Next-Generation Sequencing Revolutionizes Discovery of Novel Targeted Therapies in Breast Cancer

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The most promising novel therapeutics in development for patients with breast cancer focus primarily on targeting activating mutations in combinations that are based on findings from next-generation sequencing.

Debu Tripathy, MD

“Next-generation sequencing, which was introduced not quite 10 years ago, has really revolutionized our ability to look at the tumor genome in high frequency,” said Tripathy, a professor of Medicine and co-leader of the Women’s Cancers Program at Norris Comprehensive Cancer Center at the University of Southern California. “What we’re finding is that every tumor actually has different genetic abnormalities.”

Activating mutations in PI3K, HER2, and JAK2 represent the most promising targets for new drug development. In fact, Tripathy noted that several clinical trials are currently examining treatment combinations in this space. Additionally, other strategies of interest are targeting cyclin-dependent kinase (CDK) inhibitors and histone deacetylase (HDAC) inhibition.

In one such study, the CDK 4 and 6 inhibitor palbociclib was explored in combination with letrozole for patients with postmenopausal ER-positive, HER2-negative advanced breast cancer. In an analysis of the phase II study, the combination achieved a statistically significant median progression-free survival (PFS) of 26.1 months compared with 7.5 months for letrozole alone. Based on these findings, the FDA granted palbociclib a Breakthrough Therapy designation for the treatment of patients with breast cancer in April 2013.

“This was a smaller study, it was a phase II study. It is currently being replicated in a large phase III registrational trial that will hopefully lead to the approval of this drug, if similar results are seen,” Tripathy said. “If this is successful, this will be great.”

In another investigation, the novel HDAC inhibitor entinostat was combined with exemestane. This approach gained a Breakthrough Therapy designation from the FDA in September 2013 for its potential to reverse resistance to hormonal therapies used to treat patients with advanced ER-positive breast cancer. The FDA designation was based on results from the phase II ENCORE 301 study, which enrolled postmenopausal women with locally recurrent or metastatic ER-positive breast cancer. A phase III trial will combine endocrine therapy with entinostat for patients with hormone receptor-positive metastatic breast cancer.

In the phase II study, the median overall survival in the combination arm was 28.1 months compared with 19.8 months in the exemestane arm (HR = 0.59; P = .036). In a subset of patients (n = 49) with increased protein acetylation, the median PFS with the combination was 8.5 months compared with 2.8 months for patients without acetylation (HR = 0.32).

“You see a theme here; if you block a pathway we can improve outcomes, but unfortunately patients are still progressing,” Tripathy deduced.

In the area of triple-negative breast cancer (TNBC), several novel approaches have emerged in recent years. It was discovered that the androgen receptor is expressed in 10% of patients with TNBC. As a result, a phase II trial explored AR blockade with bicalutamide. This approach showed a clinical benefit rate but no responses.

In addition to bicalutamide, the androgen receptor inhibitors enzalutamide and abiraterone acetate are also being tested as treatments for patients with TNBC.

“Triple-negative breast cancer is an area of unmet need. We don’t have other biological therapies approved right now, other than chemotherapy, and it is a more aggressive cancer and more likely to recur,” said Tripathy. “Clearly we need more targets.”

Two novel approaches using available therapies appear to be of high interest for the treatment of patients with TNBC.

An ongoing study is focusing specifically on the treatment of patients with JAK2 mutations and amplification using the JAK2 inhibitor ruxolitinib, which is approved for the treatment of myelofibrosis. The feasibility of this approach was uncovered in an analysis of tumor samples from patients with treatment-refractory residual TNBC following neoadjuvant chemotherapy.

“Here’s a totally new gene that was just uncovered less than a year ago and now has led to a new clinical trial that is getting started,” Tripathy pointed out, highlighting the speed of new research endeavors.

In addition to targeting JAK2, there is preclinical evidence suggesting that rare mutations in HER2 may activate HER2 signaling in tumors that are HER2-negative by traditional testing. Moreover, data have indicated these patients may respond to treatment with the irreversible HER1/2-targeting kinase inhibitor neratinib.

“As we start to do more genome sequencing, at this point in time the main reason is to find clinical trials for these patients,” Tripathy said in his presentation. “One example would be neratinib if they have an activating HER2 mutation, which is not that common.”

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