Avoiding overtreatment of ductal carcinoma in situ

Ductal carcinoma in situ (DCIS), a precursor to invasive breast cancer (IBC), represents 25% of all breast neoplasms. Most are harmless, but some progress to IBC. Yet, almost all DCIS are treated. Learning how to distinguish harmless from hazardous DCIS will save many women with harmless DCIS the burden of overtreatment.

Journal Trends in Cancer
Authors Carolien L. van der Borden et al
DATE 19 June 2019
The cancer microbiome

Collectively known as the microbiota, the commensal bacteria and other microorganisms that colonize the epithelial surfaces of our body have been shown to produce small molecules and metabolites that have both local and systemic effects on cancer onset, progression and therapy response. To date, most studies focusing on the microbiome have used traditional preclinical mouse models and identified correlative relationships between microbial species and cancer phenotypes. Now, the profound influence of the microbiota on the efficacy of cancer treatments, such as immunotherapies, has begun to be extensively characterized in humans. Paramount to the development of microbiota-based therapeutics, the next challenge in microbiome research will be to identify individual microbial species that causally affect cancer phenotypes and unravel the underlying mechanisms. In this Viewpoint article, we asked four scientists working on the cancer microbiome for their opinions on the current state of the field, where the research is heading and how we can advance our understanding to rationally design microbial-based therapeutics to transform treatment strategies for patients with cancer.

Journal Nature Review Cancer
Authors Eran Elinav, Wendy S. Garrett, Giorgio Trinchieri, Jennifer Wargo
DATE 11 June 2019
Predictors of an invasive breast cancer recurrence after DCIS: a systematic review and meta-analyses

We performed a systematic review with meta-analyses to summarize current knowledge on prognostic factors for invasive disease after a diagnosis of ductal carcinoma in situ (DCIS). Eligible studies assessed risk of invasive recurrence in women primarily diagnosed and treated for DCIS and included at least 10 ipsilateral-invasive breast cancer events and 1 year of follow-up. Quality in Prognosis Studies tool was used for risk of bias assessment. Meta-analyses were performed to estimate the average effect size of the prognostic factors. Of 1,781 articles reviewed, 40 articles met the inclusion criteria. Highest risk of bias was attributable to insufficient handling of confounders and poorly described study groups. Six prognostic factors were statistically significant in the meta-analyses: African-American race [pooled estimate (ES), 1.43; 95% confidence interval (CI), 1.15-1.79], premenopausal status (ES, 1.59; 95% CI, 1.20-2.11), detection by palpation (ES, 1.84; 95% CI, 1.47-2.29), involved margins (ES, 1.63; 95% CI, 1.14-2.32), high histologic grade (ES, 1.36; 95% CI, 1.04-1.77), and high p16 expression (ES, 1.51; 95% CI, 1.04-2.19). Six prognostic factors associated with invasive recurrence were identified, whereas many other factors need confirmation in well-designed studies on large patient numbers. Furthermore, we identified frequently occurring biases in studies on invasive recurrence after DCIS. Avoiding these common methodological pitfalls can improve future study designs.

Journal Cancer Epidemiology, Biomarkers & Prevention
Authors Lindy L. Visser et al
DATE 25 April 2019
Tissue-specific oncogenic activity of KRAS^A146T

KRAS is the most frequently mutated oncogene. The incidence of specific KRAS alleles varies between cancers from different sites, but it is unclear whether allelic selection results from biological selection for specific mutant KRAS proteins. We used a cross-disciplinary approach to compare KRAS^G12D, a common mutant form, and KRAS^A146T, a mutant that occurs only in selected cancers. Biochemical and structural studies demonstrated that KRAS^A146T exhibits a marked extension of switch 1 away from the protein body and nucleotide binding site, which activates KRAS by promoting a high rate of intrinsic and guanine nucleotide exchange factor–induced nucleotide exchange. Using mice genetically engineered to express either allele, we found that KRAS^G12D and KRAS^A146T exhibit distinct tissue-specific effects on homeostasis that mirror mutational frequencies in human cancers. These tissue-specific phenotypes result from allele-specific signaling properties, demonstrating that context-dependent variations in signaling downstream of different KRAS mutants drive the KRAS mutational pattern seen in cancer.

Significance: Although epidemiologic and clinical studies have suggested allele-specific behaviors for KRAS, experimental evidence for allele-specific biological properties is limited. We combined structural biology, mass spectrometry, and mouse modeling to demonstrate that the selection for specific KRAS mutants in human cancers from different tissues is due to their distinct signaling properties.

Journal Cancer Discovery
Authors Emily J. Poulin et al
DATE 05 April 2019
Tissue-specificity in cancer: The rule, not the exception.

We are in the midst of a renaissance in cancer genetics. Over the past several decades, candidate-based targeted sequencing efforts provided a steady stream of information on the genetic drivers for certain cancer types. However, with recent technological advances in DNA sequencing, this stream has become a torrent of unbiased genetic information revealing the frequencies and patterns of point mutations and copy number variations (CNVs) across the entire spectrum of cancers. One of the most important observations from this work is that genetic alterations in bona fide cancer drivers (those genes that, when mutated, promote tumorigenesis) show a remarkable spectrum of tissue specificity: Alterations in certain driver genes appear only in cancers derived from one or a few tissue types (1). Only a handful of cancer drivers [such as telomerase reverse transcriptase (TERT), TP53, the cyclin-dependent kinase inhibitor 2A (CDKN2A) locus, and MYC] show broad tissue spectrums. Here, we discuss the concept of tissue specificity of genetic alterations in cancer and provide general hypotheses to help explain this biological phenomenon.

Journal Science
Authors Kevin M. Haigis, Karen Cichowski, Stephen J. Elledge
DATE 15 March 2019