USPSTF发布新版乳腺癌化学预防指南

美国预防服务工作组(USPSTF)日前就乳腺癌化学预防提出了新建议，强调需要让医患双方在充分知情的情况下制定决策。



USPSTF成员、美国佐治亚大学公共卫生学院的Mark Ebell博士在接受采访时指出，自最初的2002年指南被发布以来，已有大量新研究问世，包括关键性STAR试验的新数据(Cancer Prev. Res. 2010;3:696-706)和不久前有关降低风险药物的meta分析(Ann. Intern. Med. 2013;158:604-14)，这些研究使我们明白了，应当根据女性年龄、乳腺癌风险、种族和是否已接受子宫切除术等因素权衡风险与获益。

本次在《内科学年鉴》上发表的2013年指南，将上述数据插入了一系列表格中，从而列举了在不同危险因素下的净获益。例如，表1针对的是仍有子宫的白人和非西班牙裔女性。

“因此，我们要做的是查看患者的5年风险和年龄，然后就能判断是否风险更高或伤害更大。这是一项艰难的决定，危险因素相似的两名女性可能作出截然不同的决定，这完全没有问题。每个人都是与众不同的，每个人对风险和价值的判断也是不一样的。我们只想确定她们在作出决定时处于最佳的知晓状态。”

原先的和更新版本的指南包含在总体建议方面是一致的：风险处于平均或较低水平的女性不应当进行化学预防，而高危女性在没有任何禁忌证的前提下应当考虑接受治疗。不过，新版指南更明确地指出了哪些药物已被美国食品药品管理局(FDA)批准用于乳腺癌化学预防。

USPSTF建议年龄≥35岁，无乳腺癌、原位导管癌或原位小叶癌病史，且乳腺癌风险升高的无症状女性使用选择性雌激素受体调节剂他莫西芬和雷洛昔芬(易维特)预防浸润性乳腺癌。这两种药物的每日剂量分别为20 mg和60 mg，治疗5年。他莫西芬已被FDA批准用于年龄≥35岁的女性，而雷洛昔芬在这一适应证方面仅获准用于绝经后女性。Ebell博士指出，在今年4月份发布的指南草案中，这项建议的目标人群为年龄≥40岁的无症状女性，而本次发布的最终版指南则将年龄下限降至35岁，原因是乳腺癌预防试验招募的是年龄＞35岁的女性。

值得一提的是，新指南没有继续对芳香酶抑制剂依西美坦(阿诺新)表示支持。美国临床肿瘤学会(ASCO)今年早些时候发布的新版化学预防指南建议，在降低绝经后女性的浸润性雌激素受体阳性乳腺癌风险方面，应将依西美坦视为一种可选药物加以讨论。USPSTF仅考虑使用FDA批准的药物进行乳腺癌化学预防，而依西美坦目前仅获准用于乳腺癌治疗。

芳香酶抑制剂阿那曲唑(瑞宁得)则既未得到ASCO的推荐，也未获得USPSTF的支持，大家还在等待目前正在进行中的IBIS II(乳腺癌风险升高的绝经后女性采用阿那曲唑预防乳腺癌)研究的结果，这是一项Ⅲ期安慰剂对照的英国研究。

马萨诸塞大学妇产科的Joanna Cain博士指出，USPSTF有关依西美坦的决定是基于现有证据作出的。“依西美坦并未达到USPSTF要求的标准水平，而ASCO则更愿意在证据较少的情况下作出判断。他们并未完全排除依西美坦，而是说该药目前还不符合他们的标准。假如患者对他莫西芬和雷洛昔芬均不能耐受而又需要化学预防性治疗，我们还是会考虑使用依西美坦的。”

Cain博士对这份2013年指南持欢迎态度，尤其是在个体患者用药风险的合理警示因素方面，例如年龄、静脉血栓形成和子宫内膜癌等，也包括由肥胖和遗传因素(例如Lynch综合征)带来的风险。以降低风险为目的的用药并不普遍，不过那是因为仅有约5%的女性真正适宜接受化学预防，而这5%的女性中又只有少部分确实服用了药物。

USPSTF开展的一项全国调查结果显示，仅有12%的高危女性选择服用他莫西芬以降低乳腺癌风险，同时77%的女性首先拒绝了该治疗，原因是担心发生严重不良事件和治疗获益较小(Arch. Intern. Med. 2006;166:2260-5)。而且，在350名参与调查的初级保健医生中，仅有27%在过去12个月内曾为了预防乳腺癌而开具他莫西芬处方。

Ebell博士表示：“我们的确需要让所有基层医生而不仅是妇产科医生参与这种知情的决策过程，确保他们能自如、自信地应对提出化学预防问题的患者。”

Ebell博士报告称无相关利益冲突。

By: PATRICE WENDLING, Internal Medicine News Digital Network

The U.S. Preventive Services Task Force has issued updated recommendations on the use of chemoprevention for breast cancer that emphasize the need for informed, shared decision-making.

"It’s a complicated decision, and there are a lot of moving parts, if you will," USPSTF member Dr. Mark Ebell said in an interview.

New research since the original 2002 guidance, including updates from the pivotal STAR trial (Cancer Prev. Res. 2010;3:696-706) and a recent meta-analysis of risk-reducing medications (Ann. Intern. Med. 2013;158:604-14), have helped clarify the balance of benefits and harms by a woman’s age, breast cancer risk, race, and whether she’s had a hysterectomy.

The 2013 guidelines, published today in Annals of Internal Medicine, plug those data into a series of tables that present the net benefit as stratified by those risk factors. For example, Table 1 is for white, non-Hispanic women who have a uterus.

"So, you’d go there, look up [the patient’s] 5-year projected risk, look up [the patient’s] age, and it provides a general color-coded assessment of whether there are more risks or harms," Dr. Ebell said. "It’s a tough decision, and two women with similar risk factors may make different decisions, and that’s perfectly okay. Everyone’s different; everyone assesses risk differently and has different values. We just wanted to make sure they have the best possible information when they make their decision."

Both the original and updated versions carry the same overall recommendation: Women who are at an average or low risk should not use chemoprevention, while women at high risk should consider therapy if they don’t have any contraindications.

The 2013 recommendations are trying, however, to be a bit more explicit about which medications have been approved by the Food and Drug Administration (FDA) for breast cancer chemoprevention, said Dr. Ebell, a family physician with the College of Public Health, University of Georgia, Athens.

The USPSTF recommends the use of the selective estrogen receptor modulators tamoxifen and raloxifene (Evista) to reduce the incidence of invasive breast cancer in asymptomatic women aged 35 years and older who are without a prior diagnosis of breast cancer, ductal carcinoma in situ, or lobular carcinoma in situ and who are at increased risk of breast cancer. The daily doses are 20 mg and 60 mg, respectively, for 5 years.

Tamoxifen is FDA approved for this use in women aged 35 years and older, while raloxifene is approved for this indication in postmenopausal women.

In a draft version of the guidance released this April, the target audience for the recommendation was asymptomatic women aged 40 years and older, but the age limit was lowered to 35 years in the final version because the Breast Cancer Prevention Trial enrolled women over age 35, Dr. Ebell said.

Notably absent in the new guidelines is an endorsement of the aromatase inhibitor exemestane (Aromasin). Updated chemoprevention guidelines issued earlier this year by the American Society of Clinical Oncology recommend that exemestane be discussed as an alternative to reduce the risk of invasive, estrogen receptor–positive breast cancer in postmenopausal women (J. Clin. Onc. 2013;31:2942-62).

The task force only considers FDA-approved medications for the indication of breast cancer chemoprevention, and exemestane is only approved for breast cancer treatment, Dr. Ebell explained.

The aromatase inhibitor anastrozole (Arimidex) is not recommended by either ASCO or the USPSTF, with data awaited from the ongoing phase III, placebo-controlled British IBIS II (Anastrozole in Preventing Breast Cancer in Postmenopausal Women at Increased Risk of Breast Cancer) study.

Dr. Joanna Cain, professor of obstetrics/gynecology at the University of Massachusetts, Worcester, said the task force made the decision regarding exemestane on the basis of the present evidence.

"UPSTF has a level of standards that exemestane does not yet meet, while ASCO is willing to move with less evidence," she said in an interview. "They are not ruling it out but saying by their criteria, it does not yet meet this. Having said all that, if a patient is intolerant of tamoxifen and raloxifene and needs chemopreventive therapy, we would consider using exemestane as an alternative."

Dr. Cain noted that she welcomes the 2013 guidance, particularly the appropriate caution about individual patient risks for these medications such as age, venous thrombosis, and endometrial cancer, which also includes the risk conferred by obesity and genetics such as Lynch syndrome.

"In particular, the clarity around benefit, and therefore, use only for those at increased risk, is helpful," she said.

The use of risk-reducing medications is quite low, but that’s because only about 5% of women are really appropriate candidates and only a minority of these actually take the medication, Dr. Ebell said.

Just 12% of high-risk women opted to take tamoxifen to reduce their risk for breast cancer in a national survey highlighted by the task force, with 77% of women declining primarily because of concerns about serious adverse events and small therapeutic benefit (Arch. Intern. Med. 2006;166:2260-5).

Further, only 27% of the 350 primary care physicians surveyed had prescribed tamoxifen for breast cancer prevention at least once in the prior 12 months.

"We do need to engage the primary care community more broadly, not just ob.gyns., in this informed decision-making and make sure they are comfortable and confident when they have a patient with questions about chemoprevention," Dr. Ebell said.

Dr. Ebell reported having no financial disclosures.