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liruihan

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[资源] 【资源】当乳腺癌发生转移时，肿瘤生物特性如ER,PR,HER2可能发生改变

June 10, 2010 (Chicago, Illinois) — For breast cancer patients whose disease has metastasized, tumor biology often changes between primary and metastatic lesions.

According to the results of a retrospective study presented here at the American Society of Clinical Oncology 2010 Annual Meeting, a proportion of women with metastatic breast cancer required a change in therapy after rebiopsy revealed discordance in receptor status between the primary tumor and liver metastasis.

The authors found that estrogen-receptor (ER), progesterone-receptor (PgR), or HER2-receptor status of liver metastases differed from that of the primary breast tumor, necessitating a change in endocrine therapy or targeted treatment in 12.1% of the study cohort.

"There is emerging evidence that tumor receptor status may change dynamically during the natural history of the disease," said lead author Marzia Locatelli, MD, during her presentation.

Dr. Locatelli, who is from the European Institute of Oncology in Milan, Italy, added that when it is "safe and easy to perform, a biopsy of the metastatic lesion should be considered in all patients, particularly if there is a long interval from diagnosis to biopsy."

Possible Reasons and Questions for the Future

There are any number of reasons for the discordance seen in the primary tumor and metastatic lesions, said Andrea L. Richardson, MD, PhD, who served as a discussant of the paper.

Errors in assay methodology is one possible reason, although that would not explain the majority of discordances, said Dr. Richardson, who is assistant professor of pathology at Harvard Medical School in Boston, Massachusetts.

Sampling size is another possibility; liver biopsies provide a much smaller sample of tissue for evaluation of ER and PgR status, but Dr. Richardson pointed out that discordance rates for loss of ER or gain of ER are roughly the same, or even a little higher for ER gain in liver metastases. "This suggests that the smaller sample size of recurrences is not the major reason for discordance," she said.

A third possibility is delayed fixation and false negative results for the primary tumor, which could explain some of the gain of ER in recurrence. "I think we should be aware of this when thinking about the use of adjuvant therapy, and reducing false negatives on primary tumors as well," Dr. Richardson explained.

There might also be biologic reasons for discordance; genomic studies have shown that there is heterogeneity within most tumors. She noted that receptor studies are generally performed only on a single block of the primary breast tumor or limited to a core biopsy of the tumor.

"The failure to detect a significant subpopulation with different receptor expression within a large primary tumor may explain discordances," she said, and questioned whether there is an association between tumor size and the likelihood of discordance.

"Should we, as pathologists, be evaluating more areas of the primary tumors to rule out a subpopulation with a different phenotype?" she asked.

We need to treat the tumor that is present now, not the tumor that used to be there years before.
All things considered, the reason for discordance might not be important. "Therapy is determined by receptor status, and we need to treat the tumor that is present now, not the tumor that used to be there years before," Dr. Richardson said.

Biopsy of presumed metastatic disease will detect some benign lesions, new primaries, and metastases of a second cancer — all of which require different considerations for treatment and prognosis, Dr. Richardson noted.

But this does pose questions for the future, she told the audience. "Is there a subgroup with a low enough rate of discordance to suggest that rebiopsy is not necessary?"

"How do ER discordance rates vary based on expression of HER2?" she asked. "Are most of the cases with unstable expression of ER, either gains or losses, occurring in patients with HER2-positive primary tumors?"

Discordance Noted, Therapy Changed

During a press conference at which the results were highlighted, study coauthor Giuseppe Curigliano, MD, PhD, also from the European Institute of Oncology, pointed out that the premise of this study was very simple: Should liver metastasis or any metastatic site in breast cancer be biopsied to improve treatment choice?

"Determination of ER, PgR, and HER2 status is clinically relevant for the treatment choice and for breast cancer subtype determination," he said. "But despite this evidence, it is not routine practice to perform biopsies on metastatic deposits of disease. So when we choose treatments for patients with metastatic disease, we choose the treatment according to the biologic features of the primary tumor."

In this study, the authors analyzed a database of ultrasound-guided liver biopsies performed from 1995 to 2008, and identified 255 breast cancer patients with matched primary and liver tissue samples. The median time from primary diagnosis to liver biopsy was 3.4 years (range, 0 to 18.3 years).

The overall discordance rate for ER status between the primary tumor and liver metastases was 14.5%. The status of 15 patients (25.9%) changed from ER negative to ER positive, and of 22 patients (11.2%) changed from ER positive to ER negative.

For HER2, the authors observed an overall discordance rate of 13.9%. There were 7 patients (5.9%) in whom status switched from HER2 negative to HER2 positive, and 17 patients (31.5%) in whom it changed from HER2 positive to HER2 negative.

Progesterone status changed in 48.6% of the patients, and changes in therapy were made in 12.1% of patients on the basis of the results of their liver biopsy.

Biopsy More Necessary in Era of Targeted Therapy

Other studies have already shown that tumor biology can change. One study, for example, showed that half of cancers change when they spread to the sentinel node.

Biopsy of metastases is becoming increasingly more common in the United States, and is being done more and more frequently, said Eric P. Winer, MD, professor of medicine at Harvard Medical School.

Certain features of the cancer may be more prominently expressed.
Dr. Winer, who moderated the press briefing, noted that with a whole new generation of targeted therapies becoming available over the next decade, "I think that it will be that much more necessary to obtain tissue, not just when a woman first has metastatic breast cancer, but potentially over the course of her illness."

"There is the potential that the cancer can evolve over time; it may not actually change, but certain features of the cancer may be more prominently expressed," he added.

The authors have disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 2010 Annual Meeting: Abstract CRA1008. Presented June 5, 2010.
http://www.dxy.cn/bbs/post/view?bid=116&id=17427513&tpg=1&ppg=1&sty=1#17589917

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liruihan

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2010年6月10日（伊利诺州芝加哥）——对于已发生转移的乳腺癌病人来说，原发灶和转移性病变之间的肿瘤生物学常发生变化。
根据美国临床肿瘤学会2010年会上展示的一篇回顾性研究结果，一部分转移性乳腺癌病人在重新活检后发现原发肿瘤和肝转移灶之间受体状态不一致，因而她们需要重新选择治疗方案。
研究人员发现ER、PR和HER2在肝转移灶和原发灶之间有差异，根据该研究人群，有12.1%患者需要在内分泌治疗或靶向治疗发生变化。
该文的主要作者Marzia Locatelli在她的介绍中说：“新的证据表明在疾病自然史中肿瘤受体状态可发生明显改变。”
来自于意大利米兰的欧洲肿瘤研究所的Locatelli博士补充道：“当再次活检是安全和容易进行时，应对所有病人的转移性病变进行活检，特别是如果距离首次活检诊断有较长间隔时。”
可能的原因和未来的问题
原发肿瘤和转移性肿瘤不一致性有许多原因，该文的作者之一Andrea L. Richardson博士说。
检测方法错误是其中一个原因，尽管这不能解释大多数不一致性。来自于曼彻斯特波士顿的哈佛医学院的病理学助理教授Richardson博士说道。
样本大小是另一个可能的原因。肝活检虽提供了很小的标本用于ER和PR的检测，但Richardson博士指出ER失表达率和阳性率大致是相同的，在肝转移灶中甚至ER阳性率略高。她说：“这表明复发的小标本不是结果不一致的主要原因。”
第三个可能的原因是原发肿瘤延迟固定和假阴性结果，这个能解释复发病灶的ER阳性表达。“我认为当我们考虑辅助治疗时我们应知道这个，也可减少原发灶的假阴性率。”Richardson博士说道。
原发灶和转移灶激素受体不一致性可能还有生物因素，基因组研究显示大多数肿瘤内存在异质性。她指出受体研究基本上是在原发肿瘤一个蜡块上或局限于肿瘤的粗针活检标本中进行。
她说：“在一个大的原发灶内未能检出不同受体表达的亚群可解释结果不一致性。”问题是肿瘤大小和不一致的可能性之间是否存在相关性。
她问道：“作为病理医生，我们应该评价原发肿瘤的较多区域以排除不同表型的亚群。”
我们需要治疗现在存在的肿瘤，而不是3年前的肿瘤。
所有的东西都考虑过，不一致的原因可能并不重要。Richardson博士说道：“治疗是由受体状态决定的，我们需要治疗现在存在的肿瘤，而不是3年前的肿瘤。”
Richardson指出，假定转移灶的活检将检出一些良性病变，新的疾病和第二个癌的转移——所有这些需要考虑选择不同的治疗和评估病人预后。
但这个也会将来引发一些问题，她告诉听众，“有一个足够低不一致率的亚群可以提示重新活检不需要吗？”
ER不一致率如何基于HER2表达而发生改变呢？“她问道：”大多数ER不稳定表达的病例，或者获得或丢失，在HER2阳性原发肿瘤病人也发生吗？“
不一致性应注明，治疗也会改变
在该结果被突出显示的新闻发布会上，该项研究的共同作者，也是欧洲肿瘤研究所的Giuseppe Curigliano博士指出这项研究的前体非常简单，那就是乳腺癌肝转移灶和其他任何转移灶被活检能提高治疗选择吗？
“ER、PR和HER2表达状态临床上与治疗选择和乳腺癌亚型有关，”他说：“但是尽管有这个证据，但对转移灶不能常规进行活检。因此当我们对转移性疾病病人选择治疗方案是，我们根据原发肿瘤的生物学特征而选择治疗方案。”
在这项研究中，作者分析了1995-2008年间超声指导下肝活检的资料，发现了255例同时有原发灶和肝转移灶标本的乳腺癌病人。原发诊断到肝活检的平均时间是3.4年（范围0-18.3年）。

原发肿瘤和肝转移灶ER不一致率为14.5%。15例（25.9%）病人ER从阴性变为阳性，11例（11.2%）从ER阳性变为阴性。
HER2总的不一致率为13.9%。7例（5.9%）病人HER2由阴性变为阳性，17例（31.5%）则有阳性变为阴性。
48.6%病人孕激素发生改变，其中12.1%病人的治疗根据肝活检的结果发生改变。
靶向治疗时代更需要活检
我们的结果已经显示肿瘤生物学能发生改变。例如一项研究显示当癌转移到前哨淋巴结时有一半癌症发生变化。
转移灶活检在美国变得越来越常见，频率也越来越多。哈佛大学医学院医学教授Eric P. Winer博士说。
癌症的某些特征可能更加明显表达。
主持新闻发布会的Winer博士指出整体新一代靶向治疗在以后的十年将变得可行。“我认为更有必要取得组织，不仅仅当一名女性首次有转移性乳腺癌，而是在其疾病过程中都应有可能。”
他补充道：“随着时间的推移，癌症有这种恶化的可能性，它实际上可能不发生变化，但癌症的某些特征可更加显著表达。”
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