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  1. May, Brandon

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In recent years, the field of personalized cancer therapy has evolved exponentially, enabling clinicians to develop targeted approaches to therapy based on patients' carcinoma genetic profile. Genomics research has been the driving force behind better understanding of genetic mutations in cancer, research of which has been supported by various initiatives and screening programs worldwide.

  
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The Profile Cancer Research Program

The Profile initiative, a large-scale cancer genetic screening cohort, was developed by scientists from the Dana-Farber/Brigham and Women's Cancer Center, as well as Dana-Farber/Boston Children's Cancer and Blood Disorders Center, to collect genomics data for each carcinoma type. The test, called OncoPanel, performs DNA sequencing of more than 400 locations in the genome.

 

Currently, the Profile is one of the largest comprehensive precision medicine research initiatives in the field of cancer. To date, more than 30,000 cancer patients have been tested for genetic mutations. Using these data, investigators hope to construct improvements in targeted cancer treatments, in addition to personalized diagnostics and prevention strategies.

 

According to Barrett J. Rollins, MD, PhD, Chief Scientific Officer of Dana-Farber, the idea of the Profile initiative first germinated in 2009 when the institution was active in studying gene mutations, specifically EGFR, in lung cancer. Using the data their research generated, investigators obtained information that predicted individual-level patient response to targeted therapy.

 

"There's been this long-standing, almost cultural attitude about molecular oncology," Rollins noted. "With the discovery of mutations that drive oncogenesis, we learned that this is a disease of genes and that there's a rational basis for understanding all cancers. Also, our research provides the potential for the discovery of new targets and the identification of those patients who benefit from those therapies."

 

There is hope among researchers at Dana-Farber and Brigham and Women's Cancer Center that every future cancer patient will be able to have a genetic profile of their carcinoma. With this initiative, that hope is becoming a reality for thousands of patients. "In some ways, the Profile project began as an experiment to gather cancer mutations and to identify specific mutations that direct therapy," explained Rollins, "but it was also a large-scale experiment to determine if the acquisition of a broad-based genetic profile could be applied to routine clinical care."

 

In addition to genetic profiling improving clinicians' ability to understand therapy response at the individual level, DNA testing may also play an integral role in cancer diagnostics. "In some cases in cancer diagnoses, there are genetic abnormalities that are characteristic of specific cancers, and having this knowledge can help improve diagnostic specificity," Rollins said.

 

"Profile began as an attempt to advance the molecular understanding of cancer from scientific and epidemiologic perspectives and to perform prospective high-complexity genomic assessment of every cancer patient who came to Dana-Farber, Brigham and Women's Cancer Center, and Boston Children's," explained Neal I. Lindeman, MD, Director of the Center for Advanced Molecular Diagnostics at Brigham and Women's Hospital. "The program was initially designed to identify patients who might benefit from investigational therapeutics that are currently in development."

 

According to Lindeman, the screening program can help clinicians better able to recommend clinical trials among participants who will most likely benefit from these investigational drugs.

 

Instead of using mass spectrometry, which was the imaging tool of choice at the program's onset, Profile scientists are now using next-generation sequencing (NGS) for identifying genetic mutations. NGS may have been an essential component in driving the evolution of proteogenomics understanding and creating greater awareness of human proteomic variation that is encoded in the genome. These variations include those from alternative splicing (Science 2008;321(5891):956-960, Nature 2008;456(7221):470-476) and nucleotide polymorphisms (Nature 2010;467(7319):1061-1073).

 

Research Findings From Profile

In 2017, a research project from Profile investigator Rameen Beroukhim, MD, PhD, Assistant Professor of Medicine at Harvard Medical School, found that, through whole exome sequencing of hormonally active and inactive pituitary macroadenomas (n=42), sporadic pituitary tumors feature distinct copy-number profiles associated with histologic and hormonal subtypes, ultimately impacting the expression of genes (Clin Cancer Res 2017;23(7):1841-1851). "Despite performing comprehensive sequencing of essentially all genes across a large cohort of pituitary tumors," Beroukhim noted, "we found no significantly recurrent mutations that are likely to 'drive' the growth of pituitary adenomas."

 

Many of the tumors featured widespread aneuploidy and "multiple whole chromosomes and chromosome arms either present in too many or too few copies...[and this] suggests that changes in gene dosage contribute to the growth of many pituitary adenomas."

 

This small overview study of genomic mutations in pituitary adenomas by Beroukhim and colleagues represents just one of the key research findings utilizing Profile sequencing techniques that are further improving researchers' understanding of cancer. Unfortunately, findings from this genomics cancer study suggest that there may be limited utility for sequencing panels in designing personalized therapy for patients with pituitary macroadenomas.

 

"Many centers apply clinical sequencing panels covering hundreds of known cancer genes to detect mutations that give rise to each patient's cancer and which can indicate personalized therapeutic approaches," said Beroukhim. "Pituitary tumors do not exhibit frequent mutations in any of these genes, limiting the utility of those sequencing panels." Despite this apparent limitation, he suggests future genomics research may be needed "to determine which mutations are occurring in each cancer to figure out what went wrong and how those cancer cells can be distinguished from normal cells, enabling new targeted therapeutic approaches."

 

Challenges & Solutions

Although Profile shows promise for advancing the current state of cancer care, large-scale implementation of this program in clinical practice isn't without its limitations. Lindeman suggests that a current challenge related to the program is determining how these initiatives will ultimately advance patient care.

 

"One of our challenges is that the program was conceived and launched as an epidemiology program," explained Lindeman. "We need to collect that information and determine how these data have improved patient care."

 

Another challenge involves getting insurers to pay for profiling. Greater research validating its benefit in improving therapy response, as well as improving prognosis and overall survival, may help influence insurers' decision to cover profiling options in the future.

 

Reluctance among patients to participate in Profile was another concern, said Rollins. Surprisingly, patients and faculty were eager to jump on board. "Initially, we were concerned that patients would be worried about genetic testing, but they were enthusiastic about it," he noted. "There was short-term reluctance among staff, but they came around and started enjoying it as part of their routine."

 

The Future of Profile

Scientists at the Dana-Farber Cancer Institute and Brigham and Women's Hospital are looking to the future and actively discussing options for how they believe the program will evolve. "Our view of the optimal treatment of cancer has clearly broadened among molecular targeted therapies," Rollins stated.

 

Lindeman emphasizes the team's shared desire to move past tissue samples and into liquid biopsies, which have become a more intriguing and less-invasive option for obtaining samples from cancer patients. While tissue biopsies are still sometimes referred to as the "gold-standard source" for molecular analysis, the assessment of cancer-related material found in the bloodstream is becoming a more viable part of genetic cancer screening.

 

Research comparing the analysis of circulating-free DNA in tissue versus liquid biopsies in patients with non-small cell lung cancer, for example, found clinical value of the liquid biopsy option, particularly for detecting the EGFR mutation and predicting survival (Clin Cancer Res 2015;21(14):3196-203, J Thorac Oncol 2014;9(9):1345-1353). Compared with tissue samples, blood samples may assist in earlier cancer detection, particularly if there is no observable carcinoma-related lump in the tissue sample. Additionally, liquid biopsies may be preferred for tissue analyses for monitoring cancer recurrence.

 

With advancements in technology and deep learning in the field of cancer genomics, the investigators are also discussing ways in which they can leverage machine learning and artificial intelligence.

 

"When you look at immunotherapy, our one simple test isn't enough-our next step is to do the same sort of thing in immune profiling," said Rollins.

 

The Profile tumor genomic profiling database is currently supporting proposals for new clinical trials. In time, there is hope among scientists that this database will enable physicians to make more informed, timely, and cost-effective decisions that will facilitate greater care in the field of cancer.

 

Brandon May is a contributing writer.