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Early Life Events and the Risk of Breast Cancer
Posted November 17, 2004
Mads Melbye, M.D. Staten Serum Institut, Copenhagen

Understanding the causes of breast cancer should lead to improved methods of identifying women with the highest risk for developing this disease. Many studies point toward early developmental events in a woman's life (including growth rates in utero, childhood and adolescence) as influencing her risk of developing breast cancer as an adult. A team of researchers led by Dr. Mads Melbye, an FY99 Breast Cancer Research Program Idea Award recipient, took advantage of a unique opportunity to link Denmark's high-quality nationwide registries to examine associations among birth weight, childhood and pubertal growth, and breast cancer in a large cohort of 117,415 Danish women. The height and weight of these individuals had been recorded annually during the school years. This study determined that high birth weight, being tall at 14 years of age, having a low body-mass index at 14 years of age, and showing peak growth at an early age were independent risk factors for breast cancer. Height at 8 years of age and the increase in height during puberty (8 to 14 years of age) were also associated with breast cancer. The team found no effect when adjusting for parity and age at first childbirth. In contrast to other studies, there was no correlation between age at menarche and developing breast cancer. In addition, data suggested that high body-mass index at a young age protected against breast cancer. A possible explanation for this finding is that estrogens produced by adipose tissue may promote differentiation of the breast epithelium. These results provide evidence that factors influencing fetal, childhood, and adolescent growth affect the risk of developing breast cancer in adulthood. A better understanding of the association between early growth patterns and the risk of breast cancer could improve our knowledge of the mechanisms of the disease and could be important for prevention.

Publications:

Ahlgren M, Sorensen T, Wohlfahrt J, Haflidadottir A, Holst C, Melbye M. 2003. Birth weight and risk of breast cancer in a cohort of 106,504 women. Int J Cancer. 107:997-1000.

Ahlgren M, Melbye M, Wohlfahrt J, Sorensen TI. Growth patterns and the risk of breast cancer in women. N Engl J Med. 2004 Oct 14;351(16):1619-1626.

Link:

Abstract: Early Life Events and Risk of Breast Cancer

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Bryostatins: Potential breast cancer therapeutic agents from the sea?
Posted October 14, 2004
Margo Haygood, Ph.D., University of California, San Diego

Bryostatins, a unique family of naturally occurring compounds, are found only in the marine bryozoan Bugula neritina. Bryostatins work through the protein kinase C (PKC) signaling pathway to alter cellular activity unlike most chemotherapeutic drugs, which kill all rapidly growing cells in the body thereby causing serious side effects. Bryostatins also interact with many chemotherapeutic agents and enhance their effectiveness. In addition, Bryostatins sensitize human breast cancer cells to the cytotoxic effects of anticancer agents, resulting in lower dose requirements and less toxicity. Finally, bryostatin 1 holds great promise for the treatment of breast cancer and for enhancing lymphocyte survival during radiation treatment. There are 19 known bryostatins, some or all of which may be valuable therapeutic agents. However, research on and development of bryostatins, including bryostatin 1, is severely limited by an inadequate supply of these compounds. Margo Haygood, a marine biologist from the University of California, San Diego, previously demonstrated that a bacterial symbiont of B. neritina is the source of the bryostatins. Through research funded by a fiscal year 1999 Breast Cancer Research Program (BCRP) Idea Award, Dr. Haygood is looking for ways to increase production of these compounds including cloning of the genes responsible for biosynthesis of these compounds, expressing these genes in a more easily cultured organism, and/or finding ways to culture the symbiotic bacteria such that large amounts of these compounds can be produced. It is expected that this work will provide an unlimited supply of the bryostatins and will also allow for the development of analogs with improved biological activity.

Link:

Abstract: Production Of Bryostatins For Treatment Of Breast Cancer

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Making Sense Out of Too Much Noise: Information is Power in Breast Cancer Treatment
Posted August 11, 2004
John Simes, M.D. and Davina Ghersi, National Health and Medical Research Council (NHMRC) Clinical Trials Centre, Australia

In the information age, we expect answers to queries to be as close as our fingertips and the internet, but clinicians and breast cancer patients can be bewildered by the treatment options. Evidence from clinical trials is available, but its quality varies and there are many different treatments and different types of breast cancer. To help with the decisions daily facing clinicians and women with metastatic breast cancer, a team of researchers at the NHMRC Clinical Trials Centre in Australia have tackled the collage of information that overwhelms the treatment picture. They systematically reviewed and integrated the available evidence on how various treatment regimens affect survival, toxicity, and quality of life. The reviews have answered several questions a woman or a doctor might ask about treatment options. Overall, the reports laid the foundation for new ways of thinking and decision making in cancer treatment. They showed the effectiveness of endocrine (hormone) treatment and the benefit of combination chemotherapy regimens (two or more drugs rather than one). Their reviews of different intensities of chemotherapy show that the amount or the duration of the therapy might not be as important as the suitability of the selected drug itself. The investigators also directly sought the input of women with breast cancer, especially through their web site (http://www.ctc.usyd.edu.au/cochrane/). A barrage of information can be considered only noise. The group are determined to make sense out of the cacophony and better inform treatment decisions, thereby lending hope to women with breast cancer.

Publications:

Wilcken N, Hornbuckle J and Ghersi D. Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer (Cochrane Review). 2004. In: The Cochrane Library, Issue 3. Chichester, UK: John Wiley & Sons, Ltd.

Carrick S, Ghersi D, Wilcken N, Simes J. Platinum containing regimens for metastatic breast cancer (Cochrane Review). 2004. In: The Cochrane Library, Issue 3. Chichester, UK: John Wiley & Sons, Ltd.

Ghersi D, Wilcken N, Simes J, Donoghue E. Taxane containing regimens for metastatic breast cancer (Cochrane Review). 2004. In: The Cochrane Library, Issue 3. Chichester, UK: John Wiley & Sons, Ltd.

Farquhar C, Basser R, Hetrick S, Lethaby A, Marjoribanks J.. High dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with metastatic breast cancer (Cochrane Review). 2004. In: The Cochrane Library, Issue 3. Chichester, UK: John Wiley & Sons, Ltd.

Carrick S, Ghersi D, Wilcken N, Simes J. Single versus combination chemotherapy for metastatic breast cancer. (Cochrane Review). 2004. In Press: The Cochrane Library, Issue 4. Chichester, UK: John Wiley & Sons, Ltd.

Lord S, Ghersi D, Wilcken N, Simes J. Anti-tumour antibiotic containing regimens for metastatic breast cancer. (Cochrane Review). 2004. In Press: The Cochrane Library, Issue 4. Chichester, UK: John Wiley & Sons, Ltd.

Note: Cochrane reviews are kept up-to-date so the citation changes every 3 months.

Link:

Abstract: Systematic Reviews Of Randomised Controlled Trials Of Chemotherapy And Endocrine Therapy In Advanced Breast Cancer

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Early Detection of Breast Cancer by Molecular Analysis of Ductal Lavage Fluid
Posted April 23, 2004
Saraswati Sukumar, Ph.D., Johns Hopkins University School of Medicine

Early detection of breast cancer leads to better prognosis and increased survival. Currently, the most common option for detection is mammography, which has the potential limitations of sensitivity, reader error, and patient discomfort leading to late diagnosis, misdiagnosis, or attrition. Dr. Saraswati Sukumar of Johns Hopkins School of Medicine, a Breast Cancer Research Program Idea Award recipient, is investigating the possibility of designing a test for breast cancer similar in nature to the Pap smear, which is used for early detection of cervical cancer. Ductal lavage will be used to collect breast cells from women, and the DNA extracted from these cells will undergo highly sensitive methylation-specific polymerase chain reaction (MSP) to detect marker genes known to be down-regulated due to aberrant hypermethylation in breast cancer. Dr. Sukumar has developed quantitative MSP for the promoter regions of RAR ß (nuclear receptor for retinoic acid, an inhibitor of breast cancer cell proliferation), RASSF1A (a tumor suppressor gene that interacts with the ras signaling pathway), Twist (a basic helix-loop-helix transcription factor), Cyclin D2 (cell cycle protein known to be downregulated in cancer), HIN-1 (a candidate tumor suppressor gene that is high in normal breast tissue) and estrogen receptor (1, 2, 4, 5). She has adapted this assay so that analysis of all six markers may be conducted from a minimal sample size, further enhancing sensitivity of the technique. Dr. Sukumar has now extended previous clinical trials of 28 breast cancer patients (2) by collecting ductal lavage from both breasts of 25 women prior to surgery of biopsy-proven lesions. Currently, the samples are undergoing cytologic examination prior to MSP. The goal of this study is to gather information to determine the numbers needed for proper analysis in a large-scale clinical trial. The ultimate goal is to develop a breast cancer 'Pap smear' that would be capable of identifying women at high risk for, or in the early stages of, breast cancer.

Publications:

Evron E, Umbricht CB, Korz D, Raman V, Loeb DM, Niranjan B, Buluwela L, Weitzman SA, Marks J, Sukumar S. 2001. Loss of cyclin D2 expression in the majority of breast cancers is associated with promoter hypermethylation. Cancer Res. 61:2782.

Evron E, Dooley WC, Umbricht CB, Rosenthal D, Sacchi N, Gabrielson E, Soito AB, Hung DT, Ljung B-M, Davidson, NE, Sukumar S. 2001. Detection of breast cancer cells in ductal lavage fluid by methylation-specific PCR. The Lancet 357:1335.

Fackler, MJ, Evron E, Khan SA, Sukumar S. 2003. Novel agents for chemoprevention, screening methods and sampling issues. J Mammary Gland Biol Neoplasia 8:75-87.

Fackler, MJ, McMeigh M, Evron E, Garrett E, Mehrotra J, Polyak, Sukumar S, Argani P. 2003. DNA methylation of RASSF1A, HIN-1, RAR-beta, Cyclin D2 and Twist in in situ and invasive lobular breast carcinoma. Int. Journal of Cancer 107: 970-975.

Mehrotra J, Ganpat MM, Kaaan Y, Fackler MJ, McVeigh M, Lahti-Domenici J, Polyak, K, Argani P, Naab, T, Garrett E, Parmigiani G, Broome C and Sukumar S. 2004. ER/PR-negative breast cancers of young African American women have a higher frequency of methylation of multiple genes than those of Caucasian women. Clin Cancer Res. 10: 2052-2057.

Link:

Abstract: Early Detection of Breast Cancer by Molecular Analysis of Ductal Lavage Fluid

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