ATM, INCREASING ctDNA MUTATIONS
“Using plasma NGS in monitoring treatment response in pancreatic – and all – cancers can be notably impactful in helping patients live longer and live better. Plasma ctDNA can identify responding or progressing cancer activity before it is radiographically evident, avoiding continuation of ineffective therapy with needless toxicity. It can also identify resistance pathways, guiding a potentially more effective precision treatment approach. In a seminal study comparing tissue biopsies of multiple tumor sites with tissue NGS versus paired plasma NGS, the plasma ctDNA was far superior in identifying more resistant pathways and identified more mutations that are otherwise limited by tissue heterogeneity.
Very unfortunately, based upon this second plasma NGS, there is clearly active and progressing pancreatic cancer with the number of ctDNA mutations increasing from 3 to 6. If her cancer were responding, her ctDNA load should have been decreasing by 4-6 weeks after starting treatment. Continuing the same ineffective therapy at this point is pure toxicity without any benefit.
Although none of the mutations are directly targetable, they can be actionable in making a next-treatment-step recommendation and decision. The “Know Your Tumor” study was a profound proof of principle of this with a markedly better survival in those patients who received ‘matched’ therapy guided by molecular testing. ATM is a DNA damage response and repair pathway gene. ATM mutations can heighten potential response to chemotherapy, gemcitabine-abraxane in particular, PARP inhibitors and radiation therapy. The next best therapy step needs to be guided by and ‘match’ the evolving tumor biology and progressing disease findings. Certainly, a clinical trial targeting ATM is also a possibility, if available.
Precision oncology is knowing the tumor biology. Personalized cancer treatment is providing the best possible cancer treatment to get the best possible outcome for your patient. You will not know the tumor biology if you do not test it. Plasma NGS is the best monitor of cancer activity and evolving tumor biology.” – Dr. Paul Walker, Chief Medical Officer, Former Director of Thoracic Oncology at East Carolina University
– Pancreas Journal, Volume 49, Number 1, January 2020
– Pancreas (Fairfax). 2019 ; 3(1): e5–e8. doi:10.17140/POJ-3-e011
– Michael Ayars, James Eshleman & Michael Goggins (2017). Susceptibility of ATM-deficient pancreatic cancer cells to radiation, Cell Cycle, 16:10, 991-998, DOI: 10.1080/15384101.2017.1312236
– The Lancet Oncology, March 2020