Trastuzumab (herceptin)

Herceptin (trastuzumab) is a human monoclonal antibody that interferes with the HER2 receptor. It is currently the only FDA-approved therapeutic antibody for HER2-positive breast cancer. This article will present the mechanism at action as well as the clinical role at this monoclonal antibody.     

曲妥珠单抗耐药机制及对策研究进展

曲妥珠单抗是靶向人表皮生长因子2(c-erbB-2,HER2)的单克隆抗体,治疗HER2阳性乳腺癌疗效确切,然而其客观反应率并不高,而且多数患者在1年内出现获得性耐药.目前的基础研究初步解释了曲妥珠单抗耐药的分子机制,一些新的治疗策略为曲妥珠单抗耐药患者带来新的希望.本文综述了近年来有关曲妥珠单抗的耐药机制及其应对策略的研究进展.     

Metabolite production in patients with lymphoma after radiometal-labeled antibody administration.

Radiometal-labeled monoclonal antibodies are retained longer in tumors than iodinated antibodies, leading to their increased use for radioimmunotherapy. Dissociation of radioiodine from the antibody during metabolism has been documented. We now report metabolites in the plasma of lymphoma patients given 111In- and 90Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid-Lym-1 (111In/90Y-2IT-BAD-Lym-1). METHODS: Nineteen patients with non-Hodgkin's lymphoma (NHL) received 111In- and 90Y-2IT-BAD-Lym-1; 111In was used as a surrogate tracer for 90Y, which emits no gamma-photon. Plasma was obtained up to 7 d and analyzed by high-performance liquid chromatography to determine the fraction of radiolabel associated with monomeric antibody, metabolites, and complexed antibody. Planar images of conjugate views were acquired up to 7 d and used to quantitate 111In in organs and tumors. RESULTS: Metabolites and complexes were observed in the plasma of every patient who received 111In-2IT-BAD-Lym-1. At 3 d, the mean percentages of 111In in the patients' plasma in monomeric, metabolite, and complexed forms were 54%, 36%, and 10%, respectively. Metabolites of 90Y-2IT-BAD-Lym-1 were formed to a similar extent. In comparison, in groups of breast and prostate cancer patients who received the radioimmunoconjugate 111In-2IT-BAD-m170, 91% and 94% of 111In in the patients' plasma were in monomeric form, respectively. Metabolites and complexes of 111In-2IT-BAD-Lym-1 contributed a mean 10% of the total area under the time-activity curve (AUC) for blood. Little formation of metabolites and complexes occurred in vitro in NHL patient or volunteer plasma or in Raji cell culture. The clinical and in vitro data supported the processing of 111In/90Y-2IT-BAD-Lym-1 in the hepatocytes as the dominant mechanism for the production of metabolites. CONCLUSION: Metabolites of 111In/90Y-2IT-BAD-Lym-1 accounted for 10% of blood AUC in patients. The therapeutic index was adversely affected by metabolism of 111In/90Y-2IT-BAD-Lym-1 to the extent that the tumor specificity of the radioactive metabolites was lost.     

Relationship between hormonal receptors, HER-2, p53 protein, Bcl-2, and MIB-1 status and the antitumor effects of neoadjuvant anthracycline-based chemotherapy in invasive breast cancer patients

PURPOSE: The purpose of this study was to evaluate the predictive value of six different biological factors for neoadjuvant chemotherapy (NAC) in breast conservation treatment (BCT) for invasive breast cancer. MATERIALS AND METHODS: Thirty invasive breast cancer patients (31 breasts) who received NAC as BCT and needle biopsy before chemotherapy were included in this study. Breast cancer tissue was obtained with an 18G core needle with ultrasound guidance. Patients received two to five courses of CAF (cyclophosphamide 600 mg/m(2), pirarubicin 20-40 mg, 5-fluorouracil 600 mg/m(2)). Tissue sections from formalin-fixed paraffin-embedded blocks were stained for the presence of estrogen receptor (ER), progesterone receptor (PgR), HER (human epidermal growth factor receptor)-2, p53 protein, Bcl-2, and MIB-1 (Ki-67). Tumor reduction rate was assessed by MRI before and after chemotherapy. RESULTS: The tumor reduction rate did not differ according to the number of courses of chemotherapy administered. In both the univariate and multivariate analyses, HER-2-negative status was the only significant predictive factor of response (P<0.05). There was no correlation between response and hormone receptors, MIB-1, p53 protein, or Bcl-2 expression. CONCLUSION: This study suggests that breast cancer cells that overexpress HER-2 may be resistant to low-doses of anthracycline-based chemotherapy.     

The role of ultrasonographic findings to predict molecular subtype,histologic grade,and hormone receptor status of breast cancer

PURPOSE

The correlation between imaging findings and pathologic characteristics of tumors may provide information for diagnosis and treatment of cancer. The aim of this study is to determine whether ultrasound features of breast cancer are associated with molecular subtype, histologic grade, and hormone receptor status, as well as assess the predictive value of these features.

METHODS

A total of 201 consecutive invasive breast cancer patients were reviewed from the database according to the Breast Imaging and Reporting Data System (BI-RADS). Tumor margins were classified as circumscribed and noncircumscribed. Noncircumscribed group was divided into indistinct, spiculated, angular, and microlobulated. The posterior acoustic features were divided into four categories: shadowing, enhancement, no change, and mixed pattern.

RESULTS

Tumors with posterior shadowing were more likely to be of nontriple negative subtype (odds ratio [OR], 7.42; 95% CI, 2.10–24.99; P = 0.002), low histologic grade (grade 1 or 2 vs. grade 3: OR, 2.42; 95% CI, 1.34–4.35; P = 0.003) and having at least one positive receptor (OR, 3.36; 95% CI, 1.55–7.26; P = 0.002). Tumors with circumscribed margins were more often triple-negative subtype (OR, 6.72; 95% CI, 2.56–17.65; P < 0.001), high grade (grade 3 vs. grade 1 or 2: OR, 5.42; 95% CI, 2.66–11.00; P < 0.001) and hormone receptor negative (OR, 4.87; 95% CI, 2.37–9.99; P < 0.001).

CONCLUSION

Sonographic features are strongly associated with molecular subtype, histologic grade, and hormone receptor status of the tumor. These findings may separate triple-negative breast cancer from other molecular subtypes.Breast cancer is the most common malignant tumor and the major cause of death from cancer among women worldwide. Breast cancer is also a heterogeneous and complex disease with different morphologic, biologic, and molecular characteristics (1). Although histopathologic characteristics of tumors have been used to determine prognosis and treatment of breast cancer, they do not provide sufficient information due to tumor heterogeneity. For this reason, several distinct molecular subtypes of breast cancer have been defined based on gene expression patterns (2). The St. Gallen International Expert Consensus determined a new biologic classification system based on the expression of tumor markers: estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2–neu (HER2), and more recently, Ki-67, which are evaluated routinely because of their utility in guiding clinical care. The classification system categorizes invasive breast carcinomas into five molecular subtypes: luminal A, luminal B (HER 2−), luminal B (HER 2+), HER 2, and triple-negative (1–5).Molecular subtyping of breast cancer is a common practice for individualized cancer management, to understand prognosis of disease and avoid overtreatment. Radiologic imaging has an important role in diagnosis, staging, treatment, and follow-up of patients with breast cancer, and it may also help to predict molecular subtypes of patients with breast cancer for guiding treatment (4, 5). It is important for breast radiologists to understand the differences of these molecular subtypes.Many studies have already determined the imaging features of breast cancer and a few studies focused on the association between ultrasonography (US) findings, different histologic grades, and hormone receptor status. However, the relationship between US features and molecular subtypes is not clear yet. The prediction of triple-negative molecular sub-type by US may be important for diagnosis, prognosis, treatment, and understanding of the biologic behavior. It may also predict treatment efficacy of breast cancer. The purpose of our study was to investigate whether US features (e.g., tumor margins and posterior acoustic features) of breast cancer are associated with molecular subtypes, histologic grade, and hormone receptor status, as well as assess the predictive value of these features.     

18F-FDG PET/CT评估三阴性乳腺癌新辅助化疗疗效的研究进展

三阴性乳腺癌（TNBC）是一种雌激素受体（ER）、孕激素受体（PR）及人表皮生长因子受体2（HER-2）表达均为阴性的乳腺癌亚型,常发生于绝经前的女性,具有预后较差、5年生存率低、侵袭性强、易复发及发生远处转移等特征。目前TNBC主要的治疗方法是手术与化疗,其中新辅助化疗的应用也越来越广泛。近年来,18F-FDG PET/CT在乳腺癌治疗评估中的价值已被广泛研究,PET/CT监测乳腺癌新辅助化疗疗效的价值已得到肯定。该文对18F-FDG PET/CT评估TNBC新辅助化疗疗效的研究进展进行综述。     

The curability of breast cancer and the treatment of advanced disease

Breast cancer represents a major health problem, with more than 1,000,000 new cases and 370,000 deaths yearly worldwide. In the last decade, in spite of an increasing incidence, breast cancer mortality has been declining in the majority of developed countries. This is the combined result of better education, widespread screening programmes and more efficacious adjuvant treatments. Better knowledge of breast cancer biology now allows the cosmetic, physical and psychological consequences of radical mastectomy to be spared in the majority of breast cancer patients. Use of the sentinel node technique is rapidly expanding and this will further reduce the extent and the consequences of surgery. Several clinico-pathological factors are used to discriminate between patients at low (<10%), average (10-40%) and high risk of relapse. Nodal status, tumour size, tumour grade and age are accepted universally as important factors to define risk categories. Newer factors such as uPA/PAI-1, HERer2-neu, proliferative indices and gene expression profile are promising and will allow better discrimination between patients at different risk. Endocrine manipulation with tamoxifen, ovarian ablation or both is the preferred option in the case of endocrine-responsive tumours. Tamoxifen administered for 5 years is the standard treatment for postmenopausal patients; tamoxifen plus ovarian ablation is more effective than tamoxifen alone for premenopausal women. Recent data demonstrate that, for postmenopausal patients, the aromatase inhibitors are superior to tamoxifen, with a different safety profile. At present, anastrozole can be used in the adjuvant setting in cases of tamoxifen intolerance or toxicity. Chemotherapy is the treatment of choice for steroid receptor-negative tumours. Polychemotherapy is superior to single agents and anthracycline-containing regimens are superior to CMF. Six courses of FEC or FAC or the sequential administration of four doses of anthracycline followed by four of CMF are the recommended regimens. New regimens including the taxanes have produced a further improvement in risk reduction and are reasonable therapeutic options. The taxanes have been approved for adjuvant therapy in the USA, while European approval is pending. Combined endocrine-chemotherapy is the standard adjuvant treatment in high-risk patients with endocrine-responsive tumours. Endocrine manipulation is usually administered after completion of the chemotherapy programme. For HER2-neu overexpressing tumours, several rapidly accruing trials are exploring the potential additive effect of trastuzumab, a monoclonal antibody directed against the extramembrane portion of the HER2 receptor. Primary chemotherapy is increasingly used in the treatment of locally advanced and operable breast cancer, with increased rates of breast-conserving surgery. A proportion of patients achieve a pathological complete response and these patients have significantly better long-term outcomes. Twenty-five to forty percent of breast cancer patients develop distant metastases. At this stage the disease is incurable; however, treatments can assure a significant prolongation of survival, symptomatic control and maintenance of quality of life. In the case of hormone receptor positivity and in the absence of visceral, life-threatening disease, endocrine manipulation is the treatment of choice. Active treatments include tamoxifen, ovarian ablation, aromatase inhibitors, pure anti-oestrogens and progestins. Aromatase inhibitors are the most active agents, but the choice and the sequence of endocrine therapies are also dictated by prior adjuvant treatment. Chemotherapy has to be preferred in cases of receptor-negative tumours, acquired resistance to hormones and aggressive visceral disease. Combination regimens are usually associated with higher response rates and sometimes survival prolongation, and this approach should be recommended in young patients with good performance status and visceral disease. On the other hand, single agents have a better tolerability profile and should be tand should be the treatment of choice when a careful balance between activity and tolerability is needed. For HER2-neu positive tumours, the combination of trastuzumab and chemotherapy is significantly superior to chemotherapy alone in terms of both response rates and survival. Other useful palliative treatments include bisphosphonates for the control of metastatic bone disease and radiotherapy for painful bone lesions or local relapses.     

Correlation of Primary Tumor FDG Uptake with Clinicopathologic Prognostic Factors in Invasive Ductal Carcinoma of the Breast

Purpose

The purpose of this study was to investigate the correlation of primary tumor FDG uptake to clinicopathological prognostic factors in invasive ductal carcinoma of the breast.

Methods

We retrospectively reviewed 136 of 215 female patients with pathologically proven invasive ductal breast cancer from January 2008 to December 2011 who underwent F-18 FDG PET/CT for initial staging and follow-up after curative treatment with analysis of estrogen receptor (ER), progesterone receptor (PR) and human epithelial growth factor receptor 2 (HER2). The maximum standardized uptake value (SUVmax) of the primary breast tumor was measured and compared with hormonal receptor and HER2 overexpression status.

Results

The high SUVmax of primary breast tumors is significantly correlated with the clinicopathological factors: tumor size, histologic grade, TNM stage, negativity of ER, negativity of PR, HER2 overexpression and triple negativity. The recurrent group with non-triple negative cancer had a higher SUVmax compared with the non-recurrent group, though no significant difference in FDG uptake was noted between the recurrence and non-recurrent groups in subjects with triple-negative cancer. Lymph node involvement was the independent risk factor for cancer recurrence in the multivariate analysis.

Conclusions

In conclusion, high FDG uptake in primary breast tumors is significantly correlated with clinicopathological factors, such as tumor size, histologic grade, TNM stage, negativity of the hormonal receptor, HER2 overexpression and triple negativity. Therefore, FDG PET/CT is a helpful prognostic tool to direct the further management of patients with breast cancer.     

Mammographic and clinicopathological features of triple-negative breast cancer

Objective:

Triple-negative breast cancer (TNBC) lacks effective treatment and has a poor prognosis. This study assessed mammographic findings and clinicopathological features of TNBC by comparing with non-TNBC in order to improve clinical diagnosis of TNBC.

Methods:

A total of 426 patients with pathologically confirmed breast cancer were retrospectively assigned into two groups, TNBC (n = 54) and non-TNBC (n = 372), and then analysed.

Results:

TNBC frequently showed a high histological grade, presented with a mass (79.6%) and was less frequently associated with focal asymmetric density (11.1%), microcalcifications (5.6%) and distortion (3.7%) on mammography. TNBC mammographic masses were most frequently round/oval (58.1%) or lobular (30.2%) in shape and were less frequently irregular in shape (11.6%). Masses with circumscribed margins were the most frequent (37.2%), with microlobulated (25.6%) and obscured (16.3%) margins being commonly observed, but masses with spiculated margins were rare (9.3%).

Conclusion:

TNBC could have distinct mammographic and clinicopathological features compared with non-TNBC, and thus mammography may be useful in the diagnosis of TNBC.

Advances in knowledge:

This study demonstrated distinct mammographic and clinicopathological features to help in diagnosis of Chinese patients with TNBC.Breast cancer is the most common malignancy observed in females. Histologically, breast cancer is a heterogeneous disease with different subtypes and pathology, treatment options and prognosis.¹ Bryan et al² for the first time in 2006 explicitly presented the definition of triple-negative breast cancers (TNBCs) based on the expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Other studies using gene expression profiling were able to classify breast cancer into five subtypes.^3,4 To date, TNBC is used frequently as a standard procedure to classify breast cancer patients for clinical care. TNBC is similar to the basal-like subtype, which is characterized by negative ER, PR and HER2 expression, and is associated with aggressive histology, poor prognosis and unresponsiveness to the endocrine therapies.^5,6 Moreover, TNBC has been used as a surrogate marker for the basal-like breast cancer, and approximately 80–90% of TNBCs are basal-like breast cancers.⁷ Younger females have a higher rate of basal or breast cancer susceptibility gene mutation-related TNBC, whereas older females have a higher proportion of apocrine, normal-like and rare subtypes of TNBC, including neuroendocrine TNBC.⁸ Because only fewer specific targeting therapies and molecular therapies (such as endocrine or target therapy) are available than for other subtypes of breast cancer, the standard treatment for TNBC includes surgery combined with adjuvant chemotherapy and radiotherapy, but clinical outcome is poor.^7,9 Thus, early detection of this subtype of breast cancer is vital to improve the survival of patients.Although TNBC has been studied extensively in clinical and pathological literature, there are few reports on the radiological characteristics of this subtype of breast cancer. To date, mammography is known to be a precise diagnostic technique with high sensitivity and specificity in the evaluation of breast lesions, and the current reference standard in breast cancer screening is mammography with the sensitivity to detect early-stage breast cancer. Therefore, this study evaluated the mammographic and clinicopathological features of TNBC by comparing these features to those of non-TNBC in order to make a more precise diagnosis.     

Triple receptor-negative breast cancer: imaging and clinical characteristics

OBJECTIVE: The objective of our study was to retrospectively evaluate the imaging findings of patients with breast cancer negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)-so-called "triple receptor-negative cancer"-and to compare the mammographic findings and clinical characteristics of triple receptor-negative cancer with non-triple receptor-negative cancers (i.e., ER-positive, PR-positive, or HER2-positive or two of the three markers positive). CONCLUSION: Triple receptor-negative cancer was most commonly an irregular noncalcified mass with ill-defined or spiculated margins on mammography and a hypoechoic or complex mass with an irregular shape and noncircumscribed margins on ultrasound. Most triple receptor-negative cancers were discovered on physical examination. Compared with non-triple receptor-negative cancers, triple receptor-negative cancers were found in younger women and were a higher pathologic grade.     

In vitro cytotoxicity of 211At-labeled trastuzumab in human breast cancer cell lines: effect of specific activity and HER2 receptor heterogeneity on survival fraction

INTRODUCTION: Radioimmunotherapy with anti-HER2 monoclonal antibodies (mAbs) such as trastuzumab is a promising strategy for treating HER2-positive breast and ovarian carcinoma patients. The objective of this study was to determine the cytotoxic effectiveness of trastuzumab labeled with the 7.2-h half-life alpha-particle emitter 211At. METHODS: Experiments were performed on SKBr-3, BT-474 and the transfected MCF7/HER2-18 human breast carcinoma cell lines. Intrinsic radiosensitivity was determined after exposure to external beam irradiation. The cytotoxicity of 211At-labeled trastuzumab was measured by clonogenic assays. The distribution of HER2 receptor expression on the cell lines was measured using fluorescence-activated cell sorting. A pharmacokinetic (PK)/microdosimetric model was established to assess the effects of specific activity (SA), HER2 receptor expression and absorbed dose on survival fraction (SF). RESULTS: With external beam irradiation, the 2-Gy SF for BT-474, SKBr-3 and MCF7/HER2-18 cells was 0.78, 0.53 and 0.64 Gy, respectively. Heterogeneous HER2 expression was observed, with a subpopulation of cells lacking measurable receptor (14.5%, SKBr-3; 0.34%, MCF-7/HER2; 1.73%, BT-474). When plotted as a function of activity concentration, SF curves were biphasic and inversely proportional to SA; however, when the model was applied and absorbed doses calculated, the SF curve was monoexponential independent of SA. Thus, the PK model was able to demonstrate the effects of competition between cold and labeled mAb. These studies showed that the relative biological effectiveness of 211At-labeled trastuzaumab was about 10 times higher than that of external beam therapy. CONCLUSION: These in vitro studies showed that 211At-labeled trastuzumab mAb is an effective cytotoxic agent for the treatment of HER2-positive tumor cells. The SA of the labeled mAb and the homogeneity of HER2 receptor expression are important variables influencing the efficiency of cell killing.     

HER2的表达及其分子影像的研究进展

人表皮生长因子受体2（HER2）是一种具有酪氨酸激酶活性的跨膜受体，同时也是一种高表达于各种癌细胞的生物标志物。高表达HER2的肿瘤往往预后不良。HER2分子影像主要是利用放射性核素、磁性材料、发光物质等标记配体能与HER2特异性结合的特性，对患者体内HER2高表达病灶进行显像，从而协助HER2阳性疾病的诊断，筛选出抗HER2治疗有效的患者，并可用于疗效评估，是近年来肿瘤精准医疗研究的热点之一。     

Dual-labeled trastuzumab-based imaging agent for the detection of human epidermal growth factor receptor 2 overexpression in breast cancer.

Overexpression of the human epidermal growth factor receptor (HER) family has been implicated in cancer because of its participation in signaling pathways regulating cellular proliferation, differentiation, motility, and survival. In this work, we exploited the extracellular binding property of trastuzumab, a clinically therapeutic monoclonal antibody to the second member of the HER family (HER2), to design a diagnostic imaging agent, ((111)In-DTPA)(n)-trastuzumab-(IRDye 800CW)(m), that is dual labeled with (111)In, a gamma-emitter, and a near-infrared (NIR) fluorescent dye, IRDye 800CW, to detect HER2 overexpression in breast cancer cells. The stoichiometric ratios "n" and "m" refer to the number of diethylenetriaminepentaacetic acid dianhydride (DTPA) and IRDye 800CW molecules bound per trastuzumab molecule, respectively. METHODS: Fluorescence microscopy and confocal microscopy were used to determine the molecular specificity of (DTPA)(n)-trastuzumab-(IRDye800)(m) in vitro in SKBr3 (HER2-positive) and MDA-MB-231 (HER2-negative) breast cancer cells. SKBr3 cells were incubated with (DTPA)(n)-trastuzumab-(IRDye800)(m) or IRDye800CW or pretreated with trastuzumab or human IgG followed by (DTPA)(n)-trastuzumab-(IRDye800)(m) and examined under a fluorescence microscope. For in vivo characterization, athymic nude mice bearing HER2-overexpressing SKBr3-luc subcutaneous xenografts were injected intravenously with ((111)In-DTPA)(n)-trastuzumab-(IRDye800)(m) and imaged with SPECT and NIR fluorescence imaging at 48 h. Tumor-bearing mice were also injected intravenously with trastuzumab 24 h before administration of ((111)In-DTPA)(n)-trastuzumab-(IRDye800)(m). Nonspecific uptake in the SKBr3-luc tumors was analyzed by injecting the mice with IRDye 800CW and ((111)In-DTPA)(p)-IgG-(IRDye800)(q), where "p" and "q" are the stoichiometric ratios of DTPA and IRDye 800CW bound per IgG antibody, respectively. RESULTS: (DTPA)(n)-trastuzumab-(IRDye800)(m) showed significantly greater binding to SKBr3 cells than to MDA-MB-231 cells. Confocal imaging revealed that this binding occurred predominantly around the cell membrane. Competitive binding studies with excess trastuzumab before incubation with (DTPA)(n)-trastuzumab-(IRDye800)(m) abolished this binding affinity, but pretreatment with nonspecific IgG did not alter binding. In vivo nuclear and optical imaging of SKBr3-luc xenografts injected with ((111)In-DTPA)(n)-trastuzumab-(IRDye800)(m) revealed significantly more uptake in the tumor region than in the contralateral muscle region. The tumor-to-muscle ratio decreased in mice pretreated with trastuzumab and in mice injected with IRDye 800CW and ((111)In-DTPA)(p)-IgG-(IRDye800)(q). Ex vivo imaging of dissected organs confirmed these results. Finally, coregistration of histologic hematoxylin-eosin stains with autoradiography signals from tumor and muscle tissue slices indicated that ((111)In-DTPA)(n)-trastuzumab-(IRDye800)(m) bound only in tumor tissue and not to muscle. CONCLUSION: Dual-labeled ((111)In-DTPA)(n)-trastuzumab-(IRDye800)(m) may be an effective diagnostic biomarker capable of tracking HER2 overexpression in breast cancer patients.     

Current status of cancer therapy with radiolabeled monoclonal antibody

Molecular targeting therapy has become a relevant therapeutic strategy for cancer. There are several monoclonal antibodies used for the treatment of malignant tumors. Radioimmunoconjugate is composed of antibody and radionuclide showing a synergistic effect of radiation and immunemediated cellular toxicity and thereby enabling increased efficacy and minimizing toxicity. Radioimmunotherapy using 131I- and 90Y-labeled anti-CD20 monoclonal antibodies is now indicated for the treatment of patients with CD20 antigen-expressing relapsed or refractory, low-grade or transformed non-Hodgkin's lymphoma (NHL), including patients who are refractory to anti-CD20 monoclonal antibody (rituximab) therapy in the United States. It has been exhibiting favorable anti-tumor efficacy in patients with NHL as compared with rituximab. Myelosuppression is the main side effect associated with the radioimmunotherapy but is usually reversible, and nonhematologic adverse reactions are mild to moderate. Following the impressive results of therapy using radiolabeled monoclonal antibodies for NHL, radioimmunotherapy for solid tumors has been examined; however, the results were unfavorable and did warrant further clinical trials as a single agent. Future studies on radioimmunotherapy for solid tumors should focus on the new strategies of targeting such as locoregional administration for intraperitoneal dissemination, and combination therapy with chemotherapy or cytostatic therapy. Although radioimmunotherapy for NHL has shown excellent results comparable to aggressive chemotherapy without severe adverse effects, additional clinical trials should be performed to define the proper role of radioimmunoconjugates as a relevant strategy for cure of NHL.     

Prognostic value of breast MRI characteristics before and during neoadjuvant endocrine therapy in patients with ER+/HER2- breast cancer

Objective:To investigate whether BIRADS MRI characteristics before or during neoadjuvant endocrine therapy (NET) are associated with the preoperative endocrine prognostic index (PEPI) in ER+/HER2- breast cancer patients.Methods:This retrospective observational cohort study included 35 ER+/HER2- patients with 38 tumors (3 bilateral cases) treated with NET. The pre- and midtreatment (after 3 months) MRIs were evaluated by two breast radiologists for BIRADS imaging characteristics, shrinkage pattern, and radiologic response. PEPI was used as end point. PEPI is based on the post-treatment surgical specimen’s pT- and pN-stage, Ki67, and ER-status. Tumors were assigned PEPI-1 (good prognosis) or PEPI-2/3 (poor prognosis). We investigated whether pre- and midtreatment BIRADS characteristics were associated with PEPI.Results:Median patient age was 65 years (interquartile interval [IQI]: 53, 70). 17 tumors (44.7%) were associated with good prognosis (PEPI-1), and 21 tumors (55.3%) with poor prognosis (PEPI-2/3). A larger reduction in tumor size after 3 months of NET was significantly associated with PEPI; 10 mm (IQI: 5, 13.5) in PEPI-1 tumors vs 4.5 mm (IQI: 3, 7; p = .045) in PEPI-2/3 tumors. Other BIRADS characteristics, shrinkage pattern or radiologic response were not associated with PEPI.Conclusion:Only a larger reduction in tumor size on MRI after 3 months of NET was associated with PEPI-1 (good prognosis) in ER+/HER2- breast cancer patients.Advances in knowledge:MRI characteristics previously reported to be associated with prognosis during neoadjuvant chemotherapy are not necessarily associated with prognosis during NET in ER+/HER2- breast cancer patients.     

<Superscript>18</Superscript>F–FDG-PET/CT for systemic staging of patients with newly diagnosed ER-positive and HER2-positive breast cancer

Objectives

This study assesses ¹⁸F–FDG-PET/CT for patients with newly diagnosed estrogen receptor-positive/human epidermal growth factor receptor-negative (ER+/HER2-) and human epidermal growth factor receptor-positive (HER2+) breast cancer.

Methods

In this Institutional Review Board-approved retrospective study, our Healthcare Information System was screened for patients with ER+/HER2- and HER2+ breast cancer who underwent ¹⁸F–FDG-PET/CT prior to systemic or radiation therapy. The initial stage was determined from mammography, ultrasound, magnetic resonance imaging, and/or surgery.¹⁸F–FDG-PET/CT was evaluated to identify unsuspected extra-axillary regional nodal and distant metastases. The proportion of patients upstaged overall and stratified by stage and receptor phenotypes was calculated along with confidence intervals (CI).

Results

A total of 238 patients with ER+/HER2- and 245 patients with HER2+ who met inclusion criteria were evaluated. For patients with ER+/HER2-breast cancer, ¹⁸F–FDG-PET/CT revealed unsuspected distant metastases in 3/71 (4%) initial stage IIA, 13/95 (14%) stage IIB, and 15/57 (26%) stage III. For patients with HER2+ breast cancer, ¹⁸F–FDG-PET/CT revealed unsuspected distant metastases in 3/72 (4%) initial stage IIA, 13/93 (14%) stage IIB, and 13/59 (22%) stage III. The overall upstaging rate for IIB was 14% (95% confidence interval (CI): 9–20%).

Conclusions

¹⁸F–FDG-PET/CT revealed distant metastases in 14% (95% CI: 9–20%) of patients with stage IIB ER+/HER2- and HER2+ breast cancer, which is similar to upstaging rates previously seen in patients with stage IIB triple-negative breast cancer (15%, 95% CI: 9–24%). The detection of unsuspected distant metastases in these patients alters treatment and prognosis. NCCN guidelines should consider adding patients with stage IIB breast cancer for consideration of systemic staging with ¹⁸F–FDG-PET/CT at the time of initial diagnosis.

     

In vivo examination of 188Re(I)-tricarbonyl-labeled trastuzumab to target HER2-overexpressing breast cancer

IntroductionTrastuzumab (Herceptin), a humanized IgG1 monoclonal antibody directed against the extracellular domain of the HER2 protein, acts as an immunotherapeutic agent for HER2-overexpressing human breast cancers. Radiolabeled trastuzumab with β- or α emitters can be used as radioimmunotherapeutic agent for the similar purpose but with additional radiation effect.MethodsIn this study, trastuzumab was labeled with ¹⁸⁸Re for radioimmunotherapy of HER2/neu-positive breast cancer. ¹⁸⁸Re(I)-tricarbonyl ion, [¹⁸⁸Re(OH₂)₃(CO)₃]⁺, was employed as a precursor for directly labeling the monoclonal antibody with ¹⁸⁸Re. The immunoreactivity of ¹⁸⁸Re(I)-trastuzumab was estimated by competition receptor-binding assay using HER2/neu-overexpressive BT-474 human breast cancer cells. The localization properties of ¹⁸⁸Re(I)-trastuzumab within both tumor and normal tissues of athymic mice bearing BT-474 human breast cancer xenografts (HER2/neu-overexpressive) and similar mice bearing MCF-7 human breast cancer xenografts (HER2/neu-low expressive) were investigated.ResultsWhen incubated with human serum albumin and histidine at 25°C, ¹⁸⁸Re(I)-trastuzumab was found to be stable within 24 h. The IC₅₀ of ¹⁸⁸Re(I)-trastuzumab was found to be 22.63±4.57 nM. ¹⁸⁸Re(I)-trastuzumab was shown to accumulate specifically in BT-474 tumor tissue in in vivo biodistribution studies. By microSPECT/CT, the image of ¹⁸⁸Re localized BT-474 tumor was clearly visualized within 24 h. In contrast, ¹⁸⁸Re(I)-trastuzumab uptake in HER2-low-expressing MCF-7 tumor was minimal, and the ¹⁸⁸Re image at the localization of the tumor was dim.ConclusionThese results reveal that ¹⁸⁸Re(I)-trastuzumab could be an appropriate radioimmunotherapeutic agent for the treatment of HER2/neu-overexpressing cancers.     

三阴性乳腺癌的影像学研究进展

三阴性乳腺癌(triple-receptor negative breast cancer,TNBC)是指雌激素受体(estrogen receptor,ER)、孕激素受体( progesterone receptor,PR)及人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)均表达缺失的乳腺癌,具有特殊的生物学和临床痫理学特性,预后差.本文主要对三阴性乳腺癌的影像诊断进展(包括乳腺X线摄影、超声及磁共振影像)进行了综述.     

Heat shock protein 90 (Hsp90) chaperone complex inhibitor,Radicicol, potentiated radiation-induced cell killing in a hormone-sensitive prostate cancer cell line through degradation of the androgen receptor

Until now, there has not been enough information on how androgens or androgen deprivation may influence the response of cancer cells to radiation. In this study, the effect of dihydrotestosterone (DHT) on cellular proliferative activity and radiosensitivity was examined in a hormone-sensitive human prostate cancer cell line, LNCaP. In addition, the study also examined how a heat shock protein 90 (Hsp90) chaperone complex inhibitor modified the effect of DHT on the radiosensitivity of the cells, because binding of the androgen receptor (AR) to Hsp90 is required to maintain the stability and functioning of AR. The hormone-sensitive human prostate cancer cell line, LNCaP, was used. Radicicol was used as one of the known Hsp90 chaperone complex inhibitors, and the cells were incubated in the presence of this compound at a concentration of 500 nM. Cellular radiosensitivity was determined by the clonogenic assay; the changes in the protein expression were examined by Western blotting or immunofluorescence. DHT at a concentration of 1 nM caused enhancement of the proliferative activity and reduction of the radiosensitivity of the cells. Radicicol at a concentration of 500 nM abolished the DHT-induced decrease in cellular radiosensitivity and potentiated the radiation-induced cell killing synergistically. Consistent with the changes in the cellular radiosensitivity, radicicol degraded AR, Raf-1 and HER2/neu via reduced binding of AR to Hsp90, although selective degradation of HER2/neu caused by Herceptin, a monoclonal antibody against HER2, did not affect the cellular radiosensitivity. The results suggest that the Hsp90 chaperone complex may be a potential molecular target for potentiation of radiation-induced cell killing in a hormone-sensitive prostate cancer cell line.     

^131I-Herceptin在荷人乳腺癌裸鼠模型中的生物分布及抗肿瘤活性研究

目的探讨^131I-Herceptin在荷人乳腺癌裸鼠模型中的生物分布及其对人表皮生长因子2（HER2）高表达乳腺癌的放射免疫治疗疗效。方法^131I-Herceptin采用Iodogen法制备。15只HER2高表达乳腺癌裸鼠模型分为3组：^131I-Herceptin组、Herceptin组与空白对照组,每组5只。以肌肉为参照,注射后第3,6,9天显像观察肿瘤等组织的放射性摄取并计算肿瘤／肌肉（T／M）比值。注射后1～9d,测量肿瘤大小并计算肿瘤抑制率。第9天处死裸鼠,剥离肿瘤,计算肿瘤的每克组织百分注射剂量率（％ID／g）值并以Western—Blot法、反转录-聚合酶链反应（RT—PCR）法检测肿瘤组织HER2及癌胚抗原（CEA）蛋白及基因表达水平的变化。肿瘤T／M比值与其他脏器的差别、HER2及CEA基因表达水平、蛋白表达水平在各治疗组间的差异采用One—way ANOVA检验;^131I-Herceptin组和Herceptin组肿瘤抑制率的差异采用t检验。结果^131I-Herceptin的放化纯为94％,比活度约为37kBq／μg,在注射后第9天,T／M比值达4．11,显著高于其他组织（F=12．370,P〈0．05）;肿瘤摄取分数为（16．1±1．7）％ID／g,高于其他组织、器官（F=166．150,P〈0．01）。至治疗后9d,^131I-Herceptin组抑瘤率显著高于Herceptin组[（42．0±6．9）％与（23．2±3．8）％,t=5．321,P〈0．001]。^131I-Herceptin组HER2蛋白表达（0．435±0．087与0．557±0．043,t=2．811,P〈0．05）与基因表达（0．256±0．073与0．350±0．029,t=2．678,P〈0．05）均显著低于Herceptin组。^131I-Herceptin组CEA蛋白表达（0．537±0．048与0．607±0．029,t=2．800,P〈0．05）与基因表达（0．362±0．048与0．607±0．079,t=5．932,P〈0．001）均显著低于Herceptin组。结论^131I-Herceptin对HER2高表达的乳腺癌具有很高的靶向特性,能比Herceptin更有效地抑制乳腺癌细胞分裂、增殖、分化、存活,控制肿瘤生长。