Preventive drug therapy and contralateral breast cancer: summary of the evidence of clinical trials and observational studies

Figures & data

Figure 1. Forest plot of studies on preventive drug therapy and risk of contralateral breast cancer. ACE: angiotensin-converting enzyme; AI: aromatase inhibitors; CI: confidence interval; EBCTCG: Early Breast Cancer Trialists’ Collaborative Group; NSAID: non-steroidal anti-inflammatory drug; RCT: randomized controlled trial; TAM: tamoxifen; y: year. ^aMeta-analysis; ^bno confidence interval available; ^conly ER-positive and ER-unknown first breast cancer; ^dcalendar period 1999–2007; ^eincludes both new ipsilateral and contralateral breast cancer.

Table 1. Overview of clinical trials and observational studies on the association between tamoxifen and risk of contralateral breast cancer.

First author, year	Country	Study design	Number of breast cancer patients (CBC cases)	Data source of drug exposure	Follow-up time (years)	Definition of use	Risk estimate (95% CI, SD or SE)	Remarks
EBCTCG, 1998 [27]	Multi-center	Meta-analysis of 55 RCTs	36,689 (854)	Trial records	Mean: ∼10	≤1 year 2 years ∼5 years Any duration	RR 0.87; SD:0.13 RR 0.74; SD:0.09 RR 0.53; SD:0.09 RR 0.70; SD:0.06
EBCTCG, 2005 [7]	Multi-center	Meta-analysis of 12 RCTs	15,017 (575)	Trial records	Not reported	∼5 years vs. none	ER-positive and ER-unknown first breast cancer: RR 0.61 (0.50–0.73) ER-negative first breast cancer: RR 0.99 (0.70–1.36)
EBCTCG, 2011 [8]	Multi-center	Meta-analysis of 20 RCTs	21,457 (940)	Trial records	Median: 13	∼5 years vs. none	RR 0.71; SE: 0.06	Absolute risk reduction: 3.2% [SE: 0.8] at 15 years of follow-up for ER-positive first breast cancers
Hackshaw et al., 2011 [28]	Multi-center	RCT	3449 (118)	Trial records	Median: 10.1	5 years vs. 2 years	HR 0.70 (0.48–1.00)	Absolute risk reduction: 1.3% (95% CI: 0.00–2.3) at 10 years and 2.4% (95% CI: 0.0–4.2) at 15 years of follow-up
Davies et al., 2013 [14]	Multi-center	RCT	12,894 (886)	Trial records	Mean: 7.6	10 years vs. 5 years	RR 0.88 (0.77–1.00)
Rosell et al., 2017 [29]	Sweden	RCT	4128 (426)	Trial records	Not reported	5 years vs. 2 years	HR 0.73 (0.56–0.96)	HRs for TAM use by time since start of treatment
Cook et al., 1995 [16]	USA	Nested case-control	234 CBC cases/435 controls	Medical records	–	Ever use	OR 0.5 (0.3–0.9)	ORs by duration (≤12/≥13 months) of TAM and by time since last use (≤12/≥13 months)
Newcomb et al., 1999 [19]	USA	Cohort	85,411 (2648)	Cancer registry (SEER)	Mean: 3.2	Ever use of hormonal therapy	RR 0.79 (0.70–0.90)	Presumably tamoxifen as the study-period was 1983–1994. RRs for hormonal therapy use by time since first breast cancer diagnosis (<5/≥5 years)
Li et al., 2001 [24]	USA	Cohort	8981 (189)	Cancer registry (SEER)	Mean: 4	Ever use	HR 0.9 (0.7–1.2)	HRs for TAM use by ER status of CBC
Schaapveld et al., 2008 [20]	Netherlands	Cohort	45,229 (1477)	Medical records	Median: 5.8	Ever use of hormonal therapy	HR 0.58 (0.48–0.69)	Presumably tamoxifen
Bertelsen et al., 2008 [15]	Multi-center (WECARE)	Nested case-control	634 CBC cases/1158 controls	Medical records	–	Ever use	RR 0.66 (0.50–0.88)	RRs for TAM use by time since first breast cancer diagnosis (1–5, >5–10, >10 years)
Li et al., 2009 [23]	USA	Nested case-control	358 CBC cases/674 controls	Telephone interview and medical records	–	Ever use	OR 0.6 (0.5–0.8)	Only hormone receptor-positive first breast cancer patients ORs by duration of TAM use (<1, 1–4, /≥5 years) overall and according to ER status of CBC
Bouchardy et al., 2011 [22]	Switzerland	Cohort	4152 (63)	Cancer Registry (Geneva)	Median: 5.2	Ever use of anti-estrogens	HR 0.51 (0.26–0.99)	Presumably mainly TAM since AIs were prescribed only from 2004 and the study period was 1995–2007 HRs for TAM use by ER status of CBC
Vichapat et al., 2012 [21]	Sweden	Cohort	35,003 (894)	Regional clinical database	Median: 6.7	Ever use of endocrine therapy	HR 0.78 (0.68–0.90)	Presumably mainly TAM as the study period was 1992–2008
Mellemkjaer et al., 2014 [18]	Denmark	Cohort	37,533 (1405)	National clinical database (DBCG)	Not reported	Ever use	Premenopausal patients during 1999–2007: HR 0.44 (0.27–0.71) Postmenopausal patients by calendar year: 1977–1989: HR 1.40 (1.12–1.74) 1990–1998: HR 0.82 (0.68–0.99) 1999–2007: HR 0.61 (0.44-0.84)	HRs for current/past use by duration (</≥1.2 years) and by time since last use. HRs by ER/PR status of first breast cancer
Langballe et al., 2016 [17]^a	Multi-center (WECARE)	Nested case-control	1521 CBC cases/2212 controls	Medical records	–	Ever use	RR 0.76 (0.63–0.92)	RRs by current/past use, duration (</≥54 months) and time since last use (</≥37 months) and combinations of these. RRs by ER status of first and second breast cancer
Gierach et al., 2017 [25]	USA	Cohort	7541 (248)	Health plan administrative database and medical records	Median: 6.3	Current use	RR^b 0.76 (0.64–0.89) per year of TAM use	RRs^b for current use and time since last use by duration of TAM (<1, 1–<4, and ≥4 years). RRs^b by ER status of CBC Absolute risk reduction among 5-year ER-positive breast cancer survivors for ≥4 years of tamoxifen versus no tamoxifen: 3.3% at 10 years and 4% at 15 years of follow-up
Kramer et al., 2019 [26]	Netherlands	Cohort	83,144 (2816)	National clinical database	Median: 7.7	Ever use	HR 0.48 (0.44–0.53)

AI: aromatase inhibitor; CBC: contralateral breast cancer; CI: confidence interval; EBCTCG: Early Breast Cancer Trialists’ Collaborative Group; DBCG: Danish Breast Cancer Group; ER: estrogen receptor; HR: hazard ratio; OR: odds ratio; PR: progesterone receptor; RR: rate ratio; SD: standard deviation; SE: standard error; SEER: Surveillance Epidemiology and End Results; TAM: tamoxifen; USA: United States of America.

^a Update of Bertelsen et al. (2008).

^b RR: relative risk.

Table 2. Overview over clinical trials and observational studies on the association between aromatase inhibitors and risk of contralateral breast cancer.

Author, year	Country	Study design	Number of breast cancer patients (CBC cases)	Data source of drug exposure	Follow-up time (years)	Definition of use	Risk estimate (95% CI)	Remarks
EBCTCG, 2015 [34]	Multi-center	Meta-analysis of 9 RCTs	1) 9,885 (236) 2) 11,798 (226) 3) 12,799 (136)	Trial records	Mean: ∼5–10	1) 5 years AI vs. 5 years TAM 2) 2–3 years TAM + 2–3 years AI vs. 5 years TAM 3) 5 years AI vs. 2–3 years TAM + 2–3 years AI	1) RR 0.62 (0.48–0.80) 2) RR 0.67 (0.51–0.87) 3) RR 1.12 (0.80–1.57)	Only hormone receptor-positive first breast cancer patients
Goss et al., (2013) [36]	Multi-center	RCT	7576 (79)	Trial records	Median: 4.1	5 years of exemestane vs. 5 years of anastrozole	–	Only hormone receptor-positive first breast cancer patients Exemestane: 46 CBC cases Anastrozole: 33 CBC cases
Goss et al., 2016 [37]	USA/Canada	RCT	1918 (44)	Trial records	Median: 6.3	Additional 5 years of letrozole vs. placebo	HR 0.42 (0.22–0.81)	Only hormone receptor-positive and hormone receptor-unknown first breast cancer patients
Morden et al., 2017 [38]	Multi-center	RCT	4724 (131)	Trial records	Median: 10	2–3 years TAM + 2–3 years AI vs. 5 years TAM	HR 0.73 (0.52–1.03)	Only hormone receptor-positive and hormone receptor-unknown first breast cancer patients
Tjan-Heijnen et al., 2017 [39]	Netherlands	RCT	1912 (19)	Trial records	Median: 4.2	2–3 years TAM + 3 years anastrozole vs. 2–3 years TAM + 6 years anastrozole	–	Only hormone receptor-positive first breast cancer patients 3-year of AI: 15 CBC cases 6-year of AI: 4 CBC cases
Blok et al., 2018 [40]	Netherlands	RCT	1821 (37)	Trial records	Median: 6.6	Additional 5 years vs. 2.5 years of letrozole	HR 0.39 (0.19–0.81)	Only hormone receptor-positive first breast cancer patients Includes both new ipsilateral and CBC
Colleoni et al., 2018 [41]	Multi-center	RCT	4851 (44)	Trial records	Median: 5	Additional 5 years of continuous letrozole use vs. intermittent letrozole use	–	Only hormone receptor-positive first breast cancer patients Continuous AI use: 17 CBC cases Intermittent AI use: 27 CBC cases
Francis et al., 2018 [42]	Multi-center	RCT	4690 (36)	Trial records	Median: 8	Exemestane + OFS vs. TAM + OFS	–	Only premenopausal hormone receptor-positive first breast cancer patients Exemestane + OFS: 22 CBC cases TAM + OFS: 33 CBC cases
Gierach et al., 2017 [25]	USA	Cohort	7541 (248)	Health plan administrative database and medical records	Median: 6.3	1) Ever use of AI without TAM 2) Ever use of AI with TAM	1) RR^a 0.48 (0.22–0.97) 2) RR^a 0.86 (0.46–1.51)	RRs^a by ER status of CBC
Kramer et al., 2019 [26]	Netherlands	Cohort	83,144 (2,816)	National clinical database	Median: 7.7	1) Ever use of AI without TAM 2) Ever use of AI with TAM	1) HR 0.32 (0.23–0.44) 2) HR 0.45 (0.36–0.56)

AI: aromatase inhibitors; CBC: contralateral breast cancer; CI: confidence interval; EBCTCG: Early Breast Cancer Trialists’ Collaborative Group; ER: estrogen receptor; HR: hazard ratio; OFS: ovarian function suppression; RCT: randomized controlled trial; RR: rate ratio; TAM: tamoxifen; USA: United States of America.

^a RR: relative risk.

Table 3. Overview of clinical trials and observational studies on the association between non-cancer drugs and risk of contralateral breast cancer.

Drug	First author, year	Country	Study design	Number of breast cancer patients (CBC cases)	Data source of drug exposure	Definition of use	Follow-up time (years)	Risk estimate (95% CI)	Remarks
Bisphosphonates	EBCTCG, 2015 [57]	Multi-center	Meta-analysis of 26 RCTs	18,766 (254)	Trial records	Ever use	Median: 5.6	RR 0.96 (0.74–1.25)
	Monsees et al., 2011 [58]	USA	Case-control	351 CBC cases/652 controls	Medical records	Ever use	–	OR 0.53 (0.30–0.93)	Only hormone receptor-positive first breast cancer patients ORs by current/former use and duration of use (≥6, ≥12, and ≥24 months)
	Kwan et al., 2016 [59]	USA	Cohort	16,781 (494)	Health plan administrative database and medical records	≥2 prescriptions	Mean: 6.4	HR 0.96 (0.67–1.38)	Only hormone receptor-positive first breast cancer patients treated with tamoxifen HRs by duration of use (<1, 1–<2, and ≥2 years)
Statins	Ahern et al., 2011 [60]	Denmark	Cohort	18,769 (520)	Prescription registry	≥1 prescription of simvastatin	Median 6.8	HR 0.54 (0.33–0.90)
	Boudreau et al., 2014 [61]	USA	Cohort	4216 (143)	Health plan administrative database	≥1 prescription of statins	Median 6.3	HR 0.92 (0.56–1.52)	HR by type of statin and duration of use (<1, 1–2.9, +3 years)
	Langballe et al., 2018 [62]	Denmark	Cohort	52,723 (1382)	Prescription registry	≥2 prescription of statins	Median: 4.8	HR 0.88 (0.73–1.05)	HRs by current/past use, duration (</≥5 year), intensity (</≥1 DDD), consistent/inconsistent use, and type of statin. Ever use by ER status of first breast cancer and CBC
Metformin	Oppong et al., 2014 [63]	USA	Cohort	141 (7)	Medical records	Ever use within 6 months prior to baseline	Median: 7.3	–	CBC rate at 5 years Metformin: 3.4 (95% CI: 0–7.9) No metformin: 7.9 (95% CI: 0.1–15.1)
	Calip et al., 2015 [64]	USA	Cohort	4216 (153)	Health plan administrative database	≥1 prescription	Median: 6.3	HR 1.52 (0.58–3.98)	Combined HR for ipsilateral and CBC
NSAIDs	Bens et al., 2018 [65]	Denmark	Cohort	52,723 (1444)	Prescription registry	≥2 low-dose aspirin prescriptions	Median: 4.8	HR 0.91 (0.76–1.09)	HRs by current/past use, duration, consistent/inconsistent use, and tablet strength. Ever use by ER status of first breast cancer and CBC
	Bens et al., 2018 [66]	Denmark	Cohort	52,723 (1,444)	Prescription registry	≥2 non-aspirin NSAID prescriptions	Median: 4.8	HR 0.98 (0.87–1.11)	HRs by duration, intensity, and COX-2 selectivity. Ever use by ER status of first breast cancer and CBC
Anti-hypertensive drugs	Boudreau et al., 2014 [61]	USA	Cohort	4216 (143)	Health plan administrative database	≥1 prescription	Median: 6.3	ACE inhibitors: HR 1.66 (1.06–2.58) Beta blockers: HR 0.77 (0.50–1.19)
	Chen et al., 2015 [67]	USA	Case control	359 CBC cases/691 controls	Medical records	≥6 months	–	ACE inhibitors: OR 1.2 (0.9–1.8) Beta-blockers: OR 1.0 (0.7–1.4)	Only hormone receptor-positive first breast cancer patients
Fenretinide	Veronesi et al., 2006 [68]	Italy	RCT	1739 (148)	Trial records	∼5 years vs. none	Median: 14.6	HR 0.90 (0.65–1.26)	HRs by menopausal status

CBC: contralateral breast cancer; CI: confidence interval; DDD: daily defined dose; EBCTCG: Early Breast Cancer Trialists’ Collaborative Group; ER: estrogen receptor; HR: hazard ratio; OR: odds ratio; RCT: randomized controlled trial; RR: rate ratio; USA: United States of America.

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