Breast cancer survivors may have increased risk of subsequent haematologic cancer. We compared their risk of haematologic cancers with the general population during 38 years of follow-up.
Using population-based Danish medical registries, we assembled a nationwide cohort of women diagnosed with incident non-metastatic breast cancer during 1980–2017, with follow-up through 2018. We compared breast cancer survivors with the general population by computing standardised incidence ratios (SIR) and 95% confidence intervals (CI).
Among 101,117 breast cancer survivors, we observed 815 incident haematologic cancers (median follow-up: 7.9 years). We observed excess risk of acute myeloid leukaemia (AML) (SIR: 1.65, 95%CI: 1.33–2.01), particularly in women who received chemotherapy (SIR: 3.33, 95%CI: 2.24–4.75) and premenopausal women (SIR: 3.23, 95%CI: 2.41–4.25). The risk of acute lymphoid leukaemia (ALL) was increased (SIR: 2.25, 95%CI: 1.29–3.66), whereas the risk of chronic lymphoid leukaemia (CLL) was decreased (SIR: 0.66, 95%CI: 0.53–0.82). An additional analysis showed elevated risk of CLL 0–6 months after breast cancer diagnosis (SIR: 3.00 95%CI: 1.75–4.80).
Compared to the general population, breast cancer survivors had elevated risk of AML, particularly when treated with chemotherapy. The risk of ALL was elevated, whereas the risk of CLL was lower. The higher risk of CLL in the first six months after diagnosis likely reflects surveillance bias—due to intensified diagnostic efforts at breast cancer diagnosis and treatment—prompting earlier detection. This has likely reduced the long-term risk of CLL in breast cancer survivors.
- • Women undergoing contemporary breast cancer treatments are at risk of developing AML and ALL.
- • AML and ALL after breast cancer may be partly explained by chemotherapy. Shared risk factors may also contribute to this association.
- • Previous findings of decreased risk of CLL might be influenced by surveillance bias.
Breast cancer is the most commonly diagnosed malignancy in women . Population-based mammography screening, and increasingly effective treatments have contributed to increased prevalence of long-term breast cancer survivors. Hence, breast cancer survivors represent over one-third of all female five-year cancer survivors worldwide . These women are at risk of developing new primary cancers either due to shared etiologies or breast cancer-directed treatment .
Studies investigating the risk of haematologic cancer after breast cancer document an increased incidence of myeloid and lymphoid leukaemia , and non-Hodgkin’s lymphoma (NHL) . Yet, most of these studies do not include women undergoing current treatment recommendations . Guideline for breast cancer treatment has evolved over the past 30–40 years . In Denmark, during the 1980 s, guideline for chemotherapy included cyclophosphamide, metotrexane and fluorouracil (CMF) administered in nine four-week cycles (600, 40 and 600 mg/m 2 , respectively). Since 1990, CMF was gradually replaced by cyclophosphamide, epirubicin and 5-fluorouracil (CEF) administered as nine three-week cycles (600, 60 and 600 mg/m 2 , respectively). In 2007, 5-fluorouracil was replaced by taxanes administered as three cycles of docetaxel (100/m 2 ) subsequent to three cycles of epirubicin and cyclophosphamide (EC, 90 and 600 mg/m 2 , respectively) administered at three-week intervals . In 2008, this regime was supplemented with prophylactic granulocyte colony-stimulating factor (G-CSF) . Though being used throughout follow-up, docetaxel has since 2013 been gradually replaced by nine weekly cycles of paclitaxel. Tamoxifen therapy was consolidated with aromatase inhibitors for postmenopausal women from 2004 ; and the duration of tamoxifen therapy was extended to up to ten years after primary diagnosis. It is important to examine the potential influence of these changes on the risk of haematologic malignancies after breast cancer.
Recent studies including women reflecting contemporary treatments may have been prone to immortal time bias as women who developed haematologic malignancies in the first six months after breast cancer diagnosis were excluded, yet follow-up began at the time of diagnosis . Furthermore, the studies included women participating in a health insurance programme or were based on the SEER cancer registries, which may not be representative of the entire population . We therefore evaluated the risk of haematologic cancers after primary breast cancer diagnosis in a nationwide population-based study in Denmark, where all residents have access to free tax-funded healthcare, including cancer care .