كتاب
ADVANCED/METASTATIC BREAST CANCER
- Recommendations
Diagnosis, pathology and molecular biology
- At first diagnosis of MBC, a biopsy should be carried out to confirm histology and assess/re-assess tumour biology including ER, PgR, HER2 status & KI 67.
Strong recommendation, high grade evidence (1).
Staging and risk assessment
- The minimum imaging work-up for staging includes computed tomography (CT) of the chest and abdomen, and bone scintigraphy.
Strong recommendation, high grade evidence (2,3).
- 18F-FDG-PET)/CT may be used instead of CT and bone scans only as problem solving tool.
Conditional recommendation, high grade evidence (2,3).
- The interval between imaging and starting treatment should be ≤4 weeks.
Good practice statement.
- Evaluation of response should generally occur every 2-4 months depending on disease dynamics, location, extent of metastasis and type of treatment.
Good practice statement.
- Disease monitoring intervals should not be shortened as there is no evidence of an OS benefit but potential for emotional and financial harm. Less frequent monitoring is acceptable, particularly for indolent disease.
Good practice statement.
- If progression is suspected, additional tests should be carried out in a timely manner irrespective of planned intervals.
Good practice statement.
- Repeat bone scans are a mainstay of evaluation for bone-only/predominant metastases, but image interpretation may be confounded by a possible flare during the first few months of treatment. MRI may be added to define response in specific locations.
Conditional recommendation, low grade evidence (3).
- Impending fracture risk should be evaluated by CT or X-rays. In the case of suspected cord compression, MRI is the modality of choice.
Strong recommendation, high grade evidence (4).
- Symptomatic patients should always undergo brain imaging, preferably with MRI.
Strong recommendation, high grade evidence (5).
HR-positive, HER2-negative breast cancer
- A CDK4/6 inhibitor combined with endocrine therapy (ET) may be used as first-line therapy for patients with ER-positive, HER2-negative MBC. However this depends on the availability, access-ability, patient comorbidity, and budget impact.
Conditional recommendation, high grade evidence (6-8).
- Pre- and perimenopausal women should be offered OFS or ovarian ablation in addition to all endocrine-based therapies.
Strong recommendation, high grade evidence (9).
Second-line treatment
- Selection of second-line therapy (chemotherapy versus further endocrine-based therapy) should be based on disease aggressiveness, extent and organ function, and consideration of the associated toxicity profile.
Good practice statement.
- Everolimus- exemestane is a recommended option
Strong recommendation, high grade evidence(10-13).
- Tamoxifen or fulvestrant can also be combined with everolimus and is recommended. If everolimus is used, stomatitis prophylaxis must be used.
Strong recommendation, high grade evidence (10-13).
- At least two lines of endocrine-based therapy are preferred before moving to chemotherapy in the absence of endocrine refractory disease and/or imminent organ failure.
Strong recommendation, very low grade evidence (14).
- In patients with imminent organ failure, chemotherapy is the preferred option.
Strong recommendation, low grade evidence(14).
- For patients with endocrine-sensitive tumours, continuation of ET with agents not previously received in the metastatic setting is recommended.
Strong recommendation, low grade evidence (14).
Beyond second-line treatment
- Patients with tumours that are endocrine resistant should be considered for chemotherapy.
Strong recommendation, very low grade evidence (14).
- Sequential single-agent chemotherapy is generally preferred over combination strategies. In patients where a rapid response is needed due to imminent organ failure, combination chemotherapy is preferred.
Strong recommendation, high grade evidence (14).
- Available drugs for single-agent chemotherapy include anthracyclines, taxanes, capecitabine, vinorelbine,and platinums .
Strong recommendation, high grade evidence(14).
HER2-positive breast cancer
- Standard first-line treatment of HER2-positive MBC should be trastuzumab-docetaxel regardless of HR status.
Strong recommendation, high grade evidence (15,16).
- Docetaxel should be given for at least six cycles, if tolerated, followed by maintenance trastuzumab until progression.
Strong recommendation, high grade evidence(15,16).
- An alternative taxane (paclitaxel) can be substituted for docetaxel
Strong recommendation, high grade evidence(15,16).
- ET can be added to trastuzumab maintenance after completion of chemotherapy for HER2-positive, HR-positive .
Strong recommendation, high grade evidence (17).
- If chemotherapy is contraindicated in patients with HER2-positive, HR-negative MBC, HER2-targeted therapy without chemotherapy (e.g. trastuzumab) is recmmended.
Strong recommendation, low grade evidence (18).
- if taxane chemotherapy is contraindicated, a less toxic chemotherapy partner (e.g. capecitabine or vinorelbine) should be considered.
Strong recommendation, low grade evidence.
- In selected cases of HER2-positive, HR-positive MBC where the patient is not suitable for first-line chemotherapy, ET (e.g. an AI) in combination with an HER2-targeted therapy, such as trastuzumab, or lapatinib, is recommended.
Strong recommendation, high grade evidence (19,20).
- The use of single-agent ET without HER2-targeted therapy in HER2-positive, HR-positive MBC is not routinely recommended unless comorbidities (e.g. cardiac disease) preclude the safe use of HER2-directed therapies.
Conditional recommendation, low grade evidence (21).
- Patients with metastatic recurrence within 12 months of receiving adjuvant trastuzumab should follow the second-line therapy recommendations.
Strong recommendation, high grade evidence (22).
- In later lines of therapy, lapatinib is an evidence-based therapy option to be used preferably in combinations (e.g. with capecitabine, trastuzumab or ET).
Conditional recommendation, low grade evidence(23).
TNBC
- In cases of imminent organ failure, combination therapy is preferred based on a taxane and/or anthracycline combination.
Conditional recommendation, low grade evidence (14).
- After progression, all chemotherapy recommendations for HER2-negative disease also apply for TNBC, e.g. capecitabine, and vinorelbine.
Strong recommendation, low grade evidence (14).
Site-specific management
Primary stage IV disease
- For patients with newly diagnosed stage IV breast cancer and an intact primary tumour, therapeutic decisions should ideally be discussed in a multidisciplinary context.
Good practice statement.
- Locoregional treatment of the primary tumour in the absence of symptomatic local disease does not lead to an OS benefit and is not routinely recommended.
Good practice statement.
- In patients with local symptoms caused by the primary tumour or metastatic disease, the use of local treatment modalities should be evaluated.
Strong recommendation, high grade evidence(24).
- Surgery of the primary tumour is recommended for patients who may benefit from salvage surgery (e.g. those with bone-only metastases, a good response to initial systemic therapy, HR-positive tumours, HER2-negative tumours, age <55 years and those with OMD).
Strong recommendation, high grade evidence(25).
- Surgery or RT of the primary tumour should be carefully considered for circumstances in which they provide added value for symptom palliation or prevention of complications.
Conditional recommendation, very low grade evidence(25).
Oligometastatic disease
- A multidisciplinary approach is essential to manage patients with bone metastases and prevent skeletal-related events (SREs).
Good practice statement.
- Patients with OMD should be discussed in a multidisciplinary context to individualise management.
Good practice statement.
- Multimodality treatment approaches involving locoregional therapy [e.g. high conformal radiotherapy (RT), image-guided ablation,selective internal RT and/or surgery] combined with systemic treatments are recommended, and should be tailored to the disease presentation in the individual patient.
Strong recommendation, very low grade evidence (26).
- Local ablative therapy to all metastatic lesions may be offered on an individual basis after discussion in a multidisciplinary setting.
Conditional recommendation, moderate grade evidence (26).
Bone metastases and bone-modifying agents
- A multidisciplinary approach is essential to manage patients with bone metastases and prevent skeletal-related events (SREs).
Strong recommendation, very low grade evidence (26).
- An orthopaedic evaluation is advised in the case of significant lesions in the long bones or vertebrae as well as in patients with MSCC to discuss the possible role of surgery.
Strong recommendation, very low grade evidence (26).
- RT is recommended for lesions at moderate risk of fracture and those associated with moderate to severe pain.
Strong recommendation, very low grade evidence (26).
- A single 8-Gy RT fraction is as effective as fractionated schemes in patients with uncomplicated bone metastases.
Strong recommendation, high grade evidence (26).
- RT should be delivered after surgery for stabilisation or separation surgery for MSCC.
Strong recommendation, low grade evidence(26).
- Bone-modifying agents (BMAs) are recommended for patients with bone metastases,regardless of symptoms.
Strong recommendation, high grade evidence (26).
- Before the initiation of BMAs, patients should have a complete dental evaluation and ideally complete any required dental treatment. Calcium and vitamin D supplements should be prescribed.
Strong recommendation, low grade evidence (26).
- The optimal duration of BMA therapy has not been defined but it is reasonable to interrupt therapy after 2 years for patients in remission.
- The ideal sequence of therapies has not been defined but it seems reasonable to document tumour response with a systemic treatment before suggesting locoregional therapy.
Conditional recommendation, very low grade evidence(26).
Brain metastases and leptomeningeal metastases
- Brain metastases should be managed according to the recommendations outlined in the European Association of Neuro-Oncology-ESMO (EANO-ESMO) Clinical Practice Guideline (CPG) for the management of patients with brain metastases from solid tumours.
Strong recommendation, high grade evidence (27).
- Leptomeningeal metastases should be treated according to the recommendations outlined in the EANO-ESMO CPG for the management of patients with leptomeningeal metastases from solid tumours.
Strong recommendation, high grade evidence (27).
Long-term implications and survivorship
- An interdisciplinary approach is critical, including specialised oncology and/or breast care nurses to proactively screen for and manage treatment-emergent toxicities.
Good practice statement.
- Patients should be informed about treatment choices and side-effect profiles of recommended systemic treatments.
Good practice statement.
- All treatments should include formal patient education regarding side-effects of management.
Strong recommendation, high grade evidence (28).
- All efforts should be done to encourage integrated electronic medical records (EMR) in different hospitals
Strong recommendation, high grade evidence(28).
- QoL assessments should be incorporated into the evaluation of treatment efficacy.
Strong recommendation, high grade evidence(28).
- Dose reduction and delay are effective strategies to manage toxicity in advanced disease.
Strong recommendation, high grade evidence(28).
