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January 2013

News read or heard lately

Genome sequencing in recurrent triple-negative breast cancer

Whole-genome sequencing has revealed previously unreported mutations in metastatic triple-negative breast cancer, according to a study published in Molecular Cancer Therapeutics (Craig DW, et al. Nov. 19, 2012; Epub ahead of print).

The study, “Genome and transcriptome sequencing in prospective refractory metastatic triple negative breast cancer uncovers therapeutic vulnerabilities,” was sponsored by the Translational Genomics Research Institute (TGen) and US Oncology Research with support from Life Technologies.

In a sample of 14 tumors from ethnically diverse metastatic triple-negative breast cancer patients, the researchers found significant mutations and other changes in more than a dozen genes through whole-genome sequencing performed on Life Tech’s Applied Biosystems Solid 4.0 platform. The most frequently mutated gene among the tumors (seven of 14) was the TP53 tumor suppressor, and aberrations were observed in additional tumor suppressor genes, including CTNNA1, which was detected in two of six African-American patients. Alterations were also seen in the ERBB4 gene, known to be involved in mammary gland maturation during pregnancy and lactation but not previously linked to metastatic triple-negative breast cancer.

The study included an “outlier analysis,” which assessed expression patterns for each tumor when compared against the other tumors examined in the study. Specific cancer genes overexpressed among tumors in the study’s cohort included ALK, AR, ARAF, BRAF, FGFR2, GLI1, GLI2, HRAS, HSP90AA1, KRAS, MET, NOTCH2, NOTCH3, and SHH. Significantly underexpressed cancer genes included BRCA1, BRCA2, CDKN2A, CTNNA1, DKK1, FBXW7, NF1, PTEN, and SFN.

Each tumor was genomically unique, but nine of the 14 contained alterations in one or both of two particular cellular pathways: RAS/RAF/MEK/ERK and PI3K/AKT/MTOR.

Whole genome and transcriptome profiling of metastatic triple-negative breast cancer provided insights into somatic events occurring in this cancer, the authors write, adding: “These genomic data have guided patients to investigational treatment trials and provide hypotheses for future trials of this irremediable cancer.”

NIH grant for resident genomic pathology curriculum

A five-year, $1.3 million grant from the National Institutes of Health will fund a program established by Beth Israel Deaconess Medical Center and the Training Residents in Genomics Working Group to help pathologists understand genomics information and serve as primary consultants for physicians and patients.

Richard Haspel, MD, PhD, of Beth Israel Deaconess Medical Center, was awarded the grant to further develop a resident genomic pathology curriculum, based on an initiative first developed in 2009 (http://genomicmedicineinitiative.org).

In 2010, building on this work and with the backing of the Pathology Residency Program Directors Section of the Association of Pathology Chairs, the Training Residents in Genomics Working Group was formed. This group, which Dr. Haspel chairs, consists of experts in molecular pathology, genetic counseling, and medical education. The American Society for Clinical Pathology provides administrative and educational design support to the working group.

The new NIH grant will enable Dr. Haspel and his collaborators to expand on the genomic medicine training program; create educational resources, including online modules; and test efficacy at four residency programs.

Gene signature predicts response to cancer drugs

A study that identifies a gene signature associated with resistance to a range of cancer therapies in multiple cancer types was published Nov. 21, 2012 in Cell (Huang S, et al. 151:937–950).

The gene signature, discovered in collaboration with scientists from the Netherlands Cancer Institute, identifies a process that resembles epithelial-to-mesenchymal transition, or EMT, as a major determinant of response to targeted cancer therapeutics and chemotherapeutics in a variety of cancer types.

The researchers used a large-scale RNA interference screen to identify MED12, a component of the transcriptional Mediator complex that is mutated in cancers, as a determinant of response to ALK and EGFR inhibitors. The title of the study is “MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling.”

“We need to understand the mechanisms of drug resistance if we want to prevent resistance from occurring. Moreover, we have shown that blocking the EMT process with selective drugs restores sensitivity to the original drug, which suggests a way to treat patients that have undergone this type of drug resistance,” says René Bernards, senior author of the study and chief scientific officer at Agendia.

The company is in discussions with pharmaceutical companies to collaborate on the use of this gene signature in clinical studies.

Molecular subtyping in breast cancer

A retrospective study presented at the San Antonio Breast Cancer Symposium in December found that molecular subtyping of early breast cancers using Agendia’s MammaPrint and BluePrint assays led to 25 percent (51/208) of tumors being reclassified, with potential therapeutic and prognostic implications.

The authors of the study are Massimo Cristofanilli, MD, and JoEllen Weaver, BS, MT, of Fox Chase Cancer Center, Philadelphia; Karen Kaul, MD, PhD, Katharine Yao, MD, and Mary Turk of NorthShore University HealthSystem, Evanston, Ill.; Jelle Wesseling, MD, PhD, of Netherlands Cancer Institute, Amsterdam; and Lisette Stork-Sloots, PhD, and Femke de Snoo, MD, PhD, of Agendia NV, Amsterdam.

The authors concluded that 39 percent of clinical HER2 disease should have been treated with therapies for Luminal-type disease (e.g. endocrine therapy), and 20 percent of clinical triple-negative disease could have been treated with therapies for Luminal and HER2-type disease (endocrine therapy and trastuzumab-based regimens). To obtain the poster, send request to jason.horton@agendia.com.

 

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