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

Abstract

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 = .005; OS hazard ratio, 0.34; 95% CI, 0.12 to 0.94; P = .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.

Trial registration: ClinicalTrials.gov NCT00770809.

Figures

FIG 1.

Kaplan-Meier curves for relapse-free survival (RFS) and overall survival (OS) in the intention-to-treat (ITT) population. (A) Kaplan-Meier estimates of RFS at 7 years by treatment arm in the ITT population, showing a significant benefit of THL (paclitaxel, trastuzumab, and lapatinib) versus TH (paclitaxel plus trastuzumab) treatment arms. (B) Kaplan-Meier estimates of OS at 7 years by treatment arm in the ITT population, showing a significant benefit of THL versus TH treatment arms. (C) Kaplan-Meier estimates of RFS at 7 years by pathologic complete response (pCR) status in the ITT population, showing a significant improvement in outcome in pCR versus residual disease (RD). (D) Kaplan-Meier estimates of OS at 7 years by pCR status in the ITT population, showing a significant improvement in outcome in pCR versus RD. HR, hazard ratio; TL, paclitaxel and lapatinib.

FIG 2.

Association between odds ratio (OR) and hazard ratio (HR) in 16 significant biomarkers of response and survival. OR and HR values have been log transformed. Whereas all the immune-related biomarkers predicted a higher response and a longer relapse-free survival (RFS), subtype-related biomarkers showed the opposite direction for the prediction of response and survival. For subtype-related biomarkers, the correlation to each PAM50 centroid was used. CES, chemoendocrine score; HER2-E, HER2-enriched; IgG, immunoglobulin G; LumA, Luminal A; P, proliferation; pCR, pathologic complete response; ROR, risk of recurrence; S, subtype.

FIG 3.

Forest plot representing a multivariable Cox proportional hazards regression analysis within the residual disease group of patients. HER2-enriched (HER2-E) subtype was correlated with shorter relapse-free survival (RFS), whereas immunoglobulin G (IgG) signature was an independent good prognosis factor. The correlation to the HER2-E centroid and the IgG gene expression signature, both as continuous variables, were used for the multivariable Cox proportional hazards regression analysis. HR, hormone receptor; TH, paclitaxel plus trastuzumab; THL, paclitaxel, trastuzumab, and lapatinib; TL, paclitaxel and lapatinib.