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

Abstract

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.

Contralateral breast cancer risk in patients with ductal carcinoma in situ and invasive breast cancer

“…The slightly higher invasive CBC risk in DCIS patients compared with all invasive BC patients may be explained by the risk-reducing effect of adjuvant systemic therapy among invasive BC patients 6 , 20 , 21 . In our previous study using NCR data 6 we showed that adjuvant endocrine therapy, chemotherapy, and trastuzumab combined with chemotherapy were associated with overall 54%, 30%, and 43% risk reductions of CBC, respectively. In our study, a large group (57%) of patients with invasive BC received (neo)adjuvant systemic therapy.…”

“…This may be explained by underlying etiological factors and/or be related to the use of adjuvant systemic therapy among invasive BC patients. Studies have shown that adjuvant systemic therapy influences subtype-specific CBC risk, e.g., endocrine therapy strongly reduces the risk of developing ER-positive CBC, but not ER-negative CBC 6 , 21 . This is supported by our subgroup analyses in patients with stage I BC not receiving adjuvant systemic therapy, who tended to develop similar CBC subtypes compared with DCIS patients.…”

“…Contralateral breast cancer (CBC) is the most frequent second cancer reported after first invasive breast cancer (BC) 1 – 3 . The cumulative incidence of invasive CBC for women following invasive BC is ~0.4% per year 4 – 6 . Several studies have shown a decrease in CBC incidence as a result of (neo)adjuvant systemic therapies 6 – 8 .…”

“…The cumulative incidence of invasive CBC for women following invasive BC is ~0.4% per year 4 – 6 . Several studies have shown a decrease in CBC incidence as a result of (neo)adjuvant systemic therapies 6 – 8 .…”

“…On the other hand, an indirect assessment between DCIS patients and invasive BC patients has been provided by a CBC risk prediction model developed and validated in the USA, showing a higher relative CBC risk for DCIS compared with invasive BC (relative risk: 1.60, 95% confidence interval (CI) = 1.42–1.93) 18 , 19 . The reason for a potential higher CBC risk for DCIS patients is still unclear, but might relate to the risk-reducing effect of adjuvant systemic therapy among invasive BC patients 6 , 20 , 21 . In general, relatively few DCIS patients receive adjuvant systemic therapy.…”