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Metastatic, Relapsed Breast Cancer Genomic Study Reveals Relationship to Primary Tumors

NEW YORK (GenomeWeb) – Metastatic and/or relapsed forms of breast cancer tend to contain many of the same mutations found in primary tumors, suggesting these tumors arise relatively late in the disease process, new research suggests. Even so, there are clues that additional mutations that do occur in metastatic tumors might help in treating advanced forms of the disease.

For a study published online today in Cancer Cell, members of an international research team retrospectively sequenced 299 tumor samples from 170 individuals with metastatic or locally relapsed breast cancer. Using whole-genome or targeted panel sequence data from these tumors, the researchers attempted to retrace the evolution of the metastatic or locally relapsed tumors, revealing new driver mutations in some far-flung tumors that seemingly stemmed from late-stage primary tumors.

"We would not have seen these mutations by sequencing the primary tumor alone," co-corresponding author Per Eystein Lønning, an oncology researcher affiliated with the University of Bergen and Haukeland University Hospital, said in a statement. "Our results suggest that it should be more routine to biopsy the metastasis and have it genetically analyzed in order to open up clinical trials of treatment options for metastatic breast cancer."

Although past studies have delineated many of the molecular features found in primary breast cancer tumors, the team explained, fewer genomic analyses have focused on recurrent forms of the disease. Consequently, questions remain about the relationship between the genetic alterations in primary tumors and those contributing to metastatic or locally recurrent forms of the disease.

With that in mind, the researchers did whole-genome sequencing on 40 relapsed tumor samples from 17 breast cancer patients, comparing genetic patterns in these tumors with those present in matched, pre-treatment primary tumor samples taken at diagnoses, which were available for all but one individual. They also searched for point mutations and copy number shifts in a few hundred genes in tumor samples from 163 individuals with breast cancer. Matched normal and primary tumor samples were available for a subset of those cases.

The team's phylogenetic analysis revealed clonal ties between most of the metastatic tumors and corresponding primary tumors from the same individual, suggesting primary tumors do hold clues to later forms of the disease.

"As the cells that cause the spread of breast cancer leave relatively late, it means they are still quite similar to the cells in the primary tumor," co-first author Lucy Yates, a clinical oncology researcher affiliated with the Wellcome Trust Sanger Institute and the Guys and St Thomas' NHS Trust, said in statement.

Nevertheless, the researchers also detected a handful of new clinically actionable mutations that were specific to the metastatic tumors, among them alterations in genes from the JAK2-STAT or SWI-SNF pathways that appear to act as cancer drivers.

"In its restless search for a genome ideally suited to autonomous life in far-flung regions of the body, a breast cancer can access many different mutational processes and a wide repertoire of cancer genes," the authors wrote. "The result is considerable patient-to-patient variability in genomic profiles, even more pronounced than the already daunting levels seen in primary breast cancer."

They noted that still larger studies of individuals with advanced breast cancer are needed to more fully define molecular features of the disease. 

For an upcoming study in the UK and Europe supported by the Breast International Group, the Institute of Cancer Research, and the National Institute for Health Research, a team led by University of Edinburgh researcher David Cameron will profile changes that occur in breast cancer tumors that have locally recurred or spread to other parts of the body. Recruitment for that study began in late 2015 and will continue until October of this year, with the goal of enrolling roughly 1,000 breast cancer patients.