Abstract To explain bimodal relapse patterns, we have previously suggested that metastatic breast cancer growth commonly includes periods of temporary dormancy at both the single cell and avascular micrometastasis phases (with 1 year and 2 year half-lives respectively). We further suggested that primary surgery sometimes initiates growth of distant dormant disease accelerating relapse. These iatrogenic events are common in that they occur in over half of all relapses. Surgery induced angiogenesis is mostly confined to premenopausal node positive patients in which case 20% of patients are so affected. We review here how this hypothesis explains a vairety of previously unrelated breast cancer phenomenon including 1) the mammography paradox for women age 40–49 untreated with adjuvant therapy, 2) the particularly high benefit of adjuvant chemotherapy for premenopausal node positive patients, 3) the heterogeneity of breast cancer, 4) the aggressiveness of cancer in young women, 5) the outcome differences with timing of surgery within the menstrual cycle, 6) the common myths regarding cancer spreading “when the air hits it” and treatment “provoking” the tumor, 7) the excess mortality of blacks over whites, and 8) reports from physicians 2000 years ago. In parallel to physicists who have long sought to explain all of physics with a unified field theory, we now suggest temporary dormancy together with surgery induced tumor growth provides a unifying theory for much of breat cancer.

The following is a brief description of the reconstructive options available to patients undergoing mastectomy, and a review of the data available to guide clinicians who seek to safely integrate postmastectomy radiotherapy and breast reconstruction.

Citation of original article:

van der Hout AH, et al. A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting. Human Mutat 2006; 27(7): 654–666.

Abstract of the original article:

Rapid and reliable identification of deleterious changes in the breast cancer genes BRCA1 and BRCA2 has become one of the major issues in most DNA services laboratories. To rapidly detect all possible changes within the coding and splice site determining sequences of the breast cancer genes, we established a semiautomated denaturing gradient gel electrophoresis (DGGE) mutation scanning system. All exons of both genes are covered by the DGGE scan, comprising 120 amplicons. We use a semiautomated approach, amplifying all individual amplicons with the same PCR program, after which the amplicons are pooled. DGGE is performed using three slightly different gel conditions. Validation was performed using DNA samples with known sequence variants in 107 of the 120 amplicons; all variants were detected. This DGGE mutation scanning, in combination with a PCR test for two Dutch founder deletions in BRCA1 was then applied in 431 families in which 52 deleterious changes and 70 unclassified variants were found. Fifteen unclassified variants were not reported before. The system was easily adopted by five other laboratories, where in another 3593 families both exons 11 were analysed by the protein truncation test (PTT ) and the remaining exons by DGGE. In total, a deleterious change (nonsense, frameshift, splice-site mutation or large deletion) was found in 661 families (16.4%), 462 in BRCA1 (11.5%), 197 in BRCA2 (4.9%), and in two index cases a deleterious change in both BRCA1 and BRCA2 was identified. Eleven deleterious changes in BRCA1 and 36 in BRCA2 had not been reported before. In conclusion, this DGGE mutation screening method for BRCA1 and BRCA2 is proven to be highly sensitive and is easy to adopt, which makes screening of large numbers of patients feasible. The results of screening of BRCA1 and BRCA2 in more than 4000 families present a valuable overview of mutations in the Dutch population.

Most patients present with disease that appears to be confined to the breast. However, a significant proportion of women will go on to develop metastatic breast cancer with bone being the most frequent site of distant relapse. The bone microenvironment provides a fertile soil for circulating metastatic cells as resorbing bone releases growth factors that are thought to attract circulating cancer cells to the bone surface and facilitate their growth and proliferation. These infiltrating tumour cells in turn produce bone cell-activating factors, which lead to increased bone resorption and further release of growth factors in a ‘vicious cycle’. The third-generation bisphosphonate zoledronic acid is a potent inhibitor of osteoclast-mediated bone resorption. It also has effects on numerous processes in the metastatic cascade, with in vitro and animal studies showing synergistic antitumour effects with a range of cytotoxic and endocrine treatments. The addition of zoledronic acid to adjuvant therapy could therefore be a therapeutic strategy of potential importance.

To investigate this, the AZURE trial was designed to determine whether adjuvant zoledronic acid improves the disease-free and bone metastasis-free survival of women with stage II/III breast cancer. Recruitment of 3300 subjects was completed in January 2006. First efficacy data are expected in 2008. There is a potential for synergistic action with chemotherapy to manifest as enhanced toxicity. Reassuringly, initial safety data show that zoledronic acid is well tolerated and can be safely combined with adjuvant chemotherapy without any increase in myelotoxicity or effect on dose intensity.

Despite the fact that breast cancer is predominantly a disease of postmenopausal women, there have been no uniform recommendations for both locoregional and systemic therapy for women over 70. Until recently, older women have been excluded from clinical trials. This study is the first randomized trial that addresses the use of radiation therapy following lumpectomy in a favorable cohort of elderly women.

Breast cancer is one of the most commonly diagnosed cancers in pregnant women. Diagnosis and treatment in these women are particularly challenging as the necessary investigations and treatment modalities may potentially harm the developing foetus. Nonetheless, it appears that initial diagnostic investigations may be carried out as for non-pregnant women, but bearing in mind the risks of exposing the foetus to ionising radiation. Surgery can be carried out with little risk to the mother or foetus but radiotherapy is generally avoided. Chemotherapy can be given relatively safely when administered after the first trimester, but large volume prospective data and, in particular, data regarding the long-term implications of in utero exposure, are awaited.

The use of sentinel lymph node biopsy (SLNB) has revolutionized breast surgery for early stage breast cancer. SLNB accurately stages the axilla without the morbidity of axillary lymph node dissection (ALND). While allowing those patients with No disease to avoid a potentially morbid dissection, SLNB is a diagnostic procedure which identifies nodal disease and is not designed to replace ALND in patients with metastatic disease in the axilla. ALND provides regional disease control, assists physicians in making decisions for patients regarding systemic therapy, and may or may not have a survival advantage. The American College of Surgeons Oncology Group Z0011 study was constructed to determine whether there was a survival difference between completion ALND vs. observation in patients with a positive sentinel lymph node (SLN). Without strong data from randomized, controlled trials regarding the locoregional and long-term survival of patients who undergo observation after a positive SLN, patients should be offered completion ALND for a positive SLNB although ALND may offer no survival advantage.

Therapies that target cancers according to their characteristics (estrogen receptor +ve or –ve, for example) have been a major development in treating cancers successfully and have led to an increase in survival rates. These successes have led to increased research into even more tightly focused therapies. But targeted therapies do not work for everyone, raising issues of (1) identifying patients and (2) developing therapies that reflect our increasing understanding of the complex and differentiated traits of tumors. New targeted therapies such as small molecule signal transduction inhibitors and monoclonal antibodies are being developed to address tumors at all stages of the cell proliferation cycle and it is hoped that they may eventually transform cancer into a fully treatable condition.

Treatment principles of breast cancer in males are derived from studies performed among females, while the low incidence in males has so far precluded such studies. The therapy recommendations for males therefore lack the solid evidence, frequently present for females with breast cancer. The primary breast cancer diagnosis in males is not infrequently in stage III/IV and at higher age, thereby requiring multiprofessional and multimodal management including preoperative therapy and adjuvant therapies based on the tumour’s biological characteristics and the clinical circumstances. The majority of male breast cancer tumours are oestrogen-receptor positive and adjuvant/neoadjuvant tamoxifen is therefore recommended, surgery is frequently radical mastectomy and adjuvant radiotherapy should likely be used on wider indications. Chemotherapy should be considered both in the adjuvant and metastatic setting for receptor-negative cancers and for patients with biologically aggressive disease. Trastuzumab should be offered to patients with Her-2/neu-positive disease, while the use of aromatase inhibitors is more uncertain due to differences in the hormonal environment in males.

There is an increasing demand upon radiology departments for use of ultrasound as part of triple assessment of symptomatic breast disease. It has been shown that in the context of proper training both surgeons and radiologists achieve comparably high diagnostic sensitivity and specificity with ultrasound. This article outlines the arguments in favour of the use of ultrasound by surgeons in the breast clinic for diagnostic and therapeutic purposes.

Tamoxifen can be considered a classic ‘pro-drug’, requiring metabolic activation to elicit pharmacological activity. Our findings suggest that both genetic and drug-induced factors that alter CYP2D6 enzyme activity influence the clinical response to tamoxifen. Given the small differences in disease-free survival comparing tamoxifen to third-generation aromatase inhibitors, knowledge of the genetic and environmental factors that influence CYP2D6 enzyme activity may provide a robust tool to individualize the hormonal therapy to breast cancer.