Advances in Surgical Oncology and Clinical Investigation in Breast Cancer
- Lymphatic Mapping for Breast Cancer
- Identification of Women at High Risk of Hereditary Breast & Ovarian Cancer in Bermuda
- Optimization of breast cancer screening
- Efficacy of Mammography in BRCA-1 and BRCA-2 Carriers
- Identification of Women at High Risk of Breast Cancer
- The Prediction of Cancer Survival
- Breast Cancer in African Americans
Lymphatic Mapping for Breast CancerBreast cancer unfortunately commonly spreads to the lymph nodes under the armpit (axilla). The presence or absence of cancer in these nodes is the most important prognostic factor for women with potentially curable breast cancer. Most general surgeons today continue to surgically remove all of these lymph nodes to determine tumor stage in an operation referred to as an axillary dissection. This operation is associated with morbidity, including arm swelling, decreased shoulder mobility, and underarm/chest-wall numbness. Although more limited axillary dissections are associated with decreased post-operative morbidity, these types of operations may compromise the accuracy of staging.
Others and we have pioneered an alternative to this traditional approach which is a technique referred to as sentinel lymph node mapping. By using a combination of blue dye and a radioisotope, surgeons can follow the lymphatic channels draining a breast cancer to a lymph node ("sentinel node"), which is surgically removed in a much less invasive operation. We have demonstrated that the presence or absence of breast cancer in this sentinel lymph node accurately determines whether the breast cancer has spread to the axilla. The ability of a surgeon to find the sentinel node(s) during surgery is highly dependent on the number of these operations he/she has performed. Sentinel lymph node mapping surgery is less invasive than the traditional approach of removing all lymph nodes, and is therefore associated with less morbidity. Another potential advantage of this sentinel lymph node mapping is that the pathologists can focus their analysis on sentinel lymph nodes, rather than on numerous lymph nodes removed from the axilla. They are therefore able to examine more areas of the lymph node and use special stains. These techniques have been demonstrated to identify microscopic foci of breast cancer that are missed by standard techniques.
Between 18% and 35% of patients with stage I and II breast cancer will have spread of their disease to axillary lymph nodes. In many cases, the only node containing cancer will be the sentinel lymph node. It is unknown whether complete removal of axillary lymph nodes in these patients improves local control or enhances odds of survival. Several published series have shown that radiation therapy alone is effective in controlling recurrence in the axilla.
The goals of this clinical trial are:
- Determine the lymph node recurrence rates in patients with cancer in their sentinel lymph node that undergo axillary radiation
- Assess reduction in morbidity associated with sentinel lymph node mapping compared to traditional full axillary dissection
- Determine the frequency with which breast cancer is identified in sentinel lymph nodes using more sensitivity pathologic analytic methods.
Identification of Women at High Risk of Hereditary Breast & Ovarian Cancer in Bermuda The Island of Bermuda provides a unique opportunity for studying hereditary breast and ovarian cancer. The island has a population of 60,000 with only 1% immigration and emigration per year. The island is served by a single hospital and has a single tumor registry. Over the course of the last three years, we have collected family histories of patients with breast or ovarian cancer diagnosed since 1980. We are currently in the process of analyzing this data to determine the incidence of hereditary breast and ovarian cancer on the island and to develop ways of identifying and notifying those families who are high risk.
Efficacy of Mammography in BRCA-1 and BRCA-2 Carriers Mutations in the BRCA-1 and BRCA-2 gene place a woman at high risk for hereditary breast or ovarian cancer, and women with these mutations tend to develop these cancers at a younger age. While we are currently recommending mammography beginning at age 25 in this population, it is not clear that mammography will be effective in identifying cancer at an early treatable stage. The purpose of this study is to determine the characteristics of breast cancer and of breast tissue relative to mammographic identification of cancer in the BRCA-1 and BRCA-2 population. Women who are known BRCA-1 or BRCA-2 carriers or who are at high risk of carrying a mutation, will be identified, and all mammograms from these patients will be collected and digitized. We plan to collect a mammography bank on these patients. We will then use this bank to identify mammographic characteristics of breast cancers in this population, specifically looking at rate of growth, calcifications, DCIS, density relative to surrounding tissue, etc. In addition, we will study the density of the breast tissue by age and look for correlations between mammographic density and risk. We will also look at how mammographic density varies with increasing age, use of tamoxifen, use of hormone replacement therapy, oophorectomy, or other factors.
The Prediction of Cancer Survival It has long been appreciated that both tumor size and the presence of cancer in the regional lymph nodes are indicators of invasive breast cancer outcome, although it has not been obvious as to how to integrate these two qualities into an overall assessment of prognosis. The unifying concept, which makes these calculations possible, was our finding that the lethal distant spread of cancer cells, which render patients incurable by local treatment, occurs with a definable probability per cell. This lead to a simple expression relating tumor size to survival:
where F is the fraction of patients surviving, e is the exponential constant, and D is the tumor diameter, and Z and Q are coefficients whose values can be determined from survival data. We have found that this expression accurately predicts the relationship between tumor size and population-wide survival for both breast cancer and melanoma.
Eq. (1) offers the possibility of making improved population-wide estimates of cancer survival from data on tumor size, but among individuals, additional factors may need to be taken into account, especially the presence of cancer in the local lymph nodes. To address this question, we examined Kaplan-Meier survival estimates (15-years), by tumor size and nodal status, for 1352 women with invasive breast cancer seen at the Van Nuys Breast Center before 1991. To isolate the individual contributions to survival of tumor size and nodal status, the data were sorted by both tumor size and survival. These survival values revealed that for women with equivalent nodal status, tumor size was associated with increased lethality, and that for women with tumors of equivalent size, lethality increased with the number of positive nodes. Notably, it was not node positivity, per se, but the number of positive nodes that appeared to indicate extra risk of death. Women that had only a single positive node, or had either one or two positive nodes, had very similar survivals to node negative women with tumors of the same size. However, as the number of positive nodes increased, there was a graded increase in lethality with each unitary increase in the number of positive nodes, such that there was approximately an extra 3.5% chance of death for each positive lymph node. The lethal contribution from the primary site was found to be well fit to eq. (1), with the values of Q and Z estimatable from survival data of women with node negative cancer. The presence of each positive node was found to contribute an extra 3.5% lethality. The overall lethality was found to be the sum of the two components, and this provided the potential to make improved estimates of survival for individual patients.
Future studies will concern the determination of how accurately survival estimates can be made among various populations of patients, estimation of the role of local metastasis in the prediction of melanoma survival, and the extension of these methods to the estimation of lung and colon cancer survival.
Breast Cancer in African Americans While breast cancer is a less common disease in African Americans in the United States than in Caucasians, the mortality rate is higher in African Americans and cancer tends to occur at a younger age. It has been known for some time that breast cancer in African Americans presents at a higher stage. This has been felt to be due to a lack of access to screening and medical care. Overall, we wish to examine the efficacy of screening in this population and the characteristics of breast cancer. There is the possibility that in addition to under-utilization of screening, the breast cancer in African Americans is a more aggressive cancer that may not be as amenable to early detection as Caucasian breast cancer. In order to study this, we will be looking at the records of patients who have had breast cancer and compare African American and Caucasians in terms of stage at diagnosis, biologic characteristics, and mammographic features such as calcifications, breast density, etc. The ultimate goal will be to determine whether there are differences in the efficacy of screening between these two populations, to determine if there are biologic differences between the cancers in these populations, and to develop means to identify these cancers at an earlier stage and potentially increase the cure rate for these cancers.
Identification of Women at High Risk of Breast Cancer Women at high risk of hereditary breast and ovarian cancer will benefit from specific management strategies implemented at a young age. Currently we are at a disadvantage in that many women with hereditary breast and ovarian cancer risk are unaware of their status. The purpose of this research will be to develop methods of identifying high risk women either through a web-based family history questionnaire or a scannable hand-completed questionnaire. A prototype of the web site is currently being developed, and the scannable questionnaire is currently being used in mammography. The next steps will be to identify an algorithm to cull out the high risk women from this data, to develop means of contacting these women to notify them of their risk and to develop methods to see these women and care for them once they have been identified.
Optimization of Breast Cancer Screening Randomized controlled trials have shown that mammographic screening reduces breast cancers death, but it remains to be established how to use screening to its maximal life-sparing effect, particularly as regards the optimal screening interval. Over the last several years, my colleagues and I have assembled data on the rates of breast cancer growth and spread as well as on the limits of mammographic detectability. We have also developed of a computer simulation model of breast cancer growth and spread, which can calculate such things as the relationship between the screening interval and the fraction of women likely to die from breast cancer. The results of these studies have indicated that great reductions in breast cancer death should be achievable by prompt compliance with the annual screening recommendation, and that even greater numbers of lives might be saved by screening more frequently than once a year. However, from the analysis of the patterns of utilization among women who use screening, it is clear that full utilization of screening in very incomplete, and this provides a barrier to the realization of the full life-sparing potential of screening mammography.
Ongoing research concerns the collection of data for improved estimates of breast cancer growth, spread, and operational detectability, as well as data on the operational aspects of breast cancer screening. Particular interest concerns what determines whether a woman will return (or fail to return) for screening, as well as development of tools, such as computer driven automated telephony reminder systems, which can improve the utilization of screening.