Background: The Oncotype DX® (ODX) is a genomic assay that provides clinicians with a prediction of benefit of chemotherapy in node-negative, tamoxifen-treated breast cancer. However, the relationship between ODX recurrence score (RS) and diabetes, a common comorbidity in breast cancer patients, has been inadequately described in the literature. Specifically, the association of diabetes treatment with metformin and RS is inconclusive, with different studies reporting conflicting results. Because diabetes has been associated with higher RS, it has been suggested that management of diabetes with metformin in breast cancer patients may be associated with a lower RS. Objectives: We studied a large cohort of early-stage, hormone-positive breast cancer patients to determine if there is an association between RS and metformin treatment. Methods: In this study, we retrospectively examined the medical records of 514 early-stage, hormone-positive breast cancer patients who had oncotype testing performed between 2007 and 2017. Number (%) or median were used to describe the patients’ characteristics between groups and were compared by the Kruskal-Wallis test at a significance level of 5%. Results: Of this cohort, 67 (13%) had a diabetes diagnosis at the time of breast cancer diagnosis, including both diabetes mellitus and pre-diabetes. The median RS for non-diabetic patients was 16 and the median RS for diabetic patients was 15. This difference was not significant, nor was there a statistical difference in RS between diabetic patients taking metformin (median RS = 15) and diabetic patients not taking metformin (median RS = 15). These results held true even when controlling for BMI. Conclusions: We conclude that neither diabetes diagnosis nor metformin use is associated with a difference in oncotype RS in this population of diabetic patients.

Diabetes mellitus type II has previously been associated with both an increased risk of breast cancer and an increased risk for all-cause mortality in breast cancer patients [1, 2]. The biological interactions between breast cancer and diabetes remain unknown; it has been suggested that hyperinsulinemia seen in diabetes may drive breast cancer progression [3].

Diabetes management is thus an important factor to consider for improving patient outcomes. The first-line medication for type II diabetes is metformin, a drug that increases insulin sensitivity and decreases liver glucose synthesis [4]. It has been proposed that metformin may be associated with decreased mortality and recurrence in breast cancer. Though the anti-tumor effects of metformin have been clearly demonstrated in vitro [5], its effects in vivo remain inconclusive. Xu et al. [6] reported in a meta-analysis that metformin was associated with decreased risks of all-cause and cancer-specific mortalities. However, Kim et al. [7] found that metformin was associated with improved disease-free survival only in hormone receptor-positive, HER2-positive tumors. Jiralerspong et al. [8] found improved pathologic complete response rates in diabetic breast cancer patients taking metformin but interestingly, metformin did not improve the estimated 3-year relapse-free survival rate.

The impact of metformin on disease recurrence remains unclear. A well-known method for assessing risk for disease recurrence in early-stage, hormone-positive breast tumors is the Oncotype DX (ODX) genomic assay (Genomic Health Inc., Redwood City, CA, USA). It was designed to inform clinicians of the benefit of treating patients with adjuvant chemotherapy, as many early-stage tumors have excellent outcomes with endocrine therapy alone. ODX provides a recurrence score (RS) from 0 to 100, with higher scores indicating a higher probability of distant recurrence and thus more benefit gained from chemotherapy treatment than risk from side effects [9].

Though ODX is now the most widely used tumor profiling test in the United States, little remains known about the association between diabetes, metformin treatment, and Oncotype DX RS. This information may be useful for assessing recurrence risk for diabetic patients, and specifically for diabetic patients managed on metformin. In this retrospective study, we sought to explore whether diabetes and/or metformin treatment has an effect on the ODX score.

This was a retrospective single-center cohort study. Patients who were seen in our center with early-stage, hormone-positive breast cancer analyzed by the ODX between 2007 and 2017 were identified. Among these patients, only those with metformin information available were included in the analysis. Frequency (n) and percentages were used to summarize categorical variables and median and interquartile range (IQR) were used to describe continuous variables. The associations between ODX RS and confounders of interest were examined by the Mann-Whitney U tests (Kruskal-Wallis test for comparisons of more than two groups). To account for the potential impact of obesity on breast cancer risk, we included BMI as a covariate in the linear regression model to further examine the associations between diabetes factors and RS.

After exclusions, we identified 514 patients eligible for analysis. In our sample, 17 (3%) had a personal history of pre-diabetes and 50 (10%) had a personal history of diabetes. There was no significant difference in RS between these two diabetes status groups. Among patients with a diabetes diagnosis (n = 67), there was no statistically significant difference in RS by metformin group; both groups had a median RS of 15. Of the patients with diabetes diagnoses, 30 (45%) were taking metformin at the time of breast cancer diagnosis and 6 (9%) were on insulin. Median RS for patients with metformin use was 15 (IQR: 11–22) compared to 16 (IQR: 12–22) in patients who did not use metformin. This difference was not statistically significant. These results are summarized in Table 1.

Table 1.

Summary of patient characteristics and median recurrence scores

Summary of patient characteristics and median recurrence scores
Summary of patient characteristics and median recurrence scores

We also explored the relationship between BMI and RS. The mean RS for patients with a BMI <25, between 25 and 30, and >30 was 16, 15, and 15, respectively, and did not differ statistically.

The 56 patients with both diabetes and BMI available had a significantly higher BMI with a median of 31 (IQR: 27–36), compared to the non-diabetes patients who had a median BMI of 25 (IQR: 22–29) (p < 0.01). The 10 (18%) diabetic patients with a BMI <25 had a median RS of 18 (IQR: 11–24). The 14 diabetic patients (25%) with a BMI between 25 and 30 had a median RS of 15 (IQR: 11–18) and the 32 diabetic patients (56%) with a BMI >30 had a median RS of 16 (IQR: 11–20). Of note, due to the small sample size in this subgroup, especially for patients with a BMI <25, results should be interpreted with discretion.

We further ran the linear regression models including BMI (both as continuous and categorical variables) in assessing the associations between RS and confounders; the results were not significant. See Figure 1 for relationship between Oncotype, metformin use, and BMI.

Fig. 1.

Median patient Oncotype DX recurrence scores for diabetic patients based on metformin use and BMI.

Fig. 1.

Median patient Oncotype DX recurrence scores for diabetic patients based on metformin use and BMI.

Close modal

In this study, we have analyzed the effect of diabetes and its treatment on ODX RS. We have shown that in our cohort, neither diabetes diagnosis nor metformin treatment had a significant impact on ODX RS. In a prior study of 671 patients [10], metformin was associated with lower ODX recurrence score, as was diagnosis of diabetes. Of note, that study also only looked at early-stage estrogen-positive tumors, while our study more broadly analyzed early-stage, hormone-positive breast cancer, including ER+ and PR+ patients. Thus, the different outcomes in these two studies – and the disagreement in the scientific literature regarding the metformin effect on disease-free survival – may be attributed to a different degree of impact on breast cancer based on hormone receptor status. As metformin does not change insulin levels, our results may support the theory that hyperinsulinemia rather than hyperglycemia in diabetics drives breast cancer progression. This can be further explored through future studies that consider the impact of insulin treatment on ODX score.

In conclusion, early-stage, hormone-positive breast cancer patients with diabetes did not have significantly different ODX RS than their non-diabetic counterparts. Treatment with metformin did not have a significant impact on ODX RS in this population of diabetic patients.

Subjects have given their written informed consent and the study protocol was approved by the institute’s committee on human research.

Amy Tiersten has had the following financial relationships in consulting: AstraZeneca, F. Hoffman-La Roche Ltd. Novartis, Cowen, Tersera.

Industry-Sponsored Lectures: MSSM faculty occasionally give lectures at events sponsored by industry, but only if the events are free of any marketing purpose.

Amy Tiersten has served on the following Scientific Advisory Boards: Eisai Inc., Immunomedics, Novartis.

Research reported in this publication was supported in part by the National Cancer Institute Cancer Center Support Grant P30CA196521-01 awarded to the Tisch Cancer Institute of the Icahn School of Medicine at Mount Sinai and used the Biostatistics Shared Resource Facility. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Serena Tharakan took part in the design of the study, data acquisition, analysis, interpretation of data, drafting the publication, and final approval.

Brittney Zimmerman took part in the design of the study, data acquisition, analysis, interpretation of data, drafting the publication, and final approval.

Meng Ru took part in data analysis, interpretation of the data, drafting the publication, and final approval.

Julia Blanter took part in data analysis, drafting the publication, and final approval.

Krystal Cascetta took part in study conception and design, drafting of the publication, and final approval.

Amy Tiersten took part in study conception and design, drafting of the publication, and final approval.

1.
Peairs
KS
, et al
Diabetes mellitus and breast cancer outcomes: a systematic review and meta-analysis
.
J Clin Oncol
.
2011
;
29
:
40
6
.
2.
Redaniel
MT
,
Jeffreys
M
,
May
MT
,
Ben-Shlomo
Y
,
Martin
RM
.
Associations of type 2 diabetes and diabetes treatment with breast cancer risk and mortality: a population-based cohort study among British women
.
Cancer Causes Control
.
2012
;
23
:
1785
95
.
3.
Gallagher
EJ
,
LeRoith
D
.
The proliferating role of insulin and insulin-like growth factors in cancer
.
Trends Endocrinol Metab
.
2010
;
21
:
610
8
.
4.
Pernicova
I
,
Korbonits
M
.
Metformin–mode of action and clinical implications for diabetes and cancer
.
Nat Rev Endocrinol
.
2014
;
10
:
143
56
.
5.
Ben Sahra
I
, et al
The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level
.
Oncogene
.
2008
;
27
:
3576
86
.
6.
Xu
H
, et al
Metformin use is associated with better survival of breast cancer patients with diabetes: a meta-analysis
.
Oncologist
.
2015
;
20
:
1236
44
.
7.
Kim
HJ
, et al
Metformin increases survival in hormone receptor-positive, HER2-positive breast cancer patients with diabetes
.
Breast Cancer Res
.
2015
;
17
:
64
.
8.
Jiralerspong
S
, et al
Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer
.
J Clin Oncol
.
2009
;
27
:
3297
302
.
9.
Siow
ZR
,
De Boer
RH
,
Lindeman
GJ
,
Mann
GB
.
Spotlight on the utility of the Oncotype DX((R)) breast cancer assay
.
Int J Womens Health
.
2018
;
10
:
89
100
.
10.
Goldvaser
H
, et al
The association between treatment for metabolic disorders and breast cancer characteristics
.
Int J Endocrinol
.
2016
;
2016
:
4658469
.
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