Efficacy of Lower Dose Capecitabine in Patients with Metastatic Breast Cancer and Factors Influencing Therapeutic Response and Outcome

11543 Background: Within metastatic breast cancer (mBC), tumor heterogeneity limited efficacy and duration of response to treatment. In this study, circulating tumor DNA (ctDNA) was used to evaluate tumor heterogeneity as a prognostic factor and monitor therapeutic response in patients with mBC. Methods: We collected plasma samples from 37 HER2-positive mBC patients treated with pyrotinib. Target-capture deep sequencing was performed to detect somatic mutations in plasma ctDNA. Clonal population structures were identified based on variations from ctDNA using Bayesian cluster with PyClone. Molecular tumor burden index (mTBI) was calculated with the mean variant allele frequency of mutations in trunk clonal population. Results: Mutations in TP53 and genes of PI3K/Akt/mTOR pathway were associated with drug resistance for pyrotinib. The result showed that patients with resistant mutations occurring as a truncal event, who receiving monotherapy of pyrotinib, presented worse therapeutic effect (HR, 4.52; P = 0.03). The median PFS of patients with versus without resistant mutations in trunk clonal population was 7.8 weeks (95% CI 7.4 to 26.8 weeks) versus 31.6 weeks (95% CI 15.7 to 60 weeks), respectively. Patients with high heterogeneity (clonal population ≥3) had a significantly worse PFS (HR, 2.79; 95% CI 1.23 to 6.34; P = 0.014). The median PFS among patients with high versus low heterogeneity was 30.0 weeks (95% CI 13.9 to 53.5 weeks) versus 60.0 weeks (95% CI 31.4 to 84 weeks), respectively. Longitudinal monitoring of 21 patients during treatment showed positive correlation between mTBI in ctDNA and tumor size evaluated by CT imaging (P < 0.0001). Monitoring the mTBI in serial ctDNA increased sensitivity for prediction of progressive disease in 6 of 21 patients, with a mean time of 12.7 weeks earlier than using CT scan. ROC curve analysis showed an area under the curve value was 0.97 (p < 0.0001). Conclusions: Assessing tumor heterogeneity in ctDNA provides genetic predictors of treatment outcome. Molecular tumor burden in ctDNA is a potential indicator of therapeutic response. These observations might be supplements for the current therapeutic response evaluation.

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Analysis of circulating tumor DNA to monitor metastatic breast cancer patients treated with first-line chemotherapy (CAMELLIA study).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14568 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14568-e14568

Author(s):

Zongbi Yi ◽

Fei Ma ◽

Guohua Rong ◽

Jin Li ◽

Lianpeng Chang ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Therapeutic Response ◽

Metastatic Breast ◽

Circulating Tumor Dna ◽

Tumor Burden ◽

Breast Cancer Patients ◽

First Line ◽

Tumor Dna ◽

Line Chemotherapy

e14568 Background: Our precious study indicated that the dynamic changes in circulating tumor DNA (ctDNA) could reflect changes in tumor burden. We conduct this study to validate the role of ctDNA as a therapeutic response biomarker in a larger cohort prospective phase III randomized multicenter study. Methods: In this study, we collected 292 serial ctDNA samples from 125 metastatic breast cancer patients treated with first line chemotherapy. Target-capture deep sequencing of 1021 genes was performed to detect somatic variants in ctDNA. Results: 81.4% patients had detectable ctDNA at baseline. An undetectable ctDNA at baseline was associated with a lower disease volume (p < 0.05). The commonly mutated genes were PIK3CA (35.0%), TP53 (34.2%), MLL3 (9.4%) and ESR1 (9.4%). Kaplan–Meier analysis showed that TP53 gene mutations and remaining C2 (detected at base line and remaining at the second cycle of chemotherapy) were significantly associated with poor PFS. Longitudinal monitoring of 27 patients during treatment showed that the molecular tumor burden index ([mTBI] a measure of the percentage of ctDNA in samples) was positively correlated with tumor size as evaluated by computed tomography (P < 0.05). The evaluations based on mTBI values were consistent with those based on CT scans in 87.5% of cases at the endpoint of clinical observation. Conclusions: ctDNA could be used to predict treatment outcomes and the mTBI is a potential method to assess therapeutic response in metastatic breast cancer. Clinical trial information: NCT01917279.

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Tumor Therapeutic Response and Vessel Tortuosity: Preliminary Report in Metastatic Breast Cancer

Medical Image Computing and Computer-Assisted Intervention – MICCAI 2006 - Lecture Notes in Computer Science ◽

10.1007/11866763_69 ◽

2006 ◽

pp. 561-568 ◽

Cited By ~ 8

Author(s):

Elizabeth Bullitt ◽

Nancy U. Lin ◽

Matthew G. Ewend ◽

Donglin Zeng ◽

Eric P. Winer ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Preliminary Report ◽

Therapeutic Response ◽

Metastatic Breast ◽

Vessel Tortuosity

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Differences in Sensitivity to New Therapies Between Primary and Metastatic Breast Cancer: A Need to Stratify the Tumor Response?

10.21203/rs.3.rs-92580/v1 ◽

2020 ◽

Author(s):

Hubert Beaumont ◽

Nathalie Faye ◽

Antoine Iannessi ◽

Emmanuel Chamorey ◽

Catherine Kliffa ◽

...

Keyword(s):

Breast Cancer ◽

Sensitivity Analysis ◽

Metastatic Breast Cancer ◽

Therapeutic Response ◽

Growth Factor Receptor ◽

Metastatic Breast ◽

Target Lesion ◽

Trastuzumab Therapy ◽

Drug Dependent ◽

Therapeutic Responses

Abstract Objective: We compared therapeutic response of Varlitinib + Capecitabine (VC) versus Lapatinib + Capecitabine (LC) in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer after trastuzumab therapy by assessing changes in target lesion (TL) diameter and volume per location.Methods: We retrospectively analyzed the CT data of the ASLAN001-003 study (NCT02338245). We analyzed TL size and number at each location focusing on therapeutic response from baseline to Week 12. We used TL diameter and volume to conduct an inter-arm comparison of the response according to: RECIST 1.1; stratified per TL location and; considering TLs independently. Multiple pairwise intra-arm comparisons of therapeutic responses were performed. Considering TL independently, weighted models were designed by adding weighted mean TL responses grouped by location. A sensitivity analysis tested the robustness of results.Results: We evaluated 42 patients (88 TL) and 35 patients (74 TL) respectively at baseline and Week 12.We found reductions in breast TL burden in the VC arm compared to the LC arm (p=0.002 (diameter), p<0.001 (volume)). Responses and TL sizes at baseline were not correlated.Explained variabilities of volume change per TL location, patient and patient:TL interaction were 36%, 10% and 4% (VC), and 13%, 1% and 23%, (LC).A test of inter-arm difference of responses yielded p=0.07 (diameter), and p<0.001 (volume).The sensitivity analysis confirmed our findings.Conclusions: The therapeutic responses differed across locations; differential responses were drug‑dependent. Stratified analysis provides better drug comparisons and is a powerful tool to understand TL heterogeneity.

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