Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13 864 women in seven randomised trials

Abstract

Summary Background Trastuzumab targets the extracellular domain of the HER2 protein. Adding trastuzumab to chemotherapy for patients with early-stage, HER2-positive breast cancer reduces the risk of recurrence and death, but is associated with cardiac toxicity. We investigated the long-term benefits and risks of adjuvant trastuzumab on breast cancer recurrence and cause-specific mortality. Methods We did a collaborative meta-analysis of individual patient data from randomised trials assessing chemotherapy plus trastuzumab versus the same chemotherapy alone. Randomised trials that enrolled women with node-negative or node-positive, operable breast cancer were included. We collected individual patient-level data on baseline characteristics, dates and sites of first distant breast cancer recurrence and any previous local recurrence or second primary cancer, and the date and underlying cause of death. Primary outcomes were breast cancer recurrence, breast cancer mortality, death without recurrence, and all-cause mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, oestrogen receptor (ER) status, and trial yielded first-event rate ratios (RRs). Findings Seven randomised trials met the inclusion criteria, and included 13 864 patients enrolled between February, 2000, and December, 2005. Mean scheduled treatment duration was 14·4 months and median follow-up was 10·7 years (IQR 9·5 to 11·9). The risks of breast cancer recurrence (RR 0·66, 95% CI 0·62 to 0·71; p<0·0001) and death from breast cancer (0·67, 0·61 to 0·73; p<0·0001) were lower with trastuzumab plus chemotherapy than with chemotherapy alone. Absolute 10-year recurrence risk was reduced by 9·0% (95% CI 7·4 to 10·7; p<0·0001) and 10-year breast cancer mortality was reduced by 6·4% (4·9 to 7·8; p<0·0001), with a 6·5% reduction (5·0 to 8·0; p<0·0001) in all-cause mortality, and no increase in death without recurrence (0·4%, –0·3 to 1·1; p=0·35). The proportional reduction in recurrence was largest in years 0–1 after randomisation (0·53, 99% CI 0·46 to 0·61), with benefits persisting through years 2–4 (0·73, 0·62 to 0·85) and 5–9 (0·80, 0·64 to 1·01), and little follow-up beyond year 10. Proportional recurrence reductions were similar irrespective of recorded patient and tumour characteristics, including ER status. The more high risk the tumour, the larger the absolute reductions in 5-year recurrence (eg, 5·7% [95% CI 3·1 to 8·3], 6·8% [4·7 to 9·0], and 10·7% [7·7 to 13·6] in N0, N1–3, and N4+ disease). Interpretation Adding trastuzumab to chemotherapy for early-stage, HER2-positive breast cancer reduces recurrence of, and mortality from, breast cancer by a third, with worthwhile proportional reductions irrespective of recorded patient and tumour characteristics. Funding Cancer Research UK, UK Medical Research Council.

Association of Preoperative Serum Levels of CEA and CA15-3 with Molecular Subtypes of Breast Cancer

“…The difference of elevated CEA level between molecular types may chiefly be caused by the significant correlation between higher CEA levels and Her-2 status. Her-2 amplification had been identified in human breast cancer cells which may result in a more aggressive tumor type clinically and significantly related to survival in patients with breast cancer [ 22 – 26 ]. Her-2 and serum CEA level are both widely used markers for the prognosis of breast cancer.…”

Development and validation of the new HER2DX assay for predicting pathological response and survival outcome in early-stage HER2-positive breast cancer

“…1 In the early stages, (neo)adjuvant chemotherapy plus trastuzumab (plus endocrine therapy in hormone receptor-positive disease) have consistently shown significant increases in survival. 2 However, substantial clinical and biological heterogeneity exists in HER2-positive disease, which affects patients' prognosis and treatment benefit. 2 , 3 , 4 , 5 …”

“… 2 However, substantial clinical and biological heterogeneity exists in HER2-positive disease, which affects patients' prognosis and treatment benefit. 2 , 3 , 4 , 5 …”

The Role of Trastuzumab in Patients with HER2 Positive Small (pT1mi/a) Breast Cancers, a Multicenter Retrospective Study

“…A subgroup analysis included 1095 patients with tumor size ranging from 1 to 10 mm, and Trastuzumab was shown to significantly reduce the risk of recurrence even in small HER2+ breast cancer patients (HR 0.61, 95%CI 0.38–0.99). This is so far the only good quality prospective data available on Trastuzumab treatment in very small breast tumors [ 16 ].…”

“…In fact, in a recently published metanalysis, Trastuzumab was shown to significantly reduce the risk of recurrence also in very small HER2+ breast cancer patients (HR 0.61, 95%CI 0.38–0.99). However, this result is derived from a subgroup analysis conducted on 1095 merged pT1a and pT1b patients, with a limited number of events [ 16 ]. According to the NCCN Guidelines 2021, the decision to prescribe a Trastuzumab-based therapy in this group of patients must balance the known toxicities of this treatment and the uncertain benefits that can be achieved [ 17 ].…”