Breast cancer in patients with residual invasive carcinoma is more accurately staged with additive tumor size assessment.

BACKGROUND: Accurate assessment of tumor size for patients with breast cancer undergoing re-excision following breast-conserving therapy is important for appropriate staging and adjuvant treatment. We investigated the accuracy of additive vs. nonadditive size assessment in determining final tumor stage. METHODS: Patients with infiltrating carcinoma in the initial excision and in at least one additional re-excision (re-excision positive; n = 89) had tumor size assessed with additive and nonadditive techniques. This group was compared with patients undergoing re-excision but without identifiable residual carcinoma (re-excision negative; n = 105) regarding rates of lymph node (LN) metastasis. RESULTS: The re-excision positive patients had a different median final tumor size depending on the size assessment technique used (nonadditive: 1.8 cm; additive: 3.0 cm; P <.0001). Both groups of patients had a median tumor size consistent with T1c staging in nonadditive size assessment. However, re-excision positive patients had a significantly higher incidence of LN metastasis (P <.05) than did re-excision negative patients. Both groups were then separated into T1 and T2 stages and the LN metastasis rates were assessed. Compared with nonadditive size assessment, additive size assessment distributed re-excision positive patients into T stages whereby the LN metastasis rates more closely approximated those of re-excision negative patients (T1, 3% vs. 6% difference; T2, 4% vs. 13% difference). CONCLUSIONS: With regard to LN metastasis, staging for patients with residual invasive carcinoma in re-excision specimens is more accurate with additive tumor size assessment.

Methylene blue dye as an alternative to isosulfan blue dye for sentinel lymph node localization.

Isosulfan blue dye has been used with increasing frequency in localizing sentinel lymph nodes in breast cancer patients. Few alternative types of dye have been investigated. In a prospective study of 30 patients, methylene blue dye was used instead of isosulfan blue dye to localize the sentinel lymph node. The methylene blue dye localization technique was successful in 90% of patients. These results are similar to those for isosulfan blue dye. This study describes methylene blue dye localization as a successful alternative to isosulfan dye in identifying the sentinel node in breast cancer patients. The methylene blue dye technique offers a substantial cost reduction.

Breast cancer chemoprevention.

Chemoprevention of breast cancer is a rapidly growing field. Chemoprevention was initiated with the development of the antiestrogen tamoxifen. A major clinical trial in the United States found that tamoxifen reduced the incidence of breast cancer by almost 50% in women at an increased risk for the disease. Although two European trials did not confirm these findings, the Food and Drug Administration found the American studies significant enough to approve tamoxifen for the delaying of breast cancer in women at high risk for the disease. However, adverse effects associated with tamoxifen include a minimally increased rate of endometrial cancer, cataracts, and strokes. Newer classes of antiestrogens, called selective estrogen receptor modulators (SERMs), are being investigated as potential chemopreventive agents. These SERMS, such as raloxifene, will hopefully provide some of the benefits of estrogen without its inherent risks. In addition, naturally occurring compounds and their analogues are also under investigation.

Skin-sparing mastectomy with immediate breast reconstruction: a critical analysis of local recurrence.

PURPOSE: The purpose of this study was to provide follow-up data regarding the incidence of local breast cancer recurrence in patients undergoing skin-sparing mastectomy versus conventional non-skin-sparing mastectomy methods. PATIENTS AND METHODS: A retrospective follow-up study and analysis were performed of patients who underwent mastectomies for invasive breast cancer at The New York Presbyterian Hospital, Cornell University Medical College and Strang-Cornell Breast Center between 1990 and 1998. RESULTS: A total of 198 patients were identified in this study, and the mean follow-up was 49 months. This group included 71 patients who underwent skin-sparing mastectomy and 127 who underwent non-skin-sparing mastectomy procedures. No statistical differences in local recurrence rates were demonstrated between patients treated with skin-sparing mastectomy and those who underwent non-skin-sparing mastectomy. Local recurrence was present in four of 71 (5.6%) patients undergoing skin-sparing mastectomy and in five of 127 (3.9%) of those undergoing non-skin-sparing mastectomy. CONCLUSIONS: The use of skin-sparing mastectomy does not lead to an increase in local recurrence rates when compared with conventional non-sparing mastectomies and provides for improved aesthetic results after immediate reconstruction.

Comparison of rate of development and rate of change for benign and malignant breast calcifications at the lumpectomy bed.

OBJECTIVE: The study purpose was to evaluate the rate of development and the rate of change for benign and malignant breast calcifications at the lumpectomy bed. MATERIALS AND METHODS: Retrospective review identified 53 new calcifications at the lumpectomy bed in patients with available mammograms and medical records. Breast Imaging Reporting and Data System (BI-RADS) categories were retrospectively assigned on the basis of initial prospective recommendation for yearly follow-up (category 2), 6-month follow-up (category 3), or biopsy (category 4 or 5). Outcomes were defined as benign for no recurrence at the lumpectomy bed on biopsy or follow-up and malignant if biopsy-proven at the lumpectomy bed. RESULTS: The median rate of development after lumpectomy was 23 months (range, 2-174 months) for benign and 39 months (range, 15-112 months) for malignant calcifications. Fifteen (28%) of 53 calcifications were classified as BI-RADS category 3. Twelve (80%) of 15 were downgraded to BI-RADS category 2 at a median follow-up of 6.5 months (range, 6-16 months); none represented recurrent disease. Three (20%) of 15 were upgraded to BI-RADS category 4 at the 6-month follow-up, one despite stability (benign) and two for increasing pleomorphism (malignant). Nine (17%) of 53 calcifications were classified as BI-RADS category 4 or 5; six (67%) of the nine were malignant and three (33%) were benign at biopsy. Twenty-nine (55%) of 53 calcifications were classified as BI-RADS category 2, none representing recurrent disease. CONCLUSION: Benign calcifications at the lumpectomy bed usually develop earlier than malignant calcifications, but the rate of development overlaps. Most calcifications initially placed in the probably benign category evolve quickly to more benign or more malignant morphology. Most calcifications heralding recurrence appear suspicious on first presentation.

A comparison of cell cycle markers in well-differentiated lobular and ductal carcinomas.

Infiltrating lobular carcinoma (ILC) and infiltrating ductal carcinoma (IDC) are similar in many respects and their histologic features occasionally overlap. Despite the many similarities, some clinical follow-up data and the patterns of metastasis suggest that ILC and IDC are biologically distinct. Unfortunately, most breast cancer research has focused almost exclusively on the ductal subtype or has not stressed the biologic or molecular genetic distinctions between breast carcinoma subtypes. Several reports have suggested the possibility that ILCs and IDCs differ with respect to expression of antigens involved in proliferation and cell cycle regulation. Therefore, we undertook an immunohistochemical evaluation of cell cycle related antigens in ILCs, including histologic variants thought to represent aggressive neoplasms, and IDCs matched for histologic grade (Modified Bloom-Richardson Grade I). We believe that different antigen expression profiles could elucidate the biological distinctiveness of breast carcinoma subtypes and possibly provide diagnostically relevant information. We studied the expression of the following antigens in 28 archived, formalin-fixed ILCs and 34 well-differentiated IDCs: estrogen receptor (ER), progesterone receptor (PR), Her 2-neu, mib-1, cyclin D1, p27, p53, mdm-2 and bcl-2. 94% of ILCs and 100% of IDCs expressed ER; 75% of ILCs and 76% of IDCs expressed PR; 4% of ILCs and 13% of IDCs expressed c cerb B-2; ILCs and IDCs both expressed mib-1 in approximately 10% of lesional cells; 82% of ILCs and 54% of IDCs expressed cyclin D1; 90% of ILCs and 83% IDCs expressed p27 strongly; 4% of ILCs and 4% of IDCs expressed p53, 25% of ILCs and 33% of IDCs expressed mdm-2; 96% of ILCs and 100% of IDCs expressed bcl-2. None of the apparent differences were statistically significant. The ILC variants demonstrated immunophenotypes that were essentially similar to ILCs of the usual type. We conclude that ILCs and well-differentiated IDCs show similar proliferation and cell cycle control antigen profiles. Despite their unusual histologic features, most ILC variants appear to maintain a characteristic ILC immunophenotype.

Predictive factors associated with axillary lymph node metastases in T1a and T1b breast carcinomas: analysis in more than 900 patients.

BACKGROUND: Axillary lymph node metastasis (ALNM) represents the single most important prognostic indicator in patients diagnosed with breast cancer. The proportion of < or = 1-cm (T1a, T1b) invasive breast carcinomas is increasing. The incidence and predictive factors associated with ALNM in patients with < or = 1-cm tumors remains unclear and the role of axillary lymph node dissection in these patients has been questioned. The purpose of this study was to determine clinical and pathologic factors predictive of ALNM in patients with < or = 1-cm invasive breast carcinomas by univariate and multivariate analyses. STUDY DESIGN: Review analysis from a prospective database identified patients with < or = 1-cm invasive breast cancers treated at our institution between 1990 and 1996. All patients underwent a resection of the primary tumor and axillary lymph node dissections. Routine patient and tumor characteristics evaluated included: age, race, tumor size, histologic grade, estrogen and progesterone receptor status, and lymphatic and vascular invasion. Univariate and multivariate analyses were performed. Adjusted odds ratios (OR) and 95% confidence intervals (CI) are presented. RESULTS: A total of 919 patients were identified in this study with tumors < or = 1 cm. These included 199 patients (21.7%) with T1a tumors and 720 patients (78.3%) with T1b tumors. ALNM was detected in 165 patients with an overall incidence of 18.0%. Of the ALNM group, 32 patients (19.4%) had T1a tumors and 133 patients (80.6%) had T1b tumors. Four variables were found to be significant in univariate analysis. These included: increasing tumor size, poor histologic grade, presence of lymphatic or vascular invasion, and younger age of the patient. An increase in tumor size was associated with a significant risk of ALNM (OR = 2.66, 95% CI = 1.28 to 5.75; p = 0.01). Poor tumor grade and the presence of lymphatic or vascular invasion were also associated with an increased risk of ALNM (OR = 2.69, p = 0.003 and OR = 5.52, p = 0.0001, respectively). Patients with ALNM were more likely to have a tumor grade of 3 (25.0% ALNM versus 12.5% node-negative, p = 0.004) and lymphatic or vascular invasion (16.9% ALNM versus 3.5% node-negative, p < 0.0001). In multivariate analysis, an increased risk of ALNM was demonstrated with increasing tumor size (0.1-cm increments), poor histologic grade, and younger age. CONCLUSIONS: This study investigated clinical and pathologic factors influencing ALNM in patients with T1a and T1b breast carcinomas. We have identified three factors by multivariate analysis as significant independent predictors of ALNM in this group of patients. These include increasing tumor size, poor histologic grade, and younger age. Given the significant amount of ALNM demonstrated in this study (overall 18%) and the inability to identify a subgroup of patients that had an acceptable low risk of ALNM, the complete omission of assessing the axilla for metastatic disease in patients with small breast cancers cannot be advocated. Our recommendation for patients diagnosed with T1a and T1b tumors is to have their axilla investigated for metastatic disease either by traditional axillary lymph node dissections or by intraoperative lymphatic mapping and sentinel lymph node biopsy techniques.

Psychosocial aspects of cancer genetics: women at high risk for breast and ovarian cancer.

In the past five years the advent of cancer genetic testing has created concern about the negative psychosocial sequelae of genetic counseling and testing. Research indicates that the women most likely to seek genetic testing are anxious about carrying a gene mutation and developing breast cancer. Women who are at high risk have poor knowledge and the expectation of being a gene-mutation carrier. High levels of distress have been shown to interfere with decision-making about genetic testing. Further, individuals who decline genetic testing may be at increased risk for depressive symptoms even more than those who are found to be gene-mutation carriers. There is great concern that inappropriate candidates will seek genetic testing. Improved education and access to genetic counseling are essential to help women make appropriate decisions about genetic testing. Strategies for the prevention of breast and ovarian cancer are explored, and methods to reduce the adverse psychosocial effects of decision-making about genetic testing and preventive treatment strategies are suggested.

Microinvasive carcinoma (T1mic) of the breast: clinicopathologic profile of 21 cases.

Clinicopathologic data on microinvasive carcinoma of the breast (MICB) as defined by the 1997 TNM criteria (T1mic < or = 1 mm) is scarce. Histologic slides of 109 cases from 1993 through 1997, in which microinvasion was either suspected or diagnosed initially, were reviewed. A double immunoenzyme-labeling technique using antismooth muscle actin and anticytokeratin antibody on the same section was used to confirm invasion in equivocal cases. All foci of invasion were measured by ocular micrometer. Twenty-one cases were confirmed to be MICB. The mean age of the patients was 60.9 years. Thirteen patients presented with mammographic abnormalities on routine examination (60.9%). MICB was ductal in 18 patients, including one tubular carcinoma, and was lobular in three patients. The mean number of invasive foci was two per patient (range, one to seven foci). The accompanying duct carcinoma in situ had high-grade nuclei and necrosis in 16 of 18 patients (89%), 13 of which (72%) were comedo-type. Two of the 15 patients had one positive axillary lymph node each (13.3%). Eleven patients underwent mastectomy, nine received radiation therapy, one received chemotherapy, and two underwent lumpectomy only. Median follow up was 28 months (range. 18-63 months). One patient had a chest wall recurrence of infiltrating duct carcinoma and another recurred with duct carcinoma in situ.

Determination of size in invasive breast carcinoma: pathologic considerations and clinical implications.

The widespread use of mammography has made the detection of increasingly small, often impalpable, invasive breast carcinomas possible. An enhanced understanding of morphological factors, among the foremost of which is size of invasive component of carcinoma, is changing the management of breast cancer To the uninitiated, the determination of size of invasive component is seemingly simple but in practical terms is complicated by a number of ambiguous issues. Practical guidelines for the assessment of size of invasive carcinoma are proposed.

Quantifying mammary duct carcinoma in situ: a wild-goose chase?

Duct carcinoma in situ (DCIS) is a malignant neoplasm of the breast that is limited to the glandular component. The introduction of mammographic screening allows for earlier detection of carcinoma, at the stage of DCIS, before it invades the surrounding stroma. Although DCIS has been studied extensively, its quantification remains a dilemma. Several methods for measuring DCIS exist, including clinical measurement, radiographic assessment, and gross pathologic assessment. Other methods have been employedfor this purpose, such as counting the number of tissue sections involved, direct measuring of DCIS from glass slides, and even counting the number of ducts involved. Furthermore, there is no consensus for assessing adequacy of margins. The myriad of techniques for quantifying DCIS has profound implications for treatment and for prognostic evaluation. The inherent difficulties in quantifying DCIS are multifactorial, and the need to establish a standardized approach for reporting the extent of DCIS by correlating radiographic, clinical, gross, and histologic findings is imperative.

Local and distant recurrence rates in skin-sparing mastectomies compared with non-skin-sparing mastectomies.

BACKGROUND: Skin-sparing mastectomies (SSMs) are being used more frequently to treat many cases of breast cancer. This type of surgery maximizes breast skin preservation and facilitates immediate reconstruction, resulting in a superior cosmetic appearance after mastectomy and a more satisfied patient. Although SSMs are becoming more common, there are few data regarding the local and distant recurrence rates. METHODS: A total of 231 patients treated with mastectomies from 1990 to 1998 were studied, including 77 SSM and 154 non-skin-sparing (NSSM) mastectomy patients. RESULTS: The local recurrence rates for SSM and NSSM were 3.90% (3 of 77 patients) and 3.25% (5 of 154 patients), respectively. The local recurrence-free survival at 5 years was 95.3% for SSM patients and 95.2% for NSSM patients (P = .28). The distant recurrence rates of SSM and NSSM were 3.9% (3 of 77 patients) and 3.9% (6 of 154 patients), respectively. The distant recurrence-free actuarial survival at 5 years was 90.2% for SSM patients and 92% for NSSM patients (P = .07). CONCLUSIONS: Mastectomies using the skin-sparing technique do not appear to result in any increase in local or distant recurrence and improve aesthetic results of the immediate reconstruction.

Chemoprevention of breast cancer.

A critical question is, why do the European studies fail to confirm the US study? Clearly, the answers are complex and uncertain. Differences in power, age, risk, compliance, the use of ERT, and follow-up in the European studies may all be relevant. The efficacy of tamoxifen in BRCA 1 or 2 carriers is an important issue; recent data have shown a DNA repair defect in those with BRCA 1 gene alterations. This finding, coupled with the potential genotoxicity of tamoxifen, is of concern, but the NSABP study did show a significant reduction in breast cancer risk in those with first-degree relatives with breast cancer, including those likely to have a hereditary-predisposition gene. The issue will be clarified when the BRCA 1 or 2 status of these individuals is determined from the stored DNA samples of all participants in the NSABP study. The duration of use of an antiestrogen for prevention is uncertain; the adjuvant trial data for up to 5 years of tamoxifen use showed an effect on contralateral breast cancer prevention extending beyond 5 years, but experimental data show that stopping tamoxifen therapy results in the appearance of new tumors. The long-term use of tamoxifen for prevention carries significant risks. If raloxifene can be given long term, then continuing the prevention of tumors may be possible if raloxifene is proven safe. Should tamoxifen be used outside of a clinical trial? The FDA has approved its use to "delay" breast cancer so it can be prescribed for any patient at increased risk for breast cancer. The word prevention has been the subject of polemics. Every day that breast cancer is delayed is a day that it is prevented. Risk reduction is technically a more accurate phrase but lacks meaning to many women. Novel approaches to chemoprevention are being explored. Naturally occurring compounds or their analogues are being assessed. Based on experimental studies, the vitamin A analogue 4-hydroxyphenyl retinamide (4-HPR) was shown to delay and reduce carcinogen-induced breast cancer. A randomized clinical trial of 4-HPR is being tested in women in Italy to reduce contralateral breast cancer, but no results are available. New approaches using substances derived from plants, such as vegetables, are being pursued. Based on epidemiologic studies, investigators have proposed that an estrogen metabolite, C16 alpha-hydroxyesterone (16 alpha-OHE1), may have estrogen-stimulating and DNA-damaging properties of mammary epithelial cells. Strategies to reduce 16 alpha-OHE1 have been explored. Indole-3-carbinol, found in high concentration in cruciferous vegetables (i.e., cabbage, cauliflower, broccoli, rabe, brussels sprouts, kale, and bok choi), has been shown to reduce mammary cancer in rodent models and induces a metabolic pathway competing with 16 alpha-OHE1, which increases C-2 hydroxyesterone and thereby reduces substrate available for the 16 alpha-OHE1 pathway. Indole-3-carbinol has a good short-term safety profile. The minimum effective dose that favorably perturbs the ratio between 16 alpha-OHE1 and 2-OHE1 has been determined, and a pilot feasibility trial is in progress in women at risk for breast cancer at Strang Cancer Prevention Center. Future research will identify single or a combination of agents that may significantly reduce the risk for breast cancer without toxicity. A better understanding of the steps involved in the progression of normal breast cells toward cancer will permit the development of strategies to reduce the incidence of and mortality from breast cancer, with the ultimate goal of prevention.

Local tumor recurrence following breast-conservation therapy: correlation of histopathologic findings with detection method and mammographic findings.

PURPOSE: To correlate histopathologic findings with detection method and mammographic appearance in primary and locally recurrent breast carcinoma after breast-conservation therapy. MATERIALS AND METHODS: Medical records and mammographic findings were retrospectively reviewed; 26 patients with 27 local recurrences after breast-conservation therapy were identified. RESULTS: Primary histopathologic findings included six in situ and 20 invasive carcinomas. Of the 27 recurrences, 19 (70%) were at or adjacent to the lumpectomy site and eight (30%) were elsewhere in the breast. All primary ductal carcinoma in situ (DCIS) cases manifested mammographically as microcalcifications and recurred as DCIS with microcalcifications. Eleven primary invasive carcinomas (10 masses, one case of microcalcifications) were detected only mammographically, three were detected only with physical examination, and six (six masses) were detected with both. Among these 20 recurrences, 14 (five masses, nine cases of microcalcifications) were detected only mammographically, one was detected only with physical examination, and five (five masses) were detected with both. Seventeen (85%) of 20 primary invasive carcinomas recurred invasively: 16 (94%) with similar histopathologic findings and eight (47%) with similar mammographic findings. CONCLUSION: In local recurrence after breast-conservation therapy for DCIS, histopathologic findings, detection method, and mammographic findings are usually similar. Histopathologic findings of primary invasive breast carcinoma and local recurrence are usually similar, but the detection method and mammographic findings vary. This is relevant to the interpretation of new clinical or mammographic findings following lumpectomy.

Role of estradiol metabolism and CYP1A1 polymorphisms in breast cancer risk.

The endogenous metabolism of estrogens is primarily oxidative and involves hydroxylation of the steroid at either C2 (2-OHE1) or C16 (16-OHE1). While the 2-OHE1 metabolites are essentially devoid of peripheral biological activity, 16-OHE1 is an estrogen agonist. There is evidence of an association between the 2-OHE1/16-OHE1 metabolites ratio and breast cancer risk. The CYP1A1 gene may play a role in the 2-hydroxylation (2-OH) of estradiol. African-American women with the wild-type CYP1A1 gene showed a significant increase in the 2-OHE1/16-OHE1 ratio, from 1.35 +/- 0.56 at baseline to 2.39 +/- 0.98 (p = 0.006) after 5 days of treatment with indole-3-carbinol (400 mg/day), a 2-OHE1 inducer. Women with the Msp1 polymorphism showed no significant increase, (0.37% +/- 0.17%). In a case-control study involving 57 women with breast cancer and 312 female controls, the frequency of the homozygous Msp1 polymorphism was 4.2% in African-American controls and 16% in African-American breast cancer cases. The odds ratio of breast cancer with the Msp1 homozygous variant was 8.4 (95% confidence interval: 1.7-41.7). This association was not observed in Caucasian women. The other CYP1A1 polymorphisms were not associated with breast cancer. The CYP1A1 Msp1 polymorphism may be a marker of altered estradiol metabolism and of increased susceptibility to estrogen-related breast cancer in African-Americans.

Inhibition of aberrant proliferation and induction of apoptosis in HER-2/neu oncogene transformed human mammary epithelial cells by N-(4-hydroxyphenyl)retinamide.

Epithelial cells from non-cancerous mammary tissue in response to exposure to chemical carcinogens or transfection with oncogenes exhibit hyperproliferation and hyperplasia prior to the development of cancer. Aberrant proliferation may, therefore, represent a modifiable early occurring preneoplastic event that is susceptible to chemoprevention of carcinogenesis. The synthetic retinoid N-(4-hydroxyphenyl)retinamide (HPR), has exhibited preventive efficacy in several in vitro and in vivo breast cancer models, and represents a promising chemopreventive compound for clinical trials. Clinically relevant biochemical and cellular mechanisms responsible for the chemopreventive effects of HPR, however, are not fully understood. Experiments were performed on preneoplastic human mammary epithelial 184-B5/HER cells derived from reduction mammoplasty and initiated for tumorigenic transformation by overexpression of HER-2/neu oncogene, to examine whether HPR inhibits aberrant proliferation of these cells and to identify the possible mechanism(s) responsible for the inhibitory effects of HPR. Continuous 7-day treatment with HPR produced a dose-dependent, reversible growth inhibition. Long-term (21 day) treatment of 184-B5/HER cells with HPR inhibited anchorage-dependent colony formation by approximately 80% (P < 0.01) relative to that observed in the solvent control. A 24 h treatment with cytostatic 400 nM HPR produced a 25% increase (P = 0.01) in G0/G1 phase, and a 36% decrease (P = 0.01) in S phase of the cell cycle. HPR treatment also induced a 10-fold increase (P = 0.02) in the sub-G0 (apoptotic) peak that was down-regulated in the presence of the antioxidant N-acetyl-L-cysteine. Treatment with HPR resulted in a 30% reduction of cellular immunoreactivity to tyrosine kinase, whereas immunoreactivity to p185HER remained essentially unaltered. HPR exposure resulted in time-dependent increase in cellular metabolism of the retinoid as evidenced by increased formation of the inert metabolite N-(4-methoxyphenyl)-retinamide (MPR) and progressive increase in apoptosis. Thus, HPR-induced inhibition of aberrant proliferation may be caused, in part, by its ability to inhibit HER-2/neu-mediated proliferative signal transduction, retard cell cycle progression and upregulate cellular apoptosis.

The evaluation of high risk and pre-invasive breast lesions and the decision process for follow up and surgical intervention.

Atypical epithelial hyperplasia, lobular carcinoma in situ (lobular neoplasia), radial scar, and ductal carcinoma in situ are considered high-risk lesions that predispose toward the future development of non-invasive or invasive breast cancer. Generally, those women with atypical epithelial hyperplasia, radial scar, or lobular carcinoma in situ can be managed conservatively by close surveillance. The minority of women may consider prophylactic mastectomy. Ductal carcinoma in situ can usually be managed by lumpectomy with or without radiation, with some patients requiring mastectomy due to extensive disease.

Phytochemicals as modulators of cancer risk.

These results, describing antitumor activity of some of the phytochemicals that have been actively studied, suggest that dietary changes could play a role in decreasing the incidence of a variety of tumors. 13C and the other compounds discussed may well be only prototypes for other as yet unexplored phytochemicals present in the diet. There have been no attempts to explore the possibilities of synergistic action among the various phytochemicals, 13C, limonene, curcumin, epigallocatechin gallate, sulforaphene, or genistein. Mixtures of these compounds might well show potency at lower doses for each of the compounds and show even greater promise than that already demonstrated.