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Annals of Oncology
Annals of Oncology 23: 1488–1493, 2012
doi:10.1093/annonc/mdr475
Published online 2 November 2011
Proanthocyanidins and other flavonoids in relation to
pancreatic cancer: a case–control study in Italy
M. Rossi1,2*, A. Lugo1, P. Lagiou3,4, A. Zucchetto5, J. Polesel5, D. Serraino5, E. Negri1,
D. Trichopoulos3,6 & C. La Vecchia1,2,7
1
Department of Epidemiology, ‘‘Mario Negri’’ Institute for Pharmacological Research, Milan; 2Department of Occupational Medicine, University of Milan, Milan, Italy;
Department of Epidemiology, Harvard School of Public Health, Boston, USA; 4Department of Hygiene, Epidemiology and Medical Statistics, University of Athens
Medical School, Athens, Greece; 5Unit of Epidemiology and Biostatistics, IRCCS Centro di Riferimento Oncologico, Aviano, Italy; 6Bureau of Epidemiologic Research,
Academy of Athens, Athens, Greece; 7International Prevention Research Institute (IPRI), Lyon, France
3
Received 6 June 2011; accepted 13 September 2011
Background: Four cohort studies have examined the relation between flavonoids and pancreatic cancer risk
providing inconsistent results.
Patients and methods: We conducted a case–control study between 1991 and 2008 in Northern Italy. Subjects
were 326 cases with incident pancreatic cancer and 652 frequency-matched controls (admitted to the same hospitals
as cases for acute non-neoplastic conditions) who answered a reproducible and valid food-frequency questionnaire.
We computed odds ratios (ORs) using logistic regression models conditioned on gender, age and study center, and
adjusted for education, history of diabetes, tobacco smoking, alcohol drinking and energy intake.
Results: Proanthocyanidins with three or more mers were inversely related to pancreatic cancer risk. The ORs were
similar in all classes of polymers with three or more mers and in their combination (OR for the highest versus the
lowest quintile of intake, 0.41; 95% confidence interval 0.24–0.69), and did not substantially change after adjustment
for fruit and vegetable consumption, and for vitamin C and folate intakes. Eating an additional portion of fruits rich
in proanthocyanidins every day reduced the risk of pancreatic cancer by 25%.
Conclusion: Dietary proanthocyanidins—mostly present in apples, pears and pulses—may convey some protection
against pancreatic cancer risk.
Key words: diet, flavonoids, pancreatic cancer, proanthocyanidins, risk
introduction
Flavonoids are a large group of polyphenolic compounds that
are naturally occurring in plants [1]. They are the substances
responsible for the pigmentation of plants and the foods of
plant origin such as red, yellow, orange and dark green
vegetables and fruits. Flavonoids are generally grouped in six
major classes, namely flavanols, flavanones, flavonols,
anthocyanidins, flavones and isoflavones, and a family of
polymers of flavanols without added sugar called
proanthocyanidins [1]. Due to their antioxidant, antimutagenic
and antiproliferative properties in vitro, flavonoids have been
hypothesized to be responsible for the favorable effects of fruits
and vegetables against various chronic diseases, including some
common neoplasms [2, 3]. The availability of reliable food
composition data for the six classes of flavonoids and, more
recently, for proanthocyanidins has allowed epidemiological
studies to investigate the role of flavonoids in cancer risk [4, 5].
Intake of various flavonoids has been inversely, though
inconsistently with respect to specific classes, related to the risk
*Correspondence to: Dr M. Rossi, Department of Epidemiology, Istituto di Ricerche
Farmacologiche ‘‘Mario Negri’’, Via La Masa, 19, Milano 20156, Italy.
Tel: +39-02-39014541; Fax: +39-02-33200231; E-mail: [email protected]
of cancers of the upper aerodigestive tract [6–10], stomach
[11], colorectum [12–14], urogenital tract [15–17] and breast
[18]. Of these studies, only three investigations included data
also on proanthocyanidins reporting inverse associations with
the risk of stomach, colorectal and lung cancers [10, 13, 19].
With respect to pancreatic cancer, it is still unclear whether
diet may affect the risk of this tumor. There is a some evidence
suggesting that the consumption of fruits and vegetables, in
particular of those containing folate, protects against pancreatic
carcinoma [20]. The pancreas is involved in digestion, and it
seems reasonable to consider diet among the possible causal
factors for this tumor [21]. Unlike other parts of the
gastrointestinal tract, however, the pancreas is never exposed to
ingested foods or their modified products. The effects of diet on
pancreatic carcinogenesis must be via changes in the internal
metabolic environment of that organ [21]. In a murine
xenograft study, it has been shown that flavonoids were
absorbed in the circulatory system and were accumulated in
pancreatic cancer cells in vivo [22]. Moreover, studies in vitro
and in vivo showed that flavonoids can act as cancer inhibitors
at various molecular targets of the pancreas (cell cycle, nuclear
factor kB and others) [23, 24]. Flavonoids have also been
suggested for treatment of pancreatic cancer or as an adjuvant
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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original articles
Annals of Oncology
to conventional therapeutic regimens, by increasing the action
of cytostatic drugs and thus allowing decrease of dosages and
reduction of side-effects of the treatment [25, 26].
Four observational studies, all of cohort design, have
examined the relation between flavonoids and pancreatic
cancer risk [27–30]. The Finnish Alpha-Tocopherol, BetaCarotene Cancer Prevention (ATBC) study [27], a cohort of
27 111 male smokers with 306 pancreatic cancers, found an
inverse association between intake of flavonoids (computed as
the sum of selected flavanols, flavones and flavonols) and
pancreatic cancer incidence [hazard ratio (HR) 0.36, 95%
confidence interval (CI) 0.17–0.78 for the highest versus the
lowest quartile, P for trend 0.009] in subjects not consuming
supplemental a-tocopherol and/or b-carotene. In the
multiethnic cohort of 183 518 participants (529 cases of
pancreatic cancer) from Hawaii and California [28], intake of
flavonols was inversely related to pancreatic cancer risk among
current smokers (HR 0.41, 95% CI 0.22–0.74 for the highest
versus the lowest quartile, P for trend 0.002). Results from the
Iowa Women’s Health Study cohort of 34 651 postmenopausal
women (130 cases of pancreatic cancer) [29] point to
a nonsignificant inverse trend in risk for pancreatic cancer with
increasing intake of catechins (belonging to flavanols) (HRs
across quartiles: 1.00, 0.56, 0.53 and 0.74). A Finnish cohort of
62 440 subjects (29 cases of pancreatic cancer) reported fewer
cases among those with higher intake of flavonoids (computed
as the sum of selected flavones and flavonols), although the
inverse association was not significant [30]. To our knowledge,
no study has evaluated proanthocyanidins in relation to the risk
of pancreatic cancer.
We investigated whether flavonoids, including
proanthocyanidins, were associated with pancreatic cancer risk
in an Italian multicentric case–control study, in which the
consumption of fruits and vegetables has been found to be
inversely related to pancreatic cancer risk [31].
A reproducible [33] and validated [34] food-frequency questionnaire
(FFQ) was used to assess the usual diet during the 2 years before diagnosis
(for cases) or hospital admission (for controls). The FFQ included
78 foods, food groups or recipes. An additional section collected data on
history of consumption of five alcoholic beverages. Subjects were asked to
indicate the average weekly frequency of consumption for each dietary
item; intakes less than once a week, but at least once a month, were coded
as 0.5 per week.
We obtained food and beverage content of six classes of flavonoids
(flavanols, flavanones, flavonols, anthocyanidins, flavones and
isoflavones) and six classes of proanthocyanidins (monomers, dimers,
trimers, 4–6 mers, 7–10 mers, >10 mers) from databases developed by the
USA Department of Agriculture [5, 35], supplemented with others
sources when needed [36]. Nutrient and energy intakes were computed
using an Italian food composition database, integrated with other
published data [37].
Major flavonoids included in the six classes are epicatechin and catechin
for flavanols; hesperetin and naringenin for flavanones; quercetin for
flavonols; malvidin for anthocyanidins; cyanidin, apigenin and luteolin for
flavones and genistein for isoflavones. In our population, the major sources
of flavonoids in order of importance were tea, apples, pears and wine for
flavanols; citrus fruits and juices for flavanones; apples, pears and various
common vegetables for flavonols; wine, strawberries, cherries and onions
for anthocyanidins; cooked vegetables and tea for flavones; and soy, soy
products and pulses for isoflavones. Given the low consumption of
soybeans in our population, intake of isoflavones could not be reliably
estimated and we excluded this class from the analysis.
Procyanidins (polymers of [epi]-catechin) are the most common
proanthocyanidins in foods, and prodelphinidins (derived from [epi]gallocatechin) and propelargonidins (derived from afzelechin) have been
also identified [5]. Analytical technology does not allow quantification of
proanthocyanidins according to their type linkage but only according to
their degree of polymerization. The major food sources of combined
monomer and dimer proanthocyanidins were apples, pears, chocolate,
peaches, apricots, prunes and tea besides wine and those of
proanthocyanidins with three or more mers were apples, pears, pulses,
peaches, apricots and prunes besides wine.
materials and methods
statistical analysis
We conducted a case–control study of pancreatic cancer between 1991 and
2008 in the province of Pordenone and in the greater Milan area, Northern
Italy [32]. Cases were 326 patients (174 men and 152 women; median age
63 years, range 34–80) with incident pancreatic cancer, admitted to major
teaching and general hospitals in the study areas, diagnosed no longer than
1 year before the interview and with no previous diagnosis of cancer.
Controls were 652 patients (348 men and 304 women; median age 63 years,
range 34–80) admitted to the same hospitals as cases for a wide spectrum of
acute non-neoplastic conditions, unrelated to smoking, alcohol
consumption or long-term modifications of diet. They were admitted for
traumatic orthopedic disorders (31%), other orthopedic disorders (31%),
acute surgical conditions (28%) and miscellaneous other illnesses, including
eye, nose, ear, skin or dental disorders (10%). Controls were frequency
matched to cases by gender, age and study center with a control-to-case
ratio of 2:1. Less than 5% of cases and controls approached refused to
participate.
Trained interviewers administered a structured questionnaire to cases
and controls during their hospital stay. The questionnaire included
information on sociodemographic characteristics, anthropometric
measures, selected lifestyle habits (e.g. tobacco smoking, alcohol drinking),
personal medical history, family history of cancer and, for women,
menstrual and reproductive factors.
Volume 23 | No. 6 | June 2012
Odds ratios (ORs) for pancreatic cancer and their corresponding 95%
confidence intervals were estimated using conditional multiple logistic
regression models [38] conditioned on gender, age (quinquennia,
categorically), and study center. Quintiles based on the distribution of
controls were computed both directly on the flavonoids and on the
residuals of the regression of flavonoids on energy [39]. Since both analyses
yielded similar results, only findings from the first approach are presented.
All the regression models included terms for year of interview
(continuously), years of education (<7, 7–11, ‡12, categorically), history of
diabetes, tobacco smoking (never, ex, current smokers of <15 and of ‡15
cigarettes per day, categorically), alcohol drinking (never and current
drinkers of <0.5 and ‡0.5 drink per day, categorically), number of drinks
per day (continuously) and non-alcohol energy intake (quintiles,
categorically). Ex-drinkers were included in the category of drinkers.
Additional models included terms for intakes of vitamin C, vitamin E,
potassium and folate (continuously). Besides quintiles, flavonoids were
entered in the model as continuous variables, with the measurement unit
set at one standard deviation of the distribution of controls.
Tests for trend were based on the likelihood ratio test between models
with and without a linear term for each class of flavonoids and
proanthocyanidins.
Given the high correlation between some classes of proanthocyanidins,
we combined monomers with dimers, as well as polymers with three or
doi:10.1093/annonc/mdr475 | 1489
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Annals of Oncology
more mers. We further investigated foods rich in proanthocyanidins with
three or more mers and their combination.
results
Table 1 shows the distribution of 326 cases of pancreatic cancer
and 652 controls according to gender, age and other selected
covariates. By design, cases and controls had similar
distribution by gender, age and study center. Cases were more
frequently smokers than controls, and the proportion of
subjects reporting a history of diabetes was higher in cases than
in controls.
Table 2 shows the distribution of cases according to quintiles
of flavonoids among controls. The mean daily intake among
controls was 63.4 mg for flavanols, 36.2 mg for flavanones, 24.7
mg for flavonols, 18.6 mg for anthocyanidins, 0.5 mg for
flavones, 103.5 mg for monomer and dimer proanthocyanidins
combined and 261.7 mg for proanthocyanidins with three or
more mers.
Table 3 gives the ORs of pancreatic cancer according to
quintiles of intake and continuous ORs for the studied
compounds. Inverse associations were evident for
proanthocyanidins with three or more mers: the ORs were
similar in all classes of polymers with three or more mers, as
well as in their combination (OR for the highest versus
the lowest quintile of intake, 0.41; 95% CI 0.24–0.69; P for
trend = 0.001). Weak inverse associations were also found for
Table 1. Distribution of 326 patients with pancreatic cancer and 652
control patients according to gender, age, education and other selected
variables (Italy, 1991–2008)
Characteristic
Cases
No. (%)
Gender
Men
174
Women
152
Age (years)
<50
32
50–59
89
60–69
122
‡70
83
Center
Milan
151
Aviano/Pordenone
175
Education (years)a
<7
166
7–12
86
‡12
72
Smoking statusa
Never smokers
137
Ex-smokers
88
Current smokers (cigarettes per day)
<15
35
‡15
63
History of diabetes
No
269
Yes
57
a
Controls
No.(%)
(53.4)
(46.6)
348 (53.4)
304 (46.6)
(9.8)
(27.3)
(37.4)
(25.5)
64
178
244
166
(46.3)
(53.7)
302 (46.3)
350 (53.7)
(51.2)
(26.5)
(22.2)
350 (53.9)
192 (29.5)
108 (16.6)
(42.4)
(27.2)
328 (50.5)
195 (30.0)
(10.8)
(19.5)
59 (9.1)
67 (10.3)
(82.5)
(17.5)
(9.8)
(27.3)
(37.4)
(25.5)
615 (94.3)
37 (5.7)
The sum does not add up to the total because of some missing values.
1490 | Rossi et al.
flavanones (P for trend = 0.04) and flavonols (P for trend = 0.06).
No noticeable associations emerged for other flavonoids
including flavanols, anthocyanidins, flavones and monomer
and dimer proanthocyanidins. After adjustment for fruit and
vegetables, the ORs for flavonoids and proanthocyanidins did
not substantially change. After adjustment for vitamin C intake,
the OR for proanthocyanidins with three or more mers for
the highest versus the lowest quintile of intake changed from
Table 2. Distribution of 326 patients with pancreatic cancer according
to quintiles of flavonoid intakes among controls (Italy, 1991–2008)
Mean (SD)a Quintiles of flavonoid intakeb
1
2
3
4
5
Flavanols (mg)
Upper cut-off point
Cases
Flavanones (mg)
Upper cut-off point
Cases
Flavonols (mg)
Upper cut-off point
Cases
Anthocyanidins (mg)
Upper cut-off point
Cases
Flavones (mg)
Upper cut-off point
Cases
Proanthocyanidins
<3 mers (mg)
Upper cut-off point
Cases
Monomers (mg)
Upper cut-off point
Cases
Dimers (mg)
Upper cut-off point
Cases
Proanthocyanidins
‡3 mers (mg)
Upper cut-off point
Cases
Trimers (mg)
Upper cut-off point
Cases
4–6 mers (mg)
Upper cut-off point
Cases
7–10 mers (mg)
Upper cut-off point
Cases
>10 mers (mg)
Upper cut-off point
Cases
63.4 (57.8)
23.8
80
38.9
56
56.6
57
97.7 —
70
63
9.6
67
24.6
78
34.7
65
61.0 —
57
59
13.9
78
18.0
59
23.9
64
31.1 —
48
77
4.5
64
11.0
61
18.6
60
31.1 —
59
82
0.3
67
0.4
58
0.5
64
0.7 —
67
70
45.7
66
73.7 103.4 149.2 —
66
59
56
79
19.1
66
32.1
64
44.6
59
65.4 —
56
81
26.1
70
42.2
65
58.8
58
82.9 —
54
79
36.2 (32.7)
24.7 (18.8)
18.6 (16.8)
0.5 (0.3)
103.5 (71.5)
45.2 (32.6)
58.3 (39.3)
261.7 (129.9)
158.1 216.3 270.1 366.9 —
89
64
67
54
52
20.4 (11.1)
11.1
76
16.1
73
20.9
66
28.7 —
62
49
40.0
83
55.9
67
70.6
62
96.8 —
62
52
32.3
84
45.3
74
56.7
61
77.6 —
57
50
72.3
90
97.1 120.2 160.4 —
58
62
59
57
69.1 (35.5)
55.5 (28.7)
116.7 (56.5)
a
Mean intake and SD among controls.
Computed among controls. Number of controls across quintiles could
slightly vary between 129 and 131 according to the distributions of each
class of flavonoids and proanthocyanidins.
SD, standard deviation.
b
Volume 23 | No. 6 | June 2012
original articles
Annals of Oncology
0.41 to 0.57 (95% CI 0.33–0.98), whereas after adjusting for
folate intake, the OR changed to 0.50 (95% CI 0.29–0.84).
For all other flavonoids, the associations with pancreatic
cancer risk disappeared after adjusting for vitamin C or folate.
Table 4 shows the OR of pancreatic cancer according to the
number of portions per day of selected foods rich in
proanthocyanidins with three or more mers. The combination
of apples, pears, pulses, peaches, apricots and prunes was
inversely associated with the risk of pancreatic cancer: the OR
for three or more portions versus less than half portion per day
was 0.34 (95% CI 0.17–0.66) and the continuous OR per one
portion per day was 0.75 (95% CI 0.64–0.88). We found similar
ORs for combined consumption of apples and pears only.
discussion
We found that proanthocyanidins with three or more mers
were inversely related to the risk of pancreatic cancer, even after
adjusting for fruit and vegetable consumption or for vitamin C
or folate intake. We then examined the major food sources of
Table 3. Odds ratios (ORs)a for pancreatic cancer and corresponding 95% confidence intervals (CIs) according to quintiles of flavonoid intakes (Italy,
1991–2008)
Quintiles of flavonoid intakeb
1d
2
3
Flavanols
Flavanones
Flavonols
Anthocyanidins
Flavones
Proanthocyanidins <3 mers
Monomers
Dimers
Proanthocyanidins ‡3 mers
Trimers
4–6 mers
7–10 mers
>10 mers
1
1
1
1
1
1
1
1
1
1
1
1
1
0.74
1.31
0.68
0.91
0.74
1.03
1.08
0.87
0.56
0.82
0.64
0.69
0.50
(0.46–1.20)
(0.83–2.09)
(0.42–1.08)
(0.55–1.49)
(0.45–1.20)
(0.64–1.67)
(0.62–1.65)
(0.54–1.42)
(0.36–0.89)
(0.52–1.30)
(0.41–1.02)
(0.44–1.08)
(0.31–0.80)
0.65
0.95
0.72
0.75
0.93
0.77
0.73
0.71
0.63
0.72
0.61
0.58
0.57
4
(0.39–1.08)
(0.59–1.52)
(0.44–1.19)
(0.44–1.27)
(0.57–1.51)
(0.45–1.30)
(0.43–1.24)
(0.42–1.19)
(0.40–1.01)
(0.45–1.16)
(0.38–0.98)
(0.36–0.94)
(0.36–0.92)
0.85
0.89
0.41
0.72
0.81
0.67
0.69
0.59
0.49
0.62
0.59
0.56
0.53
5
(0.52–1.40)
(0.54–1.47)
(0.24–0.70)
(0.40–1.30)
(0.49–1.35)
(0.38–1.17)
(0.39–1.22)
(0.34–1.03)
(0.30–0.81)
(0.38–1.01)
(0.36–0.96)
(0.34–0.92)
(0.32–0.85)
0.63
0.68
0.69
0.83
0.88
0.72
0.82
0.68
0.41
0.46
0.41
0.41
0.48
(0.38–1.03)
(0.41–1.14)
(0.42–1.13)
(0.43–1.60)
(0.53–1.46)
(0.39–1.34)
(0.45–1.51)
(0.36–1.26)
(0.24–0.69)
(0.27–0.77)
(0.25–0.71)
(0.24–0.69)
(0.29–0.81)
v2 trend ordinal
(P-value)
OR continuousc
0.17
0.04
0.06
0.38
0.83
0.16
0.28
0.10
0.001
0.002
0.002
<0.001
0.01
0.98
0.85
0.90
1.10
0.97
0.92
0.96
0.90
0.76
0.77
0.76
0.75
0.77
(0.84–1.14)
(0.72–1.00)
(0.76–1.07)
(0.89–1.35)
(0.83–1.13)
(0.75–1.13)
(0.78–1.17)
(0.73–1.11)
(0.64–0.91)
(0.65–0.92)
(0.63–0.90)
(0.63–0.90)
(0.65–0.92)
a
Estimates from conditional logistic regression models conditioned on gender, age and center of study, and adjusted for year of interview, education, history
of diabetes, tobacco smoking, alcohol drinking and non-alcohol energy intake.
b
Computed among controls.
c
Estimated for an increment of intake equal to 1 standard deviation (computed among controls).
d
Reference category.
Table 4. Odds ratios (ORs)a for pancreatic cancer and corresponding 95% confidence intervals (CIs) according to number of portions of selected foods
rich in proanthocyanidins with three or more mers, and their combination (Italy, 1991–2008)
No of portions per day of proanthocyanidins rich foods
<0.5b
0.5 to <1
‡1 to <2
‡2 to <3
Apples and pears
No cases : No controls
121 : 187
OR (95% CI)
1
Pulses
No cases : No controls
276 : 496
OR (95% CI)
1
Peaches, apricots and prunes
No cases : No controls
231 : 453
OR (95% CI)
1
Combination of foodsc
No cases : No controls
40 : 46
OR (95% CI)d
1
3+
v2 trend
ordinal
(P-value)
OR continuous
per one
portion per day
<0.001
0.73 (0.60–0.90)
60 : 91
1.03 (0.66–1.62)
101 : 225
0.67 (0.46–0.97)
34 : 115
0.47 (0.29–0.78)
10 : 34
0.35 (0.15–0.82)
52 : 128
0.73 (0.49–1.09)
4 : 28
0.32 (0.11–0.98)
—
—
—
—
0.016
0.44 (0.22–0.88)
74 : 133
1.05 (0.73–1.52)
21 : 66c
0.75 (0.42–1.31)
—
—
—
—
0.4
0.74 (0.48–1.15)
60 : 92
0.69 (0.38–1.25)
136 : 277
0.49 (0.29–0.83)
61 : 144
0.44 (0.24–0.79)
29 : 93
0.34 (0.17–0.66)
0.001
0.75 (0.64–0.88)
a
Estimates from conditional logistic regression models conditioned on gender, age and center of study, and adjusted for year of interview, education, history
of diabetes, tobacco smoking, alcohol drinking, and non-alcohol energy intake.
b
Reference category.
c
Apples, pears, peaches, apricots, plums, and pulses.
d
One case and four controls with more than two portions of peaches, apricots or plums were included in this category.
Volume 23 | No. 6 | June 2012
doi:10.1093/annonc/mdr475 | 1491
original articles
these compounds and found that eating one more portion of
apples, pears, pulses, peaches, apricots or prunes every day
reduced the risk of pancreatic cancer by 25%. There was also
a suggestion of an inverse association of pancreatic cancer risk
with flavanone and flavonol intakes, which, however,
disappeared after adjustment for other dietary micronutrients.
To our knowledge, no previous studies investigated
proanthocyanidins and flavanones in relation to pancreatic
cancer risk. In the four cohort studies that examined the relation
between flavonoids and pancreatic cancer risk [27–30], only
flavanols, flavones and flavonols have been studied. Of these,
flavonols, in particular kaempferol, were inversely associated
with pancreatic cancer risk in two large cohort studies [27, 28]
but only in selected subgroups of their populations, i.e. among
male smokers in the placebo branch including 79 cases in the
ATBC Study [27] and among current smokers including 80 cases
in the multiethnic cohort [28]. The hazard ratios in these studies
were not adjusted for other dietary factors [20]. In our study, the
weak inverse association between flavonols and pancreatic
cancer risk did not persist after adjusting for vegetables or folate
intake. Flavanols, the monomeric form of proanthocyanidins
with added sugar, have been inversely related to pancreatic
cancer risk in the placebo branch of the ATBC Study [27] and
among postmenopausal women in the Iowa Women’s Health
Study, but in our study, the inverse association was rather weak
and statistically nonsignificant. We also found no association
between flavones and pancreatic cancer, in line with the results of
previous studies [40, 41].
Our results with respect to proanthocyanidins are supported
by several in vitro and in vivo studies reporting that these
compounds have greater antioxidant properties and superior
radical scavenging capacity compared with the monomeric
flavonoids [42–44]. The inverse relation we found between
proanthocyanidins with three or more mers and pancreatic
cancer risk points to apples, the major source of these
flavonoids, as a food with potential beneficial properties against
pancreatic cancer. Few epidemiological studies have
investigated this neoplasm in relation to consumption of apples
and their results have been inconsistent [27, 45, 46], although
apple procyanidins have been suggested to have a strong
anticarcinogenic effect on pancreatic cancer cell [24, 47]. We
also identified a combination of foods inversely associated with
pancreatic cancer that was different from that suggested by
Nothlings et al. [28]. Using data from the multiethnic cohort,
they found a flavonol-based food pattern, consisting mainly of
tea, fruit, cabbage and wine, that was inversely associated to the
risk of pancreatic cancer in that population; they could not,
however, replicate this association in the EPIC study [48].
Besides apples and pears, we found that pulses were strongly
inversely associated with pancreatic cancer risk, in agreement
with other studies [46, 49]. Further studies are needed to
evaluate the role of flavonoids, especially proanthocyanidins
and their food sources, on pancreatic cancer risk.
In our studies, the OR estimates were generally more evident
for women compared with men. This could be due to the fact
that women drink less wine than men. Wine is rich in both
alcohol, which has been reported to increase pancreatic cancer
risk [32], and in flavonoids, some of which are likely to reduce
this risk. Thus, when wine is an important contributor to
1492 | Rossi et al.
Annals of Oncology
proanthocyanidin intake, the favorable effect of these
compounds with respect to pancreatic cancer risk could be
reduced. For this reason, we did not include wine in the
proanthocyanidin-rich food combination that we suggested as
‘protective’ against pancreatic cancer risk.
Cases and controls in our study came from comparable
catchment areas, were interviewed by uniformly trained
interviewers in their hospital settings and were unaware of any
particular dietary hypothesis related to pancreatic cancer,
thereby reducing the likelihood of potential selection and recall
bias [50]. The FFQ was satisfactorily reliable [33] and valid
[34]. Participation among eligible cases and controls was
virtually complete, and we excluded from the control series
patients hospitalized for diseases likely to be related to tobacco
smoking, alcohol consumption or long-term dietary
modifications. Strengths of this study are also the relatively high
number of pancreatic cancer cases, the reliable food
composition databases [33, 34] and the ability to control for
energy and micronutrients intakes. Limitations of the study are
generic concerns about hospital-based case–control studies, and
questions concerning the adaptability of USA flavonoid food
composition data to the Italian diet. Though total flavonoid
intake may have not been accurately estimated in our study,
however, this should not have affected the comparisons
between cases and controls. The same case–control study has
generated results on other pancreatic risk factors that were in
line with those reported from most pancreatic investigations,
a fact that provides some assurance that major biases did not
operate during the implementation of the study [32].
In conclusion, we found compelling evidence that
proanthocyanidins with three or more mers and foods rich in
them are inversely associated with pancreatic cancer risk. These
compounds deserve to be further investigated as possibly
contributing against the risk of developing this serious malignancy
for which few therapeutic options are currently available.
acknowledgements
The authors thank Ivana Garimoldi for editorial assistance.
funding
This work was supported by the Italian Association for Cancer
Research (n.10068), Milan, Italy. The work in this paper was
partially supported by Assomela.
disclosure
The authors declare no conflicts of interest.
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