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To review and summarize evidence from clinical and epidemiologic studies that have examined the relationship between nutritional factors, survival, and recurrence after the diagnosis of breast cancer.
Relevant clinical and epidemiologic studies were identified through a MEDLINE search. References of identified reports also were used to identify additional published articles for critical review.
Several nutritional factors modify the progression of disease and prognosis after the diagnosis of breast cancer. Overweight or obesity is associated with poorer prognosis in the majority of the studies that have examined this relationship. Treatment-related weight gain also may influence disease-free survival, reduce quality of life, and increase risk for comorbid conditions. Five of 12 studies that examined the relationship between dietary fat and survival found an inverse association, which was not evident on energy adjustment in most of these studies. The majority of the studies that examined intakes of vegetables or nutrients provided by vegetables and fruit found an inverse relationship with survival. Alcohol intake was not associated with survival in the majority of the studies that examined this relationship.
Much remains to be learned about the role of nutritional factors in survival after the diagnosis of breast cancer. Healthy weight control with an emphasis on exercise to preserve or increase lean muscle mass and a diet that includes nutrient-rich vegetables can be recommended. Diets that have adequate vegetables, fruit, whole grains, and low-fat dairy foods and that are low in saturated fat may help to lower overall disease risk in this population.
THE HIGH INCIDENCE of breast cancer coupled with improvements in initial treatments have lead to an ever-increasing number of breast cancer survivors.1,2 Recurrence is an important issue in the management of these patients,3 but so too are risks for second primary cancers, diabetes, cardiovascular disease, and osteoporosis, because these patients are at increased risk for these comorbidities.4,5 For many of these disorders, the benefit of dietary intervention or weight management has a demonstrated role.4,5
Although cancer places individuals at increased risk, life-threatening events also can serve as powerful agents to promote lifestyle change.6 Studies conducted among women who have been diagnosed with breast cancer consistently indicate that a majority are interested in making healthful changes in their diets.7–10 A study conducted among 531 breast cancer survivors also found that 52% of patients wanted nutritional guidance at the time of diagnosis or soon after, although few reported having ever received dietary recommendations from their physicians.8
Thus, women who have been diagnosed with breast cancer are highly motivated to pursue dietary regimens and often seek nutritional guidance. Indeed, the opportunity exists for the clinician to take advantage of this interest or “teachable moment” to reinforce various components of an optimal diet aimed at promoting health in both the short and long term. Given the central role of oncologists and the credence placed on their advice, the delivery of health messages aimed at improving diet may be especially meaningful.11 However, what are the recommendations that can be supported by the current evidence?
Over the past several decades, a considerable amount of research has explored the possible relationships between various nutritional factors and the risk for breast cancer. In contrast, there are far fewer data on associations between nutritional factors and progression or recurrent disease. The purpose of this article is to review and summarize evidence on the relationship between nutritional factors and survival after the diagnosis of breast cancer— evidence based on review of recent clinical and epidemiologic studies—in order to suggest clinically useful guidelines and strategies for patient management.
Relevant clinical and epidemiologic studies of nutritional factors, survival, and disease recurrence in women who had been diagnosed with breast cancer were identified through MEDLINE search; MeSH keywords included the following: breast cancer, survival, prognosis, body weight, body fat, anthropometry, weight gain, diet, dietary intakes, nutrition, and nutritional status. References of identified reports also were used to identify further articles for critical review. In addition to the focus on epidemiologic or clinical (human) studies, we applied additional inclusion criteria. Only reports that linked nutritional factors to disease-free or overall survival, recurrence, or both were included, and we excluded studies of associations between nutritional factors and intermediate end points or tumor characteristics at diagnosis. Only articles written in the English language were included.
The two major nutritional issues that have been addressed in relation to survival are relative body weight (or indicators of obesity) and diet composition. Studies published between 1985 and February 2002 were critically reviewed. Given that a critical review and analysis of the association between overweight and survival had been reported by Goodwin and Boyd12 in 1990, this served as a benchmark, and review with regard to this topic was limited to subsequent articles published between 1990 and February 2002.
The critical review and analysis by Goodwin and Boyd12 of 13 cohort studies and one case control study on the association between obesity at diagnosis and prognosis published in 1990 concluded that increased body weight exerts a negative, albeit modest, prognostic effect. Since that time, 26 published studies have examined associations either between premorbid weight status or weight status at the time of diagnosis (estimated by relative weight for height or body mass index [BMI], expressed in kg/m2]), and breast cancer recurrence and survival. A critical review on this topic, from a slightly different perspective, also was reported by Chlebowski et al.13 A summary of these studies14–39 is listed in Table 1. In 17 of the 26 studies, increased BMI or body weight was found to be a significant risk factor for recurrent disease, decreased survival, or both14–30; seven studies produced null findings31–37; and two studies found a significant inverse association between weight status and recurrence.38,39
In those studies that found a significant positive association between overweight and progressive disease, women categorized in the higher (v lower) levels of obesity exhibited a 30% to 540% increased risk of death. Furthermore, analysis of the data suggests that this relationship may be more pronounced among women who are diagnosed initially with early-stage disease17,28 and among those who have estrogen receptor-positive tumors.15 It also should be noted that similar to many other chronic diseases, the relationship between body weight and disease progression may be curvilinear rather than linear. More research, especially studies in which the effect on risk is controlled for important influencing factors, such as smoking status and hypertension, are necessary to confirm a curvilinear association, or a J-shaped curve.40
Given that upper body fat distribution has been linked with higher unbound levels of sex hormones41 as well as insulin,42 upper body or android obesity also has been implicated as a risk factor for several diseases,43 including breast cancer,44 with speculation that android obesity may portend greater risk for mortality. In a study of both pre- and postmenopausal patients by Kumar et al,38 android body fat distribution, as indicated by a higher suprailiac:thigh ratio, was found to be a significant negative prognostic indicator, even though higher BMI status was protective. These findings contrast with those of Zhang et al,19 who found no association between android obesity, as indicated by a greater waist-to-hip ratio, and survival, but who did detect a significantly greater risk of death among women in the top tertile of BMI.
A notable feature of these studies is that the effect of obesity on prognosis was examined by using premorbid weight or weight at diagnosis. It is currently unknown whether postdiagnosis weight reduction through diet, increased physical activity, or both modifies this relationship.
Unfortunately, weight gain often occurs in women after diagnosis of breast cancer; such weight gain is more prevalent among women who were premenopausal at diagnosis and who received adjuvant chemotherapy as part of their treatment.45 Other factors found to be positively and independently associated with postdiagnosis weight gain are African-American ethnicity and current energy intake.46 Prediagnosis BMI, age at diagnosis, level of education, and usual exercise level also have been found to be inversely associated with weight gain.46 Gains in weight usually range from 2.5 to 6.2 kg; however, greater gains are not uncommon.45
There is some evidence to suggest that weight gain after diagnosis adversely affects disease-free survival. Camoriano et al21 observed 646 patients with breast cancer for a median of 6.6 years and found that women who were premenopausal at diagnosis and who gained more than the median amount of weight (5.9 kg) were 1.5 times more likely to relapse and 1.6 times more likely to die of their breast cancer. Results from a study by Chlebowski et al47 parallel these findings. In contrast, two other studies failed to identify any association between postdiagnosis weight gain and prognosis.48,49 These studies are more than 10 years old, and analysis of more current data are needed to define associations, if any, between postdiagnosis weight gain and survival.
Although it remains to be determined whether postdiagnosis weight gain influences risk for progressive disease, it is known that weight gain adversely affects risk for cardiovascular disease and diabetes, conditions for which women who have been diagnosed with breast cancer are at already at increased risk.4,5 Furthermore, several studies indicating that patients find weight gain distressing have been reported since 1983.49–54
The relationship between psychologic characteristics and weight gain have been examined in two studies. Dietary restraint and disinhibition, two characteristics of dieting behavior, were highly associated with both short-term (6 months after diagnosis) and long-term (19 months after diagnosis) weight gain (n = 73).50 In another study conducted among 56 women with breast cancer and 52 healthy women, BMI was found to be directly associated with greater depressive symptomology and abnormal eating attitudes and behavior.55 Thus, depression, eating pathology, and difficulty maintaining a desirable weight seem to be interrelated; however, from cross-sectional studies, it is impossible to determine whether depression and eating pathology beget problems with weight control or vice versa.
The weight gain that women who have been diagnosed with breast cancer experience—at least, those who receive adjuvant chemotherapy—also seems unique. Although typical weight gain is usually characterized by a gain in lean tissue as well as adipose tissue, all clinical studies that have measured body composition change, either via computed tomography, dual energy x-ray absorptiometry, or in vivo neutron capture, have consistently found either no gains in lean tissue mass or actual losses in lean tissue mass as weight and adipose tissue increase in women after the diagnosis of breast cancer.56–60 This unique type of weight gain also is manifest with conditions such as hypogonadism, hypopituitarism, and chronic physical inactivity, as well as corticosteroid use. In addition, gradual body composition changes such as these are noted during the 10-year period encompassing menopause; however, among premenopausal patients treated with chemotherapy, this aspect of aging seems to be accelerated, and these same changes in body composition are observed within the span of 1 year.59
Few interventions have been devised and tested specifically during the time when weight gain seems to be the most problematic (ie, within the year after diagnosis).45 In one report, intensive diet counseling aimed at weight maintenance produced small but insignificant reductions in energy intake and weight gain among 107 women receiving adjuvant chemotherapy for resected breast cancer.61 Likewise, insignificant differences in weight gain were observed in a small study by Winningham et al,62 in which 24 early-stage breast cancer patients receiving adjuvant chemotherapy were randomized into a group that was instructed to pursue routine aerobic activity versus a sedentary control group; gains in weight were 0.82 v 1.99 kg, respectively (not significant). In this study, however, significant differences were observed in the change in percentage of body fat (averaging −0.51% in the experimental group v +2.19% in the control group) during the study period.
In two small intervention studies that incorporated both dietary guidance and increased physical activity, a significant reduction in body weight in overweight women (or weight maintenance in those not overweight) was observed.63,64 Aerobic exercise was identified as the strongest predictor of success when the intervention components were analyzed for independent effects on weight loss.63 Other studies testing various approaches to promoting weight loss or weight maintenance in women after the diagnosis of breast cancer are under way.
Several mechanisms have been proposed to explain the adverse effect of excess adiposity on prognosis after the diagnosis of breast cancer. One proposed mechanism relates to the effect of excess adipose tissue on circulating gonadal hormones because adipose tissue serves as an important extragonadal source of estrogens from precursor adrenal androgens.65 In laboratory animal experiments, estrogens have been demonstrated to promote breast tumorigenesis.66 As has been reviewed recently,65 current evidence generally supports the hypothesis that gonadal hormones play some role in the initiation and promotion of breast cancer, although the relationship seems to be complex. Also, antiestrogen therapy has emerged as one of the most effective treatments for the management of endocrine-responsive breast cancers, which account for approximately two thirds of cases, as demonstrated in clinical trials.67–69 Obesity is consistently associated with increased circulating concentrations of estrone and estradiol in postmenopausal women, and more importantly, it is associated with decreased levels of sex hormone–binding globulin, which results in an increase in the bioavailable estrogen fraction.70,71
Another possible mechanism relates to insulin and insulin-like growth factor 1 (IGF-1) and the interactions of these factors with adiposity and weight gain.72,73 In cell culture studies, insulin and IGFs exhibit mitogenic effects that influence both premalignant and cancerous stages of cell growth.74 Both insulin and IGF-1 stimulate the synthesis of sex steroids, and thus their cancer-promoting effects in the progression of breast cancer may be mediated by an effect on gonadal hormones. Evidence from epidemiologic and clinical studies suggests that increased BMI in women is associated with increased insulin and IGFs, characteristics that are associated with increased risk or progression of breast cancer in some,30,73,75 but not all,76 studies.
Another explanation for poorer survival among those who are obese at the time of diagnosis has been offered by Madarnas et al,77 who speculate that the disease of obese women may fail to respond to treatment as a result of the common practice of chemotherapy capping at a body-surface area of 2 m2, which may offer suboptimal treatment benefit. Their data suggest that this problem may be further compounded by significantly greater dose reductions among women with BMI ≥ 25 kg/m2 in which the mean dose reduction was 6.7% ± 13.1%, as compared with women with BMIs less than 25 kg/m2, where the mean dose reduction was 4.3% ± 8.2% (P = .008).
During the past two decades, the relationships between overall survival or recurrence and dietary intakes have been examined in 13 studies involving cohorts of women who had been diagnosed with breast cancer.19,25,36,78–87 The dietary factors examined in these studies were mainly those associated with breast cancer risk. These studies are summarized in Table 2. As noted in Table 2, most of these studies used dietary data collected at the time of diagnosis or soon thereafter.
In these and other epidemiologic studies, food intake is self-reported and should be interpreted as estimates that may allow ranking rather than producing absolute values, even when the best-developed methodologies are used. Thus, a high risk for reporting bias and misclassification of subjects is inherent in this type of research. As noted in Table 2, several different methodologies were used to collect the dietary data in these studies, with self-administered food-frequency questionnaires being the most common method used. In the majority of the studies, dietary data were collected immediately after diagnosis, although the participants were often asked to report intake during the year preceding diagnosis. Associations between dietary factors, survival, and recurrence should ideally be adjusted for the effects of major nondietary determinants of survival, such as stage of cancer at diagnosis. This analysis strategy was used by some, but not all, of these studies. For the studies that analyzed associations with and without adjustment for stage and other possible influencing factors, the results summarized are the associations between dietary intake, survival, and recurrence adjusted for stage and other influencing factors.
The possible link between dietary fat and primary breast cancer risk has historically been the focus of more attention than other dietary factors, so fat intake (or selected high-fat foods) were examined in all of these studies. In addition to the general concerns described above, a major issue in the interpretation of the data relating dietary fat intake to breast cancer risk or progression is that fat intake and total energy consumption always covary (and also typically correlate with obesity), so an independent effect of total dietary fat per se is difficult to accurately assess unless the analysis is adjusted for these factors. Also, self-reported dietary assessment is known to underestimate energy intake, and this bias is most evident for high-fat foods.88,89 Underreporting affects the accuracy of dietary data more among women (v men), those categorized as overweight, minority groups, and younger (v older) adults.90 Rates of underreporting of intake among breast cancer survivors are similar to rates in the general population, with obese women being twice as likely as nonobese women to underreport intake.91 To minimize the bias introduced by underreporting, particularly in the interpretation of data on fat intake, adjustment for energy intake is the accepted approach used in the analysis of associations between dietary fat and disease risk.92
Total dietary fat intake was significantly inversely associated with survival or treatment failure (described as recurrence or new cancer of the contralateral breast) in five of the 12 studies that examined this relationship,19,36,79,81,84 although the relationship with fat intake was unadjusted for energy intake in three of these five reports.19,79,81 In one of these studies, this relationship was seen only in women with estrogen receptor–positive (but not negative) tumors.84 A trend for this relationship was observed in another study.85 In two studies in which the investigators also analyzed fat intake as an energy-adjusted variable, adjusted fat intake was unrelated to survival.19,36 In a study in which the intakes of selected foods (rather than nutrients) were examined in relation to recurrence or risk for death,25 intakes of butter, margarine, and lard were directly associated with risk of recurrence but not with risk of death.
In 10 of these studies,19,36,78,80,81,83–87 intakes of various types of fat (in addition to total fat intake) were examined in the analysis. Studies in which total fat intake was not associated with survival or recurrence generally found no relationship between survival and intakes of various types of fat, with one exception. Jain et al78 found energy-adjusted saturated fat intake (but not total fat intake) to be significantly inversely associated with survival. In two of the studies in which total fat intake was associated with survival, intake of a fat subtype also was found to be similarly associated. Holm et al84 found both energy-adjusted total and saturated fat intakes to be directly associated with risk for recurrence or new cancer, and Zhang et al19 found monounsaturated fat intake (in addition to total fat intake), unadjusted for energy intake, to be inversely related to survival. In women with node-negative disease, a protective effect of omega-3 fatty acid intake was observed in one study.87 Thus, these studies do not provide strong support for a role for specific fat types in breast cancer progression.
Results of the analysis of associations between vegetable intake (or nutrients provided by vegetables and fruit, such as carotenoids and vitamin C) suggest a protective effect, although the strength of the association is modest. Of the eight studies that examined these dietary factors,19,36,78,82,84–87 three found a significant inverse association with risk of death,78,85,86 one found that risk of dying was nonsignificantly decreased in association with frequent vegetable consumption,82 and one found a significant inverse association in women with node-negative disease, who comprised 62% of that cohort (but not in the total group that included women at all stages of invasive breast cancer).87 In the studies that found an inverse relationship with survival and intakes of vegetables, fruit and related nutrients (beta-carotene, vitamin C), the magnitude of the protective effect was a 20% to 90% reduction in risk for death. Given that there is some variability in the findings and in the vegetable-related dietary factors that have been examined in these studies, these data do not provide conclusive evidence for a beneficial effect. Further research that examines the association between survival and intakes of vegetables and the various constituent phytochemicals would be useful.
The relationship between dietary fiber intake, survival, and recurrence was examined in seven of these cohorts of breast cancer survivors.19,36,78,84–87 None of these studies found a significant relationship in the total group under study, although the point estimates in one study suggest a trend for a protective effect.84 In four studies, intakes of selected high-fiber foods (ie, vegetables, fruits, cereal-grain products) were examined in relation to survival, recurrence, or both.36,82,86,87 As noted above, a significant protective effect of vegetables and fruit was found in one study,86 one found a trend for this relationship,82 and one found a protective relationship in women with node-negative disease.87 Bread and cereal intake was inversely associated with risk for recurrence in one of the three studies that specifically examined the relationship between survival and recurrence and this food type.36
Another dietary factor of interest in this patient population is alcohol, which has been consistently and positively associated with risk for primary breast cancer in epidemiologic studies.93 In the eight studies that examined the relationship between alcohol intake and survival in women who had been diagnosed with breast cancer,19,36,78,82,84–87 no significant associations were observed, although one of these studies reported that risk of dying was slightly (but not significantly) increased in association with frequent alcohol consumption.82 In the study involving the analysis of relationships that were based on selected foods rather than nutrients,25 the consumption of beer, but not wine or liquor, was inversely associated with risk of recurrence but was not associated with risk of death. These findings are fairly consistent and suggest that alcohol intake may not increase risk for recurrence or overall survival after the diagnosis of breast cancer.
To date, no epidemiologic or clinical studies have examined or reported the relationship between soy intake and survival in women who have been diagnosed with breast cancer. Also, studies conducted to date have not identified dietary supplement use as being protective against recurrence in breast cancer survivors.
Various mechanisms by which dietary fat may promote increased risk for and progression of breast cancer have been previously reviewed.94–96 In animal studies, diets that are rich in linoleic acid (an omega-6 fatty acid) have been observed to promote tumor development in rats exposed to a mammary chemical carcinogen, possibly by a mechanism that involves tumor cell eicosanoids.96 Free-radical mediated lipid peroxidation and DNA-adduct formation has also been suggested to be another mechanism by which dietary fat could promote carcinogenesis.94 Clinical studies have suggested that low-fat diets may decrease serum estrogen concentrations, as reviewed and summarized in a meta-analysis.97 However, significant weight loss also occurred in response to the low-fat diet modification in the majority of the studies in which serum estradiol was significantly reduced in response to a low-fat diet intervention, and an energy deficit and weight reduction would be expected to produce a reduction in serum gonadal hormone concentrations independent of diet composition. In fact, the promotion of weight loss is another proposed mechanism by which lower fat intake could influence the progression of breast cancer.95
Several biologically feasible mechanisms that might explain a protective effect of vegetables and fruits have been demonstrated in cell culture and animal studies. For example, carotenoids have retinoid-like effects on cellular differentiation and apoptosis and also exhibit inhibitory effects on mammary cell growth.98–100 Vegetables of the Brassica genus, such as broccoli, demonstrate a favorable effect on estrogen metabolism via the induction of cytochrome P-450.101 In mammalian biologic systems, fiber binds estrogen in the enterohepatic circulation and interferes with reabsorption, thus reducing circulating estrogen concentrations.102,103
Two large multicenter randomized controlled trials are examining whether diet modification can influence the risk for recurrence and survival after the diagnosis of early-stage breast cancer. In both of these studies, participants will be followed up for an average of at least 6 years, and results are anticipated after 2005.
The Women’s Intervention Nutrition Study (WINS) involves 2,500 postmenopausal women who were randomized within 12 months of primary surgery for breast cancer, and the goal of the intervention is a reduction in dietary fat intake (≤ 15% energy from fat). The rationale for the WINS is based on comparisons of survival of women diagnosed with breast cancer across countries with different fat consumption patterns and evidence from cell culture and laboratory animal studies suggesting that dietary fat may affect a variety of factors involved in the progression of breast cancer.94,104
The WINS pilot and feasibility studies demonstrated that women with postmenopausal breast cancer would adhere to a low-fat diet and suggest that hormonal factors may be responsive to the dietary change. In a 6-month feasibility study, 19 of 27 postmenopausal breast cancer survivors completed the counseling sessions, with average fat intake reduced from 34% to 22% of energy, body weight reduced by an average of 2.3 kg, and serum estradiol (but not estrone) reduced by 37%.105 In a report of data from 93 women enrolled onto the feasibility phase of WINS, the low-fat diet intervention was associated with a reduction in fat intake to 21% of energy, an average weight loss of 2 kg, and an average 20% reduction in serum estradiol concentrations in subjects with baseline serum estradiol ≥ 10 pg/mL at 6 months after randomization.106 Subjects with lower serum estradiol concentrations at baseline exhibited a significant increase in serum estradiol in response to the intervention, and serum estrone, estrone sulfate, and sex hormone– binding globulin concentrations did not change in that study. In another subset of 290 WINS feasibility study subjects, fat intake was significantly reduced in the intervention group versus the control group (averaging 20% v 32% of energy) at 3 months.107
In the Women’s Healthy Eating and Living (WHEL) study, the participants are 3,109 pre- and postmenopausal women who were enrolled onto the trial and randomized after completion of initial therapies and within 4 years of diagnosis.108 The primary emphasis of the WHEL study diet intervention is on increased vegetable and fruit intake, with daily dietary goals of five vegetable servings, 16 ounces of vegetable juice, three fruit servings, 15% to 20% energy from fat, and 30 g of dietary fiber. The rationale is that a high-vegetable, high-fiber diet may influence progression of breast cancer through several mechanisms. For example, this dietary pattern may exert beneficial effects on gonadal hormones, and increased intakes of carotenoids provided by vegetables and fruit may promote normal mammary cell growth regulation.98–100 Other biologic activities of phytochemicals, such as antioxidant activity, also are hypothesized to contribute to beneficial effects of a plant-based diet on risk for cancer progression.
In the WHEL feasibility study that involved 93 women, intervention group subjects increased vegetable intake more than two-fold, from 2.8 to 7.4 servings per day, at 12 months.109 These subjects also significantly increased mean intakes of fruit (from 2.9 to 4.0 servings per day) and fiber (from 12.8 to 21.0 g/1,000 kcal/d) and reduced fat intake from 29% to 20% of energy. Plasma carotenoids, a biomarker of the high vegetable and fruit intervention, were increased nearly two-fold in the first 12 months of the feasibility study and remained significantly higher in the intervention group versus comparison group at 3 years after randomization.110,111
The position of the American Cancer Society is that the dietary guidelines for cancer prevention can form the basis of nutritional guidance for women who have been diagnosed with breast cancer.112,113 Given current evidence, a recommendation that may be particularly helpful for this target population is encouraging healthy weight control with an emphasis on exercise to preserve or increase lean body mass. Current recommendations for successful weight management include dietary therapy, increased physical activity, behavior therapy to promote sustained changes in lifestyle, and ongoing monitoring of progress.114 Also, a diet with nutrient- and phytochemical-rich vegetables, which provides an adequate intake of multiple constituents such as vitamins, fiber, and various potentially beneficial biologically active compounds, may be beneficial. Results from ongoing randomized clinical trials, which are expected within the next few years, are anticipated to expand our knowledge base in this area considerably.
The risk of morbidity and mortality from causes other than breast cancer should be considered when making dietary recommendations for breast cancer survivors, especially those diagnosed with early-stage cancers. For example, even though evidence to support a link between fat intake and breast cancer risk and prognosis is not strong, limiting saturated fat intake is a well-established strategy to reduce risk for cardiovascular disease.115 Diets that emphasize vegetables, fruit, whole grains, fiber, and low-fat dairy foods and that are low in saturated fat are advised as a prudent strategy to promote health and prevent disease.116 This dietary pattern has specifically been associated with decreased risk of all-cause mortality in women.117 Sufficient dietary calcium, adequate vitamin D, and increased physical activity are particularly appropriate recommendations to maintain bone health in these women.
Supported by National Cancer Institute grant nos. CA90413 (to C.L.R.), CA62215, CA92468, and CA81191 (to W.D.-W.) and in part by California Cancer Research Fund grant no. 99-00548V-10147 (to C.L.R.).