Advanced breast cancer is not treated with a single approach; it is managed through personalised therapy tailored to each patient who receives long-term systemic therapy that changes over time. General practitioners play a key role in ongoing care, early detection of complications, and patient support.
Advanced breast cancer includes:
- Locally advanced breast cancer, stage III
- Metastatic breast cancer, stage IV
The goals of treatment are to:
- Shrink and control tumour growth
- Relieve symptoms
- Prolong survival
- Maintain quality of life
Overview for General Practitioners
Breast cancer patients:
- Receive long-term systemic therapy
- Have treatment changes over time
Role of General Practitioners:
- Monitor for complications and manage side effects
- Identify red flags early
- Manage comorbidities
- Support patients and caregivers
- Shared care with oncology team
1. Locally Advanced Breast Cancer (Stage III)
Locally advanced breast cancer (LABC) includes large primary tumours, involvement of skin or chest wall, or extensive regional lymph node disease. Treatment aim is still curative.
Typical sequence:
- Neoadjuvant systemic therapy to downstage the tumour and improve surgical options
- Surgery – either mastectomy or breast-conserving surgery depending on response
- Radiotherapy to optimise local control
- Adjuvant systemic therapy
2. Metastatic Breast Cancer (Stage IV)
Metastatic breast cancer refers to cancer that has spread to other parts of the body, most commonly to bone, liver, lungs and brain. Unlike early breast cancer, metastatic disease is not curable, and treatment intent is predominantly palliative, balancing disease control with preservation of quality of life.
Treatment of metastatic breast cancer is determined by:
- Tumour subtype and biomarkers
- Disease burden
- Prior therapy
- Patient’s performance status and preferences
Visceral crisis refers to severe organ dysfunction due to tumour burden, such as impending liver failure or severe respiratory compromise. In these situations, chemotherapy, which provides a more rapid response, may be indicated.
3. Biomarker Testing in Advanced Breast Cancer
Biomarker testing in breast cancer is crucial, as it guides treatment selection. Core biomarkers:
- ER (oestrogen receptor) and PR (progesterone receptor) – also known as HR (hormone receptor)
- HER2 (human epidermal growth factor receptor 2)
Triple-negative breast cancer (TNBC) is an aggressive breast cancer which does not express ER/PR or HER2 receptors and therefore does not respond to either hormonal or HER2-targeted therapy.
Additional biomarkers:
- PD-L1 (Programmed death-ligand 1) expression, to identify patients who may benefit from immunotherapy
- PIK3CA and AKT pathway mutations, to guide targeted therapy
- ESR1 mutation, associated with endocrine resistance
- Germline BRCA1/2 mutations, to guide PARP inhibitor use and inform family risk
Key points for General Practitioners:
- Testing is essential for personalised treatment
- Patients may ask about genetic implications
4. Overview of Systemic Treatment Modalities
Systemic therapy is the main treatment for metastatic breast cancer. Different classes are used depending on tumour subtype, and many are used in combination to improve treatment response. Examples of commonly used agents are summarised in the table at the end of this document.
| Treatment Modality | Mechanism of Action |
| Endocrine therapy | Blocks or reduces the effect of oestrogen on tumour cells. Used in HR+ disease. |
| CDK4/6 inhibitors | Slows cancer cell division by inhibiting cell cycle progression. Used in combination with endocrine therapy. |
| Anti-HER2 targeted therapy | Blocks HER2 signalling and tumour growth. Used in the treatment of HER2+ disease. |
| Antibody-drug conjugates (ADC) | Delivers chemotherapy directly to cancer cells via targeted antibodies. Used in the treatment of all subtypes of breast cancer. |
| Immunotherapy | Activates the immune system to recognise and attack cancer cells. Used in the treatment of TNBC. |
| PARP inhibitors | Blocks DNA repair in cancer cells, leading to cell death. Used in the treatment of patients with germline BRCA1/2 mutations. |
| Chemotherapy | Kills rapidly dividing cells. Used in the treatment of all subtypes of breast cancer. |
| PI3K/AKT/mTOR inhibitors | Blocks signalling pathways that promote tumour growth and survival. Used in combination with endocrine therapy. |
| Selective oestrogen receptor degraders (SERD) | Degrades the oestrogen receptor, including resistant forms. Used in the treatment of tumours with ESR1 mutations. |
Note: HER2-low disease refers to tumours with low HER2 expression. Certain antibody-drug conjugates, particularly trastuzumab deruxtecan, are effective in this group.
Abbreviations: HR, Hormone Receptor; CDK4/6, Cyclin-Dependent Kinase 4 and 6 inhibitors; HER2, Human Epidermal Growth Factor Receptor 2; ADC, Antibody-Drug Conjugates; TNBC, Triple Negative Breast Cancer; PARP, Poly(ADP-ribose) Polymerase; BRCA, BReast CAncer genes; PI3K, Phosphoinositide 3-kinase; AKT, Protein Kinase B; mTOR, mechanistic Target of Rapamycin; SERD, Selective Oestrogen Receptor Degraders; ESR1, Oestrogen Receptor 1
5. Treatment by Subtype
5.1 Hormone Receptor-Positive Disease
Typical treatment:
- Endocrine therapy with targeted agents (CDK4/6 inhibitors, PI3K/AKT/mTOR inhibitors)
- ADCs
- Selective oestrogen receptor degraders in ESR1-mutated tumours
5.2 HER2-Positive Disease
Typical treatment:
- Anti-HER2 therapy, often with chemotherapy. Can also be combined with endocrine therapy in HR+/HER2+ disease
- ADCs
5.3 Triple-Negative Breast Cancer
Typical treatment:
- Chemotherapy
- Immunotherapy in the neoadjuvant setting, and in PD-L1 positive disease in the metastatic setting
- ADCs
6. Quick Reference: Treatment-Related Toxicities
| Treatment Type | Common Agents | Common Side Effects |
| Endocrine therapy | Tamoxifen, letrozole, anastrozole, exemestane, fulvestrant | Hot flushes, arthralgia, BMD loss, thromboembolism (tamoxifen) |
| CDK4/6 inhibitors | Palbociclib, ribociclib, abemaciclib | Myelosuppression, diarrhoea, fatigue, hepatotoxicity, QTc prolongation (ribociclib) |
| HER2-targeted therapy | Trastuzumab, pertuzumab, tucatinib, lapatinib, neratinib | Cardiotoxicity, diarrhoea, infusion reactions, hand-foot syndrome (lapatinib, tucatinib) |
| Immunotherapy | Pembrolizumab | Colitis, pneumonitis, hepatitis, thyroid dysfunction, dermatitis, adrenal insufficiency, renal dysfunction, myalgia |
| Antibody-drug conjugates (ADC) | Trastuzumab deruxtecan, trastuzumab emtansine, sacituzumab govitecan, datopotamab deruxtecan | Myelosuppression, nausea, diarrhoea, ILD/pneumonitis (potentially fatal) |
| Chemotherapy | Paclitaxel, docetaxel, capecitabine, carboplatin, anthracyclines (doxorubicin, epirubicin), gemcitabine, vinorelbine, eribulin | Myelosuppression, alopecia, neuropathy, nausea, diarrhoea |
| PARP inhibitors | Olaparib, talazoparib | Myelosuppression, fatigue, nausea, MDS/AML (rare long-term risk) |
| PI3K/AKT/mTOR inhibitors | Alpelisib, inavolisib, capivasertib, everolimus | Hyperglycaemia, rash, diarrhoea, mucositis |
| SERDs | Elacestrant | Nausea, fatigue, arthralgia |
Abbreviations: BMD, Bone Mineral Density; ILD, Interstitial Lung Disease; MDS, Myelodysplastic Syndrome; AML, Acute Myeloid Leukaemia
7. Bone-Directed Therapy
Bone modifying agents (BMA) are medications used to strengthen bone and reduce skeletal-related events such as fractures, spinal cord compression, and the need for radiation or surgery to bone. Endocrine therapy, especially aromatase inhibitors, can cause bone mineral density loss. Bone is the most common site of metastatic disease in breast cancer.
Common agents:
- Zoledronic acid
- Denosumab
- Alendronate
Side effects:
- Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)
- Hypocalcaemia
- Renal impairment
Key points for General Practitioners:
- Dental clearance is required before starting bone-directed therapy to reduce BRONJ risk
- Routine dental hygiene should be maintained during treatment
- Monitor renal function
- Calcium and vitamin D supplementation is recommended for all patients on bone-directed therapy
8. Surgery in Advanced Breast Cancer
Used for:
- Curative intent in locally advanced disease
- Local symptom control in metastatic disease and improving quality of life
Toilet mastectomy
- Used for severe local symptoms – e.g. manage uncontrolled bleeding, pain, infection, or ulceration from a locally progressive tumour that is not responding to systemic therapy or radiation.
9. Palliative Radiotherapy
Radiation therapy plays a key supportive role in advanced breast cancer.
Common Indications
- Painful bone metastases not adequately controlled with analgesia
- Brain metastases (whole-brain radiation or stereotactic radiosurgery)
- Spinal cord compression (urgent)
- Bleeding or fungating chest wall tumours
- Symptomatic soft tissue or nodal disease causing local complications
10. Fungating Tumours and Wound Care
Fungating tumours can cause significant distress due to odour, bleeding, pain, and exudate. The goal is symptom control.
| Problem | Approach | Dressing Examples |
| Odour | Topical or oral metronidazole, charcoal dressings, increase frequency of dressing change | CliniSorb, Actisorb Silver |
| Exudate | Absorbent dressings, protect surrounding skin | Melolin dressing, Alginate dressings, foam dressings |
| Bleeding | Gentle handling, haemostatic dressings | Non-adherent dressings, Tranexamic acid-soaked gauze, Surgicel |
| Pain | Analgesia before dressing, atraumatic dressings | Silicone dressings, lignocaine gel |
| Itching | Check for sensitivities to dressing materials, protect surrounding skin | Barrier film to protect surrounding tissue, and topical steroid |
Refer if:
- Infection
- Uncontrolled bleeding
- Rapid progression
11. Palliative and Terminal Care
The transition from active treatment to best supportive care occurs when the burden of treatment outweighs its benefit. Indicators include:
- Progressive disease despite multiple lines of systemic therapy
- Declining performance status limiting tolerance of further treatment
- Patient preference to prioritise comfort over further anti-cancer therapy
In Singapore, a range of home-based and inpatient palliative care services are available through various providers. For information on available palliative care services, please refer to the Singapore Hospice Council website.
Caregivers face significant physical, emotional, and financial strain.
The Singapore Cancer Society, the Breast Cancer Foundation, hospital-based and community hospice organisations offer caregiver support programmes, including counselling, respite care, and practical assistance.
Role of General Practitioners:
- Discuss Advance Care Planning (ACP)
- Direct patients and caregivers to these resources
- Partner with the oncology team in managing symptoms
12. Traditional and Complementary Medicine
Many patients in Singapore use traditional Chinese medicine (TCM) or other complementary therapies alongside conventional cancer treatment.
Certain herbal preparations can interact with cancer therapies. Examples include: St John’s wort (induces CYP3A4, reducing efficacy of many cancer drugs), and herbal products with anticoagulant properties (increased bleeding risk in thrombocytopenic patients).
Role of General Practitioners:
- Ask routinely
- Watch for interactions
- Encourage disclosure
13. Red Flags
General practitioners play a critical role in recognising complications and ensuring timely escalation of care. The following table summarises key clinical red flags which require urgent specialist referral.
| Clinical Scenario | What to Look For | Cause |
| Febrile neutropenia | Temperature ≥38°C with low neutrophil count | Chemotherapy or targeted therapy |
| Cardiac toxicity | Breathlessness, orthopnoea, peripheral oedema | HER2 therapy, Chemotherapy (anthracyclines) |
| Spinal cord compression | Back pain, limb weakness, sensory loss, bladder or bowel dysfunction | Vertebral metastases |
| Brain metastases | Headache, seizures, confusion, focal neurological deficit, personality changes | CNS involvement |
| Lung toxicity (ILD / pneumonitis) | Dry cough, progressive dyspnoea, hypoxia | ADCs, immunotherapy |
| Severe diarrhoea / colitis | ≥4 stools/day above baseline, bloody diarrhoea | Immunotherapy, ADCs, targeted therapy, chemotherapy |
| Hypercalcaemia | Confusion, constipation, nausea, polyuria, polydipsia | Bone metastases |
| Immune-related adverse events (irAE) | Any new organ-specific symptoms in a patient on immunotherapy Common: colitis, hepatitis, pneumonitis, thyroiditis, dermatitis Note: irAEs can occur weeks to months after stopping immunotherapy | Immunotherapy |
Abbreviations: CNS, central nervous system; ADC, antibody drug conjugates; irAE, immune-related adverse events
Disclaimer:
This article is intended for healthcare professionals and provides a general overview of current treatment principles in advanced breast cancer. It is not a substitute for specialist clinical judgment, multidisciplinary discussion, or institution-specific protocols. Treatment decisions should be individualised, and readers should refer to current clinical guidelines and local prescribing information where appropriate.
*Article contributed by Dr Wong Chiung Ing, Senior Consultant, Medical Oncologist at Parkway Cancer Centre
References
1. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Breast Cancer. Available at: www.nccn.org.
2. Singapore Cancer Registry. 50 Years of Cancer Registration. National Registry of Diseases Office, Singapore. Available at: www.nrdo.gov.sg.
3. Cardoso F, et al. 6th and 7th International consensus guidelines for the management of advanced breast cancer (ABC guidelines 6 and 7). Breast. 2024;76:103756.