Keywords
breast cancer - chemotherapy - secondary diabetes
Dr. Manjeshwar Shrinath Baliga
Introduction
Global reports indicate that in women, the incidence of breast cancer is on a rise,
and that today, it is the most common malignancy in many parts of the world.[1] To substantiate this recent global data obtained for the year 2012 suggests that,
with an estimated 1.67 million new cancer cases diagnosed, breast cancer amounts to
almost a quarter (25%) of all the reported cancer numbers.[1] What is more worrying is that reports also suggest that when compared with the more
developed countries, women from the less developed countries have slightly more number
of cases, indicating a disparity in the incidence and that a rise in the case of cancers
in underprivileged areas may affect the society at large.[1]
[2]
Conventionally, depending on the stage and the general health of the women, breast
cancer is treated with surgery, chemotherapy, and radiotherapy.[3] In addition to these modalities, depending on the epidermal growth factor receptor
encoded by the ERBB2 or human epidermal growth factor receptor 2 (HER2) gene, immunologicals
like trastuzumab (herceptin) may also be used to slow down the growth of the cancer.[3] Furthermore, depending on the estrogen receptor (ER) status (ER positive), modulators
like tamoxifen may also be used to inhibit the estrogenic effects responsible for
cancer cell growth or proliferation.[4] However, the uses of various classes of anticancer and supportive pharmacological
agents (such as antiemetics, analgesics, and steroids) are known to have adverse effects
and affect the quality of life in the cancer survivors.
Studies have shown that some women who were nondiabetic (normoglycemic) at the start
of the cancer chemotherapy develop treatment-induced diabetes, also known as secondary
diabetes.[5] The factors attributed to this include the stress induced by the cytotoxic chemotherapeutic
agents and the use of the dexamethasone, important in preventing chemotherapy-induced
nausea and vomiting during the course of the treatment.[5]
[6] Previous studies have shown that glucocorticoid therapy, cisplatin, everolimus,
docetaxel, and androgen deprivation therapy can contribute to uncontrolled hyperglycemia.[7] Administration of steroid to mitigate emesis and inflammatory reactions is shown
to induce steroid-induced hyperglycemia and diabetes in people undergoing therapy
for cancer.[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
Previous studies have shown that almost 20% of nondiabetic cancer patients develop
steroid-induced diabetes after antiemetic dexamethasone therapy.[5] Although not clear, these negative effects of steroids are attributed to myriad
factors, the most important being increased insulin resistance and glucose intolerance,
reduced β-cell mass from β-cell dysfunction, and increased hepatic insulin resistance.[16]
[17]
[18] In this retrospective chart-based study, an attempt was made at understanding the
incidence of development of secondary diabetes in the normoglycemic women who underwent
surgery, chemotherapy, and radiation.
Materials and Methods
This was a retrospective chart-based study which was conducted, after obtaining the
permission from the institutional ethics committee (MIOIEC/2019/15). The medical record
files of women, who had undergone surgical treatment, either radical or simplified
mastectomy, followed by curative chemotherapy treatment, which includes a combination
of drugs like anthracycline, paclitaxel/docetaxel alone or combined with other drugs,
second-line chemotherapy regimen (such as capecitabine, gemcitabine, platinums, and
vinorelbine) endocrine therapy, and HER2-targeted therapies, were considered.
The blood glucose levels are always evaluated before surgery during fitness evaluation,
before the commencement of each chemotherapy cycle, before and after the completion
of radiotherapy, and at 1 to 3 months’ intervals after the completion of the radiotherapy.
The criteria considered to be diabetic was in accordance with the World Health Organization
(WHO) guidelines of 1999 which categorizes an individual with fasting plasma glucose
≥7.0 mmol/L, a random plasma glucose ≥11.1 mmol/L, or a 2-hour plasma glucose ≥11.1
mmol/L during an oral glucose tolerance test as diabetic. The standard practice for
management of diabetes is in accordance with standard guideline[19]
[20] and includes dietary measures and prescription of oral hypoglycemic medication,
depending on the clinical condition and the judgment of physicians.
The study time point considered was from January 2017 to December 2018. The inclusion
criteria included collection of data only from women, between the ages of 20 to 80,
who were not diabetics and completed the planned treatment of surgery, chemotherapy,
and radiotherapy during the study time point. The exclusion criteria included men
who were treated for breast cancer, women known to be diabetics (Type 1 and/or Type
2) and were under medication for it, women who were newly diagnosed to have diabetes
before the start of the treatment (during their fitness test prior to surgery), women
who received neoadjuvant therapy before surgery, and women who discontinued treatment.
The data were anonymized by the in charge of medical records department (MRD) and
contained data on demographic and clinical aspects.
Three research assistants extracted the data from the provided medical records. The
demographic details such as age at the time of breast cancer diagnosis, domicile,
body mass index (BMI), type of diet, marital status, number of children, previous
history of diabetes, hypertension, and menopausal status, as well as clinical data
such as the histopathological details (tumor, node, metastasis [TNM] staging, hormonal
receptor status [estrogen, progesterone] and HER2/neu status ascertained by immunohistochemical
methods and fluorescence in situ hybridization assay to further validate the HER2-positive
status), were collected when available in the files. The details on when hyperglycemia/secondary
diabetes developed, and treatment discontinued, were entered into Microsoft Excel
by the research assistants. Only those data that met the inclusion criteria were entered
into the Excel sheet.
Statistical Analysis
The data entered into Microsoft excel were exported to SPSS version 23, IBM Corp NY,
USA for analysis. The descriptive data were subjected to frequency and percentage
and Chi-square test. The association between the demographic details and development
of and the occurrence of secondary diabetes or prediabetes conditions was done using
the Pearson’s correlation analysis. A p value of <0.05 was considered significant.
Results
During the study time point considered from January 2017 to December 2018, a total
of 535 cases of breast cancer were treated. In these, 61 cases were not included as
they did not meet the inclusion criteria. A total of 474 cases were observed to satisfy
the inclusion criteria and included for the analysis. The demographic details such
as age at the time of cancer diagnosis domicile (rural/urban), BMI, type of diet,
marital status, and number of children while the clinical data on the TNM stage, ER,
progesterone receptor (PR), and HER2 status are represented in [Table 1].
Table 1
The demographic and tumor pathology details of the study participants
|
Count (%)
|
|
Abbreviations: BMI, body mass index; ER, estrogen receptor; HER, human epidermal growth
factor receptor; PR, progesterone receptor.
|
|
Age code
|
|
18–30
|
10 (2.1)
|
|
31–40
|
85 (17.9)
|
|
41–50
|
157 (33.1)
|
|
51–60
|
128 (27.0)
|
|
61–70
|
76 (16.0)
|
|
Above 70
|
18 (3.8)
|
|
Total
|
474 (100.0)
|
|
BMI code
|
|
<18
|
43 (9.1)
|
|
18–22
|
251 (53.0)
|
|
>22
|
180 (38.0)
|
|
Total
|
474 (100.0)
|
|
Place code
|
|
Village
|
45 (9.5)
|
|
Town
|
178 (37.6)
|
|
City
|
251 (53.0)
|
|
Total
|
474 (100.0)
|
|
Tumor T
|
|
Tumor T1
|
32 (6.8)
|
|
Tumor T2
|
220 (47.0)
|
|
Tumor T3
|
119 (25.4)
|
|
Tumor T4
|
97 (20.7)
|
|
Total
|
468 (100.0)
|
|
ER code
|
|
Negative
|
175 (44.5)
|
|
Positive
|
218 (55.5)
|
|
Total
|
393 (100.0)
|
|
PR code
|
|
Negative
|
202 (51.4)
|
|
Positive
|
191 (48.6)
|
|
Total
|
393 (100.0)
|
|
HER code
|
|
Negative
|
250 (66.1)
|
|
Positive
|
113 (29.9)
|
|
Equivocal
|
15 (4.0)
|
|
Total
|
378 (100.0)
|
Table 2
Information on the development of the prediabetic and diabetic condition
|
Our observation
|
n (%)
|
Percentage (%)
|
|
Normal to normal
|
265 (55.91)
|
|
|
Normal to prediabetic
|
118 (24.89)
|
|
|
Normal to prediabetic to diabetic
|
52 (10.97)
|
10.97
|
|
Normal to directly diabetic
|
39 (8.22)
|
8.22
|
|
Total number is 474
|
474 (100)
|
By the end of radiotherapy 19.20% have developed diabetes
|
With regard to the details on the development of secondary diabetes, the results indicated
that by the end of the radiation treatment, 24.89% (118/474) were prediabetic, 10.97%
(52/474) were diabetic after being in prediabetic stage, 8.22% (39/474) became diabetic
without going through a prediabetic stage, and 55.91 (265/474) did not develop either
prediabetic or diabetic condition ([Table 2]). Analysis of development of secondary diabetes and prediabetes with BMI (p < 0.0001) and age (p < 0.024) showed a strong correlation and was significant ([Table 3]).
Table 3
Chi-square calculation to ascertain the association between various demographic features
with prediabetes and diabetes in the study subjects
|
Count (%)
|
|
|
Normal to normal
|
Normal to pre-DM
|
Normal to DM
|
p-Value
|
|
Abbreviations: BMI, body mass index; DM, diabetes mellitus; ER, estrogen receptor;
HER2, human epidermal growth factor receptor 2; PR, progesterone receptor.
|
|
Age code
|
|
18–30
|
10 (3.8)
|
0 (0.0)
|
0 (0.0)
|
0.084
|
|
31–40
|
54 (20.4)
|
18 (15.3)
|
13 (14.3)
|
|
41–50
|
82 (30.9)
|
42 (35.6)
|
33 (36.3)
|
|
51–60
|
74 (27.9)
|
34 (28.8)
|
20 (22.0)
|
|
61–70
|
35 (13.2)
|
21 (17.8)
|
20 (22.0)
|
|
Above 70
|
10 (3.8)
|
3 (2.5)
|
5 (5.5)
|
|
Total
|
265 (100.0)
|
118 (100.0)
|
91 (100.0)
|
|
BMI
|
|
<18
|
31 (11.7)
|
8 (6.8)
|
4 (4.4)
|
0.0001
|
|
18–22
|
166 (62.6)
|
49 (41.5)
|
36 (39.6)
|
|
>22
|
68 (25.7)
|
61 (51.7)
|
51 (56.0)
|
|
Total
|
265 (100.0)
|
118 (100.0)
|
91 (100.0)
|
|
Place
|
|
Village
|
30 (11.3)
|
12 (10.2)
|
3 (3.3)
|
0.102
|
|
Town
|
93 (35.1)
|
51 (43.2)
|
34 (37.4)
|
|
City
|
142 (53.6)
|
55 (46.6)
|
54 (59.3)
|
|
Total
|
265 (100.0)
|
118 (100.0)
|
91 (100.0)
|
|
Tumor stage
|
|
Tumor T1
|
19 (7.2)
|
6 (5.1)
|
8 (8.9)
|
0.57
|
|
Tumor T2
|
124 (47.1)
|
52 (44.4)
|
44 (48.9)
|
|
Tumor T3
|
65 (24.7)
|
34 (29.1)
|
21 (23.3)
|
|
Tumor T4
|
55 (20.9)
|
25 (21.4)
|
17 (18.9)
|
|
Total
|
263 (100.0)
|
117 (100.0)
|
90 (100.0)
|
|
ER status
|
|
Negative
|
113 (52.6)
|
30 (30.9)
|
32 (39.5)
|
0.001
|
|
Positive
|
102 (47.4)
|
67 (69.1)
|
49 (60.5)
|
|
Total
|
215 (100.0)
|
97 (100.0)
|
81 (100.0)
|
|
PR status
|
|
Negative
|
122 (56.7)
|
38 (39.2)
|
42 (51.9)
|
0.02
|
|
Positive
|
93 (43.3)
|
59 (60.8)
|
39 (48.1)
|
|
Total
|
215 (100.0)
|
97 (100.0)
|
81 (100.0)
|
|
HER2 status
|
|
Negative
|
138 (66.7)
|
57 (62.6)
|
55 (68.8)
|
0.044
|
|
Positive
|
69 (33.3)
|
34 (37.4)
|
25 (31.3)
|
|
Total
|
207 (100.0)
|
91 (100.0)
|
80 (100.0)
|
The details indicated that most of the women who developed prediabetes and diabetes
were in the age group 41 to 60 and 41 to 70, respectively, and a trend was observed
(p = 0.084) ([Table 3]). With regard to BMI, the observations suggest that many women with BMI more than
22 developed prediabetes (51.7%) and diabetes (56%) and was statistically significant
(p = 0.001). With regard to the tumor stage and place of domicile, there was no association.
With relation to the hormone receptor (ER and PR) status, it was observed that 69.1%
and 60.8% developed prediabetes, while 60.5 and 48.1% developed diabetes and was significant
(p = 0.01 and p = 0.016, respectively) ([Table 3]). However, with regard to HER2 status, 62.6% and 68.8% developed prediabetes and
diabetes, respectively (p = 0.044) ([Table 2]).
Discussion
Recent data from India indicate that the incidence of breast cancer is on the rise,
and that in the near future, it will be a major health issue.[2] Reports also do suggest that the incidence of diabetes is also high and that India
has the second largest population (69.2 million) with diabetes.[21]
[22] From a clinical perspective, although different in the pathogenesis and disease
progression, both ailments share the etiology and signaling pathways[23] and aspects such as old age, obesity, genetic predisposition, sedentary lifestyle,
and chronic inflammation have a forbearing on the development of these ailments.[14] In addition, to these reports also suggest that females afflicted with breast cancer
have an increased risk of developing diabetes and that this can have an adverse effect
on their general health and quality of life.
In this study, it was observed that by the end of the radiation treatment, 55.91%
did not develop either prediabetic or diabetic condition. Of the remaining 44.01%
of the study population, 24.89% were prediabetic and 19.19% were diabetic ([Table 2]). Previous studies from around the world have shown that 9.7%[23] to 13%[24] elderly women developed secondary diabetes. The most important aspect here with
is that when compared with previous studies, majority of the women who developed diabetes
were in the age group of 41 to 50 years ([Table 3]). To substantiate this, community-based studies conducted with the rural population
of Mangalore have shown that 29.6% of the women were diabetic and that this was higher
than in men (25.4%).[25] In addition, reports from other parts of Karnataka have also shown that the prevalence
of diabetes in females were more than in men.[26]
[27] The most possible reason for this high incidence is that most women in the study
area were homemakers with a sedentary lifestyle, a known factor associated with development
of type 2 diabetes.
The other important aspect observed was that 56.0% and 51.7% of the women with BMI
more than 22 developed diabetes and prediabetic conditions. Obesity is associated
with increased risk of diabetes, and a recent case-control study with diabetics published
from the study area has shown that 55% of them had BMI over 25 kg/m2 as compared with 22% of controls and that this association was statistically significant
(p < 0.05).[28] These observations are in agreement to the results published by Mohan et al where
it is clearly indicated that BMI had a strong association for all cardiometabolic
risk factors for both diabetes mellitus (DM) and prediabetes and ranged from 22.7
to 23.8 kg/m for women.[29]
In the study, it was also observed that irrespective of the place of domicile, there
was no significant difference, indicating that place of residence does not play a
role in the development of Hyperglycemia/secondary diabetes. Only possible explanation
that can be offered for this observation is that the per capita income of people living
in the study area is in the higher bracket and previous studies from India have shown
that states with higher per capita gross domestic product seemed to have a higher
prevalence of diabetes.[30] Further reports[30] also suggest that diabetes prevalence was higher in people with lower socioeconomic
status and the observations of Padmanabha et al substantiate this.[25]
With regard to association between tumor pathological details and development of diabetes,
an association was not seen with the TNM stage (0.57), while it was significant for
ER positive (0.001), PR positive (0.02), and HER2 negative status (0.04). The authors
are unaware of any reports that suggest the association between the ER, PR, and HER2
status with development of Hyperglycemia/secondary diabetes. In lieu of these observations,
it is imperative that a large study from different population is required to ascertain
the role of these three molecular markers in the development of type II diabetes.
In addition to this, suitable preclinical studies to validate the role of ER, PR,
and HER2 status in the development of type II DM is required to answer the mechanistic
basis for the observed phenomenon.
Conclusion
Our data for the first time indicate that the incidence of development of cancer treatment-induced
hyperglycemia/ diabetes is high in the Indian women being treated for their breast
cancer from this part of India. The observations that 24.89% were prediabetic and
10.97% diabetic at the end of the radiation treatment indicate that development of
diabetes in the breast cancer survivors can be a major issue. The reluctance of patients
for a regular followup care on completion of treatment is a major hurdle in asertaining
the magnanimity of the problem. Studies are underway to find the cause for development
of hyperglycemia/secondary diabetes and on how they can be mitigated. Efforts are
also underway to see the incidence of cancer metastasis/recurrence and long term effect
of development of treatment induced diabetes and other metabolic syndromes in these
patients.
