Breast cancer

Epidemiology

Breast cancer affects 1:12 women
In United Kingdom there are 24,000 new cases and 15,000 deaths annually
It is the commonest cause of cancer death in women
It accounts for 6% of all female deaths
Britain has highest breast cancer mortality in the world

WHO Classification

Epithelial
- Non-invasive
  - Ductal carcinoma in situ (DCIS)
  - Lobular carcinoma in situ (LCIS)
- Invasive
  - Ductal (85%)
  - Lobular (1%)
  - Mucinous (5%)
  - Papillary (<5%)
  - Medullary (<5%)
Mixed Connective tissue and Epithelial
Miscellaneous

Diagnosis and assessment

Most symptomatic cancers present as a painless lump

Breast pain is an uncommon presentation of breast cancer
Diagnosis is by Triple Assessment
- Clinical Evaluation – Lump and regional nodes
- Imaging (ultrasound <35 years old or mammography >35 years old)
- Cytology or Histology
Cytology is reported as:
- C1 = Inadequate sample
- C2 = Definitely benign
- C3 = Probably benign
- C4 = Suspicious of malignancy
- C5 = Definitely malignant

Aims of breast cancer surgery

To achieve cure if excised before metastatic spread has occurred
To prevent unpleasant sequelae of local recurrence

Surgical options for the breast

Breast Conserving Surgery (BCS) + radiotherapy
- BCS is regarded as either wide local excision, quadrantectomy or segmentectomy
Simple mastectomy
Radical mastectomy - obsolete
Mastectomy + reconstruction (immediate or delayed)

Tumours suitable for breast conservation

Small single tumours in a large breast
Peripheral location
No local advancement or extensive nodal involvement
For tumours that are suitable for breast conservation there is no difference in local recurrence or overall survival when BCS + radiotherapy is compared to mastectomy

Aims of axillary surgery

30-40% of patients with early breast cancer have nodal involvement
The aims of axillary surgery is to:
- To eradicate local disease
- To determine prognosis to guide adjuvant therapy
Clinical evaluation of the axilla is unreliable (30% false positive, 30% false negative)
No reliable imaging techniques available
Surgical evaluation important and should be considered for all patients with invasive cancer
Levels of axillary clearance are assessed relative to pectoralis minor
- Level 1 - below pectoralis minor
- Level 2 - up to upper border of pectoralis minor
- Level 3 - to the outer border of the 1^st rib
Axillary samplings removes more than 4 nodes
Pre-operative axillary ultrasound and biopsy may allow a tailored approach to the axilla

Arguments for axillary clearance

Axillary clearance both stages and treats the axilla
Sampling potentially misses nodes and under stages the axilla
Surgical clearance possibly gains better local control
Avoids complications of axillary radiotherapy
Avoids morbidity of axillary recurrence

Arguments for axillary sampling

Only stages the axilla
Must be followed by axillary radiotherapy
The 60% of patients with node negative disease have unnecessary surgery
Radical lymphadenectomy in other cancers (e.g. melanoma) produces disappointing results
Avoids morbidity of axillary surgery
The combination of axillary clearance and radiotherapy is to be avoided
Produces unacceptable rate of lymphoedema

Picture provided by Eldeeb Mabrouk, University Hospital, Alexandria, Egypt

Sentinel node biopsy

Currently under investigation and should still be regarded as experimental
Aims to accurately stage the axilla without the morbidity of axillary clearance
Technique used to identify the first nodes that tumour drains to
Can be located following the injection of either
- Radioisotope
- Blue dye
- Combination of isotope and blue dye
Can be injected in peritumoural, subdermal or subareolar site
Allows more detailed examination of nodes removed
Significance of micrometastatic deposits identified in sentinel nodes is unclear

Picture provided by O Olsha, Shaore Zedek Medical Centre, Jerusalem, Israel

Prognostic factors

50% women with operable breast cancer who receive locoregional treatment alone will die from metastatic disease.
Prognostic factors have three main uses:
- To select appropriate adjuvant therapy according to prognosis
- To allow comparison of treatment between similar groups of patient at risk of recurrence or death
- To improve the understanding of the disease
Prognostic factors can be:
Chronological
- Indication of how long disease has been present
- Relate to stage of the disease at presentation
Biological
- Relate to intrinsic behaviour of tumour

Chronological prognostic factors

Age
- Younger women have poorer prognosis of equivalent stage
Tumour size
- Diameter of tumour correlates directly with survival
Lymph node status
- Single best prognostic factor
- Direct correlation between number and level of nodes involved and survival
Metastases
- Distant metastases worsen survival

Biological prognostic factors

Histological type
- Some histological types associated with improved prognosis:
  - Tubular
  - Cribriform
  - Mucinous
  - Papillary
  - Micro-invasive
Histological grade
- Three characteristics allow scoring of grade into grades one, two or three depending on:
  - Tubule formation
  - Nuclear pleomorphism
  - Mitotic frequency
Lymphatic / vascular invasion
- 25% operable breast cancers have lympho-vascular invasion
- Double risk of local relapse
- Higher risk of short term systemic relapse

Biochemical measurements

Hormone and growth factor receptors
- ER positivity predicts for response to endocrine manipulation
- EGF receptors are negatively correlated with ER and poorer prognosis
Oncogenes
- Tumours that express C-erb-B2 oncogene likely to be
- resistant to CMF chemotherapy
- resistant to hormonal therapy
- respond to anthracycline
- respond to taxols
Proteases
- Urokinase and cathepsin D found in breast cancer
- Presence confers a poorer prognosis

Chemotherapy in breast cancer

Can be given as:
- Primary systemic therapy prior to locoregional treatment
- Adjuvant therapy following locoregional treatment
Post-operative adjuvant chemotherapy
Depends primarily on:
- Age / menopausal status
- Nodal status
- Tumour grade
Combination chemotherapy more effective than single drug
Most commonly used regimen = CMF (Cyclophosphamide, Methotrexate, 5-Flurouracil)
Given as six cycles at monthly intervals
No evidence that more than 6 months treatment is of benefit
Greatest benefit is seen in premenopausal women
High -dose chemotherapy with stem cell rescue produces no overall survival benefit

Primary (neoadjuvant) chemotherapy

Chemotherapy prior to surgery for large or locally advanced tumours
Shrinks tumour often allowing breast conserving surgery rather than mastectomy
70% tumours show a clinical response
In 20–30% this is response is complete
Surgery required even in those with complete clinical response
80% of these patients still have histological evidence of tumour
Primary systemic therapy has not to date been shown to improve survival

Endocrine therapy in breast cancer

It is just over 100 years since Beatson described response to oophorectomy in women with advanced breast cancer

Tamoxifen

Tamoxifen is an oral anti-oestrogen
Effective in both the adjuvant setting and in advanced disease
20 mg per day is as effective as higher doses
5 years treatment is better than 2 years
Value of treatment beyond 5 years is unknown
Risk of contralateral breast cancer reduced by 40%
Greater benefit seen in oestrogen receptor rich tumours
Little benefit seen in oestrogen receptor negative tumours
Benefit observed in both pre and post menopausal women

Aromatase inhibitors

Several new endocrine therapies are available
Reduced the peripheral conversion of androgens to oestrogens
Only effective in post menopausal women
May be superior to tamoxifen in high risk women
To date have not been shown to have survival benefit compared with tamoxifen

Biological therapy (Herceptin)

HER receptors are proteins embedded in cell membrane
Regulate cell growth, adhesion and migration
The HER2 gene is over amplified in 20% of breast cancers
HER2 positivity is an independent poor prognostic factor
Trastuzumab (Herceptin) is a monoclonal antibody that binds selectively to the HER2 receptor
Has been shown to improve survival in both the adjuvant and metastatic setting
Only works in HER2 positive cancers
Response to therapy can be predicted by immunocytochemistry and fluorescent in-situ hybridization
Major side effects are cardiac
Associated with cardiac dysfunction in 5% cases

Locally advanced breast cancer

Regarded as a tumour that is not surgically resectable
Clinical features include
- Skin ulceration
- Dermal infiltration
- Erythema over the tumour
- Satellite nodules
- Peau d'orange
- Fixation to chest wall, serratus anterior or intercostal muscles
- Fixed axillary nodes

If oestrogen receptor-positive usually treated with primary hormonal
If oestrogen receptor-negative chemotherapy may be useful
Radiotherapy may be useful in local control of disease
If adequate response a salvage mastectomy can be consider

Recurrent breast cancer

Most local recurrences are symptomatic

Often associated with the development of metastatic disease
Restaging is therefore essential
Commonest sites for ductal carcinoma are liver, bone and lung
Lobular carcinoma less predictable often spreading to bowel, retroperitoneum etc
Recurrence whilst on adjuvant tamoxifen consider:
- Further surgery for
- Isolated 'spot' recurrence after mastectomy
- Local recurrence in the conserved breast
- Radiotherapy if not previously given
- Change of hormonal agent to anastozole or megestrol acetate

Male breast cancer

1% of all breast cancers occur in men
Pathologically, the disease is similar to that which occurs in women
The principles of treatment are the same
The proportion of men undergoing mastectomy is higher
Adjuvant therapy is the same as for women

Picture provided by Faisal Ashfaq, Civil Hospital, Quetta, Pakistan

Picture provided by Namada Deivasigamani, Stanley Hospital, Chennai, India

Bibliography

Benson J R, Jatoi I, Keisch et al. Early Breast Cancer. Lancet 2009; 373: 1463-1479.

Fentiman I S, Fourquet A, Hortobagyi G N. Male breast cancer. Lancet 2006; 365: 595-604

Johnston S R D. Systemic treatment of metastatic breast cancer. Hosp Med 2001; 62: 289-295.

Nabholtz J M. Aromatase inhibitors in the management of early breast cancer. EJSO 2008; 34: 1199-1207

Noguchi M. Sentinel lymph node biopsy and breast cancer. Br J Surg 2002; 89: 21-34.

Purushotham A D, MacMillan R D, Wishart G C. Advances in axillary surgery for breast cancer - time for a tailored approach. EJSO 2005; 31: 929-931