published online Oct 17. http://dx.doi.org/10.1016/S1470-2045(12)70425-4. Frank TS, Manley SA, Olopade OI, et al. Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol 1998; 16: 2417–25. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50 302 women with breast cancer and 96 973 women without the disease. Lancet 2002; 360: 187–95. Shi L, Remer T, Buyken AE, Hartmann MF, Hoffmann P, Wudy SA. Prepubertal urinary estrogen excretion and its relationship with pubertal timing. Am J Physiol Endocrinol Metab 2010; 299: E990–97. Haslam SZ. The ontogeny of mouse mammary gland responsiveness to ovarian steroid hormones. Endocrinology 1989; 125: 2766–72. Madigan MP, Troisi R, Potischman N, Dorgan JF, Brinton LA, Hoover RN. Serum hormone levels in relation to reproductive and lifestyle factors in Cancer Causes Control 1998; 9: 199–207. Ma H, Bernstein L, Pike MC, Ursin G. Reproductive factors and breast cancer risk according to joint estrogen and progesterone receptor status: a meta-analysis of epidemiological studies. Breast Cancer Res 2006; 8: R43
www.thelancet.com/oncology Vol 13 November 2012