The benefits of adjuvant chemotherapy, endocrine therapy, and trastuzumab therapy are well-established in patients with early breast cancer. Further, there are patient and tumor characteristics that can assist in predicting which patients are more likely to benefit from specific adjuvant therapies. For example, patients whose tumors express estrogen and/or progesterone receptors (ER/PR) derive significant benefit from adjuvant endocrine therapy, whereas those whose tumors do not express these receptors derive very little or no benefit from endocrine therapy [1]. Patients whose tumors overexpress HER2 experience profound benefits from treatment with adjuvant trastuzumab [2,3]. We have recently begun to understand that ER/PR-positive breast cancer also responds differently to chemotherapy than its hormone receptor-negative counterpart. This is not, however, entirely new information. As early as 1978, it was retrospectively observed that ER-positive metastatic breast cancer had lower response rates to a variety of older chemotherapy regimens than did ER-negative disease [4].

Fibroadenomas are most common benign tumour of the breast, usually affecting pre-menopausal women. The traditional treatment aimed at symptomatic relief and confirmation of the lesion's benign nature through open surgical excision and biopsy. The rise of ‘triple assessment’ in recent years has meant that a definitive benign diagnosis is now generally possible without recourse to open biopsy. But patients would still face undergoing open surgical excision for relief of symptoms. A third option is now available – that of percutaneous vacuum-assisted excision under local anaesthetic. Performed in a similar fashion to conventional percutaneous needle biopsy, the procedure can normally be completed within 15 min and offers quicker recovery times and better cosmetic outcome than traditional excision.

Results from trials demonstrating the superiority of the third-generation aromatase inhibitors (AIs; anastrozole, letrozole and exemestane) vs. tamoxifen have led to changes in clinical practice in the treatment of postmenopausal patients with hormone-sensitive breast cancer. AIs do not inhibit ovarian oestrogen synthesis sufficiently to be a viable monotherapy for premenopausal patients but there is interest in their potential use in combination with luteinising hormone-releasing hormone analogues (LHRHas) such as goserelin (‘Zoladex’). Preliminary results from Phase II combination trials in the advanced breast cancer setting have been promising, but efficacy data in premenopausal patients with early disease are yet to be reported. Here we overview the rationale and preliminary results to date for the combination of AIs with an LHRHa and highlight ongoing trials that will more fully assess the value of such combinations in extending the treatment options for premenopausal breast cancer patients.

Trastuzumab is a monoclonal antibody targeting the human epidermal growth factor receptor-2 (HER-2) protein, the mediator of an aggressive breast cancer phenotype. Trastuzumab has an important role in the treatment of metastatic breast cancer (MBC) where it improves multiple endpoints, including overall survival. More recently, striking activity is also seen in non-MBC, with substantial benefits seen in both the neoadjuvant and adjuvant settings. Experimental data has identified synergistic therapeutic effects of platinum containing chemotherapeutic regimens when combined with trastuzumab. We review the pre-clinical and rapidly evolving clinical evidence supporting platinum and trastuzumab combinations for HER-2-positive breast cancer.

Papillary lesions of the breast are fairly common on imaging-guided breast biopsy, and the management remains controversial. Due to the heterogeneity of histological findings, papilloma can be a challenge to the pathologist when interpreting core biopsy specimens, so some may desire the entire lesion to be removed to be confident of the diagnosis of a benign papilloma. In appropriate cases, an attempt at removal with vacuum-assisted biopsy appears a reasonable approach with the hopes of establishing a diagnosis, relieving symptoms of nipple discharge, and avoiding the cost and morbidity of surgical intervention. The management of lesions with atypia on mammotome excision will remain controversial and the prudent approach is to recommend complete surgical excision.

Brachytherapy treatment consists of the insertion of radioactive sources into tissue to deliver radiotherapy directly to the tumor. Early treatment utilizing this method required intra-operative placement of 15–20 catheters by the radiation oncologist, a highly specialized procedure which limited its widespread use despite encouraging results from the first clinical trial and the benefits to the patient of receiving radiation treatment to only 2 cm of tissue beyond the borders of the lumpectomy cavity and the ability to complete the radiotherapy component of breast conserving treatment in 4–5 days, instead of the usual 4–6 weeks. The MammoSite® Radiation Therapy System allows either a radiation oncologist or a surgeon to implant a much simplified brachytherapy device, thus increasing the number of patients who can receive this treatment. The device, which received FDA approval in May 2002, works by creating a cavity inside the lumpectomy site via a balloon. A high dose-rate brachytherapy source is inserted into this cavity, evenly irradiating the tissue at highest risk of containing residual cancer cells. Data collected since its approval show that MammoSite offers tumor control equal to traditional radiotherapy with fewer side effects of radiation exposure to nearby tissues. However, the invasive nature and high cost of this treatment mean that MammoSite should not be seen as the sole future direction of radiotherapy treatment delivery methods.

In breast cancer, oligometastatic disease is a controversial concept. Generally, solitary pulmonary lesions are detected on chest imaging made for other reasons (unintentionally). The majority of these pulmonary lesions in breast cancer patients prove to be unrelated (bronchogenic carcinoma or benign lesions), 33–40% are in fact breast cancer metastases. Only a small number of breast cancer patients (0.4–1%) will have potentially resectable isolated metastasis to the lung.

Controlled studies comparing pulmonary metastasectomy to systemic therapy or best medical care are lacking. Overall survival (OS) data in patients who underwent metastasectomy are favourable despite the high incidence of recurrences. Long-term survival is seen primarily in patients with only one or two lesions and long initial disease-free interval. Radical resections with unnecessary loss of pulmonary parenchyma should be avoided, since there is no benefit of such resection in terms of survival and the incidence of complications is higher.

Foremost justification of surgical resection for lung lesions in breast cancer patients is differentiation of metastatic breast cancer from new primary lung cancer. The survival impact of pulmonary resection in ‘oligometastatic’ breast cancer is probably limited and attempts should be made to limit the amount of tissue removed.

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by Austrian Breast and Colorectal Cancer Study Group ABCSG. Clinical trials include:

1. Adjuvant therapy with CMF versus goserelin plus tamoxifen in pre-menopausal, hormone-responsive, lymph node-positive or -negative patients. Study 5

2. Adjuvant endocrine therapy in postmenopausal patients with hormone-responsive breast cancer: tamoxifen versus tamoxifen plus aminoglutethimide. Study 6

3. Pre and postoperative chemotherapy versus conventional adjuvant chemotherapy alone in patients presenting with hormone receptor-negative breast cancer. Study 7

4. Adjuvant endocrine therapy in postmenopausal patients with hormone-responsive breast cancer, G1 and G2 (ARNO). Study 8

5. Adjuvant chemotherapy in postmenopausal patients with hormone-responsive breast cancer, G3. Study 9

6. Adjuvant endocrine therapy and bisphosphonate therapy: tamoxifen in comparison to anastrozole, alone or in combination with zoledronate, in premenopausal patients presenting with hormone-responsive, Stage I and II breast cancer. Study 12

7. Effect of 3 versus 6 cycles of epidoxorubicin/docetaxel G-CSF upon the rate of complete pathological remissions in the neoadjuvant treatment of patients with primary breast cancer and no distant metastases. Study 14

8. SALSA (Secondary Adjuvant Long-term Study with Arimidex): a prospective, randomized, open, multicentre Phase III study to assess the efficacy of secondary adjuvant endocrine anastrozole therapy for 2 further years versus 5 further years in patients with hormone receptor-positive breast cancer after a 5-year primary adjuvant endocrine therapy. Study 16

9. Neoadjuvant hormonal therapy with exemestane in postmenopausal patients with primary hormone receptor-positive breast cancer and no distant metastases. Study 17

10. A randomized, double-blind, placebo-controlled, multi-centre phase 3 study to determine the treatment effect of denosumab in subjects with non-metastatic breast cancer receiving aromatase inhibitor therapy. Study 18

11. A randomised Phase II study comparing anastrozole and fulvestrant to anastrozole for adjuvant treatment of postmenopausal patients with early breast cancer and disseminated tumour cells in bone marrow. Study 21

12. A randomized Phase III study comparing epirubicin, docetaxel and capecitabine G-CSF to epirubicin and docetaxel G-CSF as neoadjuvant treatment for early HER-2 negative breast cancer and comparing epirubicin, docetaxel and capecitabine G-CSF trastuzumab to epirubicin and docetaxel G-CSF trastuzumab as neoadjuvant treatment for early HER-2 positive breast cancer. Study 24

Increasing number of small, early-staged breast cancers are detected by screening mammography. Diagnosis and determination of the prognostic factors may be made by either ultrasound (US) or stereotactically guided needle biopsy. Approximately 2000 stereotactic tables are installed at various medical centers throughout the United States and a significant number in other countries where breast cancer is common. Many surgeons and interventional radiologists are trained in the use of this technology for diagnostic purposes. Employing the same technology, these physicians may be trained to treat selected breast cancers with laser energy percutaneously. Experimental and clinical reports to-date indicate the technique to be safe. High-resolution imaging modalities including grayscale and color Doppler US, magnetic resonance imaging, mammography and needle biopsy, when necessary, will confirm the tumor kill. Newer imaging modalities such as magnetic resonance spectroscopy may also provide additional confirmation for total tumor ablation.

Determining whether cancer has spread to the lymph nodes is important in predicting survival from breast cancer and determining what treatment a patient requires. The traditional method of detecting such metastases, complete axillary node dissection, can result in lymphedema and other quality-of-life damaging side effects. The new technique of sentinel lymph node biopsy (SLNB) offers a way to test for lymph node metastases without causing the side effects of traditional axillary node dissection. Intraoperative analysis of SLNB is becoming an effective tool in assessment of the presence or absence of metastatic tumor, and therefore influences the treatment offered to the patient. Because of this central diagnostic use, as it is a new procedure, further studies need to be conducted to fully assess its role in breast cancer treatment.

According to the American Cancer Society, more than 211 000 women in the USA were diagnosed with invasive breast cancer in 2005, (American Cancer Society. www.cancer.org. 2005). Nearly 65 000 of these women had postmastectomy reconstruction – a 100% increase from just over a decade ago, (American Society of Plastic Surgeons. www.plasticsurgery.org. 2005). A significant proportion of these women, will elect to undergo bilateral mastectomy for treatment and/or prophylaxis of breast cancer. Contemporary techniques provide numerous options for bilateral, postmastectomy reconstruction. Procedure selection will be based on a range of patient variables, including: availability of local, regional, and distant donor tissues for bilateral reconstruction, size and shape of the desired breasts, surgical risk, and most importantly, patient preference. Ultimately, the individualized selection of a reconstructive technique for each patient is a predominant factor in achieving a reconstructive success.

Before the advent of diagnostic imaging, palpation was one of the main methods of clinical investigation for the evaluation of tumours. Malignant tumours feel harder that benign ones and this physical property is related to their coefficient of elasticity. Direct comparison of tissue images before and after application of a force is too crude a measure of elasticity except at extremes of differences in elasticity. Analysis of the raw imaging data, which contains very much more information than can be displayed for visual perception, can detect very much smaller differences in elasticity.

The radio frequency data of returning ultrasound echoes contain much more data than appears in an ultrasound image. Comparison, of the datasets of uncompressed tissue with compressed tissue, of a region of interest allows production of a strain (elasticity) image of that same region of interest. Change in tissue which is not visible on B-mode (greyscale) imaging can now be detected with real time strain imaging which is beginning to be developed on commercial ultrasound equipment. The information obtained with strain/elasticity imaging is now showing potential in influencing management of patients with breast problems.

Over-expression or aberrant signalling of the erbB family members epidermal growth factor receptor (EGFR) and HER2 (erbB2/neu) have been associated with the pathogenesis of the malignant phenotype. In addition, high levels of EGFR and HER2 expression have been shown to correlate with poor prognosis and also implicated in disease progression. Signal transduction inhibitors (STIs) have been developed with specifically target these receptors and include the small molecule tyrosine kinase inhibitor gefitinib (IressaTM) which targets the EGFR and the humanised monoclonal antibody trastuzumab (HerceptinTM), which has anti-tumour activity against HER2. Studies however, have indicated that de novo or acquired resistance to these agents is a major clinical problem. Cancer cells are highly adaptive and can readily switch from one receptor signalling pathway to another in order to maintain growth or cell survival, a process paradoxically, that in many instances is induced by the anti-tumour agents themselves, ultimately limiting their activity and promoting resistance. Evidence is accumulating which demonstrates that signalling interplay occurs between the EGFR/HER2 and the insulin-like growth factor -1 receptor (IGF-1R) and the article will focus on the growth factor pathway switching that occurs between these receptors which can influence the effectiveness gefitinib and trastuzumab.

Citation of original article:

S. Mukherjee, S. E. Conrad. Journal of Biological Chemistry 2005; 280: 17616–17625.

Abstract of the original article:

Oestrogen rapidly induces expression of the proto-oncogene c-Myc. c-Myc is required for oestrogen-stimulated proliferation of breast cancer cells, and deregulated c-Myc expression has been implicated in antioestrogen resistance. In this report, we investigate the mechanism(s) by which c-Myc mediates oestrogen-stimulated proliferation and contributes to cell cycle progression in the presence of antioestrogen. The MCF-7 cell line is a model of oestrogen-dependent, antioestrogen-sensitive human breast cancer. Using stable MCF-7 derivatives with inducible c-Myc expression, we demonstrated that in antioestrogen-treated cells, the elevated mRNA and protein levels of p21WAF1/CIP1, a cell cycle inhibitor, decreased upon either c-Myc induction or oestrogen treatment. Expression of p21 blocked c-Myc-mediated cell cycle progression in the presence of antioestrogen, suggesting that the decrease in p21WAF1/CIP1 is necessary for this process. Using RNA interference to suppress c-Myc expression, we further established that c-Myc is required for oestrogen-mediated decreases in p21WAF1/CIP1. Finally, we observed that neither c-Myc nor p21WAF1/CIP1 is regulated by oestrogen or antioestrogen in an antioestrogen-resistant MCF-7 derivative. The p21 levels in the antioestrogen-resistant cells increased when c-Myc expression was suppressed, suggesting that loss of p21 regulation was a consequence of constitutive c-Myc expression. Together, these studies implicate p21WAF1/CIP1 as an important target of c-Myc in breast cancer cells and provide a link between oestrogen, c-Myc, and the cell cycle machinery. They further suggest that aberrant c-Myc expression, which is frequently observed in human breast cancers, can contribute to antioestrogen resistance by altering p21WAF1/CIP1 regulation.

Breast magnetic resonance imaging (MRI) has been shown to date to be of value in the high-risk population. Challenges in interpretation are present. Maintaining a high volume of examinations in dedicated centers definitely impacts positively on experience in interpretation. MR-guided intervention is a necessity in all diagnostic centers where breast MRI is performed. Guidelines in interpretation should be used in conjunction with optimum technique and by combining kinetic and morphologic information with clinical history and conventional imaging (mammography and ultrasound) findings, a recommendation for management can be made with more assurance.