This is a great study to read! Access it at http://www.nature.com/nature/journal/v461/n7265/full/nature08489.html
Shah, SP et al.(2009) Mutational evolution in a lobular breast tumour profiled at single nucleotide resolutionNature 461, 809-813.
I am attaching the TAKE HOME message and Commentary from Axel Grothey, MD

Supplementary editorial provided by OncologySTAT

TAKE-HOME MESSAGE
In this study, Shah et al revealed the evolutionary nature of the tumor genome during progression of a low-intermediate grade, estrogen-receptor?positive lobular breast cancer. Sequencing of tumor genomes and transcriptomes from the same patient was used to compare genomic changes that occurred over a 9-year period during which the tumor had metastasized.

Of the 32 nonsynonymous coding mutations found in metastatic cells, 19 were not present in the primary tumor DNA at diagnosis. In contrast, 11 of the 32 mutations were present in the primary tumor, signifying that the primary tumor itself exhibited genetic heterogeneity. Validation of 75 RNA editing events yielded 2 high-frequency nonsynonymous mutations located within the COG3 and SRP9 genes.

The results revealed that, not only was the primary tumor genetically heterogeneous, but also that a significant amount of genetic evolution had occurred during progression. Tumor protein translation was altered, as evidenced by changes in the DNA sequence and by modifications of RNA transcripts. It is unclear whether these changes were a consequence of radiotherapy or of tumor progression.


EXPERT COMMENTARY
Axel Grothey, MD, Associate Editor

Genetic instability, one of the hallmarks of cancer, not only leads to tumor cell heterogeneity, but it also contributes to various aspects of the malignant phenotype of cancer cells, as well as to the resistance of cancer cells to tumor-directed therapy. Differences in genetic markers and gene expression between primary tumors and metastases have previously been confirmed for specific genes and proteins, but genetic differences have not been determined on a genome-wide level due to technical limitations. As exemplified by the study conducted by Shah et al, the ability to sequence whole genomes of tumors within a short time frame allows us to obtain a better understanding of genetic factors that drive tumor biology in individual patients. Success in this area of research ultimately promises to open the door for the utmost individualization of therapeutic approaches in cancer.

Ductal carcinoma in situ (DCIS), the most common non-invasive lesion of the breast, presents unique challenges for patients and providers largely because the natural course of the untreated disease is not well understood. Because most women diagnosed with DCIS are treated, it is difficult to determine the comparative benefits of different treatment strategies versus active surveillance, meaning systematic follow-up. An independent panel convened by the NIH urged the scientific community to identify appropriate biomarkers and other prognostic factors to better predict the risk of developing breast cancer.

"Instead of treating all women diagnosed with DCIS, we need to determine which individuals are likely to develop invasive breast cancer and which will not," said Dr. Carmen Allegra, panel chair and Chief of Hematology and Oncology at the University of Florida. "If we could accurately predict this, we might save some women from undergoing unnecessary invasive treatments while achieving the same positive outcomes."

DCIS is a condition in which a spectrum of abnormal cells are found in the breast duct and have not spread outside the duct to other tissues in the breast. Since the advent of widespread screening mammography in the early to mid 1980's, rates of DCIS have increased sharply. It is estimated that more than one million U.S. women will be living with a prior diagnosis of DCIS by 2020.

Despite the connotations associated with the term carcinoma, DCIS is associated with ten-year survival rates close to 100% when treated with currently available therapies. These include breast-conserving surgery (local excision, with or without radiation), removal of the breast (mastectomy), and/or tamoxifen. It is important to stress that each of these treatment options has physical and emotional impacts to patients and should be weighed accordingly. The panel recognized that there are relatively few reliable data on the comparative effectiveness of both diagnostic and therapeutic options in DCIS.

To improve our understanding of this complex disease, the panel recommended efforts to ensure detailed collection of clinical, pathological, imaging, and molecular data about DCIS using standardized reporting measures, annotated specimen repositories, and multicenter databases.

The panel emphasized the importance of patient preferences and recommended improved communication between patients and providers, and serious consideration of new nomenclature that more closely reflects the excellent survival rates for this condition.

Efforts to improve communication would also include further development of formal decision aids. Such tools would reduce misinformation and improve understanding of a DCIS diagnosis and the risks and benefits of various treatment options. Individuals who have DCIS should have access to the best possible information and guidance to aid them in making care decisions that reflect their unique circumstances, perspectives, and preferences.

The panel's updated draft state-of-the-science statement will be available later today at http://consensus.nih.gov. The conference was sponsored by the NIH Office of Medical Applications of Research and the National Cancer Institute along with other NIH and Department of Health and Human Services components. This conference was conducted under the NIH Consensus Development Program, which convenes conferences to assess the available scientific evidence and develop objective statements on controversial medical is sues.

The 14-member conference panel included experts in the fields of oncology, radiology, surgery (general and reconstructive), pathology, radiation oncology, internal medicine, epidemiology, biostatistics, nursing, obstetrics and gynecology, preventative medicine and population health, and social work. A complete listing of the panel members and their institutional affiliations is included in the draft conference statement. Additional materials, including panel bios, photos, and other related resources, are available at http://consensus.nih.gov/2009/dcismedia.htm.

In addition to the material presented at the conference by speakers and the comments of conference participants presented during discussion periods, the panel considered pertinent research from the published literature and the results of a systematic review of the literature. The systematic review was prepared through the Agency for Healthcare Research and Quality Evidence-based Practice Centers (EPC) program, by the Minnesota Evidence-based Practice Center. The EPCs develop evidence reports and technology assessments based on rigorous, comprehensive syntheses and analyses of the scientific literature, emphasizing explicit and detailed documentation of methods, rationale, and assumptions. The evidence report on diagnosis and management of DCIS is available at http://www.ahrq.gov/clinic/tp/dcistp.htm.

The panel's statement is an independent report and is not a policy statement of the NIH or the federal government. The NIH Consensus Development Program was established in 1977 as a mechanism to judge controversial topics in medicine and public health in an unbiased, impartial manner. NIH has conducted 119 consensus development conferences, and 32 state-of-the-science (formerly "technology assessment") conferences, addressing a wide range of issues. A backgrounder on the NIH Consensus Development Program process is available at http://consensus.nih.gov/backgrounder.htm.

The Office of the Director, the central office at NIH, is responsible for setting policy for NIH, which includes 27 Institutes and Centers. This involves planning, managing, and coordinating the programs and activities of all NIH components. The Office of the Director also includes program offices which are responsible for stimulating specific areas of research throughout NIH. Additional information is available at http://www.nih.gov/icd/od.

The National Institutes of Health (NIH) ? The Nation's Medical Research Agency ? includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

The National Institutes of Health (NIH) ? The Nation's Medical Research Agency ? includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Interesting research news regarding Metformin:

Please connect to the National Cancer Institute Cancer Bulletin

http://www.cancer.gov/ncicancerbulletin/092209/page3

Connect directly to the research article:

Cancer Res. 2009 Sep 14. Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth and Prolong Remission.

Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K.