Progress on Pseudoprogression
Droplet digital PCR for circulating tumor DNA could distinguish pseudoprogression from true disease progression
Well known as the most aggressive skin cancer, melanoma has a high likelihood of spreading to other parts of the body. The American Cancer Society estimates that over 9,300 people in the United States will die of metastatic melanoma this year (1). The standard of care for treating patients with metastatic melanoma is immunotherapy; an antibody to the immune checkpoint protein PD-1 is administered alone or in combination with other immunotherapeutic drugs.
Approximately one in 10 patients who receive this treatment experience a phenomenon called pseudoprogression, wherein immune cells infiltrating the tumor cause an increase in its size, mimicking the appearance of true disease progression. Radiologically, pseudoprogression can be identified by tumor enlargement or the development of new lesions, followed by shrinkage as the patient responds to continued treatment. In contrast, true progression can be seen when the tumor continues to grow and the patient remains unresponsive to immunotherapy.
Physicians treating patients with advanced melanoma often find it challenging to identify pseudoprogression at the beginning of treatment. In large part, this is because of the limitations of tumor imaging, which can sometimes return ambiguous results. Now, a group of researchers from Australia have turned to cell-free circulating tumor DNA (ctDNA) in an attempt to identify pseudoprogression more rapidly.
Jenny Lee of Macquarie University and the Melanoma Institute Australia, along with collaborators from the University of Sydney, investigated whether ctDNA could be used to differentiate between true progression and pseudoprogression in patients undergoing immunotherapy to combat melanoma (3). Previously, the researchers analyzed ctDNA profiles from immunotherapy recipients using droplet digital PCR (ddPCR) technology and found that cell-free DNA could accurately predict tumor response, progression-free survival, and overall survival (4). Lee’s work showed that elevated levels of ctDNA during the treatment period were typically tied to overall poor prognosis.
Wanting to build on these results, Lee and her team looked at specific mutations (such as BRAF and NRAS alterations) in the ctDNA profiles of 125 stage IV metastatic melanoma patients at the start of therapy and at regular intervals for up to 12 weeks. They were able to identify by serial imaging nine patients displaying classic signs of pseudoprogression. Using ddPCR, they found that the number of ctDNA copies was reduced by greater than 10-fold within 12 weeks of treatment, in all nine patients. Furthermore, the team were able to correlate these ctDNA patterns with overall survival. According to their work, the one-year survival rate for participating patients with progressive disease and declining (>10-fold) ctDNA profiles was 82 percent, compared to only 39 percent for patients with stable or increasing ctDNA profiles.
For cancer types in which pseudoprogression is prevalent and an identifiable mutation is present, a biomarker that is able to identify true progressive disease and accurately predict patient outcomes (independent of tumor imaging) would prevent physicians from prematurely discontinuing an effective treatment. If the work done by Jenny Lee and her colleagues holds true, ctDNA may be that biomarker.
- American Cancer Society, “Key Statistics for Melanoma Skin Cancer” (2018). Available at: bit.ly/2lMpQLl. Accessed April 17, 2018.
- C Robert et al., “Pembrolizumab versus ipilimumab in advanced melanoma”, N Engl J Med, 372, 2521–2532 (2015). PMID: 25891173.
- JH Lee et al., “Association between circulating tumor DNA and pseudoprogression in patients with metastatic melanoma treated with anti–programmed cell death 1 antibodies”, JAMA Oncol, [Epub ahead of print] (2018). PMID: 29423503.
- JH Lee et al., “Circulating tumour DNA predicts response to anti-PD1 antibodies in metastatic melanoma”, Ann Oncol, 228, 1130–1136 (2017). PMID: 28327969.
Viresh Patel is Global Marketing Director for Bio-Rad’s Digital Biology Group. He leads a marketing group responsible for diagnostic product development and commercialization for Droplet Digital PCR (ddPCR). Prior to joining the Digital Biology Group, Viresh held multiple roles in marketing with Bio-Rad Laboratories and MJ Research. He has managed a diverse group of genomics and gene expression product portfolios, including solutions for real-time PCR, epigenetics, and digital PCR. Before transitioning to marketing, Viresh was a Content Scientist with Ingenuity Systems (now part of QIAGEN). He obtained his Bachelor of Science degree in Genetics from the University of California, Davis and earned his Ph.D. in Microbiology and Immunology from the University of California, Los Angeles, USA.