George Sledge on insights from normal tissue banks for advances in breast cancer research

Posted by Biome on 1st May 2014 - 0 Comments

Breast cancer is the most common cancer in women in both the developed and developing world. In order to improve prevention and treatment, a greater understanding of the biology and developmental genetics of normal breast tissue is needed. In an effort to facilitate this, the non-profit organisation Susan G Komen for the Cure established a bank of normal, healthy breast tissue from volunteer donors, at the Indiana University Melvin and Bren Simon Cancer Center, USA. Susan Clare from Northwestern University, USA, and colleagues capitalised on this resource to probe how the menstrual cycle and hormonal contraceptives alter DNA expression in normal breast epithelium, as published in their study in Breast Cancer Research. Clare also discusses the importance of research into normal breast tissue in a BioMed Central guest blog. Here we ask the co-chair of the Scientific Advisory Board for Susan G Komen for the Cure, George Sledge from Stanford University, USA, about the impact of Clare’s recent findings, how this tissue bank can aid cancer research, and future directions in this field.


What is the Susan G Komen for the Cure Tissue Bank (KTB) and why is this resource useful for improving breast cancer prevention and treatment?

The Komen tissue bank is the world’s largest repository of normal breast tissue, a magnificent collection of fresh frozen and paraffin-embedded tissues obtained from volunteers without breast cancer. Because the tissue is heavily annotated, it can be used to probe many important questions regarding normal breast biology and breast carcinogenesis. The bank is the creation of a dedicated group of investigators and community volunteers at Indiana University, USA, and is funded through an ongoing grant from Susan G Komen for the Cure. It is a unique and open resource for cancer investigators.


In the study by Susan Clare and colleagues this tissue bank was used to investigate transcriptome changes in breast epithelium during the menstrual cycle and contraceptive hormone treatment. What impact do you think these insights will have our understanding of breast cancer?

One of the great and curious facts of breast biology is that we know far more about the abnormal breast than we do about the normal breast, a consequence of our having collected enormous amounts of tissue from cancer patients and relatively little from normal controls. Our ‘normal’ tissues in all too many studies come from reduction mammoplasty samples, and we now know that such tissue is anything but normal. This study creates a new baseline for what ‘normal’ actually means at the transcriptome level, and in particular tells us a great deal about what occurs at a very basic level during the menstrual cycle.


What other aspects of normal breast biology and development do you think are important to analyse using resources such as the KTB?

One of the great challenges still awaiting our improved understanding is a clear delineation of the early steps underlying breast carcinogenesis in normal risk women. We have made significant strides in our understanding of high risk women (as a result of analyses of BRCA1 and BRCA2 mutations, as well as other less common mutational events). But these represent the minority of breast cancer cases. Because of the extensive annotation, and the wide range of age group cohorts in the Komen Tissue Bank, I suspect we can learn a great deal about the early stages of carcinogenesis.


The study  by Susan Clare and colleagues uses next-generation transcriptome sequencing is used to analyze changes in breast epithelium. How have advances in next-generation sequencing changed our understanding and treatment of breast cancer ?

One of the great discoveries of the past 15 years has been the progressive unfolding of the breast cancer genome. We have progressed, in a very short time, from a ‘one size fits all’ era to a recognition that breast cancer is a family of diseases (the so-called ‘intrinsic subtypes’ characterized as Luminal A, Luminal B, HER2, and Basal breast cancers) to the recent next-generation sequencing-driven recognition that these subtypes have subtypes with specific mutational drivers. This recognition is just beginning to drive the research agenda. For instance, an analysis of the TCGA and other datasets demonstrated that perhaps two percent or so of breast cancers have a somatic mutation of HER2, distinct from the HER2 gene amplification that has been the basis of HER2 testing and treatment over the last decade. This has led to trials where the HER2 somatic mutation is tested for through gene sequencing, and where patients with this novel driver mutation are treated with a small molecule inhibitor of HER2 demonstrated to work in preclinical models.


What areas of cancer genomics do you think hold the most promise to improve cancer prevention and treatment in the future?

I suspect that we are just beginning to understand breast carcinogenesis for ‘normal risk’ women. While we have agents that we know reduce breast cancer incidence in a general population (e.g. tamoxifen and aromatase inhibitors), these agents have gained little or no traction in the broader community. I suspect that this is partly due to the toxicity of these agents, but even more so due to our relatively poor ability to identify truly high risk patients: we use a 1.7 percent risk over five years as a cut-off for initiating therapy, and this number is relatively unimpressive for many patients and physicians. If we can use resources such as the Komen Tissue Bank to identify truly high risk women, we will be much further along the road to effective chemoprevention strategies.


What do you think are the critical research gaps that need to be addressed to improve the prevention and treatment of breast cancer?

We face several important gaps in our knowledge. In women with established breast cancer, we are still ineffective at preventing late relapses in estrogen receptor-positive disease, and similarly we have inadequate therapies for early-recurring, genomically chaotic basal breast cancers. Women die of breast cancer in part because of bad biology, but also because we are unable to deliver therapies that we know would save lives to women who either might have or might get breast cancer, largely a problem of access or underuse of appropriate therapies. We need to research not only ‘bad biology’ breast cancer deaths, we need to study and prevent ‘unnecessary’ breast cancer deaths.


Read more about the importance of research into normal breast tissue in this BioMed Central guest blog by Susan Clare.


More about the author(s)

George Sledge, Professor, Stanford University, USA.

George Sledge, Professor, Stanford University, USA.

George Sledge is Professor of Medicine and Chief of the Division of Oncology at Stanford University, USA. He obtained his medical degree at Tulane University School of Medicine, USA, going on to train in internal medicine and specialise in medical oncology. Sledge established his research career at Indiana University, USA, leading to his appointment as Professor in the Department of Medicine and Pathology. His experience in the area of breast cancer includes particular expertise in anti-angiogenic drug development, breast cancer murine models of growth and metastasis, and breast cancer genomics. During the course of his career Sledge has been involved in the development of novel biologic agents for breast cancer treatment, resulting in Phase I, II and III clinical trials.

Research article

Next-generation transcriptome sequencing of the premenopausal breast epithelium using specimens from a normal human breast tissue bank

Pardo I, Lillemoe HA, Blosser RJ, Choi MR, Sauder CAM, Doxey DK, Mathieson T, Hancock BA et al.
Breast Cancer Research 2014, 16:R26

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