Hypothyroidism and the risk of breast cancer recurrence and all-cause mortality - a Danish population-based study
verfasst von:
Anne Mette Falstie-Jensen, Anders Kjærsgaard, Ebbe Laugaard Lorenzen, Jeanette Dupont Jensen, Kristin Valborg Reinertsen, Olaf M. Dekkers, Marianne Ewertz, Deirdre P. Cronin-Fenton
Hypothyroidism may occur as a late effect of breast cancer-directed treatment, particularly after radiotherapy, but little is known whether hypothyroidism affects the prognosis after breast cancer. We investigated the association between hypothyroidism and breast cancer recurrence, and all-cause mortality.
Methods
In this population-based cohort study, we used national medical registries to identify all Danish women 35 years or older diagnosed with stage I–III, operable breast cancer between 1996 and 2009. Hypothyroidism was defined as hospital diagnoses ascertained via diagnostic codes, or as prescriptions for levothyroxine. Two analytic models were used: (i) hypothyroidism present at the time of the breast cancer diagnosis (prevalent) and (ii) hypothyroidism diagnosed during follow-up as a time-varying exposure lagged by 1 year (incident). Breast cancer recurrence was defined as any local, regional, or distant recurrence or contralateral breast cancer. All-cause mortality included death from any cause in any setting. We used Cox regression models accounting for competing risks to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of breast cancer recurrence and all-cause mortality.
Results
The study cohort included 35,463 women with breast cancer with 212,641 person-years of follow-up. At diagnosis, 1272 women had hypothyroidism and 859 women developed hypothyroidism during follow-up. In total, 5810 patients developed recurrent breast cancer. Neither prevalent nor incident hypothyroidism was associated with breast cancer recurrence (adjusted HRprevalent 1.01, 95% CI 0.87–1.19; adjusted HRincident 0.93, 95% CI 0.75–1.16, respectively). Furthermore, no differences were seen for all-cause mortality for prevalent or incident hypothyroidism (adjusted HRprevalent 1.02, 95% CI 0.92–1.14, and HRincident 1.08, 95% CI 0.95–1.23, respectively). Stratification by menopausal status, oestrogen receptor status, chemotherapy, or radiotherapy did not alter the estimates.
Conclusions
Hypothyroidism present at diagnosis or during follow-up was not associated with breast cancer recurrence or all-cause mortality in women with breast cancer. Our findings provide reassurance to patients and their physicians that hypothyroidism is unlikely to impact on the clinical course of breast cancer or survival.
Breast cancer is one of the most common malignancies in women, worldwide. Over the last 25 years, mortality has decreased by 36% leading to an increased number of breast cancer survivors [1]. This considerable decline is likely attributable to advances in mammographic screening and improved surgical, radiation, and adjuvant therapies [2]. However, cancer and cancer-directed treatment can incur serious long-term negative health effects. Thus, it is critical to monitor the potential impact of such late effects on breast cancer prognosis.
Hypothyroidism is a common hormone deficiency, characterised by insufficient production of triiodothyronine and thyroxine [3]. The diagnosis of hypothyroidism is confirmed with blood tests measuring thyroid-stimulating hormone and thyroxine levels. Hypothyroidism requires substitution therapy. Despite adequate biochemical control, symptoms like fatigue or disturbed concentration do not always resolve. Hypothyroidism is diagnosed in about 3% of the population, more frequently in women, and risk increases with age; thus, some breast cancer patients develop hypothyroidism long before their breast cancer is diagnosed [4].
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Hypothyroidism is a well-documented late effect after radiation therapy in head and neck cancer [5]. Consequently, a link between breast cancer treatment and subsequent risk of hypothyroidism has been discussed, initially by case reports published on breast cancer patients who developed hypothyroidism years after treatment [6‐10]. Later, observational studies from Europe and the USA suggested that breast cancer patients may have a higher risk of hypothyroidism during follow-up [11‐13]. Furthermore, several studies have linked types of cancer-directed treatments with hypothyroidism [14‐18] and radiotherapy, particularly among those receiving radiotherapy to the supraclavicular region [12‐14, 19]. However, the scientific literature on the association of hypothyroidism with breast cancer prognosis is sparse. Laboratory-based animal models have shown that induced hypothyroidism without the use of substitution therapy may correlate with smaller, less-invasive tumours [20‐22]. Thus, breast cancer patients with hypothyroidism may have a lower risk of breast cancer recurrence.
The aim of this study was first to investigate the association between hypothyroidism prevalent at breast cancer diagnosis, or incident during follow-up, and the subsequent risk of breast cancer recurrence in a large population-based cohort of breast cancer patients. Second, we investigated the association between hypothyroidism and all-cause mortality.
Methods
This study was approved by the Danish Data Protection Agency (Aarhus University, journal number 2016-051-000001, running number 437), the Danish Medicines Agency, and the Danish Breast Cancer Group (DBCG). According to Danish Law, ethical approval is not necessary because the study uses routinely collected registry data.
In Denmark, a unique civil personal registry number is assigned to all citizens at birth or immigration, enabling accurate and unambiguous individual-level record linkage across all public registries, medical as well as non-medical [23]. Due to tax-funded healthcare, all 5.6 million citizens have free access to public hospitals, which covers more than 95% of hospitalisations including all emergencies.
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Source population
We used the DBCG clinical database to ascertain information on all women 35 years or older with incident stage I-III, operable breast cancer on protocol treatment and diagnosed between January 1, 1996, and December 31, 2009 [24]. The DBCG was established in 1977 to optimise diagnostic and therapeutic procedures across the country and to improve breast cancer prognosis [25]. All patients with invasive breast cancer in Denmark are included prospectively, and registration completeness has increased over the years to reach ~ 95% for the last decade [26, 27]. The treating physicians are responsible for entering pre-specified data on patient, tumour, and treatment characteristics. We excluded women with prevalent hyperthyroidism at the time of the breast cancer diagnosis from the analyses.
Thyroid disease
We defined hypothyroidism as a diagnostic code of hypothyroidism or the redemption of at least two prescriptions of levothyroxine. Information on diagnostic codes (International Classification of Diseases (ICD) 8: 244.00-244.03, 244.08, and 244.09, and ICD-10: E03.2-E03.9, and E89.0) was obtained from the Danish National Registry of Patients (DNRP) covering information on all discharge diagnoses for inpatient hospital contacts since 1977 and outpatient and emergency room hospital contacts since 1995 [28]. We used the Danish National Prescription Registry (DNPR) to identify patients redeeming at least two prescriptions (Anatomical Therapeutic Classification (ATC) code: H03A) and to include patients treated for hypothyroidism but not necessarily recorded in the DNRP [29].
To exclude women with hyperthyroidism from the study population, we identified diagnoses of hyperthyroidism in the DNRP by ICD-8: 242.01-242.29 and ICD-10: E05-E05.9 and E05.0B, or in the DNPR by redemption of at least two anti-thyroxine prescriptions (ATC codes: H03BB01, H03BB02, and H03BA02) during follow-up.
Outcomes
We used the DBCG definition of breast cancer recurrence as any local, regional, or distant recurrence or contralateral breast cancer [25, 26]. Regional recurrence includes recurrence in the same site as the first primary breast cancer in the axilla, supraclavicular, or parasternal lymph node region. All other recurrences are regarded as distant. When a new tumour is detected, a biopsy is taken for pathological assessment. The decision whether the new tumour is a recurrence of a previous cancer or a new primary tumour is based on this assessment in accordance with the clinical guidelines. Due to systematic follow-up, all cases of recurrence are reported in the DBCG including the date and anatomical site of recurrence. The systematic follow-up for patients with operable disease includes a clinical evaluation, biannually for the first 5 years and annually up to 10 years after diagnosis.
All-cause mortality included death from any cause in any setting. We obtained data on mortality from the Danish Civil Registration System, which has registered information on vital and migration status on all Danish inhabitants since 1968 [23].
Covariates
From the DBCG, we retrieved clinical and treatment characteristics: menopausal status at diagnosis (pre/post), histological grade (a composite score including tubule formation, mitoses, and nuclear pleomorphy) (low, moderate, and high), lymph node status (N0, N1–3, N4+), tumour oestrogen receptor (ER) status (positive ≥ 10%/negative 0–9%), HER-2 status (classified according to immunohistochemistry (Hercept test) and by fluorescent in situ hybridisation (FISH) and available from 2007) (positive HER-2 score = 3 and FISH ≤ 2.00, negative HER-2 score ≤ 2 and FISH ≤ 2.00), and chemo-, radio-, and endocrine therapy (ET) (yes, no) (intention-to-treat information). We summarised the type of primary surgery and radiotherapy into a joint variable (mastectomy with radiotherapy, mastectomy without radiotherapy, lumpectomy) and ER and ET as a joint variable (ER+/ET+, ER+/ET−, ER−/ET+, and ER−/ET−).
We ascertained information on comorbidities diagnosed up to 10 years before primary breast cancer diagnosis from the DNRP. A modified comorbidity score was calculated for each patient according to the Charlson Comorbidity Index excluding cancer in the index score [30]. Based on the score, three categories were computed (no comorbidity, low (score of 1 or 2), and high (score ≥ 3)).
Statistical analyses
We used a prevalent and an incident model for hypothyroidism as illustrated in Fig. 1. In the prevalent model, hypothyroidism was included as a baseline exposure. Women with a clinical diagnosis of hypothyroidism and/or redeemed prescriptions for thyroxine before or at the time of the breast cancer diagnosis were considered to have prevalent hypothyroidism. For incident hypothyroidism, exposed person-time started at the date of hypothyroidism or once a patient had redeemed at least two thyroxine prescriptions with prescriptions treated as a time-varying exposure lagged by 1 year (please see Additional file 1) [31].
×
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Person-time at risk of recurrence was computed from the date of primary breast cancer surgery (index date) and continued to the date of breast cancer recurrence, death, emigration, hyperthyroidism, 10 years, or the first of June 2015 whichever came first. For all-cause mortality, person-time at risk was calculated from the index date and continued to the date of death, emigration, hyperthyroidism, 10 years, or the first of June 2015 whichever came first.
Within categories of patient, clinical, and treatment characteristics, we examined the frequency and proportion of breast cancer patients according to thyroid status at baseline and during follow-up using euthyroidism as a reference group.
We used Cox regression models to compute crude and adjusted hazard ratios (HR) including 95% confidence intervals (95% CI) comparing the risk of recurrence and all-cause mortality, respectively, according to thyroid status (normal thyroid versus prevalent/incident hypothyroidism) [32]. The proportional hazard assumption was checked by visual inspection of the log of the estimated survivor function in the models involving prevalent hypothyroidism (Additional file 2). The models accounted for competing risks and included adjustments for potential confounding covariates including age at diagnosis (continuous), menopausal status, UICC stage, ET/ER status, surgery type, receipt of chemotherapy, histologic grade, comorbidity, and use of simvastatin or aspirin, respectively. Simvastatin and aspirin use were modelled as time-varying covariates lagged by 1 year after redemption of a prescription and lasting for 1 year. Simvastatin and aspirin use were included in the adjusted models as they have been linked to breast cancer prognosis, and adherence to one medication may correlate with adherence to another prescription [33, 34]. Due to the low number of events in the incident model, we used a directed acyclic graph (DAG) to identify the relevant confounders for recurrence (please see Additional file 3). The final DAG adjusted model included age at diagnosis, UICC stage, chemotherapy, type of primary surgery, and ER/ET status.
In both models, we investigated potential effect measure modification stratifying by menopausal status, chemotherapy, and ET/ER use and for the incident model also stratifying by radiotherapy. In sensitivity analyses, we increased the lag time from 1 to 2 years. For recurrence, we also performed sensitivity analyses restricting to patients who had hypothyroidism 2, 5, and 10 years before their breast cancer diagnosis to investigate the association of duration of hypothyroidism with breast cancer recurrence.
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All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).
Results
In the DBCG registry, 38,442 Danish women ≥ 35 years were diagnosed with non-metastatic breast cancer between 1996 and 2009. Due to reasons outlined in Fig. 1, 2979 (8%) women were excluded, and so the final study population included 35,463 women with early stage I-III, operable breast cancer.
At baseline, 34,191 (96%) women with breast cancer had a normal thyroid and 1272 (4%) had hypothyroidism with a follow-up time of 205,529 and 7112 person-years, respectively. Women with normal thyroid function were followed for a median of 6.0 years, and women with prevalent hypothyroidism for 5.6 years. Women with prevalent hypothyroidism were older, were more frequently post-menopausal, had more comorbidity, were less likely to be assigned chemotherapy, and were more often simvastatin users compared with their euthyroid counterparts (Table 1).
Table 1
Baseline characteristics of women diagnosed with stage I–III, operable breast cancer in Denmark from 1996 to 2009, according to thyroid status at the time of breast cancer diagnosis
Characteristics
Prevalent hypothyroidism
Incident hypothyroidism
Thyroid status
Follow-up time1
Thyroid status
Follow-up time1
Normal (n = 34,191)
Hypothyroidism (n = 1272)
Normal
Hypothyroidism
Normal (n = 33,332)
Hypothyroidism (n = 859)
Normal
Hypothyroidism
Calendar year of diagnosis, n (%)
1996–1999
8059 (24)
199 (16)
47,917
1166
7888 (24)
171 (20)
47,339
679
2000–2004
11,522 (34)
413 (32)
76,332
2562
11,226 (34)
296 (34)
75,204
1127
2005–2009
14,610 (43)
660 (52)
81,280
3383
14,218 (43)
392 (46)
80,004
1276
Age at diagnosis, n (%)
35–40 years
1172 (3)
11 (1)
7366
62
1147 (3)
25 (3)
7277
89
40–49 years
6134 (18)
115 (9)
40,077
708
5961 (18)
176 (20)
39,441
637
50–59 years
10,798 (32)
346 (27)
68,364
2089
10,511 (32)
287 (33)
67,281
1084
60–69 years
11,020 (32)
494 (39)
64,885
2901
10,759 (32)
261 (30)
63,951
934
70–79 years
4434 (13)
263 (21)
22,540
1208
4333 (13)
101 (12)
22,226
318
≥ 80 years
633 (2)
43 (3)
2296
144
621 (2)
12 (1)
2271
24
Menopausal status at diagnosis, n (%)
Premenopausal
9378 (27)
≤ 1952 (−)
61,404
1158
9118 (27)
≤ 2652 (−)
60,452
952
Postmenopausal
24,774 (72)
1083 (85)
143,944
5937
24,176 (73)
598 (70)
141,816
2128
Unknown
39 (0)
≤ 52 (−)
181
17
38 (0)
≤ 52 (−)
180
2
Modified comorbidity status, n (%)3
None
28,809 (84)
957 (75)
177,395
5510
28,093 (84)
716 (84)
174,781
2614
Low
4587 (13)
258 (20)
24,591
1356
4466 (13)
121 (14)
24,182
409
High
795 (2)
57 (4)
3542
245
773 (2)
22 (3)
3484
58
Tumour size, n (%)
≤ 20 mm
20,756 (61)
≤ 7752 (−)
128,360
4479
20,248 (61)
≤ 5152 (−)
126,463
1896
21–50 mm
12,202 (36)
480 (38)
71,284
2497
11,873 (36)
329 (38)
70,186
1098
≥ 51 mm
1045 (3)
23 (2)
4878
113
1026 (3)
19 (2)
4795
83
Unknown
188 (1)
≤ 52 (−)
1007
22
185 (1)
≤ 52 (−)
1003
4
Lymph node status, n (%)
N0
18,396 (54)
724 (57)
111,451
4040
17,986 (54)
410 (48)
109,988
1463
N1–3
10,391 (30)
353 (28)
66,956
2145
10,090 (30)
301 (35)
65,833
1123
N4+
5404 (16)
195 (15)
27,121
927
5256 (16)
148 (17)
26,625
496
UICC stage, n (%)
I
13,433 (39)
519 (41)
81,013
2939
13,139 (39)
294 (34)
79,950
1063
II
15,067 (44)
551 (43)
95,812
3206
14,654 (44)
413 (48)
94,303
1509
III
5691 (17)
202 (16)
28,704
967
5539 (17)
152 (18)
28,194
510
Histological grade, n (%)4
Low
9740 (28)
364 (29)
59,627
2029
9500 (29)
240 (28)
58,749
878
Moderate
12,742 (37)
507 (40)
78,631
2918
12,397 (37)
345 (40)
77,351
1280
High
6608 (19)
226 (18)
37,186
1170
6446 (19)
162 (19)
36,641
545
Unknown
5101 (15)
175 (14)
30,085
995
4989 (15)
112 (13)
29,705
379
ER status, n (%)
ER negative (0–9%)
6376 (19)
224 (18)
35,446
1111
6198 (19)
178 (21)
34,822
624
ER positive (≥ 10%)
26,954 (79)
1031 (81)
164,836
5894
26,294 (79)
660 (77)
162,448
2388
Unknown
861 (3)
17 (1)
5247
106
840 (3)
21 (3)
5176
70
HER-2 status, n (%)5
Negative
11,551 (34)
474 (37)
63,723
2370
11,245 (34)
306 (36)
62,732
992
Positive
2489 (7)
114 (9)
13,508
599
2426 (7)
63 (7)
13,317
191
Unknown
20,151 (59)
684 (54)
128,298
4143
19,661 (59)
490 (57)
126,398
1900
Endocrine therapy and ER status, n (%)
ET−/ER−
7010 (21)
231 (18)
39,283
1154
6819 (20)
191 (22)
38,615
667
ET+/ER+
17,592 (51)
679 (53)
113,800
4123
17,109 (51)
483 (56)
112,074
1725
ET−/ER+
9362 (27)
352 (28)
51,037
1771
9185 (28)
177 (21)
50,374
663
ET+/ER−
227 (1)
10 (1)
1410
64
219 (1)
8 (1)
1384
26
Type of primary surgery, n (%)
Mastectomy without radiotherapy
11,337 (33)
454 (36)
65,458
2379
11,101 (33)
236 (27)
64,585
873
Mastectomy with radiotherapy
6897 (20)
187 (15)
41,418
1045
6692 (20)
205 (24)
40,708
710
Lumpectomy with radiotherapy
15,957 (47)
631 (50)
98,653
3688
15,539 (47)
418 (49)
97,154
1499
Systemic therapy, n (%)
No
2091 (6)
73 (6)
10,265
269
2046 (6)
45 (5)
10,089
176
Yes
32,100 (94)
1199 (94)
195,265
6843
31,286 (94)
814 (95)
192,358
2906
Chemotherapy, n (%)
No
23,233 (68)
965 (76)
135,848
5277
22,713 (68)
520 (61)
133,933
1915
Yes
10,958 (32)
307 (24)
69,681
1835
10,619 (32)
339 (39)
68,514
1167
Endocrine therapy, n (%)
No
16,117 (47)
577 (45)
88,710
2885
15,754 (47)
363 (42)
87,396
1314
Yes
18,074 (53)
695 (55)
116,819
4227
17,578 (53)
496 (58)
115,051
1768
Radiotherapy, n (%)
No
11,337 (33)
454 (36)
65,458
2379
11,101 (33)
236 (27)
64,585
873
Yes
22,854 (67)
818 (64)
140,071
4733
22,231 (67)
623 (73)
137,862
2209
Co-medication at baseline, n (%)
Simvastatin user
1791 (5)
135 (11)
9321
716
1753 (5)
38 (4)
9217
103
Aspirin user
447 (1)
23 (2)
2540
117
439 (1)
8 (1)
2503
36
1In person-years. 2According to Danish Data Protection Law, cell with very few individuals are not allowed to be presented. 3Charlson Comorbidity Index (CCI) without cancer included (low: score of 1 or 2; high: score of 3 or more). 4Histological grade is based on a composite score including tubule formation, mitoses, and nuclear pleomorphy, all consistent of a score of 1, 2, or 3. The scores are summarised, and a total score of 3–5 is categorised as low grade, 6–7 as moderate grade, and 8–9 as high grade (http://www.dbcg.dk/PDF%20Filer/Kap_3_Patologi_22_juni_2017.pdf). 5Systematic recording of HER-2 status started in 2007 HER-2 is classified according to immunohistochemistry (Hercept test) and by fluorescent in situ hybridisation (FISH) (counts 60 dots, yet min 6 cells and max 60 cells). The ratio is given as gene/chromosome with 2 decimals. HER-2 positive includes ‘HER-2 score = 3 and FISH ≤ 2.00’. HER-2 negative includes ‘HER-2 score of 0, 1, or 2 and FISH ≤ 2.00’
During follow-up, 859 (2%) of the 34,191 women with normal thyroid at baseline developed hypothyroidism in a median follow-up time of 3.4 years. Compared with women with normal thyroid function, women who developed hypothyroidism during follow-up had a higher frequency of lymph node involvement and were more likely to be assigned chemo-, radio-, and/or endocrine therapy.
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Recurrence
In total, 5626 (16%) women with normal thyroid function and 184 (14%) women with prevalent hypothyroidism developed recurrent breast cancer including 61% and 62% distant recurrences, respectively. Among women with incident hypothyroidism, 79 (9%) developed recurrence during follow-up of which 62% were distant recurrences.
After adjusting for potential confounding factors, women with prevalent hypothyroidism had a similar risk of recurrence as women with normal thyroid function (adjusted HRprevalent 1.01, 95% CI 0.87–1.19). Likewise, there was little evidence of an association of incident hypothyroidism with breast cancer recurrence compared with normal thyroid function (adjusted HRincident 0.93, 95% CI 0.75–1.16) (Table 2).
Table 2
Breast cancer recurrence and all-cause mortality, HR, and associated 95% CIs for women diagnosed with stage I–III, operable breast cancer in Denmark from 1996 to 2009 by hypothyroidism present at breast cancer diagnosis (prevalent) or during follow-up (incident)
Recurrence
All-cause mortality
Women with breast cancer (counts (%))
Recurrent events (counts (%))
Follow-up time (years)
HR (95% CI)
Women with breast cancer (counts (%))
All-cause mortality (counts (%))
Follow-up time (years)
HR (95% CI)
Crude
Adjusted
Crude
Adjusted
Prevalent hypothyroidism
Normal thyroid
34,191 (96)
5626 (16)
20,288
1.00
1.00
34,225 (96)
9696 (96)
36,907
1.00
1.00
Prevalent hypothyroidism
1272 (4)
184 (14)
594
0.94 (0.81–1.09)
1.01 (0.87–1.19)1
1273 (4)
398 (4)
1555
1.25 (1.13–1.39)
1.02 (0.92–1.14)1
Incident hypothyroidism
Normal thyroid
33,332 (97)
5547 (17)
20,075
1.00
1.00
32,827 (96)
9422 (97)
36,599
1.00
1.00
Incident hypothyroidism
859 (3)
79 (9)
213
1.00 (0.80–1.24)
0.93 (0.75–1.16)2
1398 (4)
274 (3)
307
1.15 (1.02–1.30)
1.08 (0.95–1.23)1
HR hazard ratio
1Adjusted for age at diagnosis, UICC stage, ER/ET use, surgery type, receipt of chemotherapy, menopausal status, comorbidity, histologic grade, and use of simvastatin or aspirin (as time-varying covariates updated daily and lagged by 1 year), respectively. 2Adjusted for age at diagnosis, UICC stage, ER/ET status, type of primary surgery, and chemotherapy
The findings were similar in pre-planned sensitivity analysis with drug exposures lagged by 2 years (data not shown). Stratifying by menopausal status, ER status, and receipt of chemotherapy and radiotherapy produced little change to the effect estimates as shown in Table 3. Restricting the analysis to patients who had hypothyroidism 2, 5, and 10 years before breast cancer diagnosis did not alter the results substantially (adjusted HR2year 1.00, 95% CI 0.84–1.18; adjusted HR5year 0.88, 95% CI 0.71–1.10; adjusted HR10year 0.91, 95% CI 0.63–1.31). The sensitivity analyses omitting surgery type and chemotherapy from the adjusted model did not alter the results (please see Additional file 2).
Table 3
Breast cancer recurrence and all-cause mortality, HR, and 95% CIs associating hypothyroidism status among stage I–III, operable breast cancer women diagnosed from 1996 to 2009 stratified by menopausal status, ER status, and chemo- and radiotherapy
Prevalent hypothyroidism
Incident hypothyroidism
Recurrence
Recurrence (counts)
HR (95% CI)
Recurrence (counts)
HR (95% CI)
Crude
Adjusted1
Crude
Adjusted2
Menopausal status
Premenopausal
1653
1.00 (0.70–1.43)
1.15 (0.79–1.69)
1622
1.30 (0.91–1.87)
1.24 (0.86–1.78)
Postmenopausal
4152
0.93 (0.79–1.09)
0.99 (0.83–1.17)
3999
0.87 (0.66–1.16)
0.82 (0.61–1.08)
ER status
Positive
4236
0.94 (0.79–1.11)
1.00 (0.83–1.19)
4099
0.97 (0.75–1.25)
0.93 (0.71–1.20)
Negative
1391
1.04 (0.77–1.39)
1.05 (0.76–1.45)
1346
1.08 (0.68–1.73)
1.02 (0.64–1.62)
Chemotherapy3
Yes
–
–
–
1950
1.01 (0.72–1.50)
0.97 (0.67–1.40)
No
–
–
–
3676
0.98 (0.74–1.29)
0.91 (0.69–1.21)
Radiotherapy3
Yes
–
–
–
3643
0.96 (0.73–1.25)
0.91 (0.69–1.20)
No
–
–
–
1983
1.11 (0.75–1.63)
0.99 (0.67–1.46)
All-cause mortality
Mortality (counts)
HR (95% CI)
Mortality (counts)
HR (95% CI)
Crude
Adjusted1
Crude
Adjusted1
Menopausal status
Premenopausal
1792
1.03 (0.73–1.47)
1.19 (0.82–1.71)
1760
1.24 (0.94–1.64)
1.15 (0.85–1.55)
Postmenopausal
8298
1.17 (1.05–1.30)
1.00 (0.89–1.12)
7932
1.13 (0.99–1.29)
1.06 (0.91–1.23)
ER status
Positive
7418
1.25 (1.11–1.40)
1.00 (0.88–1.13)
7118
1.13 (0.99–1.30)
1.06 (0.91–1.23)
Negative
2354
1.32 (1.07–1.63)
1.20 (0.95–1.50)
2263
1.27 (0.98–1.64)
1.24 (0.93–1.64)
Chemotherapy
Yes
2486
1.17 (0.92–1.48)
1.15 (0.90–1.48)
2416
1.18 (0.91–1.51)
1.12 (0.85–1.47)
No
7608
1.23 (1.11–1.38)
0.98 (0.87–1.11)
7280
1.16 (1.00–1.33)
1.06 (0.91–1.23)
Radiotherapy3
Yes
–
–
–
5316
1.13 (0.96–1.33)
1.08 (0.90–1.29)
No
–
–
–
4380
1.22 (1.02–1.46)
1.11 (0.91–1.34)
HR hazard ratio
1Adjusted for age at diagnosis, menopausal status, UICC stage, histologic grade, ER/ET use, surgery type, receipt of radio- and chemotherapy, comorbidity, and use of simvastatin or aspirin, respectively. 2Adjusted for age at diagnosis, UICC stage, ER/ET use, surgery type, and receipt of chemotherapy. 3Only evaluated for incident hypothyroidism
All-cause mortality
The study cohort for all-cause mortality included a further 35 women with breast cancer that had been excluded previously due to incomplete follow-up for recurrence. Overall, 10,094 women with breast cancer died during the study period of whom 398 (3%) were women with prevalent hypothyroidism and 274 (3%) were women who developed hypothyroidism during follow-up.
Women with prevalent hypothyroidism had a higher mortality risk than women with normal thyroid function (crude HRprevalent 1.25, 95% CI 1.13–1.39), but the association attenuated after adjusting for confounders (adjusted HRprevalent 1.02, 95% CI 0.92–1.14)—histological grade, UICC stage, type of surgery, and comorbidity burden.
Compared with women with normal thyroid function, women with incident hypothyroidism had a slightly increased risk of dying (crude HRincident 1.15, 95% CI 1.02–1.30), which attenuated after adjusting for confounders (adjusted HRincident 1.08, 95% CI 0.95–1.23)—histological grade, UICC stage, type of surgery, and comorbidity burden.
Stratifying by menopausal status, ER status, and receipt of chemotherapy and radiotherapy did not alter these findings (Table 3). Furthermore, restricting to patients with prevalent hypothyroidism in 2, 5, and 10 years, or drug exposures lagged by 2 years did not affect the estimates substantially (data not shown).
Discussion
Evidence from our large cohort study does not support an association between hypothyroidism present at the time of diagnosis or during follow-up and breast cancer recurrence and all-cause mortality. For both recurrence and all-cause mortality, the near-null findings were not modified after stratification by menopausal status, ER status, chemotherapy, or radiotherapy or by duration of hypothyroidism prior to breast cancer diagnosis.
Our study has several strengths. We studied a large, nationwide cohort of women with breast cancer treated in a tax-supported and uniformly organised health care system with complete follow-up. Thus, selection bias seems unlikely. Furthermore, all breast cancer patients registered in the DBCG undergo standardised medical follow-up visits up to 10 years after primary diagnosis and any recurrent breast cancers are systematically registered in the DBCG [24]. Overall, 77% of patients diagnosed with an incident breast cancer from 2006 to 2015 attended the entire follow-up programme with higher attendance among younger patients (~ 81%) compared with patients aged over 75 years (~ 74%). In addition, the systematic collection of data on clinical, tumour, and treatment characteristics on all breast cancer patients enabled us to account for important potential confounders that could affect the risk of recurrence and mortality. The completeness of the DNPR is high [28]. The positive predictive value is 80, in general, and higher for conditions that always lead to hospitalisation. However, for conditions like hypothyroidism, the completeness may not be as high as this is often treated outside a hospital setting by a general practitioner. We therefore supplemented our study using data from the Danish National Prescription Registry. In the models of incident hypothyroidism, we used a time-varying approach to eliminate immortal time bias and lagged the exposure to eliminate reverse causation [31, 35].
Our study is also subject to some limitations. Hypothyroidism is underreported in the general population probably due to non-specific symptoms such as weight gain, fatigue, and memory loss, all of which may increase with age [4, 36]. In this study, we defined hypothyroidism from diagnosis codes or redeemed prescriptions but not by measures of hormone levels in blood samples as these were unavailable. Therefore, we cannot comment on the relationship between underlying hormone levels and breast cancer recurrence. In addition, we had no information on untreated subclinical hypothyroidism. We therefore cannot rule out the likelihood of undiagnosed and thus misclassified hypothyroidism among the women with breast cancer, which may bias our findings towards the null. Furthermore, our findings may be prone to residual confounding—for example, information on medication use (dosage and prescription compliance) and lifestyle factors associated with breast cancer or hypothyroidism (smoking, obesity, and physical activity) were not captured by the registries [37, 38]. Given the absence of data on actual hormone levels, an analysis comparing actual thyroid hormone values to recurrence risk could not be performed. Last, our definition of hypothyroidism was based on diagnostic codes and/or prescriptions for levothyroxine substitution therapy. As such, the impact of treating hypothyroidism may dilute the effect of hypothyroidism on recurrence. In total, 96.7% of the women with hypothyroidism in our study were on levothyroxine substitution. This may be a potential reason why our hypothesis of a positive effect of hypothyroidism on recurrence, as suggested by the laboratory models, was not confirmed [20, 21].
Previous studies on the association of thyroid function with survival in breast cancer patients have compared survival according to levels of thyroid hormones [39, 40] or using cancer-free controls [37, 41, 42]. To our knowledge, only two studies have investigated the association of hypothyroid disease with survival in a cohort of breast cancer patients [43, 44]. However, one of these—the Malmø Diet and Cancer Study by Brandt et al.—is not comparable to ours as thyroid hormone measurements were collected at the time of inclusion into the study, on average 5 years before the time of breast cancer diagnosis [44]. The study by Fiore et al. only included breast cancer patients with aggressive tumours and performed blood tests to assess thyroid function after surgery and before treatment [43]. By measuring actual levels of thyroid hormone, they were able to detect not only overt hypothyroidism but also subclinical hypothyroidism. However, their study was small, including only 47 patients and only two cases of subclinical hypothyroidism; thus, estimates were presented for all types of thyroid dysfunction. Similarly, a study by Jiskra et al. was hampered by a small sample size (84 patients) and consequently had a low number of cases with hypothyroidism [37]. Jiskra et al. also found no association of levels of thyroid hormones with relapse-free or overall survival in breast cancer patients compared with cancer-free controls. However, these latter two studies were likely underpowered for the hypothyroidism-breast cancer association. Thus, our prospective cohort study is the first to distinguish between the association of prevalent and incident hypothyroidism on the risk of breast cancer recurrence and overall mortality.
In our data, we note that 91% of patients with hypothyroidism were retrieved from the prescription registry, while the remainder were ascertained based on hospital diagnoses of hypothyroidism. This is not surprising as most cases of hypothyroidism are likely to be diagnosed and treated by a general practitioner. Furthermore, this highlights the importance of considering both diagnostic codes and prescription medications in future studies on hypothyroidism.
Conclusion
This prospective cohort study suggests that hypothyroidism present at the time of diagnosis or incident during follow-up is not associated with breast cancer recurrence or all-cause mortality. From a clinical point of view, this is reassuring for patients who suffer from hypothyroidism and for their physicians highlighting that hypothyroidism is unlikely to have an unfavourable impact on the clinical course of breast cancer or survival.
Acknowledgements
The authors thank the Danish Clinical Registries (RKKP) including The Danish Breast Cancer Group for their kind help with making the data available.
Funding
This work was supported by a grant from The Independent Research Fund Denmark, Medicine (DFF-4183-00359) and a grant from ‘Eva & Henry Frænkels Mindefond’.
Availability of data and materials
The data used in this study are available from the DBCG database and the national medical registries. However, data are only available for the authors due to the legislation of data protection.
Ethics approval and consent to participate
According to Danish law, ethical approval and informed content are not necessary because the study uses routinely collected data in the national registries.
Consent for publication
Not applicable (see Ethics approval)
Competing interests
The authors declare that they have no competing interests.
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Hypothyroidism and the risk of breast cancer recurrence and all-cause mortality - a Danish population-based study
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Anne Mette Falstie-Jensen Anders Kjærsgaard Ebbe Laugaard Lorenzen Jeanette Dupont Jensen Kristin Valborg Reinertsen Olaf M. Dekkers Marianne Ewertz Deirdre P. Cronin-Fenton
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