liquid biopsy in clinical practice - cme...

Allan A. Lima Pereira, MD, PhDGI Medical Oncology [email protected]

Liquid Biopsy in Clinical Practice

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DISCLOSURES

I do not have anything to disclose.


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• Risk

• Spatial heterogeneity

• Temporal heterogeneity

The issues with tissue biopsies3Liquid Biopsy in Clinical Practice

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• Risk



The issues with tissue biopsies4

Gerlinger M et al. NEJM. 2012 Mar 08;366(10):883-92


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• Risk




• Serial assessment of ctDNA 220 pts with mRCC using commercial 70-gene platform

• ctDNA profile varied across line of therapy

Pal SK et al. Eur Urol. 2017 Apr 13. PubMed PMID: 28413127.

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TP53 VHL NF1 EGFR ARID1A PIK3CA

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• Risk




Pal SK et al. Eur Urol. 2017 Apr 13. PubMed PMID: 28413127.

• Serial analysis of ctDNA from 24 pts with mCRC who responded to anti-EGFR therapy but subsequently relapsed, 23 out of 24 patients developed one or more mutations in genes involved in the MAPK signaling pathway


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What is “Liquid biopsy”7

• Non-invasive (or minimally invasive) technique for assessing tumors

• Blood, ascite fluid, urine, sputum, amniotic fluid, saliva…

• Circulating tumor cells

• Circulating cell-free DNA

• Exosomes

• Potential applications:

• Potential pitfalls


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Where does cfDNA come from?8

• Patients with cancer have higher levels of cfDNA than patients without cancer.

• Accumulation of cfDNA in plasma occurs as macrophages are unable to keep with clearance from associated apoptosis and necrosis, leading to release of cfDNA into circulation.

• Most cfDNA fragments are 180-200bp, suggesting majority arises from tumor cell apoptosis.


MD Anderson 9Liquid Biopsy in Clinical Practice

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ctDNA Plataforms10ctDNA Platforms

Commercial entities –over 60 in USA!


and more...

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AF = Allele frequency / Allele fraction11

• ctDNA is usually quantified as the allele frequency (as known as fraction of mutant alleles)

• Ratio:

• Advantage: using the wild-type copies as an intra-patient control for the exclusion of poor sample quality or poor sample handling during ctDNAextraction.

• Disadvantage: Other factors may significantly affect the number of wild-type copies, which in turn may bias the AF variable:

• Infection, inflammation, trauma, even the treatment itself..

• Problem for monitoring / comparison across timepoints…

Mutated alleles

Wild-type alleles + mutated alleles


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ctDNA is an attractive biomarker since:12

Mainly because…

• Mutations are highly specific to tumor cells

• Mutations are involved in pathogenesis

• Some mutations are actionable

• Half-life: ~ 30min


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CHALLENGE:

Move this from the “Wow!” phase to clinical application.

13Liquid Biopsy in Clinical Practice

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ctDNA – clinical applications14Liquid Biopsy in Clinical Practice

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MINIMAL RESIDUAL DISEASE

STAGE II CRC


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Minimal Residual Disease16

The Potential of Circulating Tumor DNA(ctDNA) to Reshape The Design of

Clinical Trials Testing Adjuvant Therapy in Patients with Early Stage Cancers

Jeanne Tie*, Yuxuan Wang, Cristian Tomasetti , Lu Li, Simeon Springer, Isaac Kinde, Rachel Wong, Suzanne Kosmider, Ben Tran, Jayesh Desai, Theresa Hayes, Andrew Haydon,

DesmondYip, Michael Christie, Robert L. Strausberg, Luis Diaz Jr , Nickolas Papadopoulos, Kenneth Kinzler,

Bert Vogelstein and Peter Gibbs

*WalterandElizaHallInstituteofMedicalResearch,Australia


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Minimal Residual Disease17ctDNA in Oncology

Tie et al. ASCO 2016Tie et al. Sci Transl Med. 2016

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MONITORING TREATMENT

PREDICTING RESISTANCE


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Monitoring Treatment22ctDNA in Oncology

Dynamic changes in ctDNA levels by treatment

DiehlF,etal.CirculatingmutantDNAtoassesstumordynamics.Naturemedicine.2008

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Monitoring Treatment23

Retrospective cohort of patients receiving Regorafenib or TAS102

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PI: Allan Pereira

ctDNA in Oncology

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RECURRENCE AFTER METASTASECTOMY


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Recurrence after liver resection25ctDNA in Oncology

Overman et al. 2017 ASCO annual meeting

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Recurrence after liver resection26

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P-value 0.004HR 2.6 (95%CI 1.2-5.7)

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P-value 0.06HR 3.5 (95%CI 0.8-15.7)

•Median time from preoperative blood collection to surgery was 4.5 days•Median time from surgery to postoperative blood collection was 14 days.

•Median RFS was 7.6 months for ctDNAdetected and 15.8 months for non-detected ctDNA, p=0.004•2-year RFS was 9% for ctDNA detected and 43% for non-detected ctDNA

Overall SurvivalRecurrence Free Survival

Overman et al. 2017 ASCO annual meeting

ctDNA in Oncology

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Guiding decisions in referring patients with mCRC to matched biomarker-related clinical trials.


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Matched biomarker-related clinical trials28

Pereira et al. PLoS One 2017

ctDNA in Oncology

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Potential pitfalls


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Predictors of Negative ctDNA30ctDNA in Oncology

Pereira et al. 2018 GI ASCO

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Thank You!


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Contact

32

Allan A. Lima Pereira, MD, [email protected]@gmail.com


liquid biopsy in clinical practice - cme...

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