Advanced breast cancer

Background

Cancer accounts for 13% of all deaths in 2007, making it the largest cause of mortality worldwide and is the leading cause of premature death in Scotland. 2,22 Out of the staggering figure of 27,500 new cases that were diagnosed on that same year in Scotland, 4044 of them are breast cancer cases, making breast cancer the most commonly diagnosed cancer among Scottish women.3 In the UK, 16-20% of women have advanced breast cancer and approximately 40-50% of those diagnosed with early or localised breast cancer may eventually develop metastatic disease. Breast cancer is usually defined using a staging system known as the Tumour, Node and Metastasis Staging System (TNM) and stage III and IV are known as advanced stages of the disease with stage III being locally advanced and or has spread to regional lymph nodes and stage IV describing the presence of metastases at distant sites such as the bone, brain, or lung.23

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In the elderly group of female cancer patients, the prevalence of breast cancer is highest at 4% and these post-menopausal women make up 80% of all breast cancer patients, hence proving that the risk increases with age.1 Apart from age, other factors like family history, uninterrupted oestrogen exposure, early menarche, late menopause, late first pregnancy, hormone replacement therapy, obesity, not breast feeding, taking oral contraceptives and past breast cancer may all attribute to a higher risk of developing breast cancer.9 Over the last decade, mortality rates from breast cancer have dropped by almost 14%, despite having more women diagnosed with the disease. In 2000-2004, the survival rate for breast cancer patients has also bumped up to 84% compared to a mere 64% 20 years earlier.4Improvement in prognosis, screening techniques such as mammography, ultrasound and Magnetic Resonance Imaging(MRI), earlier diagnosis of cancers in women participating in the Scottish Breast Screening Programme, a myriad of new hormonal and chemotherapy treatments, and better organisation and patient care plans has attributed to the substantial increase in incidence and survival rate of breast cancer patients.

Women today are also encouraged to perform self breast examinations, hence are familiar with the shape and feel of their breasts, as well as to look out for abnormities like a new discrete lump, nipple discharge, unilateral persistent pain especially in post-menopausal women or pain associated with a lump and skin changes comprising of skin tethering, ulceration, abscess or inflammation.However, there is still a disparity between women from different social classes in terms of combating this disease. Women from more affluent backgrounds are more likely to have their breast cancer diagnosed earlier, have slower disease progression from the time of diagnoses and higher survival rates compared to women from poorer socioeconomic backgrounds. Women from more deprived communities are more likely to be diagnosed with the advanced stage of the disease.

Pathogenesis

Cancer or malignant neoplasm which literally means new growth is a disease manifested in the form of uncontrolled cell proliferations, dedifferentiation and loss of function, invasiveness and metastasis.6 Breast cancer usually forms from the inner lining of milk ducts or the lobules that supply the ducts with milk. In patients with Breast Cancer, women who inherit a single defective copy of tumour suppressor genes BRCA1 or BRCA 2 have a marked higher risk of developing breast cancer in their lifetime. The presence of a defective BRCA1 or BRCA 2 gene can invoke changes in several cellular systems including the signaling pathways and receptors of growth factors and cell cycle tranducers, the apoptotic machinery which responsible for programmed cell death that normally disposes of abnormal cells, the secretion of telomerase, and local blood vessels which results in tumour-directed angiogenesis to supply nutrients to these tumours both aids the proliferation of cancer cells.7,8

Breast cancer cells are able to invade other tissues like the lymph nodes as they no longer exercise the same restraints as the normal cells and they also secrete enzymes like metalloproteainase to break down the extracellular matrix, conferring them mobility. Metastases are secondary tumours normally found in the advanced stage of breast cancer formed by cells released from the primary tumour and have reached and have established themselves at other sites like the lung brain or the bones which are common sites for metastatic cancers of breast origin through blood vessels and lymphatics. The tissues of lung, brain and bone origin express high levels of CXR4 chemokine receptors produced by the breast cancer cells, facilitating the selective accumulation of the cells at these sites.6

Treatment Options

There are three main approaches to treating breast cancer, namely surgical excision, irradiation and a host of systemic disease-modifying therapies or a combination and is chosen based on the stage of breast cancer. However, when caring for patients with advanced breast cancer, the goal of treatment of advanced breast cancer is to palliate symptoms, improve survival and quality of life. There are notably three types of systemic disease-modifying therapies to treat advance breast cancer namely endocrine therapy, chemotherapy and biological therapy.

Endocrine Therapy

Oestrogen exposure has been instrumental in inducing mutations that can lead to breast cancer as they can stimulate cell growth in most of human breast cancer cell lines expressing Oestrogen Receptor (ER) α .8 Clinical studies have proven that more than half of breast carcinomas are ER α positive and respond fairly well to endocrine therapy. Drugs are aimed either to change the ER signaling pathways or prevent estrogen synthesis.7 Tamoxifen and 3rd generation Aromatase Inhibitors (AI) have been used for advance breast cancer with the former being effective in premenopausal, perimenopausal and post menopausal women. Pre-menopausal and perimenopausal cancer patients with ER positive tumours should be offered Tamoxifen tablets 20 mg daily, an oestrogen -receptor antagonist and ovarian ablation or the administration of LHRH agonists such as Buserelin or Goserelin as first-line treatment.5,12 Both options are just as effective in terms of tumour response and overall survival rates.

The latter group of drugs, AI, are the preferred choice for post-menopausal women only with no prior history of endocrine therapy or have been previously been treated with Tamoxifen. AI work predominantly by suppressing oestrogen levels in post-menopausal women by blocking the conversion of androgens to oestrogens in the peripheral tissues. However, they do not inhibit ovarian oestrogen synthesis, hence can cause an elevation in oestradiol levels in pre-menopausal women. Anastrozole and Letrozole are non-steroidal AIs are known to be as efficacious as Tamoxifen as first -line treatment of metastatic breast cancer. 14Exemestane is a steroidal AI used as second-line treatment in advanced breast cancer in post-menopausal women in whom anti-oestrogen therapy has failed. Fulvestrant, an oestrogen receptor antagonist also confers short term benefits in the clinical setting for post-menopausal women who was previously prescribed a non-steroidal AI, delaying the need for chemotherapy. 13AI have been associated with an increased progression-free survival and 13% decrease risk of mortality and lower incidence of vaginal bleeds and blood clots. However, patients given AI are more prone to hot flushes and gastro-intestinal symptoms. 5 Other endocrine therapies available include older and less popular therapies such as progestogen and androgen for pre-menopausal women and stilboesterol and trilostane for post-menopausal women. 5

Chemotherapy

Both ER positive and negative patients with advanced breast cancer would benefit from either a choice of two or three regiments of chemotherapy and classes of drugs commonly prescribed includes antharacyclines, taxanes, capecitabine, vinorelbine, gemcitabine, alkylating agents like cyclophosphamide and platinum based drugs like carboplatin.5 Anthracyclines such as Epirubicin, Mitoxantrone and Doxorubicin are prescribed as first line chemotherapy as they boost modest survival advantage in patients with advanced breast cancer and are superior to non-anthracycline regimens.1,5Doxorubicin is commonly given via injection into a fast running infusion at 21 day intervals as extravastation can cause severe tissue damage. It exerts a cytotoxic effect by interfering with DNA and RNA synthesis by inhibiting DNA toposiomerase II action. The metabolites are excreted through the bile, hence elevated bilirubin levels are indicative of a need to reduce the dosage. 6,12 Higher accumulation of doses may result in cardiopathy precipitating to heart failure, hence cardiac monitoring is deemed important in managing cancer patients taking it and a limit of total cumulative doses is set at 450 mg/m2.Other symptoms of toxicity includes myelodysplasia and neutropenic sepsis. Doxorubicin is also available in liposomal formulations which are safer in terms of reduced incidents of cardiotoxicity and local necrosis but is not recommended by the Scottish Medicines Consortium for treatment of metastatic breast cancer.1,12

Both Epirubicin,an anthracycline derivative, and Mitoxantrone ,an anthracenedione derivative,are structurally related to Doxorubicin, hence similar drug activity could be predicted for all three drugs.12 Mitoxantrone given intravenously is licenced to treat metastatic breast cancer and has been well tolerated by patients.However, side effects like myelosuppression and cardiotoxicity are evident and cardiac examinations are recommended after a cumulative dose of 160 mg/m2.12When both drugs are compared in a clinical trial, Epirubicin boosts higher response rates despite demonstrating a higher percentage of toxicity related side effects.20Clinical trials suggest the efficacy of Epirubicin in treating advanced breast cancer is comparable to Doxorubicin as similar response rates were recorded when equal doses were given. These trials also indicated that patients taking Epirubicin had fewer episodes of congestive heart failure and other complications resulting from cardiotoxicity. Therefore, it could be surmised that Epirubicin is the drug of choice in this regimen .However,a limit of 0.9-1 g/m2 was still imposed when Epirubicin is given to avoid cardiotoxicity. 1,12

Due to the ineffectiveness of single-agent anthracycline therapies in impeding disease progression, combination therapies are often considered for the treatment of advanced breast cancer after failure of with anthracycline monotherapy, provided that the patient is able to tolerate additional toxicity and have a higher chance of response.5 There are clinical evidence suggesting that a combination of anthracycline and taxanes like Doxorubicin and Docetaxel have resulted in better tumour response, delayed progression time compared and reduce risk of mortality to anthracycline monotherapy. The benefits of this synergistic combination, however, did not include improved survival and side effects experienced were more numerous such as thrombocytopenia, alopecia in 75% of these patients,a 10% increase in peripheral neuropathy and neutropenia in 40 to 68% of these patients.1,5 A combination of Epirubicin and Docetaxel would be a better choice as it is just as potent as the Doxycycline and Paclitaxel combination but deemed free of side effects like cardiotoxicity and fluid retention whereas neutropenia was the dose-limiting toxicity .21

Systemic chemotherapy should be offered to patients whom antrhracyclines are contraindicated in cases of cardiac disease hypertension,the elderly, those who have received myocardial irradiation ,those receiving radiotherapy for breast cancer or had receive prior adjuvant treatment with anthracycline. Docetaxel monotherapy is prescribed as the first-line drug followed by single-agent Vinorelbine or Capecitabine as the second-line treatment. Third-line treatment encompasses the use of either Vinorelbine or Capecitabine of which was not offered previously.5 Docetaxel, a member of the taxane group derived from a naturally occurring compound from the bark of yew trees, is licensed to treat locally advanced or metastatic breast cancer. It acts by stabilizing microtubules in the polymerized state, preventing cell division. Side effects associated with Docetaxel are myelosupression, peripheral neuropathy, cardiac conduction defects with arrhythmias, alopecia, muscle pain, nausea and vomiting. Patients currently on Docetaxel are also susceptible to leg oedema and hypersensitivity reactions, which can be ameliorated by taking Dexamethasone orally.1,6,12 Antimetabolites like Capecitabine is a rationally designed tumour-activated and tumour-selective fluoropyrimidine carbamate thatis metabolized to generate 5-fluorouracil at the tumour site which would then be converted to fluorodeoxyuridine monophosphate (FDUMP), a ‘fraudulent’ nucleotide and interact and inhibit thymidilate synthetase,preventing the synthesis of 2′-deoxythymidilate (DTMP),which is vital for DNA synthesis.17Capecitabine has a role in second-line or third-line treatment of chemotherapy for patients of locally advanced or metastatic breast cancer either in combination with Docetaxel or given orally alone at a dose of 1250 mg/m2 twice daily for a forthnight and subsequent courses are repeated after a 7-day interval.

Vinorelbine is a semi-synthetic analogue of vinblastine, a vinca alkaloid derived from Madagascar periwinkle. Unlike taxanes, it is targeted at tubulin of mitotic microtubules to form tubulin dimers which prevents spindle formation in dividing cells leading to mitotic arrest at metaphase resulting in cell death. 6 Besides inhibiting mitosis, its effects are also significant in inhibiting leucocyte phagocytosis, chemotaxis and axonal transport in neurons. Hence, side effects includes neutropenia which was found to be the dose-limiting, peripheral or autonomic neuropathy which manifests as peripheral paraestesia, loss of deep tendon reflexes and motor weakness,constipation and abdominal pain. Neurotoxicity caused by Vinorelbine is considered relatively mild compared to other vinca alkaloids even at maximum tolerated dose as it preferentially binds to mitotic over axonal microtubules. 6,12 Vinorelbine is an option to anthracycline or taxane pre-treated patients with advanced breast cancer as second-line or third-line chemotherapy given via intravenous administration at a dose of 30mg/m2 in 250 ml of normal saline over 1 hour. Alternatively, Vinorelbine can be given orally at a dose of 60 mg/m2 for 3 weeks and can be increased if the patient shows good tolerance to the regime to maximum dose of 160 mg once weekly. A clinical response rates of 16-60% was seen with Vinorelbine as a single agent, 28-77% in combination chemotherapy.5, 16

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A study comparing Vinorelbine in intravenous(i.v.) form used in combination with Capecitabine given orally and a combination therapy of Vinorelbine and Capecitabine both in oral formulations was done to observe the efficacy of both combinations in anthracycline and taxane pretreated patients with metastatic breast cancer. Despite showing a marginally higher percentage in control of the disease in the oral group,improved survival rates and lower incidence of neutropenia and thrombocytopenia were associated with the i.v. group.17 This study has also shown that a combination of Vinorelbine with Capecitabine therapy may confer advantages as both have unique mechanisms of action, different proposed mechanism of drug resistance and relatively non-overlapping toxicity profiles. However, this combination has yet to be recommended by the NICE or SIGN guidelines as it has yet to be proven to be cost-effective.

The recommendation for systemic chemotherapy by NICE is done following a cost-utility analysis which compares chemotherapy regiments in terms of survival, quality of life and associated costs of 17 different strategies drawn up. From the table below, strategies that gives the best survival rates and quality of life are combinations 3,4,13 and 15.However,combinations 3 and 4 that offer Gemcitabine and Docetaxel as the first line are somewhat more costly by approximately £ 10 000 in total costs compared to combinations 13 and 15.It is also proven here that offering Docetaxel as a first-line drug is also superior to Paclitaxel as survival rates and quality of life are slightly poorer in combinations 8 and 10. 5

Biological Therapy

New agents to specifically target molecular processes have been developed over the last decade like Tratuzumab, Bevacizumab and Lapatinib which are all used to treat advanced breast cancer. Tratuzumab, the sole drug of its kind recommended by NICE for use in the UK, is a recombinant humanized monoclonal antibody which binds to Human Epidermal Growth Factor (HER2) on the cancer cells with HER2 over expression and impedes the growth. Hence, HER2 status should be assessed before commencing this therapy as only a quarter of patients with advanced breast cancer have HER2 positive tumours. Tratuzumab is given intravenously in combination with Paclitaxel, Docetaxel or Vinorelbin has been well tolerated. 5,11However, once disease progression occur outside the central nervous system, Tratuzumab should be discontinued. Bevacizumab is another monoclonal antibody aimed at affecting the growth of tumour blood vessels and Lapatinib affects the metabolic pathways of the HER2 and Epidemal Growth Factor Receptor (EGFR). 5,23.

Surgery

Surgical intervention comprises of conservation surgery which involves the removal of the tumour with a rim of surrounding breast tissue with retention of the breast followed by radiation therapy and mastectomy which is usually followed by breast reconstruction. However, these surgical procedures are limited to patients diagnosed with primary operable breast cancer or as palliative surgery for locally advanced breast cancer as they may not confer much benefits to patients diagnosed with later stages of breast cancer.1,11,19 Some patients may have already underwent surgery which was not very successful in eliminating the disease.1

Treatment Recommendation

Hormonal therapies are the recommended first-line therapy for patients with an ER positive tumour, are widely used and are said to be appropriate for 70 % of patients who have hormone receptor -positive advance breast cancer. However, in circumstances whereby the disease is life-threatening or the patient has an ER negative tumour, the hormonal therapy would be of no benefit to these patients. At the time of initial diagnosis, the oestrogen receptor (ER) was accessed and the results came out positive before considering commencing on endocrine therapy. Several factors like previous endocrine therapy including adjuvant therapy, the extent and period of response to the therapy and menopausal status have to be taken into account before prescribing hormonal therapy. 5The patient is 62 years of age and is considered to be post-menopausal, hence would benefit tremendously when given aromatase inhibitors(AI),regardless of whether she is tamoxifen naïve. A choice of non-steroidal AIs of either Anastrozole 1 mg daily or Letrozole 2.5 daily could be given orally. However, if she has a prior history of non-steroidal AIs and she failed to respond well to it, she should be given either Exemestane 25 mg orally or Fulvestrant 250 mg via intramuscular injection into the gluteal muscle every 4 weeks.5,12

Chemotherapy would be the second choice of treatment following failure to respond to hormonal therapy. If anthracyclines are not contraindicated for this patient, Epirubicin would be a good choice. Initial doses of 75 mg/m 2 of Epirubicin could be given intravenously every three weeks.20The addition of Docetaxel 75 mg/m2in combination with Epirubicin 90 mg/m2 both by intravenous infusions could be given should Epirubicin monotherapy fails. Docetaxel monotherapy could also be given as an intravenous infusion at a dose of100 mg/m2 as a 1-hour intravenous infusion every 3 weeks should anthracyclines be contraindicatedas first-line chemotherapy. Vinorelbine monotherapy could be given intravenously at a dose of 30 mg/m2 for days 1 and 8 of a cycle or whereares Capecitabine monotherapy could be given orally at a dose 1250 mg/m2 twice daily for two weeks. If the patient fails to respond to the entire treatment, the last resort would be to offer support and palliative care to this patient.

Pain Management

Pain is usually associated with progression of cancer with three quarters of patients with advanced cancer reporting pain during treatment. The principles for treating pain in cancer patients are outlined by the World Health Organisation (WHO) analgesic ladder:

Patients are the prime assessor of pain and should have treatment outcomes monitored regularly using visual analogue scales, numerical rating scales. Patients usually start with non-opioids and then progress stepwise to step 2 and step 3. However, critics have debated that the progression to step 2 analgesics was obsolete as inadequate pain control was an issue despite having to endure similar adverse effects when given step 3 analgesics and recommended a immediate step up to step 3. Most patients with advanced breast cancer will be on step 3 for pain control. Oral morphine with an initial dose of 5-20 mg every four hourly, adjusted according to patient’s response, would be the first-line therapy to treat severe pain in cancer before switching to a modified release preparation once the patient is stabilized on it. Breakthrough pain should be managed while on a modified release preparation by prescribing oral morphine at 1/6th of the total daily dose to be taken when necessary. The use of adjuvants such as antidepressants like Venlafaxine and anticonvulsants like Gaba-pentin are recommended for neuropathic pain. 18

Managing Complications

Complications that may arise from treating patients with advance breast cancer includes lymphoedema,cancer-related fatigue,uncontrolled local disease,bone metastases and brain metastases. Lymphoedema may occur due to damage to lymph nodes and vessels following surgery and radiotherapy or as a sign of loco-regional disease progression. This condition can be managed through manual lymphatic drainage, multi-layer lymphoedema bandaging,goos skin care and remedial exercise. Cancer-related fatigue may be well managed by identifying the factors causing lethargy which may be a host of psychological, nutritional and cognitive factors apart from the cancer itself and them treating them accordingly. Patients may also develop local disease characterized by ulceration on the chest wall and axilla, fungating tumours that may bleed and exude discharge, causing pain and giving off repulsive odours. Hence, good wound management should be adopted in relation to preventing dire consequences when wounds are left unattended.

Out of the three categories, cancer with distant metastases is the hardest to treat and is considered an incurable disease with palliative care being the sole priority in treatment plans. A diagnosis of metastatic disease could be confirmed with the use of positron emission tomography fused with computed tomography (PET-CT) and bone scintilography.1As bone metastases may be a long-term condition, management involves prevention of skeletal events, pain control with Biphosphonates,radiotherapy and cementoplasty and treating complications such as fractures,immobility and spinal cord compression.5,18 Brain metastases may develop in multiple sites in these patients as most drugs used in chemotherapy cannot penetrate the blood brain barrier, especially in women with HER2-overexpressing tumours. Diagnosis of brain tumours ultimately mean a loss of independence, physical deterioration, communication difficulties,psychological distress and issues regarding body image.Treatment regimens includes surgery for patients who have solitary metastasis, corticosteroids for symptomatic relief of inflammation and radiotherapy.