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Genetic alterations may predict breast cancer recurrence, metastases
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Clear differences exist within the driver landscapes of relapsed breast cancers, according to research presented at European Society for Medical Oncology’s European Cancer Congress.
The discovery of genetic factors that drive breast cancers to recur may enable doctors to identify high-risk patients and tailor treatments based on their driver mutations.
“We have found that some of the genetic mutations that drive breast cancers that relapse are relatively uncommon amongst cancers that do not relapse at the point of primary diagnosis,” Lucy Yates, MBBS, MA, clinical research oncologist at Wellcome Trust Sanger Institute in Cambridge, United Kingdom, said in a press release. “We believe that the differences we have seen reflect genetic differences that can predispose a cancer to return, combined with mutations acquired throughout the period from its first diagnosis to the subsequent relapse. Some of these genetic alterations are potentially targetable with drugs.”
Current treatment approaches can cure up to 80% of women with primary breast cancers. However, metastases continue to occur in more than 20% of patients, according to study background.
Although datasets exist on the driver landscape of breast cancer, it was unclear how representative those drives are of breast cancer that is not cured by existing treatments.
Yates and colleagues sought to determine how the driver landscapes of primary and relapsed breast cancers differ. They conducted their study by analyzing massively parallel sequence data from 1,000 patients with breast cancer.
The researchers evaluated somatic mutations in 365 genes known to be involved in or related to cancer processes. They derived samples from local relapse or distant metastatic deposits from 161 patients, which they sequenced using a targeted capture pulldown approach.
The researchers gathered previously published mutation data from exome sequencing of 839 primary localized breast cancer for comparison. They performed de novo driver mutation discovery and annotated individual mutations with likely driver status based on recurrence and known driver status.
Overall, driver mutations that arose late in the cancer’s evolution represented a greater set of driver genes than those occurring earlier.
Among established tumor-suppressor genes, the genes most strongly associated with relapse and metastasis in ER-positive tumors were TP53 and ARID1A.
Changes in the PI3K-AKT pathway occurred in 57% of ER-positive cancers and 37% of triple-negative breast cancers at relapse, although these mutations occurred infrequently among primary triple-negative tumors.
Further, mutations in the estrogen-signaling genes FOXA1 and ESR1 appeared enriched at relapse and metastasis. However, the GATA3 estrogen-signaling gene did not become enriched.
Among late-stage mutations, the researchers observed tumor suppression activity of JAK2 and STAT3 signaling genes.
“Interestingly, this is in contrast to the role of JAK2 in some other cancers where over activity of the gene drives malignancy rather than suppresses it,” Yates said. “However, our findings suggest that, in a subset of cancers, inhibiting this pathway may have the opposite effect, and this requires further investigation. In general, the observation highlights the importance of understanding the diverse nature of breast cancers in the era of precision medicine.” – by Cameron Kelsall
Reference:
Yates L, et al. Abstract 1804. Presented at: European Cancer Congress; September 25-29, 2015; Vienna.
Disclosure: The researchers report no relevant financial disclosures.