CNI Monitor Basic Information

WHO NEEDS THE CNI MONITOR TEST?

WHAT DOES THE TEST DO?

HOW DOES THE PROCEDURE WORK?

The CNI MONITOR test is suitable for therapy monitoring for patients with chemotherapy or immunotherapy and for relapse monitoring after tumor resection.

There are several reasons to initiate a drug therapy, e.g. to reduce a diagnosed malignant tumor prior to surgery or if surgery is not an option. In such cases, combinations of drugs, which usually show the best anti-tumor efficacy, are used. However, the response of tumors to these drugs varies greatly from patient to patient ranging from complete regression to complete insensitivity of the tumor to the given anti-tumor substance. In some cases under a special therapy (immunotherapy), an even faster tumor growth has been observed. Early detection of either such an adverse event or insensitivity to drugs is important, in order to have an early option to switch therapy to another possibly effective substance.

The effectiveness of the various cancer therapies is difficult to measure. It is critical to know at the earliest possibility whether an alternative therapy should be used, which might be more effective for attacking an individual’s cancer. The current method for evaluation of the therapeutic effect can only be carried out after several months by, for example, radiologic examinations (e.g. Ct or MRI). An early assessment of therapy success is usually not possible.

The CNI MONITOR test gives the earliest and most accurate indication of a therapy failure. When undergoing a therapy, the analysis of the dynamics of serial samples using the CNI score can help the treating physician to recognize earlier and thus react faster to the tumor’s failure to respond to the current treatment. This is particularly important when other therapy options exist, providing actionable information.

With Chronix Biomedical’s blood test we can now usefully monitor patients by looking at changes in a patient’s CNI score. Blinded studies have shown that when the CNI score does not significantly decrease or even increase under therapy, the tumor is not responding. Studies to date have looked at patients with 11 different cancers undergoing radio-, chemo- or immunotherapy.

Before the start of a planned therapy, the initial CNI score is determined; this baseline CNI score will be the starting point for navigating through the course of treatments. If the baseline CNI score is above the normal reference range obtained in healthy persons, the patient is eligible for the follow-up during the course of treatment using the CNI MONITOR test. Before the start of the second cycle of the therapy and, if necessary, before the third cycle, another blood sampling is carried out and the measured CNI score is compared with the baseline.

The blood collection is done in a special tube, which is sent after the doctor orders the test. The result will be available within about two weeks once the sample is received at the laboratory.

The laboratory is specialized in the above-described procedures, which are highly advanced and subject to constant quality control, so that we can ensure you with the best possible laboratory quality.

The CNI MONITOR test

gives the earliest and most accurate indication of a therapy failure.

LBC

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LBC is an officially licensed Chronix laboratory offering CNI tests in Europe
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CNI Monitor is the most
accurate for:

ikonapatients with chemotherapy

ikonapatients with immunotherapy

ikonaelapse monitoring after tumor resection

VIEW PATIENT INFORMATION FORM

Distributor – UK

Emma Lane
Advanced Cancer Diagnostics, Ltd
+44 207 491 5111
emma.lane@advancedcancerdiagnostics.com
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Distributor – Poland

Elżbieta Ginalska-Markiewicz
Modern Cancer Diagnostics
+48 22 646 46 97
a.markiewicz@moderncancerdiagnostics.com
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Technology

Cancer is a disease in which mutations in the genomic DNA of an individual cell leads to a disruption of the normal checks and balances (homeostasis), which in normal state ensures that cell multiplication is matched closely to the body’s needs. A cancer cell has lost the ability to respond to homeostatic needs and continues to divide relentlessly, in one or multiple (metastatic) sites, e.g. driven by positive (oncogene) or lack of negative (suppressor gene) influences.

These mutations in the already developed tissue/organ (somatic) cells lead to cancer (e.g. breast, lung, colon) and in the overwhelming majority of adult cancers this follows after the accumulation of multiple mutations. There is evidence suggesting that aneuploidy, which appears as amplifications and/or losses of large sequences of genetic material, develops earlier than the bulk of mutations, which occur in single DNA base pairs**.  As such aneuploidy is a major hallmark of genomic changes in malignant cell transformation, which occurs early and is the underpinning foundation of our CNI scoring assays.

Next Generation Sequencing (NGS) is a method which allows scientists to determine the sequence of the whole human genome, and such DNA “mapping” can now be performed on circulating cell-free DNA (cfDNA) in the blood that is derived from dying (“turning-over”) cells. Indeed such cfDNA is continuously entering the bloodstream, with a turnover half life of some minutes, before the body digests and recycles the constituents. What has been appreciated is that tumor-derived cfDNA circulates in the bloodstream with concentrations varying from below 1% to more then 80% and can be differentiated from normal DNA by the mutational “fingerprint”-best detected by the ‘defining’ gains and losses (DNA Copy Number Instability or CNI score).

Calculation of genome - wide Copy-Number Index (CNI)

After sequencing of the cfDNA the individual fragments are uniquely mapped to the human genome according to their respective sequence. Fragment counts per genomic region are compared to the distribution obtained in normal reference samples. Genomic regions with fragment counts that significantly deviate from this normal distribution represent regions with gains and losses present in the tumor genome. These regions can be compared in the serial sampling and can indicate e. g. the appearance of a new probably more aggressive cancer clone. This information can provide actionable information.

A plot displaying the genomic regions with significant deviations in copy-number together with the most important affected onco- and tumor-suppressor -genes is provided.

Accuracy

This is the first study ever to show the real time advantage of a blood test in the evaluation of drug efficacy versus RECIST imaging criteria

Predicted-DC kopiaChronix Biomedical conducted a blinded clinical trial to study a group of patients undergoing cancer treatments. During the research study, standard of care radiological observations (RECIST) were the benchmark for the assessment of tumors. These observations distinguish progressive, stable, partial and complete responses of tumors depending on their detected size change under systemic treatment. Often, the results of the test prior to the second therapy cycle show a sharp drop of the CNI score, as compared to the baseline value, which strongly indicates a tumor’s response to treatment. If, on the other hand, the CNI-score significantly increases, then despite the therapy the disease was determined later by RECIST to be progressive. When the change of CNI score after the first therapy cycle was not significant, another blood sample is recommended before the start of the third cycle. Therefore CNI MONITOR predicted outcome results 6-9 weeks earlier than radiography.

CNI score based predictions of a therapy failure were correct in 89% of times (positive predictive value, PPV) when based on the change from baseline to cycle 2. When data from another sample obtained prior to cycle 3 was included the prediction of progressive disease was correct in 100% of the cases.

ccr-publicationIn clinical practice conventional biochemical tumor markers are often used during therapy to assess drug efficacy. When compared to the early prediction of outcome gained by CNI score, a highly significant lower accuracy was found.

With respect to patients undergoing immunotherapy, the CNI MONITOR test was able to predict clinical outcomes significantly better than conventional cancer markers.

The next figure is an example of the clinical utility of taking a deeper look into the copy number instability results. These plots depict the CNI-values of the baseline, cycle 2 and 3 sampling for two hyper-progressive patients. The red dots show a gain or loss at a unique site on the chromosome in the patient’s blood samples at the described time point. A large increase in the number of aberrant bins is seen in both patients. Compared to the baseline value the upper patient did show a ten times higher CNI Score in the cycle 2 sample, and a further increasing score at cycle 3, while interestingly the serum levels of the tumor antigen CA15-3 are not increasing. Hyper-progression was confirmed by imaging, but not earlier than at cycle 4 for both cases.

“The key finding is the ability of the test to make an early prediction of response and disease control, just three to four weeks after initiation of immunotherapy. The flexibility to switch treatments early on based on an accurate prediction has great potential to improve the treatment of many cancers.”

Glen J. Weiss, MD, MBA and principal investigator of the Clinical March Publication (Weiss, Glen J., et al. “Tumor Cell-Free DNA Copy Number Instability Predicts Therapeutic Response to Immunotherapy.” Clinical Cancer Research (2017).

Recurrence Monitoring

Once the treating physician observes that a patient has reached remission or stable disease, the CNI MONITOR blood test can be used to monitor for recurrence.

Exemplary CNI score time-courses CNI for 2 patients with head and neck cancer are depicted in the next figure. After surgical resection of the primary tumor the CNI scores decreased below the normal threshold and largely increasing CNI scores were detected in conjunction with the development of secondary metastases in both patients.

refference range

A cancer can even go from an initial response to recurrence under systemic therapy. In a study on patients under conventional cytolytic anti-cancer therapy, we have shown that in patients with a good initial response by RECIST after 3 months, a later on following increase of CNI score was associated with tumor recurrence (progression) in every found case***.

An unpublished case on file is shown in the next figure. A patient with non-small cell lung cancer had an elevated CNI-score in June 2015. The patient’s CNI-score dropped one month later under therapy and was determined to be in remission. In May 2016, the patient’s CNI score significantly increased. What is noteworthy is that the actual chromosomal regions showing gains and losses were different in the May 2016 samples as compared to the June 2015 sample. This suggests that the cancer that recurred has changed it’s genetic make-up obviously in a way to be resistant to the current therapy, guiding the treating physician to use a treatment different from the June 2015.

New Gains_Losses = New tumor profile

Prognosis

The CNI score was a significant independent predictor of progression-free survival in non-metastatic head and neck cancer patients treated by primary tumor resection and adjuvant radio- chemotherapy. Progression-free survival times were significantly shorter in patients with pre-surgical CNI score below a threshold of 31. Patients with lymph node metastases had significantly higher CNI scores as compared to node negative patients. The highest CNI scores were detected in patients with lymph node extra-capsular tumor spread.

Despite its relationship to nodal status the CNI score was found to have the highest prognostic value exceeding that of clinico-pathological features alone. Testing patients with this cancer can aid the physicians in therapy planning, such as making the decision for performing a neck dissection.

*Not currently being offered or available in the US
** Navin N. et al. “Tumour evolution inferred by single-cell sequencing.” Nature. 2011 Apr 7;472(7341):90-4.
*** Weiss, G.J., et al. “Changes in tumor cell-free DNA copy number instability (CNI) predict therapeutic response in metastatic cancers.” Cancer Research 76.14 Supplement (2016): 3138-3138.

CNI Monitor Medical Publications

  • Dr hab. n. med. Jakub Dobruch FEBU - liquid biopsy

Cell-free DNA for treatment monitoring and outcome predictor in head and neck cancer

Chronix Biomedical presents positive data on prognostic test in head/neck cancer study data at ASCO. Study finds CNI score to be a stronger predictor of time to recurrence in head and neck cancer than current method based on lymph node invasion.

  • liquid biopsy - Chronix Biomedical

Predicting Treatment Outcomes in Immunotherapy

Weiss, G. et al. Tumor Cell-Free DNA Copy Number Instability Predicts Therapeutic Response to Immunotherapy.

Genomic analysis of tissue malignancies is well recapitulated by tumor cell free DNA (cfDNA) using the power of Next Generation Sequencing (NGS).

  • predicting-treatment-outcomes-in-chemotherapy

Predicting Treatment Outcomes in Chemotherapy

Weiss, Glen J., et al. Changes in tumor cell-free DNA copy number instability (CNI) predict therapeutic response in metastatic cancers. Cancer Research 76.14 Supplement (2016): 3138-3138.

Gains and losses of chromosomal regions – as a hallmark of cancer – have been detected in plasma as copy number aberrations (CNAs), and for several cancers a relation to tumor size has been reported.