1. THE CHANGING PATIENT PATHWAY IN BREAST CANCER: FROM GP TO CURE
MR TERENCE J. BOYLE
Consultant Breast Surgeon
BEACON HOSPITAL
Clinical Lead - Beacon Breast Centre
&
ST JAMES’S HOSPITAL
Clinical Lead - Breast Care Department

2. OUTLINE Presentation/initial work-up Subsequent investigation
Triple Assessment
Subsequent investigation
Staging: Breast, axilla, systemic
Characterising the disease
Tumour GRADE, Disease STAGE
Biomarker Profile
Treatment strategies
Surgery, systemic therapies, radiotherapy
Follow-up/ongoing care issues
Psychological support (NB: Specialist Nurses)
Physiotherapy, chronic pain, ‘reconstruction’ 2

3. RAPID DIAGNOSTIC BREAST CLINIC
(Beacon Breast Centre) - Rapid Access - TRIPLE ASSESSMENT
BREAST SYMPTOM
(other reason
for referral)
CLINICAL
ASSESSMENT
BREAST IMAGING Mammogram/ ultrasound
(+/- MRI)
HISTOPATHOLOGY
- Core Biopsy
- Fine Needle
Aspiration Cytology
Discussion at weekly Breast Care Multi-Disciplinary Team Meeting (MDM - Treatment Planning)
‘Results’ Clinic

4. GP Breast Referral Guideline Development Group Meeting 7: 25/03/2019

5. CLINICAL ASSESSMENT PHYSICAL EXAMINATION HISTORY
Details of breast symptomatology
Lump, nipple changes/discharge
skin changes, change in size/shape, duration
Past history of breast disease
Previous breast imaging
Family history of breast disease
Gynaecologic history
Factors increasing risk

6. RADIOLOGY

7. BREAST PATHOLOGY - INVASIVE DISEASE
HISTOLOGIC TYPE
DUCTAL vs LOBULAR
Paget’s disease of the nipple
Inflammatory breast cancer
TUMOUR CHARACTERISTICS
Tumour size
Tumour grade (I, II, III)
Hormone receptor status
(oestrogen / progesterone)
HER-2 protein status
Ki67 Proliferation Index
NB: Triple negative breast cancer
(ER neg, PR neg, HER-2 neg)
NB: Phyllodes tumour / cystosarcoma phyllodes

8. STAGING BREAST CANCER

9. Staging-TNM T0: subclinical T1: <2cm T2: >2cm, <5cm
T4: chest wall or skin involvement

10. Staging-TNM N0: no nodes N1: ipsilateral axillary mobile nodes
N2: ipsilateral axillary fixed nodes
N3: Ipsilateral internal mammary nodes
M0: no distant metastases
M1: distant metastases

11. MANAGEMENT OF BREAST CANCER
DIAGNOSIS
(Triple Assessment)
Characterisation of Breast Disease
Axillary assessment
Systemic staging investigations
Treatment Planning:
Surgery, Systemic therapy, Radiotherapy

12. MANAGEMENT OF BREAST CANCER
Characterisation of Breast Disease
Axillary assessment
ANATOMICAL CONSIDERATIONS:
Size of tumour,
extent of disease, remainder of breast
AXILLARY NODAL STATUS:
Pre-operative staging
Intra-operative staging
NEO-ADJUVANT SYSTEMIC THERAPY
Downstage breast/axillary disease
- Breast conservation vs mastectomy
Sentinel Lymph Node Biopsy vs Axillary Clearance
Downstage disease to reduce surgical complexity

13. The Sentinel Node

14. TUMOUR BIOLOGY Biological assessment of Disease Tumour Grade
Proliferation Index
Nodal Status
BIOMARKER PROFILE
- Oestrogen receptor
- Progesterone receptor
- HER-2 status
ONCOTYPE TEST
Recurrence Score
Endocrine Rx vs Chemotherapy
‘LETHAL’ BREAST CANCER:
Triple Negative Breast Cancer (ER/PR Neg, HER-2 Neg)
HER-2 Pos Breast Cancer (NB: anti-HER-2 therapies)
‘FAVOURABLE’ BREAST CANCER:
Hormone receptor positive, HER-2 Negative
Axillary node negative

15. SYSTEMIC STAGING OF BREAST CANCER SITES OF METASTATIC SPREAD
NODAL:
Ipsilateral / contralateral axilla
Neck: supraclavicular fossa / cervical chain
Internal mammary chain
Distant / systemic
SKELETAL: anywhere
VISCERAL:
Lungs, liver, brain

16. STAGING BREAST CANCER PRE-OPERATIVE SYSTEMIC STAGING INVESTIGATIONS
Baseline bloods:
(FBC, coag, CRP, L/R/B profile, glucose, CA 153)
CXR (early disease) or
CT Thorax/Abdomen/Pelvis
Isotope bone scan
Other investigations as indicated (PET-CT, MRI)

17. TREATMENT STRATEGIES FOR BREAST CANCER
SURGICAL THERAPY
Primary vs Delayed
CHEMOTHERAPY
Adjuvant (post-operative)
Neo-adjuvant (primary / pre-operative)
Palliative
HORMONAL THERAPY
Disease must be ER / PR positive
IMMUNOTHERAPY
Disease must overexpress HER-2
RADIOTHERAPY
NOVEL THERAPIES (Anti-angiogenics etc)

18. MANAGEMENT OF BREAST CANCER
TREATMENT STRATEGIES
LOCAL THERAPY
Surgery
- Breast
- Axilla
REGIONAL THERAPY
Breast, axilla
Chest wall
Supra-clavicular fossa
SYSTEMIC THERAPY
Endocrine Rx
Chemotherapy
Immunotherapy

19. Molecular profiling to determine if patient will benefit from Chemotherapy?
Gene assay performed on paraffin-embedded archival breast cancer tissue
Predicts risk of recurrence at 10yrs
Data generated from retrospective analysis of archival tissue
Gene set has been validated across multiple validation sets using prospectively defined end points (NSABP B14 & Kaiser Permanente)
Final gene set: relapse-free interval correlations across three independent studies: testing 250 genes in 447 patients

20. ONCOTYPE DX: Prognosis & Risk of Recurrence
16 Cancer and 5 Reference Genes From 3 Studies
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
ESTROGEN ER PR
Bcl2
SCUBE2
Category
RS (0 -100)
Low risk
RS <18
Intermediate risk RS
High risk
RS ≥ 31
GSTM1
BAG1
INVASION
Stromelysin 3
Cathepsin L2
The final gene set used for the Oncotype DX™ assay includes the 16 cancer genes identified in the clinical trials: 5 genes are in the proliferation group, 2 in the HER2 group, 4 in the estrogen receptor group, 2 in the invasion group, and 3 are unaligned. Some of the genes are well known in the breast cancer literature; others are relatively new.
The 5 reference genes are used for normalizing the expression of the cancer-related genes.
As was previously stated, it is important to note that there are other genes linked to breast cancer (eg, the 250 candidate genes from which the 16 genes were selected). The 16 genes presented in this slide were selected for the Oncotype DX™ assay based on the three clinical trials, which demonstrated a consistent statistical link between these genes and distant breast cancer recurrence and the most robust predictive power across the three studies.
The Recurrence Score is calculated from the expression results for each of the 16 cancer-related genes by the equation shown in this slide.
The Recurrence Score (RS) ranges from 0 to 100.
Although the coefficients for each gene or gene group influence the RS result, the quantitative expression for each gene can have a dominant effect. For example, there is a 200-fold range of expression of ER in the quantitative RT-PCR assay. For individual tumors, the expression of any one gene can affect the Recurrence Score to a large degree.
Cut-off points for Recurrence Score risk groups were defined prior to the initiation of the validation study:
A low-risk group with an RS of <18
An intermediate-risk group with an RS between 18 and 30
A high-risk group with an RS of 31
If the right number of genes to address these questions had been 6 or 60, we would have designed the assay accordingly. As it turned out, the assay was designed to include expression of 16 genes because the development studies indicated these genes provided the most robust predictive score.
CD68
RS =
x HER2 Group Score
x ER Group Score
x Proliferation Group Score
x Invasion Group Score
x CD68
x GSTM1
x BAG1
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
HER2
GRB7
Paik et al. N Engl J Med. 2004;351:

21. ONCOTYPE DX: Recurrence Score

22. POPULATION-BASED RISK FOR BREAST CANCER

23. Modifiable Risk Factors

24. Familial Breast Cancer Risk Assessment Guidelines
LOW RISK
MEDIUM RISK
HIGH RISK
HIGH RISK
SIGNIFICANT FACTORS
• ONE 1st degree relative with breast cancer > 40 years
• ONE 2nd degree relative at any age
• ONE 1st degree relative with breast cancer < 40 years
• TWO 1st or 2nd degree relatives with breast cancer at an average age of > 50 years
• THREE 1st or 2nd degree relatives with breast cancer at an average age of > 60 years
• ONE 1st degree relative with breast cancer < 40 years
• TWO 1st or 2nd degree relatives with breast cancer at an average age of > 50 years
• THREE 1st or 2nd degree relatives with breast cancer at an average age of > 60 years
• TWO 1st or 2nd degree relatives with breast cancer < 50 years( one must be 1st degree relative)
• THREE 1st or 2nd degree relatives with breast cancer < 60 years (one must be 1st degree relative)
• FOUR Relatives with breast cancer at any age (one must be a 1st degree relative )
Ovarian Cancer
• ONE relative with ovarian cancer at any age PLUS on the same side of the family there is:
• ONE 1st or 2nd degree relative with breast cancer before age 50
• ONE additional relative with ovarian cancer at any age
• TWO 1st or 2nd degree relatives with breast cancer at average age of < 60
Bilateral Breast Cancer
• ONE 1st degree relative with cancer in both breasts before average age of 50
• ONE 1st or 2nd degree relative
Male Breast Cancer
ONE male breast cancer at any age PLUS ON SAME SIDE OF FAMILY:
• ONE 1st or 2nd degree relative with breast cancer before 50
• TWO 1st or 2nd degree relatives with breast cancer before average age of 60
*Bilateral breast cancer
*Male breast cancer
*Ovarian cancer
*Jewish ancestry
*Sarcoma in a relative<45
*Glioma or childhood adrenal cortical carcinomas
*Complicated patterns of multiple cancers at a young age
Lifetime risk of breast cancer is less than 17%
A less than 3% risk of developing breast cancer in the next 10 years for women aged 40-49
Lifetime risk of breast cancer is 17% or greater but less than 30%
A 3-8% risk of developing breast cancer in the next 10 years for women aged 40-49
IMAGING REQUIRED
• No imaging required
• Follow up in primary care
IMAGING REQUIRED
IMAGING REQUIRED
• Annual mammography for women aged between years (imaging to commence at age of 5-10 years younger than youngest affected relative)
• Women aged between ages years, mammography to take place in National Breast Screening Programme.
High Risk
• Annual mammography for women aged >40 years (imaging to commence at age 5-10 years younger than youngest affected relative)
+/-
• Annual MRI breast for women aged between for following criteria:
*TP53, BRCA1 & BRCA2 mutation carriers (or with equivalent high risk) •
Lifetime risk of breast cancer is 30% or greater
Risk of faulty BRCA1, BRCA2 or TP53 gene is 20% or greater
A greater than 8% risk of developing breast cancer for women aged 40-49

25. MULTIDISCIPLINARY MANAGEMENT OF WOMEN AT HIGH RISK FOR BREAST CANCER
BREAST CANCER GENETICS
BREAST CANCER
SURVEILLANCE
PROPHYLAXIS
-Genetics Nurse Specialists (Breast)
-Clinical Geneticist
Breast Surgeon
-Medical Oncologist
-Breast Surgeon
-Plastic Surgeon
-Gynaecologist
-Assessment
-Counselling
-Testing
-Clinical review
-Radiological assessment
-Prophylactic mastectomy
-Oophorectomy

26. Thank you!