Metastatic breast cancer and palliative care

Introduction

In all but a few rare instances, once breast cancer has metastasised, the disease is incurable. Treatment is aimed at control of the disease, potentially prolonging life, relieving symptoms or putting off the time that symptoms may occur, aiming to improve or maintain quality of life. Management may involve active anticancer treatment, but as important is an active approach to symptom management and appropriate support for patients and their families.

Although the disease is incurable, many women will derive significant benefit from anticancer treatment. Whilst prognosis is variable, dependent on the pattern of disease and response to treatment, many women will survive a number of years on and off treatment with a good quality of life. Some anticancer treatments have the potential for significant side-effects, and when considering treatment options, it is important to balance the potential benefits against the burden of treatment.

Breast cancer is now recognised as many different diseases rather that a single entity. This is based on the clinical behaviour of the disease (e.g. visceral versus bone only metastases), but increasingly on a greater understanding of the molecular basis of breast cancer. In modern practice, treatment for breast cancer is selected based on the expression of molecular markers such as oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Increasingly, novel therapies are being designed against new molecular targets as they are being identified, such that treatments may be selected according to individual molecular phenotype. Understanding molecular characteristics, as well as taking into account patient factors, such as comorbidities, performance status and social and psychological circumstances, allows us to move towards an era of individualised cancer medicine.

The management of metastatic breast cancer can be complex and requires input from members of a wide multidisciplinary team, including breast surgeons, oncologists, pathologists and diagnostic radiologists, but also from time to time other specialists including interventional radiologists, neurosurgeons, orthopaedic surgeons, cardiologists, respiratory physicians and specialists in palliative care. Of vital importance is the need for an individual to coordinate and sign-post patients through often complex pathways of care. The breast care nurse will often act as a patient’s keyworker, providing on-going information and support.

Presentation and prognosis

In the UK approximately 55 000 women are diagnosed with breast cancer each year. Whilst a relatively small number of women will have metastatic disease at the time of their initial diagnosis (6–7%), approximately 30% of patients initially diagnosed with early breast cancer will go on to develop recurrent or metastatic disease. Although the mortality rates for breast cancer are slowly falling, more than 11 000 patients die each year as a consequence of metastatic disease.

Breast cancer can metastasise by both lymphatic and haematogenous routes and can affect any organ of the body. Common sites of disease include liver and lungs, with bone being the commonest (41%). Other sites include brain, leptomeninges, mediastinum, peritoneum and pleura.

Clinically, different patterns of metastatic disease are recognised, with 26% of patients having bone-only metastatic disease, which seems to have a more indolent behaviour than visceral disease ( Fig. 17.1 ). Different biological subtypes ( Table 17.1 ) of breast cancer seem to be loosely associated with these different patterns of metastatic spread, with hormone receptor (HR)-positive, low-grade cancers (Luminal A) most commonly associated with bone-only disease, whilst patients with HR-negative, HER2-positive or triple-negative cancers more commonly develop visceral metastases. Lobular breast cancer is associated with peritoneal/pleural metastases.

Figure 17.1, Comparison of overall survival according to anatomic site of distant involvement ( P = 0.0090). CNS , Central nervous system.

Table 17.1

St Gallen 2013 consensus meeting: definitions of breast cancer subtypes

Subtype	Clinic-pathological definition
Luminal A	ER and PR positive HER2 negative Low grade (Ki67 “low”)
Luminal B (HER2 negative)	ER positive HER2 negative High grade (Ki67 “high”) or PR negative
Luminal B (HER2 positive)	ER positive HER2 overexpressed or amplified Any grade Any PR
HER2 positive (non-luminal)	HER2 overexpressed or amplified ER and PR negative
Basal-like/triple negative (ductal)	ER and PR negative HER2 negative

ER , Oestrogen receptor; HER2 , human epidermal growth factor receptor 2; PR , progesterone receptor.

Patients presenting with metastatic breast cancer can present with a wide variety of symptoms, dependent on the site of metastases. Symptoms associated with common sites of recurrence are listed ( Table 17.2 ); however there are many case reports of unusual presentations of the disease. Clinicians need to be alert to the possibility of metastatic breast cancer in patients presenting with new, progressive or unexplained symptoms.

Table 17.2

Symptoms associated with metastatic breast cancer

Site of disease	Symptoms and complications
Bone	Pain Pathological fracture Nausea, thirst, confusion (due to hypercalcaemia) Leg weakness, bowel or bladder disturbance (due to malignant spinal cord or cauda equina compression). Neurological symptoms (due to nerve root or cranial nerve compression)
Liver	Pain Jaundice
Lung	Dyspnoea Cough
Pleura	Dyspnoea (due to pleural effusion)
Brain	Headache Nausea Unilateral weakness Seizure Unsteadiness, dizziness (due to cerebellar metastases)
Leptomeninges	Unusual neurological symptoms (e.g. “numb chin syndrome”)
Choroidal metastases	Visual disturbance
Intra-abdominal	Abdominal distension (due to ascites) Pain Bowel obstruction Ureteric obstruction

Staging

For patients presenting with early breast cancer, investigations looking for metastatic disease should not be performed routinely and only in patients with symptoms suggestive of metastases, or in patients with particularly high-risk disease, although which patients and which investigations remain controversial.

Investigations for patients presenting with metastatic disease are required to establish the sites of disease, which will influence overall management. These may include a panel of blood tests (full blood count, urea and electrolytes, liver function tests and relevant tumour markers); a computed tomography (CT) scan of the chest, abdomen and pelvis; and bone scintigraphy. Magnetic resonance imaging (MRI) scan may be more sensitive in identifying bone metastases, if there are persistent symptoms at a particular site or concern about vertebral integrity. CT of the head should be performed in patients with symptoms of intracranial metastases, although MRI may be more sensitive particularly in detecting leptomeningeal disease. MRI of the whole spine should be arranged urgently for patients presenting with symptoms of malignant spinal cord compression. Positron emission tomography (PET)-CT may be considered prior to aggressive surgical intervention for solitary or oligometastases, or to detect additional sites of occult metastases.

It is now routine to perform a biopsy of sites of metastases, in order to determine the receptor status of the metastatic disease, as there may be discordance between the primary and metastatic disease which will have implications for the choice of therapy.

Discordance rates for ER, PR and HER2 status have been reported in 20%, 33% and 8% of cases, respectively.

Treatment

The management of metastatic breast cancer is frequently complex, requiring a multimodality and multidisciplinary approach. There may be requirements for systemic therapy for overall disease control; palliative radiotherapy to treat specific areas of symptomatic disease; specific supportive therapies such as bisphosphonates, surgical or radiotherapeutic approaches for isolated or oligometastases; interventional radiology for drainage of pleural effusions or ascites; as well integration with good supportive and symptomatic care.

Systemic therapy

Metastatic breast cancer is a systemic disease, due to haematogenous or lymphatic spread of tumour cells, frequently with multiple sites of detectable disease, and inevitably with additional occult non-detectable disease. Therefore, systemic therapy plays a key role in overall disease control.

In selecting systemic therapy, it is necessary to take into account the molecular phenotype of the cancer (ER, PR and HER2 status), pattern of metastatic disease (e.g. bone-only versus visceral), prior adjuvant therapy, time since prior therapy and of course patient factors (age, comorbidities, organ function, performance status, patient wishes).

As well as the traditional modalities of endocrine therapy and chemotherapy, the last few years have seen exciting developments in targeted therapies, biological therapies and immunotherapy, some of which have had a significant impact on our ability to control metastatic breast cancer.

Testing for molecular biomarkers, such as germline BRCA gene mutations and tumour expression of programmed death ligand-1 (PD-L1), has become routine, to guide the use of these new therapies.

However, choice of treatment is commonly dependent on pharmaceutical regulatory and funding approval. In England and Wales, decisions regarding routine commissioning of new treatments are made by the National Institute for Health and Care Excellence (NICE), which undertakes a detailed assessment of efficacy and cost effectiveness.

Endocrine therapy

HR-positive metastatic breast cancer is most common, with more than seventy per cent of tumours expressing ER.

In women with HR-positive disease, with bone-only or low-volume, asymptomatic visceral disease, endocrine therapy is the mainstay of treatment.

In addition, for women with HR-positive disease, where chemotherapy is indicated, for example in rapidly progressing disease with impending organ failure (visceral crisis), endocrine therapy should be commenced following chemotherapy, once a response has been achieved.

A number of endocrine therapy strategies are used either to reduce oestrogen production (ovarian ablation, luteinising hormone-releasing hormone [LHRH] agonists, aromatase inhibitors [AIs]) or to act at the ER (tamoxifen, fulvestrant). Less commonly progestogens may be used ( Table 17.3 ). The choice of therapy is determined by prior adjuvant therapy and the duration since prior therapy. There does not appear to be any benefit in combining endocrine therapy with chemotherapy.

Table 17.3

Endocrine therapies for metastatic breast cancer

Agent	Mechanism of action	Side effects
Ovarian ablation Surgical oophorectomy Ovarian irradiation LHRH agonists – Goserelin – Leuprorelin	Reduction in ovarian oestrogen production	Menopausal symptoms
Aromatase inhibitors Non-steroidal – Anastrozole – Letrozole Steroidal Exemestane	Reduction in circulating oestrogen, by blocking peripheral conversion of adrenal androgens	Menopausal symptoms Arthralgia Osteoporosis
Selective oestrogen receptor modulator (SERM) – Tamoxifen – Toremifene	Dimerisation of ER – Oestrogen antagonists in breast – Oestrogen agonist in bone and endometrium	Menopausal symptoms Thromboembolism
Selective oestrogen receptor down-regulator (SERD) – Fulvestrant	Dimerisation of ER – Pure oestrogen antagonist	Menopausal symptoms Thromboembolism
Progestogens – Megestrol acetate – Medroxy progesterone acetate		Weight gain Increased appetite Thromboembolism Glucocorticoid suppression

ER , Oestrogen receptor; LHRH , luteinising hormone-releasing hormone.

Premenopausal women

The first demonstration of the efficacy of endocrine therapy was by Beatson in 1896 by performing surgical oophorectomy for advanced breast cancer in two premenopausal women.

Tamoxifen as a single agent has activity in metastatic disease, with a similar efficacy to ovarian ablation. However, tamoxifen in combination with ovarian ablation is superior to ovarian ablation alone.

AIs should not be used in premenopausal women as a single agent, as they trigger a negative feedback loop to the pituitary increasing ovarian oestrogen production. However, they are active when used in combination with ovarian function suppression (OFS) or ablation (OFA).

Many of the trials in HR-positive disease have not included premenopausal women. However, it is generally recommended that premenopausal women receive adequate OFS/OFA and are then treated in the same way as postmenopausal women.

First-line therapy should be ovarian suppression with a LHRH agonist in combination endocrine agents, with or without additional targeted therapies.

Postmenopausal women

In postmenopausal women oestrogen is produced by the conversion of adrenal androgens by aromatase. AIs reduce circulating oestrogen to near undetectable levels.

Prior to the advent of targeted therapies, a non-steroidal AI (anastrozole or letrozole) has been considered standard first-line therapy (including in women who have previously received an AI in the adjuvant setting, but with a relapse free interval of greater than 12 months). Anastrozole is superior to tamoxifen with a median time to progression (TTP) of 11.1 versus 5.6 months.

First-line treatment should be continued until disease progression, which must be carefully assessed by a combination of symptoms, examination, imaging, tumour markers and biochemistry. Assessment of bone-only disease can be difficult.

The choice of second- and subsequent-line therapy should take into account prior treatment exposure and response. Lack of benefit with prior endocrine therapy may be associated with poor or short response to subsequent therapy. In women who continue to demonstrate a response to endocrine therapy, and in the absence of rapid progression or organ dysfunction, sequential therapy should be used. Options include exemestane, fulvestrant, tamoxifen or progestogens. The EFECT study compared exemestane with low-dose fulvestrant and demonstrated equivalence (supporting the use of a steroidal AI after disease progression on a non-steroidal AI). However, the CONFIRM trial showed high-dose fulvestrant to be more effective than low dose, with an improvement in overall survival (OS) from 22.3 to 26.4 months, suggesting that high-dose fulvestrant may be superior to exemestane.

The mechanism of action of progestogens is less clear, but they may be of benefit in later stages of the disease, with modest response rates of around 10–23%, ^, but with some of their glucocorticoid effects helping to improve appetite and reduce symptoms of cachexia.

Targeted therapies in hormone receptor positive disease

There is an increased understanding of the intracellular signalling pathways that interact with the ER, and which may be involved in resistance to endocrine therapies. These provide a number of targets for novel agents to overcome endocrine resistance and have been the subject of intense investigation ( Fig. 17.2 ).

Figure 17.2, Growth factor receptor and intracellular targets in hormone receptor-positive advanced breast cancer. CDK , Cyclin-dependent kinase; EGFR , epidermal growth factor receptor; ER , oestrogen receptor; FGFR , fibroblast growth factor receptor; HDAC , histone deacetylase; HER2/3 , human epidermal growth factor receptor 2/3; IGFR , insulin-like growth factor receptor; MDM2 , murine double minute 2; Me , methylation; mTOR , mammalian target of rapamycin; PI3K , phosphatidylinositol-3 kinase; STAT3 , signal transducer and activator of transcription 3.

Over recent years, the development of cyclin dependent kinase (CDK) 4/6 inhibitors has made a significant impact on the management of HR-positive, HER2-negative metastatic breast cancer. The agents abemaciclib, palbociclib and ribociclib, in combination with an AI compared to an AI alone as first-line endocrine therapy, have all shown significant increases in progression-free survival (PFS) of around 10 months or more ( Table 17.4 ). In patients whose disease has progressed on prior endocrine therapy, CDK4/6 inhibitors, in combination with fulvestrant compared to fulvestrant alone, have all shown increases in both PFS and OS. MONALEESA-7 looked specifically at peri- or premenopausal women and showed a benefit in both PFS and OS for the addition of ribociclib to OFS with goserelin and endocrine therapy ( Table 17.4 ). These agents are all well tolerated, with uncomplicated neutropenia being the most common adverse event for palbociclib and ribociclib, while abemaciclib is associated with less myelosuppression but is associated with diarrhoea, which is usually mild.

A CDK4/6 inhibitor in combination with endocrine therapy is now considered to be standard of care in either the first- or second-line setting.

Table 17.4

Phase III trials of CDK4/6 inhibitors in HR-positive/HER2-negative advanced breast cancer

Study	CDK4/6 inhibitor	Study population	Line of therapy	Sample size	Median PFS vs placebo	OS vs placebo
In combination with non-steroidal aromatase inhibitor (NSAI)
PALOMA 2	Palbociclib	Postmenopausal women No prior systemic treatment for advanced disease >12 months from prior adjuvant endocrine therapy	First line	666	24.8 vs 14.8
MONALEESA 2	Ribociclib		First line	668	NR vs 16.4
MONARCH 3	Abemaciclib		First line	493	NR vs 14.7
In combination with tamoxifen or NSAI + goserelin
MONALEEESA 7 ,	Ribociclib	Pre/perimenopausal women No prior endocrine therapy for advanced disease ≤1 line of chemotherapy for advanced disease	First line	672	23.8 vs 13.0	At 42 months 70.2% vs 45.9%
In combination with fulvestrant
PALOMA 3 ,	Palbociclib	Postmenopausal women/men ≤1 line of endocrine therapy for advanced disease	Second and subsequent line	521	9.5 vs 4.6	Median 34.9 vs 28.0 months
MONALEESA 3 ,	Ribociclib	Any menopausal status Progression during prior endocrine therapy ≤1 line of endocrine therapy, no prior chemotherapy for advanced disease	First and second line	726	20.5 vs 12.8	At 42 months 57.8% vs 45.9 %
MONARCH 2 ,	Abemaciclib	Any menopausal status Progression during prior endocrine therapy ≤1 line of chemotherapy for advanced disease	Second line	669	16.4 vs 9.3	46.7 vs 37.3 months

HR , Hormone receptor; HER2 , human epidermal growth factor receptor 2; PFS , progression-free survival; OS , overall survival.

The phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is important in endocrine resistance, resulting in cell survival despite oestrogen blockade. In the second-line setting (patients with recurrent or progressive disease whilst receiving a non-steroidal AI), everolimus (an mTOR antagonist) in combination with exemestane demonstrated an increase in PFS (6.9 versus 2.8 months) compared to exemestane alone. This was at the expense of additional toxicity including stomatitis, fatigue, rash and pneumonitis. Although this study predates the development of CDK4/6 inhibitors, the use of everolimus with exemestane remains an option as second- or subsequent-line endocrine therapy, in appropriate patients. Tumour PIK3CA gene mutations occur in approximately 40% of patients with HR-positive, HER2-negative breast cancer. Alpelisib is an α-specific PI3K inhibitor. In patients whose disease had progressed during or after an AI and who had a confirmed PIK3CA mutation, alpelisib in combination with fulvestrant versus fulvestrant alone showed an improvement in PFS of 11.0 versus 5.7 months. The commonest adverse effects were hyperglycaemia, diarrhoea, nausea and rash. Hyperglycaemia is an expected ‘on-target’ effect of PI3K inhibition but can be managed with oral hypoglycaemic agents such as metformin. The place of alpelisib in the treatment algorithm for HR-positive, HER2-negative breast cancer is to be established, and tumour tissue PIK3CA mutation testing is not currently routine.

Chemotherapy

Cytotoxic chemotherapy agents act on cells undergoing mitosis by a variety of mechanisms, such as DNA cross-linking, DNA stand breaks, preventing DNA unwinding or inhibiting functioning of the mitotic spindle. However, these actions are not specific to cancer cells; hence chemotherapy drugs often have a narrow therapeutic window, with a high incidence of side-effects at effective doses. A number of chemotherapy agents have shown activity in metastatic breast cancer ( Table 17.5 ).

Table 17.5

Chemotherapy agents active in metastatic breast cancer

Class of drug	Examples	Mechanism of action	Common side-effects
Anthracyclines	Epirubicin Doxorubicin (Adriamycin)	Intercalates DNA	Mucositis cardiomyopathy
Alkylating agents	Cyclophosphamide	Alkyl group cross-links DNA
Antimetabolites	Capecitabine (prodrug converted to 5FU) Gemcitabine	Analogues of nucleosides incorporated into DNA	Hand foot syndrome Mucositis, diarrhoea Transaminitis
Eribulin		Tubulin binding, inhibiting mitotic spindle formation	Peripheral neuropathy
Platinum	Carboplatin Cisplatin	Cross-links DNA	Peripheral neuropathy Renal toxicity
Taxanes	Paclitaxel Docetaxel	Inhibits mitotic spindle disassembly	Peripheral neuropathy
Vinca alkaloids	Vinorelbine	Tubulin binding, inhibiting mitotic spindle formation	Peripheral and autonomic neuropathy

All of these drugs will cause fatigue, nausea and vomiting and myelosuppression. Many cause partial or complete alopecia, but this is not universal.

While endocrine therapy is the cornerstone of treatment for HR-positive metastatic breast cancer, chemotherapy is indicated in patients with rapidly progressing disease, symptomatic visceral disease or organ dysfunction, or when the disease no longer responds to endocrine therapy. Until recently, chemotherapy was the only established systemic treatment option for triple-negative disease.

When selecting chemotherapy treatments, it is necessary to take into account the molecular phenotype of the cancer, pattern of metastatic disease, prior adjuvant therapy (time since prior therapy, agents used) and, of course, patient factors (age, comorbidities, organ function, performance status and patient wishes).

Combination chemotherapy may produce a higher response rate, but is likely to be associated with greater toxicity, without any benefit in OS, and sequential monotherapy is often preferable.

Many chemotherapy agents are given as a course of treatment over 4 to 6 months, with duration limited by cumulative toxicity. However, where possible for some chemotherapy agents (e.g. capecitabine), disease control can be maintained with low toxicity by continuing treatment until progression.

No single agent has demonstrated superiority in the treatment of patients with advanced breast cancer, although the evidence for efficacy is strongest for taxanes and anthracyclines. While many women will have received one or both of these classes of drugs as part of adjuvant therapy, rechallenge in first- or later-line therapy is possible and may be associated with a significant response that is dependent on disease-free interval (DFI) (34.8% for disease-free survival [DFS] <1 year; 42.9% for DFI 1–2 years; and 63.3% for DFI >2 years).

Until recently, there has been little evidence to support tailoring chemotherapy to specific breast cancer subtypes. However, in a study of carboplatin versus docetaxel in triple-negative metastatic breast cancer, within the cohort with known BRCA1/2 gene mutations, carboplatin was superior to docetaxel with a response rate of 68% versus 33%, while for patients receiving carboplatin, PFS was 6.8 months for patients with a BRCA mutation versus 3.1 months for patients without. This is consistent with our understanding of platinum agents causing double-stranded DNA breaks, which in the absence of BRCA1/2 -dependent homologous recombination repair mechanisms, results in apoptotic cell death. A pooled analysis of two studies of eribulin in women having received at least two prior chemotherapy regimens also suggested greater treatment benefit in triple-negative breast cancer. Otherwise in the second-line setting there is no clear evidence for the superiority of one specific drug or regimen.

Biological agents

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here