New Study of Duomeisu on Breast Cancer

Recently, the "Pegylated Liposomal Doxorubicin, Docetaxel, and Trastuzumab as Neoadjuvant Treatment for HER2-Positive Breast Cancer Patients: A Phase II and Biomarker Study" was published in Frontiers in Oncology (IF: 5.738; JCR Division: Oncology Zone 2). The study is a collaboration between CSPC and the team of Professor Song Zhenchuan of the Fourth Hospital of Hebei Medical University.

Background

Authoritative guidelines at home and abroad recommend trastuzumab as the first choice for the treatment of HER2 (human epidermal growth factor receptor 2)-positive breast cancer, and anthracyclines and taxanes have always been the cornerstones of breast cancer chemotherapy. However, the concomitant use of trastuzumab and anthracyclines is generally avoided clinically due to their cardiotoxicity. Pegylated Liposomal Doxorubicin (PLD) is a new liposomal dosage form of conventional doxorubicin. It encapsulates doxorubicin in liposomes bound to polyethylene glycol on the surface, which can protect liposomes from recognition by the mononuclear phagocyte system (MPS), thereby prolonging its presence in the blood circulation and enabling target enrichment to tumor tissue through tumor neovascularization, significantly reducing the chance of non-specific distribution to normal tissue. While enhancing the antitumor activity, it reduces the cardiotoxicity, hair loss, nausea, vomiting, and other toxic side effects of traditional doxorubicin. Based on this, we designed a prospective clinical study of this neoadjuvant treatment for HER2-positive breast cancer patients with PLD combined with docetaxel and trastuzumab to evaluate the efficacy and safety of the combined regimen.

Methodology

It was a multicenter, open-label, single-arm, and phase II study. The study enrolled patients with phase II-III HER2-positive breast cancer who received 6 cycles of PLD (40 mg/m2) combined with docetaxel (75 mg/m2) and trastuzumab (8mg/kg initial dose, 6mg/kg maintenance dose) treatment. The primary endpoint was a total pathological complete response (tpCR, ypT0/isypN0), and the secondary endpoints were breast pathological complete response (bpCR, ypT0/is), objective response rate (ORR), surgery rate, breast-conserving surgery rate, and safety. Breast cancer tissues before neoadjuvant therapy were tested for Metadherin (MTDH), glutaminyl Peptide Cyclotransferase (QPCT), Topoisomerase IIα (TOP2A), Programmed Death Ligand 1 (PD-L1), and Tumor-infiltrating Lymphocytes (TILs) to look for potential biomarkers.

Results

54 patients were enrolled between March 2019 and February 2021, of which 50 were included in the analysis. The baseline characteristics of the patients are shown in Table 1:

Table 1: Baseline Characteristics

Table 2: Efficacy Study Endpoints

Compared with data from previous studies1, tpCR was higher in this study.

Exploratory endpoints are shown in Figure 1: HE images of representative MTDH, QPCT, TOP2A, PD-L1-expressing IHCs and TILs, and the impact on tpCR. The results showed that patients with high MTDH expression (60.7%, P=0.036; Figure 1A, D) or high QPCT expression (57.7%, P=0.036; Figure 1A, E) were more likely to achieve tpCR.

Treatment-Emergent Adverse Events (TEAEs) with an incidence of >20% are shown in Table 3:

Table 3: TEAEs (>20%)

Cardiac: 9 patients (18.0%) experienced LVEF decrease ≥10%, but all were >50%, which was lower than the previously published cardiotoxicity of common anthracyclines2. Of the 9 patients with LVEF decrease, 6 recovered, including 2 patients who recovered to baseline levels after completing neoadjuvant treatment. In addition, no patient developed congestive heart failure.

Findings

PLD combined with docetaxel and trastuzumab is a potential neoadjuvant treatment for HER2-positive breast cancer patients with a high tpCR and controlled tolerability. MTDH and QPCT are potential biomarkers for predicting tpCR.

References

Untch M, Rezai M, Loibl S, et al. Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. J Clin Oncol. 2010, 28(12): 2024-2031.

Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013, 24(9): 2278-2284.