by Dr. C.H. Weaver M.D. updated 6/2021

Blood analyses of whole-genome cell-free DNA (cfDNA) can determine Molecular Progression of metastatic solid cancers a few weeks into treatment.

Most cancer patients are unnecessarily treated with chemotherapy or continue to receive chemotherapy after it has stopped working. The ineffective use of chemotherapy exposes cancer patients to unnecessary side effects, inconvenience, cost, and delays access to the next potentially beneficial treatment.

What if a simple blood test were available that could quickly determine when chemotherapy was ineffective? Research presented at the American Society of Clinical Oncology Annual Meeting on liquid biopsy analyses of serial changes in whole-genome cell free DNA suggests that such a blood test may soon become available.1,2

Current clinical practice is to begin chemotherapy treatment and then use medical imaging with CT, MRI, and PET scans to monitor any response to treatment. In this way doctors monitor or measure the “response” of a cancer to treatment. Response assessment has been performed in this manner for decades, but it usually takes several months and multiple imaging procedures to determine the effectiveness of therapy.

All medical imaging in this setting is designed to support comparisons over time, thus radiologists inspect new images to observe any changes compared with prior images from the same case. These visually observable changes in the shape, contour and density of the cancer are lagging indicators of what has already happened inside the patient biologically. The delay this creates in determining the effectiveness of any given therapy can expose patients to several courses of unnecessary chemotherapy, and all the side effects, in addition to a delay in getting access to potentially effective therapy.

Blood contains an abundance of information about a patient's cancer and immune response, from cells including cell free DNA and small vesicles from the tumor and its environment. Advances in biology and technology enable a simple blood draw - a liquid biopsy - to provide clinically actionable information about cancer diagnosis and treatment. For example, doctors can already predict which patients with breast cancer don't benefit from receiving chemotherapy and other genomic biomarker tests can match the treatment to the cancer by identifying specific genomic abnormalities that can be targeted with a precision cancer medicine.3,4

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In the current study shared at ASCO, clinical information and blood samples were collected from 69 advanced cancer patients prior to beginning treatment on average 21 and 42 days after starting treatment. Changes in the fraction of tumor-derived cell free DNA were evaluated over the initial course of treatment and used to predict whether the cancer progressed or not.2

The researchers reported that cancer progression could be accurately predicted in 63 days on average using cfDNA obtained by liquid biopsy.

The study demonstrates an ability to accurately detect early cancer progression using whole genome cell free DNA -- molecular progression -- long before conventional imaging techniques could make a definitive call. This blood-based approach was consistent across multiple types of cancer and treatments, including immunotherapy. This novel liquid biopsy could aid in clinical decision making for early treatment changes and is undergoing additional validation. 

The Emerging Role of ctDNA Based Response Assessment

Both the Natera and Guardant360 Response™ tests detect changes in circulating tumor DNA (ctDNA) levels to provide oncologists an early indication of a patient’s response to treatment. Molecular responders (those with decreasing ctDNA levels) show significantly longer progression-free and overall survival rates, compared to molecular non-responders.5-15 “With the treatment response assessments doctors can increasingly predict patient response to treatment sooner than standard radiographic assessment, to help inform clinical decisions and improve outcomes.

References:

  1. Whole-genome cell-free DNA (cfDNA) changes as a dynamic blood-based biomarker for early response assessment of advanced tumors. | 2019 ASCO Annual Meeting Abstracts
  2. A prospective study tracking longitudinal changes in genome-wide cell-free DNA (cfDNA) methylation to identify early nonresponders to cancer treatment. | 2019 ASCO Annual Meeting Abstracts
  3. Lo SS, Mumby PB, Norton J et al. Prospective multicenter study of the impact of the 21-gene recurrence score assay on medical oncologist and patient adjuvant breast cancer treatment selection. Journal of Clinical Oncology [early online publication]. January 11, 2009.
  4. Raja R, Kuziora M, Philip Z. Brohawn PZ, et al. Early Reduction in ctDNA Predicts Survival in Patients with Lung and Bladder Cancer Treated with Durvalumab. Clin Cancer Res; 2018: 24(24): 6212-6222. DOI: 10.1158/1078-0432.CCR-18-0386.
  5. Aggarwal C, Thompson JC, Chien A, et al. Dynamic monitoring of circulating tumor DNA next-generation gene sequencing as a predictive biomarker of response and progression-free survival after pembrolizumab monotherapy in patients with advanced NSCLC.J Clin Oncol; 2019: 37:15 suppl, 3040-3040. DOI:10.1200/JCO.2019.37.15.

  6. Pascual J, Cutts RJ, Kingston B, et al. Assessment of early ctDNA dynamics to predict efficacy of targeted therapies in metastatic breast cancer: Results from plasmaMATCH trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-02.DOI: 10.1158/1538-7445.SABCS20-PS5-02

  7. Mack PC, Redman MW, Moon J, et al. Residual circulating tumor DNA (ctDNA) after two months of therapy to predict progression-free and overall survival in patients treated on S1403 with afatinib +/- cetuximab.J Clin Oncol; 2020: 38:15_suppl, 9532-9532. DOI: 10.1200/JCO.2020.38.15.

  8. Modi S, Park H, Murthy RK, et al. Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low-Expressing Advanced Breast Cancer: Results From a Phase Ib Study. J Clin Oncol; 2020: 38(17):1887-1896. DOI: 10.1200/JCO.19.02318

  9. Maron SB, Chatila WK, Millang BM, et al, Pembrolizumab with trastuzumab and chemotherapy (PTC) in HER2-positive metastatic esophagogastric cancer (mEG): Plasma and tumor-based biomarker analysis. J Clin Oncol; 2020: 38:15_suppl, 4559-4559. DOI: 10.1200/JCO.2020.38.15.

  10. Zhang Q, Luo J, Wu S, et al. Prognostic and Predictive Impact of Circulating Tumor DNA in Patients with Advanced Cancers Treated with Immune Checkpoint Blockade. Cancer Discov; 2020: 10:12, 1842-1853. DOI: 10.1158/2159-8290.CD-20-0047.

  11. SURVIVAL ACCORDING CIRCULATING TUMOUR DNA STATUS IN THE STUDY OF ADJUVANT ATEZOLIZUMAB FOR HIGH-RISK MUSCLE INVASIVE UROTHELIAL CANCER

  12. Powles T, Assaf ZJ, Davarpanah N, et al. Clinical outcomes in post-operative ctDNA-positive muscle-invasive urothelial carcinoma (MIUC) patients after atezolizumab adjuvant therapy. ESMO Immuno-Oncology Virtual Congress 2020

  13. Thompson JC, Carpenter EL, Silva BA, et al. Serial Monitoring of Circulating Tumor DNA by Next-Generation Gene Sequencing as a Biomarker of Response and Survival in Patients With Advanced NSCLC Receiving Pembrolizumab-Based Therapy. JCO Precis; 2021: 5, 510-524. DOI: 10.1200/PO.20.0032.

  14. Shaw AT, Martini JF, Besse B, et al. Early circulating tumor (ct)DNA dynamics and efficacy of lorlatinib in patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC). J Clin Oncol; 2019: 37:15_suppl, 9019-9019. DOI: 10.1200/JCO.2019.37.15.

  15. Kim ST, Cristescu R, Bass AJ, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med; 2018: 24(9):1449-1458. DOI: 10.1038/s41591-018-0101-z.