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ctDNa 'liquid Biopsy" janis c. kelley, 11/18/2014 medscape.com

hopeful and opt...
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Joined: Apr 2009

http://www.medscape.com/viewarticle/835140

 

 

Will this test replace the biopsy?

hopeful and opt...
Posts: 2226
Joined: Apr 2009

(easier version to understand)

 

http://www.nytimes.com/2015/04/20/health/blood-test-shows-promise-as-alternative-to-cancer-biopsy.html?_r=0

 

In the usual cancer biopsy, a surgeon cuts out a piece of the patient’s tumor, but researchers in labs across the country are now testing a potentially transformative innovation. They call it the liquid biopsy, and it is a blood test that has only recently become feasible with the latest exquisitely sensitive techniques. It is showing promise in finding tiny snippets of cancer DNA in a patient’s blood.

The hope is that a simple blood draw — far less onerous for patients than a traditional biopsy or a CT scan — will enable oncologists to quickly figure out whether a treatment is working and, if it is, to continue monitoring the treatment in case the cancer develops resistance. Failing treatments could be abandoned quickly, sparing patients grueling side effects and allowing doctors to try alternatives.

“This could change forever the way we follow up not only response to treatments but also the emergence of resistance, and down the line could even be used for really early diagnosis,” said Dr. José Baselga, physician in chief and chief medical officer at Memorial Sloan Kettering Cancer Center.

Researchers caution that more evaluations of the test’s accuracy and reliability are needed. So far, there have been only small studies in particular cancers, including lung, colon and blood cancer. But early results are encouraging. A National Cancer Institute study published this month in The Lancet Oncology, involving 126 patients with the most common form of lymphoma, found the test predicted recurrences more than three months before they were noticeable on CT scans. The liquid biopsies also identified patients unlikely to respond to therapy.

Oncologists who are not using the new test say they are looking on with fascination. “Our lab doesn’t do it, but we are very interested,” said Dr. Levi Garraway of the Dana-Farber Cancer Institute.

“It’s exciting,” he added. “It’s a top priority.”

Researchers are finding out things about individuals’ cancers that astonish them. MarySusan Sabini, a fifth-grade teacher from Gardiner, N.Y., has lung cancer that resisted two attempts at chemotherapy and a round of radiation. Her doctors at Sloan Kettering saw cancer DNA in her blood when she began taking an experimental drug in October that was her last hope.

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Four days later, the cancer DNA shards had vanished, a sign, the doctors hoped, that the treatment was working. But they dared not tell her the good tidings. The blood test itself was so new they were afraid to rely on it.

Within weeks, Ms. Sabini began to breathe easier. Months later, she had aCT scan, an X-ray test that uses a computer to assemble detailed images of slices of tumor tissue. It confirmed her tumors were shrinking.

“Every cancer has a mutation that can be followed with this method,” said Dr. David Hyman, the oncologist at Sloan Kettering who is leading the study of the experimental drug Ms. Sabini takes. “It is like bar coding the cancer in the blood.”

The idea for the test grew out of a discovery made years ago about fetuses: They shed little pieces of DNA into the bloodstreams of mothers-to-be. It turned out that all growing cells, including tumors, shed tiny DNA fragments.

But finding those minuscule bits of DNA, floating in a sea of other molecules, is not easy. They remain in circulation for just a couple of hours before they are metabolized. And the detection method became useful only when cancer researchers, using advanced methods for DNA sequencing, found hundreds of mutations that could serve as bar codes for cancers and developed the technology for finding a snippet of DNA.

The standard methods of assessing a treatment’s effectiveness have serious drawbacks. Doctors routinely monitor patients for symptoms like pain orshortness of breath, but some people do not have any. In those who do, it can take time for such symptoms to wane — the tumor can die, but the body has to heal.

Patients often have scans to determine if tumors are shrinking, but it can take weeks or months before a tumor looks smaller on a scan, in part because a scan shows not just the cancer but also connective tissue, immune system cells and scars at the site. Doctors can be fooled into thinking a tumor is present when, in fact, it is gone.

“When you are treating a patient — and we see this many times — your treatment is quite effective but there is some residual lesion on a scan,” Dr. Hyman said. “You take the patient to surgery for a biopsy, and all you see is scar tissue. There is no visible cancer there.”

The blood tests also allow frequent monitoring of tumors as they spread and mutate or develop resistance to treatment. The only other way to know is with biopsies.

“I cannot do a weekly liver biopsy and see how things are going,” Dr. Baselga said. “But I can do a blood test every week.”

Another possible application — early diagnosis of cancer — is trickier. If a blood test showed cancer DNA, what would that mean? Where is the tumor, and would it help to find and treat it early? Some cancers stop growing or go away on their own. With others, the outcome is just as good if the cancer is found later.

One early use for DNA blood tests may be helping doctors decide which patients with Stage 2 colon cancer need chemotherapy. Eighty percent of patients with these large tumors that have not spread outside the colon are cured by surgery alone; the rest have recurrences. Six months of intense chemotherapy reduces the risk the cancer will return, but there is no way to predict who needs the treatment.

Two Australian scientists, working with Dr. Bert Vogelstein of Johns Hopkins, wondered if a cancer DNA blood test might be predictive. They began with a study of 250 patients, looking for cancer DNA in blood after surgery. The tumors recurred in 80 percent of those with cancer DNA in their blood but only 6 to 8 percent of those whose blood did not have detectable cancer DNA.

Now the Australian researchers, Dr. Jeanne Tie and Dr. Peter Gibbs of the Walter and Eliza Hall Institute of Medical Research, are starting a study of 450 patients randomly assigned to have the blood test or not. Those who have it will get chemotherapy if the test finds cancer DNA. Those who do not have the blood test will get usual care, whatever their physician prescribes.

The patients will be told their blood test results, although the investigators worry how some will react.

“If you find DNA and tell the patient there is a very high risk of recurrence, that creates a lot of anxiety,” Dr. Gibbs said. “And we are not sure chemotherapy will be helpful.”

The blood test, they hope, will answer that question.

“This will be the first real test of whether circulating tumor DNA can be clinically useful,” Dr. Vogelstein said.

A version of this article appears in print on April 20, 2015, on page A1 of the New York edition with the headli

Old Salt
Posts: 720
Joined: Aug 2014

but it will require a lot of effort to find out if this method can be applied towards finding prostate cancer.

hopeful and opt...
Posts: 2226
Joined: Apr 2009

Here is a study that discusses prostate cancers among others

 

http://stm.sciencemag.org/content/6/224/224ra24.abstract

 

ci Transl Med 19 February 2014: 
Vol. 6, Issue 224, p. 224ra24 
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3007094
  • RESEARCH ARTICLE

CANCER

Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies

  1. Chetan Bettegowda1,2,*
  2. Mark Sausen1,*,
  3. Rebecca J. Leary1,*,
  4. Isaac Kinde1,*
  5. Yuxuan Wang1,
  6. Nishant Agrawal1,2
  7. Bjarne R. Bartlett1,3
  8. Hao Wang1
  9. Brandon Luber1
  10. Rhoda M. Alani4,
  11. Emmanuel S. Antonarakis1
  12. Nilofer S. Azad1
  13. Alberto Bardelli5,6,7
  14. Henry Brem2
  15. John L. Cameron2,
  16. Clarence C. Lee8
  17. Leslie A. Fecher9,10
  18. Gary L. Gallia2
  19. Peter Gibbs11,12
  20. Dung Le1,3
  21. Robert L. Giuntoli2,
  22. Michael Goggins2
  23. Michael D. Hogarty13
  24. Matthias Holdhoff1
  25. Seung-Mo Hong2,14
  26. Yuchen Jiao1,
  27. Hartmut H. Juhl15
  28. Jenny J. Kim1
  29. Giulia Siravegna16
  30. Daniel A. Laheru1
  31. Calogero Lauricella16,
  32. Michael Lim2
  33. Evan J. Lipson1
  34. Suely Kazue Nagahashi Marie17
  35. George J. Netto2
  36. Kelly S. Oliner18,
  37. Alessandro Olivi2
  38. Louise Olsson19
  39. Gregory J. Riggins2
  40. Andrea Sartore-Bianchi16
  41. Kerstin Schmidt1,
  42. le-Ming Shih2
  43. Sueli Mieko Oba-Shinjo17
  44. Salvatore Siena16
  45. Dan Theodorescu20
  46. Jeanne Tie11,
  47. Timothy T. Harkins8
  48. Silvio Veronese16
  49. Tian-Li Wang2
  50. Jon D. Weingart2
  51. Christopher L. Wolfgang2,
  52. Laura D. Wood2
  53. Dongmei Xing2
  54. Ralph H. Hruban2
  55. Jian Wu1,21,§
  56. Peter J. Allen22
  57. C. Max Schmidt23,
  58. Michael A. Choti2,
  59. Victor E. Velculescu1,||
  60. Kenneth W. Kinzler1,||
  61. Bert Vogelstein1,||,
  62. Nickolas Papadopoulos1,|| and 
  63. Luis A. Diaz Jr1,3,||

+Author Affiliations


  1. 1Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.

  2. 2Departments of Surgery, Medicine, Pathology, Obstetrics and Gynecology, Otolaryngology, and Neurosurgery at Johns Hopkins, Baltimore, MD 21231, USA.

  3. 3Swim Across America Laboratory at Johns Hopkins, Baltimore, MD 21231, USA.

  4. 4Department of Dermatology, Boston University, Boston, MA 02215, USA.

  5. 5Institute for Cancer Research and Treatment at Candiolo, University of Torino, Candiolo, Turin 10060, Italy.

  6. 6Department of Oncology, University of Torino, Candiolo, Turin 10060, Italy.

  7. 7FIRC Institute of Molecular Oncology (IFOM), Milan 20139, Italy.

  8. 8Advanced Applications and Collaborations, Life Technologies, Foster City, CA 94404, USA.

  9. 9Division of Oncology, University of Indiana, Indianapolis, IN 46202, USA.

  10. 10Indiana University Health, Indianapolis, IN 46202, USA.

  11. 11Ludwig Institute for Cancer Research, Melbourne Branch, Royal Melbourne Hospital, Melbourne, Victoria 3084, Australia.

  12. 12Western Hospital, Melbourne, Victoria 3011, Australia.

  13. 13Division of Oncology, The Children’s Hospital of Philadelphia and the Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

  14. 14Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.

  15. 15Indivumed GmbH, Hamburg 20251, Germany.

  16. 16Niguarda Cancer Center, Ospedale Niguarda Ca’ Granda, Milan 20162, Italy.

  17. 17Department of Neurology and Pathology, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil.

  18. 18Amgen Inc., Thousand Oaks, CA 91320, USA.

  19. 19Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm SE-171 76, Sweden.

  20. 20University of Colorado Comprehensive Cancer Center, Aurora, CO 80045, USA.

  21. 21MyGenostics Inc., 801 West Baltimore Street, Baltimore, MD 21205, USA.

  22. 22Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

  23. 23Departments of Surgery, Biochemistry, and Molecular Biology, Indiana University, Indianapolis, IN 46202, USA.

+Author Notes

  • * These authors contributed equally to this work.

  • † Present address: Personal Genome Diagnostics, Baltimore, MD 21224, USA.

  • ‡ Present address: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.

  • § Present address: State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, The Fourth Military Medical University, Xi’an 710032, P. R. China.

  • ¶ Present address: Department of Surgery University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

  1. ||Corresponding authors. E-mail: ldiaz1@jhmi.edu (L.A.D.); npapado1@jhmi.edu (N.P.); vogelbe@jhmi.edu(B.V.); kinzlke@jhmi.edu (K.W.K.); velculescu@jhmi.edu (V.E.V.)

Abstract

The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction–based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.

Citation: C. Bettegowda, M. Sausen, R. J. Leary, I. Kinde, Y. Wang, N. Agrawal, B. R. Bartlett, H. Wang, B. Luber, R. M. Alani, E. S. Antonarakis, N. S. Azad, A. Bardelli, H. Brem, J. L. Cameron, C. C. Lee, L. A. Fecher, G. L. Gallia, P. Gibbs, D. Le, R. L. Giuntoli, M. Goggins, M. D. Hogarty, M. Holdhoff, S.-M. Hong, Y. Jiao, H. H. Juhl, J. J. Kim, G. Siravegna, D. A. Laheru, C. Lauricella, M. Lim, E. J. Lipson, S. K. Marie, G. J. Netto, K. S. Oliner, A. Olivi, L. Olsson, G. J. Riggins, A. Sartore-Bianchi, K. Schmidt, l.-M. Shih, S. M. Oba-Shinjo, S. Siena, D. Theodorescu, J. Tie, T. T. Harkins, S. Veronese, T.-L. Wang, J. D. Weingart, C. L. Wolfgang, L. D. Wood, D. Xing, R. H. Hruban, J. Wu, P. J. Allen, C. M. Schmidt, M. A. Choti, V. E. Velculescu, K. W. Kinzler, B. Vogelstein, N. Papadopoulos, L. A. Diaz,Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies. Sci. Transl. Med. 6, 224ra24 (2014).

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VascodaGama's picture
VascodaGama
Posts: 3029
Joined: Nov 2010

Ira

Here is another interesting post of yours.

Circulating tumor cells (CTCs) test has also been named a “liquid biopsy”. I do not know how much similarities exist in the CTC and ctDNA but they are identical. CTC is discriminatory because it looks for cells circulating in the blood from the primary tumor. Cells characteristics are compared and a low count declares treatment success. Myers had the test in the 1990th to verify cure in his case with PCa. He took the test before and after RT and linked the results to his remission. In any case, if the procedure done to count is erroneous (unreliable) then the “biopsy” could provide false positives. According to a study on the clinical relevance of CTC they found that only 0.01% of CTC may become metastases. I wonder if ctDNA is more efficient and reliable.

http://en.wikipedia.org/wiki/Circulating_tumor_cell

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195935/

Whatever the benefits may result in the diagnosis or treatment or after-care services in PCa cases, they all represent progress in the fight against the bandit, and they are very much welcomed.

I know that the subject is important to you. Thanks for bringing to us the news.

VG

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