The worldwide overview: updated (2005-6) meta-analyses of hormonal treatment trials Richard Gray, for the Early Breast Cancer Trialists Collaborative Group (EBCTCG)
Main questions, 2005-6 1) 5 years of tamoxifen, by ER & PR status (15,000 randomised) 2) 10 vs 5 years of tamoxifen (20,000 randomised) 3) Aromatase inhibitor vs tamoxifen, ER+ (20,000 randomised)
~5 years Tamoxifen vs not, split by ER status only: RECURRENCE ER-poor disease ER+ disease ER+ disease
~5 years Tamoxifen vs not, ER-poor split by PgR status: RECURRENCE
~5 years Tamoxifen vs not, ER+ split by PgR status: RECURRENCE
~5 years tamoxifen vs not: MORTALITY ~5 years tamoxifen vs. Not, ER+ BREAST CANCER MORTALITY
Main questions, 2005-6 2) 10 vs 5 years of tamoxifen
Rationale Tamoxifen for 5 years substantially reduces the risk of recurrence and death for women with ERpositive tumours But, the risk of recurrence remains high: not much lower in years 5-9 and 10-14 after surgery than in years 0-4 Since 5 years of tamoxifen is more effective than 2 years 17% fewer recurrences - 10 years may well be more effective than 5 years of treatment
Objectives of attom (UK only) and ATLAS (35 other countries): Randomise at least 20,000 women between 10 and 5 years of tamoxifen (to detect reliably, or refute reliably, a 2-3% improvement in survival) Follow-up randomised women for at least 15 years (because 10 or more years is needed to see full benefits from longer tamoxifen)
Trials of 10 vs 5 years of tamoxifen 20,000 randomised; follow-up continues ECOG, Scottish & NSABP B-14 ~1,600 attom ~7,000 ATLAS ~11,500 * Preliminary results from ATLAS and attom were presented at San Antonio BCS (Dec 2007) and at ASCO (May 2008)
10 vs 5 years of tamoxifen: ATLAS preliminary results SABCS, December 2007 Richard Peto & Christina Davies, for the ATLAS collaborative group
Accrual by country 5 others Estonia Croatia Turkey Portugal Colombia Netherlands Mexico South Africa Latvia Cuba Lithuania Belgium Japan USA Peoples' Republic of China Belarus Iran Israel Taiw an Italy Russia Egypt Hong Kong Australia/New Zealand Poland Argentina Czech Republic Brazil Chile Spain India ATLAS: 15 254 women randomised from 30+ countries: largest cancer treatment trial so far! 0 500 1000 1500 2000 2500 3000 3500
Randomised trial of 10 versus 5 years of adjuvant tamoxifen - includes 6934 women with ER+ or ER untested breast cancer - preliminary results Richard Gray et al for attom Collaborators ASCO 2008
ATLAS alone: ~10 vs ~5 years: recurrence in ER+ / ER?
ATLAS alone: ~10 vs ~5 years: Recurrence in ER+ / ER?
ATLAS alone: ~10 vs ~5 years: Breast cancer mortality (ER+/?)
ATLAS alone: ~10 vs ~5 years: Recurrence in ER+ / ER?
attom 60% had unrecorded ER (so only ~85% of women are ER+) No. of wo omen 4500 4000 3500 3000 2500 2000 1500 1000 500 0 40% ER-positive 60% ER untested
attom compliance with allocated treatment (81% vs 3% taking tamoxifen at 3 years)
Results of attom will therefore underestimate the true effect among ER+ women With ~85% ER+ and ~80% compliance, attom will achieve only ~68% of the true effect of 5 extra years of tam in ER+ disease. For example, if true RR is 0.80 (ie, 20% reduction), attom should get ~0.86 (14% redn.)
attom alone: ~10 vs ~5 years: Recurrence in ER+ / ER? % Recur rred RR=0.95 (95%CI 0.83-1.09; p=ns) Years from randomisation (year 5 after surgery)
attom and ATLAS: effect of 10v 5 years tamoxifen by follow-up period Follow-up period
Reduced recurrence rate with 5 years of tamoxifen in years 0-4 AND in years 5-9 Effect of 5 years of tamoxifen on breast cancer recurrence for women with hormone-sensitive breast cancer
New primary cancers Continue (n=3468) Stop (n=3484) Site n % n % Endometrium* 76 2.2 40 1.1 Other sites** 118 3.4 164 4.7 Total 194 5.6 204 5.8 * p<0.0007; ** p=0.007
Cause of death Deaths following endometrial cancer Continue (n=76) Stop (n=40) Endometrial cancer 11 14 Breast cancer 7 2 Other cancer 4 0 Other causes 3 4 All causes 25 20
All trials of 10 versus 5 years of tamoxifen: ER-positive or ER-untested
Conclusions PRELIMINARY results from ATLAS, attom and three earlier studies suggest that continuing tamoxifen beyond 5 years reduces recurrence over the next few years Endometrial cancer incidence is increased but not mortality Further follow-up of attom and ATLAS is essential to assess reliably the longer-term effects on recurrence and the net effects, if any, on mortality
Aromatase Inhibitor Overview Group (AIOG)* *Journal of Clinical Oncology 2009; in press (with slight numerical updates) NB Results confidential until published
ER+ early breast cancer: adjuvant trials of a 3 rd generation aromatase inhibitor (AI) versus tamoxifen (1) ~ 5 years of (AI vs tamoxifen): 2 trials, 10 000 postmenopausal women (2) 2-3 years of tamoxifen & then 2-3 years of (AI vs tamoxifen): 4 trials, 9000 postmenopausal women
5 years AI vs 5 years tamoxifen: Recurrence 9856 women with ER+ disease in 2 large trials ATAC (anastrozole vs tam) & BIG 01-98 (letrozole vs tam)
~5 years of AI vs. ~5 years of tamoxifen: Recurrence in ER+ disease
~5 years of AI vs. ~5 years of tamoxifen: Recurrence by follow-up period
~5 years of AI vs. ~5 years of tamoxifen (ER+): Recurrence by PgR status and age
~5 years of AI vs. ~5 years of tamoxifen: Recurrence by nodal status and tumour grade
~5 years of AI vs. ~5 years of tamoxifen: Site of recurrence
~5 years of AI vs. ~5 years of tamoxifen: Death without recurrence
~5 years of AI vs. ~5 years of tamoxifen: Breast cancer mortality
~5 years of AI vs. ~5 years of tamoxifen: Any death
~5 years of AI vs. ~5 years of tamoxifen: Recurrence Breast cancer death
~5 years Tamoxifen vs not, in ER+ disease Recurrence Breast cancer death
AI SWITCHING TRIALS ER+ early breast cancer: AI versus tamoxifen 2-3 years of tamoxifen & then 2-3 years of (AI vs tamoxifen): total ~ 5 years of treatment These switching trials are analysed with respect to the time since the allocated treatments would differ, ignoring women with death or recurrence before then. The graphs are labelled both with this time and (in brackets) with the approximate time since diagnosis.
2-3 yrs Tam then 2-3 yrs AI vs 5years of Tam 9015 women in 1 large trial of exemestane (IES/BIG 02-97) & 3 smaller trials of anastrozole (German, Austrian & Italian)
2-3 years of tamoxifen then 2-3 years of AI with ~5 years of tamoxifen: Recurrence
2-3 years of tamoxifen then 2-3 years of AI vs. ~5 years of tamoxifen: Recurrence by year of follow-up
2-3 years of Tam then (2-3 years of AI vs. Tam): Recurrence by PgR status and age
2-3 years of Tam then (2-3 years of AI vs. Tam): Recurrence by nodal status and tumour grade
2-3 years of Tam then (2-3 years of AI vs. Tam): Site of recurrence
2-3 years of Tam then (2-3 years of AI vs. Tam): Death without recurrence
2-3 years of Tam then (2-3 years of AI vs. Tam): Breast cancer mortality
2-3 years of Tam then (2-3 years of AI vs. Tam): All cause mortality
2-3 years of Tam then (2-3 years of AI vs. Tam): Recurrence Breast cancer death
~5 years of AI vs. ~5 years of tamoxifen: Recurrence Breast cancer death
5 years of endocrine treatment in ER+ disease: recurrence rate ratios during the first 5 years Tamoxifen vs nil: RR ~0.5 AI vs tamoxifen: RR ~0.8 Hence, by multiplication, AI vs nil: RR ~0.4
Fractures in trials of aromatase inhibitors versus tamoxifen or no treatment