Bone metastases frequently occur in advanced breast cancer patients and once incorporated into bone have profound effects on bone physiology. Bisphosphonates are potent inhibitors of osteoclastic function and are becoming increasingly important for the management of patients with breast cancer. They affect the ability of cancer cells to accelerate bone turnover and as a result control pain and reduce the risk of pathological fracture.

Furthermore ongoing clinical trials are investigating the role of bisphosphonates as an adjuvant therapy in high-risk breast cancer patients with an aim to prevent bone metastasis.

This article reviews the mechanisms of bone metastasis and will discuss present and future developments for the monitoring and treatment of metastatic bone disease.

As widespread screening for breast cancer detects more women at younger ages and earlier stages, the need for minimally invasive, cosmetically preferable approaches to its treatment grows. The combination of a superficial location on the thorax and lack of intervening organs makes the breast ideal for ablative therapies, one of which is cryoablation. Cryoablation destroys tissue through multiple cycles of localized freezing. Major advantages to cryoablation are: the ability to perform the procedure in the office under real-time ultrasound guidance, improved post-procedure cosmesis when compared to breast conserving surgery since only a 2 mm skin incision is necessary, and the avoidance of anesthesia since freezing numbs the breast. Numerous studies, reviewed here, have demonstrated success in eradication of invasive breast cancer using this modality. However, before cryoablation can be added to the armamentarium of those who treat breast cancer, prospective randomized trials are needed to determine its long-term effectiveness.

According to the National Cancer Comprehensive Network guidelines patients with breast tumours ≤1 cm should be offered systemic therapy. Multiple studies, however, have demonstrated no survival advantage between giving chemotherapy before (neoadjuvant) or after (adjuvant) surgery. There are, however, certain benefits that can be derived from patients who undergo neoadjuvant chemotherapy. Such benefits include better stratification of the patient's prognosis based on tumour and nodal response, and converting patients from mastectomy-only candidates to breast-conserving surgery candidates. Due to these advantages, many patients with early-stage breast cancer will undergo neoadjuvant chemotherapy and the surgical issues must be considered for patients who are treated in such a manner to guarantee optimal outcomes. Issues that will be discussed are the surgical preoperative evaluation, extent and timing of local resection of both the breast and regional nodes and finally, the potential future effects of this multi-modality therapy.

With an aging population, the management of elderly patients with breast cancer is recognised as an area of increasing concern. This population, however, represents a heterogeneous group whom, on the basis of age alone should not be denied any appropriate interventions in the management of their breast cancer. This article reviews the current issues in treating these patients and the paucity of evidence in this setting.

Historically, adjuvant radiotherapy for early-stage breast cancer has included treatment of the entire breast. Breast conservation therapy (BCT), which employs whole-breast radiotherapy following lumpectomy, requires daily treatment for 5–7 weeks. The length of this treatment course proves difficult for some patients. In response, accelerated partial breast irradiation (APBI) has been investigated as a possible alternative to conventional post-lumpectomy treatment. This approach not only challenges the conventional treatment paradigm of whole-breast radiotherapy by reducing the treated volume, but also intensifies the dose delivered. By limiting the volume of breast tissue treated, the radiation dose delivery can be safely accelerated and the treatment time reduced to 5 days. In the United States, APBI has been most commonly delivered via brachytherapy (by either a multi-catheter implant or Mammosite balloon device) or by three-dimensional conformal radiotherapy (3D-CRT). One of the first techniques developed for APBI was multi-catheter interstitial brachytherapy. This article reviews completed trials of ABPI using the multi-catheter approach, as well as patient selection, placement technique, and dosimetric evaluation.

At least four cell types in mouse mammary epithelium, three in human, and three in cow are now known to be proliferation competent. Some evidence indicates that pregnancy may confer proliferative competency on a new cell type. These cells are widely seen as stem and progenitor cells that maintain the epithelium and produce lactational units during pregnancy. Evolutionarily conserved developmental signaling pathways active in germinal and neuronal stem cell proliferation and differentiation in drosophila and mammalian development are implicated in mammary tumorigenesis. In adult tissues this signaling is retained, is regulated by stem cell niches and operates to create new tissue and maintain tissue form and integrity. Disruption of this signaling may abrogate maintenance of the stem cell niche and lead to preneoplastic conditions.

Physicians are testing minimally invasive ablation techniques to determine if they will be acceptable substitutes for surgical removal of primary breast tumors. In radiofrequency ablation (RFA), frictional heating of the tissue is caused by the rapid movement of ions attempting to follow a high frequency alternating current moving between two electrodes. Localization of a small electrode in the tumor is accomplished under ultrasound guidance, and a larger electrode pad is placed on the outside of the body. Five pilot studies have demonstrated that RFA can effectively ablate tumors up to 3 cm in size. In addition to treating small primary tumors, RFA may also be useful for consolidation therapy after lumpectomy, for treatment of inoperable tumors in end-stage patients, for treatment of locally advanced disease as a substitute for neoadjuvant chemotherapy, and for treatment of breast cancer metastases, such as bone, liver, and kidney. Clinical trials are needed to assess treatment outcomes and to monitor the long-term fate of ablated tissue.

Citation of original article:

B. Frank, K. Hemminki, M. Wirtenberger, J. L. Bermejo, P. Bugert, R. Klaes, R. K. Schmutzler, B. Wappenschmidt, C. R. Bartram, B. Burwinkel. The rare ERBB2 variant lle654Val is associated with an increased familial breast cancer risk. Carcinogenesis 2005; 26: 643–7.

Abstract of the original article

Overexpression of the proto-oncogene ERBB2 (HER2/NEU) has been observed in 20–30% of breast cancers involving poor prognosis. Genetic alterations within ERBB2 have been shown to induce carcinogenesis and metastasis. We investigated eight annotated single nucleotide polymorphisms for occurrence in familial breast cancer samples. The confirmed variants Ile654Val, Ile655Val and Ala1170Pro were analysed in subsequent epidemiological studies on familial breast cancer risk. While Ala1170Pro resides within a C-terminally located regulatory domain, the two adjacent polymorphisms Ile654Val and Ile655Val are part of the transmembrane domain. A case–control study analysing a cohort of 348 German familial breast cancer cases and 960 corresponding controls showed no significant association of either Ile655Val (OR = 1.05, 95% CI = 0.82–1.34, P = 0.728) or Ala1170Pro (OR = 0.94, 95% CI = 0.74–1.20, P = 0.632) with familial breast cancer risk. Differences in haplotype frequencies between cases and controls could also not be detected. The ERBB2 variant Ile654Val, however, revealed an increased risk for carriers of the heterozygous Val654 allele (OR = 2.56, 95% CI = 1.08–6.08, P = 0.028). The rare Val654 variant is linked with the more frequent Val655, resulting in two consecutive valine instead of two isoleucine residues within the transmembrane domain. Computational analyses suggest that the Val654–Val655 allele provokes receptor dimerisation and activation, thus stimulating kinase activity and cell transformation. We hypothesise that ERBB2 Val654 represents an oncogenic variant which might, in addition, influence clinical outcome and predict a worse prognosis.

Radiation therapy is an important part of the modern multimodality treatment of breast cancer, and in the past decade has had an increasing role in the treatment of patients at intermediate to high risk for local-regional recurrence after mastectomy. During the same time period, a less radical surgical approach to mastectomy has developed that is more compatible with reconstruction, and a greater number of young patients diagnosed due to screening who are more motivated and candidates for the procedure. This has led to an increased need to consider the special implications of combining radiation with breast reconstruction. This review will focus on reconstruction by tissue expander and breast implants. A multidisciplinary approach to management is needed that includes a team of a plastic surgeon, and radiation, surgical and medical oncologists. Experience with implant reconstruction and radiation in the past decade has been associated with relatively high rates of complications and/or implant loss compared with unirradiated patients. However, newer techniques of radiation, and improved patient selection and coordination between the multidisciplinary team offer the promise of low complication rates and good or excellent cosmetic results for most patients in the future.