Early Breast Cancer Predictive Diagnostics: The Cancer Initiating Cell and Personalized Prevention in Breast Cancer
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.
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.