专家视点——加强乳腺癌化学预防

美国科罗拉多州埃斯特公园——在由美国科罗拉多大学丹佛分校主办的内科学新进展讨论会上，该校的肿瘤内科专家Jennifer R. Diamond博士报告称，研究表明初级医疗保健医生似乎忽视了乳腺癌的一级化学预防。

Jennifer R. Diamond博士

化学预防使用不足的情况非常普遍。据估计美国大约有200万绝经前妇女都应该服用他莫西芬作为乳腺癌一级化学预防，现已证实该药能使乳腺癌发病风险降低50%左右。然而，其中只有大约4%的妇女服用了这种安全且普遍耐受良好的雌激素受体拮抗剂。此外，Diamond博士在发言之前对与会者进行了一项非正式调查，结果93%的与会者通过电子投票器表示并不看好乳腺癌化学预防，在临床实践中也不会经常使用，即便是用于经过认真筛选的患者。

Diamond博士说：“就我的经验而言，他莫西芬用于乳腺癌一级化学预防的最常见副作用是潮热。但许多年轻女性不会出现任何问题。鉴于使用该药能使乳腺癌风险降低50%，我认为确实有必要对那些乳腺癌发病风险较高的年轻女性使用该药。”

美国2012年新诊断为乳腺癌的患者人数接近230,000例。预计今年会有超过39,000例乳腺癌患者死于该病。二级化学预防对于已经确诊为原位小叶癌的患者最为有效。通常是由患者的肿瘤内科医生来建议其开始使用二级化学预防。

然而，应该接受一级化学预防者大多从未看过肿瘤内科医生，因此一级化学预防就成了初级医疗保健医生的工作。美国国家综合癌症网络(NCCN)最新发布的指南中就明确指出了应该接受一级化学预防的人群：一级亲属患有乳腺癌或卵巢癌；胸部放疗史；易诱发乳腺癌的基因突变；或者乳腺癌风险评估工具(Gail模型)显示5年内患乳腺癌的风险≥1.7%。Diamond博士指出，5年风险≥1.7%这个标准并不高。依照Gail模型，只要年龄在65岁以上，无论是否合并有其他危险因素，都属于这类人群。

目前有2类药物可以用于乳腺癌的一级化学预防；对于特定的高危个体选用哪种药物更好，这则取决于患者的绝经状态。建议绝经前妇女口服他莫西芬20 mg/日，坚持服药5年；但对于绝经后妇女，选用芳香酶抑制剂依西美坦(阿诺新)可能更安全有效，尽管目前该药用于乳腺癌化学预防的用法尚未正式写入该药的说明书。

这里反复提到的他莫西芬能将乳腺癌发病风险降低50%的数据是来自一项具有里程碑意义的随机、安慰剂对照NASBP (美国国家外科辅助乳房和肠道项目) P-1试验(J. Natl. Cancer Inst. 1998;90:1371-88)。在治疗结束之后，他莫西芬的保护作用仍然持续。以20 mg/日的剂量用药5年，5年内预防1例乳腺癌病例所需治疗的人数为95人，10年内为56人。年龄小于50岁的女性出现严重不良事件的风险并无增加。

Diamond博士补充道：“我们唯一担心的是他莫西芬是否会增加静脉血栓栓塞和子宫内膜癌风险，但事实上在年龄小于50岁的女性中这种情况极其罕见。”“我不建议将他莫西芬用于绝经后妇女，因为这可能会带来子宫内膜癌和血栓栓塞事件等麻烦。我认为他莫西芬可以安全用于绝经前妇女，这并不会显著增加血栓栓塞事件的风险，或者说这种风险小到和避孕药的风险差不多。”

雷洛昔芬是除了他莫西芬之外唯一一种经FDA批准可以用于乳腺癌一级化学预防的药物。NSABP STAR(他莫西芬和雷洛昔芬研究)试验表明，这2种药物在预防浸润性乳腺癌方面效果相当，但在预防原位导管癌方面雷洛昔芬的效果不及他莫西芬(JAMA 2006;295:2727-41)。因此，Diamond博士及其同事没有选择雷洛昔芬。

对于应该接受一级化学预防的绝经后妇女，Diamond博士基于加拿大国家癌症研究所CTG MAP-3试验的结果选用了依西美坦。该试验显示，与安慰剂相比，使用这种芳香酶抑制剂5年可以使乳腺癌的年发病率降低65%。以25 mg/d的剂量用药5年，3年内预防1例浸润性乳腺癌病例所需治疗的人数(NNT)为94人，5年内为26人(N. Engl. J. Med. 2011;364:2381-91)。Diamond博士说：“这样的NNT数据真是相当低了，我们日常临床实践中遇到的很多患者可能都在MAP-3试验的目标人群范围之内。”

此外，在MAP-3试验中没有出现任何与依西美坦相关的严重风险。虽然潮热和其他绝经症状的发生率高于安慰剂组，但在生活质量指标方面两组间并无显著差异。依西美坦组患者的骨密度有逐渐减少的趋势，但骨折风险并无增加。因此，Diamond博士建议服用依西美坦的患者定期监测骨密度，如果骨密度明显下降，则考虑皮下注射地诺单抗，每6个月1次。地诺单抗已经获得FDA批准，可以用于接受芳香酶抑制剂辅助治疗的乳腺癌患者以增加骨量。

Diamond博士声明无相关经济利益冲突。

爱思唯尔版权所有  未经授权请勿转载

By: BRUCE JANCIN, Internal Medicine News Digital Network

ESTES PARK, COLO. – Primary care physicians appear to have dropped the ball when it comes to primary chemoprevention of breast cancer, studies suggest.

Chemoprevention is enormously underutilized. An estimated 2 million American premenopausal women are candidates for primary chemoprevention of breast cancer with tamoxifen, an agent shown to reduce their risk by 50%. Yet only 4% of them are on this safe and generally well-tolerated estrogen receptor antagonist, Dr. Jennifer R. Diamond said at an update in internal medicine sponsored by the University of Colorado at Denver.
 
Moreover, when she informally polled her audience at the outset of her talk, 93% indicated via electronic clicker that they were not comfortable with chemoprevention for breast cancer and didn’t commonly use it in appropriately selected patients in their practice.

"The most common side effect I see with tamoxifen for primary chemoprevention is hot flashes. But many young women will do fine. They don’t have any problems. And the opportunity to reduce the risk of breast cancer by 50% in these young women makes this an option I think you really need to be offering to young women" who are at increased risk for breast cancer, said Dr. Diamond, a medical oncologist at the university.

Nearly 230,000 American women will receive a new diagnosis of breast cancer in 2012. More than 39,000 women will die this year from the malignancy.

Secondary chemoprevention is most effective for women who have been diagnosed with lobular carcinoma in situ. The recommendation to embark on secondary chemoprevention usually comes from the patient’s medical oncologist.

In contrast, most candidates for primary chemoprevention have never seen a medical oncologist. Thus, primary chemoprevention falls within the bailiwick of primary care physicians. The latest guidelines from the National Comprehensive Cancer Network identify appropriate candidates for primary chemoprevention as women who have a first-degree relative with breast or ovarian cancer; a history of thoracic irradiation; mutations predisposing to breast cancer; or a 5-year risk of breast cancer of at least 1.7% according to the breast cancer risk assessment tool (the Gail model).

A 5-year risk of 1.7% or greater is not a high bar. It equates on the Gail model to being 65 years old without additional risk factors. "You’ll find that many of your patients are candidates," Dr. Diamond predicted.

Two options are available for primary chemoprevention; the determining factor as to which is best in a given high-risk individual is menopausal status. Premenopausal women can benefit from 5 years of oral tamoxifen at 20 mg/day. In postmenopausal women, however, exemestane (Aromasin), an aromatase inhibitor, is the safer, better choice, even though the drug’s use in chemoprevention is, for now, off label, she continued.

The oft-cited figure of a 50% reduction in breast cancer risk conferred by tamoxifen comes from the landmark randomized, placebo-controlled NASBP (National Surgical Adjuvant Breast and Bowel Project) P-1 trial (J. Natl. Cancer Inst. 1998;90:1371-88). The protective effect continued after treatment ended. The number needed to treat at 20 mg/day for 5 years in order to prevent one additional case of breast cancer was calculated at 95 in 5 years and 56 in 10 years. Women younger than age 50 years experienced no excess risk of serious adverse events.

"The risks of venous thromboembolism and endometrial cancer are what we all worry about with tamoxifen, but they’re actually incredibly uncommon" in women younger than age 50, she said. "I don’t recommend that you use tamoxifen in your postmenopausal women; that’s where you get into trouble with endometrial cancer and thromboembolic events. I believe that you can safely use tamoxifen in premenopausal women without a significantly increased risk of thromboembolic events. I equate the risk to that of birth control pills."

Raloxifene joins tamoxifen as the only other proved drug with Food and Drug Administration approval for primary breast cancer chemoprevention. The NSABP STAR (Study of Tamoxifen and Raloxifene) trial showed that the two medications are equivalent for prevention of invasive breast cancer, but that raloxifene is less effective in preventing ductal carcinoma in situ (JAMA 2006;295:2727-41). For this reason, Dr. Diamond and her colleagues don’t use it.

For postmenopausal women who are candidates for primary chemoprevention, Dr. Diamond said that she turns to exemestane on the basis of the National Cancer Institute of Canada CTG MAP-3 trial, which showed a 65% reduction in the annual incidence of breast cancer with 5 years of the aromatase inhibitor, compared with placebo. (N. Engl. J. Med. 2011;364:2381-91).

The number needed to treat with exemestane at 25 mg/day for 5 years in order to prevent one invasive breast cancer was 94 in 3 years and 26 in 5 years.

"I would argue that this is a really low NNT, and a lot of patients in your practice probably would fall into the category of qualifying for the MAP-3 study," Dr. Diamond said.

There were no serious risks associated with exemestane in MAP-3. Hot flashes and other menopausal symptoms were more common than with placebo, yet reassuringly there was no difference between the exemestane and control groups on quality of life measures.

Bone mineral density decreased over time in the exemestane group; however, patients on the aromatase inhibitor had no increased risk of fractures. Dr. Diamond advised monitoring bone density in exemestane-treated women, and if it drops significantly, consider prescribing denosumab as a subcutaneous injection once every 6 months. Denosumab is already FDA approved to increase bone mass in patients on adjuvant aromatase inhibitor therapy for breast cancer.

Dr. Diamond reported having no financial conflicts.