Breast Cancer

Breast cancer is a diverse and heterogenous disease. Over the years due to increased understanding of the pathophysiology and genetic drivers treatment has become more and more individualised.

Over the following sections I will highlight useful learning resources as well as links to relevant papers. I hope to provide a basic overview of treatment that is required for successful sitting of the FRCR exams.

Anatomy

Breasts

- Extend from 2nd to 6th rib

- consist of 4 quadrants and a central portion. 50% occur in UOQ and these have best prognosis.

- lymphatic drainage to axillary nodes and internal mammary which lie alongside the internal thoracic artery

link to radiopaedia for more detail on breast anatomy

Axillary nodes

  • level I: below the lower edge of the pectoralis minor muscle
  • level II: underneath/posterior the pectoralis minor muscle
  • level III: above/medial the pectoralis minor muscle

link to radiopaedia for more detail on axillary node anatomy

Staging

AJCC 8th ed
AJCC
AJCC 8th ed

Pathology

Almost all are adenocarcinoma.

Graded according to Nottingham grading system - G1, 2 or 3

ER and PR

Assessed by IHC. ER more common in post-menopausal, <50% of pre-menopausal.

Allred score combines a score based on % of positive cells and intensity of reaction. Gives a score out of 8 with 0 and 2 considered negative.

About 20% of ER neg tumours are PR pos – reasons include a low level of ER expression or a false negative ER result. Account for 5% of all tumours and are likely to respond to hormone treatment.

HER2

Can be assessed by IHC with 3+ pos. if 2+ then confirm by measuring number of gene copies with FISH (positive if HER2/CEP17 ratio >2 by ISH or HER2 copy number >6 regardless of ISH (if copy number 4-6 then this is equivocal and needs alternative ISH)).

Molecular subtyping

Identifies 4 different subtypes and these correlate with prognosis

- Luminal A; ER/PR pos, low Ki67 (G1-2), molecular marker ‘favourable’

- Luminal B; ER pos/PR low, Ki67 high (G3), molecular marker ‘unfavourable’

- HER2 pos; ER/PR pos or neg, generally G3

- Basal like; Triple neg, generally G3

Gene expression patterns of breast carcinomas
Sorlie et al
PNAS 2001

Original paper describing the 4 molecular subtypes of breast cancer

Screening and Assessment

Screening

  • In the UK between 50-70 yrs old every 3 yrs.
  • Mammogram with mediolateral oblique and cranio-caudal.
  • Recall rate is 4% with 1% going on to biopsy most of whom will have either invasive or in-situ disease.

If assessed as being at high or moderate risk (>17% lifetime risk) may be offered annual MMG or MRI scanning according to age and risk category.

- Aged 40-49; annual MMG

- Aged 30-49 if known or >30% risk of BRCA; annual MRI

- Age 20-49 if Li-Fraumeni(TP53); annual MRI

Assessment

  • Triple assessment – P(physical exam), M (MMG), U (USS) and C (cytology)/B(biopsy).
  • All scored 1-5 with 1=inadequate, 2= benign, 3= suspicious probable benign, 4=suspicious probably malignant and 5= malignant.
  • If T3 or N2 then need staging for metastatic disease such as CT CAP and bone scan. In T3> up to 15-20% incidence of M+.
  • If T2N1 only do distant staging if reasons to be concerned – symptoms/abnormal bloods.
  • Consider PET in locally advanced disease IIIB+ to look for distant disease especially patients with inflammatory breast cancer.

Surgery

General principles

Breast surgeons should follow the Oncoplastic Breast Reconstruction Guidelines for Best Practice

Patients should be treated by an oncoplastic team (oncoplastic unit or centre); units that do not have oncoplastic breast surgery on site should seek to establish a patient pathway that is in line with these guidelines.

Where surgery is the first treatment, this should take place within 31 days of the diagnosis being made. In medically fit patients, non-reconstructive breast cases should be done as day-case/23-hour surgery.

Patients should have all surgical options which may apply (breast conservation, mastectomy with or without reconstruction and, if appropriate, oncoplastic conservation procedures) discussed with them in the presence of their key worker/clinical nurse specialist (CNS).

The patient’s choice must always be respected.

The National Mastectomy Audit reported unacceptable levels of pain in women having mastectomy alone or mastectomy plus reconstruction. Protocols should exist to manage and assess post-operative pain in these patients.

Choice of breast operation

Surgery may be the initial treatment or it may be undertaken after primary chemotherapy or endocrine therapy. The same principles will apply in either case. The majority of cases will be suitable for breast conservation. However, it is important to ensure that conservation surgery will leave the patient with an aesthetically acceptable breast (preserved breast shape and well placed scars).

Indications for mastectomy:

  • Unfavourable tumour: breast volume ratio (i.e. a large tumour in a small breast). In these circumstances, consideration should be given to oncoplastic resections (therapeutic mammoplasty, Grissoti flap or round block resections). If these techniques are not available locally, patients should be given the option of referral to an oncoplastic surgeon. Also consider downsizing the tumour with primary medical treatment.
  • Where there is a recurrent tumour in a breast that has previously been irradiated with whole breast radiotherapy.
  • Where radiotherapy may be contraindicated – excessive photosensitivity, vasculitis, severe pulmonary fibrosis, scleroderma, previous mantle radiotherapy. Previous mantle radiotherapy is not an absolute indication for mastectomy and breast conservation with partial breast radiotherapy should be discussed with the patient as an alternative.
  • Where there is extensive ductal carcinoma in situ (DCIS) of high or intermediate grade. If there is extensive low grade DCIS, the patient should be informed of the uncertainty over the natural history of low grade DCIS. Observation may be considered within the context of a clinical trial such as the LORIS trial. Consideration should also be given to biopsy of more than one focus of microcalcification prior to proceeding with mastectomy. A second biopsy should ideally be taken from the edge of suspected extent.
  • Where there are multifocal/multicentric tumours, whether invasive or non-invasive. In some circumstances, oncoplastic techniques may obviate the need for mastectomy and can be considered

Breast reconstruction

  • All patients for whom mastectomy is a treatment option should have the opportunity to receive advice on breast reconstructive surgery. Not all patients will be physically fit for or wish to consider reconstruction. The reason a patient declines or is advised against immediate breast reconstruction (IBR) should be recorded. IBR rates will be compared across Trusts and should not be lower than national average.
  • For patients who express an interest in breast reconstruction, discussions should take place on the ideal timing of the reconstruction. This should include the risks and benefits of immediate versus delayed breast reconstruction techniques.
  • The full range of suitable reconstructive techniques should be discussed with the patient. These should include tissue expansion/implant reconstruction with or without acellular dermal matrix reinforcement, latissimus dorsi flap reconstruction (autologous or with implant), and free flap reconstruction (muscle- sparing TRAM, DIEP, TMG, SGAP or IGAP).
  • If PMRT is likely, full information regarding the potentially unfavourable longer term impact of radiotherapy on both implants and autologous tissue needs to be discussed and considered.
  • Expanders incorporating metal ports with the radiotherapy field may interfere with radiotherapy planning and dosage and should be avoided.

Management of the axilla

  • Pre-operative staging of the axilla should be undertaken in all invasive cancers using ultrasound and, if indicated, guided fine needle aspiration cytology or core biopsy.
  • If pre-operative staging of the axilla reveals metastases (C5 or B5), a Level II/III axillary lymph node dissection (ALND) should be recommended.
  • If pre-operative staging of the axilla is normal both clinically and on imaging, the axilla should be further staged by SLNB. Patients with abnormal imaging but a normal lymph node biopsy should also be offered SLNB.
  • SLN localisation technique must include radio-isotope as a minimum.
  • In March 2015 the Association of Breast Surgeons (ABS) issued a consensus statement to guide management following a positive sentinel node and this is supported by the RCR postoperative radiotherapy for breast cancer: UK consensus statements published in November 2016.
    • Isolated tumour cells (ITC) and micrometastases: If the sentinel node(s) shows isolated tumour cells and/or micrometastases no further axillary treatment is required in addition to breast conserving surgery or mastectomy.
    • 1–2 positive sentinel nodes with macrometastases: Further axillary treatment is no longer mandatory in patients who are receiving breast conservation with whole breast radiotherapy, who are post-menopausal and have T1, grade 1 or 2, ER positive and HER2 negative tumours. These patients could also be entered into the POSNOC or equivalent clinical trial.
    • Further axillary treatment should be recommended if 3 or more positive sentinel nodes.
    • Further axillary treatment should usually be recommended for patients undergoing mastectomy, or with tumours with one or more of the following features: T3, grade 3, ER- or HER2+. These patients could also be entered into the POSNOC or equivalent clinical trial.

Important papers that are relevant to these current recommendations include;

  • EORTC AMAROS study which randomised patients with T1-2 primary breast cancer and no palpable lymphadenopathy to either axillary radiotherapy or axillary lymph node dissection after a positive sentinel node. Axillary recurrence in both arms was low <1% but due to low event rate study underpowered to statistically meet the non-inferiority test. Lymphoedema at 5 yrs was higher (23%) than in the radiotherapy group (11%).
  • The American Z0011 study randomised patients with T1-2 invasive breast cancer with no palpable lymphadenopathy and 1-2 SLNs were randomised to ALND or no further treatment. All patients underwent lumpectomy and tangential whole breast irradiation. There was no significant difference in survival however criticism of the lack of radiotherapy QA means there is concern regarding the generalisability of the findings to current practice.

The current POSNOC trial is a UK trial which is randomising patients with T1-2 invasive breast cancer and 1-2 SLN to either further axillary treatment (ANC or axillary radiotherapy) or adjuvant therapy alone.


EORTC AMAROS study
Rutgers et al
Lancet oncol 2014

Z0011 study
Giulliano et al
JAMA 2011

POSNOC trial protocol
POSNOC trial group
2017

Systemic therapy

Teaching session on metastatic breast cancer treatment, Dr Comins, 2020

Endocrine therapy

Supportive treatments

Radiotherapy

Adjuvant radiotherapy