Endocrine therapy is now established as the treatment option of choice for postmenopausal women with hormone receptor-positive advanced breast cancer. The benefit of the third-generation aromatase inhibitors (AIs) in this setting has prompted their evaluation in the treatment of early breast cancer. This article reviews the current clinical status of AIs as adjuvant therapy for early-stage breast cancer in postmenopausal women, focusing on the largest adjuvant breast cancer study till date to provide data, the ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial.

Since 1985, 5411 patients were randomized in four large randomized clinical trials assessing the role of adjuvant radiotherapy and/or tamoxifen in breast conserving surgery for patients with ductal carcinoma in situ (DCIS).

First the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 trial proved relevance of postoperative radiotherapy in breast conserving surgery in DCIS patients: an approximately 50% reduction of ipsilateral tumour recurrences. This is confirmed by longer time of follow-up and validated by data from the European Organization for Research and Treatment of Cancer (EORTC) 10853 and UK Coordinating Committee on Cancer Research (UKCCCR) DCIS trials. A subset of patients who do not benefit of adjuvant radiotherapy cannot be identified. Completeness of excision proved to be the most important treatment variable to reduce local recurrence.

Both the NSABP B-24 and UKCCCR DCIS trials investigated the effect of tamoxifen resulting in contradictory findings. In addition a possible benefit seems to be restricted to oestrogen receptor-positive DCIS lesions nourishing the existent reserve in prescribing tamoxifen for all patients with DCIS.

The failure to materialize a difference in survival by the effect of either adjuvant radiotherapy or tamoxifen endorses the favourable outcome of DCIS. Currently, four other randomized clinical trials investigate the role of radiotherapy, tamoxifen, anastrazole, or no further treatment for a selected group of patients.

A significant effect of hospital case volume on perioperative mortality has been documented for a variety of malignancies that require technically challenging operative procedures and complex perioperative management. The effect of case volume on outcome is less clear for the more common cancers, such as breast and colon cancers, that are less technically challenging and require little in the way of specialized care in the postoperative period. For these cancers perioperative mortality is minimal and one must look at other end points such as long-term survival and functional results. The literature demonstrating improved outcomes in terms of mammographical sensitivity, breast-conservation rates, specimen to tumour volume ratios in breast-conserving surgery, sentinel node biopsy success rates, and 5-year survival is reviewed.

For the majority of women with early-stage breast cancer, conservative management with breast conserving surgery plus radiotherapy is widely embraced. However, in patients with germline mutations of BRCA1 and BRCA2, the safety of breast conservation therapy remains controversial. These breast cancer susceptibility genes are associated with an increased risk of second cancers, although the prognosis of BRCA1 or BRCA2 breast cancer is similar to patients with sporadic breast cancer. Preclinical evidence for radiosensitivity has prompted concern for radiation-induced complications in patients with genetic breast cancer. There is limited literature on the safety breast conservation therapy in patients with BRCA1 and BRCA2 mutations. The largest published study reported acute and chronic radiation toxicity results and noted no adverse sequelae in the genetic cohort [1]. Selected published studies demonstrate recurrence rates and overall survival comparable to sporadic controls [1–3]. A series with longer follow-up reported an increase in late second-primary breast cancers, highlighting the need for preventative strategies [4]. Tamoxifen and oophorectomy have a potential role in modifying the rate of second events, and thereby improving the safety of breast conservation therapy.

This article examines the experimental and clinical evidence of the effect of growth factor signalling in an attempt to reconcile the seeming paradox of, on the one hand, evidence that growth factor signalling can facilitate the activity of oestrogen receptor-α (ER-α), and on the other hand, evidence that extreme growth factor signalling can promote loss of ER function and expression, thereby promoting an endocrine insensitive and ultimately ER− phenotype. The results of this analysis lead to the therapeutic possibility that ER negativity may, in some instances, be reversible to generate endocrine response and improve patient prognosis.

Mammographic density is a well-documented independent risk factor for breast cancer. Measurements of density come in various forms, ranging from qualitative descriptions to quantitative assessments or a combination of both. The different means of examining density lead to variations in density–risk relationship. Currently there is no consensus on which method is preferable. The interrelation of mammographic density with other risk factors is crucial to density–risk assessments, since each of these risk factors can influence density on its own. Mammographic density can be modified through hormonal and chemical means, which can have important implications on mammographic sensitivity, accuracy in cancer diagnosis and cancer prevention.

Tissue-specific stem cells play a key role in organ homoeostasis. They are relatively well characterized in systems which undergo constant proliferation and production of differentiated cells, including the haemopoietic system, skin and intestine. However, little is known about the role and regulation of stem cells in the mammary gland. This review briefly summarizes the current understanding of the role of breast-specific stem cells in normal and cancerous tissues, and how this may identify new targets for breast cancer prevention and therapy.

A large number of studies in the last three decades have identified only a handful of biological features in the evolution of human premalignant breast lesions (PBL). They have shown that PBL have a positive growth balance, which may be driven/regulated by oestrogen receptor, erbB-2, and p53. There is marked genetic diversity in PBL, and use of newer technologies such as SAGE, DNA microarrays, and high-throughput proteomics will significantly improve our understanding of evolution of PBL over the next decade.

Efficacy of preoperative (primary, neoadjuvant) systemic chemotherapy significantly improved over the last two decades. Only about 3% of patients reached a pathological complete remission after preoperative treatment with cyclophosphamide, methotrexate and 5-fluorouracil in the late 1980s, whereas today up to 18% have no viable tumour cell detected at histological examination when taxane-containing regimens, for example adriamycin/cyclophosphamide followed by docetaxel or docetaxel/adriamycin/cyclophosphamide, are being used. This improvement has implications on current treatment recommendations and should be considered when this approach gains a broader use in routine practice.

Five to ten per cent of all breast cancers are associated with a proven genetic predisposition for the disease or a strong family history of breast cancer in which yet unknown genetic predisposition is suspected. Carriers of germline mutations in genes breast cancer 1 or 2 (BRCA1/2) have up to 85% chance of developing breast cancer during their lifetime. The majority of these women develop the disease before the age of 50 years. Consequently, breast-cancer screening programmes aimed at reducing mortality in this population may only be effective if they start at much younger age than the general breast-cancer screening programmes. Unfortunately, the efficacy of conventional X-ray mammography in premenopausal women is often limited by dense fibroglandular tissue that obscures suspicious lesions. As a result, more advanced breast-imaging techniques have been considered, such as contrast-enhanced (CE) magnetic resonance imaging (MRI). In symptomatic patients, the sensitivity of CE MRI to detect invasive breast cancer is known to be high, regardless of the density of the fibroglandular tissue. Conversely, the specificity of CE MRI to discriminate between benign and malignant lesions is variable, and depends on the indication of the examination. Low specificity could result in many recalls on benign lesions, thus negatively affecting the cost–benefit ratio of CE MRI as a screening technique. Several single- and multi-institutional studies have been performed to investigate the efficacy of CE MRI as a screening tool exclusively for asymptomatic women at increased lifetime risk of breast cancer. Mounting evidence suggests that the addition of CE MRI results in cost-effective detection of tumours at earlier stage in BRCA1/2 mutation carriers. The value of CE MRI in other populations at risk is currently uncertain, and it is unlikely that CE MRI will be cost efficient in the general screening population of women who are not at increased lifetime risk.