Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonamplified metastatic breast cancer

Cynthia X. Ma, Ron Bose, Feng Gao, Rachel A. Freedman, Melinda L. Telli, Gretchen Kimmick, Eric Winer, Michael Naughton, Matthew Philip Goetz, Christy Russell, Debu Tripathy, Melody Cobleigh, Andres Forero, Timothy J. Pluard, Carey Anders, Polly Ann Niravath, Shana Thomas, Jill Anderson, Caroline Bumb, Kimberly C. BanksRichard B. Lanman, Richard Bryce, Alshad S. Lalani, John Pfeifer, Daniel F. Hayes, Mark Pegram, Kimberly Blackwell, Philippe L. Bedard, Hussam Al-Kateb, Matthew J.C. Ellis

Research output: Contribution to journalArticle

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Abstract

Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) 24 weeks, in HER2mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection. Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut). Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2mut (lobular 7.8% vs. ductal 1.6%; P ¼ 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31–74) years and three (2–10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%–55%], including one CR, one PR, and three SD 24 weeks. Median PFS was 16 (90% CI, 8–31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%–94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%–100%). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. Conclusions: Neratinib is active in HER2mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation.

Original languageEnglish (US)
Pages (from-to)5687-5695
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number19
DOIs
StatePublished - Oct 1 2017

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Breast Neoplasms
Mutation
DNA
Neoplasms
DNA Sequence Analysis
Confidence Intervals
Disease-Free Survival
N-(4-(3-chloro-4-(2-pyridinylmethoxy)anilino)-3-cyano-7-ethoxy-6-quinolyl)-4-(dimethylamino)-2-butenamide
Loperamide
Gene Frequency
Estrogen Receptors
Diarrhea
Research Design
Clinical Trials

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ma, C. X., Bose, R., Gao, F., Freedman, R. A., Telli, M. L., Kimmick, G., ... Ellis, M. J. C. (2017). Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonamplified metastatic breast cancer. Clinical Cancer Research, 23(19), 5687-5695. https://doi.org/10.1158/1078-0432.CCR-17-0900

Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonamplified metastatic breast cancer. / Ma, Cynthia X.; Bose, Ron; Gao, Feng; Freedman, Rachel A.; Telli, Melinda L.; Kimmick, Gretchen; Winer, Eric; Naughton, Michael; Goetz, Matthew Philip; Russell, Christy; Tripathy, Debu; Cobleigh, Melody; Forero, Andres; Pluard, Timothy J.; Anders, Carey; Niravath, Polly Ann; Thomas, Shana; Anderson, Jill; Bumb, Caroline; Banks, Kimberly C.; Lanman, Richard B.; Bryce, Richard; Lalani, Alshad S.; Pfeifer, John; Hayes, Daniel F.; Pegram, Mark; Blackwell, Kimberly; Bedard, Philippe L.; Al-Kateb, Hussam; Ellis, Matthew J.C.

In: Clinical Cancer Research, Vol. 23, No. 19, 01.10.2017, p. 5687-5695.

Research output: Contribution to journalArticle

Ma, CX, Bose, R, Gao, F, Freedman, RA, Telli, ML, Kimmick, G, Winer, E, Naughton, M, Goetz, MP, Russell, C, Tripathy, D, Cobleigh, M, Forero, A, Pluard, TJ, Anders, C, Niravath, PA, Thomas, S, Anderson, J, Bumb, C, Banks, KC, Lanman, RB, Bryce, R, Lalani, AS, Pfeifer, J, Hayes, DF, Pegram, M, Blackwell, K, Bedard, PL, Al-Kateb, H & Ellis, MJC 2017, 'Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonamplified metastatic breast cancer', Clinical Cancer Research, vol. 23, no. 19, pp. 5687-5695. https://doi.org/10.1158/1078-0432.CCR-17-0900
Ma, Cynthia X. ; Bose, Ron ; Gao, Feng ; Freedman, Rachel A. ; Telli, Melinda L. ; Kimmick, Gretchen ; Winer, Eric ; Naughton, Michael ; Goetz, Matthew Philip ; Russell, Christy ; Tripathy, Debu ; Cobleigh, Melody ; Forero, Andres ; Pluard, Timothy J. ; Anders, Carey ; Niravath, Polly Ann ; Thomas, Shana ; Anderson, Jill ; Bumb, Caroline ; Banks, Kimberly C. ; Lanman, Richard B. ; Bryce, Richard ; Lalani, Alshad S. ; Pfeifer, John ; Hayes, Daniel F. ; Pegram, Mark ; Blackwell, Kimberly ; Bedard, Philippe L. ; Al-Kateb, Hussam ; Ellis, Matthew J.C. / Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonamplified metastatic breast cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 19. pp. 5687-5695.
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title = "Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonamplified metastatic breast cancer",
abstract = "Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) 24 weeks, in HER2mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection. Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut). Results: Nine of 381 tumors (2.4{\%}) sequenced centrally harbored HER2mut (lobular 7.8{\%} vs. ductal 1.6{\%}; P ¼ 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31–74) years and three (2–10) prior metastatic regimens] received neratinib. The CBR was 31{\%} [90{\%} confidence interval (CI), 13{\%}–55{\%}], including one CR, one PR, and three SD 24 weeks. Median PFS was 16 (90{\%} CI, 8–31) weeks. Diarrhea (grade 2, 44{\%}; grade 3, 25{\%}) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79{\%}; 90{\%} CI, 53{\%}–94{\%}) and correctly assigned 32 of 32 informative negative cases (specificity, 100{\%}; 90{\%} CI, 91{\%}–100{\%}). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. Conclusions: Neratinib is active in HER2mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation.",
author = "Ma, {Cynthia X.} and Ron Bose and Feng Gao and Freedman, {Rachel A.} and Telli, {Melinda L.} and Gretchen Kimmick and Eric Winer and Michael Naughton and Goetz, {Matthew Philip} and Christy Russell and Debu Tripathy and Melody Cobleigh and Andres Forero and Pluard, {Timothy J.} and Carey Anders and Niravath, {Polly Ann} and Shana Thomas and Jill Anderson and Caroline Bumb and Banks, {Kimberly C.} and Lanman, {Richard B.} and Richard Bryce and Lalani, {Alshad S.} and John Pfeifer and Hayes, {Daniel F.} and Mark Pegram and Kimberly Blackwell and Bedard, {Philippe L.} and Hussam Al-Kateb and Ellis, {Matthew J.C.}",
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T1 - Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonamplified metastatic breast cancer

AU - Ma, Cynthia X.

AU - Bose, Ron

AU - Gao, Feng

AU - Freedman, Rachel A.

AU - Telli, Melinda L.

AU - Kimmick, Gretchen

AU - Winer, Eric

AU - Naughton, Michael

AU - Goetz, Matthew Philip

AU - Russell, Christy

AU - Tripathy, Debu

AU - Cobleigh, Melody

AU - Forero, Andres

AU - Pluard, Timothy J.

AU - Anders, Carey

AU - Niravath, Polly Ann

AU - Thomas, Shana

AU - Anderson, Jill

AU - Bumb, Caroline

AU - Banks, Kimberly C.

AU - Lanman, Richard B.

AU - Bryce, Richard

AU - Lalani, Alshad S.

AU - Pfeifer, John

AU - Hayes, Daniel F.

AU - Pegram, Mark

AU - Blackwell, Kimberly

AU - Bedard, Philippe L.

AU - Al-Kateb, Hussam

AU - Ellis, Matthew J.C.

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) 24 weeks, in HER2mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection. Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut). Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2mut (lobular 7.8% vs. ductal 1.6%; P ¼ 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31–74) years and three (2–10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%–55%], including one CR, one PR, and three SD 24 weeks. Median PFS was 16 (90% CI, 8–31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%–94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%–100%). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. Conclusions: Neratinib is active in HER2mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation.

AB - Purpose: Based on promising preclinical data, we conducted a single-arm phase II trial to assess the clinical benefit rate (CBR) of neratinib, defined as complete/partial response (CR/PR) or stable disease (SD) 24 weeks, in HER2mut nonamplified metastatic breast cancer (MBC). Secondary endpoints included progression-free survival (PFS), toxicity, and circulating tumor DNA (ctDNA) HER2mut detection. Experimental Design: Tumor tissue positive for HER2mut was required for eligibility. Neratinib was administered 240 mg daily with prophylactic loperamide. ctDNA sequencing was performed retrospectively for 54 patients (14 positive and 40 negative for tumor HER2mut). Results: Nine of 381 tumors (2.4%) sequenced centrally harbored HER2mut (lobular 7.8% vs. ductal 1.6%; P ¼ 0.026). Thirteen additional HER2mut cases were identified locally. Twenty-one of these 22 HER2mut cases were estrogen receptor positive. Sixteen patients [median age 58 (31–74) years and three (2–10) prior metastatic regimens] received neratinib. The CBR was 31% [90% confidence interval (CI), 13%–55%], including one CR, one PR, and three SD 24 weeks. Median PFS was 16 (90% CI, 8–31) weeks. Diarrhea (grade 2, 44%; grade 3, 25%) was the most common adverse event. Baseline ctDNA sequencing identified the same HER2mut in 11 of 14 tumor-positive cases (sensitivity, 79%; 90% CI, 53%–94%) and correctly assigned 32 of 32 informative negative cases (specificity, 100%; 90% CI, 91%–100%). In addition, ctDNA HER2mut variant allele frequency decreased in nine of 11 paired samples at week 4, followed by an increase upon progression. Conclusions: Neratinib is active in HER2mut, nonamplified MBC. ctDNA sequencing offers a noninvasive strategy to identify patients with HER2mut cancers for clinical trial participation.

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