Citation of original article:

C. Wang et al. Cancer Research 2005; 65(15): 6557–6567.

Abstract of the original article:

The cyclin D1 gene is frequently overexpressed in human breast cancer and is capable of inducing mammary tumorigenesis when overexpressed in transgenic mice. The BRCA1 breast tumor susceptibility gene product inhibits breast cancer cellular growth and the activity of several transcription factors. Herein, cyclin D1 antagonized BRCA1-mediated repression of estrogen receptor α(ERα)-dependent gene expression. Cyclin D1 repression of BRCA1 function was mediated independently of its cyclin-dependent kinase, retinoblastoma protein, or p160 (SRC-1) functions in human breast and prostate cancer cells. In vitro, cyclin D1 competed with BRCA1 for ERα binding. Cyclin D1 and BRCA1 were both capable of binding ERα in a common region of the ERα hinge domain. A novel domain of cyclin D1, predicted to form a helix-loop-helix structure, was required for binding to ERα and for rescue of BRCA1-mediated ERα transcriptional repression. In chromatin immunoprecipitation assays, 17β-estradiol (E2) enhanced ERα and cyclin D1 recruitment to an estrogen response element (ERE). Cyclin D1 expression enhanced ERα recruitment to an ERE. E2 reduced BRCA1 recruitment and BRCA1 expression inhibited E2-induced ERα recruitment at 12 h. Cyclin D1 expression antagonized BRCA1 inhibition of ERα recruitment to an ERE, providing a mechanism by which cyclin D1 antagonizes BRCA1 function at an ERE. As cyclin D1 abundance is regulated by oncogenic and mitogenic signals, the antagonism of the BRCA1-mediated ERα repression by cyclin D1 may contribute to the selective induction of BRCA1-regulated target genes.

The role of estradiol and the estrogen receptor (ER-α) in the etiology of breast cancer have long been appreciated. This understanding has been complicated by two discoveries in the 1990s: (1) a second estrogen receptor (ER-β) whose expression pattern and activity overlap with but are distinct from those of ER-α; and (2) a pool of ERs located at the plasma membrane. This plasma membrane-localized ER constitutes a distinct pool of receptors whose protein interactions, signaling mechanisms, and cellular functions are not the same as that of the cytoplasmic- and nuclear-localized ER and are not as well understood. Here, we will consider the structure and function of the membrane-localized ER protein. We will then discuss what is known about the role of the membrane ER in the development and its implications for breast cancer treatment.

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.

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by Radiation therapy Oncology group (RTOG). Clinical trials include:

1. RTOG 9804: Phase III trial of observation ± tamoxifen versus RT ± tamoxifen for good risk duct carcinoma in-situ(DCIS) of the female breast.

2. NSABP B-39/RTOG 0413: A randomized phase III study of conventional whole breast irradiation (WBI) versus partial breast irradiation (PBI) for women with stage 0, I, or II breast cancer.

3. A phase II trial to evaluate three dimensional conformal radiation therapy (3D-RT) confined to the region of the lumpectomy cavity for stage I and II breast carcinoma.

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 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].

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.

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.

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.

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.

Insulin-like growth factor I (IGF-I) and its main binding protein 3 (IGFBP-3) are multi-regulatory peptides important in tumour cell growth and survival. In the circulation, they occur in large quantities and are readily measured. Across a population, concentrations vary and this may impact on risk of cancers common in western societies. Emerging epidemiological evidence supports the notion that higher levels of IGF-I are associated with increased risk of pre-menopausal, but not post-menopausal, breast cancer. Higher levels of IGFBP-3 may also predict for increased risk of pre-menopausal breast cancer, but this is contrary to the conventional view that this peptide is tumour protective. Nutritional and lifestyle factors, important in breast cancer risk, also inter-relate with circulating levels of IGF-I, but in many circumstances, the relationships are complex. It is becoming increasingly important that the clinical breast oncologist understands the physiology of the IGF system and its potential role in cancer risk assessment and prevention.

There is an established increased risk of secondary malignancy following radiation therapy for cancer in childhood or as a young adult. Breast cancer poses a particular problem as the population risk is significant and screening methods are available raising the question of possible screening interventions for women who are at high lifetime risk.

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.

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.

Historical assumptions concerning the optimal fractionation schedules for women with breast cancer are being challenged by the early results of randomised clinical trials. Multiple small fractions of 2.0 Gy or less are optimal for squamous cell carcinomas, which are clearly less sensitive to fraction size than the surrounding dose-limiting normal tissues. Breast cancer may be different in showing comparable sensitivity to fraction size as the healthy tissues of the breast and underlying ribcage. If this is confirmed, it means that fewer, larger fractions confer the same benefit as standard 2.0 Gy schedules, provided appropriate downward corrections are made to the total dose. The approach also lends itself to tests of acceleration, shorter treatment times being of obvious interest to patients and possibly of therapeutic benefit in their own right.

The cyclooxygenase (COX) enzymes catalyse the rate-limiting step of conversion from arachidonic acid to prostaglandins (PGs). The enzyme exists in two isoforms COX-1 and COX-2. The inducible COX-2 isoform has been shown to be present in up to 80% of breast cancers, high expression correlating with low rates of apoptosis, increased angiogenesis and poor prognosis. Both non-steroidal anti-inflammatory drugs (NSAIDs) and selective inhibitors to COX-2 have been associated with anti-tumoural properties, decreasing the rates of tumour growth, increasing apoptosis and inhibiting angiogenesis. A variety of cellular mechanisms have been suggested, but the exact mechanisms of action remain unclear. COX-2 inhibitors have the potential to be used either alone, or in combination with other agents such as aromatase inhibitors (AIs), monoclonal antibodies (i.e. trastuzumab) or chemotherapeutic agents as novel therapeutic strategies against breast cancer. However the potential cardiac toxicity of the COX-2 selective compounds needs to be fully addressed, with the future development of either safe dosing regimes or new compounds.

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.

Psychiatric consultation and supportive psychotherapy provide many benefits for women with breast cancer including an opportunity to address existential, physical, emotional, social, psychosexual and relationship (family and others) concerns. The psychiatrist is a source of meaningful information and helps the patient challenge pessimistic thoughts and consider life, health, family and career priorities. The management of psychiatric symptoms and the treatment of side effects helps promote adherence to cancer treatment.