Jamie H. Von Roenn, MD

Although clinical trials are helpful in determining the effectiveness of a specific drug across a patient population, they are not as reliable at pinpointing how well a particular patient will respond to the drug or dosing regimen or how the drug may impact the patient’s quality of life from treatment-related toxicity. Now, the use of more sophisticated next-generation whole-exome sequencing and a greater understanding of the genetic diversity of tumors are leading to more comprehensive genetic testing, which include both a patient’s tumor (somatic) DNA and germ-line DNA to identify the most effective and safest therapy for that patient. The result is providing clinicians with the potential to more precisely assess a specific treatment’s benefit and risk for an individual patient.

As our data become richer, we will get to the point where we can predict all severe drug toxicities.

— Howard L. McLeod, PharmD

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“The somatic genome can assist oncologists in predicting a patient’s tumor behavior if left untreated (prognosis) or treated (efficacy prediction), and the germ-line genome can influence prognosis as well as help assess the level of drug-related toxicity the patient will likely experience,” said Howard L. McLeod, PharmD, Medical Director of the DeBartolo Family Personalized Medicine Institute and senior member in the Department of Cancer Epidemiology at Moffitt Cancer Center in Tampa, Florida.

As the cost of next-generation sequencing continues to decrease and the technology continues to advance, it will be possible to routinely identify the pharmacogenetic factors in patients’ somatic and germ-line DNA and more precisely individualize treatment decision-making for patients with cancer, according to Dr. McLeod.

In the meantime, Dr. McLeod is relying on the Clinical Genomics Action Committee he helped to establish at Moffitt to inform care for patients with advanced cancer and few treatment options. The Clinical Genomics Action Committee serves as the cancer center’s molecular tumor board and includes a multidisciplinary team of medical oncologists, pharmacists, pathologists, basic scientists, genetic counselors, and palliative care specialists charged with assessing difficult patient cases and translating tumor genetic analysis into direct patient care.

The ASCO Post talked with Dr. McLeod about how he is integrating germline and somatic genetic information into the care of his patients and how advances in sequencing technology will improve personalized care for all patients.

‘Ramping Up’ Sequencing Program

How you are using pharmacogenetics to predict cancer prognosis and treatment exposure, response, and toxicity in your patients?

Although genomic sequencing of cancer tumors is fairly common now, how comprehensive the testing is varies across cancer institutions. Generally, many of the larger cancer centers are using somatic sequencing to direct patients into appropriate clinical trials or to the off-label use of a drug. Performing germline sequencing of a patient’s DNA is not yet being done routinely. Physicians tend to focus on a patient’s tumor and assume that germline sequencing is more a quality control measure and not something that needs to be done to direct care.

What we have found is that you can’t have an accurate risk/benefit treatment discussion with patients unless you know how they will physically handle and react to a particular treatment. This is especially important when you have two or more treatment options with equal efficacy to offer.

We are now routinely performing DNA analysis of patients’ tumors and are ramping up a sequencing program that includes both germline and somatic sequencing. And the reasons for that are many. Most important, the unpredictability of a treatment response can lead to the administration of an ineffective therapy for a patient, allowing the tumor to continue to grow and making it more difficult to control the cancer with future therapies. Then there is the attendant financial costs associated with those ineffective therapies, as well as the cost in a reduced quality of life from treatment-related toxicities.

These costs make it critical to develop strategies for selecting the best treatments for each patient.

Predicting Drug Toxicities

Is next-generation sequencing technology advanced enough to provide comprehensive genomic profiles on both a patient’s somatic and germline DNA to accurately select appropriate therapies and limit drug toxicities?

Yes it is. The technology is a long way from being perfect, but the type of data we can get on a patient’s somatic and germline variants allows us to identify those patients with a high probability of treatment failure, as well as the potential for increased toxicity for problems such as neuropathy or gastrointestinal issues. As our data become richer, we will get to the point where we can predict all severe drug toxicities.

Cardiovascular Risk Factors

Are you using genomic sequencing to identify problems such as cardiovascular risk from treatment?

Currently, the cardiovascular risk factors we are evaluating are the genetic variant for cardiomyopathy or cardiac arrhythmia. We are not yet able to detect the genetic markers that are associated with a general population risk for myocardial infarction. Right now, we are trying to identify patients who may be susceptible to extreme events from treatment, such as those who are likely to experience heart failure after a few doses of doxorubicin. In time, we will be able to obtain the somatic and germline genetic information quickly, and then we can start broadening the clinical scope of implementing individualized treatment for patients.

Initiating Early Palliative Care

Please talk about the role of palliative care specialists on Moffitt’s Clinical Genomics Action Committee.

In addition to assessing what clinical actions can be taken based on a patient’s tumor genetics, our committee members, including palliative care specialists, also review the benefit and risk to that patient based on a recommended treatment. Because all the patient cases we review have advanced cancer and are often experiencing symptoms not just from their disease but from their treatment as well, part of our discussions include how to provide care aimed at controlling these symptoms, regardless of whether we are also recommending ongoing therapy to control the cancer.

In our review of patient cases, we often recommend the initiation of early palliative care to relieve disease or treatment-related symptoms and improve patients’ quality of life. Sometimes we recommend end-of-life palliation based on discussions with patients about their treatment goals and preferences.

In all instances, our goal is to provide truly personalized care for our patients. Our inclusion of a patient’s somatic and germline genetic information into our Clinical Genomics Action Committee discussions helps us select not just which treatment might be most effective for that patient, but which dosage might be most tolerable to avoid unwanted side effects.

We are not looking for perfection with next-generation sequencing technology to help us predict with absolute precision a cancer prognosis as well as a patient’s response to therapy and potential side effects from that therapy. We just want to be smarter than we are now in making therapy decisions by using all adequate genomic data. Our current sequencing technology is not sufficient to allow us to be perfect in that decision-making, but having some adequate data is better than not having any data.

If we have to give a patient a drug, why not use the genetic information from a patient’s tumor and germ line to guide more precise treatment as opposed to the standard-of-care therapy oncologists are most comfortable prescribing?

Don’t think for a second that we know exactly how to interpret the information gleaned from pharmacogenetics in treatment decision-making, but we are getting better, and the technology is getting better as well. Our great hope is that someday we will indeed find perfection in the use of pretreatment pharmacogenetic testing to enable us to offer patients truly personalized care and improve their outcomes. ■

Disclosure: Dr. McLeod reported no potential conflicts of interest.