Management

Management varies considerably depending on the stage of the malignancy. As breast cancer is exceptionally common, there has been significant research into the area and there are good guidelines for the various stages of disease. Some controversy exists, particularly with regards to sentinel node biopsy/axillary dissection, post-mastectomy radiotherapy, dose choice in radiotherapy and choice of hormonal therapies.

Non-invasive Breast Cancer

Please see the Non Invasive Breast Cancer topic.

Early Breast Cancer (Stage I, IIA, and consider IIB or T3 disease)

Based on the NCCN guidelines, other texts and clinical experience

Essential and Landmark Studies

There are several important studies in the development of breast cancer therapy:

  • Milan I: 701 patients with T1 N0 disease; randomised to radical mastectomy vs quandrantectomy + RT
    • This was the first study which supported the use of radiotherapy and breast conservation
    • Long term follow up shows that radical mastectomy had lower rates of local recurrence (2% vs 8%)
    • Overall survival and disease specific survival were identical
  • NSABP B-04: A 1000 patient study that randomised into radical mastectomy, total mastectomy, and total mastectomy + post-mastectomy radiotherapy (PMRT); an additional arm randomised patients with clinically positive nodes to radical mastectomy or total mastectomy + RT (no axillary surgery)
    • This trial demonstrated equivalent overall and disease specific survival for each group, and assisted in the reduction of radical mastectomy cases performed
    • Importantly, it showed that radiotherapy was not always needed in patients treated with mastectomy
  • NSABP B-06: 1851 patients with stage I/II disease, randomised to total mastectomy vs breast conservation vs breast conservation + RT
    • Demonstrated equivalent overall survival and disease free survival.
    • Radiotherapy reduced local recurrence from 40% to 15%
  • EORTC 10801: 902 patients with Stage I/II disease, randomised to modified radical mastectomy vs lumpectomy + 50 Gy RT + boost
    • Identical overall survival
    • Reduced local recurrence in the mastectomy group (12% vs 20%)
    • Criticised for high rates of positive margins in the lumpectomy group (48%)

In summary:

  • Breast conservative surgery + radiotherapy is equivalent to radical or modified radical mastectomy in terms of overall survival and disease specific survival
  • Breast conservative surgery without radiotherapy is associated with a high rate of local recurrence (20-40%)
    • Radiotherapy reduces this risk to 10%

Surgery and Radiotherapy

The patient and surgeon decide on the preferred treatment of the primary tumour - breast conservation or mastectomy. Breast conservation + RT is the standard of care, with mastectomy chosen in patients unable or unwilling to be treated with radiotherapy.

Breast Conservation
  • Wide local excision of the primary preserves the breast, but should always be followed by radiotherapy and is not done if the patient has strong objections to radiation treatment. It is not always possible if the tumour is located in a difficult position (eg. retroareolar). Radiation is mandantory if four or more lymph nodes are involved and strongly recommended if there are any lymph nodes involved. Radiotherapy techniques are discussed in detail here
    • Absolute contraindications include: Previous radiotherapy to the site, current pregnancy, positive surgical margins, and disease that is unable to be resected with adequate cosmesis
    • Relative contraindications include: Systemic fibrotic diseases (scleroderma), large tumours (over 5 cm), focally positive margins and patients with BRCA1/2 genetic abnormalities
    • Some early breast cancers may be too large for wide local excision to be achieved, but otherwise suitable for breast conservation. In these cases neoadjuvant chemotherapy may be employed to reduce the size of the malignancy - see the systemic treatment topic. In general, choice of systemic agents mirrors those for adjuvant systemic treatments.
    • Radiation dose to the breast ranges from 42 Gy / 15 # (short course) to 50 Gy / 25 # (long course), with a 10 Gy boost to the tumour bed. See the radiotherapy topic.

Margin status is particularly important, with higher rates of recurrence reported with close or positive margins despite radiotherapy. In general, margins should be clear by at least 2 mm. Close or involved margins should be re-excised when possible.

Mastectomy
  • Mastectomy frequently requires no further treatment, but has a higher risk of morbidity. Reconstruction is possible after mastectomy. Although patients without positive lymph nodes may avoid radiotherapy treatment, the presence of lymph node metastases is a strong indication for post-mastectomy radiotherapy to the chest wall, axilla and supraclavicular fossa. Other indications for radiotherapy include positive tumour margins, tumour size over 5 cm (T3). Smaller tumours, with margins > 1 mm, can have radiotherapy withheld with no additional risk.

Systemic Therapy

Patients may be referred to a medical oncologist. There are three important decisions to be made:

  • Use of endocrine therapy
  • Use of trastuzumab
  • Use of cytotoxic chemotherapy

These choices are dictated by the histopathology and receptor status of the breast carcinoma, as well as the patient's wishes. The most potent chemotherapy regimens contain an anthracycline and a taxane; the use of both these agents may be poorly tolerated and various regimes for their administration exist.

Tubular and Colloid Carcinomas

These are special types of breast carcinoma; they have a good prognosis and patients often do well in the absence of additional therapy. These tumours are nearly always hormone receptor positive; if receptors are negative they should be rechecked prior to further decisions being made. Hormone receptor negative tubular/colloid carcinomas are treated in a similar way to other breast carcinomas (below).
Small tumours (< 1 cm) do not require adjuvant therapy; endocrine therapy should be discussed with the patient if the tumour size is 1 - 3 cm in size and is definitely recommended for larger tumours. Nodal disease warrants a discussion of chemotherapy with the patient and depends on patient age and wishes.

Hormone Receptor Positive and ERBB2 Negative disease

The most common variant. Very small tumours (< 0.5 cm) without nodal disease do well with endocrine therapy alone; larger tumours warrant a discussion of adjuvant chemotherapy. Macroscopic nodal disease requires systemic chemotherapy unless there are strong contraindications. An important consideration is the use of genetic prediction tests; these involve determination of gene activity within the tumour to give an estimate of how aggressive it will behave. These are still somewhat novel but their availability is increasing.

Hormone Receptor Negative, ERBB2 Positive disease

Also known as "HER2 positive" disease. These tumours are more difficult to treat as they do not respond to the relatively well tolerated endocrine therapies. This is complicated by the more aggressive behaviour of these malignancies. Trastuzumab is always given in combination with chemotherapy for adjuvant treatments.

  • Very small tumours (< 0.5 cm) have no added benefit from trastuzumab and chemotherapy.
  • Small tumours (0.5 - 1 cm) are on the cusp; the potential benefits and disadvantages should be discussed.
  • Tumours over 1 cm, regardless of nodal status, should receive adjuvant treatment
  • The presence of nodal disease necessitates systemic treatment

Hormone Receptor and ERBB2 negative disease ('Triple Negative')

Triple negative breast cancers are usually highly aggressive. This is combined with an absence of useful, non-cytotoxic agents for treatment. Systemic therapy is often recommended to prevent a recurrence of disease, which is usually rapidly fatal.

  • Tumours under 0.5 cm do not require systemic treatment (unless microscopic metastatic is present in sentinel nodes)
  • Tumours from 0.5 - 1 cm warrant a discussion of potential benefits and risks of systemic treatment
  • Tumours over 1 cm, or the presence of macroscopic nodal disease, is a strong indication for initiation of systemic chemotherapy

Triple Positive Breast Carcinoma

An uncommon finding that presents unique opportunities. In general, management follows that of HER2 positive disease, with adjuvant endocrine therapy added to treatment. For small tumours under 0.5 cm endocrine therapy alone should be discussed with the patient.

Locally Advanced Breast Cancer (T4a-b OR N2+)

Locally advanced breast cancer is a less common presentation (about 5% of breast cancers), and includes:

  • Patients with matted axillary lymph nodes (Stage N2)
  • Patients with clinically detected level III axillary nodes or supraclavicular lymph nodes (Stage N3)
  • Patients with skin or chest wall involvement (Stage T4a/T4b)

Patients with locally advanced cancer have typically neglected their tumour and may have other co-morbid conditions. Staging of the malignancy to exclude distant disease is very important.
Management is directed at:

  • Neo-adjuvant systemic therapy to render the malignancy operable
    • Systemic agents are targeted to the tumour histology and receptor status. They are similar to those used for adjuvant systemic treatment. Trastuzumab and hormonal therapies may be incorporated.
    • 80% of patients will have significant reduction in tumour size and nodal metastases
    • Ineffective chemotherapy can be identified (as opposed to adjuvant therapy where there is no visible disease to observe)
    • Two large studies have shown equivalence between neo-adjuvant and adjuvant chemotherapy (NSABP B18 and EORTC 10902) with trends for younger women to have improved outcomes with neo-adjuvant treatment
    • About 27% of patients are able to have breast conservation therapy following neo-adjuvant therapy.
  • Surgical resection if there is a clinical response to systemic therapy
    • Surgical resection should include mastectomy and axillary clearance
    • Post-operative radiotherapy to the level III axillary nodes and supraclavicular fossa is mandantory
    • A full course of systemic therapy should be completed, depending on the amount of systemic therapy given prior to surgery/radiotherapy
  • Further systemic therapy or local radiotherapy to the breast if neo-adjuvant systemic therapy is unsuccessful; this may lead to an operable situation in some patients.
  • In the event of a lack of response, individual (and likely palliative) measures should be instituted

Management of metastatic disease is discussed below.

Inflammatory Breast Cancer (T4c)

Inflammatory breast cancer is defined by the presence of erythema and oedema that covers at least one third of the breast, usually associated with malignant infiltration of dermal lymphatics. Staging must be performed to exclude distant disease.
Initial management is with neo-adjuvant systemic therapy, ideally including an anthracycline and a taxane. In the event of ERBB2 positivity, trastuzumab is included. Neo-adjuvant hormonal manipulation is also possible.

  • If a response is achieved, the patient proceeds to mastectomy and post-operative radiotherapy to the chest wall, axilla and supraclavicular fossa.
  • In the absence of response, further chemotherapy or neo-adjuvant radiotherapy may be considered (similar doses to adjuvant therapy)
  • If response is unobtainable then palliative measures are instituted

Metastatic Breast Cancer (M1)

Metastatic breast cancer on diagnosis is often well palliated with systemic therapy, particularly if there is positivity for HER2 or hormonal receptors. This dictates the management approach. Another important consideration is the presence of bony metastases - if present, addition of a bisphosphonate is suggested (zoledronate, palmidronate)

  • Hormone-receptor positive disease is ideally treated through reduction in circulating oestrogens.
    • In pre-menopausal women, this involves ovarian ablation and initiation of an aromatase inhibitor
    • Post-menopausal women are treated with aromatase inhibitors
    • Patients with extensive visceral disease (typically liver or lung metastases) should be considered for cytotoxic therapy immediately. If ERBB2 status is positive, trastuzumab can be considered.
  • Triple negative patients require chemotherapy; this should be administered as necessary until symptoms are controlled or the patient is not fit for further treatment
    • Failure of three lines of chemotherapy sequentially suggests that the patient should commence fully palliative measures
  • ERBB2 positive patients should be treated with trastuzumab, either alone or combined with cytotoxic treatments. Lapatanib, a tyrosine kinase inhibitor directed against ERBB2, may also be included if there is lack of response to initial therapy.

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