Significance of Tyrosine Kinase Inhibitors in the Treatment of Metastatic Breast Cancer

Zusammenfassung

Vorklinische und klinische Studien zeigen, dass Tyro-sinkinase-Inhibitoren (TKI) Standardtherapien beim metastasierten Mammakarzinom (MBC) ergänzen könnten. HER-2 ist als Therapieziel unverändert interessant. Etliche neue zielgerichtete Substanzen richten sich gegen die epithelialen Wachstumsfaktorrezeptoren EGFR und HER-2 und werden, nach vorhergehender Trastuzumab-Therapie, gerade in klinischen Studien getestet. Lapatinib inhibiert HER-2 und EGFR. Als Monosubstanz hatte es nur eine niedrige Aktivität. Kombiniert mit zytotoxischen Substanzen zeigte Lapatinib eine gute Aktivität (Gesamt-Response-Rate (ORR) 24-27%) und moderate Toxizitäten. Neratinib, ein Pan-ErbB-TKI, zeigte eine ORR von 26%. Kombiniert mit Trastuzumab wurde es gut toleriert und war aktiv (ORR = 27%). Nach den positiven Bevacizumab-Studien bleibt die Anti-Angiogenese im Blickpunkt. Sunitinib hemmt den vaskulären endothelialen Wachstumsfaktorrezeptor (VEGFR), den Plättchen-Wachstumsfaktorrezeptor (PDGFR), c-kit und den Kolonien stimulierenden Faktor 1 (CSF-1)-Rezeptor. Die Monotherapie wurde vertragen und war mäβig effektiv. Kombinationsstudien laufen gerade. Die Toxizitäten von Docetaxel ± Sunitinib waren akzeptabel (ORR 72.2%). Pazopanib hemmt VEGFR, PDGFR und c-kit. Pazopanib ± Lapatinib war in der Kombination überlegen (progressionsfreies Überleben (PFS) = 27% vs. 19%). Axitinib hat ähnliche Targets und war mit Docetaxel dem Plazeboarm überlegen (ORR 40% vs. 23%), bei akzeptablen Nebenwirkungen. Imatinib blockt PDGFR und c-kit. Als Monotherapie hat es keine klinische Aktivität. Kombinationsstudien mit Chemothe-rapeutika laufen aktuell.     

Detection and Significance of Occult Axillary Metastatic Disease in Breast Cancer Patients

▪ Abstract: After clinical staging, the single most important prognostic factor for patients with newly diagnosed primary breast cancer is the presence or absence of detectable metastases to axillary lymph nodes when examined by conventional light microscopy. More sensitive methods of determination of lymph node status, such as evaluation of serial sections, immunohistochemical staining, and use of molecular biological assays increase the rate of detection of micrometastases. Although the feasibility of enhanced detection of occult axillary metastatic disease is well established, the prognostic significance of such detection is only recently starting to emerge. Furthermore, the enormous recent interest in the application of sentinel lymph node biopsy as an alternative to the evaluation of the entire axilla in patients with breast cancer makes the first-time detailed evaluation for micrometastases practically feasible. In this review the different methods of detecting micrometastatic disease in the axilla and the significance of such findings are discussed. ▪     

Prognostic Significance of the Combination of Biological Parameters in Breast Cancer

To evaluate whether the combination of biological parameters increases their prognostic value, the expression of epidermal growth factor receptor (EGFR), DNA ploidy, and estrogen receptor (ER) status were analyzed on 998 patients with breast cancer. Poor findings for each biological parameter were positive for EGFR, aneuploid for DNA ploidy, and negative for ER. According to the number of poor findings in these three parameters, the groups with none (309 cases), one (377 cases), two (161 cases), and three (151 cases) poor findings were classified. A significant ( P < 0.0001) difference was found in the disease-free survival (DFS) among the four groups. A multivariate analysis indicated the combination of three biological parameters to be an independently significant factor for DFS, while the relative risk gradually increased as the number of poor findings increased. In conclusion, the present study indicated a gradual increase in the prognostic significance as the number of combined biological parameters increased.     

Clinical Significance of the Metastatic Lymph-Node Ratio in Early Gastric Cancer

The metastatic lymph-node ratio has important prognostic value in gastric cancer; this study focused on its significance in early gastric cancer. In total, 1,472 patients with early gastric cancer underwent curative gastrectomy between 1992 and 2001. Of these, 166 (11.3%) had histologically proven lymph-node metastasis. Prognostic factors were identified by univariate and multivariate analyses. Metastasis was evaluated using the Japanese Classification of Gastric Carcinoma (JGC) and the Union Internationale Contre le Cancer/Tumor, Node, Metastasis (UICC/TNM) Classification. The metastatic lymph-node ratio was calculated using the hazard ratio. The cut-off values for the metastatic lymph-node ratio were set at 0, <0.15, ≥0.15 to <0.30, and ≥0.30. The numbers of dissected and metastatic lymph nodes were correlated, but the number of dissected lymph nodes and the metastatic lymph-node ratio was not related. The JGC and UICC/TNM classification demonstrated stage migration and heterogeneous stratification for disease-specific survival. The metastatic lymph-node ratio showed less stage migration and homogenous stratification. The metastatic lymph-node ratio may be a superior method of classification, which provides also accurate prognostic stratification for early gastric cancer patients.     

Modeling Metastatic Breast Cancer in Mice

Metastatic disease is the major cause of death in breast cancer patients. Patients presenting with metastases cannot be cured, and as a consequence, treatment is palliative and focuses on prolonging survival and maintaining quality of life. Numerous mouse models have been generated in which human breast cancer development and metastasis have been studied, ranging from spontaneous and carcinogen-induced models to transplantation models and genetically engineered mouse models. Here, we summarize past progress and highlight present developments in modeling breast cancer invasion and metastasis in genetically modified mice, and the impact it may have on the development of innovative anticancer therapies.     

Imaging Response and Residual Metastatic Axillary Lymph Node Disease after Neoadjuvant Chemotherapy for Primary Breast Cancer

Background

Although surgical management of the breast after neoadjuvant chemotherapy (NAC) may be governed by treatment response, axillary management continues to be determined by stage at presentation. Axillary ultrasound (AUS) with fine-needle aspiration (FNA) is used to detect lymph node (LN) metastases for pre-NAC staging, but imaging assessment of treatment response in the axilla remains undefined. We evaluated post-NAC axillary imaging and surgical pathology to understand how imaging might direct axillary surgery.

Methods

We evaluated pre- and post-NAC axillary imaging and clinicopathologic data in 272 patients who received NAC for primary breast cancer and underwent operation at our institution from 2010 to 2012. Treatment response on imaging was categorized as complete (CR), partial (PR), and none/progression (NR).

Results

Pre-NAC axillary staging classified patients as AUS negative/no FNA (n = 61), FNA/LN negative (n = 42), and FNA/LN positive (n = 169). Post-NAC axillary imaging included AUS (n = 146), MRI (n = 139), and PET-CT (n = 38). At operation, 128 of 272 patients (47 %) were LN positive: 23.3 % (24 of 103) of cN0 and 61.5 % (104 of 169) of cN1-AUS/FNA-positive patients at presentation. Of the 65 cN1-ypN0 patients, 58.1 % (25 of 43) had an imaging CR by US, 58.6 % (17 of 29) by MRI, and 84.6 % (11 of 13) by PET-CT. The sensitivity of post-NAC axillary imaging in detecting persistent LN metastases for cN1-AUS/FNA-positive patients was 69.8 % for US, 61.0 % for MRI, and 63.2 % for PET-CT.

Conclusions

Performance characteristics of AUS, MRI, and PET-CT, while informative, were inadequate to preclude surgical axillary staging of in breast cancer patients after NAC. Whether this information might be used to tailor surgical and postsurgical treatment requires further investigation.     

Ⅳ型胶原在乳腺癌中的表达及其意义

目的探讨Ⅳ型胶原蛋白在乳腺癌中的表达情况及其与临床病理间的关系.方法应用Ⅳ型胶原蛋白单克隆抗体,采用链亲和素(LSAB)法检测93例乳腺恶性肿瘤及5例良性肿瘤组织中Ⅳ型胶原蛋白的表达.结果Ⅳ型胶原蛋白表达与乳腺癌患者腋窝淋巴结受累、生存时间及肿瘤大小有关.Ⅳ型胶原蛋白表达缺乏组5年生存率为29.69%,明显低于表达完整组的5年生存率(81.43%),P＜0.05; 随着肿瘤的长大,Ⅳ型胶原表达完整率由53.8%降至10.3%,两者间呈正相关(r=0.219).结论检测Ⅳ型胶原在乳腺癌基底膜中的表达状况,将有助于乳腺癌预后的判断及治疗方案的制订.     

ADAM9在乳腺癌中的表达及意义

目的探讨去整合素金属蛋白酶9(ADAM9)在乳腺癌中的表达及意义。方法采用逆转录多聚酶链聚合反应(RT-PCR)法和免疫组织化学方法检测乳腺癌组织、距离癌旁≥5cm的正常乳腺组织及腋窝淋巴结组织中ADAM9的表达,并分析ADAM9表达与乳腺癌临床病理特征之间的关系。结果 ADAM9mRNA在乳腺癌组织中的表达较正常乳腺组织(未检测到ADAM9mRNA的表达)明显增强。ADAM9蛋白表达阳性率在乳腺癌组织中明显高于正常乳腺组织(P0.05),其在乳腺癌转移淋巴结中的表达明显高于非转移淋巴结及相应原发灶中的表达(P0.05).乳腺癌组织中ADAM9蛋白表达阳性率与其淋巴结转移和组织学分级有关(P0.05).结论ADAM9在乳腺癌中表达上调,可能参与了乳腺癌发生、发展过程。     

直肠末端系膜解剖在直肠癌根治术中的意义

目的　了解直肠末端系膜附着缘的解剖标志及其形态分布对全直肠系膜切除 (TME)手术的影响。方法　收集由同一组医师连续手术切除的 2 2 0例中、低位直肠癌大体标本 ,分为两组。Ⅰ组 (保肛组 ) :又分为Ⅰa组 ,低位直肠前切除术 (LAR术 ) ,81例 ,限直肠癌下缘距肛缘 5～ 6cm者 ;Ⅰb组 ,直肠前切除术 (AR术 ) ,68例 ,限直肠癌下缘距肛缘 7～ 8cm者。Ⅱ组 (切肛组 ) :腹会阴联合直肠切除术 (APR术 ) ,71例 ,限直肠癌下缘距肛缘<5cm者。结果　①直肠末端系膜环形附着缘位于肛提肌的肛缝以上 1 .0cm肠壁上 ,但该水平恰好与低位直肠癌下缘齐平。因此 ,为了满足 2～ 3cm下切端 ,在肛缝以下分离直肠肌性管道行LAR术时 ,要小心避免损伤肠壁。②直肠末端系膜附着于肠壁上呈环形片状 ,而非环形线状 ,与直肠后壁间仅有少量脂肪组织 ,其纵向附着长度约为 (1 .2 69± 0 .1 71 )cm(LAR组 81例 +APR组 71例 ) ,当行AR术时 ,其下切缘恰好位于系膜的片状附着区内 ,在裸化直肠时 ,要小心谨慎 ,以免损伤肠壁。结论　直肠末端系膜呈环形片状附着于肛提肌的肛缝上 1 .0cm处 ,在行低位或超低位直肠前切除 ,裸化直肠壁时要仔细分离 ,以免损伤肠壁 ,导致术后肠瘘     

Prognostic Significance of Residual Breast Disease and Axillary Node Involvement for Patients Who Had Primary Induction Chemotherapy for Advanced Breast Cancer

Background We performed this study to determine the prognostic significance of clinical tumor size, pathologic measurement of residual tumor, and number of positive axillary nodes in the surgical specimen relative to overall survival for patients who underwent primary induction chemotherapy for advanced breast cancer. Methods Data, collected prospectively between 1997 and 2002, included clinical tumor-node-metastasis stage, age at diagnosis, hormone receptor status, type of preoperative chemotherapy, histological type, surgical procedure, pathologic measurement in centimeters of residual breast tumor, and the number of positive axillary nodes in the surgical specimen. Univariable correlates of residual breast disease were assessed by using the χ² test. Recursive partitioning analysis was used to determine the prognostic significance of clinical tumor size, residual tumor size, and pathologic node involvement relative to overall survival. Survival was estimated by using the method of Kaplan and Meier and compared by using the log-rank test. A P value of < .05 was considered significant. Results Data were available for 85 patients with advanced breast cancer. Although univariable analysis identified increasing age, clinically involved axillary nodes, and a higher clinical tumor-node-metastasis stage as predictors of an increased risk of residual disease, recursive partitioning analysis identified more than three involved axillary nodes in the surgical specimen, with or without any measurable residual breast disease, as the most significant predictor of decreased survival (P < .001). Conclusions Pathologic axillary node involvement was the most significant predictor of decreased survival for patients who had undergone primary induction chemotherapy for advanced breast cancer.     

Survival Impact of Integrative Cancer Care in Advanced Metastatic Breast Cancer

Abstract: Integrative cancer treatment is of substantial interest to many cancer patients. Research is needed to evaluate the effects of integrative treatment on patient outcomes. We report survival data for a consecutive case series of advanced metastatic breast cancer patients who received a comprehensive clinical program combining conventional treatments with nutrition and supplementation, fitness and mind‐spirit instruction at the Block Center for Integrative Cancer Treatment. Treatment outcomes using integrative care for this disease have not previously been documented; survival data will thus contribute to decisions concerning future research directions and design. Ninety consecutive patients with metastatic breast cancer diagnosed during 1984–1997 who received chemotherapy at the integrative cancer center were included. Prognostic factors, treatments and survival from onset of metastases were determined from analysis of scans, labs, pathology and medical records. The log‐rank test and Cox proportional hazards analyses were used, and a Kaplan–Meier curve was calculated. All patients had metastatic disease at baseline, 96% were relapsed and 52% had received prior chemotherapy for metastatic disease. Median age at onset of metastasis was 46 years. Median survival was 38 months (95% CI 27,48). Published literature on populations with somewhat more favorable prognostic factors treated in conventional clinics showed median survivals of 20 to 23 months. Through the 1990s, median survival reported in metastatic breast cancer trials or observations generally ranged from 12 to 24 months. Five‐year survival was 27% for Center versus 17% for comparison patients. Despite a higher proportion of younger and relapsed patients, survival of metastatic breast cancer patients at the Center was approximately double that of comparison populations and possibly even higher compared to trials published during this period. Explanations for the advantage relative to conventional treatment alone may include the nutritional, nutraceutical, exercise and psychosocial interventions, individually or in combination; self‐selection of patients cannot be ruled out. Further research to evaluate the impact of integrative breast cancer treatment on survival is warranted.     

Primary Cutaneous Angiosarcoma of the Scalp with Cranial Invasion in a Patient with Metastatic Breast Cancer

Idiopathic cutaneous angiosarcoma (CA) of the head and neck is a distinct subtype of angiosarcoma most commonly presenting as a single or multiple purple, bruise-like patches that arise de novo and enlarge over several months. In clinical practice, both misdiagnosis and delayed diagnosis are frequently encountered. Here, we present a case of idiopathic CA on the scalp with invasion to the cranium in a patient with breast cancer metastatic to the brain. The patient was initially misdiagnosed and mistreated with herpes zoster and breast cancer metastatic to the skin, which led to a delayed diagnosis by two months until dermatologic evaluation. The diagnosis was then firmly established as CA based on consistent clinical and histological features. Since the tumor was inoperable, radiotherapy and chemotherapy were been considered as the appropriate adjuvant modes of therapy. Despite an initial favorable response, the disease demonstrated a rapidly progressive course and the patient succumbed to the disease within six months. This report briefly reviews the clinical and histological portrait and management options for this aggressive tumor.