Locally advanced breast cancers are more likely to present as Interval Cancers: results from the I-SPY 1 TRIAL (CALGB 150007/150012, ACRIN 6657, InterSPORE Trial).

Interval cancers (ICs), defined as cancers detected between regular screening mammograms, have been shown to be of higher grade, larger size, and associated with lower survival, compared with screen-detected cancers (SDCs) and comprise 17% of cancers from population-based screening programs. We sought to determine the frequency of ICs in a study of locally advanced breast cancers, the I-SPY 1 TRIAL. Screening was defined as having a mammogram with 2 years, and the proportion of ICs at 1 and 2 years was calculated for screened patients. Differences in clinical characteristics for ICs versus SDCs and screened versus non-screened cancers were assessed. For the 219 evaluable women, mean tumor size was 6.8 cm. Overall, 80% of women were over 40 and eligible for screening; however, only 31% were getting screened. Among women screened, 85% were ICs, with 68% diagnosed within 1 year of a previously normal mammogram. ICs were of higher grade (49% vs. 10%) than SDCs. Among non-screened women, 28% (43/152) were younger than the recommended screening age of 40. Of the entire cohort, 12% of cancers were mammographically occult (MO); the frequency of MO cancers did not differ between screened (11%) and non-screened (15%). ICs were common in the I-SPY 1 TRIAL suggesting the potential need for new approaches beyond traditional screening to reduce mortality in women who present with larger palpable cancers.

Breast Cancer Risk-Associated SNPs in the mTOR Promoter Form De Novo KLF5- and ZEB1-Binding Sites that Influence the Cellular Response to Paclitaxel.

ZEB1 (a positive enhancer) and KLF5 (a negative silencer) affect transcription factors and play inherently conserved roles in tumorigenesis and multidrug resistance. In humans, the rs2295080T-allele at the mTOR promoter locus has been associated with human cancer risk; however, the 63 bp spacing of another SNP rs2295079 has not been identified. Here, we discovered, for the first time, that rs2295079 (-78C/G) and rs2295080 (-141G/T) formed linkage haplotypes, with Ht1 (-78C/-141G) and Ht2 (-78G/-141T) being dominant, which were associated with distinct susceptibility to breast cancer, response to paclitaxel, and clinical outcomes in breast cancer. At the cellular level, compared with Ht1, Ht2 exhibits a much stronger effect on promoting mTOR expression, leading to enhanced tumor cell growth and strengthened resistance to PTX treatment. Mechanistically, the -141T allele of Ht2 creates a novel ZEB1-binding site; meanwhile, the -78C allele of Ht1 exists as an emerging KLF5-binding site, which synergistically induces promote/inhibit mTOR expression, cell proliferation, and excretion of cytotoxic drugs through the ZEB1/KLF5-mTOR-CCND1/ABCB1 cascade, thereby affecting the response to paclitaxel treatment in vivo and in vitro. Our results suggest the existence of a ZEB1/KLF5-mTOR-CCND1/ABCB1 axis in human cells that could be involved in paclitaxel response pathways and functionally regulate interindividualized breast cancer susceptibility and prognosis. IMPLICATIONS: This study highlights the function of haplotypes of mTOR -78C/-141G and -78G/-141T, in affecting breast cancer susceptibility and paclitaxel response regulated by ZEB1/KLF5-mTOR-CCND1/ABCB1 axis.