“Big Data, Better Treatment”: The work of the Early Breast Cancer Trialists’ Collaborative Group Rory Collins BHF Professor of Medicine & Epidemiology

“Big Data, Better Treatment”: The work of theEarly Breast Cancer Trialists’ Collaborative Group

Rory CollinsBHF Professor of Medicine

& Epidemiology

Nuffield Department of Population HealthUniversity of Oxford

Oxford, UK

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)?

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)

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

Probability of a 35-year-old dying of breast cancer aged 35-69

Risks halved, 1990-2015UK: 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

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

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 survival1995-98: Polychemotherapy benefits many different subgroups1995-98: Tamoxifen benefits by treatment duration in many subgroups

2000-05: Chemo & endocrine therapy additively affect 15-year survival2000-05: Radiotherapy after mastectomy in N+ affects 15-year survival2005-10: Aromatase inhibitor (AI) vs tamoxifen delays recurrence

Past 5 years: 2011-152011: 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 havechanged guidelines and worldwide practice

~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

Recurrence Breast cancer mortality

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






Past 5 years: 2011-152011: Radiotherapy after breast conservation improves 15-year survival 2011: 5y of tamoxifen improves 15-year survival in all ER+ subgroups2012: Chemotherapy improves survival in many types of ER+ disease


Chemotherapy (any anthracycline-based regimen) vs no adjuvant chemotherapy: benefit in ER- & ER+ disease

ER-Negative ER-Positive

Chemo-endocrine* vs same endocrine alone: ADDITIVE and similar benefits for younger and older women (ER+ disease)

ER+ age <55 ER+ age 55-69


*chemo=standard anthracycline-based regimen or CMF; endocrine is for 5 years

Modern chemotherapy vs older chemotherapy:moderate further benefit on recurrence and mortality

(anthracycline-based regimen ± a taxane)



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)





Past 5 years: 2011-152011: Radiotherapy after breast conservation improves 15-year survival 2011: 5y of tamoxifen improves 15-year survival in all ER+ subgroups2012: Chemotherapy improves survival in many types of ER+ disease2015: AI vs tamoxifen improves survival; bisphosphonates add benefit2015: Current smoking critically increases long-term RT side-effects

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)

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

More examples from the 2011-15EBCTCG Lancet publications

• Radiotherapy after surgery: 10,000 women

• Late side-effects of radiotherapy: 40,000 women


Effects of giving radiotherapy (RT) to a conserved breast: 10,000 randomised


More examples from the 2011-15EBCTCG 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

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 BursteinDana-Farber Cancer Institute

Lancet; July 2015

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)


EBCTCG, Lancet; online July 24, 2015

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

1985-2015: The EBCTCG meta-analyses have formed the basis for clinical practice guidelines worldwide:

This has been a major contributor to the almost halvingof 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

2011-2015: EBCTCG meta-analyses continueto 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

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 thatmay emerge during long-term follow-up

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

Probability of a 35-year-old dying of breast cancer aged 35-69

Risks halved, 1990-2015UK: 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

Documents

“Big Data, Better Treatment”: The work of the Early Breast Cancer Trialists’ Collaborative Group Rory Collins BHF Professor of Medicine & Epidemiology