Genomic Assays Expediting Adoption of Personalized Cancer Therapy in Clinical Practice
Washington, DC—Cancer is now recognized as a disease of the genome. The use of genomic assays and measurement of protein expression are permitting the use of personalized cancer therapy in the clinical setting on a scale not seen previously. In many cases, the use of these assays will also enhance the cost-effectiveness of cancer therapy, although the overall cost of cancer care may not decline as a result, said Gerald Messerschmidt, MD, FACP, Chief Medical Officer, Precision for Medicine, at the Sixth Annual Conference of the Association for ValueBased Cancer Care.
The cost of treating cancer will continue to rise, because treating multiple cancer clones with multiple drugs is the future of cancer therapy, Dr Messerschmidt said. As cancer continues to mutate, multiple clones arise, and treatment based on the clone present at the initial biopsy will eventually fail.
“If you only use a single agent that is getting after that particular clone, you may not kill other clones” and the cancer will recur, he said.
“What is coming in the future for the treatment of cancer is not 1 drug, not 2 drugs, but many drugs that are going to be used in combinations of chemotherapy, radiation therapy, immunotherapy, targeted cell therapies, and anticancer vaccines,” Dr Messerschmidt predicted. “I anticipate that 2 to 12 drugs will become standard within the next 5 years, and maybe more than that as time goes on. Getting these kinds of combinations is really the trick.”
Changing Nature of Clinical Trials
Uniting disparate assays into a single, tissue-sparing assay to be used as a universal companion diagnostic is an area generating excitement. The use of such an assay may prequalify a candidate for a clinical trial with DNA-based eligibility, said Vincent Miller, MD, Chief Medical Officer, Foundation Medicine, Cambridge, MA.
More knowledge of the exons of clinically and biologically relevant cancer genes and the introns of genes frequently rearranged in human cancer is needed, he said. The emphasis at Foundation Medicine is putting a floodlight, rather than a penlight, on the tumor through the use of a broad-based comprehensive genomic profile. “We sequence the entire coding sequence of what we believe is the oncogenome or the cancer gene universe,” said Dr Miller. “Precision medicine—we’re getting increasing data—is working.”
He noted the improved response rates and progression-free survival (PFS) rates with personalized, biomarker-targeted cancer therapy compared with empiric therapy, which he defined as choosing therapy without measuring whether the target is present.
Early results from the MyPathway study (Figure), an open-label phase 2a multiple basket study in which targeted therapy for advanced solid tumors is based on molecular profiles, showed that of 129 patients treated, 29 (22%) patients with 12 different tumor types had objective responses based on the molecular profiling strategy; 15 of the responses were ongoing at 3 months to more than 11 months.
Methods beyond immunohistochemistry are proving to be more robust predictors of response to immunotherapy. Dr Miller discussed the concept of tumor mutation burden, which is a measure of the total number of coding somatic base substitution and indel mutations occurring in a tumor specimen, per megabase of coding genome assessed. In the context of immunotherapy, “The more mutations a tumor has, the more likely it is to create something the immune system indeed recognizes as foreign and, in turn, unleash a robust T-cell response,” he said.
Mutation load has been shown to correlate with response to immunotherapy, as well as median PFS and overall survival.
Proteins: Where the Action Is
Combining proteomics with genomic interpretation can provide a holistic understanding of the progression of disease and the universe of options for individualized care, said Gary Palmer, MD, JD, MPH, Chief Medical Officer and President, GPS Operations, NantHealth, Culver City, CA. In fact, whole genome sequencing followed by genomic, transcriptomic, and proteomic analysis can allow the guided use of low-cost chemotherapy, making it a personalized treatment option.
The measurement of proteins can be used to make chemotherapy a targeted therapy, he said. Every protein has its own unique degradation pattern, as do peptides. These peptides can be measured to calculate the amount of protein present before degradation. “We can do this now…on paraffin slides, the same things that are normally in the pathology laboratories,” Dr Palmer explained.
For example, hENT1 is a transported protein whose expression is necessary for a response to gemcitabine chemotherapy. Proteins such as hENT1 can be measured quantitatively to predict chemotherapy sensitivity or resistance. Similarly, a threshold of ERCC1 expression exists above which overall survival suffers when cisplatin or pemetrexed is used for the treatment of lung cancer.
The same type of protein analysis can be used to personalize the use of targeted therapies. “We think that the quantified protein analysis is going to be the way that HER2 therapy, trastuzumab, is going to be given in the future,” said Dr Palmer. “More data are needed, but at least that’s the thought process going forward.”
Quantified protein analysis could help in the selection of a cancer treatment when multiple regimens are deemed acceptable by the National Comprehensive Cancer Network, he added.