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  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P3-09-09-P3-09-09
    Abstract: 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 over time in patients (pts) with and without BRCA1/2 mutations 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 mutations. Methods: Pts with mBC and germline or somatic BRCA1/2 mutations were identified on a banking protocol of prospectively-collected serial samples of blood and plasma. Control pts without a BRCA1/2 mutation 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 mutations 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 mutations 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) mutation and banked blood and plasma samples at 2-9 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 mutations received a PARPi and/or platinum chemotherapy at some point during sample collection. Half of control pts received platinum chemotherapy. Germline BRCA1/2 mutations were confirmed in all 7 pts with known germline mutations. Somatic BRCA2 mutations were confirmed in ctDNA in 2 of 3 patients. Among all samples, median TFx was 0.05 (range 0-0.80) with 35% of samples having TFx & gt;0.10. There was no significant difference in TFx by age, receptor status, or active treatment with a PARPi or platinum. There was no significant change in the percent of genome with a SCNA over time. A reversion mutation of a germline BRCA2 mutation, restoring the open reading frame of BRCA2, was discovered at the last timepoint from 1 pt while receiving carboplatin. She had radiographic progression 4 weeks later. A germline BRCA1/2 reversion mutation in this cohort occurred in 2.3% of samples, 14.3% of pts. The somatic mutation landscape and clonal evolution of TPS using PyClone will be presented. Clonal evolution can show emerging and responding clusters of variants. For pts with available tissue specimens, somatic variants in ctDNA will be compared to somatic mutations detected in tissue with TPS. Conclusions: Evaluation of serial ctDNA samples for TFx, SCNAs, and somatic mutations from banked plasma and blood from pts with mBC is feasible. SCNAs were stable over time. The frequency of reversion mutations in BRCA1/2 was low, suggesting that either their incidence is low or ctDNA TPS is not sensitive enough to detect them. Citation Format: Katharine A Collier, David Tallman, Zachary T. Weber, Marcy Haynam, Elizabeth J. Adams, Janet Jenison, Sarah Asad, Maryam Lustberg, Mathew Cherian, Bhuvaneswari Ramaswamy, Sagar Sardesai, Nicole Williams, Robert Wesolowski, Jeffrey Vandeusen, Margaret E. Gatti-Mays, Ashley Pariser, Amir Mortazavi, Daniel G. Stover. Serial circulating tumor DNA from patients with metastatic breast cancer with and without BRCA1/2 mutations [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-09.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 2
    In: BMC Cancer, Springer Science and Business Media LLC, Vol. 20, No. 1 ( 2020-12)
    Abstract: To assess metastatic breast cancer (MBC) patient psychological factors, perceptions, and comprehension of tumor genomic testing. Methods In a prospective, single institution, single-arm trial, patients with MBC underwent next-generation sequencing at study entry with sequencing results released at progression. Patients who completed surveys before undergoing sequencing were included in the present secondary analysis ( n  = 58). We administered four validated psychosocial measures: Center for Epidemiologic Studies Depression Scale, Beck Anxiety Inventory, Trust in Physician Scale, and Communication and Attitudinal Self-Efficacy scale for Cancer. Genetic comprehension was assessed using 7-question objective and 6-question subjective measures. Longitudinal data were assessed ( n  = 40) using paired Wilcoxon signed rank and McNemar’s test of agreement. Results There were no significant differences between the beginning and end of study in depression, anxiety, physician trust, or self-efficacy (median time on study: 7.6 months). Depression and anxiety were positively associated with each other and both negatively associated with self-efficacy. Self-efficacy decreased from pre- to post-genomic testing ( p  = 0.05). Objective genetics comprehension did not significantly change from pre- to post-genomic testing, but patients expressed increased confidence in their ability to teach others about genetics ( p  = 0.04). Objective comprehension was significantly lower in non-white patients ( p  = 0.02) and patients with lower income ( p  = 0.04). Conclusions This is the only study, to our knowledge, to longitudinally evaluate multiple psychological metrics in MBC as patients undergo tumor genomic testing. Overall, psychological dimensions remained stable over the duration of tumor genomic testing. Among patients with MBC, depression and anxiety metrics were negatively correlated with patient self-efficacy. Patients undergoing somatic genomic testing had limited genomic knowledge, which varied by demographic groups and may warrant additional educational intervention. Clinical trial information NCT01987726 , registered November 13, 2013.
    Type of Medium: Online Resource
    ISSN: 1471-2407
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
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  • 3
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 3 ( 2019-12), p. 1-11
    Abstract: To evaluate the impact of targeted DNA sequencing on selection of cancer therapy for patients with metastatic breast cancer (MBC). PATIENTS AND METHODS In this prospective, single-center, single-arm trial, patients with MBC were enrolled within 10 weeks of starting a new therapy. At enrollment, tumor samples underwent next-generation sequencing for any of 315 cancer-related genes to high depth ( 〉 500×) using FoundationOne CDx. Sequencing results were released to providers at the time of disease progression, and physician treatment recommendations were assessed via questionnaire. We evaluated three prespecified questions to assess patients’ perceptions of genomic testing. RESULTS In all, 100 patients underwent genomic testing, with a median of five mutations (range, 0 to 13 mutations) detected per patient. Genomic testing revealed one or more potential therapies in 98% of patients (98 of 100), and 60% of patients (60 of 100) had one or more recommended treatments with level I/II evidence for actionability. Among the 94 genomic text reports that were released, there was physician questionnaire data for 87 patients (response rate, 92.6%) and 31.0% of patients (27 of 87) had treatment change recommended by their physician. Of these, 37.0% (10 of 27) received the treatment supported by genomic testing. We did not detect a statistically significant difference in time-to-treatment failure (log-rank P = .87) or overall survival ( P = .71) among patients who had treatment change supported by genomic testing versus those who had no treatment change. For patients who completed surveys before and after genomic testing, there was a significant decrease in confidence of treatment success, specifically among patients who did not have treatment change supported by genomic testing (McNemar’s test of agreement P = .001). CONCLUSION In this prospective study, genomic profiling of tumors in patients with MBC frequently identified potential treatments and resulted in treatment change in a minority of patients. Patients whose therapy was not changed on the basis of genomic testing seemed to have a decrease in confidence of treatment success.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P5-10-03-P5-10-03
    Abstract: Background: Little is known regarding the effect of somatic tumor genomic testing on patient perceptions and psychological well-being. We previously demonstrated that patient perceptions of care can be negatively affected if their next cancer treatment is not supported by the genomic test. To further understand this, we investigated psychological effects of genomic testing, as well as sociodemographic and genomic comprehension factors that may attenuate these effects. Methods: In a prospective, single institution, single-arm trial, patients with metastatic breast cancer underwent next-generation sequencing (NGS) using Foundation Medicine at study entry, with sequencing results released to providers at time of next disease progression. We evaluated patient survey data before and after NGS, including questions about psychosocial characteristics, genetic comprehension, and perceived risks and expectations of the genomic testing. We evaluated psychosocial characteristics using 4 validated psychology measures: the Center for Epidemiologic Studies Depression Scale (CES-D), the Beck Anxiety Inventory (BAI), the Trust in Physician Scale (TPS), and the Communication and Attitudinal Self-Efficacy scale for Cancer (CASE-cancer). CASE-cancer measures self-efficacy, how confident patients are in their ability to navigate their cancer care. Genetic comprehension was assessed with a 7-question objective measure and a 6-question subjective measure. No formal genetic education was provided, but the informed consent process included an introduction to NGS. We included exploratory questions on perceived risks and expectations of NGS. Results: Among the 58 patients who completed the pre-NGS survey, we found high rates of depression (38%) and anxiety (47%) using validated metrics. Depression and anxiety were positively correlated (Pearson’s r=0.61; p & lt;0.0001) but both were negatively correlated with self-efficacy (Pearson’s r=-0.43 and -0.42 for depression and anxiety, respectively; p=0.001 for both). Baseline genetic knowledge was significantly lower for non-white and lower income status patients (p=0.04 and 0.001, respectively). Genetic knowledge was not associated with any of the 4 validated psychological measures. The validated psychological measures were not associated with demographic characteristics, treatment decisions, or number of treatment options offered by the NGS test. The average time between pre-test and post-test surveys was 7.6 months. Additionally, the validated psychology measures did not significantly change from pre- to post-study (n=40 patients). However, there was a strong trend of self-efficacy decreasing from pre- to post-NGS testing (p=0.05). Subjectively, patients gained confidence in their ability to teach others about genetics from the start (33% “confident”) to the end of study (46%). Yet, objective comprehension of genetics remained modest throughout the study, with an average score of 72% in both the pre- and post-NGS surveys. The exploratory patient perception questions revealed that 33% of patients felt learning their cancer had a high chance of progressing would be too much to cope with emotionally. Conclusions: This is the first study, to our knowledge, to longitudinally evaluate multiple validated psychological metrics in MBC. NGS did not have a significant effect on depression, anxiety, or trust, but there was a trend towards decreased self-efficacy. This may be influenced by the already high rates of depression, anxiety, and trust in this population. In this study, patient genetic knowledge was limited and associated with race and income. These findings raise important questions about how to support MBC patient emotional well-being and how to improve comprehension of somatic genomic testing in future studies. Citation Format: Elizabeth J Adams, Sarah Asad, Mahmoud Abdel-Rasoul, Raquel E Reinbolt, Robert Wesolowski, Kaitlyn Tolliver, Susan Gillespie, Katherine A Collier, Anne Noonan, Sargar Sardesai, Jeffrey VanDeusen, Nicole Williams, Charles L Shapiro, Erin R Macre, Bhuvaneswari Ramaswamy, Clara N Lee, Maryam B Lustberg, Daniel G Stover. Perceptions of somatic genomic testing in patients with metastatic breast cancer: Psychosocial factors, emotional well-being, and genetic comprehension [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-10-03.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. PD9-11-PD9-11
    Abstract: Purpose: Immune infiltration is associated with better treatment response and outcomes in breast cancer, yet data regarding the role of modifiable patient factors in immune infiltration are limited. Patients and Methods: This population-based, prospective observational study evaluated 882 Nurses’ Health Study (NHS) and NHSII participants diagnosed with invasive breast cancer with detailed exposure and gene expression data. Of these, 262 women (training cohort) had breast tumor immunohistochemistry (IHC) for four canonical immune cell markers: CD8, CD4, CD20, CD163. In this training cohort, 105 published immune cell-specific gene expression signatures were calculated, then lasso regression was used to derive four immune cell-specific scores based on association with IHC. In the remaining 620 patient testing cohort, we evaluated association of each immune-cell specific score as outcomes, with body mass index (BMI) change since age 18, physical activity, and the empirical dietary inflammatory pattern (EDIP) score as predictors, using multivariable-adjusted linear regression. Results: Among women with paired expression/IHC data from breast tumor tissue, we identified robust correlation between novel immune cell-specific expression scores and IHC (Spearman’s rho range 0.42-0.54; all p & lt;0.001). BMI change since age 18 was positively associated with CD4+ (β=0.16; SE=0.06; p=0.009), and CD163+ scores (β=0.14; SE=0.07; p=0.04) in multivariable analyses. Neither physical activity nor EDIP were significantly associated with any immune cell-specific expression score in multivariable analyses. Conclusions: BMI change since age 18 was positively associated with novel CD4+ and CD163+ cell scores in breast cancer, supporting further study of the effect of modifiable factors like weight gain on the immune microenvironment. Citation Format: Daniel G. Stover, Adrienne Damicis, Yujing J. Heng, Katharine A. Collier, Elizabeth J. Adams, Kevin H. Kensler, Gabrielle M. Baker, Robert Wesolowski, Sagar Sardesai, Margaret Gatti-Mays, Bhuvaneswari Ramaswamy, A. Heather Eliassen, Susan E. Hankinson, Fred K. Tabung, Rulla M. Tamimi, Sarah Asad. Association of body mass index and inflammatory dietary pattern with breast cancer pathologic and genomic immunophenotype in the nurses’ health study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD9-11.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 6
    In: BMC Cancer, Springer Science and Business Media LLC, Vol. 21, No. 1 ( 2021-12)
    Abstract: Triple-negative breast cancer (TNBC) is a heterogeneous disease and we have previously shown that rapid relapse of TNBC is associated with distinct sociodemographic features. We hypothesized that rapid versus late relapse in TNBC is also defined by distinct clinical and genomic features of primary tumors. Methods Using three publicly-available datasets, we identified 453 patients diagnosed with primary TNBC with adequate follow-up to be characterized as ‘rapid relapse’ (rrTNBC; distant relapse or death ≤2 years of diagnosis), ‘late relapse’ (lrTNBC; 〉  2 years) or ‘no relapse’ (nrTNBC: 〉  5 years no relapse/death). We explored basic clinical and primary tumor multi-omic data, including whole transcriptome ( n  = 453), and whole genome copy number and mutation data for 171 cancer-related genes ( n  = 317). Association of rapid relapse with clinical and genomic features were assessed using Pearson chi-squared tests, t-tests, ANOVA, and Fisher exact tests. We evaluated logistic regression models of clinical features with subtype versus two models that integrated significant genomic features. Results Relative to nrTNBC, both rrTNBC and lrTNBC had significantly lower immune signatures and immune signatures were highly correlated to anti-tumor CD8 T-cell, M1 macrophage, and gamma-delta T-cell CIBERSORT inferred immune subsets. Intriguingly, lrTNBCs were enriched for luminal signatures. There was no difference in tumor mutation burden or percent genome altered across groups. Logistic regression mModels that incorporate genomic features significantly outperformed standard clinical/subtype models in training ( n  = 63 patients), testing ( n  = 63) and independent validation ( n  = 34) cohorts, although performance of all models were overall modest. Conclusions We identify clinical and genomic features associated with rapid relapse TNBC for further study of this aggressive TNBC subset.
    Type of Medium: Online Resource
    ISSN: 1471-2407
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2041352-X
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 1025-1025
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 8
    In: Breast Cancer Research, Springer Science and Business Media LLC, Vol. 24, No. 1 ( 2022-11-14)
    Abstract: Breast tumor immune infiltration is clearly associated with improved treatment response and outcomes in breast cancer. However, modifiable patient factors associated with breast cancer immune infiltrates are poorly understood. The Nurses’ Health Study (NHS) offers a unique cohort to study immune gene expression in tumor and adjacent normal breast tissue, immune cell-specific immunohistochemistry (IHC), and patient exposures. We evaluated the association of body mass index (BMI) change since age 18, physical activity, and the empirical dietary inflammatory pattern (EDIP) score, all implicated in systemic inflammation, with immune cell-specific expression scores. Methods This population-based, prospective observational study evaluated 882 NHS and NHSII participants diagnosed with invasive breast cancer with detailed exposure and gene expression data. Of these, 262 women (training cohort) had breast tumor IHC for four classic immune cell markers (CD8, CD4, CD20, and CD163). Four immune cell-specific scores were derived via lasso regression using 105 published immune expression signatures’ association with IHC. In the remaining 620 patient evaluation cohort, we evaluated association of each immune cell-specific score as outcomes, with BMI change since age 18, physical activity, and EDIP score as predictors, using multivariable-adjusted linear regression. Results Among women with paired expression/IHC data from breast tumor tissue, we identified robust correlation between novel immune cell-specific expression scores and IHC. BMI change since age 18 was positively associated with CD4+ ( β  = 0.16; p  = 0.009), and CD163 novel immune scores ( β  = 0.14; p  = 0.04) in multivariable analyses. In other words, for each 10 unit (kg/m 2 ) increase in BMI, the percentage of cells positive for CD4 and CD163 increased 1.6% and 1.4%, respectively. Neither physical activity nor EDIP was significantly associated with any immune cell-specific expression score in multivariable analyses. Conclusions BMI change since age 18 was positively associated with novel CD4+ and CD163+ cell scores in breast cancer, supporting further study of the effect of modifiable factors like weight gain on the immune microenvironment.
    Type of Medium: Online Resource
    ISSN: 1465-542X
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2041618-0
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