Early Breast Cancer Predictive Diagnostics: The Cancer Initiating Cell and Personalized Prevention in Breast Cancer
Disease Team Planning
Breast cancer mortality usually results from systemic metastases not eradicated by chemotherapy. Early detection and improved therapy including specific target therapies (i.e. Herceptin) have converted a subset of breast cancer patients from likely mortality to likely cure. Unfortunately, this is only a subset. Many patients prove to have incurable disease even with early detection, and many cancers do not respond to the new therapies. Emerging evidence suggests that the initiation of cancer creates “cancer stem cells” which are defined by the functional ability to replenish themselves but also to reestablish the cancer. Persistence of some of these cells (perhaps a single one of these cells) during treatment results in disease recurrence and eventual mortality. The idea that cancers harbor such cells is not new, and has been shown in many contexts. Often missing from the discussion, however, is the question: When do these cells first arise and how early can their progression be stopped? There is emerging evidence from our experience and from top breast cancer researchers around the globe that these cells arise in breast cancer at a very early stage, initiating the preinvasive lesions recognized as ductal carcinoma in situ (DCIS). Improved detection of this preinvasive DCIS is the basis for an enormous investment in improved imaging technologies, and our colleagues in radiology and biomedical engineering will likely develop ways to accurately and efficiently detect DCIS in the next generations of the mammogram. Unfortunately, the only current therapy for DCIS, once it is detected, is complete excision sometimes requiring complete mastectomy and/or radiation therapy. It is likely that some of these patients with DCIS will not progress to invasive breast cancer, but there is not currently any way to stratify patients into prognostic categories. Furthermore, many of these DCIS lesions may be exquisitely sensitive to anti-hormonal or other specific therapy, but assays for predicting responses have not been developed because proper medical care and ethics requires DCIS eradication treatment. The goal of this Breast Cancer Disease Team concept is to develop diagnostic testing of DCIS using cancer stem cell isolation followed by malignant potential analysis (prognosis) and intervention analysis (prediction). The challenge is to prove that the prognostic and predictive analyses are correct, even though the DCIS lesions detected in patients will be treated by complete surgical removal and/or radio-eradication. The importance of this work is clear in the context of the expected increase in DCIS detection, with the possibility that not all of these women will benefit from surgery and the promise that old (anti-hormonal) and new targeted therapies may be even better with less risk of complication. In short, this proposal is about improving women's health through optimized and individual prevention therapy for pre-invasive breast cancer.
Statement of Benefit to California:
Breast cancer is the most commonly diagnosed cancer and the second most common cause of cancer-related mortality among women in California and in the United States. From 1988 to 1999, 224,137 California women were diagnosed with new cases of invasive breast cancer, representing one of every three invasive cancers diagnosed among women in our state. Almost 35,000 were diagnosed with noninvasive carcinoma or ductal carcinoma in situ (DCIS). During this same 12 years, 50,556 women died of breast cancer. Most of the 224,137 women with invasive breast cancer had undetected DCIS prior to their diagnosis. This early stage of breast cancer is non-lethal, but progresses to potentially lethal invasive breast cancer with a variable period of latency ranging from months to decades. Improved detection of DCIS through improved breast imaging technology promises a much higher rate of pre-invasive stage diagnosis. A National investment in imaging technology is currently funded through the National Cancer Institute, National Institutes of Health, the Congressionally Mandated Breast Cancer Research Program and private enterprise including both the imaging equipment companies and health care corporations. The success of these investments will produce an increase in detection of breast cancer at the DCIS stage resulting in a marked increase in patients undergoing breast surgery and radiation therapy. It is not known if this increase will be transient implied by catching breast cancer earlier in the population, or if a subgroup of patients with DCIS (now detected) which will never progress to invasive cancer for whom surgery and radiation may be unnecessary. Improvement in health of women with DCIS requires: 1) A way to assess the risk for invasive and metastatic cancer at this early stage. 2) Non-surgical therapy to prevent high risk DCIS from progressing. This planning grant proposes to assemble a highly synergistic group of investigators to address this emerging problem in breast cancer diagnosis and therapy. The vision of our Disease Team is cell-based analyses of the potential risk of DCIS. Clearly, not all breast cancers behave the same. We are fighting not one, but many different diseases. It is thus imperative that ways to predict the response of individual breast cancers to specific therapies be developed. While this has some clear benefit in patients with advanced stage disease, the benefit to women's health is much greater and the cost of the care much lower if methods can be applied to very early stage disease, preventing invasive cancer. We have assembled an international consortium to deal with the science and technology. This proposal is an opportunity for the State of California to lead international investment in Breast Cancer diagnosis, prevention and treatment. Even before the expected full proposal funding, this Planning Grant funding will sponsor a high profile international workshop in the state.
Executive Summary The goal of the proposed research is the development of methods that would permit early intervention in the progression of breast cancer, for which the investigator plans to isolate mammary intraepithelial neoplasia (MIN) cells and determine their “trajectory” to invasive cancers. These studies will serve as a prelude to the development of improved diagnostics and stem cell-specific therapies. The core of the planning team will include a clinical pathologist, a stem cell biologist, and an expert in the molecular biology of breast cancer. Key features of the planning process will involve the establishment of collaborative commitments, workshops to facilitate team interaction, identification of proposal components, and planning of regulatory and administrative aspects of the research proposal. This proposal is focused on a highly significant clinical problem, breast cancer, and on the important goal of facilitating early intervention in breast cancer progression. However, the reviewers’ enthusiasm was limited by the absence of sufficient preliminary evidence and base knowledge about breast cancer stem cells, and the low probability for developing clinical trials within five years. The concept is based on the isolation, propagation, and analysis of breast cancer stem cells. The proposed target cells remain poorly characterized, and evidence for the existence of this cell population is meager. Reviewers were concerned that even if such cells could be isolated and characterized, it is unclear how early predictors of cancer progression would be identified and, moreover, how such information would lead to the development of a clinical trial. The PI is a distinguished breast cancer pathologist. Reviewers were concerned about lack of evident experience in leading disease team-based research initiatives or clinical trials, though he/she has published extensively on breast cancer tumorigenesis. The planning approach is clearly described and follows a reasonable and appropriate progression. A clear strength of this aspect of the proposal is the collaboration of two institutions with excellent research capabilities and resources. Individuals with appropriate expertise are identified as prospective team members. The absence of a record of prior, substantial collaborations between proposed team members diminished reviewer enthusiasm, but firming up the collaborations was a stated goal of the planning process. Reviewer Synopsis The persistence of cancer stem cells has been proposed to underlie recurrence, metastases, and resistance to treatment of some or many types of cancer. The applicant Disease Team and others in the breast cancer field have shown that these cells arise in breast cancer at a very early stage, initiating the preinvasive lesions recognized as ductal carcinoma in situ (DCIS). The objectives of the disease team are to isolate, propagate, and biologically assess breast stem cells to provide improved diagnostics, devise predictive assays, and develop stem cell-specific therapies. The first goal of this planning grant is to establish milestones toward the conduct of clinical trials to prove the specificity and sensitivity of prognostic assays. The second goal of the planning phase is to investigate cell isolations and propagations for predicting response to therapies. Finally, the disease team will consider the use of cell growth and differentiation or senescence assays from the DCIS stem cells as a form of personalized medicine. Reviewer One Comments Concept: The key aim in this proposal is to develop methods that would permit early intervention in the progression of breast cancer by isolating mammary intraepithelial neoplasia (MIN) cells and determining their “trajectory” with respect to invasive disease. The PI states that one can grow MINs as mammospheres (equivalent to DCIS) and then characterize these cells by gene expression profiling, etc. The hypothesis is attractive, but designing and executing a trial is challenging. At present there are no guarantees that suitable predictors of malignancy can be defined in MINs in the short term. If the goal is developing trials within 5 years, it is this reviewer’s view that this proposal falls short in this regard. In addition to the upfront issues, the length of time to follow effects of therapy in this setting is very long. If one could define early predictors in DCIS/MIN, the impact on management of breast cancer therapy could be enormous. Nonetheless, as a CIRM disease target in the short term, I do not think this is of the highest priority. Principal Investigator: The PI is a senior and respected pathologist who has contributed significantly to the breast cancer field, particularly in his role as an authority on breast cancer pathology in the mouse. Experience in leading a human disease trial team is not evident but he has assembled a disease team with suitable expertise. His background in the pathology of breast cancer fits nicely with the proposed hypothesis. Planning Approach: The planning approach is reasonable with assembly of the disease team, a focused workshop, followed by identification of specific proposals to put forward for development and planning. Reviewer Two Comments Concept: This proposal targets cancer stem cells, which currently remain poorly characterized, but share the potential for self-renewal and regeneration of entire mature tumors. The presence of these cells has been reported in breast cancer, thus the isolation and characterization of the cells represent significant and high-priority endeavors. Despite the PI’s claim for the evidence supporting the existence of these cells, the scientific evidence remains very poor, and thus does not seem mature enough at the basic level to provide a strong platform for disease approach at this point. That the approach offered in the proposal will offer a revolutionary approach to disease of breast cancer does not at this point seem justified. The main elements of the concept are: 1) use of pre-cancer stem cell like cells for prognostic and diagnostic; and 2) to grow the stem cell like pre-cancer cells in mice and optimize the culture system. The other innovative approaches suggested by the applicant have already been shown to not yield any positive results so far, including screens for compounds that change the differentiation of a stem cell to a benign state. The strength of the proposal overall remains the significance of the target disease and the collaboration between UCD and Burnham. The weaknesses include poor preliminary base knowledge of cancer stem cells of the breast, and the ambitious nature of the approach. Principal Investigator: Dr. Robert Cardiff, MD. PhD is a pathologist. He has 5% effort committed to this proposal. He earned the PhD at UC Berkeley in 1968 in Zoology. The team also includes Dr. Jan Nolta, PhD, an expert in stem cell isolation and propagation. She is a cell biologist who will assist with future regulatory requirements. Another core member is Dr. Robert Oshima, PhD., Burnham Institute. He is an expert in breast cancer, cell biology, mouse stem cells and mammalian tumor biology. Planning Approach: This proposal combines the efforts of UCD Cancer Center, UCD stem cell program and the Burnham Institute. Six phases are proposed. Phase 1 is the commitment which involves two parts: the agreement of various investigators at UCD, as stated above and the commitment of a team of advisors, including Dr. Altrock (UCSB) and a shopping list of other local talent. Phase 2 is a workshop. Despite the claim of the PI, no extensive record of collaboration among the team members is documented. A face-to-face workshop is scheduled for August 2008, which will then focus on Phase 3. Phase 3 has a couple of subparts focused on the development of novel technology required for the project, and development of diagnostic/clinical trial designs. Phase 4 will focus on regulatory planning. Dr. Altrock has initial IRB protocol to obtain cells from women at high risk of breast cancer. Phase 5 is administrative planning under the joint leadership of the co-PIs who will oversee project assessment. Phase 6 is proposal submission