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Background: We explored the efficacy and safety of inetetamab combined with sirolimus and chemotherapy for the treatment of human epidermal factor receptor 2 (HER2)-positive metastatic breast cancer patients with abnormal activation of the PI3K/Akt/mTOR (PAM) pathway after trastuzumab treatment. Methods: For this prospective multicenter clinical study, HER2-positive metastatic breast cancer patients with PAM pathway mutations confirmed by histology or peripheral blood genetic testing were enrolled from July 2021 to September 2022. Patients were randomly assigned to a trial or control group. The patients in the trial group received inetetamab combined with sirolimus and chemotherapy, while the control group patients received pyrotinib and chemotherapy. The RECIST v1.1 standard was used to evaluate efficacy. Descriptive statistics were used to summarize the clinicopathological features, and the Kaplan-Meier method was used to generate survival curves. The log-rank test was used to compare progression-free survival (PFS) between the two groups. Results: A total of 59 HER2-positive metastatic breast cancer patients with abnormal activation of the PAM pathway were included, of which 37 received inetetamab combined with sirolimus and chemotherapy treatment and 22 received pyrotinib and chemotherapy treatment. The median PFS was 4.64 months in the inetetamab group and 5.69 months in the pyrotinib group, with no statistically significant difference (p = 0.507). The objective response rates were 27.3% for the inetetamab group and 29.4% for the pyrotinib group. The safety assessment indicated that the adverse event (AE) incidences were 86.1% (31/36) in the inetetamab group and 78.9 (15/19) in the pyrotinib group, with 9 (25%) and four (21.1%) Grade 3/4 AEs in the inetetamab and pyrotinib groups, respectively. Conclusions: For metastatic HER2-positive breast cancer patients with abnormal PAM pathway activation and previous trastuzumab treatment, the combination of inetetamab with sirolimus and chemotherapy is equivalent to the combination of pyrotinib and chemotherapy. Therefore, this regimen could be a treatment option for PAM pathway-activated metastatic HER2-positive breast cancer patients.
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OBJECTIVE: Intra-tumoral heterogeneity of 18F-fluorodeoxyglucose (18F-FDG) uptake has been proven to be a surrogate marker for predicting treatment outcome in various tumors. However, the value of intra-tumoral heterogeneity in metastatic Human epidermal growth factor receptor 2(HER2) positive breast cancer (MHBC) remains unknown. The aim of this study was to evaluate 18F-FDG uptake heterogeneity to predict the treatment outcome of the dual target therapy with Trastuzumab and Pertuzumab(TP) in MHBC. METHODS: Thirty-two patients with MHBC who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) scan before TP were enrolled retrospectively. The region of interesting (ROI) of the lesions were drawn, and maximum standard uptake value (SUVmax), mean standard uptake value (SUVmean), total lesion glycolysis (TLG), metabolic tumor volume (MTV) and heterogeneity index (HI) were recorded. Correlation between PET/CT parameters and the treatment outcome was analyzed by Spearman Rank Test. The ability to predict prognosis were determined by time-dependent survival receiver operating characteristic (ROC) analysis. And the survival analyses were then estimated by Kaplan-Meier method and compared by log-rank test. RESULTS: The survival analysis showed that HI50% calculated by delineating the lesion with 50%SUVmax as threshold was a significant predictor of patients with MHBC treated by the treatment with TP. Patients with HI50% (≥ 1.571) had a significantly worse prognosis of progression free survival (PFS) (6.87 vs. Not Reach, p = 0.001). The area under curve (AUC), the sensitivity and the specificity were 0.88, 100% and 63.6% for PFS, respectively. CONCLUSION: 18F-FDG uptake heterogeneity may be useful for predicting the prognosis of MHBC patients treated by TP.
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Neoplasias de la Mama , Fluorodesoxiglucosa F18 , Humanos , Femenino , Trastuzumab/uso terapéutico , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OPINION STATEMENT: Approximately 20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2+), conferring a particularly aggressive subtype of the disease with an increased risk for the development of systemic and brain metastases. However, the advent of trastuzumab and more recently several other HER2-targeting novel therapies has led to significant improvements in the prognosis, making the diagnosis a "double-edged sword." The current standard first-line therapy for patients with HER2+ metastatic breast cancer (MBC) is a taxane combined with trastuzumab and pertuzumab. Trastuzumab deruxtecan should be used preferentially in the second line, with the only caveat being patients with CNS involvement where the tucatinib, capecitabine, and trastuzumab regimen could be considered. In the third line setting, given the survival benefits demonstrated with the tucatinib regimen in patients with and without CNS metastases, this is the preferred strategy. In the fourth line and beyond, there is no clear standard. Options include margetuximab in combination with chemotherapy, neratinib + capecitabine, or trastuzumab + chemotherapy. There are several novel therapies under investigation reporting promising results in the late-line setting. The treatment landscape of HER2-positive advanced disease is evolving constantly, with several active therapies being moved to the early-stage setting. Accordingly, it will be critical to identify biomarkers and mechanisms of resistance to optimize therapy selection and maximize patient outcomes and quality of life. Here, we provide an overview of the current and future management of HER2-positive advanced breast cancer and address the specific scenarios which may impact treatment selection including triple-positive breast cancer and the presence of brain metastases. Finally, we highlight promising novel treatments and ongoing trials that may impact future treatment sequencing.
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Neoplasias Encefálicas , Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/etiología , Neoplasias de la Mama/metabolismo , Capecitabina , Calidad de Vida , Trastuzumab/uso terapéutico , Receptor ErbB-2/metabolismo , Neoplasias Encefálicas/secundario , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: The presence of anti-HER2 agents, such as trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1), significantly improved the prognosis of metastatic HER2-positive (HER2+) breast cancers (BC). However, drug resistance and disease progression are still common. In order to further improve the treatment efficacy, new clinical trials about anti-HER2 agents in combination with chemotherapy are growing rapidly. We conducted the network meta-analysis to synthesize evidences of clinical trials to identify the best therapy for metastatic HER2+ BC. METHODS: A systematic search of randomized controlled trials regarding anti-HER2 agents in combination with chemotherapy for advanced or metastatic breast cancers up to May 2020 was conducted in Embase, PubMed, and the Cochrane Library. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS), objective response rate (ORR), and safety. Bayesian network meta-analysis was conducted to synthesize the results and rank the therapies. RESULTS: Twenty-six studies, including 16 studies for first-line treatments and 10 studies for second- or later-line treatments were included in the network meta-analysis. For first-line studies, the THP (taxanes + trastuzumab + pertuzumab) regimen exhibited the highest probability to be the optimal treatment in all efficacy outcomes and moderate safety. For second- or later-line studies, the T-DM1 and XHTuC (capecitabine + trastuzumab + tucatinib) regimens ranked top two in all efficacy outcomes according to the surface under the cumulative ranking (SUCRA) results. T-DM1 ranked first in PFS and OS whereas XHTuC ranked first in ORR. The safety outcomes of T-DM1 and XHTuC were acceptable. CONCLUSIONS: THP was still the optimal first-line treatment for metastatic HER2+ BC. T-DM1 and XHTuC were recommended for second-line treatments. SYSTEMATIC REVIEW REGISTRATION: INPLASY.com, identifier (INPLASY202090086).
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Despite therapeutic gains in the treatment of HER2-positive (HER2: human epidermal growth factor receptor 2) advanced/metastatic breast cancer, there remains an urgent need for more effective treatment options. At present, there is no definitive approved standard therapy beyond second-line treatment. One of the major challenges is overcoming treatment resistance. Depending on the underlying resistance mechanism, different strategies are being pursued for new innovative treatment concepts in HER2-positive breast cancer. Specifically designed antibodies for targeted therapy are one important focus to successfully meet these challenges. Trastuzumab deruxtecan (T-DXd, DS-8201a), an optimised antibody drug conjugate (ADC) is in clinical trials, showing promising outcomes in patients with advanced, nonoperable or metastatic HER2-positive breast cancer who had already undergone intensive prior treatment. Based on this data, T-DXd has already been approved in the US and Japan for HER2-positive advanced nonoperable and metastatic breast cancer - in the US after at least two prior anti-HER2 targeted treatment lines and in Japan after prior chemotherapy. T-DXd represents successful "antibody engineering". Since the beginning of the year, T-DXd has also been approved in Europe as monotherapy for inoperable or metastatic HER2-positive breast cancer in patients who are pretreated with at least two anti-HER2 directed therapies. This paper presents strategies for improving treatment options in advanced nonoperable and metastatic HER2-positive breast cancer, with the development of T-DXd as an example.
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Trastuzumab-based treatment has dramatically improved the outcomes of HER2-positive (HER2+) metastatic breast cancer (MBC) patients, with some patients achieving prolonged survival times. In this study, we aim to identify factors that are associated with long-term survival. Patients with HER2+ MBC treated with anti-HER2 target therapy were identified. Patients were grouped according to overall survival (OS) and categorized as long-term survivors (LTS, OS ≥ 5 years), or non-long-term survivors (non-LTS, OS < 5 years). Descriptive statistics and multivariable logistic regression modeling were used. A sensitivity analysis was carried out, including only patients diagnosed before 2007; therefore, 5 years of potential follow-up was possible. 1063 patients with HER2+ MBC diagnosed between 1994 and 2012 and treated with anti-HER2 therapy were identified. Among them, 154 (14.5 %) patients were categorized as LTS (median OS 92.2 months). Among LTS, 63.4 % were HR-positive and 32 % had de novo stage IV disease. Hormone receptor positivity (OR) 1.69; 95 % CI 1.17-2.44), resection of metastases (OR 2.38; 95 % CI 1.53-3.69), and primary breast surgery in patients with de novo stage IV (OR 2.88; 95 % CI 1.47-5.66) were associated with improved long-term survival. Greater number of metastatic sites (≥3 vs. 1, OR 0.41; 95 % CI 0.23-0.72) and visceral metastases (OR 0.61; 95 % CI 0.4-0.91) were associated with poor survival. Hormone receptor positivity, low burden of disease, metastasis to soft and bone tissues, and surgical management with resection of the metastatic site and the primary tumor were associated with long-term survival in patients with MBC who received anti-HER2 treatment.