mRNA expression of DOK1-6 in human breast cancer

AIM:To examine the expression of downstream of tyrosine kinase(DOK)1-6 genes in normal and breast cancer tissue and correlated this with several clinicopathological and prognostic factors.METHODS:DOK1-6 m RNA extraction and reverse transcription were performed on fresh frozen breast cancer tissue samples(n = 112) and normal background breast tissue(n = 31). Tissues were collected between 1991 and 1996 at two centres and all patients underwent mastectomy and ipsilateral axillary node dissection. All tissues were randomly numbered and the details were only made known after all analyses were completed. Transcript levels of expression were determined using real-time polymerase chain reaction and analyzed against TNM stage, tumour grade and clinical outcome over a 10-year follow-up period.RESULTS:DOK-2 and DOK-6 expression decreased with increasing TNM stage. DOK-6 expression decreased with increasing Nottingham Prognostic Index(NPI) [NPI-1 vs NPI-3(mean copy number 15.4 vs 0.22, 95%CI:2.7-27.6, P = 0.018) and NPI-2 vs NPI-3(mean copy number 7.6 vs 0.22, 95%CI:0.1-14.6, P = 0.048)]. After a median follow up period of 10 years, higherlevels of DOK-2 expression were found among patients who remained disease-free compared to those who developed local or distant recurrence(mean copy number 3.94 vs 0.0000096, 95%CI:1.0-6.85, P = 0.0091), and distant recurrence(mean copy number 3.94 vs 0.0025, 95%CI:1.0-6.84, P = 0.0092). Patients who remained disease-free had higher levels of DOK-6 expression compared to those who died from breast cancer.CONCLUSION:Decreasing expression levels of DOK-2 and DOK-6 with increased breast tumour progression supports the notion that DOK-2 and DOK-6 behave as tumour suppressors in human breast cancer.

Emerging gene-based prognostic tools in early breast cancer: First steps to personalised medicine

Breast cancer remains a major cause of neoplastic disease in much of the developed world. The majority of cases are diagnosed with oestrogen receptor(ER)-positive and human epidermal growth factor receptor-2 negative invasive ductal carcinoma and are treated predominantly by surgery which includes sentinel node biopsy and adjuvant endocrine therapy ± adjuvant radiotherapy. It is believed that an indeterminate subset of the patient population is needlessly incurring chemotherapy related morbidity without attaining any increase in survival due to therapy. Furthermore in the era of extended adjuvant endocrine therapy it is important to identify those patients who can be safely treated with 5 years rather than 10 years of endocrine therapy thus optimising the benefit-risk balance. This perception has propelled the development of more personalised prognostic tools for newly diagnosed cases of ER-positive breast cancer. In this article, we shall review the evidence regarding the currently available gene assays for human breast cancer.

Evidence for Tumour Suppressor Function of DOK7 in Human Breast Cancer

Introduction: Downstream of tyrosine kinase 7 (DOK-7) is a member of the DOK family, which has been associated with the development and progression of various humancancers. Previously, identification of CpG hypermethylation in DOK-7 promoter was identified in breast cancer. Method: DOK-7 mRNA extraction and reverse transcription were performed on fresh frozen breast cancer tissue samples and normal background breast tissue. Transcript levels of expression were analyzed against TNM stage, tumour grade and clinical outcome over a 10-year follow-up period. Results: Levels of DOK-7 expression decreased significantly with increasing TNM stage. Higher DOK-7 expression was correlated with longer disease free and overall survival times. Conclusion: To our knowledge, this is the first study to investigate DOK-7 expression in human breast cancer. We identify a potential DOK-7 tumour suppressor role. DOK-7 as a prognostic biomarker in human breast cancer should be included in future validation studies.

Towards optimal management of the axilla in the context of a positive sentinel node biopsy in early breast cancer

The sentinel lymph node biopsy(SLNB) was initially pioneered for staging melanoma in 1994 and it has been subsequently validated by several trials, and has become the new standard of care for patients with clinically node negative invasive breast cancer. The focussed examination of fewer lymph nodes in addition to improvements in histopathological and molecular analysis has increased the rate at which micrometastases and isolated tumour cells are identified. In this article we review the literature regarding the optimal management of the axilla when the SLNB is positive for metastatic disease based on level 1 evidence derived from randomised clinical trials.

Skin-Sparing Mastectomy and Breast Reconstruction: An Update for Clinical Practice

Aim: To provide an up-to-date review of the literature on skin-sparing mastectomy (SSM) for breast cancer (BC). The article also reviews the oncological safety, effects of radiotherapy (RT) on immediate breast reconstruction (IBR), the indications for preserving the nipple-areola complex (NAC) and the emerging role of allogenic grafts as adjuncts to implant in IBR. Methods: Review of the English literature from 1965 to 2013 was carried out using Medline and PubMed research engines. Results: SSM is oncologically safe in appropriately selected cases of invasive breast cancer (IBC) and ductal carcinoma in-situ (DCIS) including IBC 5 cm, multi-centric tumours, DCIS and for risk-reduction surgery. Inflammatory breast cancer and tumours with extensive skin involvement represent contra-indications to SSM due to an unacceptable risk of local recurrence. Prior breast irradiation or the need for post-mastectomy radiotherapy (PMRT) do not preclude SSM with IBR, however the aesthetic outcome may be compromised by radiation. Preservation of the nipple-areola complex (NAC) has aesthetic and psychological benefits and is safe for peripherally located node negative unifocal tumours. An intraoperative frozen section protocol for the retro-areolar tissue should be performed when NAC preservation is considered. The advent of acellular dermal matrix has enhanced the scope of implant-based immediate reconstruction following SSM. Cell-assisted fat transfer is emerging as a promising technique to optimise the aesthetics outcome. There is no sufficient evidence to support the role of endoscopic mastectomy in clinical practice. Conclusion: Numerous retrospective and prospective studies show that SSM is oncolgically safe in appropriately selected cases and is aesthetically superior to non-SSM mastectomy. New tech-niques such as the use of acellular dermal matrix (ADM) and cell-assisted fat transfer have increased the use of implants for volume replacement following SSM. In the absence of randomized clinical trials, an updated systematic meta-analysis of published studies is required in order to consolidate the evidence.

Evolving role of skin sparing mastectomy

Skin sparing mastectomy(SSM) can facilitate immediate breast reconstruction and is associated with an excellent aesthetic result. The procedure is safe in selected cases; including invasive tumours < 5 cm, multi-centric tumours, ductal carcinoma in situ and for risk-reduction surgery. Inflammatory breast cancers and tumours with extensive involvement of the skin represent contraindications to SSM due to an unacceptable risk of local recurrence. Prior breast irradiation or the need for post-mastectomy radiotherapy do not preclude SSM, however the aesthetic outcome may be compromised. Preservation of the nipple areola complex is safe for peripherally located node negative tumours. An intraoperative frozen section protocol for the retro-areolar tissue should be considered in these cases. The advent of acellular tissue matrix systems has enhanced the scope of implant-based immediate reconstruction following SSM. Cell-assisted fat transfer is emerging as a promising technique to optimise the aesthetic outcome.

Towards optimal treatment of ductal carcinoma in situ

Ductal carcinoma in situ(DCIS) is a non-obligate precursor of invasive breast cancer with a variable biological behavior which is difficult to accurately predict using the current clinico-pathological parameters. Randomized controlled trials have demonstrated that adjuvant radiotherapy(RT) reduces the risk of local recurrence after adequate local excision of DCIS. Tamoxifen may be considered as an adjuvant endocrine treatment in patients with high risk estrogen receptor positive disease. There is however a growing consensus that RT can be safely omitted in a subgroup of patients with favorable biological features in order to avoid overtreatment. The sentinel node biopsy is not routinely indicated but should be considered in women undergoing mastectomy for DCIS. The discovery of molecular signatures that accurately predict the biological behavior of this common malignancy will facilitate a personalized treatment approach in the future.

Current Treatment of DCIS

Abstract: Ductal carcinoma in-situ DCIS is a heterogeneous entity in breast neoplasm with unpredictable biological behavior. This poses challenge in the management of DCIS. Various trials on DCIS have shown good outcome with integral treatment of adequate surgery, radiotherapy and hormonal therapy. Identification of subgroup of DCIS for radiotherapy and hormonal therapy could improve recurrence rate, contralateral tumours incidence and perhaps overall survival. Various risk score calculations could help to direct radiotherapy and hormonal treatment verses surgery alone and to avoid over treatment. Oncotype DX assay could be a new way of risk calculation to direct types of DCIS treatment. The recent increased use of MRI could increase the detection of DCIS and a more accurate extent of disease estimation. This article is a summary of major literatures and major trials result for DCIS.

Skin-Sparing Mastectomy: An Update for Clinical Practice

Aim: To review the oncological safety and aesthetic advantage of skin-sparing mastectomy (SSM) for invasive breast cancer (IBC) and ductal carcinoma in-situ (DCIS). Controversies including the impact of radiotherapy (RT) on immediate breast reconstruction (IBR), preservation of the nipple-areola complex (NAC) and the role of endoscopic mastectomy are also considered. Methods: Literature review using Medline and PubMed. Results: SSM is safe in selected cases;including IBC 5 cm, multi-centric tumours, DCIS and for risk-reduction surgery. Inflammatory breast cancers and tumours with extensive involvement of the skin represent contra-indications to SSM due to an unacceptable risk of local recurrence. SSM can facilitate IBR and is associated with an excellent aesthetic result. Prior breast irradiation or the need for post-mastectomy radiotherapy (PMRT) do not preclude SSM, however the cosmetic outcome may be adversely affected. Nipple/areola preservation is safe for peripherally located node negative tumours. A frozen section protocol for the retro-areolar tissue should be considered in these cases. The advent of acellular tissue matrix systems has widened the applicability of implant-based immediate reconstruction following SSM. Data on endoscopic mastectomy is limited and superiority over conventional SSM has not been demonstrated. Conclusion: SSM is safe in selected cases and is associated with advantages over simple mastectomy, including a superior aesthetic outcome and a potential reduction in the number of reconstructive procedures per patient.