The Influence of Adjuvant Systemic Regimens on Contralateral Breast Cancer Risk and Receptor Subtype

Iris Kramer; Michael Schaapveld; Hester S. A. Oldenburg; Gabe S. Sonke; Danielle McCool; Flora E. van Leeuwen; Koen K. Van de Vijver; Nicola S. Russell; Sabine C. Linn; Sabine Siesling; C. Willemien Menke-van der Houven van Oordt; Marjanka K. Schmidt


J Natl Cancer Inst. 2019;111(7):709-718. 

In This Article

Abstract and Introduction


Background: An increasing number of breast cancer (BC) survivors are at risk of developing contralateral breast cancer (CBC). We aimed to investigate the influence of various adjuvant systemic regimens on, subtype-specific, risk of CBC.

Methods: This population-based cohort study included female patients diagnosed with first invasive BC between 2003 and 2010; follow-up was complete until 2016. Clinico-pathological data were obtained from the Netherlands Cancer Registry and additional data on receptor status through linkage with PALGA: the Dutch Pathology Registry. Cumulative incidences (death and distant metastases as competing risk) and hazard ratios (HRs) were estimated for all invasive metachronous CBC and CBC subtypes.

Results: Of 83 144 BC patients, 2816 developed a CBC; the 10-year cumulative incidence was 3.8% (95% confidence interval [CI] = 3.7% to 4.0%). Overall, adjuvant chemotherapy (HR = 0.70, 95% CI = 0.62 to 0.80), endocrine therapy (HR = 0.46, 95% CI = 0.41 to 0.52), and trastuzumab with chemotherapy (HR = 0.57, 95% CI = 0.45 to 0.73) were strongly associated with a reduced CBC risk. Specifically, taxane-containing chemotherapy (HR = 0.48, 95% CI = 0.36 to 0.62) and aromatase inhibitors (HR = 0.32, 95% CI = 0.23 to 0.44) were associated with a large CBC risk reduction. More detailed analyses showed that endocrine therapy statistically significantly decreased the risk of estrogen receptor (ER)-positive CBC (HR = 0.41, 95% CI = 0.36 to 0.47) but not ER-negative CBC (HR = 1.32, 95% CI = 0.90 to 1.93) compared with no endocrine therapy. Patients receiving chemotherapy for ER-negative first BC had a higher risk of ER-negative CBC from 5 years of follow-up (HR = 2.84, 95% CI = 1.62 to 4.99) compared with patients not receiving chemotherapy for ER-negative first BC.

Conclusion: Endocrine therapy, chemotherapy, as well as trastuzumab with chemotherapy reduce CBC risk. However, each adjuvant therapy regimen had a different impact on the CBC subtype distribution. Taxane-containing chemotherapy and aromatase inhibitors were associated with the largest CBC risk reduction.


Breast cancer (BC) survival has increased considerably, largely as a result of increasing use of (neo)adjuvant therapies.[1] As a consequence, a greater number of women are at risk of developing a second primary tumor in the contralateral breast. Studies have shown that the 10-year risk of contralateral breast cancer (CBC) is 4–7%.[2–5]

There is increasing evidence that patients who received adjuvant endocrine therapy or chemotherapy for their first BC have a lower risk of developing CBC. The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) showed that 5-year tamoxifen use was associated with a 38% reduction in CBC risk after 10 years of follow-up,[6] and adjuvant chemotherapy was associated with a 20% decrease.[7]

CBC patients may have a worse prognosis compared with patients with unilateral BC.[2,4,8,9] An explanation for this worse prognosis, besides having been diagnosed with yet another cancer, may be found in the impact of adjuvant systemic therapy on CBC tumor biology,[9] or misclassification of metastatic disease as a CBC.[8]

Little is known about the influence of adjuvant systemic therapy on the (hormone) receptor subtype of CBC. Some studies showed a higher proportion of estrogen receptor (ER)-negative CBC among patients who received endocrine therapy for their first BC compared with those who did not.[10–14] The studies that evaluated the effects of adjuvant therapy on subtype-specific CBC risk, however, were based on small numbers. Since adjuvant trastuzumab was introduced for early-stage BC in 2005, the impact on CBC risk has not yet been described.

We therefore aimed to investigate the influence of different regimens of adjuvant endocrine therapy, chemotherapy, and trastuzumab on CBC risk overall and by (hormone) receptor subtype within a large population-based cohort of women diagnosed with invasive BC.