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Table 2 Summary of epidemiological studies investigating exposure to environmental chemical disruptors and breast cancer aggressivity/progression or survival

From: Environmental chemicals, breast cancer progression and drug resistance

Year/Country Studies (ref) Study design Study population (percentage premenopausal) Type of chemicals investigated Measurment of exposure Time at measurement Outcome(s) Results - hazard ratios Conclusion/Comments
2000
Danemark
[69] Cohort 195 women with breast cancer Organochlorines Serum
Dieldrin
HCB
DDE, DDT and their metabolites
27 PCB
(28, 42, 66, 74, 99, 101, 105, 110, 118, 138,146, 153, 156, 170, 172, 177, 178, 180, 183, 187, 189, 193,194, 195, 201, 203, and 206)
At diagnosis;
from 1976 to 1978
Association DDT and DDE levels and breast cancer survival Dieldrin exposure was associated with a decrease overall survival
OR = 4.6 (95% CI = 1.8–11.5)
Exposure to estrogenic organochlorines such as dieldrin may affect breast cancer survival
2000
Canada
[58] Case control 315 women newly diagnosed with breast cancer
307 controls
Organochlorines Serum
14 PCB congeners (28,52,99,101,105,118,128,138,153,156,170,180,183,187)
11 chrorinated pesticides or their metabolites (aldrin, α-chlordane, γ-chlordane, p,p′-DDT, p,p′-DDE, hexachlorobenzene, β-HCH, mirex, cis-nonachlor, trans-nonachlor, oxychlordane)
At diagnosis; from 1994 to 1997 Association between organochlorine concentrations and tumor size and axillary lymph node involvement ↑ risk of lymph node involvement with exposure to p,p′-DDE
OR = 2.54 (95% CI = 1.20–5.35)
(comparison between highest and lowest tertiles)
Dose related increased risk for DDE and large tumors withlymph node involvement
Associations between
tumor size and lymph-node involvement for betaHCH, oxychlordane, and trans-nonachlor
↑ risk of lymph node involvement with PCB 153 (chosen as a surrogate for all the highly prevalent PCBs)
OR = 2.12 (95% CI = 1.5–4.30)
No interaction between organochlorine exposure and the hormonal status of the tumor with regard to either axillary-lymph-node involvement or tumor size (204 patients)
p,p’-DDE and PCB 153 exposure could be associated with a more aggressive breast cancer phenotype regardless of ER status
2001
USA
[80] Case control 88 women with unilateral invasive breast cancer and pulmonary metastatic disease matched with 176 controls patients without metastatic disease Tabacco smoke Smoking “dose” not available
No chemicals measured
At diagnosis; no information about period Association between cigarette smoking and the development of pulmonary metastatic disease −24.1% in case patients active smokers vs 15.3% in control
Unadjusted OR = 1.76 (no IC), p = 0,06
-Multivariate analysis including hormonal therapy and presence of other metastatic sites:
OR = 1,96 (95%IC = 0.96–4.02), p = 0.06
Cigarette smoking could increase pulmonary metastatic disease risk
2001
Danemark
[59] Case control 240 women with breast cancer and 477 controls Organochlorines Dieldrin
HCB
27 PCB
(28, 42, 66, 74, 99, 101, 105, 110, 118, 138,146, 153, 156, 170, 172, 177, 178, 180, 183, 187, 189, 193,194, 195, 201, 203, and 206)
At diagnosis;
from 1976 to 1978
Association between organochlorine concentrations and breast cancer risk and survival according to estrogen receptor status Sum of PCB was significantly associated with risk of death among women with ER+ tumors
OR = 2.5 (95%CI = 1.1–5.7)
Dieldrin exposure was associated with elevated mortality among women with ER+ tumors
Suggests a link between PCB & dieldrin exposure and ER tumors progression
2002
Canada
[60] Case control 314 women with breast cancer and 523 controls Polychlorinated biphenyls Serum
14 PCB
(28, 52, 99, 101, 105, 118, 128, 138, 153, 156, 170, 180, 183 and 187)
At diagnosis; from 1994 to 1996 Association between PCB exposure and breast cancer risk No association was found between PCB congeners and both tumor size and lymph node involvement N/A
2003
USA
[61] Cohort 224 women with nonmetastatic breast cancer Organochlorines Serum and adipose tissue
7 pesticides including DDE and DDT
DDE
trans-nonachlor, oxychlordane, β-HCH)
14 PCB (74, 99, 118, 138, 146, 153, 156, 167, 170, 172, 178, 180, 183, 187)
At diagnosis; from 1994 to 1996 Association between organochlorine concentrations and breast cancer recurrence Total PCB levels were associated with an increased risk of breast cancer recurrence
OR = 2.9, 95% CI = 1.02–8.2)
(comparison between highest and lowest tertiles)
Higher risk for PCB 118
OR = 4.0 (95% CI, 1.3–4.9)
ORs for most PCB congeners were elevated, ORs > 2 for 118, 138,
153, 167, 183, and 187.
Association DDT and DDE levels and breast cancer recurrence
Statistically unstable elevated risk of recurrence associated with HCB, β-HCH, and trans-nonachlor
PCB, DDT and DDE exposure could be associated with cancer recurrence
2012
Brasil
[93] Case control 81 women
38 controls, 9 benign tumors (fibroadenoma) and 34 breast cancer (both in situ and infiltrating ductal carcinomas)
Total of 106 samples of breast tissue (34 from premonopausal patient)
Medical record available for 57 patients
Trace element Breast tissue total amount of Iron (Fe), Copper (Cu), Calcium (Ca) and Zinc (Zn)
+
Amount 2 cm away from the tumor (benign and malignant tumor)
At diagnosis; from 2003 to 2006 Overall survival Patients with positive expression for Cu presented a poor overall survival (p < 0.001) Exposure to copper could be associated with a decreased overall survival of breast cancer patients
2016
USA
[68] Cohort 633 women with a first primary invasive or in situ breast cancer
(66% postmenopausal)
Organochlorines Serum DDT, DDE and chlordane At diagnosis; from 1996 to 1997 Association between organochlorine concentration and overall and breast cancer-specific 5-year and 15-year mortality −5-year overall mortality
(comparison between highest and tertiles 2 and 3)
DDT
HR = 2.19 (95% CI = 1.02, 4.67)
− 5-year breast cancer-specific mortality
HR = 2.72 (95% CI = 1.04, 7.13)
- At 15 years, concentrations of DDT and chlordane were modestly associated with overall and breast cancer-specific mortality (HR = 1.42 (95% CI =0.99, 2.06) and HR = 1.42 (95% CI = 0.94, 2.12) respectively)
DDT concentration was associated with all-cause and breast cancer-specific mortality
2016
USA
[63] Cohort 627 women with a first primary invasive or in situ breast cancer Polychlorinated biphenyls Serum
22 PCB individually and by estrogenic group (101, 174, 177, 187, 199), antiestrogenic group (66, 74, 105, 118, 138, 170) and cytochrome P450 enzyme inducing group (99, 153, 180, 183, 203)
At diagnosis; from 1996 to 1997 Association between polychlorinated biphenyls
concentration and overall and breast cancer-specific 5-year and 15-year mortality
−5-year overall mortality
(comparison between highest and tertiles 2 and 3)
PCB 174
HR = 2.22 (95% CI = 1.14–4.30)
PCB177
HR = 2.12 (95% CI = 1.05–4.30)
− 5-year breast cancer-specific mortality
HR = 3.15 (95% CI = 1.23–8.09)
−15-year breast cancer-specific mortality
PCB 174
HR = 1.88 (95% CI = 1.05–3.36)
PCB118 and antiestrogenic group
inversely associated with overall mortality
HR = 0.60 (95% CI = 0.39–0.83 and HR = 0.63 (95% CI = 0.43–0.92) respectively
See left column
2016
Spain
[62] Cohort 103 women newly diagnosed with breast cancer
(40.8% postmenopausal)
Organochlorines Serum and adipose tissue
p,p’-DDE, HCB
PCB 138
PCB 153
PCB 180
From 2012 to 2014 Association between exposure to a group of organochlorines and tumor prognostic markers HCB levels were associated with:
-ER and PR expression (p-trends = 0.044 and 0.005, respectively)
-decreased E-Cadherin expression (p-trends = 0.012) and p53 expression (p-trends = 0.027)
PCB 180 adipose tissue levels were associated with HER2 expression (p-trend = 0.036)
PCB 138 Serum were associated with - ER and PR expression (p-trends = 0.052 and 0.042, respectively)
Exposure to certain persistent organic pollutants (HCB, PCB 138 & 180) might be related to breast cancer aggressiveness
2017
Ukraine
[92] Case control 40 samples of breast cancer tissue and 20 samples of intact breast tissue Toxic metals Breast tissue total amount of Iron (Fe), Copper (Cu), Zinc (Zn), Lead (Pb), Chromium (Cr) and Nickel (Ni) At diagnosis Link between chemical composition of neoplasic breast tissue and DNA methylation level, O6-methyguanine-DNA methyltransferase levels
and prognostic-important receptors expression
The growth of toxic metals in neoplastic tissue is accompanied with:
↑ HER2/neu (r = 0.36, p < 0.05)
↑ p53 (r = 0.53, p < 0.01)
↑ Ki-67 (r = 0.47, p < 0.01)
↑ O6-methyguanine-DNA methyltransferase (r = 0.34, p < 0.05)
↓ ER (r = − 0.71, p < 0.01)
↓ PR (r = − 0.66, p < 0.01)
↑ pathological DNA methylation in tumor tissue (r = 0.41, p < 0.01)
Several toxic metals could stimulate the progression of breast cancer and reduce its sensitivity to treatment
2019
USA
[70] Case control 456 white and 292 black women with breast cancer Organochlorines Serum
lipid-standardized DDT and DDE levels
4.1 months after diagnosis; patient included from 1993 to 1996 Breast cancer-specific 5-year mortality
Overall 20-year mortality conditional on 5-year survival
−20-year conditional overall mortality
1/ DDE: HR =1.95 (95% CI = 1.31–2.92)
(comparison between
highest versus lowest DDE tertile)
2/DDT: HR = 1.64 (95% CI = 1.10–2.44) (comparison highest vs undetectable DDT quantile)
- 20-year conditional breast cancer-specific mortality
1/DDE: comparison levels above versus below the median)
Among women overall:
HR = 1.69 (95% CI = 1.06–2.68)
Among black women:
HRs =2.36 (95% CI = 1.03–5.42)
Among white women: OR = 1.57 (95% CI = 0.86–2.89) (PInteraction = 0.42).
Among women with ER- tumors:
OR = 3.24 (95% CI = 1.38–7.58)
Among women with ER+ tumors:
OR = 1.29 (95% CI = 0.73–2.28) (PInteraction = 0.03).
Exposure to DDE/DDT may impact overall and breast cancer-specific survival
2019
France
[56] Case control 91 women newly diagnosed with breast cancer
53 nonmetastatic and 38 metastatic (lymph node involvement)
49 persistent organic pollutants including PCB, PBDE, PBB and HBCD Serum and adipose peritumoral tissue At diagnosis; 2013–2017 Association between pollutants concentrations and lymph node involvement 2.3.7.8-TCDD concentrations in adipose tissue are associated with the risk of lymph node metastasis in patients with BMIs equal or higher than 25 kg/m2
OR = 4.48 (95%CI = 1.32–20.71)
2.3.7.8-TCDD concentrations and PCB 77 and 169 in adipose tissue are associated with risk of lymph node metastasis and tumor size
2.3.7.8-TCDD could contribute to the development of tumor metastasis in overweight patients