TY - JOUR
T1 - Survival, pathologic response, and genomics in CALGB 40601 (Alliance), a neoadjuvant Phase III trial of paclitaxel-trastuzumab with or without lapatinib in HER2-positive breast cancer
AU - Fernandez-Martinez, Aranzazu
AU - Krop, Ian E.
AU - Hillman, David W.
AU - Polley, Mei Yin
AU - Parker, Joel S.
AU - Huebner, Lucas
AU - Hoadley, Katherine A.
AU - Shepherd, Jonathan
AU - Tolaney, Sara
AU - Lynn Henry, N.
AU - Dang, Chau
AU - Harris, Lyndsay
AU - Berry, Donald
AU - Hahn, Olwen
AU - Hudis, Clifford
AU - Winer, Eric
AU - Partridge, Ann
AU - Perou, Charles M.
AU - Carey, Lisa A.
N1 - Funding Information:
Supported by National Cancer Institute, National Institutes of Health, Grants No. U10CA180821, U10CA180882, and U24CA196171 (to the Alliance for Clinical Trials in Oncology); R01CA229409, UG1CA233160, UG1CA233180, UG1CA233290, UG1CA233329,
Funding Information:
Supported by National Cancer Institute, National Institutes of Health, Grants No. U10CA180821, U10CA180882, and U24CA196171 (to the Alliance for Clinical Trials in Oncology); R01CA229409, UG1CA233160, UG1CA233180, UG1CA233290, UG1CA233329, UG1CA233333, UG1CA233373, and P50CA58223 (L.A.C. and C.M.P.); U10CA180888 and UG1CA233160 (SWOG); and by The Breast Cancer Research Foundation (Alliance, L.A.C., and C.M.P.), Susan G. Komen (L.A.C. and C.M.P.), GlaxoSmithKline and SEOM (Becas FSEOM para Formación en Investigación en Centros de Referencia en el Extranjero 2016 to AF-M). For additional support acknowledgment: https://acknowledgments.alliancefound.org.
Publisher Copyright:
© 2020 by American Society of Clinical Oncology
PY - 2020/12/10
Y1 - 2020/12/10
N2 - PURPOSE CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) -targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival. PATIENTS AND METHODS Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples. RESULTS One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; P 5.005; OS hazard ratio, 0.34; 95% CI, 0.12 to 0.94; P 5.037), with no difference between TH and TL. Of 688 previously described gene expression signatures, significant associations were found in 215 with pCR, 45 with RFS, and only 22 with both pCR and RFS (3.2%). Specifically, eight immune signatures were significantly correlated with a higher pCR rate and better RFS. Among patients with residual disease, the immunoglobulin G signature was an independent, good prognostic factor, whereas the HER2-enriched signature, which was associated with a higher pCR rate, showed a significantly shorter RFS. CONCLUSION In CALGB 40601, dual HER2-targeting resulted in significant RFS and OS benefits. Integration of intrinsic subtype and immune signatures allowed for the prediction of pCR and RFS, both overall and within the residual disease group. These approaches may provide means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer.
AB - PURPOSE CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) -targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival. PATIENTS AND METHODS Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples. RESULTS One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; P 5.005; OS hazard ratio, 0.34; 95% CI, 0.12 to 0.94; P 5.037), with no difference between TH and TL. Of 688 previously described gene expression signatures, significant associations were found in 215 with pCR, 45 with RFS, and only 22 with both pCR and RFS (3.2%). Specifically, eight immune signatures were significantly correlated with a higher pCR rate and better RFS. Among patients with residual disease, the immunoglobulin G signature was an independent, good prognostic factor, whereas the HER2-enriched signature, which was associated with a higher pCR rate, showed a significantly shorter RFS. CONCLUSION In CALGB 40601, dual HER2-targeting resulted in significant RFS and OS benefits. Integration of intrinsic subtype and immune signatures allowed for the prediction of pCR and RFS, both overall and within the residual disease group. These approaches may provide means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer.
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U2 - 10.1200/JCO.20.01276
DO - 10.1200/JCO.20.01276
M3 - Article
C2 - 33095682
AN - SCOPUS:85097451093
SN - 0732-183X
VL - 38
SP - 4184
EP - 4193
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 35
ER -