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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