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Risk Factors for Estrogen Receptor Subtype-Specific Contralateral Breast Cancer in Women Under Age 55 Years
Anne S Reiner1, Kathleen E Malone2, Charles F Lynch3
1Memorial Sloan Kettering Cancer Center, New York, New York, USA.
International Journal of Cancer
|August 7, 2026
Summary
Estrogen receptor negative (ER-) contralateral breast cancer (CBC) is deadlier than ER+ CBC. This study identified distinct risk factors, including lifestyle and genetics, for ER- and ER+ CBC subtypes.
Area of Science:
- Oncology
- Epidemiology
- Genetics
Background:
- Estrogen receptor negative (ER-) contralateral breast cancer (CBC) presents a significantly higher mortality risk (50%) compared to estrogen receptor positive (ER+) CBC.
- Understanding the distinct risk factors for ER- and ER+ CBC is crucial for developing targeted prevention and treatment strategies.
Purpose of the Study:
- To comprehensively investigate and identify differential risk factors associated with ER subtype-specific contralateral breast cancer (CBC).
- To explore the influence of lifestyle, reproductive history, and genetic factors on ER- and ER+ CBC risk.
- To inform the development of individualized risk prediction models for clinical application.
Main Methods:
- A population-based, case-control study (Women's Environmental Cancer and Radiation Epidemiology Study) involving 1521 CBC cases and 2212 matched unilateral breast cancer controls under age 55.
- Data collection included interviews, medical record abstraction for risk factors and ER status, and genome-wide association studies (GWAS) for genetic variants.
- Conditional logistic regression models were used to estimate multivariable rate ratios and 95% confidence intervals, adjusting for known and suspected risk factors.
Main Results:
- For ER+ CBC, decreased risk was associated with chemotherapy, hormone therapy, and increased pregnancies, while increased risk was linked to drinking, smoking, lobular histology, family history, and polygenic risk scores (PRS).
- For ER- CBC, decreased risk was associated with over 2 years of breastfeeding, whereas increased risk was associated with family history of breast and ovarian cancer. No PRS was significantly associated with ER- CBC risk.
- Differential risk factors were identified for ER- and ER+ CBC, highlighting the heterogeneity between these subtypes.
Conclusions:
- Distinct risk factor profiles exist for estrogen receptor negative (ER-) and estrogen receptor positive (ER+) contralateral breast cancer (CBC).
- Lifestyle, reproductive factors, and genetic predispositions play differential roles in the development of ER- and ER+ CBC.
- Further research is needed to elucidate the unexplained genetic component contributing to ER- CBC risk and to refine predictive models.
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