December 2012, Vol 1, No 6

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Genetic Targets Identified in Triple-Negative Breast Cancer

Alice Goodman

Uncategorized

Triple-negative breast cancer carries a poor prognosis compared with other types of breast cancer because it lacks 3 treatment targets that occur in other types of breast cancer (estrogen receptor, progesterone receptor, and HER2). But triple-negative breast cancer has potential genetic targets of its own, according to a study presented at the CTRC-AACR San Antonio Breast Cancer Symposium.

The study found that 90% of patients had mutations in 5 targetable biological pathways. These pathways have drugs on the market or in development that could be targeted in clinical trials, according to Justin Balko, PharmD, PhD, of the Breast Cancer Program at the Vanderbilt-Ingram Cancer Center in Nashville, TN.

Currently, there are no approved targeted drugs for triple-negative breast cancer, which occurs in about 15% of all breast cancers, he continued. About 30% of patients with triple-negative breast cancer have a complete response to neoadjuvant chemotherapy and have good outcomes following surgery. But outcomes for patients with residual disease are typically poor.

Balko and colleagues analyzed samples of residual tumors to determine if any candidate genes for resistant cancers could be identified. They studied 114 samples from tumors of women with triple-negative breast cancer using 3 different methods, including gene expression profiling, deep sequencing, and immunohistochemistry. They examined 182 oncogenes and tumor suppressors known to be altered in human cancers. Instead of finding similar genetic alterations among patients, they found alterations in a diverse set of genes. Median age of patients was 48 years, and the majority of cancers were stage III.

“We already knew that triple-negative cancer is driven by a diverse group of alterations, so in one way, we fell further down this rabbit hole. But we also identified some genes that could be promising therapeutically, such as frequent MYC, MCL1, and JAK2 amplifications, as well as alterations in the PI3K pathway.

Overall, with all 3 methods, dozens of genes were amplified, deleted, or mutated, with the most common gene being TP53, which was abnormal in 90% of tumor samples. MCL1 (56% abnormal) and MYC (33% abnormal) were the next most common genetic alterations. Amplified JAK2 was observed in 11% of tumors. Alterations in the KI67 gene were not associated with relapse-free survival or overall survival in this triple-negative cohort.

“We arranged the genetic alterations into clinically targetable pathways,” he explained. These were the 5 pathways he discussed:

  • PI3K/mTOR pathway, involved in intracellular signaling and death
  • DNA repair genes (eg, BRCA1 and BRCA2)
  • RAS/MAPK pathway (involved in cell proliferation, differentiation, and death)
  • Cell cycle genes
  • Growth factor receptors, including epidermal growth factor receptor
  • The combination of MEK kinase genes and amplified MYC oncogene was potentially predictive of relapse

Women who had only MEK kinase or MYC gene activation/amplification were significantly less likely to experience relapse compared with women who had both variants (P=.03).

“Ninety percent of patients had at least 1 genetic aberration in these pathways. We believe this has therapeutic implications and should be studied,” Balko said. “Targeted drugs exist for each of these 5 pathways. We believe these data provide rationale for adjuvant studies of appropriate targeted therapeutics in triple-negative breast cancer patients who do not achieve pathological complete responses to neoadjuvant chemotherapy.”

Uncategorized - December 20, 2012

Ibrutinib: Proof of Concept Pays Off

Ibrutinib as a single agent and in combination with ri­tuximab achieved unprecedented response rates in studies of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) presented at the 54th Annual Meeting of the American Society of Hematology (ASH). The drug is being studied in several B-cell malignancies, including CLL/small [ Read More ]

The Last Word - December 21, 2012

Companion Diagnostics and the Paradoxical Return of the Blockbuster Drug

In my article in the inaugural issue of Personalized Medicine in Oncology, I got a bit dogmatic in proclaiming that personalized medicine (PM) drug treatment selectivity spelled the end of population-based medicine, and with it, the blockbuster drug. This is true only insofar as we define blockbuster drug from within [ Read More ]