Medicine for Members

Breast Cancer Research12/10/2016

Sue Hartup

Breast Care Research Sister

St James’s University Hospital

Breast Cancer Trials

• Background

• Where were we?

• Where are we?

• Where are we going?

A few facts

• Breast Cancer is the most common cancer in

women with 45,000 new cases diagnosed every

year in the UK

• 80% of breast cancers are diagnosed in women

aged 50 and over

• Disease free survival has increased significantly

with 85% of women now surviving the disease

compared to 50% in the 1970s

• Most cancers are treated with a combination of

surgery, radiotherapy, chemotherapy, biological

therapies and endocrine (hormone) treatments

Breast Cancer Timeline

• Ancient Egyptians were the first to

document the incidence of breast cancer

• 1757 Henri Le Dran, suggested that the

surgical removal of the tumour could help

treat breast cancer, as long as the lymph

nodes in the armpit were also removed.

• Radical surgery was developed by William

Halsted in the19th-century involving

removing the breast and also the underarm

lymph nodes and the chest wall muscles

Historical developments

1895 - Scottish surgeon George Beatson

discovered that removing the ovaries shrank

the breast tumour of his patient

1896 – radiation therapy invented

1930s – introduction of radiotherapy

1948 – Paley introduced modified radical

mastectomy

1955 - George Crile suggested that cancer

could spread throughout the body. Bernard

Fisher also suggested the capability of breast

cancer to spread (metastasise)

1950s – Chemotherapy introduced

1967 – Jenson discovered oestrogen

receptors

1972 - First randomised trial of breast

conservation with radiotherapy v mastectomy

1972 – Tamoxifen approved in UK

1970s – development of breast reconstruction

1980s – Development of Third Generation

Aromatase Inhibitors (Anastrozole, Letrozole,

Exemestane)

Bernard Fisher“clinical trials are a major step

toward transforming medicine

from an art to a science”

• 1971 - National Surgical Adjuvant Breast and

Bowel Project (NSABP)

• 1976 - Published results of a trial of breast-

conserving surgery followed by radiation or

chemotherapy

• 1991- breast cancer prevention trial: testing

tamoxifen in preventing breast cancer in

high-risk women.

Michael Baum

• First to demonstrate the effectiveness of

tamoxifen for early breast cancer, (30 per

cent reduction in mortality)

• Proved Tamoxifen effective in the prevention

of breast cancer in susceptible women

• Responsible for the largest-ever international

cancer trial (ATAC - Arimidex, Tamoxifen,

Alone or in Combination. This proved that

Anastrozole was better than Tamoxifen

Major changes

• Surgery: Breast Conservation, Sentinel

Node Biopsy, Reconstruction

• Endocrine Treatment: Tamoxifen,

Aromatese Inhibitors

• Radiotherapy: length of treatment, partial

breast RT, intra-operative RT

• Chemotherapy: types & duration of

• Biological therapies: Herceptin

• Targeted therapies

Changes to surgery

• Milan trial, NSABP B-06 trial, and EORTC

10801 trial were pioneering trials in breast

conservation surgery

• Breast conserving surgery was compared to

total mastectomy in early breast cancer.

Whole breast radiotherapy was given in

lumpectomy

• Almanac – proved that Sentinel Lymph Node

Biopsy is safe and with less side effects than

Axillary Node Clearance

Breast Reconstruction

1895 – First attempted breast reconstruction

1906 – First Pedicled flap

1942 – First reconstruction using abdominal flap

1963 – First implant reconstructions

1977 – First autologous latimus dorsi (LD)

reconstruction

1982 – First use of skin expanders

1979 - The transverse rectus abdominis

myocutaneous flap (TRAM) by Holmstrom

Endocrine Treatment

Tamoxifen

NASBP B-14: Showed a significant survival

benefit from taking Tamoxifen in ER+ early

breast cancer v placebo

First Oxford EBCTCG meta-analysis involved

almost 30,000 women in 28 trials showed a

clear reduction in mortality in women at least

50 years of age treated with tamoxifen

Trials showed a greater mortality reduction

with 5 versus 2 years of tamoxifen

Endocrine treatment – the

next generation

Aromatase Inhibitors

An alternative strategy to deprive breast

tumours of oestrogen in post-menopausal

women.

• ATAC study

Some studies have shown that switching to an

aromatase inhibitor after 2 years of tamoxifen

improves outcome

• BIG 1-98: sequencing of endocrine therapy

Extended Endocrine therapy

Endocrine therapy reduces the risk of recurrence

and death from breast cancer in women with

hormone receptor-positive early breast cancer.

Traditionally, treatment has been given for 5

years, but many women remain at risk of relapse

for 10 years or more. AIs, and more recently

tamoxifen, have been shown to reduce further

the risk of late recurrence if given for a further 5

years.

• MA17 trial: 5 years of tamoxifen followed by 5

years of Letrozole

Radiotherapy (RT)

The international standard radiotherapy

schedule for early breast cancer was 50 Gy in

25 fractions (fr) of 2·0 Gy over 5 weeks.

Researchers developed hypofractionation

(using lower total dose using fewer, larger

fractions.

• START trial: showed that 40 Gy in 15 fr

provides the same level of cancer control as

of 50 Gy in 25 fractions

This is now the standard RT regime

Improving radiotherapy

• Surgeons now put clips in the tumour bed

to help identify the area on planning CT

• IMPORT Low - standard 15 fr/3 weeks v

partial breast radiotherapy in low risk early

breast cancers

• FAST Forward – 1-week course of whole

breast RT v standard 3-week course

• IMPORT High – dose escalated intensity

modulated radiotherapy (IMRT) for breast

conservation surgery requiring a boost

Cancer cells grow by dividing in a disorderly

and uncontrolled way. Chemotherapy targets

fast growing cells. Drugs started to be

developed following WWII

1957 – introduction of 5 fluorouracil chemo

1970s – CMF developed

(cyclophosphamide+methotrexate+5-

fluorouracil)

1990s - Anthracyclines chemotherapy:

doxorubicin+cyclophosphamide (AC)

FEC (5FU+epirubicin+cyclophosphamide)

Development of chemotherapy

Tailoring of regimes

Block-sequential trials of chemotherapy helped

identify the best regimes

1970s – Taxanes developed. First used in

adjuvant treatments in early 2000s

• (BCIRG)-001 trial, in which the 5-fluorouracil

component of FAC was replaced by

docetaxel

Chemotherapy regimes are tailored depending

on tumour type and in the neoadjuvant setting

by response (monitored with MRIs)

A treatment revolution

1979 – HER2 gene identified

1987 - Slamon and Ullrich suggest that

cancers overexpressing HER-2 are more

likely to recur and spread more quickly

1989 – Herceptin developed

1995 – Pivotel trials of Herceptin in

metastatic breast cancer

2000 – Trials of Herceptin in adjuvant

setting (HERA 2001)

NHS Breast Screening

Programme

• Evidence on the effectiveness of screening

for breast cancer came from trials in the USA

(HIP trial), Sweden (two counties study) and

the Netherlands (Nijmegen), and two trials in

the UK (UKTEDBC and Edinburgh trials).

• The NHS Breast Screening Programme was

established in March 1987 and began

inviting women in 1988

• 3 yearly mammograms from the age of 50

(reducing to 47) to 70 (increasing to 73)

The NCRI and NIHR/NCRN

The National Cancer Research Initiative is a

UK-wide partnership between government,

charity and industry which promotes co-

operation in cancer research

The National Cancer Research Network is part

of the National Institute for Health Research

Its aim is to improve the coordination,

integration, quality and speed of delivery of

cancer research for the benefit of everyone

involved.

The NCRI spend has risen to over £500 million

There are 23 NCRI Clinical Studies Groups

(CSGs) who develop new clinical studies and

oversee on-going studies in their areas of

responsibility.

• Prior to introduction of the NCRN, less than 4

per 100 cancer patients entered clinical trials

Elements to successful

research

Development of new trials

Engaging all staff in

research

Offering opportunities

for all patients

Delivering projects on time and

target

NCRI Breast Clinical studies Group

Excellent local

Surgical and Oncological

skills

Family History

• FH01 – annual mammograms in Family History patients from age 40

(FH02 is on-going and will show if starting mammograms at age 35 is better than 40)

• IBIS I/TamiPlac – Studies that proved that Tamoxifen could be used to reduce the incidence of cancer in those at increased risk

UK guidelines now recommend Tamoxifen for prevention in family history patients of at least medium risk.

• IBIS II (ongoing) – Testing AIs for risk reduction in those at increased risk

• COMICE – Can pre-op MRI’s reduce re-

excision rates in breast conservation?

The study found that additional imaging with

MRI pre-operatively did not reduce the

number of re-excisions.

However….it did show that the use of MRI in

lobular cancers is helpful in identifying multi-

focal masses

Do trials always prove their

primary aim?

NO!!!

Patient follow up and

quality of life

• The Government's Cancer Reform Strategy

(2009) recommends that patients be

supported in self-management and have

personalised follow-up to meet their needs

Treat everyone as an individual

How do we affect quality of life with the

treatments we use?

Challenging traditional follow up methods

Direct Leeds involvement in

developing recent trials

Mammo-50 - annual mammography versus

less frequent in patients aged >50 at diagnosis

and are 3 years post-diagnosis (Sue Hartup)

CHERNAC – characterising early response to

neoadjuvant chemotherapy with MRI (Prof

David Buckley, UoL)

MicroNACT – Can contrast enhanced

ultrasound of the axilla detect response to

neoadjuvant chemotherapy, avoiding extensive

axillary surgery? (Dr Nisha Sharma)

Beacon – new metastatic drug development

(Prof Chris Twelves)

eRAPID/ePOCS – The development of

internet based follow up programmes and

patient self-reporting of side effects in early

breast cancer and chemotherapy treatment

(Prof Galina Velikova)

FLIC – Fatigue in chemotherapy – is it a

similar process to fatigue in chronic fatigue

symdrome?

Lab based research - Tamoxifen resistance,

male breast cancer, identifying new targets

(Prof Val Spiers, Prof Andy Hanby)

The need for more evidence

• LORIS - Can patients with newly

diagnosed low-risk DCIS safely avoid

surgery

• Bridging the Age Gap: Improving

Outcomes for Older Women. For over

70yrs, Quality of Life, decision tools

• POSNOC- POsitive Sentinel NOde:

adjuvant therapy alone versus adjuvant

therapy plus axilla clearance or axillary

radiotherapy

Does everyone discuss trials?

Why talk about trials?

• Important to explain that we are a research

active hospital and that this is how we gain

evidence to make improvements in the care

we offer.

• We should:

- mention the trial by name

- explain trials are safe & voluntary

- Managing expectation – be honest!!

If we had all the answers, research would not

be necessary

• “The Leeds Teaching Hospitals

NHS Trust is characterised by

the pursuit of excellence in

healthcare. Our ambition is to

be a global leader in clinical

research and innovation which

is translated into patient benefit

at pace and scale. Research

and innovation is central to our

ambition to develop our

specialist services and ensure

we secure our future as a

leading clinical research centre

in the UK.”

LTHT R&I Vision Statement(2015-2020 Strategy)

LTHT R&I Mission Statement (2015-2020 Strategy)

What trials do we currently do?

• Wide variety & multi-disciplinary

approach to trials and include: pre-

surgical, diagnostic, peri-operative,

endocrine, radiotherapy, Quality of

Life, chemotherapy, family history, risk

reduction, imaging, and metastatic

trials

Sept16 trials`

BREAST TRIALS OPEN - non metastatic

NEO ADJUVANT - OPEN

Bridging the Age Gap

Age 70 & over EBC.

2 years FU Patient or carer

consent. questionnaires

OPENING SOON

CHERNAC

NACT with fixed EC X3 & Doc X3. MRIs to assess

early response to NACT

MarginProbe

Due to open Feb but having problems with meetings, contracts &

paperwork etc

PALLET Phase II palbociclib with Letrozole as

neoadjuvant in ER +ve EBC

14 weeks pre-surgery

STAKT

ER+VE scheduled for chemo±surgery

4.5 days of AKT inhibitor + biopsies

prior to chemo/surgery

POSNOC

EBC with 1-2 positive SLNB. Randomised to standard therapy alone or additional

axilla treatment (RT or ANC)

LORIS

Surgery V active

monitoring for low risk DCIS

OLYMPIA

Assessing efficacy & safety of olaparib V

placebo in patients with germaline BRAC1/2

mutations and high risk HER2 neg BC

Mammo-50

Annual mammos V less frequent

mammos in over 50s

Add Aspirin

High risk EBC. Assessing the effects of aspirin on disease recurrence and survival

microNACT

NACT patients with +ve axilla at diagnosis. SLNB microbubbles pre & post post NACT to assess residual nodal malignancy

FAST Forward Nodal sub study

(Adj) The lymphatic RT

sub-study

ADJUVANT - OPEN

eRAPID

electronic self-reporting of AEs

Feasibility stage/potential new studies - ADJUVANT

TIP trial

Thrombin Inhibition Preoperatively in Early Breast Cancer - a window study

BR23 update

Update of EORTC BR23 breast QoL

questionnaire.

Sept 16

BREAST TRIALS OPEN - metastatic

METASTATIC/LOCALLY ADVANCED

KEYNOTE 119

Metastatic, TNBC, 1st line

BIOMARIN

BMN 673 V Physicians choice in germline BRCA mutation pts with locally advanced or metastatic BC who have received no more than 2 prior chemo regimes for

metastatic

FAKTION Phase 1b/2 randomised

placebo trial of Fulvestrant +/-

AZD5363 in post-menopausal; women

with advanced BC previously treated with

a 3rd generation AI

PAKT

Placebo controlled study of AKT inhibitor

AZD5363 in combination with

Paclitaxel in metastatic TNBC

ASTELLAS

To assess the

efficacy & safety of Enzalutamide with

Trastuzumab in HER2+, AR+

Metastatic or locally advanced BC

Recently closed studies

BOUDICA

Post-menopausal with ER+ locally

advanced/metastatic BC treated with Everolimus in

combination with exemestane after

progression following therapy with a non-

steroidal AI

Where are we going?

Latest developments:

- Personalised medicine: Oncotype DX

- Imaging studies

- Quality of Life

- Self management

- Targeted therapies e.g. AKT inhibitors

Oncotype Dx

The Oncotype DX test is a molecular diagnostic

test that analyses the individual biology of a

breast cancer tumour by examining the activity

of 21 genes in the tumour tissue.

The results of the analysis gives a Recurrence

Score result. This score helps the oncologists

and patient decide if chemotherapy is needed.

2015: TAILORx trial (of more than 10,000

women): 99% of women with low Oncotype

DX® Recurrence Score® results are free of

breast cancer recurrence after five years of

hormone therapy alone.

RxPONDER Trial (ongoing): will answer if

chemotherapy benefits patients with node

positive breast cancer who have low to

intermediate Oncotype DX score

Development of Oncotype Dx

Imaging studies

• Better identification of cancers

• Tailoring treatments

• Monitoring treatments

• Reducing need for extensive surgery

• For use in targeted therapies (e.g.

drugs delivered direct to a cancer

using USS guidance

Quality of Life

With a much improved survival rate, quality of

life is more important than ever.

• EORTC QoL group – developing

questionnaires for use in specific cancers

• Better monitoring of side effects

• Encouraging self-management

• Use of remote monitoring

• Ensuring new treatments do not unduly affect

quality of life

On-going trials

• Two randomised trials - Suppression of

Ovarian Function Trial (SOFT) and Tamoxifen

and Exemestane Trial (TEXT) - are evaluating

the addition of Ovarian Suppression to

tamoxifen and also the role of AIs in pre-

menopausal women with ER+ early BC.

AKT and mTOR inhibitors

Mutations in the PI3K pathway are frequent in

breast cancer occurring in up to one quarter of

breast cancers. Some proteins which help control

cell growth start to behave abnormally. One such

protein is called AKT.