scholarly journals Circulating tumor DNA in neoadjuvant treated breast cancer reflects response and survival

2020 ◽  
Author(s):  
Mark Jesus M. Magbanua ◽  
Lamorna Brown-Swigart ◽  
Hsin-Ta Wu ◽  
Gillian L. Hirst ◽  
Christina Yau ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Residual Disease ◽  
Pathologic Complete Response ◽  
Circulating Tumor Dna ◽  
Patient Specific ◽  
Breast Cancer Patients ◽  
Metastatic Recurrence ◽  
Excellent Outcome ◽  
Increased Risk ◽  
Tumor Dna

AbstractPathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence in 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL. Cell-free DNA (cfDNA) was isolated from 291 plasma samples collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect 16 patient-specific mutations (from whole exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. At T0, 61 of 84 (73%) patients were ctDNA-positive, which decreased over time (T1-35%; T2-14%; T3-9%). Patients who remained ctDNA-positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared to those who cleared ctDNA (52% non-pCR; OR 4.33, P=0.012). After NAC, all patients who achieved pCR were ctDNA-negative (n=17, 100%). For those who did not achieve pCR (n=43), ctDNA-positive patients (14%) had significantly increased risk of metastatic recurrence (HR 10.4; 95% CI, 2.3–46.6); interestingly, patients who did not achieve pCR but were ctDNA-negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI, 0.15–13.5). Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival regardless of pCR status. Personalized monitoring of ctDNA during NAC may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.

scholarly journals Personalized circulating tumor DNA analysis to detect residual disease after neoadjuvant therapy in breast cancer

2019 ◽  
Vol 11 (504) ◽  
pp. eaax7392 ◽  
Author(s):  
Bradon R. McDonald ◽  
Tania Contente-Cuomo ◽  
Stephen-John Sammut ◽  
Ahuva Odenheimer-Bergman ◽  
Brenda Ernst ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Therapy ◽  
Dna Analysis ◽  
Residual Disease ◽  
Circulating Tumor Dna ◽  
Patient Specific ◽  
Molecular Response ◽  
Curative Intent ◽  
Current Limit ◽  
Tumor Dna

Longitudinal analysis of circulating tumor DNA (ctDNA) has shown promise for monitoring treatment response. However, most current methods lack adequate sensitivity for residual disease detection during or after completion of treatment in patients with nonmetastatic cancer. To address this gap and to improve sensitivity for minute quantities of residual tumor DNA in plasma, we have developed targeted digital sequencing (TARDIS) for multiplexed analysis of patient-specific cancer mutations. In reference samples, by simultaneously analyzing 8 to 16 known mutations, TARDIS achieved 91 and 53% sensitivity at mutant allele fractions (AFs) of 3 in 104 and 3 in 105, respectively, with 96% specificity, using input DNA equivalent to a single tube of blood. We successfully analyzed up to 115 mutations per patient in 80 plasma samples from 33 women with stage I to III breast cancer. Before treatment, TARDIS detected ctDNA in all patients with 0.11% median AF. After completion of neoadjuvant therapy, ctDNA concentrations were lower in patients who achieved pathological complete response (pathCR) compared to patients with residual disease (median AFs, 0.003 and 0.017%, respectively, P = 0.0057, AUC = 0.83). In addition, patients with pathCR showed a larger decrease in ctDNA concentrations during neoadjuvant therapy. These results demonstrate high accuracy for assessment of molecular response and residual disease during neoadjuvant therapy using ctDNA analysis. TARDIS has achieved up to 100-fold improvement beyond the current limit of ctDNA detection using clinically relevant blood volumes, demonstrating that personalized ctDNA tracking could enable individualized clinical management of patients with cancer treated with curative intent.

scholarly journals Circulating tumor DNA as a predictive marker of recurrence for patients with stage II-III breast cancer treated with neoadjuvant therapy

2021 ◽  
Author(s):  
Po-Han Lin ◽  
Ming-Yang Wang ◽  
Chiao Lo ◽  
Li-Wei Tsai ◽  
Tzu-Chun Yen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
Neoadjuvant Therapy ◽  
Cancer Patients ◽  
Pathologic Complete Response ◽  
Circulating Tumor Dna ◽  
Stage Ii ◽  
Breast Cancer Patients ◽  
Her2 Breast Cancer ◽  
Tumor Dna

Abstract Background:Patients with stage II to III breast cancer have a high recurrence rate. The early detection of recurrent breast cancer remains a major unmet need. Circulating tumor DNA (ctDNA) has been shown to be a marker to detect disease progression in metastatic breast cancer. We aimed to evaluate the prognostic value of ctDNA in the setting of neoadjuvant therapy (NAT).Methods:Plasma was sampled at the initial diagnosis (defined as before NAT) and after NAT and breast surgery (defined as after NAT). We extracted ctDNA from the plasma and performed deep sequencing of a target gene panel. The detection of alterations, such as mutations and copy number variations, were considered to indicate ctDNA positivity.Results:A total of 95 patients were enrolled in this study; 60 patients exhibited ctDNA positivity before NAT, and 31 patients had ctDNA positivity after NAT. A pathologic complete response (pCR) was observed in 13 patients, including one ER(+)Her2(-) patient, six Her2(+) patients and six triple-negative breast cancer (TNBC) patients. Among the entire cohort, multivariate analysis showed that an N3 classification and ctDNA positivity after NAT were independent risk factors that predicted recurrence (N3, hazard ratio (HR) 3.34, 95% confidence interval (CI) 1.26 – 8.87, p = 0.016; ctDNA, HR 4.29, 95% CI 2.06 – 8.92, p < 0.0001). The presence of ctDNA before NAT did not affect the rate of recurrence-free survival. For patients with Her2(+) or TNBC, non-pCR breast cancer patients were associated with a trend of higher recurrence (p = 0.105). Advanced nodal status and ctDNA positivity after NAT were significant risk factors for recurrence (N2 – 3, HR 3.753, 95% CI 1.146 – 12.297, p = 0.029; ctDNA, HR 3.123, 95% CI 1.139 – 8.564, p = 0.027). Two patients who achieved a pCR had ctDNA positivity after NAT; one TNBC patient had hepatic metastases six months after surgery, and one Her2(+) breast cancer patient had brain metastasis 13 months after surgery.Conclusions:This study suggested that the presence of ctDNA after NAT is a robust marker for predicting relapse in stage II to III breast cancer patients.

scholarly journals Detection of residual disease after neoadjuvant therapy in breast cancer using personalized circulating tumor DNA analysis

2018 ◽  
Author(s):  
Bradon R. McDonald ◽  
Tania Contente-Cuomo ◽  
Stephen-John Sammut ◽  
Ahuva Odenheimer-Bergman ◽  
Brenda Ernst ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Therapy ◽  
Dna Analysis ◽  
Residual Disease ◽  
Early Stage ◽  
Complete Response ◽  
Circulating Tumor Dna ◽  
High Accuracy ◽  
Patient Specific ◽  
Tumor Dna

AbstractAccurate detection of minimal residual disease (MRD) can guide individualized management of early stage cancer patients, but current diagnostic approaches lack adequate sensitivity. Circulating tumor DNA (ctDNA) analysis has shown promise for recurrence monitoring but MRD detection immediately after neoadjuvant therapy or surgical resection has remained challenging. We have developed TARgeted DIgital Sequencing (TARDIS) to simultaneously analyze multiple patient-specific cancer mutations in plasma and improve sensitivity for minute quantities of residual tumor DNA. In 77 reference samples at 0.03%-1% mutant allele fraction (AF), we observed 93.5% sensitivity. Using TARDIS, we analyzed ctDNA in 34 samples from 13 patients with stage II/III breast cancer treated with neoadjuvant therapy. Prior to treatment, we detected ctDNA in 12/12 patients at 0.002%-1.04% AF (0.040% median). After completion of neoadjuvant therapy, we detected ctDNA in 7/8 patients with residual disease observed at surgery and in 1/5 patients with pathological complete response (odds ratio, 18.5, Fisher’s exact p=0.032). These results demonstrate high accuracy for a personalized blood test to detect residual disease after neoadjuvant therapy. With additional clinical validation, TARDIS could identify patients with molecular complete response after neoadjuvant therapy who may be candidates for nonoperative management.One Sentence SummaryA personalized ctDNA test achieves high accuracy for residual disease.

scholarly journals 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 ◽  
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.

scholarly journals Patient-Specific Circulating Tumor DNA Detection during Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer

2017 ◽  
Vol 63 (3) ◽  
pp. 691-699 ◽  
Author(s):  
Francesca Riva ◽  
Francois-Clement Bidard ◽  
Alexandre Houy ◽  
Adrien Saliou ◽  
Jordan Madic ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Minimal Residual Disease ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Residual Disease ◽  
Circulating Tumor Dna ◽  
Tp53 Mutations ◽  
Tumor Dna ◽  
Minimal Residual

Abstract BACKGROUND In nonmetastatic triple-negative breast cancer (TNBC) patients, we investigated whether circulating tumor DNA (ctDNA) detection can reflect the tumor response to neoadjuvant chemotherapy (NCT) and detect minimal residual disease after surgery. METHODS Ten milliliters of plasma were collected at 4 time points: before NCT; after 1 cycle; before surgery; after surgery. Customized droplet digital PCR (ddPCR) assays were used to track tumor protein p53 (TP53) mutations previously characterized in tumor tissue by massively parallel sequencing (MPS). RESULTS Forty-six patients with nonmetastatic TNBC were enrolled. TP53 mutations were identified in 40 of them. Customized ddPCR probes were validated for 38 patients, with excellent correlation with MPS (r = 0.99), specificity (≥2 droplets/assay), and sensitivity (at least 0.1%). At baseline, ctDNA was detected in 27/36 patients (75%). Its detection was associated with mitotic index (P = 0.003), tumor grade (P = 0.003), and stage (P = 0.03). During treatment, we observed a drop of ctDNA levels in all patients but 1. No patient had detectable ctDNA after surgery. The patient with rising ctDNA levels experienced tumor progression during NCT. Pathological complete response (16/38 patients) was not correlated with ctDNA detection at any time point. ctDNA positivity after 1 cycle of NCT was correlated with shorter disease-free (P &lt; 0.001) and overall (P = 0.006) survival. CONCLUSIONS Customized ctDNA detection by ddPCR achieved a 75% detection rate at baseline. During NCT, ctDNA levels decreased quickly and minimal residual disease was not detected after surgery. However, a slow decrease of ctDNA level during NCT was strongly associated with shorter survival.

scholarly journals Circulating tumor DNA is readily detectable among Ghanaian breast cancer patients supporting non-invasive cancer genomic studies in Africa

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Samuel Terkper Ahuno ◽  
Anna-Lisa Doebley ◽  
Thomas U. Ahearn ◽  
Joel Yarney ◽  
Nicholas Titiloye ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Grade ◽  
Circulating Tumor Dna ◽  
Sub Saharan Africa ◽  
Health Study ◽  
Breast Cancer Patients ◽  
Cancer Driver ◽  
Sequencing Studies ◽  
Sub Saharan ◽  
Tumor Dna

AbstractCirculating tumor DNA (ctDNA) sequencing studies could provide novel insights into the molecular pathology of cancer in sub-Saharan Africa. In 15 patient plasma samples collected at the time of diagnosis as part of the Ghana Breast Health Study and unselected for tumor grade and subtype, ctDNA was detected in a majority of patients based on whole- genome sequencing at high (30×) and low (0.1×) depths. Breast cancer driver copy number alterations were observed in the majority of patients.

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