Systemic therapy for early breast cancer

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Kwok Leung Cheung
MB BS DM FRCSEd FCSHK FHKAM(Surg) FACS
Senior Lecturer/Consultant Breast Surgeon
Professorial Unit of Surgery
Nottingham City Hospital
Nottingham
UK
E:[email protected]

Although neoadjuvant or preoperative systemic therapy is recognised as one of the standard therapeutic options in locally advanced or larger tumours, studies are ongoing to evaluate its use in operable primary breast cancer, with surgery currently being the standard initial treatment. Surgery serves to attain locoregional control and obtain important information (eg, nodal status) to guide subsequent therapies (eg, postoperative radiotherapy or adjuvant systemic therapy) as required.

This article focuses on the latest developments in the use of adjuvant systemic therapy following surgery in early breast cancer. Neoadjuvant systemic therapy, radiotherapy and surgery will not be examined.

Indications
Adjuvant systemic therapy (both chemotherapy and endocrine therapy) significantly improves survival in patients with early breast cancer, as demonstrated by the randomised trials analysed in the Oxford overview.(1–3) Not only could this therapy delay relapse, but it could also produce an absolute gain in survival, as a potentially curative treatment. The indication for adjuvant systemic therapy is, therefore, related to the risk of relapse, in particular distant relapse, from which patients die. The decision to use this therapy is currently based on prognostic factors identified at the time of surgery, with nodal status being the predominant factor and histological grade and size being among other possible factors. Using a combination of these prognostic factors (such as the Nottingham Prognostic Index),(4,5) patients can be classified into different prognostic or risk groups, in which survival can be predicted. Patients whose predicted survival is worse than that of the normal population would benefit from receiving systemic therapy. These are often node-positive patients, to whom adjuvant systemic therapy should be recommended. In patients with an excellent prognosis (eg, <-1cm, grade I, node-negative), systemic therapy is not indicated, as per our local practice as well as international recommendations (eg, in the recent St Gallen Consensus Guidelines).(6) Furthermore, as will be illustrated below, other factors, including the patient’s expectations, also need to be considered.

Therapeutic options
Once a patient is considered appropriate to receive adjuvant systemic therapy, treatment classically takes the form of endocrine therapy, chemotherapy or a combination of both. The precise treatment depends on the risk of relapse (predicted survival or prognostic group), side-effects of treatment, oestrogen receptor (ER) and menopausal status, fitness for treatment and patient’s wishes or expectations. Patients with ER-positive tumours receive endocrine therapy. Chemotherapy produces additive survival benefit to endocrine therapy and should be considered in a fit patient who falls into the high-risk category (eg, high grade, node-positive). Its value diminishes in older patients (late 60s onwards) and is negligible in women with an ER-positive, grade II, node-negative tumour, in which the risk would probably outweigh the benefit. For the ER-negative group, chemotherapy is the treatment of choice, although its risk–benefit ratio increases in the low-risk group (eg, ER-negative, <-1cm, grade III, node-negative) and in older patients, as mentioned above. Under these difficult circumstances, the patient’s comorbid conditions, as well as her wishes and expectations, need to be considered seriously.

Endocrine therapy
Endocrine therapy, using ovarian suppression,
tamoxifen or both, produces significant benefit only  in ER-positive tumours.

The Oxford overview has shown the benefits of ovarian suppression (largely achieved by oophorectomy in early studies) in both node-negative and node-positive disease in disease-free and overall survival for ER-positive tumours. (1,6) With ovarian ablation, the absolute gain in overall survival at 15 years is 6.3%, and 12.5% for all patients and node-positive patients, respectively. The Zoladex Early Breast cancer Research Association (ZEBRA) and other similar trials using a luteinising hormone-releasing hormone (LHRH) agonist (eg, goserelin) with or without tamoxifen have demonstrated effects equivalent to those of chemotherapy including regimens such as cyclophosphamide , methotrexate and fluorouracil (CMF) and fluorouracil, epirubicin and cyclophosphamide (FEC).(7–11)

Tamoxifen has been the gold standard for both pre- and postmenopausal women until recently, when its role has been challenged by third-generation, selective aromatase inhibitors. These new compounds, however, are efficacious only in postmenopausal women. Tamoxifen, given for a duration of five years, produces at least 30–40% risk reduction of relapse at 10 years, with a mortality reduction of approximately 25%.(2) It is generally well tolerated, with an excellent side-effect profile and clinical experience for more than three decades. The superiority of selective aromatase inhibitors over tamoxifen was first noted in the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial, the largest ever randomised endocrine therapy study, which, at four-year follow-up, revealed a significantly longer disease-free survival when anastrozole (Arimidex) was compared directly with tamoxifen as adjuvant therapy. (12,13) No advantage was seen in the combination arm. In terms of adverse events, anastrozole is statistically associated with significantly fewer cerebrovascular events, venous thromboembolism, vaginal symptoms, hot flushes and endometrial carcinoma, but more musculoskeletal problems, including fractures. This could be accounted for by its oestrogen deprivation effect (tamoxifen, which acts as an antioestrogen on the ER, also has oestrogen agonist properties in relation to the bones and endometrium). Three randomised trials – the National Cancer Institute of Canada (NCIC) MA-17 trial, the Italian Tamoxifen Anastrozole (ITA) trial and the Intergroup Exemestane Study (IES) – looked into sequencing tamoxifen with an aromatase inhibitor. These studies again showed the superiority of aromatase inhibitors in terms of disease-free survival and incidence of contralateral breast cancer, although the patient groups and designs were different in these trials (see Table 1).(14–16) While it is envisaged that aromatase inhibitors will become the adjuvant endocrine therapy of choice, overall survival data are awaited from all these trials. It is unlikely that the superior outcome would change, as studies such as the ATAC trial are huge and statistically powered to show early benefit. Potential long-term problems also need to be addressed. For example, there has been concern about cognitive function impairment, which could be significant for patients with potentially curable early breast cancer.(17) Efforts are also being made to tackle side-effects on the bones (eg, fractures). Trials are ongoing to investigate the use of bisphosphonates (eg, zoledronic acid) in this setting. While aromatase inhibitors have not been shown to produce any benefit in ER-negative tumours, some data within the ER-positive subgroup suggest they may work best in patients who are HER2-positive and/or progesterone receptor (PgR)-negative.(18,19) The degree of benefit is more comparable to that of tamoxifen if the tumour is ER-positive, HER2-negative and PgR-positive.

[[HPE16_table1_42]]

Chemotherapy
Meta-analyses of randomised trials in the Oxford overview suggest an approximately 24% reduction in the annual risk of relapse with adjuvant chemotherapy.(3) Increasing evidence, including that from the Oxford overview,(3) has now confirmed that an anthracycline-containing regimen is superior to conventional CMF, with an absolute survival benefit of 3% when both are compared. Anthracycline- containing regimens should be considered the minimum standard in patients who require chemotherapy. Nevertheless, for women with significant cardiac disease and a moderate prognostic tumour, CMF may be an acceptable regimen.

Recently, large randomised trials have been conducted to evaluate the addition of a taxane (paclitaxel or docetaxel) to an anthracycline-containing regimen in the treatment of node-positive breast cancer (see Table 2).(20–22) Improvement in disease-free survival was seen in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28, the Breast Cancer International Research Group (BCIRG) 001 and the Cancer And Leukemia Group B (CALGB) 9344 trials. Overall survival benefit was also observed in the latter trial for patients in the taxane arm (80% versus 77% at five years). However, in this trial, the benefit was seen exclusively in hormone receptor-negative patients. Such improvements in overall survival have not yet been demonstrated in the other two trials. Whether more intensive anthracycline-containing regimens could produce similar benefit remains to be demonstrated; in addition, taxane-containing regimens also appear to produce more severe myelosuppression. Nonetheless, these data support the consideration of a taxane in addition to an anthracycline-containing regimen for patients with ER-negative, poor-prognostic tumours.

[[HPE16_table2_43]]

At present, no data support the use of the HER2 monoclonal antibody trastuzumab (Herceptin) as an adjuvant systemic therapy for early breast cancer. Evidence is also lacking for the use of high-dose chemotherapy with autologous bone marrow support, even in very high-risk patients.

Current recommendations
Adjuvant systemic therapy, following surgery for early breast cancer, is indicated in patients at risk of future distant relapse. The risk is estimated using prognostic factors, which can be factored into predicted survival. For patients with ER-positive tumours, the systemic therapy of choice is endocrine therapy, with addition of chemotherapy for those with poor prognosis. For those with ER-negative tumours, chemotherapy is indicated. The endocrine therapy of choice in premenopausal women is ovarian suppression/ablation, which can be medically achieved with a two-year treatment with an LHRH agonist (eg, goserelin) in addition to a five-year treatment with tamoxifen. For postmenopausal women, tamoxifen is currently the licensed agent in Europe, but a selective aromatase inhibitor (eg, anastrozole) should be considered in patients who cannot have tamoxifen (eg, a patient with intolerance or a history of thromboembolism). An anthracycline-containing regimen is the standard for patients requiring chemotherapy. CMF regimens may be acceptable in women with high cardiac risk.

Future directions
Technological advances, such as the use of tissue arrays, identify different genetic signatures for patients with early breast cancer.(23) Thus, it is envisaged that the use of adjuvant systemic therapy could be tailored according to biological information rather than the prognostic factors that are currently employed, which could just reflect statistical risk.

As previously discussed, information on the status of HER2, ER and PgR, bone mineral density and history of thromboembolic events would help to suggest the best form of endocrine therapy and/or chemotherapy (including possible addition of taxanes and/or trastuzumab) regimens.

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