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Reproductive factors, exogenous hormone use, and risk of pancreatic cancer in postmenopausal women
Cancer Epidemiology 49 (2017) 1–7
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Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Reproductive factors, exogenous hormone use, and risk of pancreatic cancer in postmenopausal women Geoffrey C. Kabat* , Victor Kamensky, Thomas E. Rohan Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, United States
A R T I C L E I N F O
A B S T R A C T
Article history: Received 22 February 2017 Received in revised form 3 May 2017 Accepted 4 May 2017 Available online xxx
Introduction: The epidemiologic literature on menstrual and reproductive factors associated with pancreatic cancer has yielded weak and inconsistent evidence of an association. Furthermore, few cohort studies have examined the association of exogenous hormone use, including type and duration, with this disease. The aim of this study was to assess the association of these exposures with risk of pancreatic cancer in a large cohort of postmenopausal women. Methods: We used data from the Women’s Health Initiative on 1003 cases of pancreatic cancer diagnosed among 158,298 participants over 14.3 years of follow-up. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the associations of interest. Results: Being parous vs. nulliparous was associated with reduced risk (HR = 0.84, 95% CI 0.70–1.00), and women who had 1–2 and 3–4 births were at decreased risk compared to nulliparous women, whereas women who had >5 births showed no decrease in risk. Compared to women who gave birth between the ages of 20–29, women who gave birth at age 30 or above were at increased risk (HR 1.23, 95% CI 1.00–1.53, p for trend 0.003). Other reproductive factors and exogenous hormone use were not associated with risk. Conclusions: Together with the existing literature on this topic, our results suggest that reproductive and hormonal exposures are unlikely to play an important role in the etiology of pancreatic cancer. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Reproductive factors Exogenous hormones Hormone therapy Pancreatic cancer Cohort studies Postmenopausal women
1. Introduction Although pancreatic cancer is the eleventh most common cancer in males and the ninth most common cancer in females in the United States, it is the fourth leading cause of cancer death in both sexes [1]. Cancer of the pancreas has the lowest 5-year survival rate (7%) among the 24 leading cancer sites [2]. A number of risk factors or protective factors for pancreatic cancer have been identified, including smoking, obesity, diabetes, chronic pancreatitis, infection with Helicobacter pylori, ABO blood type, allergies, and fruit or folate intake [3,4]. Because pancreatic cancer occurs more commonly in males compared to females [5] and because there is some evidence that steroid hormones, including estrogen, may inhibit pancreatic cancer development [6–8], a number of epidemiologic studies have examined the association of menstrual and reproductive factors, as well as exogenous hormone use, with risk of the disease [9–22]. The epidemiologic literature indicates that any association of reproductive factors or hormone use with pancreatic cancer is
* Corresponding author. E-mail address: [email protected] (G.C. Kabat). http://dx.doi.org/10.1016/j.canep.2017.05.002 1877-7821/© 2017 Elsevier Ltd. All rights reserved.
weak and inconsistent. A number of studies have reported one or two of the factors investigated to be associated with risk, but different factors have been associated with risk in different studies, and in most cases the associations and trends reported have been weak. In the main, there is little reproducible evidence indicating that menstrual and reproductive factors are associated with risk. Few studies have examined exogenous hormone use in relation to pancreatic cancer [10,18,20–22], particularly the type of hormone therapy (estrogen alone or estrogen plus progestin) and duration of use. Given the paucity of cohort studies that had information about the type of hormone therapy and duration of use, and the inconsistent findings for menstrual and reproductive factors, we used data from the Women’s Health Initiative cohort to examine the association of hormonal, menstrual, and reproductive factors with risk of pancreatic cancer. 2. Methods The Women’s Health Initiative (WHI) is a large, multi-center, multi-faceted study designed to advance understanding of the determinants of major chronic diseases in postmenopausal women. It is composed of a Clinical Trial component (CT,
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N = 68,132) and an Observational Study component (OS, N = 93,676) [23]. The clinical trial component included three randomized controlled interventions: hormone therapy, low fat diet modification, and calcium-vitamin D supplementation. Women between the ages of 50 and 79 and representing major racial/ethnic groups were recruited from the general population at 40 clinical centers throughout the United States between 1993 and 1998. Details of the design and reliability of the baseline measures have been published [23,24]. 2.1. Data collection and variable definition At study entry, self-administered questionnaires were used to collect information on demographics, medical, reproductive and family history, and on dietary and lifestyle factors, including smoking history, alcohol consumption, and recreational physical activity. In the reproductive history questionnaire, women were asked about age at first menstrual period, whether periods were regular “for most of [their] life,” age at last regular menstrual period, whether ever pregnant, number of pregnancies, number of pregnancies lasting at least 6 months, and number of births, stillbirths, and spontaneous miscarriages. Participants were also asked whether they had ever taken oral contraceptives (OC) and, if so, the age at which they started and the age of stopping, how many years and months they had used OCs, whether they had used OCs before a first full-term pregnancy, and, if so, for how many years and months. Information on lifetime use of menopausal hormones was obtained using structured questionnaires and charts displaying colored photographs of various hormone preparations. Detailed information was collected on the type of preparation, estrogen and progestin doses, schedule, and route of administration. Ages of starting and stopping the use of each preparation were recorded. Diabetes at enrollment was defined as an affirmative response to the question “did a doctor ever say that you have sugar diabetes or high blood sugar when you were not pregnant?” Incident diabetes was ascertained during follow-up based on reported prescribed diabetes treatment with pills or insulin injections on a follow-up questionnaire. A validation study indicated that reporting of diabetes had high reliability: 92% for prevalent diabetes and 82% for incident diabetes, and evidence of diabetes was found in only 5% of women who did not report it [25]. Age at menopause was defined as the youngest age at which the participant experienced any of the following: last menstrual bleeding (all participants were >12 months after the last menstrual period at baseline), removal of both ovaries, or initiation of menopausal hormone therapy. Age at first birth was defined as the age at first pregnancy lasting 6 months or longer. Clinical outcomes (including new cancer diagnoses) were updated semi-annually in the CT and annually in the OS using in-person, mailed, or telephone questionnaires. Self-reports of pancreatic cancer were verified by trained physician adjudicators who examined records of hospitalizations, surgeries, pathology reports, and procedures [26]. As of September 20, 2015 a total of 1027 incident cases of pancreatic cancer (occurring as the first cancer) had been diagnosed among the 161,808 participants in the OS and CT after a median of 16.9 years of follow-up (mean, 14.3 years). For the analyses reported here, we excluded women who were missing information on smoking status (N = 2105) or body mass index (N = 1427). After exclusions, 1003 cases and 157,295 noncases were available for analysis. Four hundred and forty-five cases were from the CT and 558 from the OS. Among 1003 pancreatic cancers, 762 had an ICD morphology code. However, 140 cases were coded only as “neoplasm malignant,” “tumor cells malignant,” “carcinoma NOS,”or “carcinoma anaplastic NOS.” Of the 622
cases with a specific morphology code, 584 (94.0%) were adenocarcinomas. 2.2. Statistical analysis Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI) for the associations of reproductive and hormonal exposures with the risk of pancreatic cancer, with days to event as the time scale. Cases contributed person-time to the study from their date of enrollment until their date of diagnosis. Non-cases contributed person-time from enrollment and were censored as of the end of follow-up, date of death, or date of withdrawal from the study, whichever occurred earliest. We computed both age-adjusted and multivariable-adjusted HRs and 95% CI. We examined the association of each variable of interest with risk by adjusting for a common set of covariates in the final multivariable model: age (continuous), smoking status (never smoked, former smoker, current smoker), pack-years of smoking (continuous); history of diabetes (yes, no); body mass index (weight (kg)/height (m)2); education (less than high school graduate, high school graduate/some college, college graduate, post-college); ethnicity (white, black, other); and enrollment in the Observational Study or intervention vs. placebo or control arm of the four clinical trials (estrogen alone; estrogen + progestin; calcium + vitamin D; and low-fat diet). Because diabetes is a risk factor for pancreatic cancer, a diagnosis of diabetes (self-reported at enrollment or taking anti-diabetes medication at a subsequent clinic visit) was treated as a timedependent covariate. For categorical variables, tests for trend were performed by assigning the median value to each category and modeling this variable as a continuous variable. In further analyses, we repeated the main analyses restricted to: (1) women with no history of a cancer diagnosis (other than non-melanoma skin cancer) prior to enrollment; (2) women who were not in the treatment arms of the hormone therapy clinical trials; and (3) cases of adenocarcinoma of the pancreas. 3. Results Compared to non-cases, women subsequently diagnosed with pancreatic cancer were somewhat older at enrollment, and had more pack-years of smoking (Table 1). Age at first birth, breastfeeding (ever, never), hysterectomy, bilateral oophorectomy, oral contraceptive use (ever, never), hormone therapy use (ever, never), and ethnicity differed between cases and non-cases; however, most differences were modest. Age at menarche, age at menopause, and history of miscarriage and stillbirth did not differ between cases and non-cases. In age-adjusted and multivariable adjusted analyses, being parous vs. nulliparous was associated with reduced risk (HR = 0.84, 95% CI 0.70–1.00), and women who had 1–2 and 3–4 births were at decreased risk compared to nulliparous women, whereas women who had 5+ births showed no decrease in risk (Table 2). Compared to women who gave birth between the ages of 20–29, women who gave birth at age 30 or older were at increased risk, and the trend of increasing risk with increasing age at first birth was significant (0.003). When the associations of parity and age at first birth were mutually adjusted among parous women, the inverse association with parity (for fewer than 5 births) and the positive association with age at first birth were still evident (HR for 1–2 births 0.68, 95% CI 0.52–0.89; HR for 3–4 births 0.68, 95% CI 0.52–0.87; HR for >5 births 0.83, 95% CI 0.63–1.10; p for linear trend 0.35; HR for age at first birth <20 years 0.74, 95% CI 0.60–0.92; HR for >30 years 1.27, 95% CI 1.01–1.58; p for trend 0.001). Other reproductive factors (age at menarche, age at menopause, total years of menstruation,
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3
Table 1 Distribution of selected characteristics among pancreatic cancer cases and non-cases in the Women’s Health Initiative. Characteristics
Cases (N = 1003)
Non-cases (N = 157,295)
P-value
Means (SD) Age (yrs) Parity Age at menopause (yrs) Body mass index (kg/m2) Physical activity (MET-h/wk) Alcohol intake (servings/wk) Smoking (pack-years)
65.5 (7.0) 2.6 (1.8) 47.4 (6.6) 28.1 (5.8) 11.7 (13.2) 2.7 (5.2) 11.7 (21.0)
63.2 (7.2) 2.6 (1.7) 47.3 (6.7) 28.0 (5.9) 11.9 (13.7) 2.3 (4.9) 9.7 (18.1)
<0.0001 0.8 0.6 0.5 0.6 0.05 0.003
23.5 11.9 47.9 46.2 23.6 33.2 4.2 34.0 52.6 7.2
21.9 9.1 51.4 41.9 20.0 33.5 4.6 41.6 56.3 5.9
0.5 0.0001 0.03 0.001 0.004 0.5 0.60 < 0.0001 0.02 0.09 0.13
50.1 41.1 9.0 30.4
51.0 42.0 7.0 28.5
85.2 8.1 6.7
82.8 9.0 8.2
55.6 44.4
57.7 42.3
Proportions Age <12 yr at menarche (%) Age 30 yrs at first birth (%) Never breastfed 1 mth (%) Hysterectomy (%) Bilateral oophorectomy (%) Miscarriage ever (%) Stillbirth ever (%) Oral contraceptive use ever (%) Hormone therapy ever (%) Diabetes (%) Smoking status (%) Never Former Current Education (% post-college) Ethnicity (%) White Black Other
Study component OS CT
0.38 0.04
0.2
breast-feeding, stillbirth, number of miscarriages, hysterectomy, and bilateral oophorectomy) were not associated with risk. Exogenous hormone use, including ever use of oral contraceptives and duration of use, and ever use of hormone therapy, as well as type and duration, showed no associations with risk (Table 3). Use of hormone therapy for 10 or more years showed a borderline reduction in risk; however, there was no evidence of trend with increasing duration. In sensitivity analyses restricted to participants who did not report a history of cancer at enrollment, and when women in the HRT intervention arms were excluded (sensitivity analyses 1 and 2, respectively), with one exception, most estimates for reproductive factors and exogenous hormone use were materially unchanged or were weakened (closer to the null value): the inverse HRs associated with level of parity were slightly strengthened: HR for parous vs. nulliparous: 0.79, 95% CI 0.66–0.96 (analysis #1) and 0.79, 95% CI 0.65–0.95 (analysis #2). However, the HR for >5 births did not differ from the null in either analysis. When the analysis was repeated restricting cases to the 584 women with adenocarcinoma of the pancreas (analysis #3), the direction of the associations was unchanged; however, the magnitude was attenuated (data not shown). 4. Discussion In the present study we observed a modest inverse association of parity, particularly of having 1–4 children, and a modest positive association of age at first birth with risk of pancreatic cancer. Other reproductive and hormonal exposures showed no clear evidence of an association or of trends with increasing duration of exposure. The observed associations were either unchanged or were
somewhat attenuated when the analysis was restricted to women without prevalent cancer, women not in the intervention arms of the hormone therapy clinical trials, and women with histologically-confirmed adenocarcinoma of the pancreas. Based on a review of the epidemiologic literature concerning the association of reproductive factors and exogenous hormone use with risk of pancreatic cancer, including all cohort studies [9– 13,15,17,19–21] and several large case-control studies [14,16,18,22], this literature is characterized by scattered reports of associations for some specific factor against a background of an overall lack of consistent evidence of robust associations. Individual studies have reported associations with parity (both positive [15] and inverse [9,11]); age at menarche (both older [12] and younger age [16]); age at menopause (older age at menopause associated with decreased risk [13]); age at first birth [18] (older age at first birth associated with increased risk); and hysterectomy [22], whereas other studies found no association with these specific variables [9–11,15,17,21]. In addition, most reported associations were of modest magnitude and trends with increasing exposure tend to be weak. Two metaanalyses of the association of parity with pancreatic cancer risk appear to show conflicting results [27,28]. One [27] concluded that parity was associated with reduced risk and showed a significant dose-response relationship, while the other [28] indicated that giving birth to two children was associated with the greatest reduction in risk, but there was no evidence of a linear trend with increasing parity. The largest cohort study [17], with 1182 incident cases of pancreatic cancer, found no association of any reproductive factor with risk. Although most associations with specific factors have been either weak or null, when combinations of factors have been examined, in some cases the results appear to have been
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Table 2 Association of menstrual and reproductive factors, with risk of pancreatic cancer in the Women’s Health Initiative. N of cases
N of non-cases
HRa
95% CI
HRb
95% CI
Age at menarche (yrs) <12 12 13 14 Missing P for trend
235 248 288 227 5
34,414 40,922 45,347 36,159 453
1.00 0.84 0.87 0.86
Ref. 0.70–1.00 0.73–1.03 0.71–1.03
1.00 0.95 0.98 0.98
Ref. 0.80–1.14 0.82–1.16 0.82–1.18
Age at menopause (yrs) <45 45–54 55 Missing P for trend
264 525 94 120
Total yrs menstruation <30 30–<35 35–<40 40 Missing P for trend
168 194 231 163 247
Parity Nulliparous Parous 1–2 3–4 5 Missing P for trend
139 863 307 371 185 1
Age at first birth (yrs) <20 20–29 30 Missing P for trend
20 694 96 193
Breast fed (>1 mo) No Yes Missing
Duration of breast feeding (mo) Never breast fed 1–6 7–12 12 Missing P for trend
0.14
39,472 82,303 15,046 883
1.14 1.00 0.89
0.25
0.98–1.32 Ref. 0.71–1.10
0.21
27,765 26,521 38,985 22,075 41,949
1.00 1.12 0.90 1.06
1.00 0.80 0.80 0.74 0.97
Ref 0.91–1.38 0.73–1.09 0.86–1.32
0.92 1.00 1.21
1.00 1.18 1.00 1.19
Ref. 0.96–1.46 0.82–1.23 0.95–1.48
0.45
Ref. 0.66–0.95 0.64–0.95 0.61–0.90 0.78–1.21
0.31
4108 111,896 11,552 29,739
0.91–1.23 Ref. 0.75–1.15
0.93
0.72
18,575 137,880 53,032 61,777 23,071 840
1.05 1.00 0.93
1.00 0.84 0.83 0.80 0.96
Ref. 0.70–1.00 0.68–1.02 0.65–0.97 0.75–1.20
0.67
0.75–1.12 Ref. 0.98–1.50
0.5
0.82 1.00 1.23
0.67–1.00 Ref. 1.00–1.53
0.003
519 477 7
75,688 80,063 1544
1.00 0.81
Ref. 0.72–0.92
1.00 0.88
Ref. 0.76–1.02
519 240 98 136 10
75,688 40,373 17,294 21,940 2000
1.00 0.82 0.78 0.82
Ref. 0.70–0.95 0.63–0.96 0.68–0.99
1.00 0.88 0.83 0.89
Ref. 0.75–1.02 0.67–1.03 0.74–1.07
0.03
0.35
Ever had stillbirth No Yes Missing
839 37 127
134,490 6529 16,276
1.00 0.96
Ref. 0.69–1.33
1.00 0.89
Ref. 0.64–1.24
Number of miscarriages 0 1 2+ Missing
592 197 97 117
94,265 31,130 16,353 15,547
1.00 1.00 0.93
Ref. 0.85–1.17 0.75–1.15
1.00 1.01 0.88
Ref. 0.86–1.18 0.71–1.09
G.C. Kabat et al. / Cancer Epidemiology 49 (2017) 1–7
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Table 2 (Continued) N of cases
N of non-cases
HRa
95% CI
HRb
95% CI
Hysterectomy No Yes Missing
538 462 3
91,424 65,788 83
1.00 1.21
Ref. 1.07–1.37
1.00 1.09
Ref. 0.95–1.25
Bilateral oophorectomy No Yes Missing
746 231 26
123,116 30,717 3462
1.00 1.23
Ref. 1.06–1.43
1.00 1.13
Ref. 0.97–1.31
a
Age-adjusted hazard ratios. Adjusted for age (continuous), smoking status (never smoked, former smoker, current smoker), pack-years of smoking (continuous), body mass index (kg/m2continuous), educational level (less than high school grad, high school grad/some college, college grad, post-college), ethnicity (white, black, other), allocation to the OS or treatment/placebo/control arm of clinical trials, and diabetes (reported at enrollment or taking anti-diabetes medication at a subsequent visit) as a time-dependent covariate. b
Table 3 Exogenous hormone use and risk of pancreatic cancer in the Women’s Health Initiative. N of cases
N of non-cases
HRa
95% CI
HRb
95% CI
662 341 0
91,888 65,404 3
1.00 0.89
Ref. 0.77–1.02
1.00 0.92
Ref. 0.80–1.06
662 75 123 70 73
91,940 14,128 22,028 14,854 14,345
1.00 0.87 0.98 0.82 0.84 0.10
Ref. 0.68–1.10 0.80–1.20 0.64–1.06 0.66–1.07
1.00 0.87 1.01 0.88 0.88 0.26
Ref. 0.68–1.10 0.83–1.23 0.69–1.13 0.69–1.12
Hormone therapy Never Ever Missing
475 528 0
68,740 88,552 3
1.00 0.89
Ref. 0.78–1.00
1.00 0.91
Ref. 0.80–1.03
Hormone therapy status Never used Past user Current user Missing
475 173 354 1
68,740 25,193 63,229 133
1.00 0.96 0.85
Ref. 0.81–1.15 0.74–0.99
1.00 0.96 0.88
Ref. 0.80–1.14 0.76–1.02
475 202 114 212 0
68,740 34,169 19,899 34,481 6
1.00 0.95 0.91 0.82
Ref. 0.80–1.12 0.74–1.12 0.70–0.97
1.00 0.94 0.97 0.84
Ref. 0.80–1.11 0.79–1.20 0.72–1.00
Oral contraceptive use Never Ever Missing
Duration of OC use (yrs) Never <1 1–<5 5–< =10 10 P for trend
Duration of hormone therapy (yrs) Never >0 to <5 5–<10 10 Missing P for trend
0.33
0.29
Type of hormone therapy None Estrogen (E) alone Estrogen + progestin (E + P) Both types Missing
475 310 165 53 0
68,740 47,477 32,384 8691 3
1.00 0.94 0.81 0.84
Ref. 0.81–1.08 0.68–0.97 0.63–1.12
1.00 0.91 0.91 0.87
Ref. 0.79–1.06 0.76–1.09 0.65–1.15
Duration of E alone (yrs) Never >0–<7 7
475 145 165
68,740 20,961 26,515
1.00 1.05 0.86
Ref. 0.87–1.27 0.72–1.02
1.00 1.00 0.87
Ref. 0.83–1.24 0.72–1.04
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G.C. Kabat et al. / Cancer Epidemiology 49 (2017) 1–7
Table 3 (Continued)
Missing P for trend
Duration of E + P Never >0–<7 7 Missing P for trend
N of cases
N of non-cases
218
41,079
HRa
95% CI
0.10
475 100 65 363
68,740 20,335 12,047 56,173
1.00 0.85 0.78
HRb
95% CI
0.13
Ref. 0.68–1.06 0.60–1.01
0.04
1.00 0.92 0.91
Ref. 0.73–1.15 0.70–1.17
0.40
a
Age-adjusted hazard ratios. b Adjusted for age (continuous), smoking status (never smoked, former smoker, current smoker), pack-years of smoking (continuous), body mass index (kg/m2continuous), educational level (less than high school grad, high school grad/some college, college grad, post-college), ethnicity (white, black, other), allocation to the OS or treatment/placebo/control arm of clinical trials, and diabetes (reported at enrollment or taking anti-diabetes medication at a subsequent visit) as a time-dependent covariate.
strengthened. For example, in the analysis of a Norwegian cohort study [15], neither parity nor duration of breastfeeding was associated with risk when adjusted for only demographic factors; however, when the two variables were mutually adjusted, parity showed a significant positive association, and breast-feeding showed a significant inverse association. We were unable to replicate this finding in our data. Analysis of the largest cohort study [17] failed to provide support for an association with breastfeeding or parity. Furthermore, our results were unchanged when parity and age at first birth among parous women were mutually adjusted. Few studies have addressed the association of exogenous hormone use with risk of pancreatic cancer. Three cohort studies found no association of ever use of oral contraceptives with risk [10,13]; however, longer duration of oral contraceptive use was associated with increased risk in two studies [18,21] but not in other studies [9,11]. Three studies found no association of postmenopausal hormone and risk [10,14,18], but in another study [21] current users of estrogen only therapy, but not of estrogenplus-progestin had reduced risk compared to never users. In a pooled analysis of 11 case-control studies [22], hormone therapy was not associated with risk; however, women who had a hysterectomy and had used hormone therapy were at reduced risk (pooled OR 0.64, 95% CI 0.48–0.84). Our results, together with those of other large cohort studies [9–11,17], suggest that there is little consistent evidence of an association of reproductive or hormonal factors with risk of pancreatic cancer, and that where isolated associations have been reported, these are likely due to chance, confounding, or other biases [6]. A detailed assessment of the evidence in terms of 3 specific hypotheses relating to exposure to estrogen [6] has concluded that there is little support for the hypothesis that hormonal exposures are associated with pancreatic cancer risk. Strengths of the present study include its prospective nature, the large number of cases, and the availability of information on the type of postmenopausal hormone therapy used (estrogen along, estrogen-plus-progestin) and duration of use. Furthermore, because diabetes is a risk factor for pancreatic cancer, we included diabetes as a time-dependent covariate in the analysis. Limitations include the observational nature of the study, the fact that exposures measured at enrollment could have changed during follow-up, leading to misclassification of exposure, and the difficulty of recalling early reproductive events, such as age at menarche and timing of oral contraceptive use, for older women. Finally, WHI is restricted to postmenopausal women; however, pancreatic cancer incidence is low below age 50, and incidence increases sharply with age [3].
5. Conclusion In conclusion, in the present study, several reproductive factors, including parity, age at first birth, and bilateral oophorectomy were associated with risk. However, the associations were modest, and there were no trends with increasing years of exposure. Furthermore, other factors including age at menarche, age at menopause, total years of menstruation, and exogenous hormone use were not associated with risk. Together with the existing literature on this topic, our results suggest that reproductive and hormonal exposures are unlikely to play an important role in the etiology of pancreatic cancer. Authors’ contributions GCK reviewed the literature, analyzed the data, and drafted the paper. VK contributed to the statistical programming. GCK and TER discussed the appropriateness of the analyses and the interpretation of the data. TER gave detailed comments on the manuscript. Funding This work was supported by institutional funds from the Albert Einstein College of Medicine. Conflicts of interest None. Acknowledgements Short list of whi investigators Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller; Clinical Coordinating Center: Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg; Investigators and Academic Centers: (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA)
G.C. Kabat et al. / Cancer Epidemiology 49 (2017) 1–7
Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, WinstonSalem, NC) Sally Shumaker Women’s Health Initiative Memory Study: (Wake Forest University School of Medicine, WinstonSalem, NC) Sally Shumaker.
[17]
[18]
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Contents lists available at ScienceDirect
Cancer Epidemiology The International Journal of Cancer Epidemiology, Detection, and Prevention journal homepage: www.cancerepidemiology.net
Reproductive factors, exogenous hormone use, and risk of pancreatic cancer in postmenopausal women Geoffrey C. Kabat* , Victor Kamensky, Thomas E. Rohan Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461, United States
A R T I C L E I N F O
A B S T R A C T
Article history: Received 22 February 2017 Received in revised form 3 May 2017 Accepted 4 May 2017 Available online xxx
Introduction: The epidemiologic literature on menstrual and reproductive factors associated with pancreatic cancer has yielded weak and inconsistent evidence of an association. Furthermore, few cohort studies have examined the association of exogenous hormone use, including type and duration, with this disease. The aim of this study was to assess the association of these exposures with risk of pancreatic cancer in a large cohort of postmenopausal women. Methods: We used data from the Women’s Health Initiative on 1003 cases of pancreatic cancer diagnosed among 158,298 participants over 14.3 years of follow-up. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the associations of interest. Results: Being parous vs. nulliparous was associated with reduced risk (HR = 0.84, 95% CI 0.70–1.00), and women who had 1–2 and 3–4 births were at decreased risk compared to nulliparous women, whereas women who had >5 births showed no decrease in risk. Compared to women who gave birth between the ages of 20–29, women who gave birth at age 30 or above were at increased risk (HR 1.23, 95% CI 1.00–1.53, p for trend 0.003). Other reproductive factors and exogenous hormone use were not associated with risk. Conclusions: Together with the existing literature on this topic, our results suggest that reproductive and hormonal exposures are unlikely to play an important role in the etiology of pancreatic cancer. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Reproductive factors Exogenous hormones Hormone therapy Pancreatic cancer Cohort studies Postmenopausal women
1. Introduction Although pancreatic cancer is the eleventh most common cancer in males and the ninth most common cancer in females in the United States, it is the fourth leading cause of cancer death in both sexes [1]. Cancer of the pancreas has the lowest 5-year survival rate (7%) among the 24 leading cancer sites [2]. A number of risk factors or protective factors for pancreatic cancer have been identified, including smoking, obesity, diabetes, chronic pancreatitis, infection with Helicobacter pylori, ABO blood type, allergies, and fruit or folate intake [3,4]. Because pancreatic cancer occurs more commonly in males compared to females [5] and because there is some evidence that steroid hormones, including estrogen, may inhibit pancreatic cancer development [6–8], a number of epidemiologic studies have examined the association of menstrual and reproductive factors, as well as exogenous hormone use, with risk of the disease [9–22]. The epidemiologic literature indicates that any association of reproductive factors or hormone use with pancreatic cancer is
* Corresponding author. E-mail address: [email protected] (G.C. Kabat). http://dx.doi.org/10.1016/j.canep.2017.05.002 1877-7821/© 2017 Elsevier Ltd. All rights reserved.
weak and inconsistent. A number of studies have reported one or two of the factors investigated to be associated with risk, but different factors have been associated with risk in different studies, and in most cases the associations and trends reported have been weak. In the main, there is little reproducible evidence indicating that menstrual and reproductive factors are associated with risk. Few studies have examined exogenous hormone use in relation to pancreatic cancer [10,18,20–22], particularly the type of hormone therapy (estrogen alone or estrogen plus progestin) and duration of use. Given the paucity of cohort studies that had information about the type of hormone therapy and duration of use, and the inconsistent findings for menstrual and reproductive factors, we used data from the Women’s Health Initiative cohort to examine the association of hormonal, menstrual, and reproductive factors with risk of pancreatic cancer. 2. Methods The Women’s Health Initiative (WHI) is a large, multi-center, multi-faceted study designed to advance understanding of the determinants of major chronic diseases in postmenopausal women. It is composed of a Clinical Trial component (CT,
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N = 68,132) and an Observational Study component (OS, N = 93,676) [23]. The clinical trial component included three randomized controlled interventions: hormone therapy, low fat diet modification, and calcium-vitamin D supplementation. Women between the ages of 50 and 79 and representing major racial/ethnic groups were recruited from the general population at 40 clinical centers throughout the United States between 1993 and 1998. Details of the design and reliability of the baseline measures have been published [23,24]. 2.1. Data collection and variable definition At study entry, self-administered questionnaires were used to collect information on demographics, medical, reproductive and family history, and on dietary and lifestyle factors, including smoking history, alcohol consumption, and recreational physical activity. In the reproductive history questionnaire, women were asked about age at first menstrual period, whether periods were regular “for most of [their] life,” age at last regular menstrual period, whether ever pregnant, number of pregnancies, number of pregnancies lasting at least 6 months, and number of births, stillbirths, and spontaneous miscarriages. Participants were also asked whether they had ever taken oral contraceptives (OC) and, if so, the age at which they started and the age of stopping, how many years and months they had used OCs, whether they had used OCs before a first full-term pregnancy, and, if so, for how many years and months. Information on lifetime use of menopausal hormones was obtained using structured questionnaires and charts displaying colored photographs of various hormone preparations. Detailed information was collected on the type of preparation, estrogen and progestin doses, schedule, and route of administration. Ages of starting and stopping the use of each preparation were recorded. Diabetes at enrollment was defined as an affirmative response to the question “did a doctor ever say that you have sugar diabetes or high blood sugar when you were not pregnant?” Incident diabetes was ascertained during follow-up based on reported prescribed diabetes treatment with pills or insulin injections on a follow-up questionnaire. A validation study indicated that reporting of diabetes had high reliability: 92% for prevalent diabetes and 82% for incident diabetes, and evidence of diabetes was found in only 5% of women who did not report it [25]. Age at menopause was defined as the youngest age at which the participant experienced any of the following: last menstrual bleeding (all participants were >12 months after the last menstrual period at baseline), removal of both ovaries, or initiation of menopausal hormone therapy. Age at first birth was defined as the age at first pregnancy lasting 6 months or longer. Clinical outcomes (including new cancer diagnoses) were updated semi-annually in the CT and annually in the OS using in-person, mailed, or telephone questionnaires. Self-reports of pancreatic cancer were verified by trained physician adjudicators who examined records of hospitalizations, surgeries, pathology reports, and procedures [26]. As of September 20, 2015 a total of 1027 incident cases of pancreatic cancer (occurring as the first cancer) had been diagnosed among the 161,808 participants in the OS and CT after a median of 16.9 years of follow-up (mean, 14.3 years). For the analyses reported here, we excluded women who were missing information on smoking status (N = 2105) or body mass index (N = 1427). After exclusions, 1003 cases and 157,295 noncases were available for analysis. Four hundred and forty-five cases were from the CT and 558 from the OS. Among 1003 pancreatic cancers, 762 had an ICD morphology code. However, 140 cases were coded only as “neoplasm malignant,” “tumor cells malignant,” “carcinoma NOS,”or “carcinoma anaplastic NOS.” Of the 622
cases with a specific morphology code, 584 (94.0%) were adenocarcinomas. 2.2. Statistical analysis Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI) for the associations of reproductive and hormonal exposures with the risk of pancreatic cancer, with days to event as the time scale. Cases contributed person-time to the study from their date of enrollment until their date of diagnosis. Non-cases contributed person-time from enrollment and were censored as of the end of follow-up, date of death, or date of withdrawal from the study, whichever occurred earliest. We computed both age-adjusted and multivariable-adjusted HRs and 95% CI. We examined the association of each variable of interest with risk by adjusting for a common set of covariates in the final multivariable model: age (continuous), smoking status (never smoked, former smoker, current smoker), pack-years of smoking (continuous); history of diabetes (yes, no); body mass index (weight (kg)/height (m)2); education (less than high school graduate, high school graduate/some college, college graduate, post-college); ethnicity (white, black, other); and enrollment in the Observational Study or intervention vs. placebo or control arm of the four clinical trials (estrogen alone; estrogen + progestin; calcium + vitamin D; and low-fat diet). Because diabetes is a risk factor for pancreatic cancer, a diagnosis of diabetes (self-reported at enrollment or taking anti-diabetes medication at a subsequent clinic visit) was treated as a timedependent covariate. For categorical variables, tests for trend were performed by assigning the median value to each category and modeling this variable as a continuous variable. In further analyses, we repeated the main analyses restricted to: (1) women with no history of a cancer diagnosis (other than non-melanoma skin cancer) prior to enrollment; (2) women who were not in the treatment arms of the hormone therapy clinical trials; and (3) cases of adenocarcinoma of the pancreas. 3. Results Compared to non-cases, women subsequently diagnosed with pancreatic cancer were somewhat older at enrollment, and had more pack-years of smoking (Table 1). Age at first birth, breastfeeding (ever, never), hysterectomy, bilateral oophorectomy, oral contraceptive use (ever, never), hormone therapy use (ever, never), and ethnicity differed between cases and non-cases; however, most differences were modest. Age at menarche, age at menopause, and history of miscarriage and stillbirth did not differ between cases and non-cases. In age-adjusted and multivariable adjusted analyses, being parous vs. nulliparous was associated with reduced risk (HR = 0.84, 95% CI 0.70–1.00), and women who had 1–2 and 3–4 births were at decreased risk compared to nulliparous women, whereas women who had 5+ births showed no decrease in risk (Table 2). Compared to women who gave birth between the ages of 20–29, women who gave birth at age 30 or older were at increased risk, and the trend of increasing risk with increasing age at first birth was significant (0.003). When the associations of parity and age at first birth were mutually adjusted among parous women, the inverse association with parity (for fewer than 5 births) and the positive association with age at first birth were still evident (HR for 1–2 births 0.68, 95% CI 0.52–0.89; HR for 3–4 births 0.68, 95% CI 0.52–0.87; HR for >5 births 0.83, 95% CI 0.63–1.10; p for linear trend 0.35; HR for age at first birth <20 years 0.74, 95% CI 0.60–0.92; HR for >30 years 1.27, 95% CI 1.01–1.58; p for trend 0.001). Other reproductive factors (age at menarche, age at menopause, total years of menstruation,
G.C. Kabat et al. / Cancer Epidemiology 49 (2017) 1–7
3
Table 1 Distribution of selected characteristics among pancreatic cancer cases and non-cases in the Women’s Health Initiative. Characteristics
Cases (N = 1003)
Non-cases (N = 157,295)
P-value
Means (SD) Age (yrs) Parity Age at menopause (yrs) Body mass index (kg/m2) Physical activity (MET-h/wk) Alcohol intake (servings/wk) Smoking (pack-years)
65.5 (7.0) 2.6 (1.8) 47.4 (6.6) 28.1 (5.8) 11.7 (13.2) 2.7 (5.2) 11.7 (21.0)
63.2 (7.2) 2.6 (1.7) 47.3 (6.7) 28.0 (5.9) 11.9 (13.7) 2.3 (4.9) 9.7 (18.1)
<0.0001 0.8 0.6 0.5 0.6 0.05 0.003
23.5 11.9 47.9 46.2 23.6 33.2 4.2 34.0 52.6 7.2
21.9 9.1 51.4 41.9 20.0 33.5 4.6 41.6 56.3 5.9
0.5 0.0001 0.03 0.001 0.004 0.5 0.60 < 0.0001 0.02 0.09 0.13
50.1 41.1 9.0 30.4
51.0 42.0 7.0 28.5
85.2 8.1 6.7
82.8 9.0 8.2
55.6 44.4
57.7 42.3
Proportions Age <12 yr at menarche (%) Age 30 yrs at first birth (%) Never breastfed 1 mth (%) Hysterectomy (%) Bilateral oophorectomy (%) Miscarriage ever (%) Stillbirth ever (%) Oral contraceptive use ever (%) Hormone therapy ever (%) Diabetes (%) Smoking status (%) Never Former Current Education (% post-college) Ethnicity (%) White Black Other
Study component OS CT
0.38 0.04
0.2
breast-feeding, stillbirth, number of miscarriages, hysterectomy, and bilateral oophorectomy) were not associated with risk. Exogenous hormone use, including ever use of oral contraceptives and duration of use, and ever use of hormone therapy, as well as type and duration, showed no associations with risk (Table 3). Use of hormone therapy for 10 or more years showed a borderline reduction in risk; however, there was no evidence of trend with increasing duration. In sensitivity analyses restricted to participants who did not report a history of cancer at enrollment, and when women in the HRT intervention arms were excluded (sensitivity analyses 1 and 2, respectively), with one exception, most estimates for reproductive factors and exogenous hormone use were materially unchanged or were weakened (closer to the null value): the inverse HRs associated with level of parity were slightly strengthened: HR for parous vs. nulliparous: 0.79, 95% CI 0.66–0.96 (analysis #1) and 0.79, 95% CI 0.65–0.95 (analysis #2). However, the HR for >5 births did not differ from the null in either analysis. When the analysis was repeated restricting cases to the 584 women with adenocarcinoma of the pancreas (analysis #3), the direction of the associations was unchanged; however, the magnitude was attenuated (data not shown). 4. Discussion In the present study we observed a modest inverse association of parity, particularly of having 1–4 children, and a modest positive association of age at first birth with risk of pancreatic cancer. Other reproductive and hormonal exposures showed no clear evidence of an association or of trends with increasing duration of exposure. The observed associations were either unchanged or were
somewhat attenuated when the analysis was restricted to women without prevalent cancer, women not in the intervention arms of the hormone therapy clinical trials, and women with histologically-confirmed adenocarcinoma of the pancreas. Based on a review of the epidemiologic literature concerning the association of reproductive factors and exogenous hormone use with risk of pancreatic cancer, including all cohort studies [9– 13,15,17,19–21] and several large case-control studies [14,16,18,22], this literature is characterized by scattered reports of associations for some specific factor against a background of an overall lack of consistent evidence of robust associations. Individual studies have reported associations with parity (both positive [15] and inverse [9,11]); age at menarche (both older [12] and younger age [16]); age at menopause (older age at menopause associated with decreased risk [13]); age at first birth [18] (older age at first birth associated with increased risk); and hysterectomy [22], whereas other studies found no association with these specific variables [9–11,15,17,21]. In addition, most reported associations were of modest magnitude and trends with increasing exposure tend to be weak. Two metaanalyses of the association of parity with pancreatic cancer risk appear to show conflicting results [27,28]. One [27] concluded that parity was associated with reduced risk and showed a significant dose-response relationship, while the other [28] indicated that giving birth to two children was associated with the greatest reduction in risk, but there was no evidence of a linear trend with increasing parity. The largest cohort study [17], with 1182 incident cases of pancreatic cancer, found no association of any reproductive factor with risk. Although most associations with specific factors have been either weak or null, when combinations of factors have been examined, in some cases the results appear to have been
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Table 2 Association of menstrual and reproductive factors, with risk of pancreatic cancer in the Women’s Health Initiative. N of cases
N of non-cases
HRa
95% CI
HRb
95% CI
Age at menarche (yrs) <12 12 13 14 Missing P for trend
235 248 288 227 5
34,414 40,922 45,347 36,159 453
1.00 0.84 0.87 0.86
Ref. 0.70–1.00 0.73–1.03 0.71–1.03
1.00 0.95 0.98 0.98
Ref. 0.80–1.14 0.82–1.16 0.82–1.18
Age at menopause (yrs) <45 45–54 55 Missing P for trend
264 525 94 120
Total yrs menstruation <30 30–<35 35–<40 40 Missing P for trend
168 194 231 163 247
Parity Nulliparous Parous 1–2 3–4 5 Missing P for trend
139 863 307 371 185 1
Age at first birth (yrs) <20 20–29 30 Missing P for trend
20 694 96 193
Breast fed (>1 mo) No Yes Missing
Duration of breast feeding (mo) Never breast fed 1–6 7–12 12 Missing P for trend
0.14
39,472 82,303 15,046 883
1.14 1.00 0.89
0.25
0.98–1.32 Ref. 0.71–1.10
0.21
27,765 26,521 38,985 22,075 41,949
1.00 1.12 0.90 1.06
1.00 0.80 0.80 0.74 0.97
Ref 0.91–1.38 0.73–1.09 0.86–1.32
0.92 1.00 1.21
1.00 1.18 1.00 1.19
Ref. 0.96–1.46 0.82–1.23 0.95–1.48
0.45
Ref. 0.66–0.95 0.64–0.95 0.61–0.90 0.78–1.21
0.31
4108 111,896 11,552 29,739
0.91–1.23 Ref. 0.75–1.15
0.93
0.72
18,575 137,880 53,032 61,777 23,071 840
1.05 1.00 0.93
1.00 0.84 0.83 0.80 0.96
Ref. 0.70–1.00 0.68–1.02 0.65–0.97 0.75–1.20
0.67
0.75–1.12 Ref. 0.98–1.50
0.5
0.82 1.00 1.23
0.67–1.00 Ref. 1.00–1.53
0.003
519 477 7
75,688 80,063 1544
1.00 0.81
Ref. 0.72–0.92
1.00 0.88
Ref. 0.76–1.02
519 240 98 136 10
75,688 40,373 17,294 21,940 2000
1.00 0.82 0.78 0.82
Ref. 0.70–0.95 0.63–0.96 0.68–0.99
1.00 0.88 0.83 0.89
Ref. 0.75–1.02 0.67–1.03 0.74–1.07
0.03
0.35
Ever had stillbirth No Yes Missing
839 37 127
134,490 6529 16,276
1.00 0.96
Ref. 0.69–1.33
1.00 0.89
Ref. 0.64–1.24
Number of miscarriages 0 1 2+ Missing
592 197 97 117
94,265 31,130 16,353 15,547
1.00 1.00 0.93
Ref. 0.85–1.17 0.75–1.15
1.00 1.01 0.88
Ref. 0.86–1.18 0.71–1.09
G.C. Kabat et al. / Cancer Epidemiology 49 (2017) 1–7
5
Table 2 (Continued) N of cases
N of non-cases
HRa
95% CI
HRb
95% CI
Hysterectomy No Yes Missing
538 462 3
91,424 65,788 83
1.00 1.21
Ref. 1.07–1.37
1.00 1.09
Ref. 0.95–1.25
Bilateral oophorectomy No Yes Missing
746 231 26
123,116 30,717 3462
1.00 1.23
Ref. 1.06–1.43
1.00 1.13
Ref. 0.97–1.31
a
Age-adjusted hazard ratios. Adjusted for age (continuous), smoking status (never smoked, former smoker, current smoker), pack-years of smoking (continuous), body mass index (kg/m2continuous), educational level (less than high school grad, high school grad/some college, college grad, post-college), ethnicity (white, black, other), allocation to the OS or treatment/placebo/control arm of clinical trials, and diabetes (reported at enrollment or taking anti-diabetes medication at a subsequent visit) as a time-dependent covariate. b
Table 3 Exogenous hormone use and risk of pancreatic cancer in the Women’s Health Initiative. N of cases
N of non-cases
HRa
95% CI
HRb
95% CI
662 341 0
91,888 65,404 3
1.00 0.89
Ref. 0.77–1.02
1.00 0.92
Ref. 0.80–1.06
662 75 123 70 73
91,940 14,128 22,028 14,854 14,345
1.00 0.87 0.98 0.82 0.84 0.10
Ref. 0.68–1.10 0.80–1.20 0.64–1.06 0.66–1.07
1.00 0.87 1.01 0.88 0.88 0.26
Ref. 0.68–1.10 0.83–1.23 0.69–1.13 0.69–1.12
Hormone therapy Never Ever Missing
475 528 0
68,740 88,552 3
1.00 0.89
Ref. 0.78–1.00
1.00 0.91
Ref. 0.80–1.03
Hormone therapy status Never used Past user Current user Missing
475 173 354 1
68,740 25,193 63,229 133
1.00 0.96 0.85
Ref. 0.81–1.15 0.74–0.99
1.00 0.96 0.88
Ref. 0.80–1.14 0.76–1.02
475 202 114 212 0
68,740 34,169 19,899 34,481 6
1.00 0.95 0.91 0.82
Ref. 0.80–1.12 0.74–1.12 0.70–0.97
1.00 0.94 0.97 0.84
Ref. 0.80–1.11 0.79–1.20 0.72–1.00
Oral contraceptive use Never Ever Missing
Duration of OC use (yrs) Never <1 1–<5 5–< =10 10 P for trend
Duration of hormone therapy (yrs) Never >0 to <5 5–<10 10 Missing P for trend
0.33
0.29
Type of hormone therapy None Estrogen (E) alone Estrogen + progestin (E + P) Both types Missing
475 310 165 53 0
68,740 47,477 32,384 8691 3
1.00 0.94 0.81 0.84
Ref. 0.81–1.08 0.68–0.97 0.63–1.12
1.00 0.91 0.91 0.87
Ref. 0.79–1.06 0.76–1.09 0.65–1.15
Duration of E alone (yrs) Never >0–<7 7
475 145 165
68,740 20,961 26,515
1.00 1.05 0.86
Ref. 0.87–1.27 0.72–1.02
1.00 1.00 0.87
Ref. 0.83–1.24 0.72–1.04
6
G.C. Kabat et al. / Cancer Epidemiology 49 (2017) 1–7
Table 3 (Continued)
Missing P for trend
Duration of E + P Never >0–<7 7 Missing P for trend
N of cases
N of non-cases
218
41,079
HRa
95% CI
0.10
475 100 65 363
68,740 20,335 12,047 56,173
1.00 0.85 0.78
HRb
95% CI
0.13
Ref. 0.68–1.06 0.60–1.01
0.04
1.00 0.92 0.91
Ref. 0.73–1.15 0.70–1.17
0.40
a
Age-adjusted hazard ratios. b Adjusted for age (continuous), smoking status (never smoked, former smoker, current smoker), pack-years of smoking (continuous), body mass index (kg/m2continuous), educational level (less than high school grad, high school grad/some college, college grad, post-college), ethnicity (white, black, other), allocation to the OS or treatment/placebo/control arm of clinical trials, and diabetes (reported at enrollment or taking anti-diabetes medication at a subsequent visit) as a time-dependent covariate.
strengthened. For example, in the analysis of a Norwegian cohort study [15], neither parity nor duration of breastfeeding was associated with risk when adjusted for only demographic factors; however, when the two variables were mutually adjusted, parity showed a significant positive association, and breast-feeding showed a significant inverse association. We were unable to replicate this finding in our data. Analysis of the largest cohort study [17] failed to provide support for an association with breastfeeding or parity. Furthermore, our results were unchanged when parity and age at first birth among parous women were mutually adjusted. Few studies have addressed the association of exogenous hormone use with risk of pancreatic cancer. Three cohort studies found no association of ever use of oral contraceptives with risk [10,13]; however, longer duration of oral contraceptive use was associated with increased risk in two studies [18,21] but not in other studies [9,11]. Three studies found no association of postmenopausal hormone and risk [10,14,18], but in another study [21] current users of estrogen only therapy, but not of estrogenplus-progestin had reduced risk compared to never users. In a pooled analysis of 11 case-control studies [22], hormone therapy was not associated with risk; however, women who had a hysterectomy and had used hormone therapy were at reduced risk (pooled OR 0.64, 95% CI 0.48–0.84). Our results, together with those of other large cohort studies [9–11,17], suggest that there is little consistent evidence of an association of reproductive or hormonal factors with risk of pancreatic cancer, and that where isolated associations have been reported, these are likely due to chance, confounding, or other biases [6]. A detailed assessment of the evidence in terms of 3 specific hypotheses relating to exposure to estrogen [6] has concluded that there is little support for the hypothesis that hormonal exposures are associated with pancreatic cancer risk. Strengths of the present study include its prospective nature, the large number of cases, and the availability of information on the type of postmenopausal hormone therapy used (estrogen along, estrogen-plus-progestin) and duration of use. Furthermore, because diabetes is a risk factor for pancreatic cancer, we included diabetes as a time-dependent covariate in the analysis. Limitations include the observational nature of the study, the fact that exposures measured at enrollment could have changed during follow-up, leading to misclassification of exposure, and the difficulty of recalling early reproductive events, such as age at menarche and timing of oral contraceptive use, for older women. Finally, WHI is restricted to postmenopausal women; however, pancreatic cancer incidence is low below age 50, and incidence increases sharply with age [3].
5. Conclusion In conclusion, in the present study, several reproductive factors, including parity, age at first birth, and bilateral oophorectomy were associated with risk. However, the associations were modest, and there were no trends with increasing years of exposure. Furthermore, other factors including age at menarche, age at menopause, total years of menstruation, and exogenous hormone use were not associated with risk. Together with the existing literature on this topic, our results suggest that reproductive and hormonal exposures are unlikely to play an important role in the etiology of pancreatic cancer. Authors’ contributions GCK reviewed the literature, analyzed the data, and drafted the paper. VK contributed to the statistical programming. GCK and TER discussed the appropriateness of the analyses and the interpretation of the data. TER gave detailed comments on the manuscript. Funding This work was supported by institutional funds from the Albert Einstein College of Medicine. Conflicts of interest None. Acknowledgements Short list of whi investigators Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller; Clinical Coordinating Center: Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg; Investigators and Academic Centers: (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA)
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Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, WinstonSalem, NC) Sally Shumaker Women’s Health Initiative Memory Study: (Wake Forest University School of Medicine, WinstonSalem, NC) Sally Shumaker.
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