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Although comprehensive molecular diagnostics and personalized medicine have sparked excitement among researchers and clinicians, they have yet to be fully incorporated into today's standard of care. This is despite the discovery of disease-related oncogenes, tumor-suppressor genes and protein biomarkers, as well as other biological anomalies related to cancer. Each year, new tests are released that could potentially supplement or surpass standard methods of diagnosis, including serum, protein and gene expression analyses. All of these novel approaches have shown great promise, but initial enthusiasm has diminished as difficulties in reproducibility, expense, standardization and proof of significance beyond current protocols have emerged. This review will focus on current and novel molecular diagnostic tools applied to breast cancer with special attention to the exciting new field of microRNA analysis Keywords breast cancer; microarray; microRNA; molecular diagnostics; predictive value; prognostic value Breast cancer is a major public health issue worldwide. In 2004, the most recent year available for global data, there were 1.15 million new breast cancer cases and over 500,000 deaths reported around the world [1,2]. More than half of all cases occurred in industrialized nations † Author for correspondence, Pathogenetics Unit, Laboratory of Pathology and Urological, Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, tangream@mail.nih.gov. NIH Public Access Author ManuscriptExpert Rev Mol Diagn. Author manuscript; available in PMC 2010 May 1. Published in final edited form as:Expert Rev Mol Diagn. 2009 July ; 9(5): 455-467. doi:10.1586/erm.09.25. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript [1,3]. The higher incidence of breast cancer observed in more developed regions of the world is most likely attributed to the availability of screening programs used to detect breast cancer, which may otherwise have never been diagnosed [4]. The total overall cost for the treatment of patients with breast cancer increases with higher stages of the disease [5]. Therefore, screening and diagnosis of breast cancer at earlier stages both benefits the patient and minimizes the financial burden [5].The traditional clinical approach to treat in situ and invasive breast cancer involves a combination of existing surgical-, chemical-and radiation-based therapies. Surgical options include lumpectomy, quadrantectomy, mastectomy and modified radical mastectomy. These procedures are sometimes followed by adjuvant therapy, such as hormonal and/or chemotherapy, which are administered in a case-dependent manner [6]. Hormonal therapies include selective estrogen receptor modulators (SERMs), such as tamoxifen, and aromatase inhibitors, such as anastrozole. Chemotherapy includes traditional chemotherapies as well as specific drugs such as trastuzumab, a monoclonal antibody to the HER2/neu receptor. Although these therapies have shown great promise in decreasing disease...

Two major barriers in the immunotherapy of breast cancer include tumor-induced immune suppression and the establishment of long-lasting immune responses against the tumor. Recently, we demonstrated in an animal model of breast carcinoma that expanding and reprogramming tumor-sensitized lymphocytes, ex vivo, yielded T memory (Tm) cells as well as activated CD25+ NKT cells and NK cells. The presence of activated CD25+ NKT and NK cells rendered reprogrammed T cells resistant to MDSC-mediated suppression, and adoptive cellular therapy (ACT) of reprogrammed lymphocytes protected the host from tumor development and relapse. Here, we performed a pilot study to determine the clinical applicability of our protocol using peripheral blood mononuclear cells (PBMCs) of breast cancer patients, ex vivo. We show that bryostatin 1 and ionomycin (B/I) combined with IL-2, IL-7 and IL-15 can expand and reprogram tumor-sensitized PBMCs. Reprogrammed lymphocytes contained activated CD25+ NKT and NK cells as well as Tm cells and displayed enhanced reactivity against HER-2/neu in the presence of MDSCs. The presence of activated NKT cells was highly correlated with the rescue of anti-HER-2/neu immune responses from MDSC suppression. Ex vivo blockade experiments suggest that the NKG2D pathway may play an important role in overcoming MDSC suppression. Our results show the feasibility of reprogramming tumor-sensitized immune cells, ex vivo, and provide rationale for ACT of breast cancer patients.

Our reexcision rate is low compared with other reports. This results from a policy that defines "no tumor on ink" as an adequate margin for BCS, and the use of selective irradiation boosts based on margins assessed by our pathologists. Our local recurrence rate compares favorably with those seen in other studies while minimizing the need for additional operations. A higher IBTR rate after reexcision likely reflects tumor biology.

We previously demonstrated that interleukin (IL)-7/15 was superior to IL-2 for expansion of T cells in vitro for adoptive immunotherapy. We sought to ascertain whether IL-21 would further improve yield and therapeutic efficacy of T cells in culture. Naïve T cell receptor (TcR) transgenic splenocytes or antigen-sensitized lymph node cells were harvested from PMEL-1 mice and exposed to bryostatin-1 and ionomycin (B/I) for 18 h. Cells were then cultured in IL-2, IL-21, IL-7/15 or IL-7/15/21 for six days. Harvested cells were analyzed by flow cytometry and used to treat C57Bl/6 mice injected intravenously with B16 melanoma. Lungs were harvested and metastases counted 14 days after treatment. Culturing lymphocytes in IL-7/15/21 increased expansion compared to IL-2 or IL-7/15. IL-21 and IL-7/15/21 increased CD8+ cells compared to IL-2 or IL-7/15. IL-21 preferentially expanded a CD8+CD44−CD62L+ T “naïve” population, whereas IL-7/15/21 increased CD8+CD44+CD62Lhigh central-memory T cells. T cells grown in IL-7/15/21 were more effective at reducing metastases than IL-2. The addition of IL-21 to IL-7/15 induced greater expansion of lymphocytes in culture and increased the yield of CD8+ T central-memory cells vs. IL-7/15 alone. This may have significant impact on future clinical trials of adoptive immunotherapy, particularly for generating adequate numbers of lymphocytes for treatment.

Background NRG Oncology/NSABP trial B-40 tested the impact of adding bevacizumab (bev) to neoadjuvant chemotherapy for operable breast cancer. Secondary endpoints included rates of surgical complications after surgery in patients who did or did not receive bev. Methods 1206 women with HER2-negative operable breast cancer were randomly assigned to receive one of three different docetaxel-plus-anthracycline-based regimens, without or with bev (15mg/kg every 3 weeks) for the first 6 of 8 cycles and for 10 doses postoperatively. Surgical complications were assessed from date of surgery through 24 months following study entry. Results Early surgical complications were significantly more frequent in the bev group (25.4% vs. 18.9%; trend test p=0.008), but most were grade 1–2. Early noninfectious wound dehiscences were infrequent and not significantly different (5.4% vs. 3.1%; trend test p=0.15). Long-term noninfectious wound complications were significantly higher for patients receiving bev (11.8% vs. 5.1%; trend test p=0.0007), but the incidence of grade ≥3 wound dehiscence was low in both groups (<1%). Among 193 patients undergoing expander or implant reconstructions, 19 (19.6%) of 97 in the bev-receiving group versus 10 (10.4%) of 96 in the non-bev group had grade ≥3 complications (Pearson p=0.11). Conclusions Overall, adding bev increased surgical complications, but most serious complications were not significantly increased. In particular, the need for surgical intervention in patients undergoing breast reconstruction with prosthetic implants was higher with bev, but was not statistically significantly different. With precautions, bev can safely be used peri-operatively in patients undergoing surgery for breast cancer.

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