1. Fuerst, Mark L.

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BOSTON-Cancer will become the first serious battlefield of precision medicine, according to one of the leaders in the revolution to bring genomics into clinical practice.

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"Clinical genomics will become an integral part of an oncologist's clinical practice. It will open up tremendous possibilities for physicians and their patients. Within two years, the field will make this available to practicing physicians, not just academic institutions, and will permeate every single clinical practice," said Jose Baselga, MD, Physician-in-Chief and Chief Medical Officer at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, in an interview.


Baselga presented a talk on "Bringing Precision Cancer Medicine Forward" at the 2016 Society of Surgical Oncology Annual Cancer Symposium.


The big revolution will be in so-called "liquid biopsies" using circulating tumor DNA (ctDNA), he said. "It won't take that long to bring this vision of precision medicine forward. The technology is already here and the cost of tumor sequencing is going down. We could see genomic tests for less $1,000," Baselga said, adding that the costs will need to be reimbursed.


The ability of ctDNA analysis to reveal new mutations allows monitoring of clonal heterogeneity without the need for multiple tumor biopsies. The promise of ctDNA monitoring is to allow clinicians to detect resistant mechanisms early and then tailor treatments. It may also have important applications to stratify treatment after surgery or radical radiotherapy and may play a role in patient screening.


"It's not feasible to biopsy every metastatic site to sequence tumors. We also need to improve the way we assess response. Using CT or MRI takes months. That is too long. Now it's possible to look at the presence of DNA or nucleic acids in the blood and get results within days. This will clearly change medicine," Baselga said.


Early Detection

Researchers at MSKCC have launched a comprehensive effort to study ctDNA in a Liquid Biopsy Task Force. They have collected 2,400 samples from 964 patients with breast cancer (metastatic, neoadjuvant, early) and lung cancer (metastatic and early). They are using a 504 gene pan-cancer panel to detect ctDNA and attempting to utilize this as a surrogate for multiple repeated biopsies to predict response to therapy or recurrence.


"We are starting to use this as a marker to detect early disease. We can detect stage 1 breast cancer just by taking a look at the blood," Baselga said. "In the blood, we can see everything present in tumor in a less-invasive fashion. Going forward, we are beginning to monitor ctDNA as part of routine clinical research. We are using liquid biopsy in every targeted therapy trial. We have the possibility to select patients not based on tumor biopsy, but on the presence of ctDNA in the blood."


Tumor DNA is now being checked in the blood with the hopes of capturing the presence of DNA mutations. "The principle is we can get good representation across the whole ecosystem of a particular tumor. At resistance, we can look at what's going on as well," he said.


Unlike serial biopsies that capture different mutations at different sites, "liquid biopsies detect everything," Baselga said.


Another application is to monitor response to therapy. "Early on, by day 4 to 6, we can know if the tumor is responding. If it is not shrinking within one week, we know that the treatment is not working and we need to do something else," he said.


In his talk, he mentioned an anecdote about a breast cancer patient who had an estrogen receptor clone that was noted on ctDNA testing. An antiestrogen was added to her therapy, and she has responded for more than 300 days.



At the moment, the limiting step in using ctDNA analysis is not in sequencing tumors, but in sharing information with clinicians.


"We need to provide knowledge that will enable physicians and patients to make decisions about therapy. We realize data need to be annotated for practicing physicians so they understand what the ctDNA profile means," he said.


"We need a system that provides clinical, real-time annotations, for example, that a certain tumor is eligible for a clinical trial, or that a patient should receive a certain type of therapy."


This type of system is already taking shape in academic centers, and a number of initiatives have been launched by the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO). "The goal is to improve therapies based on genomic findings," he said.


The AACR Project Genomics, Evidence, Neoplasia, Information, Exchange is a multi-phase, multi-year, international data-sharing project that catalyzes precision oncology through the development of a regulatory-grade registry that aggregates and links clinical-grade cancer genomic data with clinical outcomes from tens of thousands of cancer patients treated at multiple international institutions.


The ASCO Institute for Quality, LLC, is leading the development of CancerLinQ, a cutting-edge health information technology platform. The goal is to aggregate and analyze a massive web of real-world cancer care data to provide real-time quality feedback to providers, feed personalized insights to doctors, and uncover patterns that can improve care.


"If we sequence tumors, and especially ctDNA in the blood and monitor tumor evolution as it occurs, we will be able, for each tumor type and genomic alteration, to map out a book of rules," Baselga said. "There are only a certain number of strategies that a tumor may have to escape from selective pressure from a given therapy. If we study multiple tumor types, how they evolve and develop resistance, then we can define a book of rules so we can predict what will happen next."


Real-time monitoring of clonal composition of tumors may become possible. In a study published in Nature last year (2015;518:240-4). Baselga and colleagues found that metastatic breast cancer patients who progress on PI3K inhibitors develop specific mutations in that pathway. "If we could follow the emergence of clones of resistance, we could react much faster and better with appropriate combination therapy. If we begin to detect resistance early on, then we could intervene to wipe out a developing clone."


"For the first time, we may be ahead of the game instead of reacting," Baselga continued. "We can use cancer drugs that address the underlying mechanism of resistance instead of waiting for months, as we do now."