February 10, 2020 Advisory Board's take: Why this project is so amazing

A team of international clinicians and scientists on Wednesday published findings from a comprehensive review of more than 2,600 cancer genomes, which observers say could further pave the way for clinicians to prescribe precise treatments to cancer patients based on their genes.

Research details

The team, who published their findings in 23 papers in Nature and its affiliated journals, completed the research through a joint project of the International Cancer Genome Consortium (ICGC) and U.S.-funded Cancer Genome Atlas (TCGA) called the Pan-Cancer Analysis of Whole Genomes Project (PCAWG). The project involved more than 1,300 clinicians and scientists, including members of Harvard and the Broad Institute of MIT, from across 37 countries.

Whereas researchers in the past had only looked at 1% of the cancer genome that specifically codes for proteins, called the exome, this project analyzed the entire cancer genome. To understand this remaining 99%, a team of 16 working groups analyzed more than 2,600 whole genomes from 38 different tumor types using the field's largest publicly available whole-genome dataset. The project took six years.

Findings

The researchers were able to gain a more nuanced understanding of "driver mutations," or mutations that play a major role in driving cancer progression. While previous studies of the cancer exome had also shown common driver mutations, this study allowed the researchers to find more mutations in non-coding areas which have an impact on cancer progression. On average, the researchers found each type of cancer had four or five driver mutations. As a result of the research, only 5% of cancer tumors now have unknown genetic drivers.

These newly discovered driver mutations could potentially be new targets for new drugs and allow for more personalized care for cancer patients. Clinicians have long been frustrated that two patients with identical tumors can respond to the same treatments in different ways. This study moves the field closer to providing oncologists with a list of cancer-causing mutations that they can use to personalize treatment.

In addition, the researchers discovered a new way to "carbon date" cancer. The method allows researchers to identify old mutations involved in forming cancers and determine the relative timing between them. Using this technique, they found nearly 20% of mutations occurred years, or even decades, before the cancer was found. Fifty percent of these early mutations occurred in the same nine genes.

Why the findings matter

Gad Getz, a co-senior author of three of the papers and the director of bioinformatics at the Massachusetts General Hospital's Cancer Center and a professor of pathology at Harvard Medical School, said, "This large international effort shows the breadth of the types of research and new biological insight that are possible using whole cancer genome data."

Observers also noted that the findings could lead to better diagnostics and prevent cancer. "It's certainly true that this kind of sequencing will not mean that all cancers are cured," said Peter Campbell of the Wellcome Sander Institute, a PCAWG member. "But it points us to where we should be thinking about developing drugs for preventing resistance or treating it once it arises" (Drage O'Reilly, Axios, 2/6; McPherson, Harvard Gazette, 2/5; Kaiser, Science, 2/5).

Advisory Board's take

How amazing is this!? Over 1,300 researchers. 34 countries. 38 tumor types. 2,658 whole genomes.

The six papers published in this month's Nature (23 articles across all of Nature's journals) detail the genomic findings from this massive collaboration. Findings ranged from identifying the mutations that drive cells to become cancerous to uncovering the molecular similarities across different tumor types. All told, it represents a step forward in our journey to deliver care that is personalized to each individual tumor.

But, as our scientific understanding of cancer rapidly evolves, we have to make sure we're building the right infrastructure to put precision, or personalized, medicine into practice. What does that mean? Three big implications jump out to me:

  1. We need to get better at managing genomic data and ensuring patient privacy. Genomic tests generate enormous amounts of data that will require new capabilities to manage it, share it across stakeholders, and—importantly—integrate it with clinical data and patient-reported outcomes. One of the editorials accompanying the issue highlighted how critical it was to protect the privacy of the thousands of individuals whose genomic information was stored and shared in the cloud in this endeavor. Being able to share patient data with researchers and physicians across the globe is exciting, but also raises questions about data ownership and access—specifically how employers, law enforcement, and national governments are increasingly interested in this type of information. These authors rightfully argue that we can’t wait any longer to craft an international code of conduct governing genomic data.
  2. We need to help care teams seamlessly integrate new evidence into clinical practice. There are a number of barriers to putting precision medicine and exciting new clinical findings into practice. First, clinicians have to identify which patients are eligible for which tests and when those tests should be ordered. Second, they must interpret the results of genomic tests to craft a tailored treatment plan. Third, clinicians need to help patients understand the results and how they influence treatment options. Clinical decision support and molecular tumor boards are helpful tools that more organizations are exploring, but we still have a long way to go.
  3. We need to ensure access and ongoing support for patients who stand to benefit. This will involve not only a serious investment in patient education and care coordination, but also working across stakeholders to create a sustainable financial model that supports and encourages ongoing innovation and improved outcomes.

It won't be easy. But it'll sure be exciting.

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