Effect of Denosumab Added to 2 Different nab-Paclitaxel Regimens as Neoadjuvant Therapy in Patients With Primary Breast Cancer

Abstract

IMPORTANCEAdjuvant denosumab might improve disease-free survival in hormone receptor (HR)-positive primary breast cancer (BC). The optimal neoadjuvant nab-paclitaxel schedule in terms of efficacy and safety is unclear.OBJECTIVE To determine whether adding denosumab to anthracycline/taxane-containing neoadjuvant chemotherapy (NACT) increases the pathological complete response (pCR) rate and which nab-paclitaxel schedule is more effective in the NACT setting. DESIGN, SETTING, AND PARTICIPANTSThe GeparX was a multicenter, prospective, open-label, phase 2b, 2 × 2 randomized clinical trial conducted by GBG and AGO-B at 38 German sites between February 2017 and March 2019. The analysis data set was locked September 4, 2020; analysis was completed November 13, 2020. Patients had unilateral or bilateral primary BC, stage cT2-cT4a-d or cT1c, with either clinically node-positive or pathologically node-positive or HR-negative disease, or Ki-67 proliferation index greater than 20%, or ERBB2 (formerly HER2)-positive BC.INTERVENTIONS Patients were randomized to receive or not receive denosumab, 120 mg subcutaneously every 4 weeks for 6 cycles, and either nab-paclitaxel, 125 mg/m 2 weekly for 12 weeks or days 1 and 8 every 3 weeks for 4 cycles (8 doses), followed by 4 cycles of epirubicin/cyclophosphamide, 90/600 mg/m 2 (every 2 weeks or every 3 weeks). Carboplatin was given in triple-negative BC (TNBC), and trastuzumab biosimilar ABP980 plus pertuzumab was given in ERBB2-positive BC (ERBB2-positive substudy). MAIN OUTCOMES AND MEASURESThe primary outcome was pCR rates between arms for each randomization.RESULTS A total of 780 female (n = 779) and male (n = 1) patients (median [range] age, 49.0 [22-80] years) were randomized to the 4 treatment groups. The pCR (ypT0 ypN0) rate was 41.0% (90% CI, 37%-45%) with denosumab vs 42.8% (90% CI, 39%-47%) (P = .58) without denosumab, irrespective of BC subtype. Nab-paclitaxel weekly resulted in a significantly (significance level of α = .10) higher pCR rate of 44.9% (90% CI, 41%-49%) vs 39.0% (90% CI, 35%-43%) (P = .06) with nab-paclitaxel days 1 and 8 every 3 weeks. The pCR rates for nab-paclitaxel schedules in subgroups were only significantly different for TNBC (60.4% vs 50.0%; P = .06). Grade 3 to 4 toxic effects did not differ with or without denosumab. Nonhematologic toxic effects of grade 3 to 4 were higher with nab-paclitaxel weekly (33.7% vs 24.1%; P = .004). CONCLUSIONS AND RELEVANCEIn this randomized clinical trial, denosumab added to anthracycline/taxane-based NACT did not improve pCR rates. Nab-paclitaxel at a dosage of 125 mg/m 2 weekly significantly increased the pCR rate compared with the days 1 and 8, every-3-weeks schedule overall and in TNBC, but generated higher toxicity.

The effect of denosumab on disseminated tumor cells (DTCs) of breast cancer patients with neoadjuvant treatment: a GeparX translational substudy

“…We inquired, whether neoadjuvant add-on denosumab treatment, framed by the GeparX study [ 32 ], may eradicate DTCs in the bone marrow. Therefore, we analyzed, whether denosumab may increase the given DTC-eradication rate by NACT.…”

“…The translational GeparX linked substudy was conducted at the Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus, TU Dresden, Germany. In total, 177 patients [ 32 ] were recruited from the GeparX trial and in 167/177 of these patients, bone marrow aspirates could be obtained (Fig. 1 ).…”

“…While the ABCSG-18 trial showed that the addition of denosumab to adjuvant systemic treatment results in an improved disease-free survival [ 30 ], the D-CARE trial did not resolve any improvement of disease-related outcomes for high-risk early breast cancer patients, treated with denosumab [ 31 ]. Moreover, the phase IIb prospective randomized GeparX trial reported that denosumab, added to anthracycline/taxane-based NACT, did not improve pCR rates [ 32 ].…”

“…However, whether denosumab eradicates DTCs, as it has been reported for bisphosphonates [ 18 ], is completely unknown. Using the framework of the recent GeparX study [ 32 ], we herein analyzed the clinical relevance of DTCs for predicting response to NACT and interrogated whether neoadjuvant denosumab treatment may eradicate DTCs in the bone marrow.…”

Natural Products-Based Nanoformulations: A New Approach Targeting CSCs to Cancer Therapy

“…Although PTX can eliminate most tumor cells and reduce the size of tumors, it also enriches the CSC population, leading to acquired drug resistance, recurrence, metastasis, and progression. 92 , 93 Therefore, reducing tumor cells while targeting CSCs is a key strategy to improve the anticancer efficiency of PTX ( Figure 6 , Table 2 ).

Figure 6 Mechanism and advantages of paclitaxel and docetaxel nanoformulations.

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