Abstract 587: Genomic copy number profiling of single CTCs reveals clonal evolution in metastatic breast cancer and identifies actionable targets for informing treatment decisions

2021 ◽  
Author(s):  
Daniel Fernandez Garcia ◽  
Georgios Nteliopoulos ◽  
Robert Hastings ◽  
Amelia Rushton ◽  
Karen Page ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Copy Number ◽  
Clonal Evolution ◽  
Metastatic Breast ◽  
Treatment Decisions ◽  
Genomic Copy Number ◽  
Genomic Copy ◽  
Single Ctcs

scholarly journals Genomic profile of metastatic breast cancer patient-derived xenografts established using percutaneous biopsy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Seongyeong Kim ◽  
Dongjin Shin ◽  
Ahrum Min ◽  
Minjung Kim ◽  
Deukchae Na ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Core Needle Biopsy ◽  
Copy Number ◽  
Needle Biopsy ◽  
Metastatic Breast ◽  
Core Needle ◽  
Pdx Model ◽  
Number Variation ◽  
Pdx Models

Abstract Background Metastatic breast cancer (mBC) is a complex and life-threatening disease and although it is difficult to cure, patients can benefit from sequential anticancer treatment, including endocrine therapy, targeted therapy and cytotoxic chemotherapy. The patient-derived xenograft (PDX) model is suggested as a practical tool to predict the clinical outcome of this disease as well as to screen novel drugs. This study aimed to establish PDX models in Korean patients and analyze their genomic profiles and utility for translational research. Methods Percutaneous core needle biopsy or punch biopsy samples were used for xenotransplantation. Whole exome sequencing and transcriptome analysis were performed to assess the genomic and RNA expression profiles, respectively. Copy number variation and mutational burden were analyzed and compared with other metastatic breast cancer genomic results. Mutational signatures were also analyzed. The antitumor effect of an ATR inhibitor was tested in the relevant PDX model. Results Of the 151 cases studied, 40 (26%) PDX models were established. Notably, the take rate of all subtypes, including the hormone receptor-positive (HR +) subtype, exceeded 20%. The PDX model had genomic fidelity and copy number variation that represented the pattern of its donor sample. TP53, PIK3CA, ESR1, and GATA3 mutations were frequently found in our samples, with TP53 being the most frequently mutated, and the somatic mutations in these genes strengthened their frequency in the PDX model. The ESR1 mutation, CCND1 amplification, and the APOBEC signature were significant features in our HR + HER2- PDX model. Fulvestrant in combination with palbociclib showed a partial response to the relevant patient’s tumor harboring the ESR1 mutation, and CCND1 amplification was found in the PDX model. AZD6738, an ATR inhibitor, delayed tumor growth in a relevant PDX model. Conclusions Our PDX model was established using core needle biopsy samples from primary and metastatic tissues. Genomic profiles of the samples reflected their original tissue characteristics and could be used for the interpretation of clinical outcomes.

Prognostic role of plasma HER2 gene copy number in patients with HER2 positive metastatic breast cancer.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e13018-e13018 ◽  
Author(s):  
Ran Ran ◽  
Wenfa Huang ◽  
Shao Lin ◽  
Yunyun Niu ◽  
Hope S. Rugo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Copy Number ◽  
Gene Copy Number ◽  
Metastatic Breast ◽  
Gene Copy ◽  
Prognostic Role ◽  
Her2 Gene ◽  
Her2 Positive

Desire to address costs at time of treatment decisions among patients with metastatic breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6640-6640 ◽  
Author(s):  
Yvonne Y. Lei ◽  
Katharine M. Quain ◽  
Don S. Dizon ◽  
Rachel Jimenez ◽  
Jennifer Adrienne Shin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Care ◽  
Treatment Options ◽  
College Education ◽  
Metastatic Breast ◽  
Treatment Decisions ◽  
Feasibility Trial ◽  
Financial Issues ◽  
White Patients

6640 Background: Costs of cancer care may impact access to therapy, adherence, and distress among patients. However, the degree to which patients with metastatic breast cancer (MBC) wish to discuss financial issues when making treatment decisions is unknown. Methods: In a single arm feasibility trial, 40 women with newly diagnosed or progressive MBC completed a 1-page survey regarding goals and priorities for discussion with the oncology team. The survey included 17 potential priorities for discussion in the domains: treatment options, symptom management, emotional concerns, planning for the future, and lifestyle. We evaluated participants’ interest in prioritizing discussion of financial issues and sociodemographic and clinical correlates of this preference. We examined the relationship between desire to discuss financial issues and both distress on the Distress Thermometer (DT) and satisfaction with cancer care using Fisher’s exact test. Results: Among 40 participants, 11 (28%) reported interest in discussing financial issues when making treatment decisions, 29 (72%) were not interested. Average age was 57 (range 31-73), and the majority were white (85%) and college graduates (66%). Only 18% of white patients were interested in addressing cost, while 83% of non-white patients were interested (p < 0.01). Those with a college education were less likely to prioritize financial discussion compared to no college (16% vs. 47%, p = 0.04). Patients interested in discussing cost were more likely to have a household income < $50,000 (50% vs. 22% > $50,000, n.s.) and to have Medicaid (50% vs. 25% other insurance, n.s.). Additionally, patients with higher levels of distress (35% vs. 21% DT < 4, n.s.) and those on novel targeted or biologic therapy (42% vs. 21% other therapy, n.s.) were more likely to prioritize discussion of costs. Desire to discuss cost was not related to satisfaction with care. Conclusions: A substantial minority of patients with MBC, particularly those from less advantaged backgrounds, wish to discuss financial issues at time of treatment decisions. Financial toxicity research should recognize that not all patients desire this discussion and evaluate methods to screen for financial concerns and barriers to care.

Use of the ErbB2/CEP17 ratio to predict prognosis and response to trastuzumab-based therapy in the metastatic breast cancer setting

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11110-11110
Author(s):  
E. Fuchs ◽  
W. Köstler ◽  
R. Horvath ◽  
G. Hudelist ◽  
E. Kubista ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Metastatic Breast Cancer ◽  
Copy Number ◽  
Metastatic Breast ◽  
Chromosome 17 ◽  
Fish Analysis ◽  
Significant Difference ◽  
Group A ◽  
Her 2

11110 Background: Despite patient selection based upon detection of Her-2/neu overexpression by immunohistochemistry (IHC) and/or presence of amplification of the Her-2/neu-encoding erbB2 oncogene measured by FISH, response to trastuzumab-based therapy is only achieved in a subset of patients with Her-2/neu overexpressing breast carcinomas. Exact quantification of erbB2 copy-number relative to chromosome 17 (CEP17) (ErbB2/CEP17 ratio “R”) probably adds further important predictive information. Methods: Clinical data of 137 patients receiving trastuzumab based treatment for Her-2/neu overexpressing (IHC) metastatic breast cancer were analysed. ErbB2/CEP17 ratio (R) was determined by quantitative FISH analysis in original tumor tissue using Vysis PathVysion DNA-based FISH technology. Results: ErbB2/CEP17 (R) provided additional predictive value for progression free survival (PFS) and time to first metastasis (TTM), but not for overall survival (OS) (all from start of trastuzumab containing treatment). The following cutoffs of Her-2/neu were identified: group A: 0–2.2 R (TTM: 49.8; OS: 6.7; PFS: 6.2); group B: 2.2- 6 R (TTM: 26.2; OS: 5.3; PFS: 9.3); group C: >6 CN (TTM: 20.1; OS: 3.9; PFS: 13.7) Kaplan-Maier analysis showed significant longer TTM for group A (p<0.01 vs. B/C), significant longer PFS for group C (p<0.01 vs. A/B). Significant differences in complete response (B/C: 16.9% vs C:44.4%), partial response (B/C: 20.2% vs. C: 33.3%) and progressive disease (B/C: 27% vs. 11.1%) were noted. No significant difference in overall survival between the groups was seen. Conclusions: ErbB/CEP17 R provides important prognostic information and, in metastatic patients, allows one to better predict response to trastuzumab-based treatment than the widely used binary classification of ErbB2 amplification that is based on a cut-off at a copy number of >2.2. No significant financial relationships to disclose.

Impacts of toxicity on patient treatment choices for metastatic breast cancer.

2012 ◽  
Vol 30 (34_suppl) ◽  
pp. 18-18 ◽  
Author(s):  
Carol B. White ◽  
Mary Lou Smith ◽  
Oyewale O. Abidoye ◽  
Deepa Lalla
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Online Survey ◽  
Metastatic Breast ◽  
Treatment Decisions ◽  
Subsequent Treatment ◽  
Patient Treatment ◽  
Treatment Choices ◽  
Almost All ◽  
The Impact

18 Background: Most patients with metastatic breast cancer (MBC) are treated with chemotherapy and/or targeted therapy with varying toxicity profiles. Experience with adverse events (AE) may vary and factor into subsequent treatment decisions. As newer agents and combinations become available, it becomes increasingly important to understand which AEs impact treatment decisions. Methods: The objective was to assess patient experience with AEs and preferences for future treatments. Following focus groups and pretests, an online survey was released by breast cancer organizations to recruit patients with MBC. The survey assessed the impact of experiences on future treatment choices and measured preferences via conjoint analysis (CA). Results: A total of 551 respondents completed the online survey. Among the AEs studied to assess their impact on either treatment stops or breaks, neutropenia topped the list, particularly for a required break. Fatigue, hand and foot syndrome, diarrhea, joint pain and peripheral neuropathy (PN) were high for chosen stops. Five AEs (fatigue, alopecia, diarrhea, PN, neutropenia) were studied extensively. Almost all respondents report experiencing fatigue, ~80% experienced alopecia, and ~66% each of the other 3 AEs. For each AE, the majority of respondents reported their prior experience would not impact a future decision involving the same AE; about 1/3 report they’d be more likely to take a treatment with the same AE; 8% to 18% would be less likely to take a treatment with the same AE. CA was also used to assess influence of the 5 AEs on future decisions. Within the tested ranges of likelihood, severity and duration, alopecia had the highest impact; PN, diarrhea, and neutropenia were in the middle; and fatigue was lowest. Further analysis is ongoing and final results will include differences in patient subgroups. Conclusions: This information informs priorities for development of new therapies allowing additional attention on AEs that matter most to patients. In addition, these results may generate discussion and consideration of patient preferences in conversations about care and treatment selection.

Measuring on-treatment genome-wide tumor copy number alterations in cell-free DNA (cfDNA) in plasma is highly prognostic in metastatic breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1097-1097
Author(s):  
Adriana Aguilar ◽  
Josiane Lafleur ◽  
Susie Brousse ◽  
Cristiano Ferrario ◽  
Graham McLennan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Copy Number ◽  
Tumor Response ◽  
Treatment Time ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Copy Number Alterations ◽  
Genome Wide ◽  
Metastatic Setting

1097 Background: The clinical management of metastatic breast cancer depends on the measurement of tumor response to successive drugs by serial imaging and changes in blood tumor markers, which remain the standard of care despite poor sensitivity and specificity. Highly sensitive and specific cfDNA secreted from the tumor can detect the changes in tumor-specific aberrations that have been shown to be associated with patient response in the metastatic setting. However, most approaches require prior sequencing of the tumor to target specific known mutations. Methods: Using low coverage genomic sequencing, a genomic instability number (GIN) was measured in cfDNA based on the detection of genome-wide tumor-specific DNA copy number alterations for 27 patients with metastatic breast cancer. The GIN value and its variation from baseline before treatment, as well as within 10 days and 3 weeks after start of therapy were compared with tumor response, progression free survival (PFS) and overall survival (OS) of the patients. Patients were followed for a median of 22 months and we used a previously published GIN threshold at 170 for high vs low GIN values. Sequencing was performed blinded to the clinical results. Results: Baseline GIN values were not associated with tumor response at 3or 6 months, but showed a trend towards lower OS with higher GIN (p = 0.12). GIN values fell by an average of 28% in responders (stable disease or response) and 23% in those with progression (p = 0.85), but remained lower at 3 weeks only in the responders. High GIN values within 10 days and 3 weeks were associated with markedly worse OS (p = 0.014 and p = 0.009 respectively) and those at 3 weeks with worse PFS (p = 0.017). Hence the median survival of patients with high GIN at 10 days or 3 weeks was 12 months vs not reached for those with low GIN. The percentage drop of GIN at 10 days but not at 3 weeks was significantly associated with PFS (p = 0.016). Conclusions: These results demonstrate that GIN values of cfDNA measured at early on-treatment time points can predict PFS and OS with a high degree of accuracy. These findings deserve further study in a larger cohort but hold the promise of early prediction of clinical outcomes in a tumor-independent genome-wide approach.

Serial circulating tumor DNA samples from patients with metastatic breast cancer and BRCA1/2 mutations.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1025-1025
Author(s):  
Katharine Collier ◽  
David Tallman ◽  
Zachary Weber ◽  
Marcy Haynam ◽  
Elizabeth J. Adams ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Clonal Evolution ◽  
Metastatic Breast ◽  
Circulating Tumor Dna ◽  
Plasma Samples ◽  
Significant Difference ◽  
Platinum Chemotherapy ◽  
Tumor Dna ◽  
Over Time

1025 Background: Analysis of circulating tumor DNA (ctDNA) over time allows non-invasive evaluation of tumor genomic evolution. We characterize changes in tumor fraction (TFx), somatic copy number alterations (SCNAs), and somatic mutations (muts) over time in patients (pts) with BRCA1/2 muts and metastatic breast cancer (mBC) who received a PARP inhibitor (PARPi) or platinum chemotherapy. Specifically, we seek to identify the frequency of BRCA1/2 reversion muts. Methods: Pts with mBC and germline or somatic BRCA1/2 muts were identified on a banking protocol of prospectively-collected serial samples of blood and plasma. Control pts without a BRCA1/2 mut were matched 2:1 by age and hormone receptor (HR) status. Ultra-low-pass whole genome sequencing (ULPWGS) with 0.1x depth was performed on all plasma samples (n = 103) and the ichorCNA algorithm was used to determine TFx and SCNAs. Targeted panel sequencing (TPS) of 402 cancer-related genes was performed at 10,000x depth on plasma samples, and one blood sample per pt. The panel includes BRCA1/2 and 38 other DNA damage repair (DDR) genes. Somatic muts were identified by joint calling with Mutect2 across plasma timepoints with paired pt normal blood. Germline variant calling from TPS on blood with HaplotypeCaller was used to confirm germline muts in BRCA1/2.Results: We identified 10 pts with mBC with a germline (n = 7) or somatic (n = 3) BRCA1 (n = 2) or BRCA2 (n = 8) mut and banked blood and plasma samples at 3-9 timepoints at a median of 8 weeks apart (range 1-43). The control cohort of 20 pts with mBC and wildtype BRCA1/2 was well matched by age and HR status. All pts with BRCA1/2 muts received a PARPi and/or platinum chemotherapy at some point during sample collection. Half of control pts received platinum chemotherapy. Germline BRCA1/2 muts were confirmed in all 7 pts with known germline muts. Among the BRCA1/2 mut cohort, median TFx was 0.04 (range 0-0.57) with 20% of samples having TFx > 0.10. A median of 1.5 (range 0-39) somatic muts per pt were found in DDR genes. Four pts (40%) had secondary non-reversion muts in BRCA1/2. A reversion mut of a germline BRCA2 mut, restoring the open reading frame of BRCA2, was discovered at the last timepoint from 1 pt while receiving carboplatin. A germline BRCA1/2 reversion mut in this cohort occurred in 2.3% of samples, 14.3% of pts. There was no significant difference in the percent of genome with a SCNA between the first and last time point, nor before and after PARPi/platinum. The somatic mut landscape and clonal evolution of TPS using PyClone will be presented. Conclusions: Evaluation of serial ctDNA samples for TFx, SCNAs, and somatic muts from banked plasma and blood from pts with mBC is feasible. The frequency of reversion muts in BRCA1/2 was low, suggesting that either their incidence is low or ctDNA TPS is not sensitive enough to detect them. Secondary non-reversion muts in BRCA1/2 and other somatic DDR muts were more common. SCNAs were stable over time.

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