“Liquid biopsy has a variety of unique applications across distinct cancer types. In lung cancer, for instance, resistance mutations can be documented after certain EGFR-directed therapies and used for therapeutic selection. In gastrointestinal and genitourinary cancers, a range of potential uses is envisioned.”
- Sumanta Pal, MD, ASCO Expert
National guidelines recommend testing lung tumor samples for changes in a whole range of cancer-related genes, as there are a number of matched targeted therapies available now.2 In reality, however, very few patients receive testing for more than one genomic abnormality, due to insufficient amount of tumor sample from the initial, diagnostic biopsy. There is some risk associated with tissue biopsies. For example, it is virtually impossible to perform a lung biopsy each time the cancer worsens. With the advent of noninvasive liquid biopsies that test for multiple genomic changes at a time, more patients may benefit from treatments tailored to the genetic makeup of the tumor.
Using a commercially available 54-gene panel ctDNA test, in a recent study researchers found at least one genomic change in 83% of patients with stage I-IV lung cancer.3 Of those, 39% had a genomic change matched with an FDA-approved therapy in a different indication, and 82% had a genomic change that was matched to an experimental treatment in a clinical trial. Although early, these findings suggest that ctDNA testing is a viable choice when there is insufficient tissue for genomic testing and/or repeated tumor biopsy is not possible.
The largest lung cancer ctDNA study to date found genomic changes in 86% of 5,206 patients with advanced cancer, including changes that signal emerging treatment resistance.4 The patterns of genomic changes in the ctDNA were consistent with previously published results from large-scale tumor sample analyses, and with individual patient’s tumor testing reports. In a subset of patients who had insufficient initial biopsy sample for genomic testing, the ctDNA test uncovered genomic changes that were matched to approved targeted therapies.
Another early study showed that ctDNA blood tests could be used to follow genomic changes in pancreatic cancer during the course of treatment.5 Researchers found that the types and abundance of genomic changes in ctDNA were linked to the amount of cancer in the body (tumor burden). This finding suggests that ctDNA tests could be useful for early assessments of treatment efficacy and development of resistance.
Similarly, other researchers found an association between the relative abundance of certain genomic changes and tumor size.6 Among patients with colorectal cancer who received BRAF inhibitor vemurafenib, the abundance of BRAF V600E mutations in the ctDNA samples decreased as tumors shrunk over the course of treatment.
Kidney, Bladder, and Prostate Cancers
Research presented at the 2017 Genitourinary Cancers Symposium highlights possible roles of ctDNA testing in different genitourinary cancers – from following response to therapy to uncovering molecular targets for development of new treatments.
An analysis of ctDNA from patients with advanced kidney cancer found clinically relevant genomic changes in nearly 80% of patients.7 The pattern of genomic changes (particularly genes in the p53 and mTOR pathways) appears to evolve with treatment – and these new genomic changes may be linked to the cancer’s resistance to initial treatment.
In advanced prostate cancer, researchers were able to detect genomic changes in 94% of ctDNA samples tested.8 This is very encouraging because traditional tumor biopsy is difficult to obtain in metastatic prostate cancer. Having a high number of genomic changes overall and changes in the androgen receptor gene were associated with worse treatment outcomes, including a tendency for shorter survival.
Using the same commercial blood test, other researchers reported that ctDNA might provide clinically important information in patients with advanced bladder cancer.9 The researchers were able to collect ctDNA from 89% of patients in the study, finding recurrent changes in several genes, one of which, FGFR1 was associated with shorter survival in a small group of patients. New changes in genes involved in DNA repair evolved after chemotherapy.
In both the prostate and the bladder cancer study, the genomic changes found in the ctDNA samples were consistent with changes previously seen in tumor biopsy samples, suggesting that the ctDNA blood test may be a valid alternative when tumor biopsy is not possible. Taken together, the findings from ctDNA analyses offer early leads for development of new molecularly targeted medicines for kidney, prostate, and bladder cancers.
Limitations and Future Directions
Despite the various advantages of liquid biopsy tests, ctDNA testing is not intended to replace traditional tumor biopsy testing entirely. Thorough pathological assessment of the tumor tissue will remain critical to establish an accurate diagnosis initially. Once the diagnosis is established, ctDNA blood tests could be used for genomic analyses instead of repeated invasive biopsy. Many studies have shown that ctDNA tests are highly accurate for “ruling in” genomic changes that have approved therapies.
Experts argue, however, that a negative ctDNA test result (no genomic change found) is not as reliable as tissue biopsy. For one commercial test, the estimated “false-negative” rate is 15%.1 Whenever possible, patients with a negative liquid biopsy test should have tumor tissue tested to confirm there are no genomic changes.
The utility of ctDNA testing also varies with cancer type and stage. Generally, advanced-stage and actively growing cancers seem to be better suited to this test because they release larger amounts of genetic material into the bloodstream. There has been little success so far with collecting ctDNA from patients with brain cancer.
Finally, the clinical implications of genomic changes will also differ by cancer type. The fact that a cancer has a specific molecular target is promising, but there is no guarantee that the matched therapy will work against that cancer, even if it is effective against another type of cancer with the same target. Even with the most high-tech molecular test, predictions in biology are tricky.
A study of a new approach to detect ctDNA in blood samples was highlighted in the 2017 ASCO Annual Meeting Press Program.
Read Part I.
1. Lanman RB, Mortimer SA, Zill OA, et al: Analytical and Clinical Validation of a Digital Sequencing Panel for Quantitative, Highly Accurate Evaluation of Cell-Free Circulating Tumor DNA. PLoS One 10:e0140712, 2015
2. Ettinger DS, Wood DE, Akerley W, et al: NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 4.2016. J Natl Compr Canc Netw 14:255-64, 2016
3. Villaflor V, Won B, Nagy R, et al: Biopsy-free circulating tumor DNA assay identifies actionable mutations in lung cancer. Oncotarget 7:66880-66891, 2016
4. Mack PC, Banks KC, Zill OA, et al: O.02: Plasma Next Generation Sequencing of Over 5,000 Advanced Non-Small Cell Lung Cancer Patients With Clinical Correlations. J Thorac Oncol 11:S168-S169, 2016
5. Ko AH, Bekaii-Saab T, Van Ziffle J, et al: A Multicenter, Open-Label Phase II Clinical Trial of Combined MEK plus EGFR Inhibition for Chemotherapy-Refractory Advanced Pancreatic Adenocarcinoma. Clin Cancer Res 22:61-8, 2016
6. Hong DS, Morris VK, El Osta B, et al: Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation. Cancer Discov 6:1352-1365, 2016
7. Pal SK SG, Agarwal N, et al. : Evolution of circulating tumor DNA (ctDNA) profile from first-line (1L) to second-line (2L) therapy in metastatic renal cell carcinoma (mRCC). J Clin Oncol 35, 2017
8. Sonpavde G NR, Sartor AO, et al. : Circulating tumor (ct)-DNA alterations in metastatic castration-resistant prostate cancer (mCRPC): Association with outcomes and evolution with therapy. J Clin Oncol 35 35, 2017
9. Grivas P NR, Pond GR, et al. : Circulating tumor (ct)-DNA alterations in advanced urothelial carcinoma: Association with outcomes and evolution with therapy. J Clin Oncol 35, 2017