Keywords:
Breast neoplasms - Obesity - Prognosis.
Descritores:
Neoplasias mamárias - Obesidade - Prognóstico.
INTRODUCTION
Breast cancer is the most common malignant neoplasm in women.[1] Determinant risk factors include reproductive history, family history, and lifestyle.
These factors are responsible for clinical and pathological differences.[2] Although widely studied, the main risk factors associated with the occurrence of
breast cancer in women from different regions of Brazil are poorly understood perhaps
because of the large geographical area involved in Brazilian studies.
Previous Brazilian studies suggest classic risk factors for breast cancer development
and aggressiveness such as aging and menopausal status.[3]
[4] Other studies show more complex associations such as more aggressive disease and
worse prognostic tumors such as triple-negative tumors in overweight and/or obese
women.[5] Factors such as social vulnerability[6] and history of psychological stress[7] are also possible risks particularly in southern Brazil. These factors do not explain
the occurrence of disease alone and have been widely reported as associated with each
other.
Thus, we seek more detailed information about the profile of breast cancer patients
in Brazil where studies on regional risk factors are still scarce and inconclusive.
There is no official documentation of such data from specific regions of the country
including southwestern Paraná. Thus, this study characterized the epidemiological
profile and possible regional risk factors identified in women diagnosed with breast
cancer treated between 2015 and 2017 in a cancer referral hospital of 27 municipalities
that make up the 8th Regional Health of Paraná.
METHODS
This is a retrospective descriptive observational study which proposal was submitted
to the Institutional Ethics and Human Research Committee approved under the CAAE (certificate
of presentation of ethical appreciation) number 35524814.4.0000.0107 and under opinion
No. 810.501. All participants gave informed consent on the study objectives. Their
anonymity was ensured, and they could withdraw at any time. The inclusion criteria
were patients referred for surgery with lesions suggestive of unilateral infiltrative
ductal carcinoma (ICD) at any clinical stage attended by the Francisco Beltrão Cancer
Hospital from May 2015 to August 2017. These patients were from the 8th Regional Health of Paraná covering an estimated population of 350,000 inhabitants
located at 27 municipalities ([Figure 1]).
Figure 1 Geographic limitation of the study population corresponding to the Eighth Health
Region of Western Paraná and its municipalities.
Patients who do not meet this criterion were excluded. Thus, from this initial cohort
of 200 women, there were 126 women with a histologicallyconfirmed diagnosis of breast
cancer by biopsy. These women had complete clinicopathological data for subsequent
frequency analysis. The medical records were consulted for data collection.
The data were compared for possible existing correlations with age at diagnosis; tumor
size; histological grade; expression pattern of receptors and molecular subtypes;
lymph node invasion; presence of angiolymphatic emboli; TNM (tumor, lymph nodes, and
metastasis) clinicopathological staging; menopausal status; body mass index (BMI);
and recurrence risk stratification. Data were categorized and analyzed using Statistical
Package for Social Science (SPSS) statistical software (version 25.0.0, IBM) to obtain
the frequencies and apply the chi-square test and logistic regression analysis. Only
the significant correlations/associations were shown in the results, considering p<0.05 as significant.
RESULTS
This study compiled sequential data from 200 serially collected biopsy specimens from
women presenting with lesions suggestive of breast cancer diagnosed by imaging exams
such as mammography, ultrasound, or magnetic resonance imaging (MRI) as well as physical
examination. Ten patients were excluded due to a lack of clinicopathological data.
Of the 190 samples, 127 were confirmed as breast cancer (66.8%). One patient was excluded
for a lack of sufficient data leaving 126 participants.
Since there was no statistically significant difference between the overweight and
obese groups (the obese group was only 6% of the sample), we decided to combine these
two BMI categories into one group and compare them with the eutrophic patients. [Table 1] shows the main clinicopathological findings regarding such groups.
Table 1
Clinicopathological data of breast cancer patients distributed according to their
trophic-adipose levels
|
Subgroups
|
Eutrophic
|
Overweight/obese
|
|
Percentage of individuals
|
57.1%
|
42.9%
|
|
Molecular subtypes Luminal A
|
34.5%
|
65.5%
|
|
Luminal B
|
37.0%
|
63.0%
|
|
Luminal HER-2
|
60.0%
|
40.0%
|
|
HER-2
|
50.0%
|
50.0%
|
|
Triple negative
|
31.8%
|
68.2%
|
|
Histological grade Low
|
32.3%
|
67.7%
|
|
Intermediate
|
42.6%
|
57.4%
|
|
High
|
29.6%
|
70.4%
|
|
Tumor size Up to 1cm
|
66.7%
|
33,3%
|
|
1-2cm
|
45.2%
|
54.8%
|
|
2-5cm
|
37.5%
|
62.5%
|
|
Over 5cm
|
5.9%
|
94.1%
|
|
Recurrence Yes
|
35.0%
|
65.0%
|
Legends: LN - = Negative lymphnodal commitment; LN + = Presence of lymphnodal metastasis;
HER-2 = Human epidermal growth factor receptor 2.
We found that 57.1% of the patients were overweight at diagnosis, and the mean BMI
was 27.54kg/m2 (18.22kg/ m2 to 44.15kg/m2, [Figure 2]). Regarding the frequency of molecular subtypes of tumors, 68.3% of patients with
triple-negative tumors fell into the overweight subgroup with an equal distribution
of the other subtypes between the eutrophic and overweight groups. Further, overweighed/obese
patients had larger tumors: 62.5% of tumors with diameters between 2 to 5cm and 94.1%
of tumors with diameter greater than 5cm.
Figure 2 Distribution of women with breast cancer included on the study according their body
mass index (BMI). The boxplot expresses the average (central-line) and the minimum
and maximum gap.
There was also a predominance of high histological grade tumors in overweight/obese
patients (70.4% of the tumors diagnosed in the study within this category), with a
high recurrence rate (65%). Statistical analyses ([Table 2]) showed significant associations only in the overweight/obese patients, including
the presence of intermediate histological grade luminal B subtype tumors (β=0.630;
95%CI: 0.184-1.075 and p=0.006). There was a positive association between tumors of intermediate grade and
tumors between 2 and 5cm in diameter (β=0.294; 95%CI=0.057-0.531 and p=0.016). There was positive association between the presence of angiolymphatic emboli
and high stratification. There was a higher-risk of recurrence in this group (β=0.169;
95%CI: 0.039-0.298 and p=0.012). No significant association was found in the eutrophic group.
Table 2
Significant associations regarding the clinicopathological variables from breast cancer
patients
|
Overweight/obese patients associations[*]
|
B-value
|
p-value
|
Confidence interval
|
|
Luminal B x intermediary grade
|
0,630
|
0,006
|
0,184 - 1,075
|
|
Tumor size between 2 and 5cm x intermediary grade
|
0,294
|
0,016
|
0,057 - 0,531
|
|
Angiolymphatic emboli x high recurrence probability
|
0,169
|
0,012
|
0,039 - 0,298
|
Legends:
* Chi-square test and logistic regression analysis.
DISCUSSION
In recent decades, obesity has emerged as an important risk factor associated with
the development of several cancers including breast cancer. In postmenopausal women,
excess body fat is directly implicated in the development of triple negative tumors
with worse prognostic outcomes regardless of age.[8] A wide range of mediators are implicated in this context including molecules that
perpetuate chronic inflammation that have a wellestablished role in breast cancer
carcinogenesis and progression.[9]
[10]
Similar to other studies, we found that Brazilian women with a BMI over 30kg/m2 have an elevated risk of developing breast cancer.[3] In addition, both obesity and overweight are risk factors for the development of
triple negative tumors in a Brazilian population.[5] In fact, we found that the excessive body weight seems to be the main risk factor
in this population. Adipose tissue is known to fuel a chronic inflammatory state that
can influence breast tissue transformation via the production of carcinogenesis-promoting
mediators resulting in worse outcomes.[11]
A predominance of triple negative tumors in obese/ overweight women was identified
in our study. The presence of triple negative tumors in women with excess body fat
is already well established in the literature and is common in people of African descendants.[12] We note that the population studied here is predominantly Caucasian (over 90%),
which rules out the association between a high prevalence of triple negative tumors
and race or BRCA (breast cancer) gene mutations.[13] Our patients were screened for germinative pathological variants and we found a
low prevalence of pathogenic variants in BRCA (2 cases).
Excessive body weight was also associated with tumors larger than 2cm. This finding
suggests that deregulation of fat metabolism may occur locally in breast tissue and
lead to carcinogenesis. Indeed, breast tissue is in a continuous proinflammatory state
in high BMI subjects - especially in patients with excess visceral fat.[14] Furthermore, localized excess breast fat can induce adipocyte death and activate
macrophage recruitment including activation of important pathways that maintain chronic
inflammation such as NFĸB (factor nuclear Kappa B).[15] Such metabolic and immunological changes would eventually generate a microenvironment
that is conducive not only to carcinogenesis but also cellular phenotypic transformation,
increased proliferation, and increased tumor mass.[16]
Malignant transformation also seems to be associated with excess fat, and this could
explain the high prevalence of high histological grade tumors found in the overweight/obese
cohort. Mediators such as leptin - whose production is increased proportionally to
the increase in body fat - are positively associated with the development of highgrade
breast tumors[17] as well as the occurrence of triple-negative tumors[18] seen here. In addition, increased waist circumference in women with breast cancer
has also been described as a predictor of the development of high-grade tumors[19] suggesting that fat may affect the process of breast tissue differentiation. In
this sense, experimental evidence suggests that suppression of endogenous lipogenesis
may reverse the malignant breast cancer cell phenotype and reprogram breast cells
to follow the normal process of cell differentiation.[20]
Our study showed some important associations between the parameters evaluated in overweight
women. There was a positive association between tumors of intermediate histological
grade and luminal molecular subtype B. There was also correlation of intermediate
grade with 2-5cm tumors. Both associations suggest that tumors formed in the presence
of excess body fat have greater proliferative capacity. This implies the formation
of larger masses and accelerated cellular de-differentiation.
There was also an association between the presence of angiolymphatic emboli and the
high-risk of recurrence in the overweight/obese cohort. Increased embolus formation
is common in both cancer and obesity alone due to the endothelial activation triggered
by chronic inflammation.[21] Such formation may be correlated to the development of hypoxia in the tumor tissue
- this process that can be potentially aggravated in overweight or obese patients
with breast cancer and hypercoagulability states.[22]
Despite the total number of individuals included in the study is good, the small sample
size observed for each group is an important limitation for further conclusions. Also,
the retrospective design limited data collection limited for some clinical parameters
as survival information and chemotherapy response.
CONCLUSION
Immunological and endocrine changes in the tumor microenvironment due to excess body
fat might trigger the development of more proliferative tumors, larger tumors, and
tumor with accelerated cell de-differentiation. The endothelial injury caused by a
continuous and systemic proinflammatory state due to obesity can lead to neoplastic
cell dissemination leading in turn to metastatic disease and more advanced clinical
staging.
Bibliographical Record
Daniel Rech, Daniel G Tebaldi, Jessica Malanowski, Thalita B Scandolara, Hellen dos
Santos Jaques, Fernanda Mara Alves, Gessica T Teixeira, Janaína Carla da Silva, Maria
Eduarda Vasselai, Juliana B Moura, Rayana T Damo, Carolina Panis. Clinicopathological
correlation between trophic-adipose levels and poor prognosis outcomes in Brazilian
women diagnosed with breast cancer. Brazilian Journal of Oncology 2021; 17: e-20210027.
DOI: 10.5935/2526-8732.20210027
