Drug treatment of breast cancer

Introduction
Over half the women with localised breast cancer will ultimately develop metastases. This has led to the belief that breast cancer is frequently a systemic disease from the outset. While surgery, with or without radiotherapy, is the cornerstone of management of the primary cancer, micrometastases can be present even in the very early stages. Consequently, drug treatment has to be considered for all women and in all stages of breast cancer.

Metastatic breast cancer is the leading cause of death in women aged 40-55. The morbidity and loss caused by this disease is a serious concern for health professionals and the public. Metastatic breast cancer, though currently incurable, is sensitive to drug treatment. Endocrine therapy and chemotherapy are both effective and improve the patient's quality of life and survival. Advanced (metastatic or locally advanced) disease is the proving ground for new treatments. Drugs which are shown to be effective in advanced disease can then be studied in the earlier stages in the hope of contributing to cure.

Treatment of advanced disease
Three forms of treatment are useful: endocrine agents, cytotoxic chemotherapy and supportive agents such as the bisphosphonates. The choice of treatment should be made jointly by the clinician and patient (see 'Patient choice in managing cancer' Aust Prescr 1996;19:55).

In general, about one third of an unselected group of patients is likely to respond to hormonal manipulation. Women with oestrogen receptor (ER)-positive tumours have about a 50-60% chance of response. Patients who are elderly, those with disease confined to soft tissue or bones, or with a long disease-free interval before metastases developed are more likely to have endocrine therapy-responsive tumours. Those who respond to one endocrine therapy are likely to respond to subsequent hormonal manipulations. Conversely, patients who are younger, or with ER-negative tumours, or with metastases in viscera, or with a short disease-free interval are best treated with combination chemotherapy.

Endocrine therapy
The endocrine treatment of breast cancer has improved substantially in the last 10-15 years because of new drugs and an enhanced knowledge of the factors associated with tumour response. The range of effective drug treatments has relegated most ablative surgery (with the exception of oophorectomy) to history.

Almost all ablative or additive endocrine therapies cause a reduced oestrogen action resulting in direct inhibition of tumour cell proliferation. Some drugs have additional mechanisms, including suppression of other growth factors and cytokines.

Antioestrogens
The antioestrogens, such as tamoxifen, are the drugs of first choice for endocrine therapy of postmenopausal breast cancer. In advanced breast cancer, response rates (the number of patients whose tumour responds as a percentage of the total number treated) of 16-52% have been reported. The median duration of response is 8-14 months. In comparisons with other endocrine therapies (oestrogens, androgens, high-dose progestins and aminoglutethimide), tamoxifen is similar or better in efficacy and has a better toxicity profile. Tamoxifen is well tolerated, with the only adverse effects being hot flushes (17-60%), mild nausea (3-21%) or fluid retention (2-25%). Tamoxifen has partial oestrogenic activity which accounts for a mixture of beneficial and adverse effects. Beneficial effects include inhibition of bone loss in postmenopausal women and reduced LDL-cholesterol, but there is also an increased risk of thrombosis (1%) and endometrial cancer (2-5 times after 5 years' treatment). These effects are not an issue in therapy of advanced disease, but may require consideration in the adjuvant setting, and in chemoprevention of breast cancer.

Newer antioestrogen analogues of tamoxifen, such as toremifene, droloxifene and idoxifene, are being investigated. Antioestrogens lacking oestrogenic activity are currently in the early phases of clinical development.

Progestins
Medroxyprogesterone acetate, megestrol acetate and norethisterone have all been tested in advanced disease, with response rates varying from 10-67%. Adverse effects are generally more prominent than with tamoxifen, with weight gain (18-50% of patients), increased appetite (>50%) and fluid retention predominating. In addition, endometrial bleeding can occur on withdrawal.

Aromatase inhibitors
The aromatase enzyme system converts androgens into oestrogens. In postmenopausal women, aromatases present in fat, liver, muscle and normal and neoplastic breast tissue convert circulating androstenedione into oestriol. Inhibition of aromatases causes a marked decrease in tissue oestrogen levels.

Aminoglutethimide has been used since the 1970s and functions by inhibiting corticosteroid synthesis and also inhibiting aromatase. Adverse effects include pruritic rash (20-30% of patients; self-limiting after 5-10 days), lethargy (36%), dizziness (16%) and nausea and vomiting (14%).

A number of new drugs have been developed to inhibit aromatase enzymes specifically. Steroidal inhibitors are androstenedione derivatives which compete with the substrate and inhibit the enzyme. Unlike aminoglutethimide, replacement corticosteroids are not required. Formestane (4-hydroxy-androstenedione) is now approved for use in many countries, but requires weekly injections. Several potent selective non-steroidal inhibitors, such as letrozole, anastrozole, vorozole and fadrozole, can be taken orally. They are highly effective at reducing oestrogen levels in breast cancer patients and are remarkably free of significant adverse effects.^1,2,3 Recent studies suggest that they may rival tamoxifen in efficacy and will become a preferable alternative to aminoglutethimide.⁴

Oestrogens and androgens
These drugs are largely of historical significance. They can induce remissions in the small proportion of advanced breast cancer patients who continue to display hormone sensitivity after the use of multiple therapies.

Ovarian ablation
In premenopausal patients, oophorectomy should be considered before any other endocrine manipulation. In the past, ablation was by surgery or radiation, but a third option now exists. The agonists of gonadotrophin releasing hormone (buserelin, goserelin, leuprolide and triptorelin) suppress pituitary release of FSH and LH, resulting in lack of gonadal endocrine stimulation and castration levels of circulating oestradiol. These drugs may be given intramuscularly or as implants. Responses similar to surgical castration have been observed, although sometimes of slower onset. Toxic effects include hot flushes and other symptoms of menopause.

Chemotherapy
Patients with advanced breast cancer who have visceral disease, aggressive disease, or in whom initial or subsequent endocrine therapy has failed, should be considered candidates for chemotherapy. In general, combinations are more effective than single drugs. The responding patients enjoy a reduction in symptoms (bone pain, dyspnoea, anorexia, nausea, etc.) and therefore an improvement in quality of life.⁵ The response rates for most currently used regimens are 50-70% (10-20% complete response - complete disappearance of all known disease assessed by clinical examination and investigations). Few patients experience complete or durable remissions with single agents (20-40% response). Prognostic factors portending unfavourable outcomes to chemotherapy (lack of response, failure to improve quality of life or survival) are poor general clinical condition, bulky widespread disease and brain metastases. Factors such as age, menopausal status, disease-free interval and ER status do not influence the outcome of chemotherapy. Many new biological and molecular prognostic markers have been promoted, but they are not better than the clinical prognostic factors.

Regimens
Standard combinations include:

– CMF(V)(P) (cyclophosphamide, methotrexate and fluorouracil with or without vincristine or prednisone)

– AC (anthracycline - either doxorubicin or epirubicin - and cyclophosphamide)

– FAC

– MMM (methotrexate, mitoxantrone, mitomycin)

These combinations result in response rates of 40-65% with a median duration of response of 6-12 months. Newer drugs (see box) are likely to find roles as components of first-line combination chemotherapy or in patients who fail to respond or relapse after first-line treatment. For example, an early study of paclitaxel 200 mg/m² and doxorubicin 60 mg/m² given to 32 women as first-line treatment showed a 94% response rate (95% confidence interval, 79-99%), including 41% complete responses.⁶ These promising results were not without increased toxicity. Subsequent studies of doxorubicin and paclitaxel using different doses and schedules have produced similar response rates, but with less toxicity. Research efforts continue to improve the therapeutic index of combination chemotherapy, by defining doses and schedules which maximise the antitumour effects, yet with acceptable adverse effects.

High-dose chemotherapy, in which reinfusion of autologous peripheral blood stem cells is used to rescue the patient from lethal myelosuppression, has not yet been proven to be more effective than standard chemotherapy in the management of advanced breast cancer.⁷ Similarly, moderately high doses, requiring G-CSF support but not autologous stem cell reinfusion, are the subject of a study being conducted by the Australian-New Zealand Breast Cancer Trials Group.

As with endocrine therapy, patients who respond to first-line chemotherapy and subsequently relapse may respond to further second-line treatment with different drugs. However, the value of any chemotherapy beyond second-line is dubious. The low probability of response is outweighed by the effects of toxicity on quality of life.

Duration of treatment
The appropriate duration of chemotherapy in women whose tumours respond or stabilise is unclear. An Australasian study compared continuous therapy (CMFP or AC) given until disease progression was evident, with intermittent therapy (stopped after 3 cycles and then reintroduced when disease progression occurred).⁵ Intermittent therapy showed a significantly worse outcome in terms of response, time to disease progression, and more importantly quality of life, as well as a trend towards poorer survival. In general, oncologists recommend 5-6 months of chemotherapy. Treatment can continue if it is well tolerated with little impact on quality of life and there is evidence of worthwhile tumour shrinkage and control of symptoms. Continuing chemotherapy for more than a year can rarely be justified.

Adverse effects
The toxicity of cytotoxic chemotherapy is of concern to patients, but, with judicious dosing and the use of modern supportive agents, this problem can be minimised. Most combinations can cause nausea and vomiting (first 24-48 hours), myelosuppression (7-14 days), mouth ulceration (7-14 days) and diarrhoea (7-14 days) (see 'Complications of cytotoxic chemotherapy' Aust Prescr 1995;18:65-8 and 105-7).

Bisphosphonates
There is increasing evidence that bisphosphonates are useful as adjuncts to endocrine or cytotoxic chemotherapy in patients with bony metastases. Bisphosphonates inhibit osteoclastic bone resorption and have a clear role in the control and prevention of hypercalcaemia in metastatic disease. Randomised studies using clodronate or pamidronate in conjunction with either hormone therapy or chemotherapy have shown a reduced incidence of skeletal complications (fracture, need for palliative radiation, hypercalcaemia).⁸ It is likely that these drugs will be more commonly used in the future.

Adjuvant therapy
The rationale underlying the use of adjuvant therapy after management of primary breast cancer is that there is a significant probability of micrometastatic disease. Early treatment will therefore increase the probability of cure or lengthen survival.
Treatments with proven efficacy in advanced disease and an acceptable toxicity profile are used (Table 1).⁹ Two factors are taken into account when decisions are made about adjuvant therapy:

– the risk of systemic relapse

– the ER status of the primary tumour

Prognostic factors for relapse are the absence or presence (and number) of affected axillary lymph nodes and the tumour's histologic grade and ER status (Table 2).¹⁰

Effectiveness
The likelihood of benefit from various adjuvant therapies was clarified in a meta-analysis (Table 3).¹¹ Highly significant reductions in the annual rates of recurrence and death are produced by tamoxifen (25% and 17% respectively), by ovarian ablation in women under age 50 (26% and 25% respectively) and by polychemotherapy (28% and 16% respectively). Reductions in recurrence and mortality were sustained up to 10 years after treatment.

Polychemotherapy for longer than 6 months did not confer additional benefit compared to 6 months treatment only, but polychemotherapy was better than single drug treatment. Conversely, longer tamoxifen regimens (2-5 years) are significantly better than shorter regimens. The benefit of tamoxifen is seen even in ER-negative patients, although much less than in ER-positive patients. In women aged 50-69, chemotherapy plus tamoxifen may be better than chemotherapy or tamoxifen alone. In those under age 50, chemotherapy and ovarian ablation have similar efficacy. Combined chemo-endocrine therapy may confer an additional benefit in women under age 50 of the order of 30-40% relative reduction in risk of recurrence and death. The relative reduction in risk is independent of nodal status; however, the absolute reduction in risk is greater for node positive than for node negative patients.

Some studies have shown that lower dose-intensity (dose of drug per unit time, e.g. mg/week) regimens of chemotherapy result in poorer survival.¹² While these studies do not show that more intensive regimens are better (i.e. higher than standard dose intensity, such as those requiring routine support with G-CSF or reinfusion of autologous stem cells), they suggest strongly that standard doses should not be reduced if the maximal benefit is to be achieved. Other studies have shown that one cycle of peri-operative chemotherapy is not enough, but that 3 cycles may be adequate in postmenopausal women.

Several issues remain unclear in the adjuvant therapy of breast cancer, and are currently the subject of clinical study:

– the role of endocrine therapy in ER-negative patients
– oophorectomy versus chemotherapy in premenopausal patients
– the value of high-dose chemotherapy and stem cell rescue in women with high risk of recurrence (greater than 10 axillary lymph nodes involved, or greater than 5 nodes involved and ER-negative)
– the role of peri-operative versus standard postoperative chemotherapy

In addition, the long-term toxicity of various treatments is uncertain. Tamoxifen causes an increased risk of uterine cancer and thrombosis. Even though these risks are small, they may outweigh any further benefits after several years of treatment. Anthracyclines (doxorubicin and epirubicin) are now being used increasingly because of their more acceptable acute toxicity profile and their proven efficacy in advanced disease. However, anthracyclines may cause an increased incidence of long-term cardiac effects and possibly leukaemia.

Pregnancy, contraception and hormone replacement therapy
Premenopausal women should be advised to avoid pregnancy while undergoing treatment for breast cancer as the treatment (chemotherapy or hormone therapy) may be teratogenic, and the changing hormone levels may stimulate cancer cell growth. If breast cancer is discovered during a pregnancy, surgery can be performed with minimal risk to the fetus. The risk of chemotherapy in the second and third trimesters is probably low.

The effects of pregnancy after treatment of early breast cancer are not known, although recent studies suggest no increased risk of recurrence.¹³ Similarly, the effects of hormone replacement therapy on recurrence are hotly debated and are currently the subject of clinical trials.

Conclusion
As a consequence of extensive clinical trials in breast cancer, there are now many proven drug treatments available for adjuvant therapy and management of metastatic disease. These trials have resulted in better understanding of the disease and better use of drugs to reduce risk of recurrence in early breast cancer, and provide longer survival and better quality of life in metastatic disease. Current trials using new drugs and new combinations are likely to improve health outcomes even further, and lower the toll which breast cancer inflicts on society.

(See also Dental implications)