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Mayo Researchers Use Whole-Genome Sequencing, Mouse 'Avatars' to Study Breast Cancer Resistance

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This article has been updated to clarify the BEAUTY project design and with additional comments from Matthew Goetz.

In a novel study involving whole-genome sequencing and "avatar" mice, researchers at the Mayo Clinic are attempting to personalize neoadjuvant chemotherapy treatment for high-risk, early-stage breast cancer patients and discover ways in which new treatments can tackle disease metastases and resistance.

In the first phase of the study, called the Breast Cancer Genome Guided Therapy Study, or BEAUTY, Mayo researchers led by Matthew Goetz and Judy Boughey are planning to enroll 200 women who have high- risk, early-stage breast cancer. All study participants will receive standard taxane and anthracycline based chemotherapy prior to surgery. However, before receiving neo-adjuvant treatment, Goetz and his colleagues will analyze patients' healthy cells and tumor tissue by whole-genome sequencing.

After receiving chemo and having their tumors removed, study participants with residual disease will have their tumor genomes sequenced again.

"The literature suggests that about half of the women [in the study] or slightly more will have residual disease in the breast after surgery," Goetz, a Mayo oncologist, told PGx Reporter. Additionally, researchers expect that between 5 percent and 10 percent of study participants will experience distant recurrence in a span of five years, at which point, their tumor tissue will be collected and sequenced also.

Another unique feature of the BEAUTY project is that Mayo researchers will keep patients' cancer cells viable in mice, which will help advance new hypotheses about which drugs work best in patients without having to expose human study participants to toxic drugs. Study investigators will implant tumor samples taken before chemotherapy into two mice per patient.

"The idea is to take these high-risk patients, sequence the genome, and get a better idea of what … genetic markers and pathways [are] associated with resistance to chemotherapy, and then be able to immortalize those cancer cells so we have the ability to test new drugs in the so-called avatars," Goetz explained.

As knowledge about the molecular underpinnings of breast cancer advances, oncologists know that neoadjuvant chemotherapy works best in certain patients, for example those who have tumors low in estrogen receptor, have triple-negative cancer, or HER2 positive tumors.

In BEAUTY, researchers will not be using a molecular diagnostic such as Genomic Health's Oncotype DX to help decide whether patients should receive chemotherapy, since such tests are normally used to guide adjuvant, not neoadjuvant, treatment. However, researchers will take into account the molecular profile of the patients' tumors to decide whether they are high-risk breast cancer patients who are candidates for neoadjuvant chemotherapy and then enroll them in the trial.

Goetz couldn't provide a cost estimate for the study, which is being funded by Mayo's Center for Individualized Medicine and a number of benefactors. For the next few months, Mayo researchers will be performing exome sequencing on patients' tumors, and will switch to whole-genome sequencing by July or August.

"The cost of exome sequencing will be close to the whole-genome sequencing cost," Goetz said, adding that the cost of performing the entire study, including clinical cost, sequencing, and imaging tests, "runs in the millions of dollars."

In the later phases of BEAUTY, Mayo researchers will focus on applying what they learned about the mechanisms of resistance in the first part of the study and advancing new personalized treatments. "The sequencing will be done. We will obviously identify genetic alterations associated with resistance. We will use informatics to identify drug targets," Goetz said. "But the real question is does that have any relevance?"

At this point, instead of testing in humans their hypotheses about which drugs may mediate molecular targets associated with disease resistance, study investigators will use cell lines in the mouse avatars. Previously published studies suggest that between 30 percent and 40 percent of breast cancer patients whose cells take to xenografts often have the worst outcome and are therefore high-risk patients, Goetz noted.

Therefore, the mouse avatars in BEAUTY will facilitate research to discover new therapies for those with limited treatment options, such as patients with triple-negative breast cancer. "The overall goal is to identify and validate new drug targets in patients at highest risk for disease recurrence," Goetz said.

In these later phases of BEAUTY, Mayo researchers will seek collaborations with drug developers to advance new neoadjuvant breast cancer treatments. Study investigators haven't entered into any formal agreements with drug companies yet, "but that's where we want to move," Goetz said.

Neoadjuvant breast cancer is a growing area of investment for drug developers, particularly when it comes to advancing personalized treatments.

For example, in the Phase II NEOSPHERE trial, Roche is comparing the investigational agent pertuzumab in combination with Herceptin and docetaxel versus just Herceptin/docetaxel in early-stage, HER2-positive breast cancer patients. Data presented at the San Antonio Breast Cancer Symposium showed that the pertuzumab-containing regimen given to patients in the neoadjuvant setting before surgery reduced their tumor by more than half compared to patients receiving just Herceptin/docetaxel. Based on these results, Roche has decided to study pertuzumab in the neoadjuvant setting in a Phase III trial.

In Goetz's view, pharma companies developing drugs in the neoadjuvant breast cancer setting will likely be interested in the molecular targets associated with resistance uncovered in BEAUTY. "We want to accelerate drug development here" by discovering new gene targets and pathways, he said. "So, drug target discovery, validation, and that sort of thing will be an important part of this study."

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