Radioactivity thresholds for sentinel node biopsy in breast cancer

AIMS: The aim of the present study is to clarify the level of radioactive lymph node should be biopsied after the most radioactive SN is removed. METHODS: SNB using radionuclide was performed in our hospital for 1179 primary breast cancers between April 2000 and October 2005; most (1177/1179) were performed successfully. Our criterion for harvesting SNs is to remove tissue until no radioactive site is present. The level of radioactivity and the order of removal of each lymph node were compared with pathologic results. RESULTS: More than 2 (overall average 1.9) radioactive SNs were biopsied in 686 of 1177 breasts. Cancer positive results were recorded for 142 breasts with multiple SNs. In 142 breasts, 64 showed metastasis to the most radioactive node only, 39 showed metastasis other than the most radioactive node only, and 39 showed the most radioactive node and other radioactive nodes. Moreover, if several other criteria were applied, false-positive cases were increased significantly. CONCLUSIONS: It is necessary to harvest radioactive lymph nodes other than the most radioactive. Moreover, efforts to remove every radioactive lymph node will minimize false-negative results.     

Molecular signatures of lymph node status by intrinsic subtype: gene expression analysis of primary breast tumors from patients with and without metastatic lymph nodes

Background

Identification of a gene expression signature in primary breast tumors that could classify patients by lymph node status would allow patients to avoid the morbidities of surgical disruption of the lymph nodes. Attempts to identify such a signature have, to date, been unsuccessful. Because breast tumor subtypes have unique molecular characteristics and different sites of metastasis, molecular signatures for lymph node involvement may vary by subtype.

Methods

Gene expression data was generated from HG U133A 2.0 arrays for 135 node positive and 210 node negative primary breast tumors. Intrinsic subtype was assigned using the BreastPRS. Differential gene expression analysis was performed using one-way ANOVA using lymph node status as the variable with a False-discovery rate <0.05, to define significance.

Results

Luminal A tumors were most common (51%) followed by basal-like (27%), HER2-enriched (14%) luminal B (7%) and normal-like (1%). Basal-like and luminal A tumors were less likely to have metastatic lymph nodes (35% and 37%, respectively) compared to luminal B or HER2-enriched (52% and 51%, respectively). No differentially expressed genes associated with lymph node status were detected when all tumors were considered together or within each subtype.

Conclusions

Gene expression patterns from the primary tumor are not able to stratify patients by lymph node status. Although the primary breast tumor may influence tumor cell dissemination, once metastatic cells enter the lymphatics, it is likely that characteristics of the lymph node microenvironment, such as establishment of a pre-metastatic niche and release of pro-survival factors, determine which cells are able to colonize. The inability to utilize molecular profiles from the primary tumor to determine lymph node status suggest that other avenues of investigation, such as how systemic factors including diminished immune response or genetic susceptibility contribute to metastasis, may be critical in the development of tools for non-surgical assessment of lymph node status with a corresponding reduction in downstream sequelae associated with disruption of the lymphatics.

     

超声判断乳腺癌患者腋淋巴结转移的多因素分析

目的 观察乳腺癌患者原发灶及腋下淋巴结（LN）的超声诊断图像和彩色Doppler特点,分析淋巴结转移（LNM）的相关因素,以获得超声诊断乳腺癌患者腋下LNM的较佳组合指标。方法 超声观察113例乳腺癌患者的原发灶和腋LN。观察原发灶的位置、最大径、数量、内部钙化灶边带回声、边界、肿瘤内部的血流丰富程度分级（0-Ⅲ级）、最高流速和阻力指数;观察患侧腋LN目最大径、纵横比、纵切面皮质厚度与淋巴门厚度比值（皮／门比）、皮质局部最大厚径、淋巴结的血流分布类型、最高流速和阻力指数。全部患者均进行乳房改良根治术,以腋LN清扫的病理结果作为金标准,对与LNM相关的影像及临床因素进行单因素及多因素分析（Logistic回归）,并利用受试者工作率性（ROC）曲线评价诊断指标。结果 113例乳腺癌患者的超声观察指标单因素分析结果显示,原发灶的最大径、多发或弥漫、血流丰富度,对腋LNM有影响,差异有统计学意义（P=0．029-0．005）腋LN的纵横比、皮／门比、皮质局部最大厚径、血流分布类型与腋LNM有关,差异有统计学意义（P=0．000）。将单因素分析有意义的指标进行多因素分析,与腋LNM有关的影响因素为：LN的皮／门比LN的纵横比以及原发灶的最大径,利用ROC曲线评价各单项指标及其不同组合指标的诊断价值结果显示,LN皮／门比＋LN纵横比＋原发灶最大径这一组合指标最优,其ROC曲线的线下面积最大,即灵敏度和特异度之和最大。结论 对乳腺癌患者进行腋LN超声扫查,综合考虑原发灶大小LN的纵横比、皮质厚度及其与淋巴门厚度的比例关系,将有助于提高超声诊断腋LNM的正确率,较为准确地判断腋LN的状态。     

Weight changes after adjuvant treatment in Korean women with early breast cancer

Background Weight gain is a common problem in breast cancer patients and is reported to be associated with poorer survival. However, most data are limited to Western women. We evaluated weight changes after adjuvant treatment in Korean women with early breast cancer. Methods The authors reviewed the records of 260 patients with stage I–III breast cancer treated between June 2003 and February 2006. Body weight, body mass index (BMI) and menopausal status at baseline and after 3, 6, 12 and 24 months of adjuvant treatment were reviewed. Results Mean patient age was 47.0 years and 61.1% of women were premenopausal. Among them, 195 patients (75.8%) received chemotherapy and 186 (71.5%) received hormonal therapy. Mean baseline weight was 57.5 ± 9.8 kg and mean BMI was 23.5 ± 1.6 kg/m² (22.8 ± 3.0 vs. 24.7 ± 3.2 kg/m² for pre- vs. post-menopausal women, P = 0.286). Mean weight changes were; 0.30 kg at 3 months (P = 0.019); 0.16 kg at 6 months (P = 0.367); −0.34 kg at 1 year (P = 0.082); −0.40 kg at 2 years (P = 0.097). Twenty-three patients (10.4%) gained more than 5% of baseline body weight at 1 year, but no clinical variable was found to be associated with these weight gains. Conclusion This study shows that Korean women with early breast cancer do not gain weight after adjuvant treatment. Further studies are needed to determine differences between Asian and Western women in terms of weight changes and prognosis in early breast cancer.     

核素淋巴显像识别前哨淋巴结在乳腺癌治疗中的应用

目的评价核素淋巴显像和γ探针定位在乳腺癌中确定前哨淋巴结(SLN)的应用价值,验证前哨淋巴结活检替代腋窝淋巴结清除术用于乳腺癌治疗的安全性与价值。方法选择1999年6月至2009年11月本院住院的女性乳腺癌患者206例(体检时腋窝均未扪及肿块),应用99Tcm-DX37～74 MBq或99Tcm-SC74 MBq经皮下注射,行核素淋巴显像后,术中注射专利兰1 ml和(或)术中用γ探针定位并行前哨淋巴结活检,与术中冰冻病理检查结果对照。若术中冰冻发现有前哨淋巴结转移,则行腋窝淋巴结清除术,若前哨淋巴结阴性,则不做腋窝淋巴结清除,术后定期随访。结果 206例乳腺癌术中成功活检SLN204例,成功率为99.0%(204/206)。本组有64例仅行SLN切除,术后病理检查证实64例SLN均阴性,故未行腋窝淋巴结清除,其中仅1例于术后1年时出现腋窝淋巴结转移,其余63例患者在随访期间均未发现腋窝淋巴结转移,也未出现同侧上肢水肿、感觉及活动异常;另140例行腋窝淋巴结清除,其中6例经病理证实SLN阳性但腋窝淋巴结为阴性,134例经病理证实SLN阳性35例,阴性99例,腋窝淋巴结阳性37例,阴性97例。核素淋巴显像和γ探针定位法的灵敏度为94.6%(35/37例),准确率为98.5%(138/140),假阴性为5.4%(2/37)。结论核素淋巴显像和γ探针定位应用于乳腺癌是切实可行和可能的,对预测腋窝淋巴结转移有很大的临床实用价值。如技术方法规范,早期乳腺癌前哨淋巴结活检则能取代常规的腋窝淋巴结清除术,乳腺癌手术上肢并发症的发生率可大大降低。     

Prognostic value of lymph node ratio in node-positive breast cancer in Egyptian patients

BackgroundBreast cancer in Egypt is the most common cancer among women and is the leading cause of cancer mortality. Traditionally, axillary lymph node involvement is considered among the most important prognostic factors in breast cancer. Nonetheless, accumulating evidence suggests that axillary lymph node ratio should be considered as an alternative to classical pN classification.Materials and methodsWe performed a retrospective analysis of patients with operable node-positive breast cancer, to investigate the prognostic significance of axillary lymph node ratio.ResultsFive-hundred patients were considered eligible for the analysis. Median follow-up was 35 months (95% CI 32–37 months), the median disease-free survival (DFS) was 49 months (95% CI, 46.4–52.2 months). The classification of patients based on pN staging system failed to prognosticate DFS in the multivariate analysis. Conversely, grade 3 tumors, and the intermediate (>0.20 to ⩽0.65) and high (>0.65) LNR were the only variables that were independently associated with adverse DFS. The overall survival (OS) in this series was 69 months (95% CI 60–77).ConclusionThe analysis of outcome of patients with early breast cancer in Egypt identified the adverse prognostic effects of high tumor grade, ER negativity and intermediate and high LNR on DFS. If the utility of the LNR is validated in other studies, it may replace the use of absolute number of axillary lymph nodes.     

Sentinel lymph node biopsy in breast cancer using blue dye with or without isotope localization

BACKGROUND: The purpose of this study was to determine the feasibility of sentinel lymph node (SLN) biopsy using blue dye with or without isotope localization to predict the presence of axillary and internal mammary lymph node (IMN) metastases in patients with breast cancer. We also investigated whether multiple sectioning of the SLN could improve the accuracy of frozen section examination. METHOD:One-hundred twenty-six patients underwent dye-guided or dye- and gamma probe-guided SLN biopsy followed by complete axillary lymph node dissection (ALND). No ALND was performed in the 14 patients with small tumors and a negative SLN. In addition, 69 patients underwent IMN biopsy. RESULTS: The axillary SLN was identified in 123 of 140 (88%) patients. An accuracy rate of 90% was obtained by frozen section examination of the SLN, which increased to 100% in patients examined with a greater number of sections. Lymphatic flow to the IMN and/or a radioactive hot spot in the IMN was found in 9 of 102 (9%) patients, while a hot node was detected using a gamma probe in only 2 of these patients. No involvement of the IMNs was found histologically in these 9 patients. IMN involvement was found in 7 of 61 (11%) patients without lymphatic flow to the IMNs or a hot spot by lymphoscintigraphy or who did not undergo lymphoscintigraphy. CONCLUSION: ALND can be avoided in patients with small breast cancers and a negative SLN. SLN biopsy guided by lymphatic mapping is unreliable for identifying metastases to IMNs.     

预防性治疗食管癌淋巴结转移

目的：评价化疗及放疗预防食管癌淋巴结转移的疗效。方法：70例食管癌患者随机分为化疗预防组（A组）35例，放射预防组（B组）35例。结果：治疗后2年，总的淋巴结转移率A组34．29％，B组48．57％（χ^2=1.472,P=0.225).锁骨上颈部、纵隔、贲门胃左动脉旁、腹腔淋巴结转移率A组分别为8．57％，11．43％，8．57％，5．71％，B组分别为5．71％，31．43％，5．71％，5．71％χ^2与P值分别为：χ^2＝0．215，P＝0．643；χ^2＝4．158，P＝0．041；χ^2＝0．215，P＝0．643；χ^2＝0，P＝1．00。A组（CR＋PR）91．43％，B组为71．43％（χ^2＝4．629，P＝0．031），两组生存率差异有显著意义（χ^2＝4．629，P＝0．031）。结论：食管癌淋巴结转移预防性治疗，以化疗放疗合并预防优于单独放疗预防。     

Axillary lymph node status of operable breast cancers by combined steroid receptor and HER-2 status: triple positive tumours are more likely lymph node positive

Aims To examine the frequency of axillary lymph node (ALN) invasion of operable breast cancers by their combined oestrogen receptor (ER), progesterone receptor (PR) and HER-2 status. Methods 2227 recently operated cases in one centre were retrieved from the Multidisciplinary Breast Centre database and stratified according to their combined immunohistochemical (IHC) expression of ER/PR/HER-2 status. An equivocal HER-2 status was further analysed by Fluorescence in situ Hybridisation (FISH). The following 6 groups were considered: ER⁻PR⁻HER-2⁻ (NNN; triple negative), ER⁻PR⁻HER-2⁺ (NNP), ER⁺PR⁻HER-2⁻ (PNN), ER⁺PR⁻HER-2⁺ (PNP), ER⁺PR⁺HER-2⁻ (PPN), ER⁺PR⁺HER-2⁺ (PPP; triple positive). For ALN, the following variables were tested in uni- and multivariate models: age at diagnosis (years), tumour size (mm), tumour grade, ER, PR, HER-2 and the combined steroid receptor and HER-2 status. Likelihood ratio χ²-tests were used for univariate analysis and logistic regression for multivariate analysis. Results Triple positive tumours had a higher likelihood of being ALN positive than others (56.2% versus 35.7%; P < 0.0001). Univariate logistic regression also withheld age, size, grade and HER-2 as predictors of ALN involvement. Final multivariate logistic regression revealed age, size, grade and PPP versus non-PPP to be independent predictors of ALN involvement; the odds ratio (OR) and 95% CI for PPP versus non-PPP tumours was 2.169 (1.490–3.156). Conclusion Our data provide insight into the natural history of triple positive breast carcinomas. Such tumours are more likely ALN positive than those with another steroid receptor and HER-2 status. How these findings correlate with breast cancer prognosis remains to be investigated.     

Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

Biotransformation of tamoxifen to the potent antiestrogen endoxifen is performed by cytochrome P450 (CYP) enzymes, in particular the CYP2D6 isoform. CYP2D6*4 is one of the most frequent alleles associated with loss of enzymatic activity. The incidence of CYP2D6*4 among Caucasians is estimated up to 27%, while it is present in up to 90% of all poor metabolizers within the Caucasian population. The hypothesis under question is whether the presence of one or two non-functioning (null) alleles predicts an inferior outcome in postmenopausal women with breast cancer receiving adjuvant treatment with tamoxifen. The numerous existing studies investigating the association of CYP2D6 with treatment failure in breast cancer are inconsistent and give rather conflicting results. Currently, routine CYP2D6 testing among women with breast cancer is not recommended and the significance of CYP2D6 phenotype in decision making regarding the administration of tamoxifen is unclear. The present study summarizes current literature regarding clinical studies on CYP2D6*4, particularly in terms of response to tamoxifen therapy and breast cancer outcome.     

Sentinel node biopsy to avoid axillary lymph node dissection in breast cancer

The role of sentinel node biopsy in breast cancer has increased over the last few years. Sentinel nodes can predict the status of all axillary lymph nodes precisely and select patients with negative nodes for whom axillary dissection is unnecessary. Many problems remain, such as the ideal injection technique, ideal agents, and ideal histological detection of sentinel node metastases, and must be addressed before sentinel node biopsy becomes the standard of care for patients with breast cancer.     

Treatment of depressive symptoms in patients with early stage breast cancer undergoing adjuvant therapy

Background Studies have shown that there is a high prevalence of depression in cancer patients. Women with breast cancer may have an even higher risk of depression particularly in a postmenopausal or estrogen deficiency state. A small number of randomized controlled trials have examined the efficacy of antidepressants compared to that of a placebo in cancer patients, but some results have been difficult to interpret due to a heterogeneous patient group. In the current investigation, we screened newly diagnosed early stage breast cancer patients for depressive symptoms prior to the initiation of adjuvant therapy and investigated whether the oral antidepressant fluoxetine affected depressive symptoms, completion of adjuvant treatment, and quality of life. Methods Patients with newly diagnosed early stage breast cancer were screened for depressive symptoms prior to the initiation of adjuvant therapy. Patients with depressive symptoms were randomized to a daily oral fluoxetine or a placebo. Patients were then followed for 6 months and evaluated for quality of life, completion of adjuvant treatment, and depressive symptoms. Results A high percentage of patients with newly diagnosed early stage breast cancer were found to have depressive symptoms prior to the initiation of adjuvant therapy. The use of fluoxetine for 6 months resulted in an improvement in quality of life, a higher completion of adjuvant treatment (chemotherapy, hormonal therapy, chemotherapy plus hormonal therapy), and a reduction in depressive symptoms compared to patients who received placebo. Conclusions An antidepressant should be considered for early stage breast cancer patients with depressive symptoms who are receiving adjuvant treatment.     

Heterogeneity of breast cancer and implications of adjuvant chemotherapy

Historically, in selecting adjuvant chemotherapy for patients with breast cancer, anatomy, including tumor size and nodal status, has played the primary role. As a result of analyses of genomic and clinical data, breast cancers are now thought to be a family of diseases. Major subtypes of breast cancer include HER-2 positive disease, basal-like or triple negative tumors, and at least two types of hormonally sensitive cancers. Using the nomenclature developed in the gene expression array studies, these two types are often referred to as luminal A and luminal B. Estrogen receptor negative tumors relapse earlier than estrogen receptor positive tumors. In general, estrogen receptor negative cancers are also more responsive to chemotherapy. In contrast, estrogen positive tumors appear to be somewhat less responsive to chemotherapy, but endocrine therapy can be of substantial benefit in decreasing the risk of disease recurrence. Women with HER-2 positive disease derive significant benefit with the use of trastuzumab. The role of chemotherapy in preventing disease recurrence in patients with estrogen receptor positive tumors is being reevaluated. Recent data suggests that chemotherapy has the greatest benefit in those patients with estrogen receptor positive cancers whose tumors are HER-2 positive disease, weakly ER positive, and/or have high nuclear grade. In the future, breast cancer treatment will be more targeted to the tumor and tailored to the individual with the use of genomic and clinical data. This article is based on an invited lecture delivered at the 15th Annual Meeting of the Japanese Breast Cancer Society, held in Yokohama 29–30 June 2007.     

Toremifene in the treatment of breast cancer

Although more widespread screening and routine adjuvant therapy has improved the outcome for breast cancer patients in recent years, there remains considerable scope for improving the efficacy, safety and tolerability of adjuvant therapy in the early stage disease and the treatment of advanced disease. Toremifene is a selective estrogen receptor modifier (SERM) that has been widely used for decades in hormone receptor positive breast cancer both in early and late stage disease. Its efficacy has been well established in nine prospective randomized phase III trials compared to tamoxifen involving more than 5500 patients, as well as in several large uncontrolled and non-randomized studies. Although most studies show therapeutic equivalence between the two SERMs, some show an advantage for toremifene. Several meta-analyses have also confirmed that the efficacy of toremifene is at least as good as that of tamoxifen. In terms of safety and tolerability toremifene is broadly similar to tamoxifen although there is some evidence that toremifene is less likely to cause uterine neoplasms, serious vascular events and it has a more positive effect on serum lipids than does tamoxifen. Toremifene is therefore effective and safe in the treatment of breast cancer. It provides not only a useful therapeutic alternative to tamoxifen, but may bring specific benefits.     

174例乳腺癌生存因素分析

目的 分析影响乳腺癌生存率的相关因素。方法 收集174例乳腺癌病人的完整临床资料与病理,随访5年以上,观察其生存时间,制作Kaplan-Meier评价生存曲线,并做比较分析。结果 乳腺癌高发年龄在40~49岁;Ⅰ期、Ⅱ期与Ⅲ期乳腺癌患者总体生存曲线不同;乳腺癌的肿块大小与腋窝淋巴结转移成正相关;绝经后患者5年生存率低于未绝经患者;ER(-)病例平均无病存活时间小于ER(+)病例。结论 必须重视乳腺癌的早期检查、早期诊断和早期系统治疗;全社会应普及乳腺癌的筛查工作。     

Sentinel lymph node biopsy is associated with improved survival compared to level I & II axillary lymph node dissection in node negative breast cancer patients

Objective

The few long-term follow-up data for sentinel lymph node (SLN) negative breast cancer patients demonstrate a 5-year disease-free survival of 96–98%. It remains to be elucidated whether the more accurate SLN staging defines a more selective node negative patient group and whether this is associated with better overall and disease-free survival compared with level I & II axillary lymph node dissection (ALND).

Methods

Three-hundred and fifty-five consecutive node negative patients with early stage breast cancer (pT1 and pT2 ≤ 3 cm, pN0/pN_SN0) were assessed from our prospective database. Patients underwent either ALND (n = 178) in 1990–1997 or SLN biopsy (n = 177) in 1998–2004. All SLN were examined by step sectioning, stained with H&E and immunohistochemistry. Lymph nodes from ALND specimens were examined by standard H&E only. Neither immunohistochemistry nor step sections were performed in the analysis of ALND specimen.

Results

The median follow-up was 49 months in the SLN and 133 months in the ALND group. Patients in the SLN group had a significantly better disease-free (p = 0.008) and overall survival (p = 0.034). After adjusting for other prognostic factors in Cox proportional hazard regression analysis, SLN procedure was an independent predictor for improved disease-free (HR: 0.28, 95% CI: 0.10–0.73, p = 0.009) and overall survival (HR: 0.34, 95% CI: 0.14–0.84, p = 0.019).

Conclusions

This is the first prospective analysis providing evidence that early stage breast cancer patients with a negative SLN have an improved disease-free and overall survival compared with node negative ALND patients. This is most likely due to a more accurate axillary staging in the SLN group.