Key Pathways Identified in Triple-negative Breast Cancer 


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Five key biologic pathways have become evident in triple-negative breast cancer tumors, and these pathways may be targetable with agents that are currently available or in development, results from an international genetic analysis revealed at the 2012 San Antonio Breast Cancer Symposium.

Justin M. Balko, PharmD, PhD, Postdoctoral Research Fellow at Vanderbilt-Ingram Cancer Center in Nashville, reported that 90% of patients in the study had mutations in five well-recognized pathways.

“Neoadjuvant chemotherapy is increasingly used in patients with triple-negative breast cancer. It can induce a pathologic complete response in about 30% of patients, which portends a favorable prognosis, while those patients with residual disease in the breast at surgical resection exhibit worse outcomes,” Dr. Balko said.

“There are currently no targeted therapeutic options for triple-negative patients with residual disease after neoadjuvant chemotherapy to be used in the adjuvant setting,” he noted. “We hypothesized that molecular analysis of the residual disease would identify genetic alterations that are ultimately responsible for disease recurrence and could be targeted with clinically available medications,” he said.

Genetic Analysis

The investigators conducted a genetic analysis of residual tumor tissue from 114 women. Ultimately, 81 samples were sequenced for 182 oncogenes and tumor suppressors. Additionally, gene expression (mRNA) was measured for 450 genes.

They found amplifications, deletions, or mutations of known or implied functional significance in about two dozen genes, and approximately 90% of all patients had at least one aberration in pathways related to P13K/mTOR (involved in signaling and cellular death), DNA repair genes (such as BRCA1 and BRCA2), Ras/MAP kinase (cellular proliferation, differentiation and death), cell-cycle genes, and growth factor receptors. Novel mutations of unknown significance could not be assessed due to the lack of normal controls, he added.

The most common aberrations were mutations in the well-known tumor-suppressor protein p53 and amplifications of MCL1 and MYC. Amplification of MCL1 was observed in 56% of tumors, while MYC amplification was observed in 33%. The two genes were coamplified in many patients, suggesting that MCL1 amplification may circumvent oncogene-induced apoptosis and senescence.

Higher-risk Factors

For some combinations of genetic alterations, prognosis was worse. A univariate analysis of 62 patients showed that high expression of the MEK kinase gene plus amplification of the MYC oncogene was synergistic, and was associated with a greater risk of relapse compared with the presence of just one of the variants.

“MYC amplification coinciding with high MEK pathway transcriptional output identified a subset with short survival,” Dr. Balko reported.

About 40% of patients with only one of these aberrations were alive at 6 years, but in cases where both genes were amplified, essentially no patient lived beyond 2 years.

UCSF Study

Further implication of MYC was provided by different investigators, as reported by Andrei Goga, MD, PhD, Associate Professor of Cell & Tissue Biology and Medicine at the University of California, San Francisco.2

“MYC expression and signaling is increased in triple-negative breast cancer and is associated with worse prognosis,” Dr. Goga said.

In his study, a MYC synthetic-lethality screen of the human kinases identified 13 targets, including metabolic, MAP kinase signaling pathways, and PIM1 in triple-negative cancers. PIM1 is overexpressed in triple-negative and basal-like tumors, and it correlated with MYC expression and poor prognosis.

“We are now asking whether PIM1 inhibition can provide a new therapy for patients with triple-negative breast cancer,” he said.

In addition, the JAK2 pathway appears to be involved in these tumors, added Dr. Balko, whose research identified novel JAK2 amplifications in 11% of patients, and these were associated with very poor survival. Pan-JAK and JAK2 inhibitors are currently in clinical trials.

“These data provide a ‘targetable’ catalog of the alterations present in residual triple-negative disease after neoadjuvant chemotherapy, and support genomically driven adjuvant trials in this patient population,” Dr. Balko concluded. ■

Disclosure: Drs. Balko and Goga reported no potential conflicts of interest.

References

1. Balko JM, Giltnane JM, Shwartz LJ, et al: Profiling of triple-negative breast cancers after neoadjuvant chemotherapy identifies targetable molecular alterations in treatment-refractory residual disease. 2012 San Antonio Breast Cancer Symposium. Abstract S3-6. Presented December 6, 2012.

2. Goga A, Samson S, Horiuchi D: Identification of novel synthetic-lethal targets for MYC-driven triple-negative breast cancer. 2012 San Antonio Breast Cancer Symposium. Abstract S3-8. Presented December 6, 2012.


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