Daniel Stover, MD, assistant professor of internal medicine at Ohio State University Comprehensive Cancer Center, Columbus, said the results are exciting, particularly since they follow similar findings from a 2018 ctDNA analysis conducted as part of the PALOMA-3 trial, which was also led by Dr Turner’s group. “It’s building evidence that we have the potential to have an early time point where we can detect whether patients are likely to respond or not to treatment,” said Dr Stover. The possibility that ctDNA levels could predict outcomes means it could also help avoid unnecessary toxicity from a treatment that isn’t working. “We can’t say that now,” said Dr Stover. But, he noted, detecting a response is a necessary step toward avoiding adverse events. 

The prospect of knowing whether a drug works within 8 days is conducive to trying new therapies, said Rebecca Shatsky, MD, who treats advanced breast cancer and is a professor at the University of California, San Diego. “It allows you to do things that are a little bit riskier,” said Dr Shatsky. 

But she also said she sees barriers restricting the routine use of ctDNA. Without insurance coverage, community-based oncologists may be unable to offer this diagnostic to patients. And, sampling ctDNA as an outcome surrogate could cost up to $8,000. 

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In addition, interpreting the results isn’t simple. Mutations present in the blood that may be irrelevant to breast cancer or its treatment could be mistaken as indicative of changes to the cancer. For example, 30% of patients in the current study showed clonal hematopoeisis of indeterminate potential, or CHIP, in their samples, a marker that was irrelevant to PFS or treatment tolerance. An inexperienced physician, said Dr Shatsky, “could misinterpret that and think the patient is not responding to therapy.” 

Despite these limitations, ctDNA is emerging as a potentially powerful diagnostic tool, for not only breast cancer but also lung cancer,4,5 noted Chris Abbosh, MD, clinical research associate at University College London. Dr Abbosh noted that the tool may be particularly useful in informing go/no-go decisions in drug development. 

The real test, noted Dr Abbosh, will require a study examining whether treatment decisions made as a result of ctDNA suppression (or lack thereof) “can improve overall survival outcomes in metastatic disease … and reduce toxicities from treatments that would otherwise be continued.” Oncologists everywhere await such a study. 

Disclosure: Dr Turner disclosed he receives research funding from AstraZeneca, makers of capivasertib, and several study coauthors are employees of AstraZeneca. For a full list of disclosures, please refer to the original Annals of Oncology article.

References

  1. Turner NC, Alarcón E, Armstrong AC, et al. BEECH: A dose-finding run-in followed by a randomised phase 2 study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with oestrogen receptor-positive advanced or metastatic breast cancer, and in PIK3CA mutant sub-population [published online March 12, 2019]. Ann Oncol. doi: 10.1093/annonc/mdz086
  2. Hrebien S, Citi V, Garcia-Murillas I, et al. Early ctDNA dynamics as a surrogate for progression free survival in advanced breast cancer in the BEECH trial [published online March 12, 2019]. Ann Oncol. doi: 10.1093/annonc/mdz085.
  3. O’Leary B, Hrebien S, Morden JP, et al. Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. Nature Commun. 2018;9(1):896.
  4. Goldberg SB, Narayan A, Kole AJ, et al. Early assessment of lung cancer immunotherapy response via circulating tumor DNA. Clin Cancer Res. 2018;24(8):1872-1880.
  5. Phallen J, Leal A, Woodward BD, et al. Early noninvasive detection of response to targeted therapy in non-small cell lung cancer. Cancer Res. 2019;79(6):1204-1213.