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Review
. 2022 Apr;7(2):100433.
doi: 10.1016/j.esmoop.2022.100433. Epub 2022 Mar 8.

Survival after neoadjuvant therapy with trastuzumab-lapatinib and chemotherapy in patients with HER2-positive early breast cancer: a meta-analysis of randomized trials

V Guarneri  1 , G Griguolo  2 , F Miglietta  3 , P F Conte  2 , M V Dieci  2 , F Girardi  4
Affiliations
Review

Survival after neoadjuvant therapy with trastuzumab-lapatinib and chemotherapy in patients with HER2-positive early breast cancer: a meta-analysis of randomized trials

V Guarneri et al. ESMO Open. 2022 Apr.

Abstract

Background: Studies testing the addition of lapatinib to neoadjuvant trastuzumab + chemotherapy reported an increase in pathologic complete response (pCR), with, nevertheless, discordant results in terms of survival, mainly due to suboptimal power. We here leverage the meta-analytic approach to resolve these inconsistencies.

Methods: We conducted a meta-analysis of randomized phase II/III studies testing lapatinib + trastuzumab in combination with neoadjuvant chemotherapy for human epidermal growth factor receptor (HER2)-positive early breast cancer (BC). Recurrence-free survival (RFS) and overall survival (OS) were adopted as survival endpoints. Pooled hazard ratios (HR) were obtained for the effect of lapatinib + trastuzumab versus trastuzumab, pCR versus no-pCR in the whole study populations and pCR versus no-pCR according to hormone receptor status.

Results: Four phase II/III randomized trials were included in the meta-analysis (CALGB 40601, Cher-LOB, NSABP-B41, NeoALTTO) for an overall population of 1410 patients receiving neoadjuvant chemotherapy in association with either trastuzumab, lapatinib or their combination. RFS was significantly improved with dual HER2 blockade as compared to trastuzumab [HR 0.62, 95% confidence interval (CI) 0.46-0.85]. Dual blockade also led to significantly improved OS (HR 0.65, 95% CI 0.43-0.98). For all treatments combined, patients achieving pCR had better RFS and OS than those with residual disease (HR 0.45, 95% CI 0.34-0.60, and HR 0.32, 95% CI 0.22-0.48, for RFS and OS, respectively). In patients with hormone receptor-negative tumors, pCR was associated with 65% and 73% relative reduction of risk of relapse and death, respectively. Patients with hormone receptor-positive tumors also experienced improved RFS if they achieved pCR; however, the benefit was smaller than that in hormone receptor-negative disease.

Conclusion: Findings from this meta-analysis further validate the role of pCR as a strong predictor of outcome in patients with HER2-positive BC, especially in hormone receptor-negative disease. Moreover, we provide robust evidence that dual blockade with lapatinib + trastuzumab in combination with neoadjuvant chemotherapy prolongs OS, suggesting that the role of lapatinib could be reconsidered in the early setting.

Keywords: HER2-positive breast cancer; lapatinib; meta-analysis; neoadjuvant treatment; trastuzumab.

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Conflict of interest statement

Disclosure VG reports personal fees from Roche, Novartis, Eli Lilly, MSD, GSK and Gilead, all outside the submitted work. GG reports personal fees from Novartis and Eli Lilly all outside the submitted work. MVD reports personal fees from Lilly, Genomic Health, Novartis and Celgene, all outside the submitted work. PFC reports personal fees from Novartis, Eli Lilly, AstraZeneca, Tesaro, BMS and Roche, all outside the submitted work.All other authors have declared no conflicts of interest.

Figures

Figure 1
Figure 1
PRISMA flowchart. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Figure 2
Figure 2
Hazard ratios according to treatment arm (chemotherapy + trastuzumab versus chemotherapy + trastuzumab + lapatinib). (A) Recurrence-free survival analysis. (B) Overall survival analysis. CI, confidence interval; HR, hazard ratio; TL, trastuzumab+lapatinib; T, trastuzumab.
Figure 3
Figure 3
Hazard ratios for recurrence-free survival according to pCR (pCR versus no-pCR). (A) Overall population. (B) Hormone receptor-negative subgroup. (C) Hormone receptor-positive subgroup. CI, confidence interval; HR, hazard ratio; pCR, pathologic complete response.
Figure 4
Figure 4
Hazard ratios for overall survival according to pCR (pCR versus no-pCR). (A) Overall population. (B) Hormone receptor-negative subgroup. (C) Hormone receptor-positive subgroup. CI, confidence interval; HR, hazard ratio.
See this image and copyright information in PMC

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