Contraception and cancerepidemiological

Contraception and cancerepidemiological evidence Hormonal contraception Combined Progestogen-only Philip C Hannaford University of Aberdeen Breast cancer and combined oral Re-analysis of individual data from 53,297 cases and 100,239 controls, 54 studies vs never users: adjusted RR 1.07 (1.03-1.11) Breast cancer and combined oral Comparison group: never users Odds ratio Breast cancer and combined oral vs never users- tumours spread beyond breast compared with localised cancers: Adjusted Relative Risk 0.88 (0.81-0.95) 1

Breast cancer and combined oral Meta-analysis of published data on breast cancer in pre-menopausal women or those <50 years 34 case-control studies, in or after 1980- Age when started: <20 RR (95% CI) 20-24 RR (95% CI) 25-29 RR (95% CI) Current 1.59 (1.41-1.77) 1.17 (1.04-1.30) 1.16 (1.01-1.31) Stopped <5 yr 1.49 (1.31-1.67) 1.15 (1.02-1.27) 1.09 (0.95-1.23) Stopped 5-9 yr 1.07 (0.93-1.21) 1.09 (1.00-1.18) 1.01 (0.99-1.11) Stopped 10-14 yr 1.13 (0.99-1.27) 0.93 (0.85-1.01) 1.06 (0.96-1.16) Stopped 15+ yr 1.14 (0.99-1.29) 1.01 (0.92-1.10) 1.01 (0.99-1.11) Ever vs Never: Pooled OR 1.19 (1.09-1.29) Kailhenborn et al, Mayo Clin Proc 2006, 81, 1290-1302 Meta-analysis of published data on breast cancer in pre-menopausal women or those <50 years 34 case-control studies, in or after 1980- Ever vs Never: Pooled OR 1.19 (1.09-1.29) Parous women who used before first fullterm pregnancy: Pooled OR 1.44 (1.28-1.62) Parous women who used after first full-term pregnancy: Pooled OR 1.15 (1.06-1.26) Kailhenborn et al, Mayo Clin Proc 2006, 81, 1290-1302 Estimated cumulative excess breast cancer risk per 10,000 European or North American users Age when used OCs 10 years after stopping 16 to 19 0.5 20 to 24 1.5 25 to 29 4.7 30 to 34 11.1 35 to 39 21.0 40 to 44 32.0 Breast cancer and progestogen only Limited data Collaborative Group found similar pattern for PO (mostly pills & injections) as COCs Subsequent studies- inconsistent Assume PO have similar risk to COCs 2

Cervical cancer and combined oral Cervical cancer and combined oral : Re-analysis of individual data from 16,573 cases and 33,509 controls, 24 studies Collaborative Group, Lancet 2007, 370, 1609-21 Collaborative Group, Lancet 2007, 370, 1609-21 Estimated cumulative excess cervical cancer risk per 10,000 users Cervical cancer and progestogen only Length of use, starting at age 20 Developed countries by age 50 Less developed countries by age 50 5 years 2 2 10 years 7 10 Collaborative Group had insufficent data for PO pills- injections similar pattern to COCs (albeit at a lower level) Subsequent South African study similar pattern Assume PO have similar risk to COCs Collaborative Group, Lancet 2007, 370, 1609-21 Hepatocellular cancer and combined oral 12 case-control studies, ever vs never summary OR 1.57 (0.96 2.54) Maheshwari et al, J Hepatology 2007, 47, 506-13 3

Hepatocellular cancer and combined oral Hepatocellular cancer and progestogen only 12 case-control studies, ever vs never summary OR 1.57 (0.96 2.54) No data short duration ORs between 0.3 & 2.0 longer duration ORs between 2.0 & 20.1 hepatitis B endemic areas- no relationship Maheshwari et al, J Hepatology 2007, 47, 506-13 Ovarian cancer and combined oral Re-analysis of individual data from 23,257 cases and 87,303 controls, 45 studies vs never users: adjusted RR 0.73 (0.70 0.76) Collaborative Group, Lancet 2008, 371, 303-14 Ovarian cancer and combined oral Ovarian cancer and combined oral Collaborative Group, Lancet 2008, 371, 303-314 Collaborative Group, Lancet 2008, 371, 303-314 4

Estimated number of ovarian cancer cases prevented globally since the introduction of combined oral Ovarian cancer and progestogen only 200,000 new cases 100,000 deaths Limited data (mostly DMPA-containing injectables)- suggest also protective, especially among long term users Collaborative Group, Lancet 2008, 371, 303-314 Hepatocellular cancer and combined oral 11 studies up to 1997 Schlesselmann. Hum Reprod 1997, 12, 1851-63 Endometrial cancer and combined oral Endometrial cancer and combined oral Schlesselmann. Hum Reprod 1997, 12, 1851-63 Schlesselmann. Hum Reprod 1997, 12, 1851-63 5

Endometrial cancer and progestogen only Limited data (mostly DMPA-containing injectables)- suggest also protective, especially among long term users Colorectal cancer and combined oral Colorectal cancer and combined oral 18 studies summary RR 0.81 (0.75 0.89) 18 studies summary RR 0.81 (0.75 0.89) <10 years since stopping RR 0.51 (0.35-0.74) 10+ years since stopping RR 0.77 (0.60-0.99) Bosetti et al, Hum Reprod Update 2009, 15, 489-98 Bosetti et al, Hum Reprod Update 2009, 15, 489-98 Colorectal cancer and progestogen only No data 6

Thyroid cancer and combined oral Re-analysis of published data from 13 case-control studies summary RR 1.2 (1.0-1.4) Current users RR 1.5 (1.0-2.1) Increase disappears within 10 of stopping Other cancers and combined oral Melanoma 10 case-control studies Pooled OR use 1+ year vs never/<1 year: 0.86 (0.74 1.01) Lung Few studies No significant risk Neuroblastoma Few studies No significant risk Lymphoma Few studies No significant risk Renal Few studies No significant risk Oesphageus Few studies No significant risk Gastric Few studies No significant risk Pancreatic Few studies No significant risk Gallbladder Few studies No significant risk La Vecchia et al, Cancer Cause Control 1999, 10, 157-66 Combined oral contraception and cancer Combined oral contraception and cancer Breast Cervix (Liver) ((Thyroid)) Ovary Endometrium Colorectum Breast Cervix (Liver) ((Thyroid)) Ovary Endometrium Colorectum Mostly during current & recent use During current use; sustained after stopping Mostly during current & recent use During current use; sustained after stopping So what is the lifetime risk of any cancer in ever users? Incident cancer to December 2004 : BMJ 2007 n Relative risk (95% confidence interval) All cancer 3877 345 390 0.88 (0.83-0.94) Royal College of General Practitioners Oral Contraception Study Large bowel / rectum 323 26 36 0.72 (0.58-0.90) Gallbladder / liver 27 2 4 0.55 (0.26-1.17) Lung 297 27 26 1.05 (0.82-1.35) Melanoma 146 13 14 0.92 (0.87-1.29) Breast 1339 122 124 0.98 (0.87-1.10) Invasive cervix 154 15 11 1.33 (0.92-1.94) Uterine body 156 11 20 0.58 (0.42-0.79) Ovary 189 13 25 0.54 (0.40-0.71) CNS 49 5 4 1.34 (0.73-2.47) Site unknown 99 7 11 0.64 (0.43-0.95) Other cancer 1367 120 136 0.88 (0.79-0.98) Woman-years observation 744,717 339,349 7

Incident cancer to December 2004 : BMJ 2007 Relative risk (95% confidence interval) Absolute rate reduction All cancer 345 390 0.88 (0.83-0.94) - 45 Incident cancer to December 2004 : BMJ 2007 Relative risk (95% confidence interval) Absolute rate reduction All cancer 345 390 0.88 (0.83-0.94) - 45 Large bowel / rectum 26 36 0.72 (0.58-0.90) - 10 Gallbladder / liver 2 4 0.55 (0.26-1.17) - 2 Lung 27 26 1.05 (0.82-1.35) + 1 Melanoma 13 14 0.92 (0.87-1.29) - 1 Breast 122 124 0.98 (0.87-1.10) - 2 Invasive cervix 15 11 1.33 (0.92-1.94) + 4 Uterine body 11 20 0.58 (0.42-0.79) - 9 Ovary 13 25 0.54 (0.40-0.71) - 12 CNS 5 4 1.34 (0.73-2.47) + 1 Site unknown 7 11 0.64 (0.43-0.95) - 4 Other cancer 120 136 0.88 (0.79-0.98) - 12 Large bowel / rectum 26 36 0.72 (0.58-0.90) - 10 Gallbladder / liver 2 4 0.55 (0.26-1.17) - 2 Lung 27 26 1.05 (0.82-1.35) + 1 BUT: does this translate into a mortality Melanoma 13 14 0.92 (0.87-1.29) - 1 Breast 122 benefit? 124 0.98 (0.87-1.10) - 2 Invasive cervix 15 11 1.33 (0.92-1.94) + 4 AND what is the overall balance of deaths in Uterine body 11 20 0.58 (0.42-0.79) - 9 ever users? Ovary 13 25 0.54 (0.40-0.71) - 12 CNS 5 4 1.34 (0.73-2.47) + 1 Site unknown 7 11 0.64 (0.43-0.95) - 4 Other cancer 120 136 0.88 (0.79-0.98) - 12 Mortality results to June 2007: BMJ 2010 Mortality results to June 2007: BMJ 2010 n Relative risk (95% CI) All causes 4611 366 417 0.88 (0.82-0.93) - Cancer 2088 165 195 0.85 (0.78-0.93) - Circulatory disease 1264 99 115 0.86 (0.77-0.96) - Digestive disease 195 16 17 0.95 (0.71-1.27) - Accidents & violence 207 19 13 1.49 (1.09-2.05) - Other causes 851 66 78 0.84 (0.74-0.97) Woman-years observation 819,175 378,006 Relative risk (95% CI) Absolute rate reduction All causes 366 417 0.88 (0.82-0.93) - - 51 - Cancer 165 195 0.85 (0.78-0.93) - 30 - Circulatory disease 99 115 0.86 (0.77-0.96) - 16 - Digestive disease 16 17 0.95 (0.71-1.27) - 1 - Accidents & violence 19 13 1.49 (1.09-2.05) + 6 - Other causes 66 78 0.84 (0.74-0.97) - 12 What about today s pills? Association does not mean causation! 8

In this UK cohort: oral were associated with an overall decreased risk of cancer the balance of risks and benefits may vary internationally depending on patterns of OC use and incidence of different cancers 9