The Human Genome Project, ENCODE and Cancer Care

Genomics in Oncology

A newly diagnosed cancer patient and their family might have barely moved from the first stage to the next of the five stages of grief but, regardless of the course of their emotional journey, their cancer vocabulary begins to grow from day one. Biopsy, staging, chemo, neutropenia,… words that had meant nothing to them before, take on a very tangible meaning invoking thoughts of hospital beds and days spent being sick. As the battle with cancer continuous, their vocabulary continues to evolve as well. Remission, transplant, … relapse, metastasis, morphine, …hospice; relief alternating with despair, a roller coaster ride with too many ups and downs.

In the last few years, a newer set of words  are beginning to make their way into the cancer lexicon- whole genome sequencing (WGS), targeted therapies, biomarkers… words that are becoming associated with some recent successes and cautious optimism as we relentlessly search for a cure to cancer. These partial successes, the understanding that cancer is a genetic disease, and the decreasing cost of whole genome sequencing raise important questions about making tumor sequencing an integral part of cancer treatment.

Central to this discussion are several different scientific and social issues. On the scientific side, intratumor heterogeneity, challenges with data interpretation and management, and physician training in genomics dominate the conversation. In the social area, cost and insurance coverage, and ethical issues remain center stage.

Intratumor heterogeniety refers to the existence of genetically divergent tumor cell clones within a tumor as well as evolutionary divergence between primary tumors and metastatic outgrowths. If greater that 60% of all somatic mutations are not detectable across every tumor region as a New England Journal of Medicine study showed, then even finding an adequate sample on biopsy is a challenge. Issues of quality and quantity are also important as tumor heterogeneity analysis relies on genome amplification methods that produce a representation not a replica of the tumor genome. With respect to distant metastasis, which are responsible for the majority of cancer related deaths, radically different patterns of allelic loss and genetic divergence from the primary tumor have been documented in the metastasis. This further complicates the process of obtaining a biopsy and identifying therapeutic targets in these patients.

Management of WGS data for clinical applications implies the ability to detect actionable variants from the WGS data, the ability to store genomic data in the electronic medical record and the ability to integrate the use of this genomic data into patient care. While companies such as NextBio use Big Data technologies to scale their platform for storing and interpreting genomic data, and have passed HIPAA audits to enable secure integration into the clinical workflow, the discovery and understanding of actionable variants of clinical significance is still ongoing within the scientific community.

My fellow physician colleagues and I are familiar with targeted genomic tests in oncology, but the use of WGS continues to be a measure of last resort in the majority of cases. Presenting the option of whole genome sequencing to our patients as a part of routine oncology care and providing them with information of sufficient depth to allow them to make an informed decision will require a paradigm shift.

The social issues such as reimbursement of WGS remain unresolved. Dr. Jeffery Roche, Coverage and Analysis officer at CMS announced at a Capitol Hill briefing last October that WGS is unlikely to be covered by CMS anytime soon. Ethical issues around WGS for clinical use are being actively addressed and the Presidential Commissions final report to be presented this fall might provide guidance on at least a few.

The ENCODE project, designed to interpret the human genome, recently made headlines as it infused the findings of the Human Genome Project with meaning. The  discovery that a full 80% of the human genome is associated with biochemical function caught our attention.  In the same news announcements, this quote by renowned researcher Michael Snyder “In my mind, it is a no-brainer to get your genome sequenced if you have cancer” continued to emphasize the role of genomics in the treatment of cancer.

Perhaps, the time has come to make the inclusion of WGS in cancer care a clinical, scientific, and social priority by, investigating options for adaptive therapy, fast tracking the discovery of actionable clinical variants, reimbursing WGS where it is appropriate, and focusing on resolving the ethical issues. Clinicians can play an especially important role by helping their patients make sense of the confusing landscape, educating them, discussing pros and cons and helping them make good informed decisions. This may be our chance to finally introduce a new word into the cancer vocabulary , “Cure”.

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