Breast CancerBALIBISTRANCT03992521
Breast Cancer Liquid Biopsy Stratification
An observational study of Breast Cancer, run by Medical University of Graz at 1 site in Austria.
Trial summary
Breast cancer is the most common cancer in Austrian women. Estimation of prognosis and treatment strategies is increasingly being dependent on stratification of tumors into different entities or classes. Read more about this study
- Who is it for?
- Ages 18 to 99 years, women only
- Conditions the study is for
- Breast Cancer
- What is being tested?
- Nucleosome positioning
- How many people
- 59 participants
- Where
- 1 siteAustria
- Study dates
- 1 Oct 2018to Oct 2023
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 99 years
- Women only
- No healthy volunteers
- Adult, Older adult
Study population: The study includes women with proven histological diagnosis of breast cancer and appropriate clinical data. Participants were recruited at the Medical University Hospital of Graz.
Who may be able to join
- Histological diagnosis of breast cancer, availability of primary tumor tissue and plasma DNA with a high ctDNA content.
Who cannot join
- Patient rejects the participation.
Trial locations and contacts
1 site in 1 country.
About this study
Breast cancer is the most common cancer in Austrian women. Estimation of prognosis and treatment strategies is increasingly being dependent on stratification of tumors into different entities or classes. Currently, clinical routine stratification of tumors is mostly based on hormone receptor, HER2 status, and estimation of proliferation. However, a more robust and objective classification of tumors can be achieved by elucidation of further biological properties, which is also of increasing significance, as novel anticancer therapies are based on biological mechanisms. Consequently, available information from molecular analyses is increasingly being implemented in routine diagnostic assays with the aim to improve stratification for optimal treatment selection. To date the most extensive molecular-based taxonomy of breast cancer has been achieved by a classification based on combining gene expression and somatic copy number alterations (SCNAs), referred to as integrative clusters. Tissue biopsies are the current gold standard to attain such a classification. However, they can often be difficult to obtain in the metastatic setting and are subject to sampling bias due to intratumor heterogeneity. "Liquid biopsies" are, among other analytes, based on the analysis of cell-free DNA (cfDNA) which contains circulating tumor DNA (ctDNA), i.e. DNA fragments shed from normal and tumor cells into the blood, in patients with cancer. cfDNA can be obtained minimally invasive with a blood draw, allows for the "real time" analysis of tumor DNA from the circulation, and blood samples can be repeated at any time point, which is especially important for monitoring response to therapy. The investigator's group has extensive expertise in the analysis of cfDNA and has developed a plethora of approaches for ctDNA analysis. Recently, the investigators have developed a new approach, which relates to nucleosome positions and gene expression. cfDNA fragments have been associated with the release of DNA from apoptotic cells after enzymatic processing and hence consist mainly of mono-nucleosomal DNA. By performing whole-genome sequencing of cfDNA the investigators could demonstrate that at transcriptional start sites, the nucleosome occupancy results in different read-depth coverage patterns in expressed and silent genes. By employing machine learning for gene classification, the investigators were able to classify genes in cells releasing their DNA into the circulation as expressed. The main hypothesis of the project is that integrative breast cancer clusters can be established from directly blood without the need for an invasive tissue biopsy. Hence, the study aims include refining stratification of patients for an improved selection of treatment strategies. Furthermore, the investigators will obtain novel insights into the biology of metastatic breast cancer, so that this project will have important implications for patients, clinical oncologists, pathologists, pharmacologists, and all basic researchers interested in cancer.
Read the detailed description
The investigators collected 340 plasma samples from 144 clinically annotated patients with detailed clinical data. All plasma samples were already analyzed by plasma-Seq, an approach, which measures copy number from sequence read depth, for a first evaluation of somatic copy number alterations (SCNAs). As this project represents a feasibility study, the investigators want to evaluate to what extend cis-acting alterations can be determined, i.e. establish the corresponding gene expression changes via nucleosome position mapping as previously published by our group. The results will be corroborated by analyses of the corresponding primary tumor by SCNA-seq and RNA-seq.
From the 340 plasma samples the investigators selected 59 as representative for being either luminal (i.e. those with amplifications at 17q23, 11q13/q14, 8p12, 8q, and gains of 16p and 1q; n=25), basal (i.e. gains of 8q, 10p, 12p and various amplifications occurring due to the high-genomic instability; n=25), and ERBB2/HER2 (i.e. high-level amplification on 17q, centered and including the HER2 gene; n=9). These samples will be sequenced with high coverage (70x) so that both mutations and nucleosome positions can be extracted from the obtained sequences.
- Conditions
- Breast Cancer
- Being tested
- Nucleosome positioning
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nucleosome positioningGenetic
Stratification of patients based on nucleosome positioning from plasma DNA.
What is being measured
The primary outcome is the main question the study is designed to answer.
Evaluating as proof-of-concept the ability to stratify patients solely based on a detailed plasma DNA analysis
Clinico-pathological characteristics including prior and subsequent therapies were recorded for each patient. For each patient a standard classification into luminal, basal, ERBB2/HER2 was conducted and is available.
Measured: Three years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Jun 2019
- Study start1 Oct 2018
- Primary completionOct 2023 (estimated)
- Study completionOct 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- More trials run by Medical University of GrazThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Other
- Time perspective
- Other
- Enrolment
- 59 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Medical University of Graz
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Michael R Speicher, MD, Principal investigator, Medical University of Graz
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03992521
- Sponsor's protocol ID
- BreastctDNA01
- Acronym
- BALIBISTRA
- Status last verified
- Oct 2022
- First submitted
- 18 Jun 2019
- Last updated
- 10 Oct 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Ulz P, Thallinger GG, Auer M, Graf R, Kashofer K, Jahn SW, Abete L, Pristauz G, Petru E, Geigl JB, Heitzer E, Speicher MR. Inferring expressed genes by whole-genome sequencing of plasma DNA. Nat Genet. 2016 Oct;48(10):1273-8. doi: 10.1038/ng.3648. Epub 2016 Aug 29.
PubMed 27571261Heitzer E, Haque IS, Roberts CES, Speicher MR. Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat Rev Genet. 2019 Feb;20(2):71-88. doi: 10.1038/s41576-018-0071-5.
PubMed 30410101Ulz P, Belic J, Graf R, Auer M, Lafer I, Fischereder K, Webersinke G, Pummer K, Augustin H, Pichler M, Hoefler G, Bauernhofer T, Geigl JB, Heitzer E, Speicher MR. Whole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer. Nat Commun. 2016 Jun 22;7:12008. doi: 10.1038/ncomms12008.
PubMed 27328849Ulz P, Heitzer E, Speicher MR. Co-occurrence of MYC amplification and TP53 mutations in human cancer. Nat Genet. 2016 Feb;48(2):104-6. doi: 10.1038/ng.3468. No abstract available.
PubMed 26813759
Study at a glance
From the registry record, last updated by the sponsor on 10 Oct 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Breast Cancer Liquid Biopsy Stratification
- ClinicalTrials.gov ID
- NCT03992521
- Acronym / sponsor ID
- BALIBISTRA / BreastctDNA01
- Conditions
- Breast Cancer
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 59 participants (estimated)
- Lead sponsor
- Medical University of GrazUniversity, hospital or other
- Study start
- 1 Oct 2018 (actual)
- Primary completion
- Oct 2023 (estimated)
- Study completion
- Oct 2023 (estimated)
- First posted
- 20 Jun 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Breast cancer is the most common cancer in Austrian women. Estimation of prognosis and treatment strategies is increasingly being dependent on stratification of tumors into different entities or classes. Currently, clinical routine stratification of tumors is mostly based on hormone receptor, HER2 status, and estimation of proliferation. However, a more robust and objective classification of tumors can be achieved by elucidation of further biological properties, which is also of increasing significance, as novel anticancer therapies are based on biological mechanisms. Consequently, available information from molecular analyses is increasingly being implemented in routine diagnostic assays with the aim to improve stratification for optimal treatment selection. To date the most extensive molecular-based taxonomy of breast cancer has been achieved by a classification based on combining gene expression and somatic copy number alterations (SCNAs), referred to as integrative clusters. Tissue biopsies are the current gold standard to attain such a classification. However, they can often be difficult to obtain in the metastatic setting and are subject to sampling bias due to intratumor heterogeneity. "Liquid biopsies" are, among other analytes, based on the analysis of cell-free DNA (cfDNA) which contains circulating tumor DNA (ctDNA), i.e. DNA fragments shed from normal and tumor cells into the blood, in patients with cancer. cfDNA can be obtained minimally invasive with a blood draw, allows for the "real time" analysis of tumor DNA from the circulation, and blood samples can be repeated at any time point, which is especially important for monitoring response to therapy. The investigator's group has extensive expertise in the analysis of cfDNA and has developed a plethora of approaches for ctDNA analysis. Recently, the investigators have developed a new approach, which relates to nucleosome positions and gene expression. cfDNA fragments have been associated with the release of DNA from apoptotic cells after enzymatic processing and hence consist mainly of mono-nucleosomal DNA. By performing whole-genome sequencing of cfDNA the investigators could demonstrate that at transcriptional start sites, the nucleosome occupancy results in different read-depth coverage patterns in expressed and silent genes. By employing machine learning for gene classification, the investigators were able to classify genes in cells releasing their DNA into the circulation as expressed. The main hypothesis of the project is that integrative breast cancer clusters can be established from directly blood without the need for an invasive tissue biopsy. Hence, the study aims include refining stratification of patients for an improved selection of treatment strategies. Furthermore, the investigators will obtain novel insights into the biology of metastatic breast cancer, so that this project will have important implications for patients, clinical oncologists, pathologists, pharmacologists, and all basic researchers interested in cancer.
Detailed description
The investigators collected 340 plasma samples from 144 clinically annotated patients with detailed clinical data. All plasma samples were already analyzed by plasma-Seq, an approach, which measures copy number from sequence read depth, for a first evaluation of somatic copy number alterations (SCNAs). As this project represents a feasibility study, the investigators want to evaluate to what extend cis-acting alterations can be determined, i.e. establish the corresponding gene expression changes via nucleosome position mapping as previously published by our group. The results will be corroborated by analyses of the corresponding primary tumor by SCNA-seq and RNA-seq.
From the 340 plasma samples the investigators selected 59 as representative for being either luminal (i.e. those with amplifications at 17q23, 11q13/q14, 8p12, 8q, and gains of 16p and 1q; n=25), basal (i.e. gains of 8q, 10p, 12p and various amplifications occurring due to the high-genomic instability; n=25), and ERBB2/HER2 (i.e. high-level amplification on 17q, centered and including the HER2 gene; n=9). These samples will be sequenced with high coverage (70x) so that both mutations and nucleosome positions can be extracted from the obtained sequences.
Study design
- Observational model
- Other
- Time perspective
- Other
Who may qualify
- Ages
- 18 to 99 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- The study includes women with proven histological diagnosis of breast cancer and appropriate clinical data. Participants were recruited at the Medical University Hospital of Graz.
Key inclusion criteria (1 listed)
- Histological diagnosis of breast cancer, availability of primary tumor tissue and plasma DNA with a high ctDNA content.
Key exclusion criteria (1 listed)
- Patient rejects the participation.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nucleosome positioningStratification of patients based on nucleosome positioning from plasma DNA. | Genetic | – |
Primary outcome
Evaluating as proof-of-concept the ability to stratify patients solely based on a detailed plasma DNA analysis
Time frame: Three years
Clinico-pathological characteristics including prior and subsequent therapies were recorded for each patient. For each patient a standard classification into luminal, basal, ERBB2/HER2 was conducted and is available.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Oct 2022.
- Background: PubMed 27571261Ulz P, Thallinger GG, Auer M, Graf R, Kashofer K, Jahn SW, Abete L, Pristauz G, Petru E, Geigl JB, Heitzer E, Speicher MR. Inferring expressed genes by whole-genome sequencing of plasma DNA. Nat Genet. 2016 Oct;48(10):1273-8. doi: 10.1038/ng.3648. Epub 2016 Aug 29.
- Background: PubMed 30410101Heitzer E, Haque IS, Roberts CES, Speicher MR. Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat Rev Genet. 2019 Feb;20(2):71-88. doi: 10.1038/s41576-018-0071-5.
- Background: PubMed 27328849Ulz P, Belic J, Graf R, Auer M, Lafer I, Fischereder K, Webersinke G, Pummer K, Augustin H, Pichler M, Hoefler G, Bauernhofer T, Geigl JB, Heitzer E, Speicher MR. Whole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer. Nat Commun. 2016 Jun 22;7:12008. doi: 10.1038/ncomms12008.
- Background: PubMed 26813759Ulz P, Heitzer E, Speicher MR. Co-occurrence of MYC amplification and TP53 mutations in human cancer. Nat Genet. 2016 Feb;48(2):104-6. doi: 10.1038/ng.3468. No abstract available.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Michael R Speicher, MD principal investigator
Medical University of Graz
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Breast Cancer, run by Medical University of Graz at 1 site in Austria.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 10 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Austria. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Evaluating as proof-of-concept the ability to stratify patients solely based on a detailed plasma DNA analysis (time frame: Three years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03992521, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Oct 2022.