1. “Big Data, Better Treatment”: The work of the Early Breast Cancer Trialists’ Collaborative Group Rory Collins BHF Professor of Medicine & Epidemiology Nuffield Department of Population Health University of Oxford Oxford, UK

2. AIM: To assess the effects of various treatments for early breast cancer on LONG-TERM survival more reliably than can be done by any individual randomised controlled trial METHOD: Collaboration between hundreds of trial groups sharing individual patient data for “meta-analyses”, often involving 10-20,000 randomized women in each question BENEFITS: Really reliable identification of treatments that can each MODERATELY improve breast cancer survival and, in combination, improve survival SUBSTANTIALLY What is the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)?

3. Requirements for the RELIABLE assessment of plausibly MODERATE treatment effects SYSTEMATIC ERRORS (i.e. biases) and RANDOM ERRORS (i.e. play of chance) must BOTH be small compared with the difference between any MODERATE effects and NO effect This is achieved with large-scale evidence based on meta-analyses of randomised controlled trials (but not with non-randomised database studies)

4. Several MODERATE treatment effects have almost HALVED breast cancer mortality at ages 35-69 since 1990 EBCTCG helped reduce national breast cancer mortality rates by demonstrating the moderate effects on long-term survival of endocrine therapy (if ER+), chemotherapy, and radiotherapy

5. Probability of a 35-year-old dying of breast cancer aged 35-69 Risks halved, 1990-2015 UK: 2.4% down to 1.2% US: 1.9% down to 1.1% (& risks are still falling) UK & USA: Breast cancer mortality 1950-2015 at ages 35-69

6. Several MODERATE treatment effects have almost HALVED breast cancer mortality at ages 35-69 since 1990 EBCTCG helped reduce national breast cancer mortality rates by demonstrating the moderate effects on long-term survival of endocrine therapy (if ER+), chemotherapy, and radiotherapy It has also fostered respect for the value of conducting much larger randomised trials than was customary and of combining their results in systematic meta-analyses of all related trials Demonstrating the need for “Big (randomised) Data” to assess the effects of treatment properly

7. Selected EBCTCG NEJM/Lancet reports History: 1985-2010 1985-88: Chemo & endocrine therapy additively affect 5-year survival 1990-92: Chemo & endocrine therapy additively affect 10-year survival 1995-98: Polychemotherapy benefits many different subgroups 1995-98: Tamoxifen benefits by treatment duration in many subgroups 2000-05: Chemo & endocrine therapy additively affect 15-year survival 2000-05: Radiotherapy after mastectomy in N+ affects 15-year survival 2005-10: Aromatase inhibitor (AI) vs tamoxifen delays recurrence Past 5 years: 2011-15 2011: Radiotherapy after breast conservation improves 15-year survival 2011: 5y of tamoxifen improves 15-year survival in all ER+ subgroups 15,000 citations: EBCTCG findings have changed guidelines and worldwide practice

8. ~5 years of tamoxifen vs no tamoxifen in ER+ disease: value of long-term follow-up, particularly for mortality (Highly significant mortality gains in years 0-4, then in 5-9, then in 10-14) EBCTCG, Lancet 2011; 378: 771 RecurrenceBreast cancer mortality

9. RARE EXAMPLE of a real difference in efficacy in different patients: ER status is predictive of response to tamoxifen ER negative ER POSITIVE ER positive EBCTCG, Lancet 2011; 378: 771

10. Selected EBCTCG NEJM/Lancet reports History: 1985-2010 1985-88: Chemo & endocrine therapy additively affect 5-year survival 1990-92: Chemo & endocrine therapy additively affect 10-year survival 1995-98: Polychemotherapy benefits many different subgroups 1995-98: Tamoxifen benefits by treatment duration in many subgroups 2000-05: Chemo & endocrine therapy additively affect 15-year survival 2000-05: Radiotherapy after mastectomy in N+ affects 15-year survival 2005-10: Aromatase inhibitor (AI) vs tamoxifen delays recurrence Past 5 years: 2011-15 2011: Radiotherapy after breast conservation improves 15-year survival 2011: 5y of tamoxifen improves 15-year survival in all ER+ subgroups 2012: Chemotherapy improves survival in many types of ER+ disease

11. EBCTCG, Lancet 2012; 379: 432 Chemotherapy (any anthracycline-based regimen) vs no adjuvant chemotherapy: benefit in ER- & ER+ disease ER-Negative ER-Positive

12. Chemo-endocrine* vs same endocrine alone: ADDITIVE and similar benefits for younger and older women (ER+ disease) ER+ age <55 ER+ age 55-69 EBCTCG, Lancet 2012; 379: 432 *chemo=standard anthracycline-based regimen or CMF; endocrine is for 5 years

13. Modern chemotherapy vs older chemotherapy: moderate further benefit on recurrence and mortality (anthracycline-based regimen ± a taxane) EBCTCG, Lancet 2012; 379: 432 RecurrenceBreast cancer mortality

14. 10-year effects of modern chemotherapy Proportional reduction of about 1/3 in breast cancer mortality, even in postmenopausal women with endocrine-treated ER+ disease (which is contrary to strongly-held previous beliefs)

15. Selected EBCTCG NEJM/Lancet reports History: 1985-2010 1985-88: Chemo & endocrine therapy additively affect 5-year survival 1990-92: Chemo & endocrine therapy additively affect 10-year survival 1995-98: Polychemotherapy benefits many different subgroups 1995-98: Tamoxifen benefits by treatment duration in many subgroups 2000-05: Chemo & endocrine therapy additively affect 15-year survival 2000-05: Radiotherapy after mastectomy in N+ affects 15-year survival 2005-10: Aromatase inhibitor (AI) vs tamoxifen delays recurrence Past 5 years: 2011-15 2011: Radiotherapy after breast conservation improves 15-year survival 2011: 5y of tamoxifen improves 15-year survival in all ER+ subgroups 2012: Chemotherapy improves survival in many types of ER+ disease 2015: AI vs tamoxifen improves survival; bisphosphonates add benefit 2015: Current smoking critically increases long-term RT side-effects

16. Side-effects of modern radiotherapy regimens in today’s patients, according to smoking habits Lancet, submitted Oct 2015 (confidential until published) Lung cancer mortality Cardiac mortality (if the excess risk is half (if mean heart dose is 2 Gy; that in the old trials) 1/3 that in old trials)

17. Having ALL the main trials in the EBCTCG meta-analyses increases the numbers of outcomes (so is more precise), and avoids undue emphasis on positive studies (so no bias) Meta-analyses involving “big data” help distinguish between “true negatives” (e.g. endocrine therapy in ER- disease) and “false negatives” (e.g. chemotherapy in ER+ disease) Finding many MODERATE (but then additive) treatment effects on LONG-TERM survival

18. More examples from the 2011-15 EBCTCG Lancet publications Radiotherapy after surgery: 10,000 women Late side-effects of radiotherapy: 40,000 women

19. EBCTCG, Lancet 2011; 378: 1707 Effects of giving radiotherapy (RT) to a conserved breast: 10,000 randomised Recurrence Breast cancer mortality

20. More examples from the 2011-15 EBCTCG Lancet publications Radiotherapy after surgery: 10,000 women Late side-effects of radiotherapy: 40,000 women Chemotherapy: 10,000 women per question Endocrine therapy: 10,000 women per question Bisphosphonates: 10,000 women per question

21. Editorial: Postmenopausal breast cancer – a best endocrine strategy? “……For decades, the Early Breast Cancer Trialists’ Collaborative Group meta-analyses have informed clinical practice in early stage breast cancer, and the present report in The Lancet on over 30,000 women treated with adjuvant tamoxifen, aromatase inhibitors, or a sequence of those agents continues that tradition.” Erica Mayer & Harold Burstein Dana-Farber Cancer Institute Lancet; July 2015

22. 5 years of aromatase inhibitor (AI) vs 5 years tamoxifen in ER+ early breast cancer trials: Effects on 10-year outcome (AIs are for postmenopausal only; & side-effects include ~50% increase in fracture rates) Recurrence Breast cancer mortality EBCTCG, Lancet; online July 24, 2015

23. 2-5 years of a bisphosphonate vs none: Effects on 10-year breast cancer mortality in post-menopausal subgroup only (for whom bisphosphonate can protect those at risk of AI-induced bone fracture) EBCTCG, Lancet; online July 24, 2015

24. 1985-2015: The EBCTCG meta-analyses have formed the basis for clinical practice guidelines worldwide: This has been a major contributor to the almost halving of national death rates in many countries over this period EBCTCG meta-analyses have also resulted in a better understanding of who does and does not derive worthwhile benefit from breast cancer treatment: This has been especially important for ER+ disease (which is 75-80% of US/UK breast cancer), showing the long-term gains from the combination of endocrine and chemotherapy

25. 2011-2015: EBCTCG meta-analyses continue to resolve major clinical uncertainties For example: Bisphosphonates improve breast cancer survival, although they are not currently recommended Starting with AI is better than starting with tamoxifen, whereas either option is currently recommended Radiotherapy after mastectomy improves survival for women with 1-3 positive lymph nodes, although it is not currently recommended

26. 2015 onwards: EBCTCG’s large-scale randomized evidence will help identify extra MODERATE benefits 10 vs 5 years of tamoxifen Aromatase inhibitor use beyond year 5 Dose-dense chemotherapy Sequencing of taxanes Herceptin (trastuzumab) vs not Duration of herceptin treatment Avastin (bevacizumab) vs not Radiotherapy to internal mammary nodes Mammographic screening as well as help identify any side-effects that may emerge during long-term follow-up

27. 2015 onwards: EBCTCG’s large-scale randomized evidence will help investigate who does and does not derive worthwhile benefit from different treatments Studies of prognostic factors to identify low risk of recurrence (and, hence, small potential benefit from adjuvant treatment) Studies of tumour and patient characteristics that may predict response to particular treatments, hence avoiding ineffective treatment: ◦ Chemotherapy efficacy by tumour genotype ◦ Chemotherapy efficacy in older women ◦ Herceptin efficacy by HER-2 level ◦ Influence of other molecular markers

28. Probability of a 35-year-old dying of breast cancer aged 35-69 Risks halved, 1990-2015 UK: 2.4% down to 1.2% US: 1.9% down to 1.1% (& risks are still falling) UK & USA: Breast cancer mortality 1950-2015 at ages 35-69