The Diversity of Liquid Biopsies and Their Potential in Breast Cancer Management
Abstract
:Simple Summary
Abstract
1. Introduction
1.1. Breast Cancer
1.2. Liquid Biopsy (LB)
1.2.1. cfDNA
1.2.2. CTC
1.2.3. EV
1.2.4. Analytical Dimensions
2. Liquid Biopsies for Early Breast Cancer Detection
2.1. cfDNA
2.2. cfDNA and Other Analytes Proposed by Small Non-Interventional Trials
3. Liquid Biopsies for Detailed BC Diagnostic
3.1. cfDNA and Nucleosomes
3.2. Multimodal LB
3.3. Circulating RNA in or Independent of EVs
3.4. CTCs
4. Liquid Biopsies before (Neo)Adjuvant Treatment for Therapy (De)Escalation
4.1. Tissue Analysis
4.2. cfDNA
4.3. CTCs
4.4. EVs and miRNAs
5. Liquid Biopsies under Neoadjuvant Therapy for Therapy Switch/(De)Escalation
6. Liquid Biopsies to Anticipate Minimal Residual Disease
6.1. Persistence of LB Signals under Neoadjuvant Treatment to Anticipate MRD
6.1.1. cfDNA
6.1.2. CTCs
6.2. Liquid Biopsies after Neoadjuvant Treatment to Anticipate MRD
6.2.1. cfDNA
6.2.2. CTCs
6.2.3. Other Analytes
6.2.4. Interventional Trials
6.3. Longitudinal LB Analysis for MRD Detection
6.3.1. CTCs
6.3.2. Multimodal LB
6.3.3. cfDNA
7. Liquid Biopsies for Prognostication in the Metastatic BC Setting
7.1. Other Analytes
7.2. cfDNA
7.3. CTCs
7.4. Multimodal LB
8. Liquid Biopsies for Therapy Guidance in Breast Cancer Management
8.1. Chemotherapy (CTX)
8.2. PARP Inhibition
8.3. Anti-HER2 Therapy
8.4. PIK3CA Inhibition
8.5. Endocrine Therapy (ET)
8.6. AKT Inhibition
8.7. Immune Checkpoint Inhibitors (ICI)
8.8. Tyrosine Receptor Kinase (TRK) Inhibition
8.9. Androgen Receptor Inhibition
8.10. Cylin Dependent Kinase 4/6 (CDK4/6) Inhibition
8.11. Predictive Biomarkers for BC Therapy Guidance
9. Liquid Biopsies for Therapy Monitoring in Breast Cancer
9.1. Circulating Proteins
9.2. CTCs
9.3. CTCs and EVs
9.4. cfDNA
9.5. CTC and cfDNA Results and a Multimodal Approach
10. Challenges for Liquid Biopsy in Breast Cancer Management
11. Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
References
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Early Detection | |||
---|---|---|---|
Specific Analyte | Clinical Setting | Conclusion | Reference |
(1) cfDNA | |||
targeted cfDNA mutation analysis combined with the evaluation of circulating proteins | DETECT-A study, n = 10,006 | specificity of 99% and a sensitivity of 33% to detect eight tumor types, including BC | 10.1126/science.aar3247 |
different dimensions for cfDNA analysis | CCGA, NCT02889978 | Whole genome bisulphite sequencing for methylation analysis and targeted sequencing single nucleotide variants with paired white blood cell background removal showed the lowest limit of detection | 10.1016/j.ccell.2022.10.022 |
targeted methylation cfDNA sequencing | CCGA sub-study 2 and the STRIVE study (NCT03085888) | The specificity within all covered cancer entities was 99.3% and the sensitivity to detect BCs with stage I disease was <10% (stage I), 50% (stage II) and >80% (stage III or IV). | 10.1016/j.annonc.2020.02.011 |
targeted methylation cfDNA sequencing panel of >100,000 regions | CCGA sub-study 3 | specificity was 99.5% (low false-positive rate of 0.5%). Overall sensitivity across cancer classes and stages was 51.5%, but for BC only 30.5% across all stages | 10.1016/j.annonc.2021.05.806 |
targeted methylation cfDNA sequencing panel of >100,000 regions | CCGA sub-study 3 in patients with symptoms only | increased overall sensitivity of 64.3% (52.8% for BC) and the overall accuracy of the cancer site of origin prediction in true positives was 90.3% | 10.1200/PO.22.00679 |
targeted cfDNA methylation-based MCED test, here referred to as Galleri (MCED-Scr; 30,000 CpG fragments covered) | PATHFINDER study (NCT04241796), in adults with elevated cancer risk | Adding Galleri test to standard of care screening more than doubled the number of cancers detected. Half of the cancers detected with the blood test, were stage I or II. Accuracy of tissue of origin was 97.1%. In total, 71% of participants with a Galleri detected cancer had cancer types with no routine screening test available. PPV was 43.1% and the false-positive rate was less than 1% | 10.3390/diagnostics12051244 and ESMO Congress 2022 |
cfDNA concentration | 61 patients with breast cancer, 33 control patients with benign breast diseases and 27 healthy control individuals | cfDNA concentration in the BC patients was significantly higher than that in the control patients or healthy control. | 10.1016/j.canlet.2005.11.027 |
cfDNA PIK3CA mutations | sensitivity of 93.3% and a specificity of 100% for detecting early-stage BC | 10.1158/1078-0432.CCR-13-2933 | |
cfDNA methylation (pyroseq of 3 genes: SPAG6, PER1 and ITIH5; SNiPER) | plasma cohort (n = 125) | 64% sensitivity for breast cancer detection using SPAG6, PER1 and ITIH5 | 10.18632/oncotarget.27303 |
cfDNA methylation (one gene: APC) | meta-analysis of 12 studies | low sensitivity (20%) but high specificity (96%) for detecting breast cancer | 10.1111/1759-7714.12580 |
cfDNA methylation (2 genes) | 94.1% sensitivity | 10.1016/j.ygyno.2010.04.016 | |
cfDNA methylation (8 genes) | 90% sensitivity | 10.1371/journal.pone.0016080 | |
cfDNA methylation (3 genes) | greater sensitivity than the serum markers CEA and/or CA15-3 | 10.1007/s10549-011-1575-2 | |
cfDNA methylation (EGFR and PPM1E promoter) | patients with BC had significantly higher methylation levels than healthy controls | 10.1007/s13277-016-5190-z | |
cfDNA integrity index | patients with confirmed malignancy had significantly greater DNA damage than those with benign breast lesions and healthy controls | 10.1007/s13277-015-4624-3 | |
cfDNA mutations in breast milk | 10 women diagnosed with BC during pregnancy and 9 diagnosed during breastfeeding: 12 healthy donors | Variants in cfDNA from breast milk detected in 87% of the cases, while undetected in 92% of matched plasma. Overall clinical sensitivity of 71.4% and specificity of 100%. In two cases, ctDNA was detectable in BM collected 18 and 6 months prior to standard diagnosis. | 10.1158/2159-8290.CD-22-1340 |
(2) CTCs | |||
CTCs by nuclease-activated probe technology | discrimination between BC patients and healthy controls | 10.1016/j.omtn.2017.08.004 | |
(3) EVs | |||
EVs with specific proteomic profiles, including immunoglobulins | 426 human samples | 95% sensitivity/90% specificity in detecting cancer | 10.1016/j.cell.2020.07.009 |
EVs with CD82 | quantification for early diagnosis of BC | 10.1002/mc.22960 | |
EVs including unique tRNAs and miR-10b and miR-21 | EVs BC patients contain miR-10b and miR21 and unique tRNA (in contrast to healthy controls that do not convert pre-miRNA of these two types) | 10.1158/1541-7786.MCR-14-0533 | |
EVs including miR-21 and miR-1246 | significant higher concentration in BC patients than in healthy controls | 10.1186/s13058-016-0753-x | |
EVs with long non-coding RNA (lncRNA H19) | H19 expression in EVs was significantly upregulated in the serum of patients with BC as compared to patients without malignancy | 10.2147/OTT.S243601 | |
(4) other blood analytes | |||
circulating miRNAs (8 miRNAs) | Serum samples from 116 malignant breast lesions and 64 benign breast lesions | area under the curve (AUC) of 0.9542 with eight-miRNA signature | 10.3390/cancers11121872 |
circulating miRNAs (5 miRNAs) | Combination of miR-1246, miR-1307-3p, miR-4634, miR-6861-5p, and miR-6875-5p was shown to detect early-stage BC with sensitivity of 97.3%, specificity of 82.9% and accuracy of 89.7%. | 10.1111/cas.12880 | |
circulating miRNAs | 55 patients with metastatic breast cancer and 20 healthy donors | miR-21, miR-146a, and miR-210 could discriminate patients from healthy individuals | 10.1373/clinchem.2015.253716 |
proteins (afamin, apolipoprotein E, alpha-2-macroglobulin and ceruloplasmin) | 68 women diagnosed with BC within three years after enrollment, with 68 matched controls | Afamin, apolipoprotein E and ITIH4 were found in higher concentration in pre-diagnostic breast cancer (p < 0.05), while alpha-2-macroglobulin and ceruloplasmin were lower (p < 0.05). | 10.1186/1471-2407-11-381 |
proteins (integrin subunit alpha, Filamin A, Ras-associated protein-1A and Talin-1) | 20 patients with BC and 20 female control individuals with positive mammograms and benign pathology at biopsy | 4 proteins classified breast cancer patients with 100% sensitivity and 85% specificity (AUC of 0.93) | 10.1186/s13058-020-01373-9 |
proteins (Cyr 61) in plasma | 544 patients BC and 427 healthy controls | specificity of 99.0% and sensitivity of 80.0% for cancer detection | 10.1093/clinchem/hvab153 |
volatile organic compounds in the urine | sensitivity of 93.3% and specificity of 83.3% | 10.1038/s41598-021-99396-5 | |
(5) multiple blood analytes | |||
cfDNA mutation and cfDNA methylation as well as circulating miRNA information | 205 patients with stage I, II, or III cancer prior to cancer therapy and 15 healthy controls | combination of three different analytes could improve the sensitivity for cancer detection | 10.3390/cancers14020462 |
cfDNA fragmentation combined with cfDNA mutation analysis | sensitivity 91% and specificity 98% with combined workflow | 10.1038/s41586-019-1272-6 | |
cfDNA integrity, in combination with the detection of CTCs | 84 patients with no-distant metastatic BC and 30 patients with benign breast tumors | Combination of CTCs with cfDI: false positive rate 10.71% andarea under the curve value 0.68. | 10.4149/neo_2017_417 |
combination of circulating mRNAs and a protein | Eight mRNAs (S100A8, GRIK1, GRM1, H6PD, IGF2BP1, CSTA, MDM4,and TPT1) and the CA6 protein were able to distinguish BC patients and healthy controls. Diagnostic accuracy: 92% (sensitivity of 83% and specificity of 97%). | 10.1371/journal.pone.0015573 |
Diagnostic | ||
---|---|---|
Specific Analyte | Conclusion | Reference |
(1) cfDNA | ||
nucleosome position and accessibility of cfDNA | differentiate ER-positive from ER-negative MBCs | 10.1038/s41467-022-35076-w |
ctDNA fraction | High ctDNA fraction itself has already been shown to correlate with TNBC status, and also high tumor grade and metastatic status | 10.1038/s41523-021-00319-4 |
(2) CTCs | ||
CTC number | A significantly increased number of CTCs, determined by CellSearch, before therapy was reported for MBCs with lobular compared to ductal histology | 10.3390/cells9071718 |
AR on CTCs | androgen receptor (AR) expression on CTCs was correlated with bone metastasis | 10.1158/1541-7786.MCR-17-0480 |
number of apoptotic CTCs | higher number of apoptotic CTCs was detected in early in contrast to metastatic BC patients | 10.1158/1535-7163.MCT-12-1167 |
(3) EVs | ||
EV miRNA-373 | EV miRNA-373 was increased in the blood of TNBCs patients compared to patients with other BC subtypes | 10.18632/oncotarget.2520 |
EV mRNA | Profiling of PAM50 transcripts in EVs showed good concordance with tissue results. | 10.1021/acs.analchem.3c00624 |
45 miRNAs in EVs | panel of 45 miRNAs detected in plasma EVs of BC patients differentiated HER2-positive from TNBC patients | 10.1186/s12916-018-1163-y |
EV miR-21 | MBCs were shown to have significantly higher EV miR-21 levels compared to BC patients with no metastases | 10.1186/s13058-019-1109-0 |
EV miR-223-3p | EV miR-223-3p was significantly increased in invasive ductal carcinoma patients compared to subjects with ductal carcinoma in situ (DCIS) | 10.3892/ol.2018.8457 |
(4) other blood analytes | ||
Circular RNA, circ_0001785 | circ_0001785 is proposed to be correlated with distant metastasis and histology | 10.1016/j.cca.2017.10.011 |
(5) multiple blood analytes | ||
56-gene cfDNA Panel (including SNV, CNV, MSI, TMB analysis) and ER and HER2 protein expression and ERBB2 amp in/on CTCs | to subtype MBC | https://www.epicsciences.com/press-releases/epic-sciences-announces-medicare-coverage-for-breast-cancer-focused-ctdna-gene-panel/?goal=0_8c04e2abda-5ca6438936-71670485&mc_cid=5ca6438936 |
Therapy (De)Escalation | |||
---|---|---|---|
Specific Analyte | Clinical Setting | Conclusion | Reference |
(1) cfDNA | |||
ctDNA quantity | before neoadjuvant therapy | ctDNA quantity predicted the risk of relapse and OS | 10.1016/j.ctrv.2022.102362 |
ctDNA quantity | before neoadjuvant chemotherapy in TNBC patients | predicting the risk for recurrence | 10.18632/oncotarget.23520 |
PIK3CA and/or TP53 mutation detection in cfDNA | NeoALTTO trial (before neoadjuvant anti-HER2 treatment in HER2-positive BC patients) | PIK3CA and/or TP53 mutations in cfDNA correlated with lower pCR rates | 10.1158/1078-0432.CCR-18-2521 |
cfDNA methylation of GASTP1, RASSF1A and RARB2 | before neoadjuvant treatment in early BC patients | cfDNA methylation of GASTP1, RASSF1A and RARB2 was associated with OS independent of pCR | 10.1159/000342083 |
ctDNA clearance | I-SPY 2 study (neoadjuvant therapy with an AKT inhibitor); 84 high risk early BC patients; from baseline to three weeks after therapy initiation | ctDNA clearance from baseline to three weeks was related to an increased pCR rate and even in patients with no pCR, the ctDNA clearance within the first three weeks of therapy was correlated with improved survival compared to patients achieving no pCR and no ctDNA clearance | 10.1016/j.annonc.2020.11.007 |
mutations in cfDNA | under neoadjuvant therapy | Detection of mutations in cfDNA based on tumor-informed personalized assays under neoadjuvant therapy were correlated with a lower chance of pCR | 10.1126/scitranslmed.aax7392 |
(2) CTCs | |||
CTC detection by CellSearch | NeoALTTO trial (before neoadjuvant anti-HER2 treatment in HER2-positive BC patients) | CTC detection resulted in numerically lower pCR rates (pCR in 27.3% patients with detectable CTCs and pCR in 42.5% with no detectable CTCs). | 10.1016/j.breast.2013.08.014 |
CTC detection | GeparQuattro trial (before neoadjuvant chemotherapy) | CTC detection correlated significantly with disease-free (DSF) and OS | 10.1158/1078-0432.CCR-17-0255 |
CTC quantity by CellSearch | BEVERLY-1 and -2 trials (before neoadjuvant chemotherapy) | CTC quantity did not show any correlation to pCR rates, but CTC detection was associated with significantly decreased DFS and OS | 10.1093/annonc/mdw535 |
CTC detection | 2000 early BC patients (before neoadjuvant therapy) | presence of CTCs was an independent predictor of poor DSF, distant disease free (DDSF) and OS. | 10.1158/1078-0432.CCR-15-1603 and 10.1093/jnci/djy018 |
(3) EVs | |||
EV miRNA (miR-30b, miR-328 and miR-423) | before neoadjuvant therapy in BC patients | levels of specific EV miRNA (miR-30b, miR-328 and miR-423) forecast pCR | 10.3390/curroncol29020055 |
miR-141, miR-34a, miR-182 and miR-183 in EVs | after the first dose of neoadjuvant therapy | miR-141, miR-34a, miR-182 and miR-183 in EVs after the first dose of neoadjuvant therapy predicted pCR/non-pCR | 10.3390/curroncol29020055 |
(4) other blood analytes | |||
miRNAs in plasma | TNBC patients before neoadjuvant therapy | miRNAs in plasma correlate with relapse and OS | 10.1158/1078-0432.CCR-14-2011 |
miRNAs in plasma | before neoadjuvant therapy | miRNAs in plasma correlate with pCR | 10.3390/cancers12071820 and 10.1007/s10549-022-06642-z |
miR-145 in plasma | HER2-positive BC, before neoadjuvant therapy | Reduced miR-145 levels were related to pCR in HER2-positive BC | 10.1097/SLA.0000000000005613 |
let7a in plasma | luminal BC, before neoadjuvant therapy | let7a correlated with pCR | 10.1097/SLA.0000000000005613 |
level of circulating nucleosomes | before neoadjuvant therapy in early BC patients | level of circulating nucleosomes had prognostic value | 10.1016/j.canlet.2013.04.013 |
circulating miR-148a-3p and miR-374a-5p | from baseline to two weeks of trastuzumab-based neoadjuvant chemotherapy in the NeoALTTO trial | increased levels of circulating miR-148a-3p and miR-374a-5p from baseline to two weeks were related to pCR | 10.3390/ijms21041386 |
thymidine kinase activity in the plasma | early under neoadjuvant treatment | prognostic value | 10.1016/j.esmoop.2021.100076 |
Minimal Residual Disease Detection | |||
---|---|---|---|
Specific Analyte | Clinical Setting | Conclusion | Reference |
(1) cfDNA | |||
ctDNA dynamics | before and after neoadjuvant treatment | ctDNA clearance during neoadjuvant therapy was informative regarding the existence of MRD | 10.1158/1078-0432.CCR-21-3231 |
ctDNA dynamics by personalized mutation assays | I-SPY 2 study (neoadjuvant therapy with an AKT inhibitor); 84 high risk early BC patients; from baseline to end of neoadjuvant treatment | cfDNA clearance from baseline to the end of treatment correlated with a pCR. Patients with ctDNA detection after therapy showed a significantly increased risk for metastatic recurrence. In particular, patients not achieving a pCR but with no ctDNA detection after therapy had an excellent outcome, similar to the patients who achieved a pCR. | 10.1016/j.annonc.2020.11.007 |
ctDNA dynamics by targeted digital sequencing | before and after neoadjuvant treatment | patients with a pCR showed a larger decrease in ctDNA during neoadjuvant therapy compared to the patients with no pCR | 10.1126/scitranslmed.aax7392 |
ctDNA dynamics by BC-specific methylation pattern | before and after neoadjuvant treatment | ctDNA persistence even after neoadjuvant therapy indicated the existence of MRD | 10.1016/j.annonc.2019.11.014 |
cfDNA integrity | before and after neoadjuvant treatment | longitudinal cfDNA integrity analysis indicated tumor shrinkage | 10.4149/neo_2017_417 |
cfDNA integrity index | after neoadjuvant treatment | Patients who achieved a pCR, but showed an reduced cfDNA integrity index after neoadjuvant therapy had a higher risk for distant metastases | 10.4149/neo_2017_417 |
ctDNA detection by mutation analysis | after neoadjuvant treatment | prognostic value of ctDNA detection by mutation analysis in all BC subgroups after neo-adjuvant therapy | 10.1016/j.ctrv.2022.102362 and 10.1001/jamaoncol.2019.1838 and 10.1038/s41523-017-0028-4 and 10.15252/emmm.201404913 and 10.1126/scitranslmed.aab0021 and 10.1001/jamaoncol.2020.2295 |
ctDNA concentration and presence | after neoadjuvant treatment | ctDNA presence after neoadjuvant therapy was detected in 12/13 patients with no pCR, but also in 5/9 patients achieving a pCR. ctDNA concentration but not ctDNA presence after neoadjuvant therapy was significantly correlated with a pCR | 10.1126/scitranslmed.aax7392 |
ctDNA detection | IMPASSION031 trial, TNBC patients, after neoadjuvant treatment | Patients achieving a pCR and who had no detectable ctDNA showed the best DSF and OS while the non-pCR cohort could be differentiated by ctDNA presence in patients with increased DSF and OS (ctDNA negative) and patients with worse DSF and OS (ctDNA positive) | 10.1016/esmoop/esmoop101220 |
ctDNA detection by personalized mutation sequencing panels | in the follow-up | sensitivity of 89% for MRD detection with a lead time of up to 24 months (median 8.9 months) with a specificity of 100% with none of the non-relapsing patients being ctDNA-positive | 10.1158/1078-0432.CCR-18-3663 |
ctDNA detection by patient-specific digital droplet PCR (ddPCR) panels | within one year after surgery | MRD was detected with 19% sensitivity and median lead time from first positive test to recurrence was 18.9 months | 10.1158/1078-0432.CCR-19-3005 |
ctDNA detection by RaDaR assays | high-risk HR-positive, HER2-negative BC patients with no evidence of recurrence five years after diagnosis, serial blood analysis | RaDaR assays identified all patients with distant metastatic recurrences (7.2%) with a median ctDNA lead time of 12.4 months. However, 2/8 patients with ctDNA-positive results had not had clinical recurrence. In total, 1.2% of patients had no MRD but local recurrence. | 10.1200/JCO.22.00908 |
(2) CTCs | |||
CTC detection | before and after neoadjuvant treatment | presence of persisting CTCs correlated with shorter DSF and OS | 10.1093/jnci/dju066 |
CTC detection | before and after neoadjuvant treatment | presence of persisting CTCs correlated with an increased risk of relapse | 10.1245/s10434-015-4600-6 |
CTC number | in TNBC patients after neoadjuvant chemotherapy | one or more CTCs present after neoadjuvant chemotherapy predicted relapse and survival in TNBC patients | 10.1245/s10434-015-4600-6 |
TWIST transcripts in CTCs | early BC patients after surgery and before adjuvant therapy | prognostication of DSF in early BC patients after surgery and before adjuvant therapy | 10.3390/cells8070652 |
CK19 mRNA positive CTCs | during the first five years of BC follow-up | persistent detection of CK19 mRNA positive CTCs during the first five years of BC follow-up increased the risk of late relapse | 10.1186/bcr2897 |
(3) EVs | |||
EV miR-21 | before and after neoadjuvant treatment | Persisting high levels of circulating miR-21 after neoadjuvant treatment were associated with poor prognosis | 10.1186/s13058-019-1109-0 |
(4) other blood analytes | |||
circulating miR-21 | before and after neoadjuvant treatment | Persisting high levels of circulating miR-21 after neoadjuvant treatment were associated with poor prognosis | 10.1007/s10549-022-06642-z |
circulating miRNAs | NeoALTTO trial, after completion of neoadjuvant therapy | miR-185-5p, miR-146a-5p and miR-22-3p are prognostic marker independent of pCR | 10.3389/fonc.2022.1028825 |
lymphocyte-to-monocyte ratio | after surgery and neoadjuvant therapy | lymphocyte-to-monocyte ratio was shown to be significantly associated with worse prognosis | 10.2147/CMAR.S292048 |
expression of TLR4 on peripheral blood mononuclear cells | at the time point of surgery in early BC patients | the expression of TLR4 on peripheral blood mononuclear cells predicted high risk of relapse | 10.3390/cancers14041053 |
(5) multiple blood analytes | |||
cfDNA and CTC analysis | TNBC patients after neoadjuvant treatment | MRD sensitivity was 79% with ctDNA analysis alone, 62% with CTC analysis alone and 90% with the combination of both analytes | 10.1001/jamaoncol.2020.2295 |
CTC quantification, phenotypic, transcriptomic, and genomic profiling of CTCs as well as mutation and methylation profiling of cfDNA | early BC patients in the follow-up | Multimodal approach identified a relapse at least four years earlier than metastases could clinically be detected | 10.1038/s41598-022-25400-1 |
Prognostification in MBCs | |||
---|---|---|---|
Specific Analyte | Clinical Setting | Conclusion | Reference |
(1) cfDNA | |||
genome-wide cfDNA methylation | MBCs, at baseline or week four after therapy initiation and dynamics | Methylation pattern on genome-wide scale in cfDNA was shown to correlate with OS—even prognostic in case evaluated at week four after therapy initiation and dynamics from baseline to four weeks were informative about OS as well. | 10.1200/JCO.2015.66.2080 |
cfDNA methylation (5 genes) | at baseline in MBCs | correlate with OS | 10.1038/s41388-018-0660-y |
copy number changes and genomic instability score from cfDNA | MBCs, at baseline, after one week and two weeks after treatment initiation | The genomic instability score at baseline, after one week and two weeks after treatment initiation were significantly associated with poor OS. | 10.3390/cancers13061331 |
Tumor-derived cfDNA fractions | MBC | associated with clinical outcome (PFS and OS) | 10.3390/cancers11081171 |
ctDNA abundance by mutation-specific ddPCR | BEECH trial, ER-positive advanced BCs, after four weeks of therapy | ctDNA abundance after four weeks of therapy revealed significant correlation with PFS | 10.1093/annonc/mdz085 |
pathogenic or likely pathogenic variants in the cfDNA | MBCs | Higher number of pathogenic or likely pathogenic variants in the cfDNA associated with worse OS | 10.1007/s00018-019-03189-z |
mean variant allele frequency of cfDNA mutations | from baseline to cycle two in advanced BC patients treated with ICI | It was also described that a decrease in the mean variant allele frequency of cfDNA mutations in any of the 425 genes sequenced from baseline to cycle two was related to a longer PFS | 10.1200/PO.22.00509 |
cfDNA ESR1 mutations | 42 pre-treated MBCs | cfDNA ESR1 mutations were found to indicate worse OS and were associated with shorter duration of endocrine treatment effectiveness | 10.18632/oncotarget.18479 |
cfDNA TP53 and/or PIK3CA | MBCs | TP53 and/or PIK3CA mutations detected in cfDNA of MBCs were shown to indicate worse OS | 10.1016/S1470-2045(17)30376-5 and 10.1016/j.clbc.2016.05.004 |
cfDNA specific BRCA1 mutation | 44 HR-positive/HER2-negative MBC | Specific BRCA1 mutation detected in the cfDNA was associated worse OS | 10.1007/s00018-019-03189-z |
(2) CTCs | |||
CTCs number by the CellSearch system | 177 MBC patients before therapy initiation of any therapy in any therapy line | A cut-off of five CTCs in 7.5ml blood differentiated patients with good (mean 7.0 months) versus worse (mean 2.7 months) PFS and correlated significantly with OS | 10.1056/NEJMoa040766 |
CTCs number by the CellSearch system | 83 newly diagnosed, measurable MBC who were about to start their first line of systemic therapy | cut-off of five CTCs per 7.5ml blood was applied: 52% of patients had ≥ five CTCs and these patients had a decreased PFS and OS compared to the patients with no or less than five CTCs | 10.1200/JCO.2005.08.140 |
CTCs number by the CellSearch system | meta-analysis including 1944 MBC pa-tients | significant association of CTC quantity (cut-off: 5 CTCs) regarding PFS and OS | 10.1016/S1470-2045(14)70069-5. |
CTC clusters | MBCs (first line treated) | presence of CTC clusters has additional prognostic value when compared to the single CTC quantification alone. number of CTCs within the clusters might also be related to OS | 10.1007/s10549-016-4026-2 and 10.1186/s13058-018-0976-0 |
CTC detection by positive immunomagnetic selection and molecular characterization | MBCs | CTC presence was significant associated with PFS; patients with CTCs showing high PALB2 or MYC transcript expression had a shorter PFS and OS; patients with CTCs showing epithelial-stem cell like features also showed shorter PFS and OS | 10.1007/s10549-008-0143-x and 10.3390/cancers11121941 |
CTC isolation by a microfluidic chip and molecular characterization | MBC patients before eribulin treatment | entirety of epithelial and mesenchymal CTCs, as well as only the epithelial or mesenchymal CTCs was related to OS | 10.1007/s12032-019-1314-9 |
CTC isolation by density and EpCAM expression and molecular characterization | MBCs | univariate Cox regression model showed prognostic value for the presence of CTCs with either CK-19 overexpression, HER2 overexpression or CTCs with CD44high/CD24low or ALDH1high/CD24low features | 10.3390/diagnostics11030513 |
HER2+ CTCs | HER2-negative MBC | reduced OS in case CTCs with strong HER2 staining were detectable | 10.1016/j.esmoop.2021.100299 |
mitotic activity of CTCs | MBCs | characterization of CTCs with regard to their mitotic activity increased the hazard ratio for association with OS dramatically compared to CTC quantification itself | 10.1186/s13058-016-0706-4 |
CTC mRNA profile | MBCs (first-line aromatase inhibitor (AI) treated patients vs. treated with other therapy regimens | a-8-gene predictor (EEF1A, PTRF, CXCL14, ERBB3, EGFR, PTPRK, KRT81, TWIST1) was published to be related to PFS in first-line aromatase inhibitor (AI) treated patients, while the same predictor was not related to PFS in MBCs treated with other therapy regimens | 10.1186/s12885-016-2155-y |
(3) EVs | |||
metastasis- and stemness-related mRNAs in EVs | A set of metastasis- and stemness-related mRNAs were higher expressed in EVs from BC patients with poor OS than in those patients with increased OS | 10.18632/oncotarget.5818 | |
(4) other blood analytes | |||
circulating miR-200 family members | at baseline of new line of systemic therapy in MBCs | miR-200a, miR-200b, miR-141, and miR-429 were shown to significantly correlate with progression-free survival (PFS) | 10.1007/s00404-022-06442-2 |
thymidine kinase 1 (sTK1) in plasma | EFECT trial in MBCs, at baseline | prognostic value | 10.1016/j.ejca.2019.04.002 |
LAMP2 protein levels in red blood cells | MBCs | related to OS | 10.1016/j.mcpro.2022.100435 |
(5) multiple blood analytes | |||
CTC counts and total cfDNA level | MBCs | CTC counts and total cfDNA level were associated with OS in MBCs and thus, concluded CTCs and cfDNA to be equally valuable OS markers. the combined analysis of CTCs and cfDNA was more informative regarding OS than the sole analysis of one of the analytes | 10.1158/1078-0432.CCR-16-0825 and 10.1186/s13058-019-1235-8 and 10.1016/j.ejca.2018.10.012 |
CTC counts by CellSearch and ctDNA identified by targeted NGS | UCBG COMET study (NCT01745757), first-line paclitaxel and bevacizumab | CTC counts and ctDNA had non-overlapping profiles and correlated in sole and also in combined analysis with OS | 10.1038/s41523-021-00319-4 |
ESR1 variants in CTCs and cfDNA | MBCs | ESR1 variants in CTCs and cfDNA to indicate worse OS | 10.3390/cancers12051084 |
SOX17 promotor methylation in cfDNA and CTCs | MBCs | SOX17 promotor methylation in cfDNA and CTCs to be of prognostic relevance | 10.18632/oncotarget.18679 |
HER2+ CTCs and HER2+ EVs | MBCs | the heterogeneity of CTCs or EVs within one blood sample was shown to be inversely associated with OS | 10.1186/s13058-020-01323-5 |
CTCs and disseminated tumor cells (DTCs) in the bone marrow | MBCs | DTCs as well as CTCs were significantly associated with worse OS, no significant association of DTC and CTC results | 10.1007/s10549-014-3113-5 |
cfDNA, CTC genomic DNA, CTC mRNA and EV mRNA | ELIMA project, MBCs | additive value for prognostication: ‘ELIMA.score’ showed a significant correlation with OS with a decreased p-value when compared to each single analyte | 10.1186/s13073-021-00902-1 |
Decision for/against CTX | |||
---|---|---|---|
Specific Analyte | Clinical Setting | Conclusion | Reference |
(2) CTCs | |||
CTC quantity by CellSearch | STIC CTC trial, first-line therapy selection in HER2-negative MBCs, before therapy initiation | Therapy selection was conducted either based on the CTC quantity or clinicians’ choice. In general, PFS and OS were equally distributed in all groups, however, in patients with no concordant stratification status (high risk by clinicians/low CTC number or low risk by clinicians/high CTC number), chemotherapy prolonged PFS and OS compared to endocrine therapy | 10.1001/jamaoncol.2020.5660 |
(3) EVs | |||
Ubiquitin carboxyl-terminal hydrolase-L1 protein levels in EVs | before therapy initiation | Ubiquitin carboxyl-terminal hydrolase-L1 protein levels in EVs were shown to predict response to CTX | 10.1002/jso.24614 |
(4) other blood analytes | |||
Circulating miR-125b | before therapy initiation | Circulating miR-125b was shown to predict response to CTX | 10.1371/journal.pone.0034210 |
Decision for/against PARP Inhibition | |||
---|---|---|---|
Specific Analyte | Clinical Setting | Conclusion | Reference |
(1) cfDNA | |||
Somatic BRCA1/2 mutations (from cfDNA) | Olaparib Expanded trial, MBCs | The Olaparib Expanded trial also showed the effectiveness of Olaparib in MBC patients with somatic BRCA1/2 mutations. Olaparib therapy is rated as an option for MBC patients with somatic BRCA1/2 mutations (ESCAT scale IIA) by the ESMO guideline | 10.1200/JCO.20.02151 and 10.1016/j.annonc.2021.09.019 |
(4) other blood analytes | |||
Germline BRCA1/2 mutations (from blood cells) | OLYMPIA trial, HER2-negative early BC patients | In early BC, gBRCA1/2 mutations are of prognostic value to achieve a pCR under chemotherapy and forecast DFS under PARP inhibition. Olaparib is recommended for early TNBC patients showing no pCR and harboring gBRCA1/2 mutations as well as for high risk gBRCA1/2 mutant HR-positive/HER2-negative early BC patients as proven in the OLYMPIA trial. Standard to test HER2-negative BC patients for gBRCA1/2 mutations (ESCAT scale IA | 10.1159/000531578 and 10.1016/j.annonc.2022.09.159 and 10.1093/annonc/mdz036 |
Germline PALB2 mutations (from blood cells) | Olaparib Expanded trial, MBCs | The Olaparib Expanded trial also showed the effectiveness of Olaparib in MBC patients with germline PALB2 mutations. Olaparib therapy is rated as an option for MBC patients with germline PALB2 mutations (ESCAT scale IIA) by the ESMO guideline | 10.1200/JCO.20.02151 and 10.1016/j.annonc.2021.09.019 |
Decision for/against Anti-HER2 Therapy | |||
---|---|---|---|
Specific Analyte | Clinical Setting | Conclusion | Reference |
(1) cfDNA | |||
cfDNA ERBB2 mutations | MBCs | MBC patients with ERBB2 mutations were resistant to lapatinib, but sensitive to neratinib | 10.1158/2159-8290.CD-12-0349 and 10.1038/nature25475 and 10.1158/1078-0432.CCR-17-0900 |
cfDNA ERBB2 mutations | plasmaMATCH trial, cohort B, MBC patients | Cohort B in the plasmaMATCH trial also showed a benefit of neratinib treatment in ERBB2 mutant MBC patients | 10.1016/S1470-2045(20)30444-7 |
(2) CTCs | |||
CK19-positive CTCs | HER2-negative early BC patients | Treatment with trastuzumab prolonged the DFS in HER2-negative patients with CK19-positive CTCs present before and after adjuvant chemotherapy compared to observation. The fraction of patients with CK19-positive CTCs after trastuzumab treatment was reduced down to 14%, while observation led to 17.9% of patients with CK19-positive CTCs. | 10.1093/annonc/mds020 |
Decision for/against PIK3CA Inhibition | |||
---|---|---|---|
Specific Analyte | Clinical Setting | Conclusion | Reference |
(1) cfDNA | |||
cfDNA PIK3CA mutation | BELLE-2 trial, HR-positive/HER2-negative MBC patients progressing under aromatase inhibitor (AI) therapy | addition of buparlisib improved the PFS in PIK3CA mutant patients | 10.1016/S1470-2045(17)30376-5 and 10.1016/j.ejca.2018.08.002 |
cfDNA PIK3CA mutation | SOLAR-1 study, MBCs | Worse PFS of PIK3CA mutant MBC patients was improved by the application of alpesilib to an extend of a PFS achieved in PIK3CA wildtype MBC patients, that did not benefit from alpesilib treatment. | 10.1056/NEJMoa1813904 |
cfDNA PIK3CA mutation | HR-positive/HER2-negative MBC patients after progression under AI | Alpelisib in combination with fulvestrant for PIK3CA mutant HR-positive/HER2-negative MBC patients after progression under AI is recommended by the ESMO stating that ctDNA assessment for PIK3CA mutation analysis is an option besides mutational profiling in tissue samples. In patients with no available archival tumor tissue, ctDNA assessment is recommended. PIK3CA mutations are classified as tier IA by the ESMOs’ ESCAT scale. Recommendation for PIK3CA mutation profiling in primary tumor tissue, metastasis or plasma was confirmed in 2023. | 10.1016/j.annonc.2021.09.019 and 10.1016/j.annonc.2020.09.010 and 10.1159/000531579 |
cfDNA PIK3CA mutation | NCT02379247, HER2-negative heavily pre-treated patients | Alpesilib might be applied in more HER2-negative patients because its application demonstrated that in combination with nab-paclitaxel a prolonged PFS could be achieved in heavily pre-treated patients with PIK3CA mutation in tumor or plasma compared to PIK3CA wildtype patients | 10.1158/1078-0432.CCR-20-4879 |
(2) CTCs | |||
CTC PIK3CA mutations | MBCs | 16% to 33% of all MBCs were reported to harbor PIK3CA mutant CTCs | 10.1016/j.molonc.2014.12.001 and 10.1016/j.molonc.2013.07.007 |
(5) multiple blood analytes | |||
PIK3CA mutation in cfDNA and CTCs | MBCs | PIK3CA mutational status was found concordant in cfDNA and CTCs isolated from the same sample from MBC patients | 10.1002/1878-0261.12540 |
Decision for/against Endocrine Therapy | |||
---|---|---|---|
Specific Analyte | Clinical Setting | Conclusion | Reference |
(1) cfDNA | |||
cfDNA ESR1 mutations | SoFEA trial, HR-positive MBC patients | Direct comparison of fulvestrant (SERD) with exemestane (AI), showed a significantly prolonged PFS using fulvestrant compared to exemestane in ESR1 mutant HR-positive MBC patients | 10.1200/JCO.2016.67.3061 |
cfDNA ESR1 mutations | SoFEA and EFECT trial | OS benefit for ESR1 mutant MBC patients treated with fulvestrant compared to exemestane | 10.1158/1078-0432.CCR-20-0224 |
cfDNA ESR1 mutations | PADA-1 trial | Longitudinal monitoring via ESR1 mutation detection in the plasma under AI treatment and switch to fulvestrant plus CDK4/6i compared to continuation of AI after emergence of ESR1 mutations without radiographic evidence for progression increased the PFS from 5.7 months to 11.9 months. | 10.1016/S1470-2045(22)00555-1. |
cfDNA ESR1 mutations | EMERALD trial, ER-positive/HER2-negative MBC in the second or more therapy line after progression under CDK4/6i and one previous chemotherapy line at maximum | Elacestrant was recently shown to significantly increase the PFS compared to standard endocrine monotherapy. This effect was shown for both, ESR1 mutant and ESR1 wild-type patients. The hazard ratio however, showed a greater effect of PFS prolongation from elacestrant compared to fulvestrant in ESR1 mutant patients compared to all patients, independent of their ESR1 status. | 10.1200/JCO.22.00338 |
cfDNA ESR1 mutations | ER-positive/HER2-negative MBCs at the time of recurrence or progression on endocrine therapy | Testing for the emergence of ESR1 mutations is now recommended by the ASCO. Blood-based ESR1 mutation detection is preferred over tumor tissue testing due to the higher sensitivity. In HR-positive/HER2-negative MBC patients with prior CDK4/6i therapy and presence of ESR1 mutation in blood or tissue, elacestrant is recommended by the ASCO. | 10.1016/S1470-2045(20)30444-7 and 10.1200/JCO.23.00638 |
cfDNA ESR1 promotor methylation | Methylation of the ESR1 promotor in cfDNA might become relevant for selection of an endocrine therapy | 10.1158/1078-0432.CCR-17-1181 | |
(2) CTCs | |||
CTC ESR1 promotor methylation | Methylation of the ESR1 promotor in CTCs might become relevant for selection of an endocrine therapy | 10.1158/1078-0432.CCR-17-1181 |
Decision for/against AKT Inhibition | |||
---|---|---|---|
Specific Analyte | Clinical Setting | Conclusion | Reference |
(1) cfDNA | |||
cfDNA AKT1 mutation | plasmaMATCH trial, cohort C, ER-positive/HER2-negative MBC patients | Patients with AKT1 mutation in the cfDNA received capivasertib plus fulvestrant and this cohort met or exceeded the target number of responses with 4/18 patients | 10.1016/S1470-2045(20)30444-7 |
cfDNA PIK3CA, AKT1 or PTEN alterations | PAKT trial, metastatic TNBC | Addition of capivasertib to paclitaxel compared to paclitaxel alone correlated with a prolonged PFS and OS, especially in patients with PIK3CA, AKT1 or PTEN alterations. | 10.1200/JCO.19.00368 |
Decision for/against Tyrosine Receptor Kinase (TRK) Inhibition | |||
---|---|---|---|
Specific Analyte | Clinical Setting | Conclusion | Reference |
(1) cfDNA | |||
cfDNA NTRK1/2/3 fusion | BC patients | Trk inhibitors for BC patients with NTRK fusions are recommended. FDA approved blood-based evaluation of NTRK1/2/3 fusions in cfDNA available. | 10.1159/000531579 and 10.1016/j.annonc.2020.09.010 and 10.1200/JCO.22.01063 |
Decision for/against Androgen Receptor Inhibition | |||
---|---|---|---|
Specific Analyte | Clinical Setting | Conclusion | Reference |
(2) CTCs | |||
AR + CTCs | metastatic TNBC patients | AR protein expression analysis on CTCs in the blood might be usable as predictive marker for anti-AR therapy. | 10.1002/ijc.32209 |
CTC AR_v7 mRNA | early TNBC patients | CTC mRNA analysis showed a minority of early TNBC patients to potentially benefit from anti-AR therapy based on AR_v7 transcript expression. | 10.3389/fonc.2020.01658 |
Decision for/against CDK4/6i | |||
---|---|---|---|
Specific Analyte | Clinical Setting | Conclusion | Reference |
(1) cfDNA | |||
Tumor fraction in cfDNA | MBCs, before CDK4/6i initiation | Correlation of tumor fraction in cfDNA with PFS but not OS | 10.1038/s41467-023-36801-9 |
cfDNA PIK3CA mutation | MBCs, before CDK4/6i initiation, n = 30 or in the MONALEESA-7 trial | potential of plasma PIK3CA mutations before CDK4/6i as predictive markers | 10.1016/j.phrs.2020.105241 and 10.1200/PO.20.00445 |
cfDNA KRAS mutation | MONALEESA-7 trial, MBCs, before CDK4/6i initiation | Patients treated with palbociclib and fulvestrant with baseline KRAS mutations had a worse median PFS compared to patients with KRAS wild-type | 10.1200/PO.20.00445 |
cfDNA RB1 mutation | PALOMA-3 trial, MBCs, before CDK4/6i initiation | patients with RB loss (17.3% prevalence) at baseline had a significantly worse PFS under palbociclib plus fulvestant compared to RB wild-type patients | 10.1093/jnci/djaa087 |
cfDNA RB-LOH signature | 245 patients treated with ET + CDK4/6i from two independent cohorts | RB-LOH signature, consisting of 224 copy number features in the entire cfDNA genome showed a strong correlation with poor response and poor survival following CDK4/6i plus endocrine therapy | 10.1038/s41467-023-36801-9 |
(2) CTCs | |||
Single CTC RB1 transcript expression | within the TREnd trial, small cohort of MBC before Palbociclib | Gene expression regarding RB1 in single CTCs revealed a prolonged PFS | 10.1186/s13058-021-01415-w |
(3) EVs | |||
EV CDK4 mRNA expression | 40 HR-positive/HER2-negative advanced BC patients receiving palbociclib plus endocrine therapy, at baseline | High mRNA expression levels of CDK4 in EVs correlated significantly with a longer PFS | 10.1007/s10549-019-05365-y |
Gene | Alteration | Cancer Type | Drugs | ESCAT Scale 2019/2020 | ASCO 2022 | AGO 2023 |
---|---|---|---|---|---|---|
PIK3CA | C420R, E542K, E545A, E545D, E545G, E545K, Q546E, Q546R H1047L, H1047R, H1047Y and other oncogenic mutations | Breast Cancer | Alpelisib + Fulvestrant | IA | recommended | ++ |
ERBB2 | Amplification | Breast Cancer | Trastuzumab, Trastuzumab + Chemotherapy | IA | ||
ERBB2 | Amplification | Breast Cancer | Trastuzumab Deruxtecan | IA | ||
ERBB2 | Amplification | Breast Cancer | Trastuzumab + Pertuzumab + Chemotherapy | IA | ||
ERBB2 | Amplification | Breast Cancer | Trastuzumab + Tucatinib + Capecitabine | IA | ||
NTRK1 | Fusion | All Solid Tumors | Larotrectinib | IC | recommended | + |
NTRK2 | Fusion | All Solid Tumors | Larotrectinib | IC | recommended | + |
NTRK3 | Fusion | All Solid Tumors | Larotrectinib | IC | recommended | + |
NTRK1 | Fusion | All Solid Tumors | Entrectinib | IC | recommended | + |
NTRK2 | Fusion | All Solid Tumors | Entrectinib | IC | recommended | + |
NTRK3 | Fusion | All Solid Tumors | Entrectinib | IC | recommended | + |
Microsatellite Instability-High | All Solid Tumors | Pembrolizumab | IC | recommended | + | |
Tumor Mutational Burden-High | All Solid Tumors | Pembrolizumab | IC | recommended | ||
ESR1 | D538, E380, L469V, L536, S436P, Y537, V422del | Breast Cancer | Elacestrant | IIA | not recommended in 2022, but recommended in 2023 | + |
ERBB2 | Amplification | Breast Cancer | Ado-Trastuzumab Emtansine | |||
ERBB2 | Amplification | Breast Cancer | Lapatinib + Capecitabine, Lapatinib + Letrozole | |||
ERBB2 | Amplification | Breast Cancer | Margetuximab + Chemotherapy | |||
ERBB2 | Amplification | Breast Cancer | Neratinib, Neratinib + Capecitabine | |||
BRAF | V600E | All Solid Tumors (excluding Colorectal Cancer) | Dabrafenib + Trametinib | |||
NTRK1 | G595R | All Solid Tumors | Resistance to Larotrectinib | |||
NTRK3 | F617L | All Solid Tumors | Resistance to Larotrectinib | |||
NTRK3 | G623R | All Solid Tumors | Resistance to Larotrectinib | |||
NTRK3 | G696A | All Solid Tumors | Resistance to Larotrectinib | |||
RET | Fusion | All Solid Tumors (excluding Thyroid Cancer, Non-Small Cell Lung Cancer) | Selpercatinib |
Therapy Monitoring | |||
---|---|---|---|
Specific Analyte | Clinical Setting | Conclusion | Reference |
(1) cfDNA | |||
cfDNA methylation (9 marker) | TBCRC 005 study, MBCs, under therapy | 9-marker cfDNA methylation assay was shown to forecast disease progression three months earlier than radiographic staging in MBC patients | 10.1158/1078-0432.CCR-22-2128 |
genomic instability of cfDNA | 25 MBC patients, at baseline, one week under therapy, three months after therapy initiation | More than 50% reduction in genomic instability number (GIN) from low-pass WGS of cfDNA at baseline to one week under therapy was shown to associate with the stable disease proven by staging after 3 months and also with OS. A rise in GIN from baseline to two weeks under therapy associated with poor response, evaluated three months after therapy initiation by staging. | 10.3390/cancers13061331 |
cfDNA CNVs | HR-positive/HER2-negative MBC patients treated with CDK4/6i, at baseline and under therapy | comparison of z-scores at baseline and under therapy (z-score trajectories) has monitoring value | 10.1002/1878-0261.12870 |
mean allele frequency dynamics in cfDNA | LOTUS and INSPIRE trials, MBCs treated with different therapy regimens, baseline to a time point under therapy | Mean allele frequency dynamics from baseline to a time point under therapy related to therapy response at the time of blood draw or to PFS and OS | 10.1200/PO.20.00345 and 10.1200/PO.20.00345 and 10.1002/mgg3.1079 and 10.1038/s41523-021-00218-8 and 10.1016/S1470-2045(17)30450-3 and 10.1186/s40425-019-0541-0 |
ctDNA mutations | POSEIDON and SUMMIT trials, under therapy | In the POSEIDON and SUMMIT trials, early evaluation of ctDNA changes forecasted the radiologic treatment response and the emergence of specific mutations correlated with clinical drug resistance. Allele frequency of HER2 mutations in cfDNA decreased under pan-HER inhibitor neratinib, but increased upon radiographically proven progression. | 10.1158/1078-0432.CCR-19-0508 and 10.1158/1078-0432.CCR-17-0900. |
ctDNA in CSF and plasma | HER2-positive MBCs with brain metastases | dynamic changes in ctDNA in CSF and plasma under therapy revealed decreased allele frequencies in the plasma to be consistent with extra-CNS disease control and increased allele frequencies in the CSF to be related to poor treatment benefit in CNS | 10.1136/esmoopen-2017-000253 |
ctDNA level | INSPIRE trial, TNBC patients and patients with other tumor entities, from baseline to six weeks under treatment with pembrolizumab | ctDNA level changes from baseline to six weeks under treatment forecasted the therapy benefit. In all patients who responded to therapy, ctDNA clearance was detected before visible radiological response. | 10.1038/s43018-020-0096-5 |
cfDNA PIK3CA mutations | PALOMA-3 trial, palbociclib treated patients from baseline to two weeks | cfDNA PIK3CA mutation dynamics had significant monitoring value. Decrease in PIK3CA mutations in the cfDNA correlated significantly with increased PFS and long-term clinical benefit. | 10.1038/s41467-018-03215-x |
cfDNA level and mutations | ALCINA trial, at day 15/30 under palbociclib plus fulvestrant | cfDNA evaluation showed a decrease in all patients independent of their PFS. On day 30, undetectable cfDNA mutations (PIK3CA, TP53 and AKT1 studied) associated with improved PFS. | 10.1186/s13058-021-01411-0 and 10.1038/s41388-020-1174-y |
cfDNA ESR1 mutations | MBCs under first-line AI treatment | ESR1 mutation detection in the plasma revealed a direct association with progressive disease with a 100% specificity. ESR1 mutations were detectable prior to progression with median lead time of 110 days. | 10.1186/s13058-020-01290-x |
cfDNA ESR1 mutations | PADA-1 trial, under palbociclib and AI | Rising allele frequencies of cfDNA ESR1 mutations were used to identify patients with no radiographically proven progressive disease suitable for therapy switch of endocrine therapy. Significant clinical benefit with regard to PFS in case the therapy switch was conducted in patients with rising ESR1 mutations detectable under therapy | 10.1016/S1470-2045(22)00555-1 |
(2) CTCs | |||
CTC count by CellSearch | 3–5 or 6–8 weeks after initiation of therapy | It was shown that the CTC count itself by CellSearch evaluated 3–5 or 6–8 weeks after initiation of therapy was significantly associated with PFS and OS | 10.1016/S1470-2045(14)70069-5. |
CTC count | from baseline to a time point under therapy | A decrease in CTC counts from baseline to a time point under therapy was related to an increased PFS and OS. Persistently high CTC counts from baseline to under therapy, despite radiologically proven therapy response, associated with worse outcome | 10.1158/1078-0432.CCR-05-2821 and 10.1158/1078-0432.CCR-05-1769 |
apoptotic CTCs | baseline to under therapy | number of apoptotic CTCs from baseline to under therapy revealed a 50% apoptotic CTC reduction to differentiate between patients showing stable versus progressive disease and in case the apoptotic CTC number decreased from baseline to under therapy by less than 10%, progressive disease was identified with 74% specificity | 10.3390/cancers12041055 |
HER2+ CTCs | MBC patients treated with anti-HER2 treatment lapatinib | significant decrease in HER2-positive CTCs was only detected in MBC patients responding to anti-HER2 treatment with lapatinib, but not in patients progressing under lapatinib | 10.1371/journal.pone.0123683 |
RANK-positive CTCs | MBCs treated with Denosumab, baseline to day 2 | increase in RANK-positive CTCs from baseline to day 2 and persistence of RANK-positive CTCs was related to a longer time to progress of the bone metastasis | 10.1038/s41598-020-58339-2 |
CTCs overexpressing EpCAM, MUC1 or HER2 | under therapy in MBCs | The persistence of CTCs overexpressing EpCAM, MUC1 or HER2 transcripts under therapy in MBC patients correlated with shorter OS | 10.1007/s10549-008-0143-x |
CTCs overexpressing either EMT markers or the stem cell marker ALDH1 | MBCs, at the staging time point | 74% of all patients with progressive disease have CTCs overexpressing either EMT markers or the stem cell marker ALDH1 in contrast to only 10% of patients with stable disease | 10.1186/bcr2333 |
CTC mRNA profile | MBCs, at the staging time point | overexpression of ERBB2, ERBB3, ERCC1 alone or in combination with AURKA in CTCs of MBCs was significantly more prevalent in patients showing progressive disease at the time of blood draw compared to patients with stable disease. Identification of CTCs with overexpression of ERBB2, ERBB3, ERCC1 alone or in combination with AURKA during therapy in MBCs was furthermore related to a shorter OS. ERBB2 overexpression in CTCs was related to therapy failure at the time of blood draw and to a reduced OS | 10.18632/oncotarget.9528 |
CTC mRNA profile | MBCs, at the staging time point | Patients with progressive disease at the time of blood draw were more likely to have CTC overexpression signals than patients with stable disease. Two different gene expression patterns in CTCs were shown for patients with progressive disease, but a homogeneous expression pattern in patients with stable disease | 10.1373/clinchem.2016.269605 |
ERBB2 and/or ERBB3 overexpression in CTCs | MBCs, at the staging time point | ERBB2 and/or ERBB3 overexpression in CTCs was significantly correlated with progressive disease at the time of blood draw | 10.1373/clinchem.2017.283531 |
(4) other blood analytes | |||
CEA, CA 15-3, and CA 27-29 | BC | The circulating proteins CEA, CA 15-3, and CA 27-29 were recommended for therapy monitoring in 2015 by the ASCO | 10.1200/JCO.2015.61.1459 |
(5) multiple blood analytes | |||
CTC and EV mRNA profiles | MBCs, at the staging time point | Stronger correlation of ERBB2 and ERBB3 signals in CTCs and EVs with disease progression was identified compared to ERBB2 and ERBB3 signals in CTCs alone, revealing a synergistic value of CTCs and EVs for therapy monitoring. mTOR overexpression signals in EVs of MBCs under therapy was related to consecutive therapy failure while mTOR overexpression in CTCs was related to patients showing therapy response over at least six months | 10.1373/clinchem.2017.283531 |
ctDNA, CTC, CA 15-3 | MBCs | ctDNA evaluation was shown to have a higher sensitivity and higher correlation with tumor burden compared to CA 15-3 and CTC evaluations. | 10.1056/NEJMc1306040 |
cfDNA, CTC genomic DNA, CTC mRNA and EV mRNA | MBCs, at the staging time point | Additive value of these analytes in treatment monitoring. Presence of either ERBB3 overexpression signals or ERBB2 overexpression signals in CTCs were related significantly to the staging result. Combined evaluation of ERBB3 in all three analytes associated with therapy response. Dynamics from one time point to the next time point were more informative than single time point evaluations. Overexpression signals in EVs were the most dynamic ones during therapy and newly occurring ERCC1 overexpression signals in EVs from one time point to the next had a specificity of 97% but sensitivity of 18% to determine therapy response. The accuracy for detecting disease progression was 70% and 66% for PIK3CA and ESR1 variant appearances and the combined evaluation of ESR1 or PIK3CA allele frequency development was significantly correlated with disease progression. | 10.3390/cells10020212 |
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Keup, C.; Kimmig, R.; Kasimir-Bauer, S. The Diversity of Liquid Biopsies and Their Potential in Breast Cancer Management. Cancers 2023, 15, 5463. https://doi.org/10.3390/cancers15225463
Keup C, Kimmig R, Kasimir-Bauer S. The Diversity of Liquid Biopsies and Their Potential in Breast Cancer Management. Cancers. 2023; 15(22):5463. https://doi.org/10.3390/cancers15225463
Chicago/Turabian StyleKeup, Corinna, Rainer Kimmig, and Sabine Kasimir-Bauer. 2023. "The Diversity of Liquid Biopsies and Their Potential in Breast Cancer Management" Cancers 15, no. 22: 5463. https://doi.org/10.3390/cancers15225463