Sensitive detection of mono- and polyclonal ESR1 mutations in primary tumors, metastatic lesions, and cell-free DNA of breast cancer patients

Peilu Wang, Amir Bahreini, Rekha Gyanchandani, Peter C. Lucas, Ryan J. Hartmaier, Rebecca J. Watters, Amruth R. Jonnalagadda, Humberto E. Trejo Bittar, Aaron Berg, Ronald L. Hamilton, Brenda F. Kurland, Kurt R. Weiss, Aju Mathew, Jose Pablo Leone, Nancy E. Davidson, Marina N. Nikiforova, Adam M. Brufsky, Tadeu F. Ambros, Andrew M. Stern, Shannon L. Puhalla & 2 others Adrian V. Lee, Steffi Oesterreich

Research output: Contribution to journalArticle

Abstract

Purpose: Given the clinical relevance of ESR1 mutations as potential drivers of resistance to endocrine therapy, this study used sensitive detection methods to determine the frequency of ESR1 mutations in primary and metastatic breast cancer, and in cell-free DNA (cfDNA). Experimental Design: Six ESR1 mutations (K303R, S463P, Y537C, Y537N, Y537S, D538G) were assessed by digital droplet PCR (ddPCR), with lower limits of detection of 0.05% to 0.16%, in primary tumors (n = 43), bone (n = 12) and brain metastases (n = 38), and cfDNA (n = 29). Correlations between ESR1 mutations in metastatic lesions and single (1 patient) or serial blood draws (4 patients) were assessed. Results: ESR1 mutations were detected for D538G (n = 13), Y537S (n = 3), and Y537C (n = 1), and not for K303R, S463P, or Y537N. Mutation rates were 7.0% (3/43 primary tumors), 9.1% (1/11 bone metastases), 12.5% (3/24 brain metastases), and 24.1% (7/29 cfDNA). Two patients showed polyclonal disease with more than one ESR1 mutation. Mutation allele frequencies were 0.07% to 0.2% in primary tumors, 1.4% in bone metastases, 34.3% to 44.9% in brain metastases, and 0.2% to 13.7% in cfDNA. In cases with both cfDNA and metastatic samples (n = 5), mutations were detected in both (n = 3) or in cfDNA only (n = 2). Treatment was associated with changes in ESR1 mutation detection and allele frequency. Conclusions: ESR1 mutations were detected at very low allele frequencies in some primary breast cancers, and at high allele frequency in metastases, suggesting that in some tumors rare ESR1-mutant clones are enriched by endocrine therapy. Further studies should address whether sensitive detection of ESR1 mutations in primary breast cancer and in serial blood draws may be predictive for development of resistant disease.

Original languageEnglish (US)
Pages (from-to)1130-1137
Number of pages8
JournalClinical Cancer Research
Volume22
Issue number5
DOIs
StatePublished - Mar 1 2016
Externally publishedYes

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Breast Neoplasms
Mutation
DNA
Mutation Rate
Neoplasm Metastasis
Gene Frequency
Neoplasms
Bone and Bones
Brain
Limit of Detection
Research Design
Therapeutics
Clone Cells
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Wang, P., Bahreini, A., Gyanchandani, R., Lucas, P. C., Hartmaier, R. J., Watters, R. J., ... Oesterreich, S. (2016). Sensitive detection of mono- and polyclonal ESR1 mutations in primary tumors, metastatic lesions, and cell-free DNA of breast cancer patients. Clinical Cancer Research, 22(5), 1130-1137. https://doi.org/10.1158/1078-0432.CCR-15-1534

Sensitive detection of mono- and polyclonal ESR1 mutations in primary tumors, metastatic lesions, and cell-free DNA of breast cancer patients. / Wang, Peilu; Bahreini, Amir; Gyanchandani, Rekha; Lucas, Peter C.; Hartmaier, Ryan J.; Watters, Rebecca J.; Jonnalagadda, Amruth R.; Trejo Bittar, Humberto E.; Berg, Aaron; Hamilton, Ronald L.; Kurland, Brenda F.; Weiss, Kurt R.; Mathew, Aju; Leone, Jose Pablo; Davidson, Nancy E.; Nikiforova, Marina N.; Brufsky, Adam M.; Ambros, Tadeu F.; Stern, Andrew M.; Puhalla, Shannon L.; Lee, Adrian V.; Oesterreich, Steffi.

In: Clinical Cancer Research, Vol. 22, No. 5, 01.03.2016, p. 1130-1137.

Research output: Contribution to journalArticle

Wang, P, Bahreini, A, Gyanchandani, R, Lucas, PC, Hartmaier, RJ, Watters, RJ, Jonnalagadda, AR, Trejo Bittar, HE, Berg, A, Hamilton, RL, Kurland, BF, Weiss, KR, Mathew, A, Leone, JP, Davidson, NE, Nikiforova, MN, Brufsky, AM, Ambros, TF, Stern, AM, Puhalla, SL, Lee, AV & Oesterreich, S 2016, 'Sensitive detection of mono- and polyclonal ESR1 mutations in primary tumors, metastatic lesions, and cell-free DNA of breast cancer patients', Clinical Cancer Research, vol. 22, no. 5, pp. 1130-1137. https://doi.org/10.1158/1078-0432.CCR-15-1534
Wang, Peilu ; Bahreini, Amir ; Gyanchandani, Rekha ; Lucas, Peter C. ; Hartmaier, Ryan J. ; Watters, Rebecca J. ; Jonnalagadda, Amruth R. ; Trejo Bittar, Humberto E. ; Berg, Aaron ; Hamilton, Ronald L. ; Kurland, Brenda F. ; Weiss, Kurt R. ; Mathew, Aju ; Leone, Jose Pablo ; Davidson, Nancy E. ; Nikiforova, Marina N. ; Brufsky, Adam M. ; Ambros, Tadeu F. ; Stern, Andrew M. ; Puhalla, Shannon L. ; Lee, Adrian V. ; Oesterreich, Steffi. / Sensitive detection of mono- and polyclonal ESR1 mutations in primary tumors, metastatic lesions, and cell-free DNA of breast cancer patients. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 5. pp. 1130-1137.
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abstract = "Purpose: Given the clinical relevance of ESR1 mutations as potential drivers of resistance to endocrine therapy, this study used sensitive detection methods to determine the frequency of ESR1 mutations in primary and metastatic breast cancer, and in cell-free DNA (cfDNA). Experimental Design: Six ESR1 mutations (K303R, S463P, Y537C, Y537N, Y537S, D538G) were assessed by digital droplet PCR (ddPCR), with lower limits of detection of 0.05{\%} to 0.16{\%}, in primary tumors (n = 43), bone (n = 12) and brain metastases (n = 38), and cfDNA (n = 29). Correlations between ESR1 mutations in metastatic lesions and single (1 patient) or serial blood draws (4 patients) were assessed. Results: ESR1 mutations were detected for D538G (n = 13), Y537S (n = 3), and Y537C (n = 1), and not for K303R, S463P, or Y537N. Mutation rates were 7.0{\%} (3/43 primary tumors), 9.1{\%} (1/11 bone metastases), 12.5{\%} (3/24 brain metastases), and 24.1{\%} (7/29 cfDNA). Two patients showed polyclonal disease with more than one ESR1 mutation. Mutation allele frequencies were 0.07{\%} to 0.2{\%} in primary tumors, 1.4{\%} in bone metastases, 34.3{\%} to 44.9{\%} in brain metastases, and 0.2{\%} to 13.7{\%} in cfDNA. In cases with both cfDNA and metastatic samples (n = 5), mutations were detected in both (n = 3) or in cfDNA only (n = 2). Treatment was associated with changes in ESR1 mutation detection and allele frequency. Conclusions: ESR1 mutations were detected at very low allele frequencies in some primary breast cancers, and at high allele frequency in metastases, suggesting that in some tumors rare ESR1-mutant clones are enriched by endocrine therapy. Further studies should address whether sensitive detection of ESR1 mutations in primary breast cancer and in serial blood draws may be predictive for development of resistant disease.",
author = "Peilu Wang and Amir Bahreini and Rekha Gyanchandani and Lucas, {Peter C.} and Hartmaier, {Ryan J.} and Watters, {Rebecca J.} and Jonnalagadda, {Amruth R.} and {Trejo Bittar}, {Humberto E.} and Aaron Berg and Hamilton, {Ronald L.} and Kurland, {Brenda F.} and Weiss, {Kurt R.} and Aju Mathew and Leone, {Jose Pablo} and Davidson, {Nancy E.} and Nikiforova, {Marina N.} and Brufsky, {Adam M.} and Ambros, {Tadeu F.} and Stern, {Andrew M.} and Puhalla, {Shannon L.} and Lee, {Adrian V.} and Steffi Oesterreich",
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T1 - Sensitive detection of mono- and polyclonal ESR1 mutations in primary tumors, metastatic lesions, and cell-free DNA of breast cancer patients

AU - Wang, Peilu

AU - Bahreini, Amir

AU - Gyanchandani, Rekha

AU - Lucas, Peter C.

AU - Hartmaier, Ryan J.

AU - Watters, Rebecca J.

AU - Jonnalagadda, Amruth R.

AU - Trejo Bittar, Humberto E.

AU - Berg, Aaron

AU - Hamilton, Ronald L.

AU - Kurland, Brenda F.

AU - Weiss, Kurt R.

AU - Mathew, Aju

AU - Leone, Jose Pablo

AU - Davidson, Nancy E.

AU - Nikiforova, Marina N.

AU - Brufsky, Adam M.

AU - Ambros, Tadeu F.

AU - Stern, Andrew M.

AU - Puhalla, Shannon L.

AU - Lee, Adrian V.

AU - Oesterreich, Steffi

PY - 2016/3/1

Y1 - 2016/3/1

N2 - Purpose: Given the clinical relevance of ESR1 mutations as potential drivers of resistance to endocrine therapy, this study used sensitive detection methods to determine the frequency of ESR1 mutations in primary and metastatic breast cancer, and in cell-free DNA (cfDNA). Experimental Design: Six ESR1 mutations (K303R, S463P, Y537C, Y537N, Y537S, D538G) were assessed by digital droplet PCR (ddPCR), with lower limits of detection of 0.05% to 0.16%, in primary tumors (n = 43), bone (n = 12) and brain metastases (n = 38), and cfDNA (n = 29). Correlations between ESR1 mutations in metastatic lesions and single (1 patient) or serial blood draws (4 patients) were assessed. Results: ESR1 mutations were detected for D538G (n = 13), Y537S (n = 3), and Y537C (n = 1), and not for K303R, S463P, or Y537N. Mutation rates were 7.0% (3/43 primary tumors), 9.1% (1/11 bone metastases), 12.5% (3/24 brain metastases), and 24.1% (7/29 cfDNA). Two patients showed polyclonal disease with more than one ESR1 mutation. Mutation allele frequencies were 0.07% to 0.2% in primary tumors, 1.4% in bone metastases, 34.3% to 44.9% in brain metastases, and 0.2% to 13.7% in cfDNA. In cases with both cfDNA and metastatic samples (n = 5), mutations were detected in both (n = 3) or in cfDNA only (n = 2). Treatment was associated with changes in ESR1 mutation detection and allele frequency. Conclusions: ESR1 mutations were detected at very low allele frequencies in some primary breast cancers, and at high allele frequency in metastases, suggesting that in some tumors rare ESR1-mutant clones are enriched by endocrine therapy. Further studies should address whether sensitive detection of ESR1 mutations in primary breast cancer and in serial blood draws may be predictive for development of resistant disease.

AB - Purpose: Given the clinical relevance of ESR1 mutations as potential drivers of resistance to endocrine therapy, this study used sensitive detection methods to determine the frequency of ESR1 mutations in primary and metastatic breast cancer, and in cell-free DNA (cfDNA). Experimental Design: Six ESR1 mutations (K303R, S463P, Y537C, Y537N, Y537S, D538G) were assessed by digital droplet PCR (ddPCR), with lower limits of detection of 0.05% to 0.16%, in primary tumors (n = 43), bone (n = 12) and brain metastases (n = 38), and cfDNA (n = 29). Correlations between ESR1 mutations in metastatic lesions and single (1 patient) or serial blood draws (4 patients) were assessed. Results: ESR1 mutations were detected for D538G (n = 13), Y537S (n = 3), and Y537C (n = 1), and not for K303R, S463P, or Y537N. Mutation rates were 7.0% (3/43 primary tumors), 9.1% (1/11 bone metastases), 12.5% (3/24 brain metastases), and 24.1% (7/29 cfDNA). Two patients showed polyclonal disease with more than one ESR1 mutation. Mutation allele frequencies were 0.07% to 0.2% in primary tumors, 1.4% in bone metastases, 34.3% to 44.9% in brain metastases, and 0.2% to 13.7% in cfDNA. In cases with both cfDNA and metastatic samples (n = 5), mutations were detected in both (n = 3) or in cfDNA only (n = 2). Treatment was associated with changes in ESR1 mutation detection and allele frequency. Conclusions: ESR1 mutations were detected at very low allele frequencies in some primary breast cancers, and at high allele frequency in metastases, suggesting that in some tumors rare ESR1-mutant clones are enriched by endocrine therapy. Further studies should address whether sensitive detection of ESR1 mutations in primary breast cancer and in serial blood draws may be predictive for development of resistant disease.

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