Rising Circulating Tumor DNA As a Molecular Biomarker of Early Disease Progression in Metastatic Breast Cancer

PURPOSE Accurate monitoring of therapeutic response remains an important unmet need for patients with metastatic breast cancer (MBC). Analysis of tumor genomics obtained via circulating tumor DNA (ctDNA) can provide a comprehensive overview of tumor evolution. Here, we evaluated ctDNA change as an early prognostic biomarker of subsequent radiologic progression and survival in MBC. PATIENTS AND METHODS Paired blood samples from patients with MBC were analyzed for levels of ctDNA, carcinoembryonic antigen, and cancer antigen 15-3 at baseline and during treatment. A Clinical Laboratory Improvement Amendments–certified sequencing panel of 73 genes was used to quantify tumor-specific point mutations in ctDNA. Multivariable logistic regression analysis was conducted to evaluate the association between ctDNA rise from baseline to during-treatment (genomic progression) and subsequent radiologic progression and progression-free survival (PFS). RESULTS Somatic mutations were detected in 76 baseline samples (90.5%) and 71 during-treatment samples (84.5%). Patients with genomic progression were more than twice as likely to have subsequent radiologic progression (odds ratio, 2.04; 95% CI, 1.74 to 2.41; P < .0001), with a mean lead time of 5.8 weeks. Genomic assessment provided a high positive predictive value of 81.8% and a negative predictive value of 89.7%. The subset of patients with genomic progression also had shorter PFS (median, 4.2 v 8.3 months; hazard ratio, 2.97; 95% CI, 1.75 to 5.04; log-rank P < .0001) compared with those without genomic progression. CONCLUSION Genomic progression, as assessed by early rise in ctDNA, is an independent biomarker of disease progression before overt radiologic or clinical progression becomes evident in patients with MBC.

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Circulating tumor DNA as a dynamic biomarker of response to palbociclib and fulvestrant in metastatic breast cancer patients

Breast Cancer Research ◽

10.1186/s13058-021-01411-0 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Lauren Darrigues ◽

Jean-Yves Pierga ◽

Alice Bernard-Tessier ◽

Ivan Bièche ◽

Amanda Bartolini Silveira ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Metastatic Breast Cancer ◽

Disease Progression ◽

Somatic Mutations ◽

Metastatic Breast ◽

Circulating Tumor Dna ◽

Prognostic Impact ◽

Radiological Evaluation ◽

Tumor Dna

Abstract Background Following the PALOMA-3 study results, the combination of palbociclib, a CDK4/6 inhibitor, with fulvestrant, a selective estrogen receptor degrader, has become a standard therapy in women with estrogen receptor-positive (ER+) HER2-negative (HER2−) metastatic breast cancer (MBC). Palbociclib has been shown to increase the progression-free survival (PFS) overall but no predictive biomarker of palbociclib efficacy has been validated so far. We thus evaluated whether early changes of circulating tumor DNA (ctDNA) levels are associated with palbociclib plus fulvestrant efficiency. Methods ER+ HER2− MBC patients were included in a prospective observational cohort before treatment initiation. Tumor response was assessed by radiological evaluation (RECIST v1.1) every 3 months. Plasma samples were collected before treatment (baseline), at day 15 (D15), at day 30 (D30), and at disease progression. We searched for somatic mutations from archived tumor tissues by targeted deep sequencing. For patients with somatic mutations identified, circulating tumor DNA (ctDNA) was tracked using digital droplet PCR. Ratios of ctDNA levels ([D15/baseline] and [D30/baseline]) were then correlated with prospectively registered patient characteristics and outcomes. Results Twenty-five of the 61 patients enrolled had a somatic mutation testable in plasma (NPIK3CA = 21, NTP53 = 2, NAKT1 = 2). At baseline, 84% of patients had detectable ctDNA levels but ctDNA levels had no prognostic impact on PFS (p = 0.10). Among those patients, ctDNA was still detected in 82% at D15 and 68% at D30. ctDNA clearance observed at day 30 was associated with longer PFS (HR = 7.2, 95% CI = 1.5–32.6, p = 0.004). On the contrary, a [D30/baseline] ctDNA ratio > 1 was associated with a shorter PFS (HR = 5.1, 95% CI = 1.4–18.3, p = 0.02) and all 5 patients with increased ctDNA levels at D30 showed disease progression after 3 months under palbociclib-fulvestrant. Finally, at the time of radiological tumor progression, ctDNA was detected in all patients tested. Conclusion Our study demonstrates that the efficiency of palbociclib and fulvestrant can be monitored by serial analyses of ctDNA before radiological evaluation and that early ctDNA variation is a prognostic factor of PFS.

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Abstract P4-08-08: Genomic progression, detected by circulating tumor DNA (ctDNA) sequencing, as an early predictor of disease progression in metastatic breast cancer (MBC)

10.1158/1538-7445.sabcs18-p4-08-08 ◽

2019 ◽

Author(s):

M Velimirovic ◽

D Juric ◽

A Niemierko ◽

LM Spring ◽

N Vidula ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Disease Progression ◽

Metastatic Breast ◽

Circulating Tumor Dna ◽

Tumor Dna ◽

Early Predictor

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Abstract PD2-03: Circulating tumor DNA (ctDNA) and circulating tumor cells (CTC) predictive value in HER2 negative metastatic breast cancer patients treated with first line weekly paclitaxel and bevacizumab: Results of a prospective cohort from the French Breast Cancer InterGroup Unicancer (UCBG): COMET study

10.1158/1538-7445.sabcs18-pd2-03 ◽

2019 ◽

Author(s):

J-Y Pierga ◽

A Silveira ◽

V Lorgis ◽

M-L Tanguy ◽

O Tredan ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Patients ◽

Tumor Cells ◽

Predictive Value ◽

Metastatic Breast ◽

Circulating Tumor Dna ◽

Breast Cancer Patients ◽

First Line ◽

Tumor Dna

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Early, On-Treatment Levels and Dynamic Changes of Genomic Instability in Circulating Tumor DNA Predict Response to Treatment and Outcome in Metastatic Breast Cancer Patients

Cancers ◽

10.3390/cancers13061331 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1331

Author(s):

Adriana Aguilar-Mahecha ◽

Josiane Lafleur ◽

Susie Brousse ◽

Olga Savichtcheva ◽

Kimberly A. Holden ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Genomic Instability ◽

Metastatic Cancer ◽

Metastatic Breast ◽

Circulating Tumor Dna ◽

Response To Treatment ◽

Breast Cancer Patients ◽

T1 And T2 ◽

Tumor Dna

Background: Circulating tumor DNA (ctDNA) offers high sensitivity and specificity in metastatic cancer. However, many ctDNA assays rely on specific mutations in recurrent genes or require the sequencing of tumor tissue, difficult to do in a metastatic disease. The purpose of this study was to define the predictive and prognostic values of the whole-genome sequencing (WGS) of ctDNA in metastatic breast cancer (MBC). Methods: Plasma from 25 patients with MBC were taken at the baseline, prior to treatment (T0), one week (T1) and two weeks (T2) after treatment initiation and subjected to low-pass WGS. DNA copy number changes were used to calculate a Genomic Instability Number (GIN). A minimum predefined GIN value of 170 indicated detectable ctDNA. GIN values were correlated with the treatment response at three and six months by Response Evaluation Criteria in Solid Tumours assessed by imaging (RECIST) criteria and with overall survival (OS). Results: GIN values were detectable (>170) in 64% of patients at the baseline and were significantly prognostic (41 vs. 18 months OS for nondetectable vs. detectable GIN). Detectable GIN values at T1 and T2 were significantly associated with poor OS. Declines in GIN at T1 and T2 of > 50% compared to the baseline were associated with three-month response and, in the case of T1, with OS. On the other hand, a rise in GIN at T2 was associated with a poor response at three months. Conclusions: Very early measurements using WGS of cell-free DNA (cfDNA) from the plasma of MBC patients provided a tumor biopsy-free approach to ctDNA measurement that was both predictive of the early tumor response at three months and prognostic.

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