Pneumothorax caused by metastatic carcinoma of the breast

We report a rare case of pneumothorax caused by metastatic carcinoma of the breast, in a 69-year-old woman who was admitted to our hospital with severe chest pain. Four years previously, she had undergone modified radical mastectomy for a left breast tumor. Chest X-ray examination and computed tomography (CT) scan on current admission revealed right pneumothorax and bilateral pulmonary tumors. Although operation is not usually indicated in such circumstances, the patient had persistent air leakage for 7 days, despite receiving effective closed cather drainage, making right thoracotomy necessary. During the operation, an open bronchopleural fistula in the metastatic tumor of the upper lobe, infiltrating close to the visceral pleura, was observed. Wedge resection, including the necrotic tumor, was thus performed. Microscopic examination of the resected specimen showed poorly differentiated adenocarcinoma, consistent with metastasis from breast carcinoma. This is the second reported case of pneumothorax caused by metastatic carcinoma of the breast. Received: February 17, 1999 / Accepted: October 4, 1999     

Biomarkers for HER2-positive metastatic breast cancer: Beyond hormone receptors

The overexpression of human epidermal growth factor receptor-2 (HER2) results in a biologically and clinically aggressive breast cancer (BC) subtype. Since the introduction of anti-HER2 targeted agents, survival rates of patients with HER2-positive metastatic BC have dramatically improved. Currently, although the treatment decision process in metastatic BC is primarily based on HER2 and hormone-receptor (HR) status, a rapidly growing body of data suggests that several other sources of biological heterogeneity may characterize HER2-positive metastatic BC. Moreover, pivotal clinical trials of new anti-HER2 antibody-drug conjugates showed encouraging results in HER2-low metastatic BC, thus leading to the possibility, in the near future, to expand the pool of patients suitable for HER2-targeted treatments. The present review summarizes and puts in perspective available evidence on biomarkers that hold the greatest promise to become potentially useful tools for optimizing HER2-positive metastatic BC patients' prognostic stratification and treatment in the next future. These biomarkers include HER2 levels and heterogeneity, HER3, intrinsic molecular subtypes by PAM50 analysis, DNA mutations, and immune-related factors. Molecular discordance between primary and metastatic tumors is also discussed.     

Parathyroid hormone-related protein in breast cancer tissues: Relationship between primary and metastatic sites

The expression of parathyroid hormone-related protein (PTHrP) at primary and metastatic sites was studied retrospectively in specimens obtained at operation and autopsy from 11 patients. The anti-human PTHrP monoclonal antibody, 4B3, was used in the immunohistochemical studies. The 11 cases showed metastases to the liver and the lung, and 9 showed bone metastases at autopsy. At primary sites, PTHrP was positive in the 9 cases with bone metastases, while the other 2 cases were negative for PTHrP. Regardless of the intensities of immunohistochemical staining of PTHrP at primary sites, cancer cells at metastatic sites in the liver and the lung were almost all negative for PTHrP. On the other hand, all PTHrP-positive cases at primary sites at operation showed skeletal metastases at autopsy, and the intensity of the immunohistochemical staining of PTHrP was strongly positive at all the sites of skeletal metastasis. These results suggest that while PTHrP is an important factor that causes cancer cells to erode and grow in skeletal bone, the expression of PTHrP is, concurrently, affected by an osseous microenvironment. Supported in part by Grant-in-Aid from Ministry of Education of Japan.     

乳腺癌耐药蛋白在乳腺癌原发灶和转移灶中表达的比较

目的研究乳腺癌耐药蛋白(breast cancer resistance protein,BCRP)在乳腺癌原发灶和转移灶中的表达并进行比较,分析两者间有无差异及其与预后的关系.方法采用免疫组织化学方法(IHC)检测44例手术切除的乳腺癌原发灶组织以及相应的淋巴结转移灶中,BCRP的表达.结果(1)BCRP在乳腺癌原发灶组织中的高表达率为43.2%(19/44例),在淋巴结转移灶中的高表达率为56.8%(25/44例);(2)经统计分析两者之间的表达并无差异(P＞0.05);(3)Kaplan-Meier生存分析结果表明,乳腺癌原发灶和转移灶中BCRP表达与患者的无病和总生存期皆无关(P＞0.05).结论BCRP在乳腺癌组织中具有一定的表达水平,原发灶与转移灶之间表达无明显差异且与预后无关.     

Docetaxel combined with targeted therapies in metastatic breast cancer

The treatment of metastatic breast cancer (MBC) is essentially palliative and should be based on hormone therapy or optimized chemotherapy designed to delay disease progression and maximize survival with good quality of life. Novel chemotherapeutic agents introduced in the 1990 s include the taxanes (notably docetaxel), which are among the most potent of current anticancer drugs. Current research is also focusing on molecular targeted agents including those against the HER family of transmembrane receptors and vascular endothelial growth factor. Optimal effects are obtained when these compounds are used in combination with chemotherapy, as shown in preclinical models and more recently in clinical trials. Results of a large randomized trial have demonstrated a significant survival advantage for trastuzumab plus docetaxel compared with docetaxel monotherapy. Docetaxel plus bevacizumab combinations have recently been shown to significantly improve progression-free survival and objective response rate compared with docetaxel monotherapy. Overall, docetaxel in combination with novel targeted agents in MBC appears to be highly active in patients with MBC, and such combinations represent promising treatment regimens for clinical investigation.     

双侧原发性乳腺癌的分子生物学特征

目的:探讨双侧原发性乳腺癌(bilateral primary breast cancer,BPBC)的分子生物学特征。方法:回顾性分析325例BPBC与650例单侧乳腺癌(unilateral breast cancer,UBC)患者的临床病理资料,应用单因素分析和Logistic回归多因素分析,寻找BPBC发生的相关分子生物学依据。结果:与UBC患者比较,BPBC患者第一癌发病年龄早、有乳腺癌家族史、肿瘤直径>5cm及临床Ⅲ期患者较多(P均<0.05)。在分子生物学特征方面,BPBC第一癌患者雌激素受体(estrogen receptor,ER)和孕激素受体(progesterone receptor,PR)阴性比率、p53阳性率和细胞增殖核抗原Ki67高表达者均高于UBC患者(P<0.05);人表皮生长因子受体2(human epidermal growth factor receptor2,Her-2)表达在二者间的差异无统计学意义(P>0.05)。其中乳腺癌家族史、肿瘤直径>5cm、p53阳性为BPBC发生的独立危险因素,ER(+)或PR(+)者发生BPBC的风险下降。结论:BPBC与UBC在生物学行为上存在一定的差异,对于年轻、有乳腺癌家族史、激素受体阴性,p53阳性及Ki67高表达的乳腺癌患者要注意检查对侧乳腺癌的发生。     

Impact of radiotherapy in the risk of esophageal cancer as subsequent primary cancer after breast cancer

PURPOSE: To assess the risk of esophageal cancer as second cancer among breast-cancer patients treated with radiotherapy. METHODS AND MATERIALS: The records of the Finnish Cancer Registry from 1953 to 2000 were used to assess the risk of esophageal cancer as second cancer among 75,849 breast-cancer patients. Patients were treated with surgery (n = 33,672), radiotherapy (n = 35,057), chemotherapy and radiotherapy (n = 4673), or chemotherapy (n = 2,447). The risk of a new primary cancer was expressed as standardized incidence ratio (SIR), defined as the ratio of observed to expected cases. RESULTS: By the end of 2000, the number of observed cases esophageal cancers was 80 vs. 72 expected cases (standardized incidence ratio (SIR) = 1.1, 95% Confidence Interval (CI) = 0.9 to 1.5). Among patients followed for 15 years and treated with radiotherapy, the SIR for esophageal cancer was 2.3 (95% CI = 1.4 to 5.4). No increase in risk was seen for patients treated without radiotherapy. The risk of esophageal cancer was increased among patients diagnosed during 1953 to 1974, although age at the treatment did not have marked effect on the risk estimate. CONCLUSION: Increased risk of second cancer in the esophagus was observed for breast-cancer patients in Finland, especially among patients with over 15 years of follow-up and treated in the earliest period, which may relate to the type of radiotherapy.     

HER2 discordance between primary and metastatic breast cancer: Assessing the clinical impact

Background

In the setting of breast cancer relapse, treatment decisions are typically made by utilizing HER2, estrogen, and progesterone receptor expression status of the primary breast cancer. Recently, concern regarding receptor discordance has led to recommendations for rebiopsy for all cases of metastatic disease. However, whether this is an appropriate recommendation is uncertain, particularly as the clinical implications for HER2 discordance are unknown.

Methods

We performed a literature review to identify studies assessing HER2 discordance between primary and metastatic breast cancer. These studies were then reviewed for data relating to (1) impact of clinical factors on discordance rates, (2) prognostic impact of discordance, or (3) clinical outcomes from treatment alteration due to receptor discordance. Results were analyzed qualitatively.

Results

From 60 HER2 discordance studies identified, 24 contained information of interest for this review. No clear factor promoting HER2 discordance was identified. Loss of HER2 seemed to result in worse post-relapse survival and overall survival, although these data were often confounded by lack of treatment in the setting of receptor loss. Conversely, HER2 discordance was not associated with shorter DFS. Individual patients with receptor gain appear to have benefited from addition of targeted treatment, although data are limited to case reports.

Conclusion

Evidence of HER2 discordance leading to alterations in patient outcomes is limited, highlighting the need for further research in this area. Furthermore, lack of alteration in patient outcomes suggests that a more pragmatic approach to the decision to rebiopsy may be appropriate.     

Excision of the primary tumour in patients with metastatic breast cancer: a clinical dilemma

Background

Approximately 10% of new breast cancer patients will present with overt synchronous metastatic disease. The optimal local management of those patients is controversial. Several series suggest that removal of the primary tumour is associated with a survival benefit, but the retrospective nature of those studies raises considerable methodologic challenges. We evaluated our clinical experience with the management of such patients and, more specifically, the impact of surgery in patients with synchronous metastasis.

Methods

We reviewed patients with primary breast cancer and concurrent distant metastases seen at our centre between 2005 and 2007. Demographic and treatment data were collected. Study endpoints included overall survival and symptomatic local progression rates.

Results

The 111 patients identified had a median follow-up of 40 months (range: 0.6–71 months). We allocated the patients to one ot two groups: a nonsurgical group (those who did not have breast surgery, n = 63) and a surgical group (those who did have surgery, n = 48, 29 of whom had surgery before the metastatic diagnosis). When compared with patients in the nonsurgical group, patients in the surgical group were less likely to present with T4 tumours (23% vs. 35%), N3 nodal disease (8% vs. 19%), and visceral metastasis (67% vs. 73%). Patients in the surgical group experienced longer overall survival (49 months vs. 33 months, p = 0.01) and lower rates of symptomatic local progression (14% vs. 44%, p < 0.001).

Conclusions

In our study, improved overall survival and symptomatic local control were demonstrated in the surgically treated patients; however, this group had less aggressive disease at presentation. The optimal local management of patients with metastatic breast cancer remains unknown. An ongoing phase iii trial, E2108, has been designed to assess the effect of breast surgery in metastatic patients responding to first-line systemic therapy. If excision of the primary tumour is associated with a survival benefit, then the preselected subgroup of patients who have responded to initial systemic therapy is the desired population in which to put this hypothesis to the test.     

Reconsidering the benefit of intermittent versus continuous treatment in the maintenance treatment setting of metastatic colorectal cancer

Colorectal cancer is one of the most frequent solid tumors in the western world, with low survival rates in patients with metastatic disease. Doublet chemotherapy regimens such as FOLFOX or FOLFIRI are the mainstay of standard first-line chemotherapy in the metastatic setting. The conventional treatment as a first-line approach is continuous application until progression or intolerable toxicities. However, only one third of patients are treated until progression mainly due to the side effects of chemotherapy. Notably, oxaliplatin-containing regimens such as FOLFOX/CapOx or FOLFOXIRI are associated with oxaliplatin-induced neuropathy, which is the main reason for treatment discontinuation or treatment de-escalation. On this basis, recent studies have investigated the clinical benefits of bevacizumab-based intermittent and continuous treatment regimens in the metastatic colorectal setting, together with various strategies to optimize maintenance therapy including regimens with targeted therapies, such as cetuximab, ziv-aflibercept and regorafenib. Recent studies have also investigated when maintenance therapy should be initiated as well individualizing treatment based on patient, tumor and treatment characteristics, as well as molecular biomarkers. This article reviews the current evidence for the clinical benefit of intermittent versus continuous treatment in the maintenance treatment setting of metastatic colorectal cancer, and also evaluates the effect of RAS and BRAF mutational status on maintenance strategies.     

A serum nuclear magnetic resonance-based metabolomic signature of advanced metastatic human breast cancer

Breast cancer (BC) displays a high heterogeneity from histology to prognosis, metastatic evolution and treatment responses. We report here a ¹H NMR-based metabolic phenotyping study aiming at identifying coordinated metabolic serum changes associated with advanced metastatic breast cancer (MBC) in comparison to the localized early disease (EBC). A model discriminating EBC and MBC patients is obtained (n = 85: 46 EBC and 39 MBC), and validated with an independent cohort (n = 112: 61 EBC and 51 MBC; 89.8% sensitivity, 79.3% specificity). We identify 9 statistically significant metabolites involved in this discrimination: histidine, acetoacetate, glycerol, pyruvate, glycoproteins (N-acetyl), mannose, glutamate and phenylalanine. This work illustrates the strong potential of NMR metabolic phenotyping for the diagnosis, prognosis, and management of cancer patients.     

基于穿刺活检的复发转移性结直肠癌患者源性异种移植模型的建立

背景与目的:现行的结直肠癌患者源性异种移植(patient-derived xenografts,PDXs)模型建模样本多来源于外科手术,但复发转移性结直肠癌(metastatic colorectal cancer,mCRC)患者手术机会少,难以获取标本.该研究旨在利用穿刺活检术建立mCRC的PDXs模型.方法:入组12例结直肠癌根治术后患者,存在临床症状和(或)影像学提示术后复发和(或)转移,需行穿刺活检明确诊断、且不存在穿刺活检禁忌证者,保留用于常规病理诊断包括基因检测的组织量后,剩余的标本用于PDXs模型的建立.结果:共成功建立7例mCRC的PDXs模型,成功率为77.8%.结论:基于穿刺活检术建立mCRC的PDXs模型成功率高,可较完整的复制原始肿瘤特性,且操作安全、简便.     

Mitoxantrone and paclitaxel combination chemotherapy in metastatic breast cancer

This study evaluated mitoxantrone and paclitaxel combination chemotherapy in the treatment of patients with metastatic breast cancer. Thirty-seven patients who had developed progressive disease after prior chemotherapy were treated with mitoxantrone (14 mg/m²) and paclitaxel (150 mg/m²) every 21 days for a maximum of six cycles. The most frequent grade 3 or 4 nonhematological toxicities were fever and nausea. Grade 4 neutropenia occurred in 71% of patients. Cardiotoxicity occurred in 2 patients, both of whom had previously received doxorubicin. Objective response was achieved in 35% of patients (5% complete response and 30% partial response) and 41% had stable disease. Median time to disease progression and median survival were 6 and 12 months, respectively. The percent of patients with an objective response was not different for those who had received prior doxorubicin or had chemotherapy in the preceding 6 months. This regimen appears to be effective and well tolerated as salvage therapy and merits further evaluation.     

顺铂为主的联合化疗方案治疗复发转移性乳腺癌

目的：观察比较以顺铂为主的GP方案和NP方案治疗复发转移性乳腺癌的疗效和不良反应。方法：94例经病理确诊复发转移性乳腺癌患者随机分为GP（顺铂＋吉西他滨）和NP（顺铂＋长春瑞滨）两组方案治疗,2周期后评判疗效。结果：GP组有效率（RR）为45．3％,疾病控制率（DCR）为71．7％;中位疾病进展时间（mTTP）为6个月,中位生存期（MST）为14个月;NP组RR为43．9％,DCR为70．7％;mTTP为5个月,MST为11个月,两组差异无显著性（P〉0．05）。不良反应主要为骨髓抑制和消化道反应,GP组Ⅲ～Ⅳ度白细胞下降发生率为15．1％、Ⅲ～Ⅳ度血小板下降发生率为24．5％,Ⅲ～Ⅳ度恶心呕吐发生率为17．0％;NP组Ⅲ～Ⅳ度白细胞下降发生率为26．8％、Ⅲ～Ⅳ度血小板下降发生率为7．3％,Ⅲ～Ⅳ度恶心呕吐发生率为14．6％,两组除血小板下降有显著性差异（P〈0．05）外,其余均无统计学意义（P〉0．05）;未见Ⅲ～Ⅳ度肾脏及肝脏损害。结论：GP和NP两组方案治疗复发转移性乳腺癌疗效较好,两组疗效相似,不良反应轻。两组方案均可作为治疗复发转移性乳腺癌的解救方案。     

Exploration of serum metabolomic profiles and outcomes in women with metastatic breast cancer: a pilot study

BackgroundMetabolomics, a global study of metabolites and small molecules, is a novel expanding field. In this pilot study, metabolomics has been applied to serum samples from women with metastatic breast cancer to explore outcomes and response to treatment.Patients and methodsPre-treatment and serial on-treatment serum samples were available from an international clinical trial in which 579 women with metastatic breast cancer were randomized to paclitaxel plus either a targeted anti-HER2 treatment (lapatinib) or placebo. Serum metabolomic profiles were obtained using 600 MHz nuclear magnetic resonance spectroscopy. Profiles were compared with time to progression, overall survival and treatment toxicity.ResultsPre- and on-treatment serum samples were assessed for over 500 patients. Unbiased metabolomic profiles in the biologically unselected overall trial population did not correlate with outcome or toxicity. In a subgroup of patients with HER2-positive disease treated with paclitaxel plus lapatinib, metabolomic profiles from patients in the upper and lower thirds of the dataset showed significant differences for time to progression (N = 22, predictive accuracy = 89.6%) and overall survival (N = 16, predictive accuracy = 78.0%).ConclusionsIn metastatic breast cancer, metabolomics may play a role in sub selecting patients with HER2 positive disease with greater sensitivity to paclitaxel plus lapatinib.     

Symptom management in metastatic breast cancer

Approximately 40,000 women die as a result of breast cancer each year and many more live with advanced disease. When breast cancer recurs, the goals of treatment often shift from one of cure to controlling the disease for as long as possible while palliating symptoms interfering with the patient's functional status and quality of life. This requires ongoing discussions with the patient and family about the goals of care. Many symptoms depend on the site of metastasis, with bone being the most frequent, and commonly occur with fatigue, depression, insomnia, and pain. The purpose of this paper is to identify and provide an overview of the management of the most common symptoms in patients with breast cancer metastases.     

乳腺原发癌和转移淋巴结肿瘤浸润淋巴细胞体外抗乳腺癌研究

目的探讨同个体乳腺原发癌和转移淋巴结肿瘤浸润淋巴细胞(TIL)抗瘤活性。方法从35例乳腺癌伴有腋窝淋巴结转移患者的乳腺原发癌组织及转移淋巴结组织中分离出乳腺原发癌TIL和转移淋巴结TIL,观察不同部位获得的TIL体外对不同部位乳腺癌细胞的杀伤活性。结果乳腺原发癌TIL对乳腺原发癌癌细胞与转移淋巴结TIL对转移淋巴结癌细胞均具有很高的杀伤活性[杀伤率分别为(71.31±3.11)%和(69.38±2.51)%],明显高于乳腺原发癌TIL对转移淋巴结癌细胞和转移淋巴结TIL对乳腺原发癌癌细胞的杀伤活性[杀伤率分别为(50.31±2.89)%和(49.80±3.21)%]。结论同一个体乳腺癌其原发癌和转移淋巴结TIL抗瘤活性有差别。