A Randomized Phase IIb Study of Low-dose Tamoxifen in Chest-irradiated Cancer Survivors at Risk for Breast Cancer.

PURPOSE: Low-dose tamoxifen reduces breast cancer risk, but remains untested in chest-irradiated cancer survivors-a population with breast cancer risk comparable with BRCA mutation carriers. We hypothesized that low-dose tamoxifen would be safe and efficacious in reducing radiation-related breast cancer risk. PATIENTS AND METHODS: We conducted an investigator-initiated, randomized, phase IIb, double-blinded, placebo-controlled trial (FDA IND107367) between 2010 and 2016 at 15 U.S. sites. Eligibility included ≥12 Gy of chest radiation by age 40 years and age at enrollment ≥25 years. Patients were randomized 1:1 to low-dose tamoxifen (5 mg/day) or identical placebo tablets for 2 years. The primary endpoint was mammographic dense area at baseline, 1 and 2 years. IGF-1 plays a role in breast carcinogenesis; circulating IGF-1 and IGF-BP3 levels at baseline, 1 and 2 years served as secondary endpoints. RESULTS: Seventy-two participants (low-dose tamoxifen: n = 34, placebo: n = 38) enrolled at a median age of 43.8 years (35-49) were evaluable. They had received chest radiation at a median dose of 30.3 Gy. Compared with the placebo arm, the low-dose tamoxifen arm participants had significantly lower mammographic dense area (P = 0.02) and IGF1 levels (P < 0.0001), and higher IGFBP-3 levels (P = 0.02). There was no difference in toxicity biomarkers (serum bone-specific alkaline phosphatase, lipids, and antithrombin III; urine N-telopeptide cross-links) between the treatment arms. We did not identify any grade 3-4 adverse events related to low-dose tamoxifen. CONCLUSIONS: In this randomized trial in chest-irradiated cancer survivors, we find that low-dose tamoxifen is effective in reducing established biomarkers of breast cancer risk and could serve as a risk-reduction strategy.

Subsequent Neoplasms After a Primary Tumor in Individuals With Neurofibromatosis Type 1.

PURPOSE: Fundamental gaps in knowledge regarding the risk of subsequent neoplasms (SNs) in children with pathogenic neurofibromatosis type 1 (NF1) variants exposed to radiation and/or alkylator chemotherapy have limited the use of these agents. METHODS: We addressed these gaps by determining the SN risk in 167 NF1-affected versus 1,541 non-NF1-affected 5-year childhood cancer survivors from the Childhood Cancer Survivor Study and 176 nonoverlapping NF1-affected individuals with primary tumors from University of Alabama at Birmingham and Children's Hospital of Philadelphia exposed to radiation and/or chemotherapy. Proportional subdistribution hazards multivariable regression analysis was used to examine risk factors, adjusting for type and age at primary tumor diagnosis and therapeutic exposures. RESULTS: In the Childhood Cancer Survivor Study cohort, the 20-year cumulative incidence of SNs in NF1 childhood cancer survivors was 7.3%, compared with 2.9% in the non-NF1 childhood cancer survivors (P = .003), yielding a 2.4-fold higher risk of SN (95% CI, 1.3 to 4.3; P = .005) in the NF1-affected individuals. In the University of Alabama at Birmingham and Children's Hospital of Philadelphia cohort, among NF1-affected individuals with a primary tumor, the risk of SNs was 2.8-fold higher in patients with irradiated NF1 (95% CI, 1.3 to 6.0; P = .009). In contrast, the risk of SNs was not significantly elevated after exposure to alkylating agents (hazard ratio, 1.27; 95% CI, 0.3 to 3.0; P = .9). CONCLUSION: Children with NF1 who develop a primary tumor are at increased risk of SN when compared with non-NF1 childhood cancer survivors. Among NF1-affected children with a primary tumor, therapeutic radiation, but not alkylating agents, confer an increased risk of SNs. These findings can inform evidence-based clinical management of primary tumors in NF1-affected children.

Clinical and Genetic Risk Prediction of Subsequent CNS Tumors in Survivors of Childhood Cancer: A Report From the COG ALTE03N1 Study.

Purpose Survivors of childhood cancer treated with cranial radiation therapy are at risk for subsequent CNS tumors. However, significant interindividual variability in risk suggests a role for genetic susceptibility and provides an opportunity to identify survivors of childhood cancer at increased risk for these tumors. Methods We curated candidate genetic variants from previously published studies in adult-onset primary CNS tumors and replicated these in survivors of childhood cancer with and without subsequent CNS tumors (82 participants and 228 matched controls). We developed prediction models to identify survivors at high or low risk for subsequent CNS tumors and validated these models in an independent matched case-control sample (25 participants and 54 controls). Results We demonstrated an association between six previously published single nucleotide polymorphisms (rs15869 [ BRCA2], rs1805389 [ LIG4], rs8079544 [ TP53], rs25489 [ XRCC1], rs1673041 [ POLD1], and rs11615 [ ERCC1]) and subsequent CNS tumors in survivors of childhood cancer. Including genetic variants in a Final Model containing age at primary cancer, sex, and cranial radiation therapy dose yielded an area under the curve of 0.81 (95% CI, 0.76 to 0.86), which was superior ( P = .002) to the Clinical Model (area under the curve, 0.73; 95% CI, 0.66 to 0.80). The prediction model was successfully validated. The sensitivity and specificity of predicting survivors of childhood cancer at highest or lowest risk of subsequent CNS tumors was 87.5% and 83.5%, respectively. Conclusion It is possible to identify survivors of childhood cancer at high or low risk for subsequent CNS tumors on the basis of genetic and clinical information. This information can be used to inform surveillance for early detection of subsequent CNS tumors.