No abstract

Multiple mutations are required for cancer development, and genome sequencing has revealed that several cancers, including breast, have somatic mutation spectra dominated by C-to-T transitions1–9. Most of these mutations occur at hydrolytically disfavored10 non-methylated cytosines throughout the genome, and are sometimes clustered8. Here, we show that the DNA cytosine deaminase APOBEC3B (A3B) is a likely source of these mutations. A3B mRNA is up-regulated in the majority of primary breast tumors and breast cancer cell lines. Tumors that express high levels of A3B have twice as many mutations as those that express low levels and are more likely to have mutations in TP53. Endogenous A3B protein is predominantly nuclear and the only detectable source of DNA C-to-U editing activity in breast cancer cell line extracts. Knockdown experiments show that endogenous A3B correlates with elevated levels of genomic uracil, increased mutation frequencies, and C-to-T transitions. Furthermore, induced A3B over-expression causes cell cycle deviations, cell death, DNA fragmentation, γ-H2AX accumulation, and C-to-T mutations. Our data suggest a model in which A3B-catalyzed deamination provides a chronic source of DNA damage in breast cancers that could select TP53 inactivation and explain how some tumors evolve rapidly and manifest heterogeneity.

Epidemiologic evidence suggests that cancer incidence is associated with diabetes as well as certain diabetes risk factors and treatments. This consensus statement of experts assembled jointly by the American Diabetes Association and the American Cancer Society reviews the state of science concerning 1) the association between diabetes and cancer incidence or prognosis; 2) risk factors common to both diabetes and cancer; 3) possible biologic links between diabetes and cancer risk; and 4) whether diabetes treatments influence the risk of cancer or cancer prognosis. In addition, key unanswered questions for future research are posed. CA Cancer J Clin 2010;60: 207-221.

Background: This randomized controlled trial assessed the safety and effects of twice-weekly weight training among recent breast cancer survivors. Outcomes included body size and biomarkers hypothesized to link exercise and breast cancer risk. Methods: A convenience sample of 85 recent survivors was randomized into immediate and delayed treatment groups. The immediate group trained from months 0 to 12; the delayed treatment group served as a no exercise parallel comparison group from months 0 to 6 and trained from months 7 to 12. Measures at baseline, 6 and 12 months included body weight, height, body fat, lean mass, body fat %, and waist circumference, as well as fasting glucose, insulin, insulin resistance, insulin-like growth factor-I (IGF-I), IGF-II, and IGF-binding protein-1, IGFBP-2, and IGFBP-3. Injury reporting was standardized.

Background I-SPY 2 is a phase 2 standing multicenter platform trial designed to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to matching experimental regimens with responding patient subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin (VC). Methods Eligible women had ≥2.5 cm stage II/III breast cancer, categorized into 8 biomarker subtypes based on HER2, hormone-receptor status (HR) and MammaPrint. Patients are adaptively randomized within subtype to better performing regimens compared to standard therapy (control). Regimens are evaluated within 10 signatures, prospectively defined combinations of subtypes. VC plus standard therapy was considered for HER2-negative tumors and therefore evaluated in 3 signatures. The primary endpoint of I-SPY 2 is pathologic complete response (pCR). MR volume changes during treatment inform the likelihood that a patient will achieve pCR. Regimens graduate if and when they have a high (Bayesian) predictive probability of success in a subsequent phase 3 neoadjuvant trial within the graduating signature. Results VC graduated in triple-negative breast cancer with 88% predicted probability of phase 3 success. A total of 72 patients were randomized to VC and 44 to concurrent controls. Respective pCR estimates (95% probability intervals) were 51% (35%–69%) vs 26% (11%–40%). Greater toxicity of VC was manageable. Conclusion The design of I-SPY 2 has the potential to efficiently identify responding tumor subtypes for the various therapies being evaluated. VC added to standard therapy improves pCR rates specifically in triple-negative breast cancer.