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Molecular Secrets of Breast Cancer Being Uncovered in BEACON Study

Susman, Ed

doi: 10.1097/01.COT.0000461158.69028.46
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SAN ANTONIO—An intra-molecular evaluation of circulating tumor cells recovered from metastatic breast cancer patients could open a window that will allow scientists to learn how anti-cancer drugs work—and how cancer cells respond to therapy, researchers suggested here at the San Antonio Breast Cancer Symposium.

“As you know, for most drugs we actually do not understand how they work and we are always looking for biomarkers,” said Edith Perez, MD, Deputy Director at Large for Mayo Clinic Cancer Center in Jacksonville, Florida. “This technology being used in the BEACON trial allows us a glimpse of what is possible in understanding the working of cancer cells.”

In an interview at her poster presentation, Perez, who is also the Serene M. and Frances C. Durling Professor at Mayo Clinic College of Medicine, explained that the substudy of the Phase III, 852-patient BEACON trial was successful in finding circulating tumor cells in 97 percent of the women who voluntarily allowed the researchers to draw serial blood samples.

About 80 percent of the patient population participated in the substudy, and the mean number of circulating tumor cells collected for each 7.5 mL of blood drawn from the patients was 472.

The donation of blood samples for circulating tumor cell analysis was collected from 649 women prior to the first dose of etirinotecan pegol; 631 women at Day 1 of Cycle 2; 627 women at Day 1 of Cycle 4, and 611 women at the end of treatment. Patients on etirinotecan pegol received a dose of 145 mg/m2 every 21 days.

She said the expectation is that the team will be able to correlate the changes in biomarkers in various cohorts of women with the overall survival and progression-free survival data from the main BEACON trial. The topline outcomes are expected to be announced in the first quarter of 2015, the researchers said.

BEACON, an open-label study sponsored by Nektar Therapeutics, compared the investigative topoisomerase 1 inhibitor etirinotecan pegol (NKTR-102) with physician's choice of treatment in patients diagnosed with locally recurrent or metastatic breast cancer who had previously received an anthracycline, a taxane, and capecitabine. The study was completed in the third quarter of 2013.

“One of the accomplishments of this study was that we were able to collect specimens from around the world in a very high number of patients,” Perez noted. Patients were recruited from North America, Europe, and Asia. “This contributes to the idea that these studies can be performed globally.”

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‘Breakthrough in Field of Circulating Markers in Advanced Cancer’

The study has also made strides in cancer research, she added: “I think this is a breakthrough in the entire field of circulating markers in the setting of advanced cancer. We had previously identified some markers that could be relevant to the mechanism of action of this topo1 inhibitor and we were able to measure the markers within tumor cells.”

In addition, she said, “We are going to attempt to be able to correlate these markers with the ultimate clinical impact of this drug. We have the ability to look at tumor cells while they are still viable so we can do molecular studies in these circulating tumor cells. This will be extremely fascinating if we can do this.”

The study of these circulating tumor cells might become the most important outcome in the trial, noted Cynara Coomer, MD, Chief of Breast Surgery and Director of the Florina Rusi-Marke Comprehensive Breast Center at Staten Island University Hospital in New York, who was asked for her perspective for this article.

“Favorable results have been demonstrated in the Phase III BEACON study, which is expected to provide topline data in the next few months. Etirinotecan pegol, a long-acting topoisomerase 1 inhibitor, has been identified in circulating tumor cells at baseline and over time.

“This will provide even more information than the primary objective of overall survival. It could demonstrate a reason for the variations in response as well as duration of response. Potentially, this could allow for more personalized treatment in regards to dosing and length of treatment,” she said.

Perez, who is also Chair of the Mayo Clinic Breast Cancer Translational Genomics Program and the Breast Cancer Specialty Council, noted that previous studies involving circulating tumor cells were based on older technology that simply looked at the number of tumor cells and then treated patients with chemotherapy regimens. “I was not surprised that those studies failed to show an advantage of treatment guided by number of circulating tumor cells,” she said.

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90% vs. 50%

“With this new study we will look at everything—for example, topoisomerase1; markers of apoptosis; and proliferation markers. We are using novel technology to capture an increased number of tumor cells in patients. With older technology we were able to get cells in 50 percent of patients, and in this technology we are able to detect cells in more than 90 percent of patients. So we have better technology for detection,” she said.

The BEACON trial is expected to build on results from a Phase II dose-finding study of etirinotecan pegol on which 29 percent of patients with metastatic breast cancer responded to treatment. Etirinotecan pegol is known to target topoisomerase I, the nuclear enzyme that plays an essential role in DNA replication, transcription, recombination, and repair. SN38, the active metabolite of etirinotecan pegol, stabilizes the DNA-topoisomerase 1 complex subsequently, resulting in DNA-double strand breaks.

Etirinotecan pegol is the first long-acting topoisomerase I inhibitor with an extended half-life and a unique structure that is designed to concentrate the drug in tumors, she said.

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Prolonged Plasma SN38 Exposure Compared with Irinotecan

In patients, etirinotecan pegol has been shown to lead to greatly prolonged plasma SN38 exposure compared with what is possible with irinotecan. Similarly, the elimination half-life of etirinotecan pegol is estimated at 50 days compared with only two for irinotecan. However, peak SN38 concentrations are substantially reduced, which may give the drug a favorable tolerability profile.

Perez and colleagues noted that circulating tumor cells using immunomagnetic EpCAM-based methods have been conceptually accepted as a ‘liquid tumor biopsy’: “To circumvent the limited recovery of circulating tumor cells these methods provide for molecular profiling applications, we isolated circulating tumor cells based on an antibody-independent, continuous-flow dielectrophoresis technology (ApoStream®),” the researchers explained.

“We developed quantitative multiplex immunofluorescent assays for target-specific pharmacodynamics biomarkers for epithelial protein in circulating tumor cells isolated pre-treatment and post-treatment.

“Over the years we have learned a lot about breast cancer,” Perez continued. “At one point we thought that genetic study would tell us everything, but we have learned that we may not know much about what the driver mutations are in breast cancer and how breast cancer is able to develop newer mutations.

“We are trying to figure out what impact these changes have on tumor invasion, and how learning about these changes will impact the benefit of therapy.”

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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