Lactation Reduces Breast Cancer Risk in Shandong Province, China
Tongzhang Zheng1,
Li Duan2,
Yi Liu2,
Bing Zhang3,
Yan Wang2,
Yongxiang Chen4,
Yawei Zhang1 and
Patricia H. Owens1
1 Department of Epidemiology and Public Health, Yale University School of Medicine and Yale Cancer Center, New Haven, CT.
2 Department of Toxicology and Epidemiology, Institute of Occupational Medicine, Shandong Academy of Medical Science, Jinan, China.
3 Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada.
4 Department of Epidemiology and Disease Surveillance, Chinese Academy of Preventive Medicine, Beijing, China.
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ABSTRACT
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Results from studies of western populations investigating lactation and breast cancer risk have been inconsistent. To examine this issue, the authors conducted a hospital-based case-control study in Shandong Province, China, in 19971999. A total of 404 cases and an equal number of controls were included. Detailed information regarding lactation, menstruation, and reproduction was collected through in-person interview. The authors found a significant inverse association between duration of lactation and breast cancer risk. For women who breastfed for more than 24 months per child, the odds ratio was 0.46 (95% confidence interval (CI): 0.27, 0.78) when compared with those who breastfed for 16 months per child. A significantly reduced risk of breast cancer was also found for those whose lifetime duration of lactation totaled 73108 months (odds ratio = 0.47, 95% CI: 0.23, 0.95) and for those who breastfed for
109 months (odds ratio = 0.24, 95% CI: 0.11, 0.53). The test for trend was statistically significant for both mean duration of lactation per child (p = 0.02) and lifetime duration of lactation (p = 0.00). Further stratification by menopausal status resulted in the same conclusion. These data suggest that prolonged lactation reduces breast cancer risk.
breast feeding; breast neoplasms; case-control studies; lactation; reproductive history
Abbreviations:
CI, confidence interval
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INTRODUCTION
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Studies of western populations (1





















24
have provided inconsistent results regarding the relation between lactation and breast cancer risk. Studies from China and Japan, however, where the prevalence of prolonged lactation is high, have shown a reduced risk associated with a longer duration of lactation (25


29
).
Three studies conducted in the early 1980s in three of the largest cities in China (Shanghai, Beijing, and Tianjin) (25
27
) have suggested that a protective effect against breast cancer development exists with a longer duration of lactation (table 1). The Shanghai study (25
), which included 429 breast cancer cases and an equal number of controls, found a 63 percent risk reduction for those who reported a lifetime duration of lactation of more than 109 months when compared with those who had never breastfed a child. The Beijing study (26
), involving 442 pairs of breast cancer cases and controls, reported a crude odds ratio of 0.36 for those who had breastfed for more than 109 months when compared with those who had never breastfed a child. The Tianjin study (27
), including 246 pairs of breast cancer cases and controls, also reported a reduced risk of breast cancer associated with prolonged breastfeeding.
A limitation of all three of these earlier Chinese studies (25
27
) is that they investigated the association between lifetime duration of lactation and breast cancer risk only, and all women were grouped together. Recent studies of western populations, however, suggest that the protective effect of lactation may be limited to only premenopausal women (11

14
) and that other factors associated with lactation (such as number of children breastfed and age at first lactation) may also be important in reducing breast cancer risk (13
15
, 20
).
In 19971999, we conducted a hospital-based case-control study in Shandong Province, China, to investigate the relation between lactation and breast cancer risk. Shandong Province, when compared with Shanghai, Beijing, and Tianjin, is less industrialized; because of the potential for lifestyle differences, it is possible that an association between lactation and breast cancer risk may differ between more industrialized and less industrialized areas. Detailed information on menstrual and reproductive factors was collected from subjects through in-person interview. Also collected was information on various other factors related to lactation, such as number of children breastfed, mean duration of lactation for each child breastfed, lifetime duration of lactation, and age at first lactation. In previous studies, all of these factors have been inconsistently associated with a reduced risk of breast cancer.
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MATERIALS AND METHODS
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Study population
After hospital approvals were obtained, histologically confirmed incident breast cancer cases were ascertained from June 1997 to April 1999 from four large hospitals in Shandong Province (Shandong Provincial Hospital, Jinan City Hospital, Provincial Cancer Hospital, and The Second Provincial Hospital). Cases diagnosed at several smaller hospitals (Qianfusan Hospital, Jining City Hospital, Zhibo Cancer Hospital, Yiantai Cancer Hospital, Shandong Meitan Hospital, and Tenzhou Hospital) were also ascertained. Cases were restricted to women aged 2080 years with no previous diagnosis of cancer, with the exception of nonmelanoma skin cancer. A total of 404 female breast cancer cases were identified from participating hospitals, and all of them participated in the study and were included in the analyses.
Controls were randomly selected from among noncancer patients who received medical care: 12 percent of the controls were admitted for various injuries or traumas; 8 percent for acute upper respiratory infection (cold, flu, tonsilitis, etc.); 9 percent for tooth extraction and for ear, nose, and throat conditions; 7 percent for cataracts; 8 percent for stomach flu or other acute digestive infections; 21 percent for surgery (appendix, strangulated hernia, hemorrhoids, or other conditions); 9 percent for lower back pain and disk problems; 4 percent for diabetes; 14 percent for irregular heart rates and other acute circulatory conditions; 3 percent for acute urinary tract infection; and 5 percent for various other conditions. Because cases were newly diagnosed breast cancer patients, selection of controls was restricted to patients whose current hospital admission was for a condition diagnosed within 1 year of the interview to reduce the proportion of controls who may have modified their habits as a result of having a chronic disease.
Controls were selected on the basis of the following: 1) If the case was identified at a general hospital, the corresponding control was then selected from the same hospital; 2) if the cancer case was identified at a cancer hospital (Provincial Cancer Hospital, Zhibo Cancer Hospital, or Yiantai Cancer Hospital), the corresponding control was then selected from the general hospital from which the cancer patient was referred initially; and 3) if the cancer case was not referred from a general hospital, the control was selected from the general hospital that usually refers cases to that hospital (most often from the neighboring general hospital). One control was selected for each case and was matched on hospital (as described above), sex, and age (±5 years). A total of 98 percent (404/412) of the controls identified initially participated in the study.
Interviews
After approval was obtained from their physicians, patients who agreed to participate in the study were interviewed by trained study interviewers in an area of each hospital allocated for the study. Interviewers were not informed of the study hypotheses. A standardized, structured questionnaire was used to obtain information on menstrual and reproductive factors. Respondents were asked whether they had ever been pregnant and how many livebirths they had had; at what age they had had their first, second, third, and final livebirth; and whether they had only breastfed their infants or had only formula-fed their children since birth. Those patients who had breastfed for less than 1 month before switching to formula feeding were considered nonbreastfeeders and were included in the never-breastfed group. Respondents who reported having only breastfed their children (377 cases and 366 controls) were then asked how many months on average they had breastfed each infant. Other information regarding family breast cancer history, medical history, tobacco use, alcohol consumption, and demographic factors was also collected.
Data analysis
We used both conditional and unconditional logistic regression to assess the relation between lactation and breast cancer risk, and our analysis of study data resulted in the same conclusion. Therefore, to facilitate control of other unmatched confounders, we presented only those results for which an unconditional logistic regression model was used. Data were stratified by menopausal status to replicate prior analyses performed in western studies, which have suggested that lactation may affect pre- and postmenopausal women differently. We included data on various lactation-related factors that have been inconsistently associated with breast cancer risk in the literature, including number of children breastfed, mean duration of lactation for each child, lifetime duration of lactation, and age at first lactation.
We calculated the results after adjustment for age and residence only and then with additional adjustments for body mass index (<23.0, 23.025.9,
26.0 kg/m2), age at menarche (
15, 1617, >17 years), age at last menstrual period (<45, 4550,
51 years), age at first full-term pregnancy (<22, 2227,
28 years), number of livebirths (0, 1, 2,
3), residence, and family breast cancer history. While the additional adjustments for menstrual factors, reproductive factors, and family breast cancer history did not change the risk estimates materially, results of both types of adjustments are presented in this paper so that readers can decide about the effect of potential confounders. Odds ratios and 95 percent confidence intervals were calculated by using SAS statistical software (30
). Tests for trend were conducted by using a likelihood ratio statistic in a logistic regression model.
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RESULTS
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Selected characteristics of breast cancer cases and controls are presented in table 2. Age was a matched variable; hence, the mean age for cases (49.0 years) and for controls (49.1 years) was quite comparable (p = 0.95). Later age at menarche was related to a reduced risk of breast cancer. Later age at menopause, however, was related to an increased risk. Later age at first full-term pregnancy was also related to a higher risk, although the odds ratio was not statistically significant. Body mass index was associated with an insignificantly reduced risk of breast cancer overall and among both pre- and postmenopausal women (data not shown). A positive family breast cancer history was associated with a significantly increased risk of breast cancer.
As shown in table 3, mean duration of lactation per child was significantly associated with a reduced risk of breast cancer for those women who breastfed for >24 months per child when compared with those who breastfed for 16 months per child. The test for trend was also statistically significant.
To compare our results with those of the earlier Chinese studies (25
27
), we used similar cutpoints for lifetime duration of lactation, as shown in table 1. A significantly reduced risk of breast cancer was found for those women whose lifetime duration of lactation was 73108 months and for those who breastfed for
109 months.
Further stratification by menopausal status (table 4) showed a reduced risk of breast cancer associated with a longer duration of lactation for both pre- and postmenopausal women, although the risk tended to be lower for premenopausal than for postmenopausal women. The risk reduction was also more consistent for lifetime duration of lactation, with the test for trend being significant for both pre- (p = 0.04) and postmenopausal (p = 0.01) women.
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TABLE 4. Risk of breast cancer associated with duration of lactation, by menopausal status, Shandong Province, China, 19971999
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A nonsignificantly reduced risk of breast cancer was observed for women who had breastfed more than three children. An age of <25 years at first lactation was also associated with a nonsignificantly reduced risk when compared with those who first breastfed at age
30 years, as shown in table 5. The test for trend, however, did not show a significant risk reduction as the number of children breastfed increased or with increasing age at first lactation. Further stratification by menopausal status showed a similar pattern (data not shown).
We also stratified the data (not shown) by number of livebirths (1, 23, >3) and lifetime duration of lactation (136, 3772, >72 months). While the stratification made the estimates less stable, a significantly reduced risk of breast cancer was observed for women who had two to three children and had breastfed for >72 months (odds ratio = 0.28, 95 percent confidence interval (CI): 0.10, 0.77) and for women who had four or more children and had breastfed for >72 months (odds ratio = 0.46, 95 percent CI: 0.23, 0.95) when compared with those who had had only one livebirth and had breastfed for 136 months.
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DISCUSSION
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In this study, we found a significant inverse association between lactation and breast cancer risk, which is consistent with findings from several studies from various western populations (












24
), China (25
27
), and Japan (28
, 29
) but not other studies (1






9
). A potential inverse association between prolonged lactation and breast cancer risk is biologically plausible. Several mechanisms have been proposed to explain the observed association as reviewed by others (15


19
), including the following: 1) a reduced exposure to the cyclic hormones of reproductive life because of ovulatory suppression that occurs with prolonged breastfeeding, 2) a protective effect from direct physical changes in the breast that accompany milk production, 3) a reduction in the concentrations of toxic organochlorines in the breast with increasing cumulative duration of lactation, and 4) an expression of transforming growth factor ß during lactation, a hormonally regulated negative growth factor in human breast cancer cells.
In interpreting the results from our study, several limitations must be considered. As in most of the previous studies, we collected lactation and other reproductive information by retrospective subject recall. However, a reliability study by Newcomb et al. (16
) found that both cases and controls reliably recalled lactation history; the Spearman correlation coefficient (r) for ever lactating was 0.88 for cases and 0.90 for controls. Also, all three Chinese studies (25
27
) and this one used questionnaires to collect information on reproductive history and reached the same conclusion.
Another potential limitation of our study concerns use of hospital-based cases and controls. While every effort was made to include all cases admitted to the study hospitals, we did not attempt to ascertain breast cancer patients who may not have come to these hospitals. Therefore, the generalizability of our results may be limited because of the hospital-based study design.
To avoid selection bias, similar to cases, controls were selected from among those women admitted to the study hospital, but controls were admitted for noncancerous conditions not thought to be associated with lactation (refer to the Materials and Methods section). An attempt was made to match the cases and controls by referring hospital, and the majority of the controls were chosen from the same hospitals as the cases. In our study, a small number of cases went directly to a cancer hospital instead of going to a general hospital first. Controls selected to match these cases were then chosen from the neighboring hospitals that usually referred cases to that particular cancer hospital. The number of these cases and controls was small, because the majority of cases were ascertained from the general hospitals. Also, as required by the health care system in the study area during the study period, to obtain a referral, patients typically first visited the contract hospitals belonging to their administrative areas, which are defined on the basis of residence. After diagnosis, patients usually returned to their local hospital for treatment.
In this study, 32 cases and 38 controls were considered nonbreastfeeders. This group included 16 nulliparous women (12 cases and 4 controls) and 20 cases and 34 controls who gave birth but never breastfed or breastfed for less than 1 month. We did not ask this group of parous women why they did not breastfeed or stopped breastfeeding their children. However, the reference group for all estimates of risk in relation to duration of lactation was women who had lactated for at least 1 month (not nulliparous women or women who had never breastfed). Therefore, the conclusion regarding prolonged lactation and reduced risk of breast cancer would not have been affected by the never-breastfed group. As argued by others (9
), comparisons among women who had breastfed would be less likely to be subjected to confounding by unidentified risk factors than would comparisons between women who had and had not lactated.
Two recent studies from Japan (28
, 29
) also used hospital-based case-control designs to investigate the relation between lactation and breast cancer risk and found a significantly reduced risk associated with breastfeeding. Yoo et al. (28
) reported an odds ratio of 0.62 (95 percent CI: 0.37, 1.04) for women with a positive history of lactation and an odds ratio of 0.39 (95 percent CI: 0.15, 0.97) for premenopausal women who breastfed 79 months compared with those who had never breastfed a child. The study by Hirose et al. (29
) reported an odds ratio of 0.55 (95 percent CI: 0.40, 0.76) and an odds ratio of 0.71 (95 percent CI: 0.52, 0.96) for premenopausal women lactating for 611 and
12 months, respectively.
Unlike the studies from China (25
27
) and Japan (28
, 29
), results from studies of western populations have been inconsistent. Several (1






9
), including two follow-up studies (3
, 8
), reported a lack of association between lactation and breast cancer risk even for those who breastfed their children
24 months (5


9
). Two case-control studies (19
, 20
) found a slight risk reduction, but the inverse association did not vary appreciably based on lifetime duration of lactation. On the other hand, several studies reported a strong reduction in breast cancer risk associated with lactation, with the duration of lactation necessary to achieve a significant reduction in risk ranging from
12 months (12
, 17
, 18
) to
24 months (10
, 11
, 13

16
, 21

24
).
It is still unknown why studies from China and Japan (25


29
), where the prevalence of prolonged lactation is high, consistently show a reduced risk of breast cancer associated with lactation while studies of western populations have produced inconsistent results 1





















24
). One likely explanation, as offered by Brinton et al. (18
), is related to the fact that breastfeeding in western populations is usually quite limited. The majority of study subjects from western populations had two or fewer livebirths, and the average length of time that lactation continued was 4 months per child. The length of lactation prior to supplementation was even more limited, as reported by Brinton et al. (on average 14 weeks). On the other hand, in two of the three published studies from China (25
, 27
), women lactating for <37 months were used as the baseline group. In the third study from Beijing (26
), a significant risk reduction was observed among only those who breastfed for >37 months. In our study, a significant inverse association was observed among only those whose lifetime duration of lactation was >72 months (table 3). If only prolonged lactation has a protective effect, then studies of populations in which duration of lactation is generally shorter may have limited power to detect such an association.
In conclusion, an inverse association between prolonged lactation and breast cancer risk was observed among both pre- and postmenopausal women in Shandong, a less industrialized area of China. This observation is consistent with three earlier studies (25
26
27
) conducted in the 1980s in three large Chinese cities. The reasons for the inconsistent results reported by studies of western populations are currently unknown, although it is possible that only prolonged lactation has a protective effect. If a protective effect were evident among only those populations with a longer duration of lactation, then it would be very difficult to study this association in western populations, where a shorter duration of lactation is more common.
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ACKNOWLEDGMENTS
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This study was supported in part by grant CA-62986 from the National Cancer Institute/National Institute of Environmental Health Sciences and by the Institute of Occupational Medicine, Shandong Academy of Medical Science, China.
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NOTES
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Reprint requests to Dr. Tongzhang Zheng, 129 Church Street, Suite 700-703, New Haven, CT 06510 (e-mail: tongzhang.zheng{at}yale.edu).
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Received for publication November 23, 1999.
Accepted for publication March 31, 2000.