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Several cutting-edge strategies are being used to evaluate candidate genetic risk factors for breast cancer. These include linkage analysis for mapping out BRCA1 and BRCA2, mutational screening of candidate risk genes like CHEK2, ATM, BRIP1 and PALB2, which are associated with an intermediate level of breast cancer risk. Genome-wide association studies have revealed several low-penetrance breast cancer risk alleles. The predisposition factors are associated with different levels of breast cancer risk. Relative to control population, the risk in patients harboring high-risk BRCA1 and 2 mutations is over 10-fold, with intermediate penetrance genes 2 to 4-fold and with low penetrance alleles less than 1.5-fold. Overall, these factors account for about 25% of the genetic risk for breast cancer. In the remainder, genetic factors to contribute to the risk of breast cancer remain unknown and are a subject of current investigation. With discovery and validation of newer and clinically relevant predisposition factors, additional breast cancer risk categories may be recognized. BRCA1 and BRCA2 mutation testing allows identification of individuals at increased risk of breast cancer who are offered risk-reducing interventions. Targeted therapies are being developed that may refine management of patients with BRCA1 and BRCA2 mutations. Further genome-wide studies are required to identify clinically relevant molecular factors that will allow more accurate and widely applicable genetic risk stratification. Current efforts in discovery, validation and qualification of molecular markers of breast cancer risk offer considerable promise in the future to develop more accurate breast cancer risk assessment along with development of more effective chemopreventive and therapeutic strategies.

The NCCN Colorectal Cancer Guidelines panel believes that a multidisciplinary approach is necessary for the management of the patient with colorectal cancer. The panel endorses the concept that treatment of patients in a clinical trial has priority over standard or accepted therapy. The recommended surgical procedure for resectable colon cancer is an en bloc resection; laparoscopic surgery should be done only in the context of a clinical trial. For patients with stage III disease, 5-FU-based adjuvant therapy is recommended. A patient who has metastatic disease in the liver or lung should be considered for surgical resection if he or she is a candidate for surgery and if surgery can extend survival. Surgery should be followed by adjuvant chemotherapy. The panel advocates a conservative post-treatment surveillance program for colon and rectal carcinoma patients. Serial CEA determinations are appropriate if the patient is a candidate for aggressive surgical resection, should recurrence be detected. Abdominal and pelvic CT scans should be utilized only when there are clinical indications of possible recurrence. Patients whose disease progresses during 5-FU-based therapy should be treated with irinotecan or encouraged to participate in a phase I or phase II clinical trial.

The significance of breast cancer lymph node micrometastasis has been addressed by numerous studies. Although the results of these studies are mixed, most of the larger trials strongly suggest that the presence of a lymph node micrometastasis, in the absence of other nodal disease, will have a negative impact on disease free survival and on overall survival. The focus of this article is to analyze the biologic and therapeutic significance of micrometastatic disease in the axillary lymph nodes of patients with breast cancer.

Lymphatic mapping techniques have the potential of changing the standard of surgical care of breast cancer patients. This paper reports a prospective study documenting the safety and efficacy of sentinel lymph node biopsy in 167 breast cancer patients and reviews the world literature on the procedure.One hundred sixty-seven patients with newly diagnosed breast cancers underwent a prospective trial of intra-operative lymphatic mapping using a combination of vital blue dye and filtered technetium-labeled sulfur colloid. A sentinel lymph node (SLN) was defined as a blue node and/or "hot" node with a 10/1 ex-vivo gamma-probe ratio of SLN to non-SLN. All SLN were bi-valved, step-sectioned, and examined with routine HE stains and immunohistochemical stains for cytokeratin. Cytokeratin-positive SLN were defined as any SLN with a defined cluster of positive staining cells which could be confirmed histologically on HE sections. Finally, a review of the worldwide data was undertaken using a uniform analytical method to compare the rates of sensitivity, diagnostic accuracy, and false negatives of SLN mapping.In 167 patients, 337 SLN were harvested, for an average of 2.01 SLN/patient. Fifty-two (31.1%) of the patients had metastasis in the SLN. In the 115 patients with negative SLN, 1 was found to have tumor in higher axillary nodes, for a false negative rate of 0.88%. Fifty-nine (37.8%) of the patients were diagnosed by fine-needle aspiration, 89 (53.3%) by excisional biopsy, and 19 (11.4%) by core biopsy. Positive SLN were identified in 1/17 (5.9%) patients with DCIS. Metastasis was found in 33/115 (28.7%) of the patients with infiltrating ductal tumors and in 11/19 (57.9%) of the patients with infiltrating lobular tumors. Positive SLN were identified in 7/16 (43.7%) of the patients with mixed cellularity tumors. Metastasis in the SLN was detected in 7/55 (12.7%) of the 59 patients with T1a-T1b tumors and in 21/58 (36.2%) of the patients with T1c tumors. Positive SLN were found in 17/30 (56.7%) of the patients with T2 tumors and in 6/7 (85.7%) of the patients with T3 tumors. A literature review of 731 patients (including this study) demonstrates a sensitivity rate of 95% and a diagnostic accuracy rate of 98%. The overall false negative rate is 3.1%.This study demonstrates that SLN biopsy is a highly sensitive and accurate method of predicting axillary nodal status. It is a reproducible technique that is easily learned. The future addition of more sensitive methods such as PCR evaluation of nodal involvement may reduce the need for widespread use of adjuvant chemotherapy with its high cost and attendant morbidity and mortality. We believe that this technique will eventually become the standard of care in the treatment of breast cancer, particularly for T1 and T2 lesions and perhaps also for high-grade DCIS tumors.

Current models suggest that colon cancer initiation and progression are secondary to both the activation of oncogenes and the deletion of tumor suppressor genes. The role of each, however, is still poorly understood, particularly with regard to the induction of metastasis. We hypothesized that genetic differences exist between tumors that metastasize distantly and those that do not, and that oncogenes and tumor suppressor genes participate equally in this process. To address this hypothesis, human tumor specimens from localized [tumor-node-metastasis (TNM) stage I-III] and primary colon cancers (n = 10) were directly compared with metastatic (TNM stage IV) lesions (n = 10) using comparative genomic hybridization analysis. Although several alterations were shared equally between primary tumors and metastases (+7q, +19q, and +20q), two patterns of distinguishing alterations were observed: (a) alterations that were more extensive in liver metastases than in primary tumors (+8q, +13q, -4p, -8p, -15q, -17p, -18q, -21q, and -22q); and (b) alterations that were unique to metastatic lesions (-9q, -11q, and -17q). Overall, genetic losses were more common than gains, and, more importantly, the number of losses/tumor was significantly higher for metastases than for primary tumors (9.3 + 1.3 versus 4.1 + 0.7; P = 0.00062, Wilcoxon's rank-sum test). The distinct predominance of genetic losses in the metastatic lesions when compared with the primary localized tumors provides evidence that the metastatic phenotype is induced by the deletion of tumor suppressor genes and permits the construction of physical maps targeting regions where novel tumor suppressor genes are likely to exist.

Whereas genetic paradigms are now defined for the development of human colon cancer, little is known regarding the mechanisms that regulate development of the metastatic phenotype. Recent reports have indirectly linked the expression and activation of c-Src to the process of human colon cancer metastasis. Whereas v-Src, a highly activated mutational derivative of c-Src, has been shown to induce metastasis, normal c-Src has not been tested for this property. We hypothesized that c-Src overexpression in the milieu of a poorly metastatic cancer cell might permit the development of a highly metastatic cell. Two poorly metastatic human colon cancer cell lines were stably transfected with expression vectors encoding normal human c-Src. Clones producing 4-10-fold more c-Src than controls were injected s.c. and intrasplenically into the nude mouse to assess primary tumor growth and liver metastatic potential. Whereas metastatic potential was unaffected, primary tumor growth in vivo was significantly enhanced by c-Src overexpression. No effects on rates of tumor cell proliferation were seen in vitro. Our findings suggest that normal c-Src may be necessary but is insufficient for the induction of the metastatic phenotype.

Understanding the genetic elements controlling the process of tumor metastasis to distant organ sites such as the liver may be the key to improving survivorship from colon cancer. By using standard cytogenetic techniques in combination with comparative genomic hybridization, multiple genetic imbalances within three human colon cancer cell lines previously selected for differences in liver-metastatic behavior were identified. The entire genome of one poorly metastatic cell line (KM12C) was compared directly with that of two highly metastatic cell lines (KM12SM, KM12L4A) derived from it. A number of chromosomal gains (8q, 12q15, 20q11.2) and losses (5p13, 6p21.3, 18) were common to all three cell lines and are likely related to early tumor development rather than to the selection process used to generate cell lines of increased metastatic potential. Chromosomal imbalances detected only in the highly metastatic cell lines were also observed. KM12SM showed losses of portions of 2p22, 2q24.3--2q32.2, 4p15.3--cen, 4q24 without the 13q and 15q22.3 gains noted for KM12C. Both gains (1p31.3--1p21, 2q22--2q33, 3cen--3q26.2, 5q14--5q23, 6cen--6q23) and losses (16p, 17p, 17q 19p, 19q 22q) were observed for KM12L4A but not for the other two cell lines. Identification of these alterations provides valuable insight into the process of experimental liver metastasis and is a first step towards mapping genes linked to the terminal phases of human colon cancer progression.

Breast cancer is considered a chronic disease in most women. This belief is based on natural history data that suggest that some patients with untreated, advanced disease may survive for up to and beyond 20 years after diagnosis. These data are corroborated by studies of treated patients in whom breast cancer recurred up to 15 to 20 years postmastectomy. Conversely, there are also patients who die rapidly after presentation. These divergent observations suggest that there are at least two subpopulations of patients with breast cancer-one that co-exists with the disease and one that rapidly succumbs to it. This heterogeneous biologic behavior is likely related to divergent tumor cell growth rates that have been documented as well as to other unidentified factors. These two subsets of patients, unfortunately, are quite difficult to distinguish. With the promise of the ongoing genetic revolution, the hope is that genes associated with rapidly progressing disease states can be identified. It is important to be cognizant of the prolonged natural history of this disease whenever we attempt to draw conclusions regarding a promising new treatment and we must make every attempt to ensure that patients are improving because of, rather than despite, a therapeutic intervention. Patients entered into trials examining survival as an endpoint should make every attempt to follow patients for 20 to 30 years after treatment. These considerations will ensure that patients requiring therapy are treated to derive benefit, whereas those who would normally not benefit or fare just as well without treatment are not exposed to unnecessary morbidity and mortality. Finally, it must be concluded as Bloom et al have stated that "the value of treatment of primary breast cancer cannot be measured entirely by survival statistics." The quality of a patient's remaining life once the diagnosis of breast cancer has been made should be considered. From untreated natural history data, we know that patients may suffer a painful death without intervention, and we are aware as well that overtreatment may impart untoward symptomatic consequences in the final stages of life when quality is of paramount importance to both the patient and the family.

Colorectal cancer is a common disease that frequently produces limited survival in afflicted patients. Recently a genetic model for tumorigenesis has been defined and has led to a better understanding of the interrelationships between environmental mutagens and genes. Epidemiologic studies have identified multiple chemopreventive agents that appear to reduce the risk of developing colorectal cancer. Their molecular mechanisms of action, as related to the genetic model for colorectal cancer, are discussed.

Tumor cell metastasis is an extremely complex process governed by many different classes of molecules with each class having a separate function. Metastasis is the result of multiple sequential steps and is a highly organized, nonrandom, and organ-selective process. Recent advances in tumor and molecular biology have permitted the identification of a variety of heterogeneous molecules governing invasion (degradative enzymes, motility factors), adhesion (integrins, selectins, cadherins, immunoglobulin-like superfamily, annexins), and growth (paracrine and autocrine growth factors) of tumor cells. This diverse group of biological molecules is collectively responsible for determining whether tumor cells can progress from a single malignant cell to a lethal, multiorgan, metastatic disease.

Schistosoma mansoni cercariae were used to infect CBA-J mice, a strain characterized by possessing a high level of NK cells. 4 days after infection with cercariae, the natural cytotoxic capacity of these mice, as measured by NK and ADCC, reached a peak level of enhancement significantly greater than that of uninfected controls. Infection by this parasite appears to activate natural cell-mediated immune defense systems. Further observation of the pattern of response of NK and ADCC effector cells to infection by cercariae may reveal important information regarding the inherent immunity to the schistosome infection.

Athymic nude mouse homozygotes (nu/nu) and the heterozygote nu/nu+ were injected intraperitoneally with 2 mg of cyclosporin-A (CS-A) twice, 72 and 1 h prior to analysis. We have found that in vivo administration of CS-A results in a significant suppression of natural killer (NK) cell and antibody-dependent cell-mediated cytotoxic (ADCC) activity which probably play an important role in tumor and graft rejection. T cells were also suppressed, in contrast, B cells were found to be immunocompetent as determined by cell proliferation and antibody-forming capacity in response to mitogens and antigens. The identity of cells mediating NK cell and ADCC activity and its relationship to T lymphocytes are also discussed.

The effect of human interferon (HIF) on the growth and function of normal and neoplastic proliferating human T and B cells was studied. Cell cycle analysis by flow-cytometry showed that up to 2000 units of HIF had little effect on the proliferating fraction (that is, the present S + G2 + M phases of the cell cycle) of normal T cells grown continuously wit growth-promoting factor from PHA-stimulated lymphocytes, while 500 units of HIF suppressed the percent S + G2 + M of the acute lymphocytic leukemia (ALL) T-cell line, MOLT, by 36%. Up to 2000 units of HIF had a moderate enhancing effect on the percent S + G2 + M of PWM-stimulated lymphocytes. In striking contrast, a single unit of HIF caused nearly 40% suppression of the percent S + G2 + M of Daudi, a Burkitt's lymphoma cell. One-thousand units of HIF did not decrease the number of antibody-forming normal cells, and up to 500 units of HIF did not inhibit the total Ig secreted by these cells. These results suggest that amounts of HIF affecting the proliferation of some neoplastic lymphoid cells has little effect on the proliferation of normal T and B cells. In addition, HIF does not appear to affect polyclonal induction of B-cell differentiation.

To identify the active molecule in human alpha interferon preparations, we performed several studies, using both partially purified interferon and homogeneous interferon. Our results indicated that there is little difference between the partially purified and the homogeneous interferon preparations in terms of antiviral activity, inhibition of deoxyribonucleic acid synthesis in human neoplastic cells, and enhancement of human natural killer cell activity.

Schistosoma mansoni cercariae were used to infect CBA-J mice, a strain characterized by possessing a high level of NK cells. 4 days after infection with cercariae, the natural cytotoxic capacity of these mice, as measured by NK and ADCC, reached a peak level of enhancement significantly greater than that of uninfected controls. Infection by this parasite appears to activate natural cell-mediated immune defense systems. Further observation of the pattern of response of NK and ADCC effector cells to infection by cercariae may reveal important information regarding the inherent immunity to the schistosome infection.

Previously, all carcinoid tumors were considered to occur sporadically. We present an extremely rare series of three first-degree relatives in two generations with proximal duodenal carcinoid tumors and other family-associated neoplasms. This unusual circumstance, which has never been described previously, represents the sixth case of familial clustering of carcinoid tumors reported in the world's literature.

Detection of cell surface antigens through the use of specific antisera has been possible using vital dye exclusion and radionuclide labeling. Viability determination by these and other more sophisticated methods, however, is often inconvenient. We have developed a method for analysis of cell death due to immune cytolysis that employs the Coulter counter, an electronic particle analyzer. Cell viability after treatment with antisera plus complement was determined and the values correlate well with those of Trypan blue dye exclusion tests. Future applications of this methodology are also discussed.