Micaiah Atkins

Assignment 3

IMRAD Article Analysis

Title:
Soy food intake after diagnosis of breast cancer and survival: an in-depth analysis of
combined evidence from cohort studies of US and Chinese women
Authors:
Sarah J Nechuta, Bette J Caan, Wendy Y Chen, Wei Lu, Zhi Chen, Marilyn L Kwan,
Shirley W Flatt, Ying Zheng, Wei Zheng, John P Pierce, and Xiao Ou Shu
Introduction:
Soy contains a type of organic compound called isoflavone, which may have
estrogenic properties such as mimicking estrogen and competitively binding to its
hormone receptors. Some previous research shows that estrogenic properties of soy,
when eaten in combination with anti-breast cancer drug tamoxifen, may inhibit breast
cancer tumor growth. Very little epidemiological data has been conducted to date on the
association between post-diagnosis soy consumption and breast cancer outcomes. To
address this the researchers conducted a longitudinal cohort study with US and
Chinese women to investigate the effects of soy intake on breast cancer using the After
Breast Cancer Pooling Project (ABCPP).
Methods:
The ABCPP method includes pooled data from 18,314 breast cancer survivors
from four prospective cohort studies in the US and China. The data was adjusted for
age and other confounding factors. Soy food intake was assessed using validated food-
frequency questionnaires. The survey collected data on nutrient and food intake,
particularly asking about 14 soy food items. Soy isoflavone intake for each woman was
derived based on the known isoflavone content of the soy food products listed on the
survey. A control was conducted using 200 participants who completed a baseline food
frequency questionnaire. It was found that 24-hour dietary recalls were 0.49 for soy food
and 0.41-0.66 for other food groups.
Treatment information was obtained for each woman, including tumor
characteristics and hormone levels of estrogen and progesterone, using self-reporting
via interview. These data were validated by reviewing medical records.
Participants in each of the four cohorts were evaluated for breast cancer
outcome including total mortality, breast cancer-specific mortality, and breast cancer
recurrence rates. These outcomes were obtained via in-person interviews 18, 36, and
60 months after diagnosis. This information was not supplemented with medical
records, however previous research has shown recurrence data based on self-reporting
to be reliable.
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Assignment 3

After excluding some data based on lack of isoflavone intake information, stage
IV tumors, or death before follow-up assessment, statistical analysis of the remaining
data collected was completed for each of the participants. The pooled results were
analyzed using soy isoflavone cutoffs in milligrams per day of <4, 4-9.99, and >10.
Delayed-entry Cox proportional hazard regression models were used to estimate 95%
confidence intervals. A Q statistic was used to test for heterogeneity in risk estimates
across the four cohort studies. Other confounding factors were included to adjust for
different clinical predictors of disease outcome including socioeconomic status,
hormone levels, chemotherapy or radiation treatment given, education, race/ethnicity,
physical activity, smoking, vegetable intake, BMI, menopause, and family history. All
confounding factors except family history were found to have a statistically significant
association with isoflavone intake. These potential interactions were tested using the –2
log likelihood ratio test statistic. In particular cancer stage, hormone levels, and
radiotherapy treatment use were evaluated with respect to survival time. For all
statistical analysis a P value greater than 0.05 was considered significant.
Results:
At the conclusion of the study, the mean follow-up time for participants was 7.4
years post-diagnosis. A total of 1171 deaths and 1348 cancer recurrences had been
recorded. The mean soy isoflavone intake was significantly higher overall for women in
the Chinese cohort (~45.9 mg/day) than for US women (~3.2 mg/day). For both US and
Chinese women, higher soy isoflavone intake was correlated with higher levels of
exercise and cruciferous vegetable intake, lower BMI, higher levels of education, and
non-smoking. Using the common cutoff of greater than or equal to 10 mg soy isoflavone
per day, all-cause and cancer-specific mortality were significantly reduced, along with a
significant reduction in breast cancer recurrence. This inverse association between soy
consumption and mortality was stronger for breast cancer death than for mortality due
to other causes. In this highest decile of soy isoflavone intake, risk of breast cancer
death was reduced by 29% and risk of recurrence was reduced by 36% (both with 95%
confidence interval). In China, consumption of more than 10 mg/day of isoflavone was
associated with only marginal reduction in recurrence risk while this reduction was
significant for US women. Additionally, the association was stronger for women whose
tumors did not grow in response to estrogen and for post-menopausal women. When
analyzed in conjunction with anti-cancer drug tamoxifen, users with higher isoflavone
intake had a reduced risk of recurrence compared to women who did not take the drug
and consumed less isoflavone.
Discussion:
This study found that consumption of at least 10 mg soy isoflavone per day post
breast cancer diagnosis was significantly associated with reduced all-cause and cancer-
specific mortality, as well as reduced risk of breast cancer recurrence. This inverse
association was observed in cohort studies of both US and Chinese women. Data
showed that overall Chinese women consumed many more milligrams of soy isoflavone
Micaiah Atkins
Assignment 3

per day than US women. Differences were also observed in confounding factors
between the US and Chinese cohort studies. Despite this, the inverse association
between soy isoflavone intake and positive breast cancer outcome was statistically
significant and consistent across both populations. One unique finding was that the
association was most significant in women with ER-negative tumors, meaning they don’t
grow in response to estrogen. One explanation presented for this is that the protective
effects of soy are more apparent in this group due to the poorer prognosis of the
disease. Additionally, a multiplicative interaction was discovered in which tamoxifen
users showed a greater decrease in recurrence and mortality risk. This runs contrary to
previous studies that had shown that the estrogenic properties of estrogen may interrupt
the efficacy of tamoxifen. The large sample size of this study allowed for more
statistically significant interactions to be uncovered. Several limitations of the study
include possible confounding factors not accounted for that may skew data, as well as
differences in data collection techniques across the four cohorts. Overall, this study is
the largest to date on influence of soy consumption on breast cancer post-diagnosis. It
is also the first to consider data on both US and Chinese women.
Article Analysis:
Is the topic of the paper somewhat original?
The topic of this paper is very original in that it explores a very recent and not yet
highly researched field of how nutrition relates to prevention and treatment of disease.
This study is the largest to date to conduct an exploration of the influence of soy
isoflavone consumption on breast cancer mortality and recurrence. It is also the first of
its kind to include cohort studies from around the world. The authors analyzed data from
women in the US and in China. This allowed them to draw conclusions that were
consistent across different populations, as well as find differences between the two
populations. Another quality that makes this study unique was its findings, which at
times contradicted previous research. Unlike earlier research that provided data
showing that soy isoflavones may interrupt the action of anti-cancer therapy tamoxifen,
this study concluded that in fact the opposite was the case. There is also a pervasive,
popular idea that phytoestrogens in soy may increase estrogen levels and possibly
make men more “feminine”. The topic of this paper is unique to address this myth and
draw conclusions that directly contradict it.
Who sponsored the study?
This research study is sponsored by the American Society for Nutrition as well as
the National Cancer Institute at NIH. The paper was published in the American Journal
of Clinical Nutrition.
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Assignment 3

What was the aim of the study? What hypothesis did the researchers test? Are the
conclusions reached (assuming they are valid) important to you and others (explain)?
The aim of this study was to investigate the association between post-diagnosis
soy food consumption and breast cancer outcomes among Chinese and US women.
This was accomplished using data from the After Breast Cancer Pooling Project. The
researchers conducted a prospective cohort study, where they followed groups of
women immediately post breast cancer diagnosis to assess relationships between
multiple risk factors. Because of the nature of this research method, no individual
hypothesis was tested. However, the researchers explored the connection between soy
isoflavone consumption and breast cancer outcomes. They also explored confounding
risk factors to illuminate how these affected the interactions between isoflavone and
breast cancer. Among the significant risk factors tested were how the tumor responds to
estrogen and progesterone, age of the participant, and whether she also took anti-
cancer therapy tamoxifen.
The conclusions reached in the study are important both to me personally and to
the public. My grandmother passed away recently from breast cancer, and being a
Jewish woman I carry genetic factors that increase my risk of developing the disease.
The results of this study showing the decrease in mortality and recurrence are
encouraging to me and make me feel excited for the future research in this field that will
help me and women like me to avoid developing breast cancer and fight it more
effectively if we do. On top of this, the results of the study are an important link in a
relatively new but growing field of research exploring nutrition and its relationship to
preventing and treating disease. I expect that new studies based on this research paper
can be proposed such as studying any preventative measures of soy for breast cancer
or exploring other dietary factors in cancer risk.
Are both P values and confidence intervals reported?
Both P values and confidence intervals are consistently reported in the Methods
and Results portions of the paper. In this study the authors defined statistical
significance as a 95% confidence interval. Any results that fell below this were stated in
Results and explained in Discussion, however they were noted as being an insignificant
correlation. P values were provided for each significant data correlation. Most had a P
value of 0.05, while some had P<0.01. Those with P values over this were not
considered statistically significant.
Are the results plausible?
The results of this study are plausible and well supported by the authors’ data.
Soy isoflavones mimic estrogen molecules, which is what has led to the belief that it
may increase estrogen levels by consuming it. This study and others have shown,
however, that soy consumption may actually block the effects of estrogen by
competitively binding to the hormone receptor. Because of this mechanism it is
plausible that soy consumption would be inversely proportional to breast cancer
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Assignment 3

mortality and recurrence rates. This interaction was particularly strong among women
whose tumors don’t grow in direct response to estrogen. This reinforces the proposed
mechanism, and is likely due to the poor prognosis of this variety of breast cancer.
Women in China, who eat on average significantly more soy products than US women,
had generally better breast cancer outcomes and fewer confounding factors which
further reinforced the plausibility of the study’s results.
Are the results consistent with those of other studies?
Overall, this study is consistent with results of other recent publications. Other
studies have established the antiestrogenic and anticancer properties found in soy, and
identified the root of these properties as the phytoestrogen isoflavone compound. The
authors cited several papers which identified the link between increased soy food
consumption and lower risk of developing breast cancer. However, there is one
conclusion drawn in this study which is not consistently supported by previous studies.
Past research has provided mixed conclusions on the effects of soy and its potential to
interrupt the action of the anti-cancer therapy tamoxifen. While some studies cited in the
paper showed that dietary soy isoflavone in combination with tamoxifen treatment
inhibited cancer growth, others reported that the effectiveness of tamoxifen was
reduced. The research in this study concluded that the strongest inverse association
between increased soy consumption and decreased mortality and recurrence rate was
found when women were undergoing tamoxifen therapy.
Have the authors discussed possible limitations of the study?
In the Discussion and Conclusion portion of the paper the authors addressed six
potential limitations of their work. One was the potential for confounding lifestyle factors
not accounted for in the statistical analysis. These factors have the potential to lower the
statistical power of the study and can potentially skew results. A second was that across
the four cohorts studied there were differences in the time between initial cancer
diagnosis and baseline soy food assessments. The third was a lack of detailed
information on tamoxifen therapy used, such as the length of treatment, that could
disrupt results on the multiplicative interaction between tamoxifen and soy. The fourth
limitation was the exclusion of a new treatment (aromatase inhibitors) that became
popular only after the study had begun. Fifth was any potential differences between
cohorts in the reliability of self-reported soy consumption. Finally, the sixth possible
limitation mentioned was the potential for misclassification of some food items in the
questionnaires due to increasing trends of adding soy protein powder to food in the US.