Crucially, only 4 of the 9 “complete response” patients had undetectable levels of ctDNA; tumor DNA was still present in the other 5 patients who achieved pathCR.

This initially sounds like gloomy news, since the data confirm that pathCR is an inadequate measure of success. However, Dr Pockaj said the result is helpful, as TARDIS could supply an early signal that the patient is, in fact, incompletely treated: “In those patients whom we thought we did such a good job with our therapy, some will fail,” she said. “Can we identify those patients and can we give them more therapy to move them to a total cure?”

Perhaps more crucially, the existence of 4 patients with no detectable ctDNA suggests that some women may be enduring disfiguring breast surgery for no reason. On the plus side, the results dangle the possibility that surgery may be avoided in the future in patients.

Dr Pockaj agreed that TARDIS, if validated, has the potential to someday render surgery unnecessary for some patients. Her motivation for doing the study was primarily to reduce overtreatment in breast cancer: “I think breast cancer treatment is one of the leaders in cancer therapy in terms of individualization of care … But at the same time, we still do one-size-fits-all once we get them subdivided into the biology of their cancer. Even though I’m a surgeon, at certain times I do things and I’m thinking, am I really helping patients?”

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Commenting on the TARDIS results, Christine Brezden-Masley, MD, PhD, medical director of the cancer program at Sinai Health System in NYC, said, “In the future if there is a possibility of not resecting where the original tumor was, that would be wonderful, but I don’t think we’re there yet. Not every breast cancer will spew out circulating DNA. This is usually a hallmark of the actual tumor — whether or not it sheds.”

Dr Brezden-Masley’s team worked on mutational targets in the metastatic setting and found a concordance of approximately 50% between the primary tumor and circulating tumor DNA.

Like the study authors, Dr Brezden-Masley said that a validation study is needed before practice changes. She predicted a timeline of “5+ years” before surgery is no longer the standard of care for patients with breast cancer.

Dr Brezden-Masley was more excited about the potential of TARDIS for rectal cancer, in which ctDNA levels do appear to reliably predict outcome.5 “In rectal cancer, we’re actually doing something known as nonoperative management and we’ve got to the point where we are not resecting,” she said. “And so I think that I can see this having more utility in the rectal cancer space than in the breast cancer space. And the reason why I say that is that you can imagine a small lumpectomy versus having your entire rectum removed and having a permanent colostomy — big difference.”

Dr Pockaj and colleagues have started work on a TARDIS validation trial to assess the feasibility of eliminating surgery in breast cancer. Similar work is under way at the MD Anderson Cancer Center, Houston, Texas, which is at the midpoint of a 5-year trial of no surgery on the basis of image-guided biopsy.9,10

“I think it’s important that the research continues,” said Dr Brezden-Masley. “It’s exciting that we’re having these conversations now and that there are better and better tests for microscopic residual disease, which I think is very important. This research moving forward is essential to how breast cancer treatment will emerge and change in the future.”

References

  1. McDonald BR, Contente-Cuomo T, Sammut SJ, et al. Personalized circulating tumor DNA analysis to detect residual disease after neoadjuvant therapy in breast cancer. Sci Trans Med. 2019;11(504):eaax7392.
  2. Stover DG, Parsons HA, Ha G, et al. Association of cell-free DNA tumor fraction and somatic copy number alterations with survival in metastatic triple-negative breast cancer. J Clin Oncol. 2018;36(6):543–553.
  3. Dawson S-J, Tsui DWY, Murtaza M, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368(13):1199–1209.
  4. Rothé F, Silva MJ, Venet D, et al. Circulating tumor DNA in HER2-amplified breast cancer: a translational research substudy of the NeoALTTO phase III trial. Clin Cancer Res. 2019;25(12):3581–3588.
  5. Tie J, Cohen JD, Wang Y, et al. Serial circulating tumour DNA analysis during multimodality treatment of locally advanced rectal cancer: a prospective biomarker study. Gut. 2019;68(4):663–671.
  6. Riva F, Bidard FC, Houy A, et al. Patient-specific circulating tumor DNA detection during neoadjuvant chemotherapy in triple-negative breast cancer. Clin Chem. 2017;63(3):691–699.
  7. Butler TM, Boniface CT, Johnson-Camacho K, et al. Circulating tumor DNA dynamics using patient customized assays are associated with outcome in neoadjuvantly treated breast cancer. Cold Spring Harb Mol Case Stud. 2019;5(2):a003772.
  8. Magbanua MJM, Brown-Swigart L, Hirst GL, et al. Abstract PD2-01:Personalized serial circulating tumor DNA (ctDNA) analysis in high-risk early stage breast cancer patients to monitor and predict response to neoadjuvant therapy and outcome in the I-SPY 2 TRIAL. Cancer Res. 2019;79(4 Suppl): Abstract PD2-01.
  9. Kuerer HM, Rauch GM, Krishnamurthy S, et al. A clinical feasibility trial for identification of exceptional responders in whom breast cancer surgery can be eliminated following neoadjuvant systemic therapyAnn Surg. 2017;267(5):945–931.
  10. ClinicalTrials.gov. NCT02945579. https://clinicaltrials.gov/ct2/show/NCT02945579. Accessed October 23, 2019.