NSABP FB-7: a phase II randomized neoadjuvant trial with paclitaxel + trastuzumab and/or neratinib followed by chemotherapy and postoperative trastuzumab in HER2(+) breast cancer.
Por:
Jacobs, S, Robidoux, A, Abraham, J, Perez-Garcia, J, La Verde, N, Orcutt, J, Cazzaniga, M, Piette, F, Antolin, S, Aguirre, E, Cortes, J, Llombart-Cussac, A, Di Cosimo, S, Kim, R, Feng, H, Lipchik, C, Lucas, P, Srinivasan, A, Wang, Y, Song, N, Gavin, P, Balousek, A, Paik, S, Allegra, C, Wolmark, N and Pogue-Geile, K
Publicada:
3 dic 2019
Ahead of Print:
3 dic 2019
Resumen:
PURPOSE: The primary aim of NSABP FB-7 was to determine the pathologic complete response (pCR) rate in locally advanced HER2-positive (HER2(+)) breast cancer patients treated with neoadjuvant trastuzumab or neratinib or the combination and weekly paclitaxel followed by standard doxorubicin plus cyclophosphamide. The secondary aims include biomarker analyses. EXPERIMENTAL DESIGN: pCR was tested for association with treatment, gene expression, and a single nucleotide polymorphism (SNP) in the Fc fragment of the IgG receptor IIIa-158V/F (FCGR3A). Pre-treatment biopsies and residual tumors were also compared to identify molecular changes. RESULTS: The numerical pCR rate in the trastuzumab plus neratinib arm (50% [95%CI 34-66%]) was greater than that for single-targeted therapies with trastuzumab (38% [95%CI 24-54]) or neratinib (33% [95%CI 20-50]) in the overall cohort but was not statistically significant. Hormone receptor-negative (HR(-)) tumors had a higher pCR rate than HR(+) tumors in all three treatment arms, with the highest pCR rate in the combination arm. Diarrhea was the most frequent adverse event and occurred in virtually all patients who received neratinib-based therapy. Grade 3 diarrhea was reported in 31% of patients; there were no grade 4 events. Our 8-gene signature, previously validated for trastuzumab benefit in two different clinical trials in the adjuvant setting, was correlated with pCR across all arms of NSABP FB-7. Specifically, patients predicted to receive no trastuzumab benefit had a significantly lower pCR rate than did patients predicted to receive the most benefit (P = 0.03). FCGR genotyping showed that patients who were homozygous for the Fc low-binding phenylalanine (F) allele for FCGR3A-158V/F were less likely to achieve pCR. CONCLUSIONS: Combining trastuzumab plus neratinib with paclitaxel increased the absolute pCR rate in the overall cohort and in HR(-) patients. The 8-gene signature, which is validated for predicting trastuzumab benefit in the adjuvant setting, was associated with pCR in the neoadjuvant setting, but remains to be validated as a predictive marker in a larger neoadjuvant clinical trial. HR status, and the FCGR3A-158V/F genotype, also warrant further investigation to identify HER2(+) patients who may benefit from additional anti-HER2 therapies beyond trastuzumab. All of these markers will require further validation in the neoadjuvant setting. TRIALS REGISTRATION: ClinicalTrials.gov, NCT01008150. Retrospectively registered on October 5, 2010.
Filiaciones:
Jacobs, S:
NSABP Fdn Inc, Nova Tower 2,Two Allegheny Ctr Ste 1200, Pittsburgh, PA 15212 USA
Robidoux, A:
NSABP Fdn Inc, Nova Tower 2,Two Allegheny Ctr Ste 1200, Pittsburgh, PA 15212 USA
Ctr Hosp Univ Montreal, Montreal, PQ, Canada
Abraham, J:
NSABP Fdn Inc, Nova Tower 2,Two Allegheny Ctr Ste 1200, Pittsburgh, PA 15212 USA
Cleveland Clin, Cleveland, OH 44106 USA
Perez-Garcia, J:
IOB Inst Oncol, Quironsalud Grp, Barcelona, Spain
Med Scientia Innovat Res MedSIR, Barcelona, Spain
La Verde, N:
ASST Fatebenefratelli Sacco, PO Luigi Sacco, Milan, Italy
ASST Fatebenefratelli Sacco, PO Fatebenefratelli, Milan, Italy
Orcutt, J:
NSABP Fdn Inc, Nova Tower 2,Two Allegheny Ctr Ste 1200, Pittsburgh, PA 15212 USA
Roper St Francis Healthcare, Charleston, SC USA
Cazzaniga, M:
Med Scientia Innovat Res MedSIR, Barcelona, Spain
Azienda Osped San Gerardo, Monza, Italy
Piette, F:
IDDI, Louvain La Neuve, Belgium
Antolin, S:
Hosp Univ, Coruna, Spain
Aguirre, E:
Med Scientia Innovat Res MedSIR, Barcelona, Spain
Cortes, J:
IOB Inst Oncol, Quironsalud Grp, Barcelona, Spain
Med Scientia Innovat Res MedSIR, Barcelona, Spain
:
Med Scientia Innovat Res MedSIR, Barcelona, Spain
Di Cosimo, S:
Med Scientia Innovat Res MedSIR, Barcelona, Spain
Fdn IRCCS Ist Nazl Tumori, Milan, Italy
Kim, R:
NSABP Fdn Inc, Nova Tower 2,Two Allegheny Ctr Ste 1200, Pittsburgh, PA 15212 USA
Feng, H:
NSABP Fdn Inc, Nova Tower 2,Two Allegheny Ctr Ste 1200, Pittsburgh, PA 15212 USA
Lipchik, C:
NSABP Fdn Inc, Nova Tower 2,Two Allegheny Ctr Ste 1200, Pittsburgh, PA 15212 USA
Lucas, P:
NSABP Fdn Inc, Nova Tower 2,Two Allegheny Ctr Ste 1200, Pittsburgh, PA 15212 USA
Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA
Srinivasan, A:
NSABP Fdn Inc, Nova Tower 2,Two Allegheny Ctr Ste 1200, Pittsburgh, PA 15212 USA
Wang, Y:
NSABP Fdn Inc, Nova Tower 2,Two Allegheny Ctr Ste 1200, Pittsburgh, PA 15212 USA
Song, N:
NSABP Fdn Inc, Nova Tower 2,Two Allegheny Ctr Ste 1200, Pittsburgh, PA 15212 USA
Gavin, P:
NSABP Fdn Inc, Nova Tower 2,Two Allegheny Ctr Ste 1200, Pittsburgh, PA 15212 USA
Balousek, A:
NSABP Fdn Inc, Nova Tower 2,Two Allegheny Ctr Ste 1200, Pittsburgh, PA 15212 USA
Paik, S:
NSABP Fdn Inc, Nova Tower 2,Two Allegheny Ctr Ste 1200, Pittsburgh, PA 15212 USA
Yonsei Univ, Severance Biomed Sci Inst, Coll Med, Seoul, South Korea
Yonsei Univ, Dept Med Oncol, Coll Med, Seoul, South Korea
Allegra, C:
Univ Florida Hlth, Dept Med, Gainesville, FL USA
Wolmark, N:
NSABP Fdn Inc, Nova Tower 2,Two Allegheny Ctr Ste 1200, Pittsburgh, PA 15212 USA
Univ Pittsburgh, Pittsburgh, PA 15212 USA
Pogue-Geile, K:
NSABP Fdn Inc, Nova Tower 2,Two Allegheny Ctr Ste 1200, Pittsburgh, PA 15212 USA
Green Published, gold
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