MET indicates metabolic equivalent task.
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Holmes MD, Chen WY, Feskanich D, Kroenke CH, Colditz GA. Physical Activity and Survival After Breast Cancer Diagnosis. JAMA. 2005;293(20):2479–2486. doi:10.1001/jama.293.20.2479
Author Affiliations: Channing Laboratory, Department
of Medicine, Brigham and Women’s Hospital and Harvard Medical School,
Boston, Mass (Drs Holmes, Chen, Feskanich, Kroenke, and Colditz); and Department
of Medical Oncology, Dana Farber Cancer Institute, Boston, Mass (Dr Chen).
Context Physical activity has been shown to decrease the incidence of breast
cancer, but the effect on recurrence or survival after a breast cancer diagnosis
is not known.
Objective To determine whether physical activity among women with breast cancer
decreases their risk of death from breast cancer compared with more sedentary
Design, Setting, and Participants Prospective observational study based on responses from 2987 female
registered nurses in the Nurses’ Health Study who were diagnosed with
stage I, II, or III breast cancer between 1984 and 1998 and who were followed
up until death or June 2002, whichever came first.
Main Outcome Measure Breast cancer mortality risk according to physical activity category
(<3, 3-8.9, 9-14.9, 15-23.9, or ≥24 metabolic equivalent task [MET]
hours per week).
Results Compared with women who engaged in less than 3 MET-hours per week of
physical activity, the adjusted relative risk (RR) of death from breast cancer
was 0.80 (95% confidence interval [CI], 0.60-1.06) for 3 to 8.9 MET-hours
per week; 0.50 (95% CI, 0.31-0.82) for 9 to 14.9 MET-hours per week; 0.56
(95% CI, 0.38-0.84) for 15 to 23.9 MET-hours per week; and 0.60 (95% CI, 0.40-0.89)
for 24 or more MET-hours per week (P for trend =
.004). Three MET-hours is equivalent to walking at average pace of 2 to 2.9
mph for 1 hour. The benefit of physical activity was particularly apparent
among women with hormone-responsive tumors. The RR of breast cancer death
for women with hormone-responsive tumors who engaged in 9 or more MET-hours
per week of activity compared with women with hormone-responsive tumors who
engaged in less than 9 MET-hours per week was 0.50 (95% CI, 0.34-0.74). Compared
with women who engaged in less than 3 MET-hours per week of activity, the
absolute unadjusted mortality risk reduction was 6% at 10 years for women
who engaged in 9 or more MET-hours per week.
Conclusions Physical activity after a breast cancer diagnosis may reduce the risk
of death from this disease. The greatest benefit occurred in women who performed
the equivalent of walking 3 to 5 hours per week at an average pace, with little
evidence of a correlation between increased benefit and greater energy expenditure.
Women with breast cancer who follow US physical activity recommendations may
improve their survival.
Physical activity after a breast cancer diagnosis has been strongly
linked to improved quality of life.1-3 There
is reason to believe that physical activity might extend survival in women
with breast cancer.
Physical activity also has been linked to a lower risk of breast cancer.
An expert panel of the International Agency for Research on Cancer of the
World Health Organization estimated a 20% to 40% decrease in the risk of developing
breast cancer among the most physically active women, regardless of menopausal
status, type, or intensity of activity.4
Physical activity has been linked to lower levels of circulating ovarian
hormones, which may explain the relationship between physical activity and
breast cancer.5-7 Lower
estrogen levels among physically active women with breast cancer could potentially
improve survival, although few data exist to support this hypothesis.8,9
Lack of physical activity has been shown to be related to weight gain
during breast cancer survival.10 Weight gain
after a breast cancer diagnosis is a common adverse effect of treatment.10-12 This is important
because both being overweight at the time of breast cancer diagnosis13-21 and
weight gain after diagnosis14,22 are
linked to poorer survival in many studies. Lack of physical activity is believed
to be as important a factor as changes in food intake in the ongoing obesity
Few have studied associations between physical activity and survival
and no studies have assessed physical activity level after diagnosis. Rohan
et al24 found no association between physical
activity before diagnosis and survival in a population-based prospective study
of 412 women with breast cancer. We hypothesized that higher levels of physical
activity after a breast cancer diagnosis would be associated with longer survival.
In 1976, the Nurses’ Health Study (NHS) cohort was established
when 121 700 female registered nurses from across the United States,
aged 30 to 55 years, answered a mailed questionnaire on risk factors for cancer
and cardiovascular disease. Follow-up questionnaires have been sent every
2 years until 2004 to the NHS participants. This study was approved by the
human subjects committee at Brigham and Women’s Hospital in Boston,
Mass. Completion of the self-administered questionnaires was considered to
imply informed consent.
In the NHS, incident breast cancer was ascertained by biennial mailing
of the questionnaire to participants. For any report of breast cancer, written
permission was obtained from study participants to review their medical records.
Physicians, blinded to exposure information from questionnaires, subsequently
reviewed medical records and pathology reports. Overall, 99% of self-reported
invasive breast cancers for which medical records were obtained have been
confirmed. The individuals in this analysis were NHS participants with stages
I, II, or III invasive breast cancer that was diagnosed between 1984 and 1998.
The 1984 start date was chosen to assess physical activity at least 2 years
after diagnosis and physical activity was first assessed as MET-hours per
week in 1986.
Women were followed up until death or June 2002, whichever came first.
Ascertainment of deaths included reporting by the family or postal authorities.
In addition, the names of persistent nonresponders were searched in the National
Death Index,25 which has been shown to be a
reliable resource.26 The cause of death was
assigned by physician reviewers. In the case of a woman who died from breast
cancer not previously reported, medical records were obtained to record details
of her breast cancer diagnosis. More than 98% of deaths in the NHS have been
identified by these methods.27
If, after having a breast cancer diagnosis, women reported a second
cancer diagnosis on a routine NHS follow-up, it was assumed that breast cancer
recurred if cancer was reported in the lung, liver, bone, or brain because
these are the most common sites of recurrence. In addition, women who died
from breast cancer were considered to have had a breast cancer recurrence
2 years prior to death. The numbers of cases of recurrent breast cancer calculated
in this manner are similar to the numbers expected given the recurrence rates
found in a large (N = 5569) trial of early stage breast cancer.28
Women were excluded if they were diagnosed with breast or any other
cancer (other than nonmelanoma skin cancer) prior to 1984, missing information
on physical activity at least 2 years after diagnosis or unable to walk, or
had stage IV disease at diagnosis. Women with 4 or more positive nodes but
who lacked a complete metastatic workup were also excluded because of concerns
about occult metastatic disease. A complete metastatic workup consisted of
a negative chest x-ray (or chest computed tomographic scan), bone scan, and
liver function tests (or liver scan) or documentation from a treating physician
that the patient did not have metastatic disease. Women were also excluded
if information on disease stage was missing. No women had implausible levels
of physical activity, which was defined as more than 100 MET-hours per week.
We assessed leisure-time physical activity in MET-hours per week beginning
in 1986. Women were asked: “During the past year, what was your average
time per week spent at each of the following activities?” Choices included
the following 8 activities: walking or hiking outdoors (including walking
while playing golf); jogging (>10 minutes per mile); running (≤10 minutes
per mile); bicycling (including stationary bike); swimming laps; tennis; calisthenics,
aerobics, aerobic dance, or rowing machine; or squash or racquetball. These
activities were the most common ones reported by women in the College Alumni
Health Study.29 To characterize duration, women
chose 1 of 11 categories ranging from zero to 11 or more hours per week. In
addition, participants were asked their usual walking pace: easy or casual
(<2 mph), normal or average (2-2.9 mph), brisk (3-3.9 mph), very brisk
(≥4 mph), or unable to walk. Physical activity was reassessed in 1988,
1992, 1994, 1996, 1998, and 2000. The 1992 through 2000 questionnaires included
other vigorous activities (eg, lawn mowing) and lower-intensity exercise (eg,
yoga, stretching). For this analysis, the first physical activity assessment
collected at least 2 years after the breast cancer diagnosis was used to avoid
assessment during the period of active treatment. Although only women with
stage I, II, and III disease were included in these analyses, it is presumed
that those who eventually died from breast cancer first experienced metastatic
disease. To avoid bias due to declining physical activity immediately prior
to and after diagnosis with metastatic breast cancer, physical activity was
Each activity on the questionnaire was assigned a metabolic equivalent
task (MET) score based on the classification by Ainsworth et al.30 One
MET is the energy expenditure for sitting quietly. MET scores for specific
activities are defined as the ratio of the metabolic rate associated with
that activity divided by the resting metabolic rate. For example, walking
at an average pace was assigned an MET score of 3; jogging, 7; and running,
12. MET scores for walking were assigned based on the pace reported; for other
activities, a leisurely to moderate intensity score was selected. The scores
for MET-hours per week for each activity were calculated from the reported
hours per week engaged in that activity multiplied by the assigned MET score.
The values from the individual activities were summed for a total MET-hours
per week score. Categories of MET-hours per week were defined as less than
3, 3 to 8.9, 9 to 14.9, 15 to 23.9, and 24 or more. These categories were
chosen to correspond to the equivalent of less than 1, 1 to less than 3, 3
to less than 5, 5 to less than 8, and 8 or more hours per week of walking
at an average pace. Walking was the most popular activity in this cohort,
contributing 66% of the total MET-hours per week.31
The ability of the activity questionnaire to assess total activity over
the previous year was tested in a sample of 151 women.32 Compared
with four 7-day activity diaries, the questionnaire underestimated total activity
by approximately 20%. However, the correlation for total MET-hours per week
of activity was excellent (r = 0.62; 95%
confidence interval [CI], 0.44-0.75), suggesting that the questionnaire is
a valid tool for categorical ranking of respondents. The activity questionnaire
was also compared with 4 past-week questionnaires collected seasonally during
the year. For walking, the primary activity among women of this age, the intraindividual
correlation was 0.70 (95% CI, 0.49-0.84).
Covariates included factors previously associated with breast cancer
survival in this cohort.33 The following covariates
were extracted from the medical record: tumor size and the presence and number
of metastatic lymph nodes; and estrogen receptor and progesterone receptor
status. Women also reported method of treatment (radiation, chemotherapy,
or tamoxifen). The time interval between breast cancer diagnosis and assessment
of physical activity was also adjusted for in this analysis. The following
were taken from the questionnaire most immediately preceding the breast cancer
diagnosis: menopausal status, age at first pregnancy, parity, postmenopausal
hormone use, oral contraceptive use, and body mass index (BMI; calculated
as weight in kilograms divided by the square of height in meters). Diet was
assessed using validated food frequency questionnaires in 1986, 1990, 1994,
and 1998.34,35 We controlled for
energy and protein intake taken from the dietary assessment that most immediately
followed the breast cancer diagnosis, which were shown in a previous analysis
of this cohort to be associated with survival.33
Cox proportional hazards models with time since questionnaire report
of diagnosis in months as the underlying time variable were used to calculate
the relative risk (RR) of death, death from breast cancer, or recurrence adjusted
for other risk factors for survival. In the main analysis, death from breast
cancer was the end point and deaths from any other cause were censored. In
a secondary analysis, death from any cause was the end point. In another secondary
analysis, breast cancer recurrence was the end point and all deaths were censored.
Each participant accumulated person-time beginning with the date of breast
cancer diagnosis report that was censored at the end point (death, death from
breast cancer, or breast cancer recurrence) or study end in June 2002, whichever
came first. The RRs are shown for categories of MET-hours per week of physical
activity. The less than 3 MET-hours per week category was the reference group.
The 2-tailed P value for the linear trend test across
categories was calculated by assigning the median value to each category. P = .05 was considered statistically significant. All analyses
were performed using SAS version 8.0 (SAS Institute Inc, Cary, NC).
There were 4484 women diagnosed with breast cancer during the selected
period. Women were excluded from the analysis for (1) recurrence prior to
first follow-up or at the same time as physical activity assessment (n = 38);
(2) diagnosis of cancer prior to the first follow-up period (n = 305); (3)
no report of physical activity after diagnosis (n = 829); (4) stage IV disease
at diagnosis (n = 140); (5) having 4 or more positive lymph nodes at diagnosis
and no report of metastatic workup (n = 78); and (6) missing disease stage
(n = 107). Women may have been excluded for more than 1 reason but only the
first reason is reported.
A total of 2987 women with stages I, II, or III breast cancer were included
in the analyses. There were 463 deaths: 280 were from breast cancer. There
were 370 breast cancer recurrences. Physical activity assessment occurred
a median of 38 months after diagnosis; the 10th and 90th percentiles were
27 and 59 months, respectively. The median length of follow-up for the breast
cancer mortality analyses was 96 months; the 10th and 90th percentiles were
47 and 187 months, respectively.
Age-standardized covariates according to category of physical activity
are shown in Table 1. Women who were
more active had a lower BMI, consumed more protein, and were less likely to
have gained weight between time of diagnosis and time of activity assessment.
Women who engaged in little to no physical activity (<3 MET-hours per week)
were more likely to have been smokers prior to diagnosis than women who engaged
in higher levels of activity. Women in the 2 highest categories of physical
activity were less likely to have stage I disease and were more likely to
have stage II disease than women in the lower activity categories.
Table 2 shows the age-adjusted
and multivariable-adjusted RR of death from any cause, death from breast cancer,
and breast cancer recurrence according to the category of physical activity.
Each category of activity above the reference category (<3 MET-hours per
week) was associated with a decreased risk of an adverse breast cancer outcome.
Compared with women who participated in less than 3 MET-hours per week of
activity, the multivariable RR of death from breast cancer was 0.80 (95% CI,
0.60-1.06) for 3 to 8.9 MET-hours per week; 0.50 (95% CI, 0.31-0.82) for 9
to 14.9 MET-hours per week; 0.56 (95% CI, 0.38-0.84) for 15 to 23.9 MET-hours
per week; and 0.60 (95% CI, 0.40-0.89) for 24 or more MET-hours per week (P for trend = .004). Despite a significant linear trend,
the RR was relatively flat in the 3 highest activity categories. Similar results
were found for overall survival and breast cancer recurrence. In each analysis,
adjustment for covariates strengthened the results slightly more than the
The association of physical activity was collapsed into 2 categories
with death from breast cancer as the outcome. The cutoff of 9 MET-hours per
week was chosen for these analyses because this was the predetermined category
that divided the cohort almost in half. The RR of death for women who engaged
in 9 or more MET-hours per week of physical activity was 0.63 (95% CI, 0.48-0.81)
compared with less than 9 MET-hours per week.
The 5-year survival for women who engaged in 9 or more MET-hours per
week was 97%; 3 to 8.9 MET-hours per week, 97%; and less than 3 MET-hours
per week, 93% (Figure). The corresponding
10-year survival rates were 92%, 89%, and 86%, respectively. The absolute
unadjusted risk reduction was 4% at 5 years and 6% at 10 years for women who
engaged in 9 or more MET-hours per week of physical activity compared with
less than 3 MET-hours per week.
The protective benefit of physical activity was similar among overweight
women (BMI ≥25) and normal weight (BMI <25) women (Table 3). Among overweight women, the RR of death from breast cancer
for women who engaged in 24 or more MET-hours per week of physical activity
compared with less than 3 MET-hours per week was 0.52 (95% CI, 0.26-1.06; P for trend = .01). Among normal weight women,
the RR of death from breast cancer for women who engaged in 24 or more MET-hours
per week of physical activity compared with less than 3 MET-hours per week
was 0.61 (95% CI, 0.37-0.99; P for trend = .10).
Among women with a BMI of 30 or higher and compared with women who engaged
in less than 3 MET-hours per week of physical activity, the RR of death from
breast cancer was 0.63 (95% CI, 0.26-1.52) for 3 to 8.9 MET-hours per week;
0.78 (95% CI, 0.20-3.04) for 9 to 14.9 MET-hours per week; 0.22 (95% CI, 0.03-1.82)
for 15 to 23.9 MET-hours per week; and 0.36 (95% CI, 0.08-1.55) for 24 or
more MET-hours per week (P for trend = .09).
These results suggest additional benefit of physical activity for obese women;
however, this analysis was limited by the small number of breast cancer deaths
(n = 38) among women with a BMI of 30 or higher.
Analyses of breast cancer death stratified by menopausal status, hormone
receptor status, and disease stage appear in Table 4. Because of the small number of deaths in some activity
categories, the exposure in these analyses was dichotomous (<9 and ≥9
MET-hours per week). There were no substantial differences by menopausal status.
Physical activity appeared beneficial to women whose tumors had both estrogen
and progesterone receptors (RR, 0.50; 95% CI, 0.34-0.74) and not to women
whose tumors lacked hormone receptors (RR, 0.91; 95% CI, 0.43-1.96). However,
this finding was based on a small number of deaths.
Physical activity was beneficial to women with stage I and II disease,
but appeared particularly beneficial to women with stage III disease. For
women with stage III cancer who had engaged in 9 or more MET-hours per week
of physical activity compared with less than 9 MET-hours per week, the RR
was 0.36 (95% CI, 0.19-0.71). However, these results were based on only 76
women and 15 breast cancer deaths. There was no significant difference in
the proportion of estrogen receptor–positive and progesterone receptor–positive
tumors by stage (80% for stage I, 76% for stage II, and 82% for stage III).
We assessed the comparative role of walking and vigorous exercise in
relation to the risk of breast cancer death, which was similar to an analysis
performed by Manson et al36 on cardiovascular
disease. Vigorous exercise was defined as participation in activities that
required at least 6 METs per hour, including jogging, running, bicycling,
swimming laps, racquet sports, and calisthenics. We cross-classified women’s
participation in walking and vigorous exercise in categories of MET-hours
per week (Table 5). Both walking and
vigorous activity contributed toward lowering the risk of breast cancer death.
Adjustment for category of physical activity prior to diagnosis did
not change the association of physical activity after diagnosis with risk
of breast cancer death. Compared with women who engaged in less than 3 MET-hours
per week of physical activity after diagnosis, the multivariable RR of breast
cancer death (adjusted for activity prior to diagnosis) was 0.76 (95% CI,
0.57-1.02) for 3 to 8.9 MET-hours per week; 0.54 (95% CI, 0.31-0.94) for 9
to 14.9 MET-hours per week; 0.57 (95% CI, 0.36-0.90) for 15 to 23.9 MET-hours
per week; and 0.60 (95% CI, 0.38-0.95) for 24 or more MET-hours per week.
We found that any category of activity higher than the reference category
of less than 3 MET-hours per week was associated with a decreased risk of
an adverse breast cancer outcome. Women who engaged in an amount of physical
activity equivalent to walking 1 or more hours per week had better survival
compared with those who exercised less than that or not at all. After adjusting
for factors predictive of survival after breast cancer, the RRs of adverse
outcomes including death, breast cancer death, and breast cancer recurrence
were 26% to 40% lower comparing women with the highest to the lowest category
of activity. The association was particularly apparent among women with hormone-responsive
tumors. Our results suggest a possible hormonal mechanism for improved survival
among women who are physically active.
A randomized trial of physical activity among overweight postmenopausal
women demonstrated declines in serum levels of androgen37 and
estrogen.38 Evidence from breast cancer primary
prevention studies suggests that increasing activity levels later in life
may reduce risk of incident breast cancer.39 We
did not explicitly assess whether increasing physical activity after a breast
cancer diagnosis is associated with improved survival. However, adjustment
for physical activity prior to diagnosis did not change the risk estimates
of mortality in women who engaged in physical activity after breast cancer
Physical activity might also improve survival through acute and chronic
improvements in insulin resistance and reduction in hyperinsulinemia.40 The associations we observed may change over time
as the use of aromatase inhibitors to suppress hormone levels becomes more
We addressed several methodological issues in our analyses. Women may
feel too fatigued to exercise during the period of active chemotherapy and
radiation treatment.41,42 Therefore,
we avoided the active treatment period for the physical activity assessments.
Because women with metastatic disease may also not be well enough to exercise,
we excluded women with stage IV cancer at diagnosis. Furthermore, we did not
update the assessment of physical activity over time because physical activity
decreases when a woman is diagnosed with metastatic disease.
Women with occult reasons for poor prognosis at the time of physical
activity assessment could bias results. If this were true, we might expect
physical activity to be associated with less benefit among women with a higher
disease stage. In fact, we found the opposite, although the results are based
on small numbers of events.
In the current study, the RR for each adverse outcome was lowest for
intermediate levels—not the highest levels of physical activity. It
is possible that some women at the highest levels of activity are motivated
toward a healthy lifestyle after diagnosis because of a worse prognosis. A
recent report of physical activity levels among breast cancer survivors in
the Health, Eating, Activity, and Lifestyle (HEAL) study found that women
diagnosed with a higher stage of disease reported 15% more time engaged in
physical activity compared with women diagnosed with in situ disease, although
this difference was accounted for by household and not by recreational activity.43 Consistent with this hypothesis, women in the 2 highest
categories of activity were slightly more likely to have stage II cancer,
and slightly less likely to have stage I cancer compared with women in the
lower categories of physical activity. This could create the appearance of
a higher risk of adverse outcome in the highest compared with intermediate
levels of physical activity.
High levels of vigorous activity (such as marathon training) have been
linked to increased risk of upper respiratory tract infection due to reduced
immune function.44 The fact that the RR of
mortality in the highest category of physical activity was not the lowest
(although still lower than the reference group) raises the possibility that
vigorous activity may be less beneficial than moderate activity for women
with breast cancer. However, no such detrimental effect from vigorous activity
was found (Table 5).
Women in the highest category of activity like the rest of the cohort
were primarily walkers but they walked for longer periods. Forty-five percent
reported walking 5 or more hours per week, 28% reported bicycling 1 or more
hours per week, and 28% reported participating in aerobics classes 1 or more
hours per week. We speculated that women in the highest physical activity
categories were very active before their cancer diagnosis, and that if they
developed breast cancer despite high levels of activity, their cancer might
be resistant to the beneficial effects of activity on survival. However, among
women participating in 15 or more MET-hours per week of activity after their
diagnosis, 62% were less active prior to their diagnosis. Overall, given the
uniform evidence of the benefits of moderate physical activity to health,45-47 we believe that it
is unlikely that exercise at the highest levels is detrimental to women with
Our study was limited by the fact that physical activity was self-reported.
However, the association of other diseases with physical activity in this
cohort including cardiovascular disease48,49;
breast,50 colon,51 and
pancreatic cancer52; infertility53;
cholecystectomy54; hip fracture31;
cognitive function55; and total mortality56,57 suggest that our measure of physical
activity is adequate to detect important disease relationships. We assessed
only leisure-time activity. Occupational and household activity may also affect
risk of adverse outcomes in women with breast cancer. In this occupationally
homogenous group, we expected our inability to assess other types of activity
would lead to nondifferential misclassification of the exposure. Therefore,
the association incorporating all types of physical activity may be even stronger.
Our assessment of recurrence may not be valid. However, our results for recurrence
were similar to results for mortality, which is a more definitive end point.
We were not able to determine adherence to therapy, which may be differential
across categories of physical activity. Finally, our study population is professional
and primarily non-Hispanic white, with 2% of the women self-defined as either
Hispanic, black, or Asian when presented with those choices on the 1992 questionnaire.
The range of physical activity engaged in by these women may be different
from that of the general population. However, there is little reason to believe
that the biological mechanisms by which physical activity could improve breast
cancer survival would differ in women from other groups.
Our results suggest that physical activity after a breast cancer diagnosis
may lower the risk of death from that disease. The benefit was seen particularly
among women who had tumors overexpressing estrogen receptors and progesterone
receptors. These results are consistent with a hormonal mechanism. The maximal
benefit occurred among women who performed the equivalent of walking 3 to
5 hours per week at an average pace (2-2.9 mph) with little evidence of increased
benefit for more exercise. It has been estimated that women decrease their
levels of physical activity by 2 hours per week after a breast cancer diagnosis,
with greater decreases among obese women,41 and
that less than one third of breast cancer survivors participate in levels
of activity recommended by government agencies.43 Women
with breast cancer who follow the Centers for Disease Control and Prevention
recommendations for all individuals in the United States to exercise at moderate
intensity for 30 or more minutes per day for 5 or more days per week58 may survive longer.
Corresponding Author: Michelle D. Holmes,
MD, DrPH, Channing Laboratory, 181 Longwood Ave, Boston, MA 02115 (email@example.com).
Author Contributions: Dr Holmes had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Holmes, Chen, Kroenke.
Acquisition of data: Holmes, Chen.
Analysis and interpretation of data: Holmes,
Chen, Feskanich, Kroenke, Colditz.
Drafting of the manuscript: Holmes, Colditz.
Critical revision of the manuscript for important
intellectual content: Chen, Feskanich, Kroenke.
Statistical analysis: Holmes, Feskanich.
Obtained funding: Holmes, Chen.
Administrative, technical, or material support:
Financial Disclosures: None reported.
Funding/Support: The research for this article
was funded by grant CA87969 from the National Institutes of Health.
Role of the Sponsor: The National Institutes
of Health had no role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; and preparation, review,
or approval of the manuscript.
Acknowledgment: We acknowledge the invaluable
programming assistance of Lisa Li, MD.