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Breast Cancer Treatment Protocol

Multi-disciplinary team members

Breast Clinic Coordinator: Sr Galiema Fish

Oncology: Dr David Anderson

Dr Tselane Thebe

Breast Surgery: Dr Lydia Cairncross

Dr Francois Malherbe

Prof Eugenio Panieri

Radiology: Dr Rufka Gameldien

Pathology: Dr Louis de Jager

Dr Marco Otto

Plastic Surgery: Prof Don Hudson

Genetic councilor: Nakita Laing

Dr Karen Fieggen

Social worker:

11/13/2017

UNIVERSITY OF

CAPE TOWN AND

GROOTE SCHUUR

HOSPITAL

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Breast Cancer Protocol

Index

1. Management of high risk patients

a) Genetics Testing of Unaffected individuals 1

b) Risk Reducing Surgery 1

c) Chemoprophylaxis 1

2. AJCC Staging of Breast Malignancies and Molecular profiling

a) TNM staging 2

b) AJCC staging 4

c) Molecular profiling 4

3. Management of DCIS and LCIS

a) Diagnosis of DCIS 5

b) Grading of DCIS 5

c) Surgery in DCIS 6

d) The USC / Van Nuys Prognostic Index scoring system 6

e) Margin status in DCIS 6

f) Radiotherapy for DCIS 7

g) Hormonal Therapy for DCIS 7

h) Lobular carcinoma in situ 8

4. Histological Diagnosis of Invasive Breast Carcinoma

a) Tissue diagnosis 8

5. Loco regional investigations

a) Breast 9

b) Axilla 9

6. Metastatic screening for Breast Carcinoma 10

7. Breast MDT process

a) Diagnosis and first treatment decision 10

b) Genetics referral affected individuals 10

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c) Psychology/Psychiatry referrals 10

d) Social work referral 11

8. Surgery

a) BCT 12

b) Mastectomy 13

c) Axillary surgery 13

d) Contralateral risk reducing surgery 16

e) Reconstruction 16

f) Contralateral breast reduction / Mastectomy for symmetry 17

g) Surgery for recurrence 17

9. Chemotherapy

a) Neoadjuvant Chemotherapy 17

b) Adjuvant chemotherapy 18

c) Chemotherapy in pregnant patients 19

10. Radiotherapy

a) Radical 19

b) Recurrence 22

11. Endocrine therapy 22

12. Targeted biological therapy 23

13. Treatment of Palliative / Metastatic Disease

a) General principles 23

b) Prognostic factors 22

c) Palliative Endocrine 22

d) Palliative Chemo 24

e) Palliative Targeted Therapy 24

f) Palliative RT 25

g) Palliative Surgery 25

14. Follow up 26

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1. Management of high risk patients (Patients without a cancer diagnosis)

a) Genetics Testing of Unaffected Individuals

All patients with a family history of breast or ovarian cancer affecting mother, sister,

daughter, aunt, grandparents, nephews, nieces and half siblings should have and IBIS

Risk Evaluation done. (http://ibis.ikonopedia.com/ or download file to install on desktop at

http://www.ems-trials.org/riskevaluator/)

The following patients should be referred for genetic counselling and testing:

- IBIS lifetime risk estimated >30%

- BRCA mutation risk estimated >10%

b) Risk Reducing Surgery

Bilateral risk reducing mastectomy is indicated in the following patients:

- Known genetic mutation in BRCA1/2 or P53 - Women under 50 with a high lifetime risk of >30% - Women under 50 with a >20% of a BRCA mutation - Biopsy proven high risk pathology: LCIS/Atypical Ductal

Hyperplasia/Papillomatosis

Risk reducing surgery should be offered with an individualised approach taking into

consideration the personal risk, comorbidities, psychological situation and wishes of the

patient. Extensive counselling should take place and should include senior members of

the surgical and oncology team.

Risk reducing surgery should be a bilateral mastectomy preferably with the option of

reconstruction either immediate or delayed. Skin sparing and nipple sparing

mastectomies should be considered and offered in this setting if clinically appropriate.

Lymph node surgery is not indicated in the risk reducing setting. .

c) Chemoprophylaxis

IBIS-1 study - Tamoxifen for 5y decreased breast cancer incidence (incl DCIS) from 6.3% to

4.6% at 10y

- NNT = 59

- At 20y: breast cancer incidence was reduced from 12% to 7.8%

- NNT = 22

- Not significant increase in endometrial cancer

- No OS benefit

IBISII study

- Anastrozole for 5y decreased breast cancer incidence from 5.6% to 3.3& at 7y

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- Small increase in fractures (8.5% vs 7%)

- Increase in musculo-skeletal side effects

At Groote Schuur Hospital

- Well informed woman, who are assessed as being high risk, may be offered 5y of

tamoxifen to reduce the incidence of invasive breast cancer and DCIS.

2. AJCC Staging of Breast Malignancies

a) American Joint Committee on Cancer Definition of Primary Tumor (T)—Clinical (cT)

and Pathological (pT)

Primary tumour (T) Regional lymph nodes (N) Distant metastasis (M)

TX: Primary tumor cannot be assessed

T0: No evidence of primary tumor

Tis (DCIS): Ductal carcinoma in situ (DCIS)

Tis (Paget): Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted.

T1: Tumor ≤ 20 mm in greatest dimension

T1mi: Tumor ≤ 1 mm in greatest dimension

T1a: Tumor > 1 mm but ≤ 5 mm in greatest dimension (round any measurement from >1.0-1.9 mm to 2 mm)

T1b: Tumor > 5 mm but ≤ 10 mm in greatest dimension

T1c: Tumor > 10 mm but ≤ 20 mm in greatest dimension

T2: Tumor > 20 mm but ≤ 50 mm in greatest dimension

T3: Tumor > 50 mm in greatest dimension

T4: Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or macroscopic nodules); invasion of the dermis alone does not qualify as T4

T4a: Extension to the chest wall; invasion or adherence to pectoralis muscle in the absence of invasion of chest wall structures does not qualify as T4

T4b: Ulceration and/or ipsilateral macroscopic satellite nodules and/or edema (including peau d’orange) of the skin that does not meet the criteria for inflammatory carcinoma

cNX: Regional lymph nodes cannot be assessed (eg, previously removed)

cN0: No regional lymph node metastases (by imaging or clinical examination)

cN1: Metastases to movable ipsilateral level I and II axillary lymph node(s)

cN1mic: Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)

cN2: Metastases in ipsilateral level I and II axillary lymph nodes that are clinically fixed or matted; or in ipsilateral internal mammary lymph nodes in the absence of axillary lymph node metastases

cN2a: Metastases in ipsilateral level I and II axillary lymph nodes fixed to one another (matted) or to other structures

cN2b: Metastases only in ipsilateral internal mammary lymph nodes in the absence of axillary lymph node metastases

cN3: Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I and II axillary lymph node involvement; or in ipsilateral internal mammary lymph node(s) with level I and II axillary lymph node metastases; or metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement

cN3a: Metastases in ipsilateral infraclavicular lymph node(s)

cN3b: Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)

cN3c: Metastases in ipsilateral supraclavicular lymph node(s)NX: Regional lymph nodes cannot be assessed (e.g., previously removed)

Pathologic classification (pN)

pNX: Regional lymph nodes cannot be assessed (eg, not removed for pathological study or previously removed)

M0: No clinical or radiographic evidence of distant metastasesa

cM0(i+): No clinical or radiographic evidence of distant metastases in the presence of tumor cells or and no deposits no greater than 0.2 mm detected microscopically or by using molecular techniques in circulating blood, bone marrow, or other nonregional lymph node tissue in a patient without symptoms or signs of metastases

M1: Distant metastases detected by clinical and radiographic means (cM) and/or histologically proven metastases larger than 0.2 mm (pM)

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T4c: Both T4a and T4b are present

T4d: Inflammatory carcinoma

pN0: No regional lymph node metastasis identified or ITCs only

pN0(i+): ITCs only (malignant cell clusters no larger than 0.2 mm) in regional lymph node(s)

pN0(mol+): Positive molecular findings by reverse transcriptase-polymerase chain reaction (RT-PCR); no ITCs detected

pN1: Micrometastases; or metastases in 1-3 axillary lymph nodes; and/or clinically negative internal mammary lymph nodes with micrometastases or macrometastases by sentinel lymph node biopsy

pN1mi: Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)

pN1a: Metastases in 1-3 axillary lymph nodes, at least one metastasis larger than 2.0 mm

pN1b: Metastases in ipsilateral internal mammary sentinel lymph nodes, excluding ITCs

pN1c: pN1a and pN1b combined

pN2: Metastases in 4-9 axillary lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastases

pN2a: Metastases in 4-9 axillary lymph nodes (at least one tumor deposit larger than 2.0 mm)

pN2b: Metastases in clinically detected internal mammary lymph nodes with or without microscopic confirmation; with pathologically negative axillary lymph nodes

pN3: Metastases in 10 or more axillary lymph nodes; or in infraclavicular (level III axillary) lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the presence of one or more positive level I and II axillary lymph nodes; or in more than 3 axillary lymph nodes and micrometastases or macrometastases by sentinel lymph node biopsy in clinically negative ipsilateral internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes

pN3a: Metastases in 10 or more axillary lymph nodes (at least one tumor deposit larger than 2.0 mm); or metastases to the infraclavicular (level III axillary lymph) nodes

pN3b: pN1a or pN2a in the presence of cN2b (positive internal mammary lymph nodes by imaging); or pN2a in the presence of pN1b

pN3c: Metastases in ipsilateral supraclavicular lymph nodes

(Refer http://onlinelibrary.wiley.com/doi/10.3322/caac.21393/full for more information)

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b) American Joint Commission on Cancer TNM Anatomic Stage Groups

T N M STAGE

Tis N0 M0 0

T1 N0 M0 IA

T0 N1mi M0 IB

T1 N1mi M0 IB

T0 N1 M0 IIA

T1 N1 M0 IIA

T2 N0 M0 IIA

T2 N1 M0 IIB

T3 N0 M0 IIB

T1 N2 M0 IIIA

T2 N2 M0 IIIA

T3 N1 M0 IIIA

T3 N2 M0 IIIA

T4 N0 M0 IIIB

T4 N1 M0 IIIB

T4 N2 M0 IIIB

Any T N3 M0 IIIC

Any T Any N M1 IV

c) Molecular Profiling

ER HER2 Ki67 PR

Luminal A >5/8 Neg low (<20%) Grade 1/2 +

Luminal B

(HER2-)

Pos Neg high (>20%) Grade 3 + or -

Luminal B

(HER2+)

Pos Pos Any any

HER2

Enriched

Neg Pos - -

Basal like/TNBC* Neg Neg - -

* There is ∼80% overlap between ‘triple-negative’ and intrinsic ‘basal-like’ subtype, but ‘triple-negative’ also includes some special histological types such as (typical) medullary and adenoid cystic carcinoma with low risks of distant recurrence.

IHC score

% cases % cases with amplification by b-DISH

0 / 1+ (negative) ~60% 5%

2+ (equivocal) ~20% ~20-30%

3+ (positive) ~20% 95%

Please Note

- ER 1/8 or 2/8: is most likely negative. Discuss with pathologist at CBC path meeting

- ER- and PR+ needs to repeat ER staining on a separate section of the histology

specimen

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Investigations to determine Molecular Profile

- ER: immunohistochemistry (IHC) - ALL patients

- HER 2: IHC - ALL patients

- PR IHC - To be done on ER negative (<3/8) patients

- Ki 67 - To be done on all ER positive patients

- B-DISH - To be done on ER positive, HER 2 2+ patients (Distinguish Luminal A from B

and if HER 2 3+ the patient will be candidate for neoadjuvant chemotherapy)

3. Management of DCIS and LCIS

Ductal carcinoma in situ (DCIS)

DCIS is defined as a proliferation of malignant epithelial cells within ducts and lobules of the breast, without microscopic stromal invasion beyond the basement membrane. Benign myoepithelial cells are demonstrable microscopically around the ducts and lobules containing malignant epithelial cells. Immunohistochemical markers such as p63 or calponin may be used to highlight myoepithelial cells. Macroscopically, DCIS with associated necrosis may be visible as small dilated ducts filled with “cheese-like” material on cut section. Small, mammographically detected foci of DCIS may, however, be invisible to the naked eye and not palpable clinically. Architectural patterns DCIS may show different architectural patterns which is mainly helpful in microscopic identification of disease, but this is less important for clinical outcome and management than grading and the presence or absence of necrosis. Calcification may be noted in association with necrosis or inspissated secretions.

Solid: This was previously known as comedo-type DCIS. Malignant cells fill and expand ducts. Central necrosis may be present.

Cribriform: Punched-out or “cookie cutter”-like spaces are seen within ducts harbouring DCIS.

Papillary: Finger-like projections with central fibrovascular cores are seen lined by malignant epithelial cells within ducts.

Micropapillary: Small, finger-like projections or tufts consisting of malignant epithelial cells and lacking fibrovascular cores are seen within ducts.

Flat/clinging DCIS: A single layer or a few layers of malignant epithelial cells are seen lining ducts.

Other rare types of DCIS such as neuroendocrine DCIS, spindle cell DCIS, apocrine DCIS or signet ring cell DCIS may be seen. Grading A three-tiered grading system based on the nuclear size is most widely used.

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Low grade: The cells are usually evenly spaced and nuclei are monotonous in appearance. The nuclei are less than 2x a red blood cell in size. Necrosis is uncommon.

Intermediate grade: Features intermediate between low grade and high grade DCIS are seen. Necrosis may be present and cells are usually less uniform than low grade DCIS. Nuclei are 2x to 2.5x the size of a red blood cell.

High grade: Cells are clearly malignant with large, pleomorphic nuclei. Nucleoli are frequently seen. The nuclear size is greater than 2.5x to 3x the size of a red blood cell. Necrosis is often present.

Management a) Diagnosis of DCIS: Isolated DCIS is often a screen detected lesion that presents as

calcification on a mammogram. The best diagnostic test is a stereotactic vacuum

assisted biopsy. It is mandatory for a radio-opaque marker to be left in the breast post

biopsy.

b) Surgery

i. Surgery to the breast – Breast conserving surgery is the treatment of choice for

DCIS and should be offered to all patients unless there are contraindications

Contraindications for breast conserving surgery in DCIS:

- Widespread DCIS and excision would leave unacceptable cosmetic result

- Multicentric DCIS (More than 1 quadrant in the breast)

- Patient choice to have mastectomy

- Contraindications to RT and intermediate / high grade DCIS

All patients that have a mastectomy should be offered breast reconstruction

unless contraindicated (see section on breast reconstruction)

ii. Surgery to the axilla – Sentinel lymph node biopsy is indicated in selected patients

with DCIS otherwise no axillary surgery is done.

- Indications for SLNB in patients with DCIS on biopsy specimen

- Mastectomy / (Therapeutic Mammaplasty)

- Lump on examination / Solid component on mammogram

- Large area of DCIS (> 4 cm)

- High grade DCIS

- Surgery in axillary tail of breast (relative)

c) The USC / Van Nuys Prognostic Index scoring system

The van Nuys Prognostic Index system is a post-operative scoring system that guides

treatment to try and prevent local recurrence of DCIS. The rate of DCIS recurrence in

patients who had a lumpectomy and RT is similar to early stage invasive breast cancer.

The problem is that 50% of the patients that have a local recurrence, the recurrence will

be invasive breast cancer rather than DCIS.

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Van Nuys Prognostic Index scoring system

One to three points are awarded for each of four different predictors of local breast

recurrence (size, margin width, pathologic classification, and age). Scores for each of

the predictors are totalled to yield a VNPI score ranging from a low of 4 to a high of 12.

Score 1 2 3

Size (mm) ≤ 15 16-40 > 41

Margin width (mm) ≥ 10 1-9 <1

Pathologic classification Low grade Intermediate grade high grade

Age (yr) > 60 40-60 <40

Treatment guidelines by USC/Van Nuys Prognostic Index Score

VNPI Score Treatment plan

4 to 6 Wide Local Excision alone

7 to 9 Wide Local Excision + radiation

10 to 12 Mastectomy

d) Margin status in DCIS

Margins of 2mm are accepted as adequate for DCIS. All patients with margins of less

than 2mm should be referred to the CBC path meeting for review of the histology.

Important factors that should be considered before a decision on re-excision of

margins is made are:

- Age of the patient

- Extend of DCIS excised

- Grade of DCIS

- Extend of DCIS at the margin (Extensive vs focally involved margin)

e) Radiotherapy for DCIS

After Breast Conserving Treatment

- Whole breast RT (WBRT) was become the standard of care for BCT in DCIS.

- The NSABP-17 trial showed an absolute benefit of 9% (16% vs 7%) for

invasive breast cancer.

- However, omission of RT is considered acceptable in low risk patients

Low risk VNPI

Advanced age

Co-morbidities

Patient preference

RT is not a substitute for positive margins in DCIS

In patients receiving RT, margins of 2mm are regarded as adequate

After Mastectomy

- There is no role for PMRT in patients who have no invasive cancer on histology.

- A Positive margin is not an indication for PMRT.

f) Endocrine Therapy for DCIS / LCIS

- The NSABP-24 showed an absolute benefit of 3% for tamoxifen (16% vs 13%) –

for all breast cancer recurrence, both DCIS and invasive

There is no OS benefit

There is no regional LN or distant DFS

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NNT =15

Non-significant increase in endometrial cancer and T-E events

At Groote Schuur Hospital

- Well informed woman may be offered 5y of tamoxifen to reduce the incidence of

invasive breast cancer and DCIS.

Lobular carcinoma in situ (LCIS)

LCIS is a rare lesion which is usually incidentally discovered in approximately 1% of breast biopsies. Most cases do not form a palpable mass and is invisible to the naked eye. Rarely, calcification may be associated with florid cases, and may facilitate detection by mammography. It is generally believed to be a risk factor for developing invasive lobular carcinoma, and is not managed as established in situ carcinoma. Microscopically, terminal duct lobular units (TDLU) are filled and distended by cells resembling acinar epithelial cells. The cells are usually round, relatively uniform and discohesive. As with DCIS, immunohistochemical markers such as p63 or calponin will highlight myoepithelial cells around acini. The E-cadherin immunohistochemical stain will not show any cell membrane staining (this marker shows staining of cell membranes in DCIS and infiltrating duct carcinoma). Management In isolated LCIS from a core biopsy or excision biopsy, the following applies:

- No further local surgical management or radiotherapy is indicated even in the face of

involved margins

- Any further surgery considered should be a risk reducing bilateral mastectomy. This

option should be considered and offered only after careful consideration of the patient’s

individual clinical context i.e. age, family history, comorbidities, levels of anxiety etc.

- Chemoprevention should be considered and discussed with the patient

- Close follow up with annual clinical examination and radiological evaluation with

mammogram and breast MRI should be arranged

- Radiotherapy is not indicated

4. Histological Diagnosis of Invasive Breast Carcinoma

a) Tissue diagnosis of invasive breast cancer

- The diagnosis of breast cancer is usually possible with the needle biopsy of a

palpable mass.

- Both cytology and histology should be obtained from every patient

- In the case of a malignant cytology result and an inadequate or benign histology

result, the biopsy should be repeated, preferably by ultrasound guidance.

- In cases where two sets of core biopsies are inadequate, an excision or incision

biopsy is indicated. This can be done under either general or local anaesthesia.

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- In cases where histology confirmation of a cytological proven breast cancer is not

available and breast conserving surgery (BCT) is planned, the operation can proceed

in the context of convincing radiology and clinical findings.

- In cases where the primary surgery is mastectomy, histological evidence of breast

cancer is mandatory. If this is not possible, intra operative frozen section should be

done before proceeding to mastectomy.

- Impalpable breast lesions should undergo ultrasound guided biopsy. In cases where

the suspicious radiology findings are micro calcifications without a solid lesion,

stereotactic biopsy is indicated.

- If these fail, a radio-guided occult lesion localisation (ROLL) and the surgical excision

in theatre should be performed.

5. Loco-regional investigation

a) Breast Imaging

Mammography: All patients over 35 years of age should have a preoperative

mammogram to assess the extent of the primary lesion, the presence of any secondary

lesions or DCIS and the status of the contralateral breast.

Ultrasound: All patients who are candidates for BCT should have an ultrasound of the

affected breast in addition to a mammogram to ensure that secondary lesions are not

missed. Women under 35 years of age should have primary ultrasound of both breasts.

MRI is indicated in the following circumstances:

- Breast density precludes accurate mammographic and ultrasound assessment and

BCT is being considered

- Patients with lobular carcinoma in whom BCT is being considered

- Paget’s disease where a nipple / areolar complex excision is being considered.

- Tx N1 disease to look for an occult primary

b) Axillary Imaging

Pre-treatment ultrasound evaluation of the axilla should be performed for all patients

being investigated for early invasive breast cancer. If morphologically abnormal lymph

nodes are identified, ultrasound-guided needle sampling should be performed (The

aforementioned management might not be possible at Groote Schuur due to resource

constraints and radiology waiting times).

If this is not possible due to resource constraints, the following patients should be

prioritised for this investigation:

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- All clinically N0 patients with triple negative and HER 2 positive histology who

undergo neoadjuvant chemotherapy

- All clinically N0 patients who are offered neoadjuvant chemotherapy to facilitate BCT.

6. Staging Investigations All Patients: - Chest X-Ray

- Full Blood Count, Urea, creatinine and Electrolytes, Liver function tests, Calcium

- HIV

Node positive (locally advanced resectable) add: - Bone scan

- Abdominal Ultrasound

Locally advanced (irresectable) add: - PET/CT

Only if HIV negative, Infiltrating ductal carcinoma (lobular cancer excluded), TB

negative

If patient does not meet inclusion criteria, then bone scan and abdominal

ultrasound

Recurrence - Full Blood Count, Urea, creatinine and Electrolytes, Liver function tests, Calcium

- HIV

- PET/CT

Only if HIV negative, Infiltrating ductal carcinoma (lobular cancer excluded), TB

negative

If patient does not meet inclusion criteria, then bone scan and abdominal

ultrasound

7. Breast MDT Process

a) Diagnosis and first treatment decision

- Friday rapid access diagnostic breast clinic

All new patients with suspected or already diagnosed breast cancer must be

referred to the Groote Schuur Hospital rapid access diagnostic breast clinic on a

Friday.

New patients will be seen by someone from the surgical department where a

clinical history will be taken and the patient examined.

Patients with a diagnosis of breast cancer already known (mostly patients who

had a biopsy in private or other hospital) will be referred directly to the

oncologist / oncology registrar at the breast clinic.

Patients without a palpable lump will have a same day FNAB and Core biopsy

done in the clinic. On site cytology is performed and patients with a breast

cancer diagnosis based on cytology will be seen by oncology to commence with

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booking of staging investigations. The patient is then booked for CBC

(Combined Breast Clinic) follow up in LE33 the next week.

- Wednesday LE33 Combined Breast Clinic

Pathology and mammogram from every patient is reviewed

Patients will then be seen by an oncologist and surgeon together were a final

treatment decision is made.

b) Genetics referral of affected individuals:

The following patients diagnosed with breast cancer should be referred to genetics:

- Age < 40 years

- Age < 50 with a family history of with breast or ovarian cancer

- Bilateral breast cancer in patients under 50 years

- Male patients with breast cancer

- Breast and ovarian cancer in the same patient

c) Psychology / Psychiatry referrals

- All patients who need any counselling relating to their cancer diagnosis can be

referred to the LE psychiatrist.

- Referrals are made at LE32 secretary office with a standard referral form.

d) Social work referral

Counselling

- Patients are seen as individuals or as a group for supportive counselling.

- We also provide palliative care services as well as death and dying counselling as we

deal with terminally ill patients.

Emotional support

- The newly diagnosed patients become confused, anxious and scared. There is lot of

uncertainty as far as taking treatment is concerned. The social worker looks at

patients fears and addresses those fears with patients with the hope of easing

patient’s fears.

- The oncology unit runs support groups where patients get the platform to discuss their fear and motivate each other. The group is on Tuesdays and Wednesdays at G7 at 09h00 - 10h00 am and we are assisted by volunteers in running them.

- The social worker also is involved with look good feel better workshop where 20 patients who are on treatment are pampered.

Education

- The social worker assesses patient’s insight about her/his illness. Most patients have

very poor insight about their illness except that it is fatal illness.

- The social worker educates the patients and their families about their illness and

treatment it entails.

- The oncology unit host patient empowerment week to educate patients and their

families about resources that are available in their communities.

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Financial

- All illness affects patient’s financial status. The social worker provides guidance by

informing patients about illness benefits if patients are employed (UIF-LABOR DEP).

- The unemployed patients are assisted by temporal disability grant application

(SASSA).

- The patients who need to attend the clinic on regular basis i.e. radiation treatment are

assisted with bus fare.

Community Resources

- Patients are referred for community service i.e. Hospices, home-based care, Cansa

association, Booth memorial, Life Esidimeni, frail care centres, shelters and social

development.

- We work close with Eikenhof care home (CANSA) and that is where we refer patients

who are from out of Cape Town for accommodation.

8. Surgery

a) Breast Conserving Therapy (BCT)

BCT should be offered to all patients with tumours amenable to wide local excision (WLE)

with clear margins and a cosmetically acceptable outcome.

Macroscopically clear margins should be achieved during surgery and the tumour bed

marked with liga clips for post-operative radiotherapy.

Re excision post breast conserving surgery should be for involved margins (tumour at the

inked margin) and may be scar excision or a mastectomy depending on the histology and

mammographic results and patient choice.

High risk patients (e.g. triple negative, young, extensive DCIS) or patients with a risk of

significant residual tumour burden, should be assessed on an individual basis and

adequately counselled about the risk of repeat surgery.

At CBC the following should be checked before patients are offered BCT:

- Oncological safety: Clinical examination, ultrasound and mammogram should be checked to confirm that there is a single lesion or close multifocal lesions which are amenable to surgical excision. Mammogram should be reviewed to exclude widespread DCIS. Patients with T4 disease do not qualify for BCT.

- Technical feasibility: The following should be reviewed: the size of the tumour in

relation to the size of the breast and the location of the tumour, particularly in relation to the nipple and skin

- Delivery of Radiotherapy: The patient should be assessed for contraindications

to radiotherapy (previous radiotherapy at this site, connective tissue disorders), if their weight exceeds the radiotherapy weight limit (140KG) and whether they are physically able to undergo the treatment in the supine position and can attend 15 sessions of RT.

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If the following are all confirmed, women should be offered BCT as their first choice but

also informed of the risk of re excision (10 – 15%) and the need for radiotherapy.

In cases where it is oncologically safe (see above) but not technically feasible to perform

BCT, neoadjuvant chemotherapy to down size the tumour is an option. This decision

must take place BEFORE neoadjuvant chemotherapy is given and should not be offered

to a patient where the indication is for neoadjuvant chemotherapy is for locally advanced

disease. The complete checklist for BCT should be reviewed in these cases with the

following additional steps:

- A radio opaque marker should be placed in the tumour prior to chemotherapy or at a date close to the commencement of chemotherapy

- An axillary ultrasound and ultrasound guided biopsy of any suspicious nodes

should be performed prior to chemotherapy or close to the commencement of chemotherapy

b) Mastectomy

This is recommended for the following:

1) Patient choice

2) Radiothearpy contraindicated (Previous RT, Connective tissue disorders) or

logistically not possible (see above)

3) Extensive multifocal and multicentric disease

4) Previous WLE with positive margins and not possible to re-excise margin with

adequate cosmetic outcome

5) BCT cannot offer a good cosmetic result

c) Axillary surgery

i. Sentinel lymph node biopsy (SLNB)

- It is recommended that SLN procedures should be performed by surgeons with

training in this procedure using a combination of isotope and dye techniques. The surgeon should try and identify at least 3 nodes if possible.

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- Indications for SLNB in patients with invasive cancer: Patients with T1/T2 tumours and selected T3

tumours with a clinically node negative axilla

(clinical axillary exam and axillary ultrasound)

All patients without overtly pathologic axillary

nodes should have an ultrasound of their axilla to

exclude radiological suspicious nodes preferably

before 1st CBC visit)

Small soft nodes, especially if bilateral, should be

considered reactive unless they have features on

ultrasound to suggest otherwise.

- Contra indications for SLNB:

Previous SLNB Histologically or cytology proven metastasis Clinically palpable pathological nodes T4 cancers

- Patients where axillary surgery may be omitted (all criteria should be met):

>70 years of age ER positive Node negative T1/2 tumours

- Intra operative frozen section

Intra operative frozen section is no longer routine practice when doing a sentinel lymph node biopsy

Frozen section may be used intra-operatively in selective cases at the discretion of the operating surgeon.

- If the waiting time for surgery at Groote Schuur is more than 6 weeks proceed to

ANC at secondary level hospital

ii. Axillary node clearance

- Indications for axillary node clearance (ANC)

Proven positive lymph node biopsy pre operatively

Patients with clinically overtly pathological lymph nodes

Contraindication to SLNB (see SLNB)

Failed SLNB procedure (it is acceptable to do axillary sampling if SLNB failed,

remove at least 4 nodes)

Lack of access to SLNB technique in the treating institution

Inadequate prior ANC (less than 6 nodes) with residual suspicious nodes on

examination

- In a post mastectomy patient with a positive sentinel lymph node, where the criteria for PMRT (see section 10) are not met, further management of the axilla whether with RT or Surgery should be discussed at CBC and individualised.

The features on ultrasound

of a pathological lymph

node are:

Asymmetrical cortical

thickening

Cortical thickening of >

3.5mm

Loss of fatty hilum

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iii. Axillary Surgery Post NACT

Patient for breast surgery with no clinical

or ultrasound suspicious lymph nodes

(N0)

SLNB

(No intra-op frozen section)

SLNB positive for metastasis on final

histology

Indication for breast RT

* BCT done

* 1 - 3 nodes positive and any one of:

- LVI

- Grade 3 tumour

- > 4cm in size

- ER negative tumour

- Extra capsular extension

No further axillary surgery

Include axilla in breast RT field

No indication for breast RT

Axilla only RT

SLNB negative for metastasis on final

histology

No axillary RT needed

Whole breast RT for BCT patients

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- Patients who are clinically node positive prior to NACT will proceed to ANC regardless of their clinical response

- Patients who are clinically node negative (clinical exam and ultrasound) prior to NACT qualify for SLNB

- Patients who receive NACT for T4N0 disease may have a SLNB depending on the discretion of the MDT (this will usually be patients with small tumours with local skin involvement)

d) Contralateral Risk Reducing Mastectomy

- The following Stage 1 and 2 (early breast cancer) patients should be offered a

contralateral risk reducing mastectomy:

Known genetic mutation in BRCA1/2 or P53

Patients under 35 years

Patients under 40 with two first or second degree relatives with breast cancer

Patients under 50 with three or more first or second degree relatives with

breast cancer.

Biopsy proven high risk pathology: LCIS/Atypical Ductal

Hyperplasia/Papillomatosis in the contralateral breast

Assessment of the contralateral breast made difficult due to high breast

density on mammogram or difficult clinical examination (relative indication)

- Low risk patients who request a contralateral mastectomy should be counselled

sympathetically and informed of the following:

The risk of contralateral breast cancer, while higher than the baseline

population, is approximately 0.5% per annum. Cumulative risk at 10 years 5%

(1 in 20 or 95% cancer free in contralateral breast) and at 20 years 10% (1 in

10 or 90% cancer free in contralateral breast)

Survival from breast cancer is directly related to the outcome from the

treatment of the first cancer and not affected by cancer which may be

detected in the other breast

After cancer treatment, close clinical and radiological follow up is offered for

the contralateral breast.

e) Reconstruction

Reconstruction may be performed at the time of mastectomy or delayed.

i. Immediate reconstruction

Skin sparing mastectomy with the immediate insertion of silicone breast

prosthesis should be considered for the following patients:

Risk reducing surgery – nipple sparing mastectomy indicated here

Isolated DCIS

Contraindications to immediate silicone prosthetic implant

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Smoking

BMI >35

Uncontrolled diabetes HbA1C >7

Connective Tissue disorders

Skin sparing mastectomy with the immediate insertion of expander should be

considered for the following patients:

All above and

- T1 / T2 tumour (early breast cancer)

- N0 (planned SLNB)

Contraindications to expander:

2 or more risk factors as listed above

Reconstructive surgery date that result in greater than six week delay in

operative date

ii. Delayed Reconstruction

Patients who have completed their oncology treatment may be referred for

delayed reconstruction. This may be with prosthetic material or tissue flaps. For

prosthetic reconstructions, a tissue expander is inserted initially and then

followed by the insertion of a permanent silicone breast implant. Tissue flaps

may be with a TRAM (Transverse Rectus Abdominis Myocutaneous) flap or

latissimus dorsi flap.

f) Contralateral breast reduction / Mastectomy for symmetry

Patients may require contralateral breast reduction or reshaping after any of the above

procedures, including simple mastectomy and BCS. It is most often done in patients

with gigantomastia who has a unilateral mastectomy and needs reduction of the

opposite breast to prevent severe asymmetry. This is at the discretion of the operating

surgical team.

g) Surgery for recurrence

- Patients with local recurrence need restaging for metastatic disease with a PET CT. If

no metastatic disease detected on imaging a mastectomy can be done if the first

surgery was BCT. If a mastectomy was done and the local recurrence is resectable a

wide local excision can be done followed by radiotherapy, if the patient did not receive

radiotherapy before. Some patient will need plastic surgery input for wound closure

after excision of the local recurrence.

9) Chemotherapy

a) Neoadjuvant chemotherapy (NACT)

Indications 1. Triple negative breast cancer

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2. HER2 enriched breast cancer

3. Downsizing to achieve breast conserving treatment

4. Locally advanced (unresectable)

Regimens

- AC4 x P4

- TC x 4 (>70y, anthracycline contraindicated)

- AC x 4

- FEC x 6

- Tamoxifen alone (luminal A, poor chemo candidate)

Pre-chemo workup

- In patients who are deemed to be potential BCT candidates, surgical clips should be placed prior to or early during chemo.

- Staging of the axilla (Ultrasound axilla) is important to guide post chemo treatment. - ERNA prior to first cycle.

Re-assessment

- All patients must be seen by a Doctor at cycle 3 to assess chemo response. Patients found to have progressive disease must be re-discussed at CBC for a decision regarding surgery, 2nd line chemo or 2nd line Tamoxifen alone.

- Patients must be seen at CBC at / or after cycle 7 to assess surgical options and get date for surgery

b) Adjuvant chemotherapy

Systemic treatment must start within 12 weeks of surgery (ideally <6 weeks). The benefit of chemotherapy is directly related to the molecular subtype of breast cancer. Thus, were relevant, Ki-67 and b-DISH should be requested to distinguish between subtypes.

Luminal A (ki67<20%, G1/2, strong ER+, PR+) These cancers are less responsive to chemotherapy and are endocrine responsive. Chemotherapy is indicated for ≥4LN+.

Luminal B This subgroup constitutes the most uncertainty regarding chemo. Relative indications favoring chemo are:

- Grade 3 - Low ER score - Lack of PR - High ki67 - Age <35y - Node positivity - LVI+

PREDICT and Adjuvant online can help with assessing chemo benefit. If available, Oncotype Dx and Mammprint have been validated to determine chemo benefit. Use 2nd generation chemo when calculating chemo benefit on PREDICT.

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Consider chemo if benefit >5% at 10y

Regimen - AC4 x P4

- TC x 4 (>70y)

- AC x 4

- FEC x 6

HER2 enriched / LumB HER2+ / TNBC If not chemo was received in the neo-adjuvant setting, then all patients should receive chemo in the adjuvant setting. The one exception is stage1 LumB HER2+. Discuss with consultant.

Regimen

- AC4 x P4

Radiotherapy Patients

- If indicated, patients should be booked for RT at cycle 6 (AC-P) or cycle 2 (TC).

Cardiotoxicity There is a 5% risk of cardiotoxcicity with cumulative dose of Doxorubicin 450 mg/m2 and Epirubicin 900 mg/m2.

Baseline:

- If clinical CCF, unstable angina: not for anthracycline

- If LVEF< 50% not for Adriamycin, use Epirubicin (60mg/m2) if anthracycline

indicated.

- If LVEF< 40% not for Epirubicin

Repeat ERNA/MUGA:

- At cycle 2 or 3 (depending on availability)

- If LVEF has reduced by 10% points, or has dropped below 50% then switch to

Epirubicin 60mg/m2.

- If significant drop >15% or cardiac symptoms – discuss with consultant.

c) Chemotherapy in Pregnant patients

- No chemo Trimester 1.

- Adriamycin, cyclophosphamide and taxanes can be used in Trimester 2/3

- Notify the GSH high risk antenatal clinic for patient assessment

- Not for ERNA – discuss with cardiology for ECHO

- If in 3rd trimester: preferable to have upfront surgery followed by adjuvant chemo

after delivery.

-

10) Radiotherapy

a) Radical Radiotherapy

i. Wide Local Excision (BCT)

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Unless contra-indicated, all women <70y (see “Elderly patients” below) are to receive post op RT to the whole breast. WBRT reduces overall mortality by 5% at 15y.

Doses and fractionation:

Hypofractionation schedules have shown similar effectiveness and side effect profile.

CW: 2.67Gy x 15 = 40.05Gy Sclav: 2.67Gy x 14 = 37.38Gy

Boost:

A 10-16Gy RT boost gives all women a relative 50% decrease in local failure, but no effect on OS. The absolute gains for low risk women do warrant boost RT. ESMO classification of high risk: <50y, G3, LVI, focal + margin

At GSH a boost is given to women <50y or + margin in whom repeat surgery is not feasible. Dose: 2.67Gy x 4 (START B used 10Gy/5)

Technique

3DCRT Include high tans if SLNB+ (1-2 LNs) with no completion ALND (Z11) include supaclav if : - ≥4LN+ (post ALND) - ≥3LN+ (SLNB) - 1-3LN+ and ECS

Additional risk factors to be taken into account include <10LN sampled, G3, LVI, young age, non luminal disease

Elderly patients Based on CALGB 9343 trial and PRIME II, women who fulfil all of the below criteria can forego adjuvant RT following WLE:

>70y age

- T2N0

- ER+ (who will receive 5y of adjuvant ET)

- clear margins

>65y age

- T2 (<3cm)

- ER+

- R0

- Not G3 or LVI

ii. Post Mastectomy (PMRT)

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Chest Wall only:

- T3/T4, N0

- + margin

- 1-3 LN + and no additional risk factors (see below):

Chest Wall + Supra CLAV

- ≥4LN + - NACT for irresectable disease - 1-3 LN+ (see below)

1-3LN+

All these patients should receive PMRT. The decision as to whether it is CW only vs CW+sclav is dependant on the following prognostic factors;

G3 LVI+ Age <40y T>4cm ECS <10LN sampled non luminal disease

Doses and fractionation:

CW: 2.67 Gy x 15 = 40.05Gy (5 x week) Sclav: 2.67 Gy x 14 = 37.38Gy (5 x week)

Bolus All patients with cT4 disease should be treated with PMRT. Alternate fractions are given with 0.5cm bolus to the CW, starting with bolus on. Bolus is not applied to supraclav fossa Technique

3DCRT (VIRT SIM) All patients to be CT scanned. Target v do not need to be contoured. OAR must be contoured by reg.

b) Recurrence

Discuss with consultant. NB: must document previous RT. Patients who have received previous ipsilateral RT are not candidates for re-treatment. Factors favouring Chest Wall only: Luminal disease, isolated CW recurrence, resected with R0, LVI-, no fixation to chest wall, LN negative

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All others: CW + scalv

11. Endocrine Therapy (ET)

- ER positivity is defined as ≥3/8.

- ER negative/PR positive likely represents an anomaly and should prompt re-testing

in the surgical specimen

- ET is recommended in all patients with ER positive invasive cancers

- The use of an AI at GSH is limited to patients who have

Progressed on tamoxifen

Intolerable side effects of tamoxifen

A contra-indication to tamoxifen

Proven endometrial hyperplasia/bleeding

- High risk patients are defined as ≥4LN+

Premenopausal

- Tamoxifen 20mg dly x 5yr

- OFS

Consider in high risk pts and age<35y (SOFT/TEXT)

Only if patient remains premenopausal after chemo

The gains in DFS must be balanced against the risks and side effects of OFS

OFS: EBRT15Gy in 5# + Tamoxifen

- Extended use

Offer to high risk woman

After completion of 5yr of tamoxifen, an additional 5yr can be considered if

patient is tolerating Rx well (ATLAS/ATTOM)

Postmenopausal

- Tamoxifen 20mg dly x 5yr

- AIs are a valid options as they AIs allow for an improved DFS vs tamoxifen

Can be used upfront or after 2-3y of tamoxifen. (private pts)

- There is no proven benefit for >5y of an AI.

- Extended use

High risk woman

After completion of 5y of tamoxifen, an additional 5y of an AI or tamoxifen can

be considered if patient is tolerating Rx well (private pts should be switched to

an AI)

- Woman receiving an AI should be given Vit D 5000IU weekly PO and Calcium

1200mg dly PO to prevent osteoporosis

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11) Targeted biological therapy

HER2 Positive disease (Confirmed with B-Dish)

Currently Trastuzumab is not available in the state and there have been no official national

guidelines as to which patients will qualify for treatment, the duration of such treatment and

what budgeting will be provided.

Below are current international recommendations.

- Adjuvant o T1a: no role for Trastuzumab (herceptin) o T1b, T1c: Pacli + Herceptin o Node negative: 9 weeks of Herceptin is non inferior to 1y (ASCO 2017 –

SHORT-HER trial) o Node positive: ACx4+Pacli Herceptin x 4 + 1y Herceptin

- Dual blockage o Neoadjuvant: NeoSphere trial: improved pCR for trastuzumab +

pertuzumab + docetaxel o Adjuvant: Aphinity trial (ASCO2017) reported as positive trial for

pertuzumab and trastuzumab, however the benefit in DFS is +- 2%

12) Treatment of Palliative / Metastatic Disease

a) General principles

- Early referral to palliative care is essential

- Patients and family must be counseled about prognosis, treatment options, aims of

treatment and side effects of treatments

- Assess local and systemic complications of the metastatic disease to guide initial

treatment

b) Prognostic factors

The most important prognostic factors in metastatic breast cancer are - Performance Status - Visceral vs non-visceral disease - Molecular subtype - Number of metastases - LDH - Young age

c) Palliative Endocrine Treatment

Luminal disease only

- ET therapy is the preferred option (even in the presence of visceral mets)

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- Only patients with rapidly progressing disease or a visceral crisis should proceed

with upfront chemo

- It is NB that ET is not switched before at least a trial of 3months on Rx has been

used to assess treatment response

- Rx options:

Pre-menopausal: Tamoxifen + OFS

Post-menopausal: Tamoxifen (1st L)

ET will be influenced by type of ET received in the adjuvant setting

- Treatment is continued until clinical progression. Stopping ET in metastatic breast

cancer is not recommended. At progression, patients may well be offered chemo,

after which they should be switched to 2nd/3rd line ET.

- ET available

Tamoxifen 20mg dly

Anastrazole 1mg dly

Provera 400mg dly

d) Palliative chemotherapy

Indications

Visceral crisis

Rapidly progressing disease

Patients in whom a rapid response is desirable

Non-luminal disease

PS≤2

First Line

- Adriamycin

- Paclitaxel

- AC

Second Line

- Adria or Pacli (if naïve)

- Gemcitibine + Cisplatin (TNBC previously exposed to both anthracycline and

taxane)

- Navelbine

Third Line

- CMF (oral cyclo)

- Metronomic: oral cyclophosphamide + methotrexate

- Gemcitibine

e) Targeted therapy

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Targeted Rx is not available at GSH

HER2+ - 1st L: Herceptin is commonly given with either paclitaxel or docetaxel – continued till

progression - 2nd L: Herceptin commonly given with Navelbine or Xeloda – continued to

progression - Dual blockage: trastuzumab + Peruzumab + Docetaxel (Cleopatra trial) is

considered gold standard if resources are unlimited.

ER+, HER2 negative - Everolimus + Exemestane (mTOR inhibitor)

2nd L progressing after AI (Bolero-2)

- Palbociclib + exemestane (CDK4/6 inhibitor) 2nd L progressing on AI (Paloma-3)

- Palbociclib + letrozole 1st L (Paloma-2)

- Ribociclib + letrozole (CDK4/6 inhibitor) 1st L (Monalessa-2)

f) Palliative RT

i. Breast

36Gy in 5# over 5 weeks (1/week) - Add bolus if T4 (alternate fractions – start with bolus on) - Not to s’clav (if sclav needs treatment, use 20Gy/5#)

20Gy/5 if transport issues 8Gy/1 poor PS

ii. Bone mets

Single 8Gy (SIM): if limited disease 20Gy in 5# (VIRT-SIM): extensive ds

iii. Spinal cord compression

Single 8Gy 20Gy in 5# if significant soft tissue component

iv. Brain mets

SRS: discuss with Dr Naiker if oligometastatic disease, ER+, lesion<5cm WBRT: 20Gy in 5# if PS≤3

BSC: PS=-4

g) Palliative Surgery

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Palliative surgery is seldom done at GSH due to surgical complications. Any patients

considered for palliative mastectomy MUST be discussed at CBC.

Patients with locally advanced (M0) breast cancer should undergo neoadjuvant

chemotherapy, and be considered for surgery thereafter. In Luminal A patients,

neoadjuvant Endocrine treatment is a viable option. Response should be evaluated

at 3 months and if change in tumour size is observed treatment can be continued up

to 9 months for full effect.

Radical mastectomy with complex skin flap reconstruction for locally advanced

disease (T4) is to be considered only after MDC review.

Patients with metastatic disease should not undergo mastectomy, unless motivated

for by clinician for urgent local control palliation, or if metastases are isolated and

stable. These cases must be discussed at CBC with consultant. In general, these

patients are treated with palliative RT for local control.

Patients with isolated metastasis that may benefit from surgery to the primary breast

lesion are the following:

Patients < 55 yrs

ER positive

Solitary bone metastasis

Her 2 negative patients

Local recurrence may be amenable to Wide Local Excision, even in the context of

metastases. This is best decided at MDC recommendation

14. Follow up

Due to resource constraints, the follow up policy at GSH has been developed to cope with

excessive patient numbers.

Patients who attend their local DH for a 6 monthly F/U should have a “Day Hospital Follow

up letter”.

Patients who are discharged from GSH at 5y should receive a “Discharge letter”

Palliative patients not eligible for further cancer treatment should receive a “Palliative Care

Plan” letter.

Patients treated with curative intent

After completion of surgery +-chemo +- RT, all patients are to be seen 6 monthly in

the 1st year then yearly at GSH.

All patients are advised to attend their local DH for a 6 monthly visit. Ensure the

appropriate letter with the treatment plan is given to the patient.

F/U mammography is done at the yearly GSH visit.

After 5y, discharge all patients in remission. Give the appropriate letter.

Palliative patients

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Patients with a PS 0-2 are seen 3-6 monthly at GSH. Interval between visits is

decided by; symptom control, treatment options remaining and the need to assess

treatment response.

All other patients should be discharged with a “Palliative Care Plan”. This must include what

further treatment options are available (Endocrine options/RT etc), HBC/hospice

arrangements, and how the patient can access LE33 if needed.