Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial

Publication Date:
2018-12-04
Publisher:
The American Association for Cancer Research (AACR)
Print ISSN:
1078-0432
Electronic ISSN:
1557-3265
Topics:
Medicine
Published by:
http://www.aacr.org/
_version_ 1839208240313794560
autor Paoletti, C., Schiavon, G., Dolce, E. M., Darga, E. P., Carr, T. H., Geradts, J., Hoch, M., Klinowska, T., Lindemann, J., Marshall, G., Morgan, S., Patel, P., Rowlands, V., Sathiyayogan, N., Aung, K., Hamilton, E., Patel, M., Armstrong, A., Jhaveri, K., Im, S.-A., Iqbal, N., Butt, F., Dive, C., Harrington, E. A., Barrett, J. C., Baird, R., Hayes, D. F.
beschreibung Purpose: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)–positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene ( ESR1 LBD m ). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. Experimental Design: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common ESR1 LBD m by droplet digital PCR (BioRad). Results: Before starting AZD9496, 11 of 43 (25%) patients had ≥5 CTC/7.5 mL whole blood (WB), none of whom underwent reduction to 〈5 CTC/7.5 mL WB on C1D15. Five of 11 patients had baseline CTC-ER + , two of whom had CTC-ER + reduction. CTC-Ki67 status did not change appreciably. Patients with ≥5 CTC/7.5 mL WB before treatment had worse progression-free survival (PFS) than patients with 〈5 CTC ( P = 0.0003). Fourteen of 45 (31%) patients had ESR1 LBD m + ctDNA at baseline, five of whom had ≥2 unique mutations. Baseline ESR1 LBD m status was not prognostic. Patients with persistently elevated CTC and/or ESR1 LBD m + ctDNA at C1D15 had worse PFS than patients who did not ( P = 0.0007). Conclusions: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER + and ESR1 LBD m + ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker.
citation_standardnr 6363934
datenlieferant ipn_articles
feed_id 9363
feed_publisher The American Association for Cancer Research (AACR)
feed_publisher_url http://www.aacr.org/
insertion_date 2018-12-04
journaleissn 1557-3265
journalissn 1078-0432
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Association for Cancer Research (AACR)
quelle Clinical Cancer Research
relation http://clincancerres.aacrjournals.org/cgi/content/short/24/23/5860?rss=1
search_space articles
shingle_author_1 Paoletti, C., Schiavon, G., Dolce, E. M., Darga, E. P., Carr, T. H., Geradts, J., Hoch, M., Klinowska, T., Lindemann, J., Marshall, G., Morgan, S., Patel, P., Rowlands, V., Sathiyayogan, N., Aung, K., Hamilton, E., Patel, M., Armstrong, A., Jhaveri, K., Im, S.-A., Iqbal, N., Butt, F., Dive, C., Harrington, E. A., Barrett, J. C., Baird, R., Hayes, D. F.
shingle_author_2 Paoletti, C., Schiavon, G., Dolce, E. M., Darga, E. P., Carr, T. H., Geradts, J., Hoch, M., Klinowska, T., Lindemann, J., Marshall, G., Morgan, S., Patel, P., Rowlands, V., Sathiyayogan, N., Aung, K., Hamilton, E., Patel, M., Armstrong, A., Jhaveri, K., Im, S.-A., Iqbal, N., Butt, F., Dive, C., Harrington, E. A., Barrett, J. C., Baird, R., Hayes, D. F.
shingle_author_3 Paoletti, C., Schiavon, G., Dolce, E. M., Darga, E. P., Carr, T. H., Geradts, J., Hoch, M., Klinowska, T., Lindemann, J., Marshall, G., Morgan, S., Patel, P., Rowlands, V., Sathiyayogan, N., Aung, K., Hamilton, E., Patel, M., Armstrong, A., Jhaveri, K., Im, S.-A., Iqbal, N., Butt, F., Dive, C., Harrington, E. A., Barrett, J. C., Baird, R., Hayes, D. F.
shingle_author_4 Paoletti, C., Schiavon, G., Dolce, E. M., Darga, E. P., Carr, T. H., Geradts, J., Hoch, M., Klinowska, T., Lindemann, J., Marshall, G., Morgan, S., Patel, P., Rowlands, V., Sathiyayogan, N., Aung, K., Hamilton, E., Patel, M., Armstrong, A., Jhaveri, K., Im, S.-A., Iqbal, N., Butt, F., Dive, C., Harrington, E. A., Barrett, J. C., Baird, R., Hayes, D. F.
shingle_catch_all_1 Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial
Purpose: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)–positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene ( ESR1 LBD m ). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. Experimental Design: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common ESR1 LBD m by droplet digital PCR (BioRad). Results: Before starting AZD9496, 11 of 43 (25%) patients had ≥5 CTC/7.5 mL whole blood (WB), none of whom underwent reduction to <5 CTC/7.5 mL WB on C1D15. Five of 11 patients had baseline CTC-ER + , two of whom had CTC-ER + reduction. CTC-Ki67 status did not change appreciably. Patients with ≥5 CTC/7.5 mL WB before treatment had worse progression-free survival (PFS) than patients with <5 CTC ( P = 0.0003). Fourteen of 45 (31%) patients had ESR1 LBD m + ctDNA at baseline, five of whom had ≥2 unique mutations. Baseline ESR1 LBD m status was not prognostic. Patients with persistently elevated CTC and/or ESR1 LBD m + ctDNA at C1D15 had worse PFS than patients who did not ( P = 0.0007). Conclusions: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER + and ESR1 LBD m + ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker.
Paoletti, C., Schiavon, G., Dolce, E. M., Darga, E. P., Carr, T. H., Geradts, J., Hoch, M., Klinowska, T., Lindemann, J., Marshall, G., Morgan, S., Patel, P., Rowlands, V., Sathiyayogan, N., Aung, K., Hamilton, E., Patel, M., Armstrong, A., Jhaveri, K., Im, S.-A., Iqbal, N., Butt, F., Dive, C., Harrington, E. A., Barrett, J. C., Baird, R., Hayes, D. F.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_2 Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial
Purpose: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)–positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene ( ESR1 LBD m ). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. Experimental Design: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common ESR1 LBD m by droplet digital PCR (BioRad). Results: Before starting AZD9496, 11 of 43 (25%) patients had ≥5 CTC/7.5 mL whole blood (WB), none of whom underwent reduction to <5 CTC/7.5 mL WB on C1D15. Five of 11 patients had baseline CTC-ER + , two of whom had CTC-ER + reduction. CTC-Ki67 status did not change appreciably. Patients with ≥5 CTC/7.5 mL WB before treatment had worse progression-free survival (PFS) than patients with <5 CTC ( P = 0.0003). Fourteen of 45 (31%) patients had ESR1 LBD m + ctDNA at baseline, five of whom had ≥2 unique mutations. Baseline ESR1 LBD m status was not prognostic. Patients with persistently elevated CTC and/or ESR1 LBD m + ctDNA at C1D15 had worse PFS than patients who did not ( P = 0.0007). Conclusions: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER + and ESR1 LBD m + ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker.
Paoletti, C., Schiavon, G., Dolce, E. M., Darga, E. P., Carr, T. H., Geradts, J., Hoch, M., Klinowska, T., Lindemann, J., Marshall, G., Morgan, S., Patel, P., Rowlands, V., Sathiyayogan, N., Aung, K., Hamilton, E., Patel, M., Armstrong, A., Jhaveri, K., Im, S.-A., Iqbal, N., Butt, F., Dive, C., Harrington, E. A., Barrett, J. C., Baird, R., Hayes, D. F.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_3 Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial
Purpose: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)–positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene ( ESR1 LBD m ). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. Experimental Design: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common ESR1 LBD m by droplet digital PCR (BioRad). Results: Before starting AZD9496, 11 of 43 (25%) patients had ≥5 CTC/7.5 mL whole blood (WB), none of whom underwent reduction to <5 CTC/7.5 mL WB on C1D15. Five of 11 patients had baseline CTC-ER + , two of whom had CTC-ER + reduction. CTC-Ki67 status did not change appreciably. Patients with ≥5 CTC/7.5 mL WB before treatment had worse progression-free survival (PFS) than patients with <5 CTC ( P = 0.0003). Fourteen of 45 (31%) patients had ESR1 LBD m + ctDNA at baseline, five of whom had ≥2 unique mutations. Baseline ESR1 LBD m status was not prognostic. Patients with persistently elevated CTC and/or ESR1 LBD m + ctDNA at C1D15 had worse PFS than patients who did not ( P = 0.0007). Conclusions: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER + and ESR1 LBD m + ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker.
Paoletti, C., Schiavon, G., Dolce, E. M., Darga, E. P., Carr, T. H., Geradts, J., Hoch, M., Klinowska, T., Lindemann, J., Marshall, G., Morgan, S., Patel, P., Rowlands, V., Sathiyayogan, N., Aung, K., Hamilton, E., Patel, M., Armstrong, A., Jhaveri, K., Im, S.-A., Iqbal, N., Butt, F., Dive, C., Harrington, E. A., Barrett, J. C., Baird, R., Hayes, D. F.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_4 Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial
Purpose: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)–positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene ( ESR1 LBD m ). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. Experimental Design: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common ESR1 LBD m by droplet digital PCR (BioRad). Results: Before starting AZD9496, 11 of 43 (25%) patients had ≥5 CTC/7.5 mL whole blood (WB), none of whom underwent reduction to <5 CTC/7.5 mL WB on C1D15. Five of 11 patients had baseline CTC-ER + , two of whom had CTC-ER + reduction. CTC-Ki67 status did not change appreciably. Patients with ≥5 CTC/7.5 mL WB before treatment had worse progression-free survival (PFS) than patients with <5 CTC ( P = 0.0003). Fourteen of 45 (31%) patients had ESR1 LBD m + ctDNA at baseline, five of whom had ≥2 unique mutations. Baseline ESR1 LBD m status was not prognostic. Patients with persistently elevated CTC and/or ESR1 LBD m + ctDNA at C1D15 had worse PFS than patients who did not ( P = 0.0007). Conclusions: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER + and ESR1 LBD m + ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker.
Paoletti, C., Schiavon, G., Dolce, E. M., Darga, E. P., Carr, T. H., Geradts, J., Hoch, M., Klinowska, T., Lindemann, J., Marshall, G., Morgan, S., Patel, P., Rowlands, V., Sathiyayogan, N., Aung, K., Hamilton, E., Patel, M., Armstrong, A., Jhaveri, K., Im, S.-A., Iqbal, N., Butt, F., Dive, C., Harrington, E. A., Barrett, J. C., Baird, R., Hayes, D. F.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_title_1 Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial
shingle_title_2 Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial
shingle_title_3 Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial
shingle_title_4 Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial
timestamp 2025-07-31T23:47:40.782Z
titel Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial
titel_suche Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial
topic WW-YZ
uid ipn_articles_6363934