阿帕替尼联合曲妥珠单抗对胃癌细胞的协同增敏作用

目的观察阿帕替尼联合曲妥珠单抗杀伤胃癌NCI-N87细胞的协同增敏作用并探讨可能作用机制。方法CCK-8法检测空白对照组、曲妥珠单抗组(0.1、1、10μg/ml)、阿帕替尼组(1μmol/L)及曲妥珠单抗(0.1、1、10μg/ml)+阿帕替尼(1μmol/L)组对NCI-N87细胞的增殖抑制作用,流式细胞术检测NCI-N87细胞凋亡,Western blotting检测HER-2、VEGFR2、Bax、Bcl-2蛋白表达。结果CCK-8检测提示曲妥珠单抗、阿帕替尼能够抑制NCI-N87细胞增殖,在一定浓度范围内作用呈浓度依赖性和时间依赖性(P<0.01);q值计算提示曲妥珠单抗与阿帕替尼具有协同抑制NCI-N87细胞增殖的作用。流式细胞术检测显示联合组NCI-N87胃癌细胞凋亡较单药组明显升高(P<0.05),其中空白对照组、阿帕替尼组(1μmol/L)、曲妥珠单抗(0.1μg/ml)组及曲妥珠单抗(0.1μg/ml)+阿帕替尼(1μmol/L)组的凋亡率分别为(3.0±1.28)%、(5.8±1.63)%、(8.0±3.92)%和(21.6±6.85)%。曲妥珠单抗+阿帕替尼组与空白对照组、曲妥珠单抗及阿帕替尼单药组比较,HER-2蛋白表达显著下调(P<0.05);曲妥珠单抗+阿帕替尼组与空白对照组比较,Bcl-2蛋白表达、Bcl-2/Bax比值明显降低(P<0.01)。结论阿帕替尼联合曲妥珠单抗可能通过下调HER-2蛋白及调控凋亡相关蛋白Bcl-2、Bax的表达,协同抑制NCI-N87细胞增殖和促进细胞凋亡。     

A Roundtable Discussion of the Breast Cancer Therapy Expert Group (BCTEG): Clinical Developments and Practice Guidance on Human Epidermal Growth Factor Receptor 2 (HER2)-positive Breast Cancer

Expression of human epidermal growth factor receptor 2 (HER2) in breast cancer defines a subset of patients (∼15%-20%) who are candidates for anti-HER2 therapies, most notably, trastuzumab, pertuzumab, antibody drug conjugates (eg, T-DM1), and tyrosine kinase inhibitor (TKI) drugs (eg, lapatinib and neratinib), all of which have dramatically changed the prognosis for this aggressive subtype of breast cancer. A roundtable meeting of the Breast Cancer Therapy Expert Group (BCTEG) was convened in March 2018 in an effort to discuss and clarify, from the perspective of the practicing community oncologist, recent developments in the diagnosis and treatment of HER2-positive (HER2⁺) breast cancer. Members of the group selected 4 key topics for discussion prior to the meeting, including diagnosis of HER2⁺ disease, and its treatment in the neoadjuvant, adjuvant, and metastatic settings. Approved testing methods, such as immunohistochemistry and fluorescence in situ hybridization, are used to demonstrate overexpression and/or amplification of HER2 in breast tumors, and established clinical guidelines are used to appropriately define treatment plans for patients with HER2⁺ disease. The panel acknowledges a range of treatment options now available for treatment of HER2⁺ breast cancer in the neoadjuvant, adjuvant, and advanced/metastatic settings, although it is noted that many controversies remain, including the optimal sequence of therapies, the most appropriate treatment(s) for subsets of patients with HER2⁺ disease (eg, hormone receptor-negative or -positive/HER2⁺), and uncertainties surrounding the diagnosis and definition of HER2⁺ disease. The current report summarizes the discussion of the BCTEG panel on this topic.     

Body Mass Index and Hormone Receptor Status Influence Recurrence Risk in HER2-Positive Early Breast Cancer Patients

IntroductionA reliable risk stratification on the basis of tumor biology and host factors of HER2-positive (HER2⁺) early breast cancer (eBC) patients is needed. The aim of our study was to assess the prognostic role of body mass index (BMI) and hormone receptor (HR) expression in this setting.Patients and MethodsWe retrospectively evaluated 238 women with stage I to III HER2⁺ breast cancer who completed adjuvant chemotherapy (CHT) and 1 year of treatment with trastuzumab. The end point was 3-year distant disease-free survival (3yDDFS). Survival analysis was evaluated using the Kaplan–Meier method. Multivariate analysis was performed using Cox proportional-hazards model adjusting for HR status, BMI, tumor staging, size, nodal status, and type of adjuvant CHT. Association among categorical variables was assessed using χ² test.ResultsThe early recurrence rate after 3 years resulted as 4.2% (40% HR⁺ patients and 60% HR⁻ patients). Neither HR status nor BMI alone showed an association with 3yDDFS in multivariate analysis. However, the hazard ratios for patients with HR⁻ tumors who had also BMI ≥25 (3yDDFS 86.9%; 95% confidence interval [CI], 75.0%-97.7%) were amplified compared with patients with HR⁺ tumors and with BMI <25 (3yDDFS 98%; 95% CI, 94.8%-100.0%) and other subgroups (P = .003). This observation was confirmed in multivariate analysis (hazard ratio, 1.79; 95% CI, 1.04-3.07; P = .03).ConclusionOur real-life data highlight a different risk of eBC recurrence after grouping patients according to HR status and BMI. These results might help clinicians to identify correct treatment strategies. Patients who are HR⁻ and have BMI ≥25 might benefit from escalation approaches, whereas those who are HR⁺ and have BMI <25 might be eligible for a shorter duration of adjuvant treatment with anti-HER2 agents.     

T-DM1 Efficacy in Patients With HER2-positive Metastatic Breast Cancer Progressing After a Taxane Plus Pertuzumab and Trastuzumab: An Italian Multicenter Observational Study

BackgroundT-DM1 improves progression-free survival (PFS) and overall survival (OS) in patients with metastatic human epidermal growth factor receptor 2-positive (HER2⁺) breast cancer progressing on prior trastuzumab plus a taxane. A paucity of data is available on T-DM1 efficacy after dual anti-HER2 blockade with pertuzumab and trastuzumab plus a taxane, which represents the current first-line standard of care. The present study is a retrospective/prospective evaluation of the efficacy and activity of second-line T-DM1 after front-line pertuzumab-based therapy.Patients and MethodsEligible patients were identified within the Gruppo Italiano Mammella (GIM) 14/BIOMETA study, a retrospective/prospective multicenter study on treatment patterns and outcomes of patients with metastatic breast cancer (ClinicalTrials.gov Identifier: NCT02284581). We searched for patients who received second-line T-DM1 after taxane plus trastuzumab and pertuzumab between November 15, 2013 and May 31, 2018. We calculated median PFS, median time to treatment failure (TTF), prolonged duration of therapy (PDT), objective response rate (ORR), and 1-year OS.ResultsOf 445 patients with HER2⁺ metastatic breast cancer, 77 were eligible for the analysis. At a median follow-up of 7 months, median PFS was 6.3 months (95% confidence intervals [CI], 4.8-7.7 months), and median TTF was 6.2 months (95% CI, 4-8.6 months). More than one-third of patients (37.6%; n = 29) experienced PDT with an ORR of 27.1%. At data cutoff, the median OS was not reached, and the 1-year OS was 82%.ConclusionsOur results show meaningful activity of T-DM1 after front-line pertuzumab plus trastuzumab and a taxane, with about 27% of patients having an objective response and 40% of patients achieving durable disease control.     

Cardiac toxicity of trastuzumab in elderly patients with breast cancer

Breast cancer (BC) is diagnosed in ≥ 65 year old women in about half of cases. Experts currently recommend that systemic therapy is offered to elderly patients with BC, if, based on their overall conditions and life expectancy, it can be reasonably anticipated that the benefits will outweigh the risks of treatment. Like for young subjects, the monoclonal antibody against human epidermal growth factor receptor-2 (HER-2), trastuzumab, represents a valid therapeutic option when BC over-expresses this receptor. Unfortunately, administration of trastuzumab is associated with the occurrence of left ventricular dysfunction and chronic heart failure (CHF), possibly because of interference with the homeostatic functions of HER-2 in the heart. Registry-based, retrospective analyses have reported an incidence of CHF around 25% in elderly women receiving trastuzumab compared with 10%–15% in those not given any therapy for BC, and the risk of CHF has been estimated to be two-fold higher in > 60–65 year old trastuzumab users vs. non-users. Extremely advanced age and preexisting cardiac disease have been shown to predispose to trastuzumab cardiotoxicity. Therefore, selection of older patients for treatment with trastuzumab should be primarily based on their general status and the presence of comorbidities; previous chemotherapy, especially with anthracyclines, should be also taken into account. Once therapy has started, efforts should be made to ensure regular cardiac surveillance. The role of selected biomarkers, such as cardiac troponin, or new imaging techniques (three-dimension, tissue Doppler echocardiography, magnetic resonance imaging) is promising, but must be further investigated especially in the elderly. Moreover, additional studies are needed in order to better understand the mechanisms by which trastuzumab affects the old heart.     

Enhanced Anti-tumor Effect of Trastuzumab in Combination with Cisplatin

The oncogenenic transmembrane tyrosine kinase receptor HER–2/neu is a promising target for treatment of HER–2–overexpressing cancers. The humanized anti-HER–2/neu antibody Trastuzumab is under clinical evaluation in combination with chemotherapy against breast cancer. The combination of Trastuzumab and cisplatin is expected to be active against HER–2/neu-expressing tumors. We examined the mechanisms of this combination effect against human solid tumor cells in the presence of human peripheral blood mononuclear cells (PBMCs) using an in vitro MTT assay. The growth-inhibitory effects of cisplatin (CDDP) on the tumor cells were not significantly affected by Trastuzumab in the absence of effector cells. CDDP alone at a dose of less than 12.5 μ M did not affect the viability of PBMCs, as determined by MTT assay, suggesting that PBMCs could exert antibody-dependent cell-mediated cytotoxicity (ADCC) at this CDDP concentration. The combination of Trastuzumab and CDDP showed higher cytotoxic effects against the tumor cells in the presence of PBMCs. The CDDP concentration required to inhibit tumor cell growth by 50% was reduced to ∼20% by Trastuzumab in the presence of PBMCs at an effector/target ratio of 10. It may be important to select combined chemotherapeutic agents which do not diminish the ADCC activity of Trastuzumab via PBMCs. Both the expression of HER–2/neu and the ADCC activity may be important determinants of the therapeutic benefit of the Trastuzumab/CDDP combination.     

Pathological complete response to trastuzumab and paclitaxel in a patient with inflammatory local recurrence following breast conserving surgery

We encountered a case of inflammatory local recurrence of breast cancer after breast conserving surgery which attained pathological CR after combination therapy with trastuzumab and paclitaxel. The patient was a 49-year-old premenopausal woman whose left breast cancer(T2N0M0)was treated by breast conserving surgery (Bp+Ax). The pathological diagnosis was scirrhous carcinoma, g, ly1, v0, t2, n0, ER (-), PgR (+) and stage I A. Postoperatively, the residual breast was treated by 50 Gy irradiation followed by hormone therapy(Tamoxifen citrate+LH-RH analog). At 26 months after the surgery, local recurrence developed as inflammatory breast cancer. As the recurrent tumor was confirmed to be HER2-positve (3+ by IHC), combination therapy with trastuzumab and paclitaxel was started. After the 6 courses of pharmacotherapy were completed, she was judged to have clinical CR, and subsequently underwent total breast excision(Bt)and skin grafting. No visible cancer cell was observed in the resected specimens, pathological CR was diagnosed. Postoperatively, the patient is receiving trastuzumab alone every other week, and at present 10 months after the second operation, the patient is in CR status and is visiting the outpatient clinic. No severe side effects (over grade 3) from this therapy have been observed. It is suggested that combination therapy with trastuzumab and paclitaxel for inflammatory local recurrence after breast conserving surgery is a treatment of choice.     

Translational research in breast cancer

Translational research (TR) involves both the development of novel diagnostics and novel therapeutics. These two major developmental areas are often associated with each other and these associations often bring new paradigms in the management of cancer patients. For example, the development of trastuzumab-based treatments has been conducted in harmony with the development of new methodologies to assess the expression of the Her-2 gene or protein, and from this, a therapeutic modality was established for breast cancer patients as a novel and individualized treatment system. TR covers a broad spectrum, from diagnosis to treatment, and it seems to act as a catalyst for developing novel paradigms. Therefore, it is crucial to conduct TR in clinical trials, in particular, prospective clinical trials. In this regard, TR can accelerate the development of new methodologies and increase trial efficiency. In this review, we describe the importance of TR, particularly that related to novel therapeutics.     

Current status of antibody therapy for breast cancer

Antibody therapy with trastuzumab has greatly impacted breast cancer treatment. Combination treatment with trastuzumab is regarded currently as a first-line therapy for metastatic breast cancers that overexpress Her-2. It has become routine practice to examine the status of Her-2 expression in primary tumors. The impact of this therapy might be as great as that of endocrine therapy from a historical point of view. A number of new approaches using trastuzumab for seeking individualized treatment are being tested in current clinical trials. We reviewed recent advances in trastuzumab treatment and discuss the future of antibody therapy for breast cancer.