PMID- 26429296 OWN - NLM STAT- MEDLINE DCOM- 20160630 LR - 20220318 IS - 1465-542X (Electronic) IS - 1465-5411 (Print) IS - 1465-5411 (Linking) VI - 17 IP - 1 DP - 2015 Oct 1 TI - The relationship between quantitative human epidermal growth factor receptor 2 gene expression by the 21-gene reverse transcriptase polymerase chain reaction assay and adjuvant trastuzumab benefit in Alliance N9831. PG - 133 LID - 10.1186/s13058-015-0643-7 [doi] LID - 133 AB - INTRODUCTION: The N9831 trial demonstrated the efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2 (HER2) locally positive tumors by protein or gene analysis. We used the 21-gene assay to examine the association of quantitative HER2 messenger RNA (mRNA) gene expression and benefit from trastuzumab. METHODS: N9831 tested the addition of trastuzumab to chemotherapy in stage I-III HER2-positive breast cancer. For two of the arms of the trial, doxorubicin and cyclophosphamide followed by paclitaxel (AC-T) and doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab concurrent chemotherapy-trastuzumab (AC-TH), recurrence score (RS) and HER2 mRNA expression were determined by the 21-gene assay (Oncotype DX(R)) (negative <10.7, equivocal 10.7 to <11.5, and positive >/=11.5 log2 expression units). Cox regression was used to assess the association of HER2 expression with trastuzumab benefit in preventing distant recurrence. RESULTS: Median follow-up was 7.4 years. Of 1,940 total patients, 901 had consent and sufficient tissue. HER2 by reverse transcriptase polymerase chain reaction (RT-PCR) was negative in 130 (14 %), equivocal in 85 (9 %), and positive in 686 (76 %) patients. Concordance between HER2 assessments was 95 % for RT-PCR versus central immunohistochemistry (IHC) (>10 % positive cells = positive), 91 % for RT-PCR versus central fluorescence in situ hybridization (FISH) (>/=2.0 = positive) and 94 % for central IHC versus central FISH. In the primary analysis, the association of HER2 expression by 21-gene assay with trastuzumab benefit was marginally nonsignificant (nonlinear p = 0.057). In hormone receptor-positive patients (local IHC) the association was significant (p = 0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 expression levels. CONCLUSIONS: Concordance among HER2 assessments by central IHC, FISH, and RT-PCR were similar and high. Association of HER2 mRNA expression with trastuzumab benefit as measured by time to distant recurrence was nonsignificant. A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in patients with either IHC-positive or FISH-positive tumors. Trend for benefit was observed also for the small groups of patients with negative results by any or all of the central assays. TRIAL REGISTRATION: Clinicaltrials.gov NCT00005970 . Registered 5 July 2000. FAU - Perez, Edith A AU - Perez EA AD - Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA. perez.edith@mayo.edu. FAU - Baehner, Frederick L AU - Baehner FL AD - Genomic Health, Inc, 301 Penobscot Drive, Redwood City, CA, 94063, USA. RBaehner@genomichealth.com. AD - Department of Health Sciences Research, University of California, 500 Parnassus Avenue, San Francisco, CA, 94143, USA. RBaehner@genomichealth.com. FAU - Butler, Steven M AU - Butler SM AD - Genomic Health, Inc, 301 Penobscot Drive, Redwood City, CA, 94063, USA. smbutler@genomichealth.com. FAU - Thompson, E Aubrey AU - Thompson EA AD - Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA. thompson.aubrey@mayo.edu. FAU - Dueck, Amylou C AU - Dueck AC AD - Alliance Statistics and Data Center, Mayo Clinic, 13400 E. Shea Boulevard, Scottsdale, AZ, USA. Dueck.Amylou@mayo.edu. FAU - Jamshidian, Farid AU - Jamshidian F AD - Genomic Health, Inc, 301 Penobscot Drive, Redwood City, CA, 94063, USA. FJamshidian@genomichealth.com. FAU - Cherbavaz, Diana AU - Cherbavaz D AD - Genomic Health, Inc, 301 Penobscot Drive, Redwood City, CA, 94063, USA. DCherbavaz@genomichealth.com. FAU - Yoshizawa, Carl AU - Yoshizawa C AD - Genomic Health, Inc, 301 Penobscot Drive, Redwood City, CA, 94063, USA. CYoshizawa@genomichealth.com. FAU - Shak, Steven AU - Shak S AD - Genomic Health, Inc, 301 Penobscot Drive, Redwood City, CA, 94063, USA. sshak@genomichealth.com. FAU - Kaufman, Peter A AU - Kaufman PA AD - Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH, 03766, USA. Peter.A.Kaufman@hitchcock.org. FAU - Davidson, Nancy E AU - Davidson NE AD - University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Pittsburgh, PA, 15232, USA. davidsonne@upmc.edu. FAU - Gralow, Julie AU - Gralow J AD - Seattle Cancer Care Alliance, 825 Eastlake Avenue East, Seattle, WA, 98109, USA. pink@u.washington.edu. FAU - Asmann, Yan W AU - Asmann YW AD - Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA. Asmann.Yan@mayo.edu. FAU - Ballman, Karla V AU - Ballman KV AD - Alliance Statistics and Data Center, 200 1st Street SW, Mayo Clinic, Rochester, MN, 55905, USA. Ballman.Karla@mayo.edu. LA - eng SI - ClinicalTrials.gov/NCT00005970 GR - U10 CA180821/CA/NCI NIH HHS/United States GR - U10 CA180882/CA/NCI NIH HHS/United States GR - U24 CA196171/CA/NCI NIH HHS/United States GR - U10 CA180844/CA/NCI NIH HHS/United States GR - P50 CA121973/CA/NCI NIH HHS/United States GR - U10-CA025224/CA/NCI NIH HHS/United States GR - P30 CA023108/CA/NCI NIH HHS/United States GR - U10-CA180821/CA/NCI NIH HHS/United States GR - R01 CA129949/CA/NCI NIH HHS/United States GR - U10-CA180882/CA/NCI NIH HHS/United States GR - U10 CA025224/CA/NCI NIH HHS/United States GR - UG1 CA233184/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20151001 PL - England TA - Breast Cancer Res JT - Breast cancer research : BCR JID - 100927353 RN - 0 (Antineoplastic Agents) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - P188ANX8CK (Trastuzumab) SB - IM MH - Adolescent MH - Adult MH - Antineoplastic Agents/*pharmacology/therapeutic use MH - Breast Neoplasms/drug therapy/*metabolism/mortality/pathology MH - Disease-Free Survival MH - Drug Resistance, Neoplasm MH - Female MH - Gene Expression MH - Humans MH - Middle Aged MH - Neoplasm Recurrence, Local/*metabolism/mortality/prevention & control MH - Proportional Hazards Models MH - Randomized Controlled Trials as Topic MH - Receptor, ErbB-2/genetics/*metabolism MH - Reverse Transcriptase Polymerase Chain Reaction MH - Trastuzumab/*pharmacology/therapeutic use MH - Treatment Outcome MH - Young Adult PMC - PMC4589954 EDAT- 2015/10/03 06:00 MHDA- 2016/07/01 06:00 PMCR- 2015/10/01 CRDT- 2015/10/03 06:00 PHST- 2015/01/05 00:00 [received] PHST- 2015/09/14 00:00 [accepted] PHST- 2015/10/03 06:00 [entrez] PHST- 2015/10/03 06:00 [pubmed] PHST- 2016/07/01 06:00 [medline] PHST- 2015/10/01 00:00 [pmc-release] AID - 10.1186/s13058-015-0643-7 [pii] AID - 643 [pii] AID - 10.1186/s13058-015-0643-7 [doi] PST - epublish SO - Breast Cancer Res. 2015 Oct 1;17(1):133. doi: 10.1186/s13058-015-0643-7.