http://www.med66.com/html/ziliao/07/90/06dba3a16393a74b9678d84a363b99ea.htm

Dennis Joseph Slamon (born August 8, 1948),^[1][2] is an Americanoncologist and chief of the division of Hematology-Oncology at UCLA. He is best known for his work identifying the HER2/neuoncogene that is amplified in 25-33% of breast cancer patients and the resulting treatment Herceptin.^[3]

Slamon is the son of a West Virginiacoal miner.^[4] He attended Washington & Jefferson College for its pre-med program.^[4]

He currently serves as director of Clinical/Translational Research at UCLA's Jonsson Comprehensive Cancer Center,^[5] and as director of the Revlon/UCLA Women's Cancer Research Program at JCCC. He is a professor of medicine, chief of the Division of Hematology/Oncology and executive vice chair for research for UCLA's Department of Medicine. Slamon also serves as director of the medical advisory board for the National Colorectal Cancer Research Alliance, a fund-raising organization that promotes advances in colorectal cancer.

For 12 years, Dr. Slamon and his colleagues conducted the laboratory and clinical research that led to the development of the new breast cancer drug Herceptin, which targets a specific genetic alteration found in about 25 percent of breast cancer patients. To acknowledge Slamon's accomplishments, President Bill Clinton appointed Slamon to the three-member President's Cancer Panel in June 2000.

A 1975 honors graduate of the University of Chicago's Pritzker School of Medicine, Slamon earned his Ph.D. in cell biology that same year. He completed his internship and residency at the University of Chicago Hospitals and Clinics, becoming chief resident in 1978. One year later, he became a fellow in the Division of Hematology/Oncology at UCLA, Los Angeles.

His life and research was the template for the plot of the filmLiving Proof (2008), starring Harry Connick, Jr..^[6]

Slamon and his colleagues set out to find ways to target their treatments. They took breast cancer cells and mimicked what was happening in their patients, looking at genetic alterations in the genes that regulate growth. One of them was a gene called HER-2, human epidermal growth factor receptor No. 2. The researchers saw that women who had the HER-2 alteration weren't doing as well because they had a more aggressive tumor. That made it a logical target. Slamon's group found that when they added an antibody to the receptor that the gene made when it mutated, the tumor growth rate dropped dramatically. The process of identifying the target and validating it in the laboratory worked not just for breast cancer, but for other major malignancies, he said. The UCLA researchers developed models for several cancers, seeing which antibodies worked and which didn't.

Slamon was given the Scheele Award in 2009.

 http://www.elseviermed.cn/news/detail/No_gain_adjuvant_bevacizumab_HER2_positive

圣安东尼奥——在圣安东尼奥乳腺癌研讨会上，美国加利福尼亚大学洛杉矶分校(UCLA)Jonsson综合癌症中心临床/转化研究主任/UCLA血液学与肿瘤学系主任/医学教授Dennis J. Slamon博士报告称，Ⅲ期随机BETH试验的结果表明，对于高危HER2阳性乳腺癌，当代化疗已经能达到非常好的结局，贝伐珠单抗辅助治疗并不能进一步改善患者结局。


Dennis J. Slamon博士
 
贝伐珠单抗(阿瓦斯汀)是一种血管内皮生长因子(VEGF)抗体。美国食品药品管理局(FDA)批准其用于治疗结直肠癌、成胶质细胞瘤、非小细胞肺癌和肾细胞癌。

BETH(贝伐珠单抗和曲妥珠单抗辅助治疗用于HER2阳性乳腺癌)试验总共纳入了3,509例HER2阳性、淋巴结阳性或高危淋巴结阴性乳腺癌患者；92%的化疗方案为TCH方案(多西他赛+卡铂+曲妥珠单抗[赫赛汀])。

在对整个受试人群进行了38个月(中位数)的随访后，被随机分配至接受贝伐珠单抗与不接受贝伐珠单抗的患者在3年无侵袭性疾病生存率(92%比92%)和总生存率(97%比96%)方面无显著差异。

作为这项试验的主要研究者，Slamon博士指出，根据各种患者和疾病特征分层的亚组分析也得到了一致的结果。此外，无论是在接受TCH方案(92%比92%)还是FEC方案(5-氟尿嘧啶+表阿霉素+环磷酰胺) (91%比89%)的患者队列中，加或不加贝伐珠单抗的无侵袭性疾病生存率都没有统计学差异。

在整个受试人群中，在化疗的基础上加用贝伐珠单抗使特别关注的所有3/4级不良事件的发生率翻了三倍(27%比8%，P < .0001)，比如高血压、充血性心力衰竭和胃肠穿孔。

Slamon博士总结道，化疗和HER2靶向治疗曲妥珠单抗作为标准治疗，在大约3年的中位随访期后估计仍有92%的患者无病存活，因此进一步改善患者结局的空间其实很小。

Slamon博士在新闻发布会上评论道：“加用贝伐珠单抗没能提高疗效，反而增加了一些安全性担忧。”使用贝伐珠单抗与3/4级不良事件(例如高血压和肠穿孔)的发生率增加相关。

因此，BETH试验与其他许多试验一样，都得出了抗血管生成药物治疗乳腺癌的阴性结果。他说：“除非我们发现某种新药或新的治疗策略对某个患者亚组有效，否则我认为应该放弃使用这类治疗。通过现有的治疗方法我们已经能够获得非常好的效果，改善空间很小。对于那些我们认为会获益于靶向治疗但实际无效的患者，我们应该思考新的治疗策略。”

其他试验也表明，无论所使用的化疗/曲妥珠单抗方案(取决于负责治疗的试验中心)不含有蒽环类药物(TCH方案)或者含有蒽环类药物(FEC方案)，无侵袭性疾病生存率都一致较高。

Slamon博士称，鉴于蒽环类药物的已知毒性以及同等有效但更加安全的替代药物已经问世，因此没有理由再继续使用蒽环类药物治疗HER2阳性乳腺癌。

Slamon博士也承认这个问题存在很大的争议。他指出：“现在我们没有理由再冒险了，从BCIRG-006试验(首个检验TCH方案的高质量研究)到BETH试验，已经有超过4,000例患者接受了TCH方案的治疗，他们的结局非常好。我所在的医院已经不使用蒽环类药物了。这并不意味着这类药物没有疗效；只是相比其他疗效相同并且没有安全性问题的药物而言，蒽环类药物没有额外优势。”

作为新闻发布会的主持人，美国德克萨斯大学MD Anderson癌症中心乳腺肿瘤内科副教授Jennifer Litton博士虽然称赞这项试验“做得非常好”，也同意作者对于贝伐珠单抗结果的解读，但她也表达了一些反对意见。她说：“我的观点完全相反，我认为我们不应该说放弃使用所有蒽环类药物。”“BETH试验要解答的问题是：贝伐珠单抗是否能增加疗效？答案非常明确，不能。”试验比较的是含蒽环类药物与不含蒽环类药物的治疗组。“但这并不是试验原本的设计或意图。” 此外，与其他类似试验相比，在参与BETH试验的受试者中几乎一半的患者处于疾病I期，这使得接受TCH方案的选择性偏倚几率增加。

Litton博士总结道：“但是我的确感觉到赫赛汀方案以及拉帕替尼、帕妥珠单抗和TDM1联合方案也将给HER2阳性乳腺癌的治疗带来里程碑式的改变。”“我们也需要继续寻找特定的治疗策略，而不是一种治疗方案适用于所有HER2阳性乳腺癌，毕竟我们对癌症的分子学亚集有了越来越多的了解。我们似乎已经忽略了当初我们是如何把乳腺癌按照三种受体来划分。”


Jennifer Litton博士

Slamon博士声明担任了试验资助方罗氏/基因泰克公司的顾问。

爱思唯尔版权所有  未经授权请勿转载

By: SUSAN LONDON, Ob.Gyn. News Digital Network

SAN ANTONIO – Adjuvant bevacizumab does not further improve the already very good outcomes being achieved with contemporary therapy in high-risk HER2-positive breast cancer, according to results of the randomized, phase III BETH trial.

There was little room for improvement on chemotherapy and HER2-targeted therapy with trastuzumab as the standard of care, as an estimated 92% of patients were still alive and free of disease after a median follow-up of about 3 years, lead investigator Dr. Dennis J. Slamon reported at the San Antonio Breast Cancer Symposium.

"The addition of bevacizumab didn’t add any efficacy but certainly added some safety concerns," Dr. Slamon commented in a press briefing. Increased rates of grade 3/4 adverse events, such as hypertension and bowel perforation, were associated with use of bevacizumab.

BETH thus joins a host of trials with negative results for antiangiogenic therapy in breast cancer, he said. "Unless there is a new drug or strategy where we can find the subgroup [that benefits], I think this is not going anywhere. We have gotten a pretty good effect with what we have. We have very little room at the top. We have to think about new strategies for those patients who aren’t getting the benefit that we hope they will with targeted therapy."

In other trial findings, there were consistently high rates of invasive disease–free survival regardless of whether the chemotherapy/trastuzumab regimen used (left up to the treating centers) did not contain an anthracycline (docetaxel, carboplatin, and trastuzumab [Herceptin] – TCH) or did contain an anthracycline (5-fluorouracil, epirubicin, and cyclophosphamide – FEC).

Given the known toxicity of anthracyclines and the availability of an equally effective and safer alternative, their use in HER2-positive breast cancer is no longer justified, according to Dr. Slamon, director of clinical/translational research at the University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center and professor of medicine and chief of the division of hematology/oncology at UCLA.

Acknowledging that the topic is intensely debated, Dr. Slamon noted that "there is no reason to take that risk now that we have more than 4,000 patients treated [with TCH] between BCIRG-006 [which first rigorously tested this regimen] and BETH that show that this gives a pretty favorable outcome. We at our institution do not use these drugs [anthracyclines]. It doesn’t mean they are not effective; they just don’t provide any incremental benefit over other drugs that would give you the same effect without the safety concerns."

While praising the trial as "exceptionally well run" and agreeing on interpretation of the bevacizumab results, press briefing moderator Dr. Jennifer Litton expressed an opposing view.

"I’m totally on the other side of the aisle, that we shouldn’t say that all anthracyclines should go away," maintained Dr. Litton, associate professor in the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. "The BETH trial specifically asked the question: Does bevacizumab add anything? And the answer quite clearly is no." It did it compare an anthracycline- and a non–anthracycline-containing arm. "That was not the design or intent," she said.

Additionally, in contrast to other similar trials, almost half of the patients who participated in BETH had stage I disease, raising the possibility of selection bias for who received TCH.

"But I do feel that the Herceptin story and the combination stories to come" with lapatinib, pertuzumab, and TDM1 "are really going to also be the landscape changers in HER2 disease," Dr. Litton concluded. "And we are going to be continuing to find specific strategies and not a one-therapy-fits-all for all HER2 disease because we are learning more and more about the molecular subsets of cancer. How we have broken them up into triple receptors is really going to go by the wayside."
 
Bevacizumab (Avastin) is an antibody to vascular endothelial growth factor (VEGF). It is approved for use by the Food and Drug Administration to treat colorectal cancer, glioblastoma, non–small cell lung cancer, and renal cell cancer.

The 3,509 women enrolled in BETH (Bevacizumab and Trastuzumab Adjuvant Therapy in HER2-Positive Breast Cancer) had HER2-positive, node-positive, or high-risk node-negative breast cancer; 92% received TCH as their chemotherapy.

With a median follow-up of 38 months in the trial population overall, there was no significant difference between patients randomized to receive bevacizumab and those who did not in terms of the 3-year rate of invasive disease–free survival (92% vs. 92%) and overall survival (97% vs. 96%).

The findings were consistent across subgroups stratified by a variety of patient and disease characteristics, Dr. Slamon noted.

Additionally, the rate of invasive disease–free survival was statistically indistinguishable with or without bevacizumab in both the cohort given TCH (92% vs. 92%) and the cohort given FEC (91% vs. 89%).

In the trial population overall, addition of bevacizumab to chemotherapy tripled the rate of all grade 3/4 adverse events of special interest (27% vs. 8%, P less than .0001), such as hypertension, congestive heart failure, and gastrointestinal perforation.

Dr. Slamon disclosed that he serves as an adviser to Roche/Genentech, which supported the trial.

HER2 Testing May be Underutilized in Breast Cancer

September 16, 2009 — Cancer therapies are increasingly being tailored to fit the genetic profile of the patient, but new research suggests that human epidermal growth-factor receptor (HER)2 gene testing may be underused. A literature review found only scant information about the actual use of HER2 testing in clinical practice, suggesting that there are "important variations in testing practices and key gaps in knowledge about those practices."

The review was published online September 14 in Cancer.

It concludes that a large percentage of breast cancer patients who might benefit from trastuzumab (Herceptin) treatment appear not to be receiving it. Up to 66% of women eligible for HER2 testing had no documentation of a test in their health-insurance records, and up to 20% of patients receiving trastuzumab were not tested or had no documentation of a positive test.

The researchers also note that 20% of HER2 test results might be incorrect.

"Our review of the literature suggests that there are important knowledge gaps regarding the real-world use of HER2 testing and trastuzumab," study author Elena Elkin, PhD, a researcher at Memorial Sloan-Kettering Cancer Center in New York City, said in a statement.

"Filling these gaps may help optimize limited healthcare resources and improve care for women with breast cancer," she added.

Genomic testing continues to evolve and can add significant prognostic and predictive information to standard parameters for breast cancer patients, as previously reported by Medscape Oncology.

HER2 testing was developed to identify patients with breast cancers that overexpress HER2, which occurs in 20% to 30% of cases. Trastuzumab, a humanized monoclonal antibody, binds strongly and selectively to the extracellular portion of HER2, and is highly effective in women with breast cancers that overexpress the HER2 gene, the authors explain.

Testing for HER2 is now recommended for all patients with invasive breast cancer, and the US Food and Drug Administration has approved 3 types of tests for this purpose: immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and, most recently, chromogen in situ hybridization (CISH).

But despite the proven efficacy of trastuzumab in patients with HER2-positive breast cancer, the authors point out that there is still uncertainty regarding the best approach to selecting patients for treatment. There is also uncertainty about the most appropriate and efficient testing strategy and the reliability and interpretation of test results.

The goal of this study was to evaluate what is currently known about the use and cost-effectiveness of HER2 testing in clinical practice in the United States, the authors explain.

The researchers, led by Kathryn A. Phillips, PhD, professor of health economics and health services research at the University of California-San Francisco, conducted a literature review and examined available evidence about the percentage of eligible patients tested for HER2, the test methods used, concordance of test results between community and central/reference laboratories, the use of trastuzumab by HER2 test result, and the cost-effectiveness of testing strategies.
HER2 Testing May be Underutilized in Breast Cancer
HER2检测在乳腺癌中的作用可能被低估

September 16, 2009 — Cancer therapies are increasingly being tailored to fit the genetic profile of the patient, but new research suggests that human epidermal growth-factor receptor (HER)2 gene testing may be underused. A literature review found only scant information about the actual use of HER2 testing in clinical practice, suggesting that there are "important variations in testing practices and key gaps in knowledge about those practices."
2009年9月16日－肿瘤的治疗越来越倾向针对患者的基因特征。最新研究显示人类表皮生长因子受体（HER2）基因检测作用尚未得到足够的重视。一篇综述发现HER2检测在临床仅仅得到浅显的应用，提示HER2检测在临床的作用还有重大的发展空间，认识上也有待进一步提高。

The review was published online September 14 in Cancer.
CANCER杂志9月14日在线发表了这篇综述。

It concludes that a large percentage of breast cancer patients who might benefit from trastuzumab (Herceptin) treatment appear not to be receiving it. Up to 66% of women eligible for HER2 testing had no documentation of a test in their health-insurance records, and up to 20% of patients receiving trastuzumab were not tested or had no documentation of a positive test.
综述中总结道，一大部分患者有可能从曲妥珠单抗（Herceptin）治疗中获益，但实际上并没有得到这项治疗。高达66%的女性患者本来适合进行HER2检测，但医疗保险档案中并没有此项记录。而高达20%接受曲妥珠单抗治疗的患者未进行HER2检测或者没有HER2阳性结果。

The researchers also note that 20% of HER2 test results might be incorrect.
作者还指出20%的HER2检测结果可能是错误的。

"Our review of the literature suggests that there are important knowledge gaps regarding the real-world use of HER2 testing and trastuzumab," study author Elena Elkin, PhD, a researcher at Memorial Sloan-Kettering Cancer Center in New York City, said in a statement.
作者Elena Elkin, PhD说，通过对文献的综述，我们发现现实中对HER2检测与曲妥珠单抗之间关系的认识存在严重不足。Elena Elkin是纽约Memorial Sloan-Kettering肿瘤研究中心的专家。

"Filling these gaps may help optimize limited healthcare resources and improve care for women with breast cancer," she added.
她说，通过纠正以上认识的不足有助于进一步保护有限的医疗资源及提高女性乳腺癌患者的治疗效果。

Genomic testing continues to evolve and can add significant prognostic and predictive information to standard parameters for breast cancer patients, as previously reported by Medscape Oncology.

Medscape Oncology网站上之前报道，乳腺癌疾病基因组检测水平正在不断提高，可为乳腺癌患者的预测和预后提供重要参考。

HER2 testing was developed to identify patients with breast cancers that overexpress HER2, which occurs in 20% to 30% of cases. Trastuzumab, a humanized monoclonal antibody, binds strongly and selectively to the extracellular portion of HER2, and is highly effective in women with breast cancers that overexpress the HER2 gene, the authors explain.
20%到30%的乳腺癌患者过度表达HER2，HER2检测正是用于筛查这类患者。曲妥珠单抗是一个人源化单克隆抗体，可以高度选择的紧密结合于HER2胞外段，因此对过度表达HER2的乳腺癌患者有特效。

Testing for HER2 is now recommended for all patients with invasive breast cancer, and the US Food and Drug Administration has approved 3 types of tests for this purpose: immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and, most recently, chromogen in situ hybridization (CISH).
目前常规推荐对浸润性乳腺癌患者进行HER2检测。FDA批准了3种检测方法：免疫组化法（IHC），荧光原位杂交法（FISH），和最近的显色原位杂交法。

But despite the proven efficacy of trastuzumab in patients with HER2-positive breast cancer, the authors point out that there is still uncertainty regarding the best approach to selecting patients for treatment. There is also uncertainty about the most appropriate and efficient testing strategy and the reliability and interpretation of test results.
虽然HER2阳性患者的曲妥珠单抗治疗效果已经得到证实，但是如何最优化选择合适的患者进行上述治疗尚存在问题。因为如何选择最合适的HER2检测方案和解读检测结果都还存在问题。

The goal of this study was to evaluate what is currently known about the use and cost-effectiveness of HER2 testing in clinical practice in the United States, the authors explain.
本文的目的在于评估目前美国临床HER2检测的应用现状，及HER2检测方法的费用问题。

The researchers, led by Kathryn A. Phillips, PhD, professor of health economics and health services research at the University of California-San Francisco, conducted a literature review and examined available evidence about the percentage of eligible patients tested for HER2, the test methods used, concordance of test results between community and central/reference laboratories, the use of trastuzumab by HER2 test result, and the cost-effectiveness of testing strategies.
Kathryn A. Phillips, PhD，California-San Francisco大学卫生经济学和健康服务研究所教授，她领导的研究小组对文献进行了综述，检索的资料包括HER2检测的患者比例，检测的方法，社区检测结果和中心/参考性实验室结果的一致性，HER2检测后曲妥珠单抗治疗情况，以及检测方法的成本效益。
The HER2 (human epidermal growth factor receptor 2) gene is part of a family of genes that play roles in regulating cell growth. The protein it makes is a tyrosine kinase growth factor receptor that a number of normal tissues express and which probably has a role in normal cell function, regulating growth and proliferation.

A fraction of breast cancers, as part of their development, undergo gene amplification. Instead of having two gene copies of the HER2 gene in a normal cell, there are multiple copies. As a result, there is far more expression of the HER2 protein on the cell surface, resulting in aberrant cell growth regulation. Tumors are faster growing, more aggressive and less sensitive to chemotherapy and hormone therapy.

An estimated 20 to 25 percent of breast cancers make these extra copies of the HER2 gene. A normal breast cell might have 20,000 HER2 receptors; a breast cancer cell could have as many as 1.5 million. Approximately 40,000 women are diagnosed each year in the United States with HER2-positive breast cancer.

Early Research and Discovery

The story of HER2 and breast cancer exemplifies what scientists hope to achieve on a broader scale in all cancers and in translational medicine. In the 1980s, scientists, attempting to uncover new cancer-causing oncogenes, discovered a rat gene called neu that appeared to cause breast cancer in animals. Soon after, scientists showed that human cells in culture could be turned cancerous by over expressing the equivalent gene in humans, called HER2/neu. In animal models, antibodies against the HER2/neu gene caused cancers to shrink.

In 1987, Dennis Slamon, M.D., Ph.D., chief of the division of hematology and oncology at the University of California Los Angeles, showed that node-positive breast cancers often over expressed the HER2/neu oncogene, meaning that there were more copies than normal of the HER2 protein on the cell surface. He found that women whose breast cancer had more copies of the HER2 gene spread the fastest and had a worse prognosis. This identified an important subset of breast cancers as a target for therapy.

Trastuzumab

Slamon and Genentech developed mouse monoclonal antibodies for HER2 in an attempt to block the receptors and their growth signal. Genentech subsequently "humanized" the antibody, creating a monoclonal antibody called trastuzumab that bound to the HER2 protein on the surface of cancer cells, leaving normal cells alone. Subsequent work in the laboratory dish showed that even though normal cells have some minor degree of HER2 expression, the antibody was only effective in breast cancer cells that made dramatically more protein than normal.

Slamon conducted a clinical trial comparing chemotherapy and trastuzumab as a first treatment for HER2-positive women with metastatic breast cancer to chemotherapy alone. He found that the response rate and the duration of response were all markedly improved by combining the antibody with chemotherapy. This led to FDA approval in 1998 of trastuzumab for women whose breast cancer had metastasized and had strong HER2 expression.

In 2005, results from three clinical trials reported in the New England Journal of Medicine, involving more than 6,500 women with early stage breast cancer, showed that the drug trastuzumab (Herceptin) cut the risk of relapse in half. That is, the results, from two trials in the United States and one in Europe, found that for many women with early-stage HER2-positive breast cancer, which tends to return despite treatment, adding trastuzumab to chemotherapy could cut the rate of cancer recurrence by 50 percent compared with chemotherapy alone.

In 2006, Slamon presented new data at the San Antonio Breast Cancer Symposium on 3,200 women who had been given chemotherapy plus trastuzumab or chemotherapy alone. At three years, the risk of death was reduced by 40 percent among patients with chemotherapy plus trastuzumab; 92 percent of the patients were still alive at three years.

HER2 as a Prognostic Marker

More recent research has focused on HER2 as a prognostic marker for benefit of certain cancer therapies.

At the 2007 San Antonio Breast Cancer Symposium, Slamon presented data that showed the benefit of adjuvant anthracycline-based therapy appears to be restricted to women with HER2 positive breast cancers. Anthracycline based therapies tend to improve survival by about 4 to 5 percent, but Slamon claims that the improvements are restricted to HER2 positive breast cancers. However, this finding is still in dispute.

At the American Association for Cancer Research 2008 Annual Meeting, researchers presented data that showed the benefit of a HER2 peptide E75 vaccine was restricted to patients with HER2-positive breast cancer, where the therapy reduced mortality by half. The effect was not as pronounced in patients who did not have HER2 positive breast cancer.

The HER2 (human epidermal growth factor receptor 2) gene is part of a family of genes that play roles in regulating cell growth. The protein it makes is a tyrosine kinase growth factor receptor that a number of normal tissues express and which probably has a role in normal cell function, regulating growth and proliferation.
HER2基因属于一类参与调控细胞生长的基因家族。HER2基因编译的蛋白是酪氨酸激酶生长因子受体，这种受体在多个正常组织均有表达，可能参与了细胞的正常功能，调控细胞生长与增殖。
A fraction of breast cancers, as part of their development, undergo gene amplification. Instead of having two gene copies of the HER2 gene in a normal cell, there are multiple copies. As a result, there is far more expression of the HER2 protein on the cell surface, resulting in aberrant cell growth regulation. Tumors are faster growing, more aggressive and less sensitive to chemotherapy and hormone therapy.
一部分乳腺癌在其生长过程中发生基因扩增。正常细胞中有2个HER2基因拷贝，而此类细胞中有多个HER2基因拷贝。结果这类细胞表面显著的表达HER2蛋白，导致异常的细胞生长，表现为肿瘤的加速生长，更具浸润性和对化疗及激素治疗更不敏感。

An estimated 20 to 25 percent of breast cancers make these extra copies of the HER2 gene. A normal breast cell might have 20,000 HER2 receptors; a breast cancer cell could have as many as 1.5 million. Approximately 40,000 women are diagnosed each year in the United States with HER2-positive breast cancer.
估计20%到25%的乳腺癌发生多余的HER2基因拷贝。一个正常的乳腺细胞拥有20000个HER2受体，而一个乳腺癌细胞却可以有高达150万个。美国每年大约有40000个女性被诊断为HER2阳性乳腺癌。
Early Research and Discovery
前期的研究和发现
The story of HER2 and breast cancer exemplifies what scientists hope to achieve on a broader scale in all cancers and in translational medicine. In the 1980s, scientists, attempting to uncover new cancer-causing oncogenes, discovered a rat gene called neu that appeared to cause breast cancer in animals. Soon after, scientists showed that human cells in culture could be turned cancerous by over expressing the equivalent gene in humans, called HER2/neu. In animal models, antibodies against the HER2/neu gene caused cancers to shrink.
科学家们希望在大范围的肿瘤治疗和转化医学中取得像HER2与乳腺癌的研究这样的成果。在上世纪80年代，科学家在探索致癌基因过程中发现大鼠的NEU基因可能导致乳腺癌。很快科学家又发现培养人类乳腺细胞过程中使NEU的同义基因过度表达，可以使细胞具有肿瘤性质，这个同义基因被称为HER2/NEU。
In 1987, Dennis Slamon, M.D., Ph.D., chief of the division of hematology and oncology at the University of California Los Angeles, showed that node-positive breast cancers often over expressed the HER2/neu oncogene, meaning that there were more copies than normal of the HER2 protein on the cell surface. He found that women whose breast cancer had more copies of the HER2 gene spread the fastest and had a worse prognosis. This identified an important subset of breast cancers as a target for therapy.
1987年， Dennis Slamon, M.D., Ph.D.，California 大学的血液肿瘤学研究部主任，发现NODE阳性乳腺细胞经常过度表达HER2/NEU癌基因，提示癌细胞较正常细胞表达更多的HER2蛋白。他发现HER2基因表达越多，患者肿瘤扩散越快，预后越差。此项研究从乳腺癌患者中分离出一个亚群，成为进一步的治疗目标。
Trastuzumab
曲妥珠单抗
Slamon and Genentech developed mouse monoclonal antibodies for HER2 in an attempt to block the receptors and their growth signal. Genentech subsequently "humanized" the antibody, creating a monoclonal antibody called trastuzumab that bound to the HER2 protein on the surface of cancer cells, leaving normal cells alone. Subsequent work in the laboratory dish showed that even though normal cells have some minor degree of HER2 expression, the antibody was only effective in breast cancer cells that made dramatically more protein than normal.
Slamon and Genentech研发一个鼠的HER2单克隆抗体，用以阻断受体及其生长信号。Genentech 接着将这个抗体人源化，开发出曲妥珠单抗，后者可以结合于癌细胞表面的HER2受体，而不影响正常。实验室的进一步工作证实，虽然正常细胞表达少量的HER2，但曲妥珠单抗只影响显著高表达HER2的乳腺癌细胞。
Slamon conducted a clinical trial comparing chemotherapy and trastuzumab as a first treatment for HER2-positive women with metastatic breast cancer to chemotherapy alone. He found that the response rate and the duration of response were all markedly improved by combining the antibody with chemotherapy. This led to FDA approval in 1998 of trastuzumab for women whose breast cancer had metastasized and had strong HER2 expression.
Slamon 开展了一个临床试验，受试者为发生转移的乳腺癌患者，比较了曲妥珠单抗联合化疗与单独的化疗的效果。结果发现接受前一种治疗方法的患者缓解率及缓解时间要明显优于后者。根据结果FDA于1998年批准了曲妥珠单抗用于治疗高表达HER2及肿瘤发生转移的女性乳腺癌患者。
In 2005, results from three clinical trials reported in the New England Journal of Medicine, involving more than 6,500 women with early stage breast cancer, showed that the drug trastuzumab (Herceptin) cut the risk of relapse in half. That is, the results, from two trials in the United States and one in Europe, found that for many women with early-stage HER2-positive breast cancer, which tends to return despite treatment, adding trastuzumab to chemotherapy could cut the rate of cancer recurrence by 50 percent compared with chemotherapy alone.
2005年，3个临床试验在新英格兰医学杂志报道了6500例早期乳腺癌患者应用曲妥珠单抗的结果，发现该药可以降低50%的复发率。3项临床试验2个在美国，1个在欧洲，证实对于HER2阳性乳腺癌患者－－易于复发一类人，加用曲妥珠单抗后相比单独采用化疗可以使复发率降低50%。
In 2006, Slamon presented new data at the San Antonio Breast Cancer Symposium on 3,200 women who had been given chemotherapy plus trastuzumab or chemotherapy alone. At three years, the risk of death was reduced by 40 percent among patients with chemotherapy plus trastuzumab; 92 percent of the patients were still alive at three years.
2006年，在San Antoni乳腺癌研讨会上，Slamon提交了新的研究资料。3200例患者分别接受了曲妥珠单抗联合化疗或单独化疗的方案。接受了曲妥珠单抗联合化疗方案的患者3年死亡风险降低了40%，3年生存患者率达到92%。
HER2 as a Prognostic Marker
HER2－－预后标志
More recent research has focused on HER2 as a prognostic marker for benefit of certain cancer therapies.
更多最新的研究将HER2作为肿瘤治疗效果的预测手段
At the 2007 San Antonio Breast Cancer Symposium, Slamon presented data that showed the benefit of adjuvant anthracycline-based therapy appears to be restricted to women with HER2 positive breast cancers. Anthracycline based therapies tend to improve survival by about 4 to 5 percent, but Slamon claims that the improvements are restricted to HER2 positive breast cancers. However, this finding is still in dispute.
在2007年San Antonio乳腺癌研讨会上，Slamon提交的资料表明，采用蒽环类抗生素辅助治疗对HER2阳性乳腺癌患者似乎作用有限。以往研究认为蒽环类抗生素辅助治疗可以提高4－5%的生存率，而Slamon却认为对HER2阳性患者提高非常有限。这一说法仍存在争议。
At the American Association for Cancer Research 2008 Annual Meeting, researchers presented data that showed the benefit of a HER2 peptide E75 vaccine was restricted to patients with HER2-positive breast cancer, where the therapy reduced mortality by half. The effect was not as pronounced in patients who did not have HER2 positive breast cancer.
在美国肿瘤研究协会2008年会上，有研究者提交了关于HER2多肽E75疫苗治疗HER2阳性患者研究的资料。结果提示可以降低50%的死亡率。而HER2阴性的患者采用上述治疗的效果还不明确。

HER2检测在乳腺癌中的作用可能被低估

2009年9月16日---肿瘤的治疗越来越倾向针对患者的基因特征。最新研究显示人类表皮生长因子受体（HER2）基因检测作用尚未得到足够的重视。一篇综述发现HER2检测在临床仅仅得到浅显的应用，提示HER2检测在临床的作用还有重大的发展空间，认识上也有待进一步提高。

CANCER杂志9月14日在线发表了这篇综述。

综述中总结道，一大部分患者有可能从曲妥珠单抗（Herceptin）治疗中获益，但实际上并没有得到这项治疗。高达66%的女性患者本来适合进行HER2检测，但医疗保险档案中并没有此项记录。而高达20%接受曲妥珠单抗治疗的患者未进行HER2检测或者没有HER2阳性结果。

作者还指出20%的HER2检测结果可能是错误的。

作者Elena Elkin, PhD说，通过对文献的综述，我们发现现实中对HER2检测与曲妥珠单抗之间关系的认识存在严重不足。Elena Elkin是纽约Memorial Sloan-Kettering肿瘤研究中心的专家。

她说，通过纠正以上认识的不足有助于进一步保护有限的医疗资源及提高女性乳腺癌患者的治疗效果。

Medscape Oncology网站上之前报道，乳腺癌疾病基因组检测水平正在不断提高，可为乳腺癌患者的预测和预后提供重要参考。

20%到30%的乳腺癌患者过度表达HER2，HER2检测正是用于筛查这类患者。曲妥珠单抗是一个人源化单克隆抗体，可以高度选择的紧密结合于HER2胞外段，因此对过度表达HER2的乳腺癌患者有特效。

目前常规推荐对浸润性乳腺癌患者进行HER2检测。FDA批准了3种检测方法：免疫组化法（IHC），荧光原位杂交法（FISH），和最近的显色原位杂交法。

虽然HER2阳性患者的曲妥珠单抗治疗效果已经得到证实，但是如何最优化选择合适的患者进行上述治疗尚存在问题。因为如何选择最合适的HER2检测方案和解读检测结果都还存在问题。

本文的目的在于评估目前美国临床HER2检测的应用现状，及HER2检测方法的费用问题。

Kathryn A. Phillips, PhD，California-San Francisco大学卫生经济学和健康服务研究所教授，她领导的研究小组对文献进行了综述，检索的资料包括HER2检测的患者比例，检测的方法，社区检测结果和中心/参考性实验室结果的一致性，HER2检测后曲妥珠单抗治疗情况，以及检测方法的成本效益。

详见：
http://www.medscape.com/viewarticle/709042?src=rss

HER2基因属于一类参与调控细胞生长的基因家族。HER2基因编译的蛋白是酪氨酸激酶生长因子受体，这种受体在多个正常组织均有表达，可能参与了细胞的正常功能，调控细胞生长与增殖。

一部分乳腺癌在其生长过程中发生基因扩增。正常细胞中有2个HER2基因拷贝，而此类细胞中有多个HER2基因拷贝。结果这类细胞表面显著的表达HER2蛋白，导致异常的细胞生长，表现为肿瘤的加速生长，更具浸润性和对化疗及激素治疗更不敏感。

估计20%到25%的乳腺癌发生多余的HER2基因拷贝。一个正常的乳腺细胞拥有20000个HER2受体，而一个乳腺癌细胞却可以有高达150万个。美国每年大约有40000个女性被诊断为HER2阳性乳腺癌。

前期的研究和发现

科学家们希望在大范围的肿瘤治疗和转化医学中取得像HER2与乳腺癌的研究这样的成果。在上世纪80年代，科学家在探索致癌基因过程中发现大鼠的NEU基因可能导致乳腺癌。很快科学家又发现培养人类乳腺细胞过程中使NEU的同义基因过度表达，可以使细胞具有肿瘤性质，这个同义基因被称为HER2/NEU。

1987年， Dennis Slamon, M.D., Ph.D.，California 大学的血液肿瘤学研究部主任，发现NODE阳性乳腺细胞经常过度表达HER2/NEU癌基因，提示癌细胞较正常细胞表达更多的HER2蛋白。他发现HER2基因表达越多，患者肿瘤扩散越快，预后越差。此项研究从乳腺癌患者中分离出一个亚群，可以采取针对性治疗。

曲妥珠单抗
Slamon and Genentech研发了一个鼠的HER2单克隆抗体，用以阻断受体及其生长信号。Genentech 接着将这个抗体人源化，开发出曲妥珠单抗，后者可以结合于癌细胞表面的HER2受体，而不影响正常细胞。实验室的进一步工作证实，虽然正常细胞表达少量的HER2，但曲妥珠单抗只影响显著高表达HER2的乳腺癌细胞。

Slamon 开展了一个临床试验，受试者为发生转移的乳腺癌患者，比较了曲妥珠单抗联合化疗与单独化疗的效果。结果发现接受前一种治疗方法的患者缓解率及缓解时间要明显优于后者。根据结果FDA于1998年批准了曲妥珠单抗用于治疗高表达HER2及肿瘤发生转移的女性乳腺癌患者。

2005年，3个临床试验在新英格兰医学杂志报道了6500例早期乳腺癌患者应用曲妥珠单抗的结果，发现该药可以降低50%的复发率。3项临床试验2个在美国，1个在欧洲，证实对于HER2阳性乳腺癌患者－－易于复发一类人，加用曲妥珠单抗后相比单独采用化疗可以使复发率降低50%。

2006年，在San Antoni乳腺癌研讨会上，Slamon提交了新的研究资料。3200例患者分别接受了曲妥珠单抗联合化疗或单独化疗的方案。接受了曲妥珠单抗联合化疗方案的患者3年死亡风险降低了40%，3年生存患者率达到92%。

HER2－－预后标志

更多最新的研究将HER2作为肿瘤治疗效果的预测手段

在2007年San Antonio乳腺癌研讨会上，Slamon提交的资料表明，采用蒽环类抗生素辅助治疗对HER2阳性乳腺癌患者似乎作用有限。以往研究认为蒽环类抗生素辅助治疗可以提高4－5%的生存率，而Slamon却认为对HER2阳性患者提高非常有限。这一说法仍存在争议。

在美国肿瘤研究协会2008年会上，有研究者提交了关于HER2多肽E75疫苗治疗HER2阳性患者研究的资料。结果提示可以降低50%的死亡率。而HER2阴性的患者采用上述治疗的效果还不明确。