乳房密度高不增加乳腺癌死亡风险

美国国立癌症研究所的Gretchen L. Gierach博士及其同事在对美国乳腺癌监测联盟(BCSC)的数据进行分析后发现，虽然乳房摄影密度高与患乳腺癌的风险增加相关，但并不会增加已确诊乳腺癌患者的死亡风险。而对于肥胖或者肿瘤体积大或恶性程度高的患者，乳房密度低反而与乳腺癌死亡风险增加相关。

该研究结果已于8月20日在线发表在《美国国家癌症研究所杂志》(Journal of the National Cancer Institute)上(J. Natl. Cancer Inst. 2012 Aug. 20 [doi: 10.1093/jnci/djs327])。


虽然乳腺组织极度稠密(BI-RADS 4级)，但超声检查示该患者不存在局灶性损害。

既往研究显示，乳房摄影密度高是非家族性乳腺癌的最显著危险因素之一。乳房密度高还与乳腺癌危险因素相关，包括未产妇、乳腺癌家族史阳性以及使用更年期激素治疗药物，但研究一致表明“与低密度相比，乳房高密度会使患乳腺癌的相对风险增加4~5倍，且与这些以及其他因素无关。”

不过，对于已确诊的乳腺癌患者，乳房密度与死亡风险之间的相关性尚不明确。为了评估两者间的关系，Gierach博士及其同事对来自BCSC的数据进行了分析，这是一个由国家癌症研究所资助的基于人群的乳房影像数据登记库。研究者指出：“对于这种相关性研究，BCSC具有多方面的优势，包括可以对大量的乳腺癌患者进行前瞻性追踪，并且可以获取有关其潜在混杂因素(包括体重指数[BMI])、筛查史、肿瘤特征、治疗等方面的详细信息。”

分析对象仅限于确诊时年龄≥30岁的原发性浸润性乳腺癌患者。研究者通过美国监测、流行病学与最终结果(SEER)数据库并链接至国家癌症登记库和(或)病理资料数据库来获取患者的乳腺癌病理学和身体状况数据。乳房密度数据则根据美国放射学会提出的乳房影像报告和数据系统(BI-RADS)进行采集，BI-RADS将乳房密度分为1级(几乎完全由脂肪组成)~4级(极度稠密)。

研究人群为1996~2005年被确诊为原发性浸润性乳腺癌的9,232例患者，基于BCSC的平均随访期为6.6年(60,759人年)。共有1,795例死亡，其中889例死于乳腺癌。

在校正肿瘤部位、确诊时的年龄、确诊年份、美国癌症联合会分期、BMI、检查手段、治疗以及患者收入等因素之后，与BI-RADS 2级(散在纤维腺体密度)相比，BI-RADS密度4级与乳腺癌死亡(危险比[HR]，0.92)或全因死亡 (HR，0.83)之间无显著相关性。

此外，BI-RADS密度分级为1级的患者其乳腺癌死亡风险增加(HR，1.36)，并且在肿瘤直径≥2.0 cm(HR，1.55)以及肿瘤恶性程度高(HR，1.45)的患者中，这一风险会进一步增加。

结果还显示，BMI可能会改变乳房密度与乳腺癌死亡风险之间的相关性(P=0.007)。研究者报告称，在乳腺组织“几乎完全由脂肪组成”的肥胖患者中，危险比达到了2.02，并且即使将BMI大于40 kg/m2的病态肥胖患者排除在外，这种相关性仍然很明显。

研究者指出，对于乳腺组织“几乎完全由脂肪组成”的肥胖(BMI≥30 kg/m2)患者，乳腺癌死亡风险明显增加；但在超重或者体重偏瘦的患者中却不存在这种相关性。“这可能是因为乳腺脂肪含量高所形成的肿瘤微环境会促进癌症的生长和进展。”

研究者表示，虽然这项研究存在一些局限性，比如BI-RADS密度分级的“观察者间信度可能不够高”，关于患者确诊后的治疗、合并症、体重变化等方面的详细累积数据也有限，但上述研究结果对乳房密度、其他患者特征与后续治疗之间的潜在相关性提出了进一步的疑问。

研究者总结道：“这项大规模前瞻性研究表明，乳房密度高虽然是一个普遍且显著的乳腺癌危险因素，但与乳腺癌死亡或任何原因导致的死亡风险增加无关。”“对于部分乳腺癌亚组患者，乳房密度低反而与预后不良相关，这提示可能需要将乳房密度数据与流行病学数据以及其他检测指标相结合来进一步了解乳腺癌变的机理，并识别出哪些患者的病情可能会进展很快以便尽早发现并加以预防。”

研究者还补充道，上述研究结果强调了有必要进一步了解导致乳房密度个体间差异的乳腺组织成分的生物学特征及其潜在的相关性。

该研究得到了来自美国国立卫生研究院校内研究项目、国家癌症研究所(NCI)以及NCI出资的BCSC的支持。

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By: SHARON WORCESTER, Ob.Gyn. News Digital Network

High mammographic breast density is associated with increased risk of developing breast cancer, but not with increased risk of death among those diagnosed with breast cancer, according to an analysis of data from the U.S. Breast Cancer Surveillance Consortium.

Low breast density is associated with an increased risk of breast cancer death, however, in women who are obese or who have large or high-grade tumors, Gretchen L. Gierach, Ph.D., of the National Cancer Institute and her colleagues reported.

Specifically, the elevated risk was apparent for obese women (body mass index 30 kg/m2 or greater) with "almost entirely fatty breasts." This association was not apparent in overweight or lean women.

The breast tissue is extremely dense (BI-RADS 4) but ultrasonography shows no focal lesions in this patient.
 
"One explanation for the increased risks associated with low density among some subgroups is that breasts with a higher percentage of fat may contribute to a tumor microenvironment that facilitates cancer growth and progression," the investigators suggested.

The findings were published Aug. 20 online in the Journal of the National Cancer Institute.

Prior studies have demonstrated that elevated mammographic breast density is among the strongest risk factors for nonfamilial breast cancer. High breast density is also associated with breast cancer risk factors including nulliparity, a positive family history of breast cancer, and menopausal hormone therapy use, but studies have consistently demonstrated that "compared with low density, high density confers relative risks of four- to fivefold for breast cancer, independent of these and other factors," the investigators said.

The association between breast density and death among those diagnosed with breast cancer has remained unclear, however. To assess this relationship, they analyzed data from the U.S. Breast Cancer Surveillance Consortium (BCSC) – a National Cancer Institute–sponsored population-based registry of breast imaging facilities.

"The BCSC offers several advantages for studying these associations relative to other studies, including the prospective follow-up of a large number of breast cancer patients with detailed information regarding potential confounding factors, including BMI, as well as on screening history, tumor characteristics, and treatment," the investigators noted.

The analysis was restricted to women aged 30 years and older at the time of diagnosis with primary incident invasive breast carcinoma. Breast cancer pathology and vital status data were obtained through the Surveillance, Epidemiology, and End Results (SEER) program and by linkage to state cancer registries and/or pathology databases. Breast density data were collected according to the American College of Radiology’s Breast Imaging Reporting and Data System, or BI-RADS, which rates density in categories from 1 (almost entirely fat) to 4 (extremely dense).

The study population comprised 9,232 women diagnosed with primary invasive breast cancer between 1996 and 2005 and followed for a mean of 6.6 years (60,759 person-years) as part of the consortium. Of these 1,795 died, including 889 who died from their breast cancer.

After adjustment for site, age at diagnosis, year of diagnosis, American Joint Committee on Cancer stage, BMI, mode of detection, treatment, and income, no significant association was found between BI-RADS 4 density and death from breast cancer (hazard ratio, 0.92) or death from all causes (HR, 0.83), compared with BI-RADS 2 (scattered fibroglandular densities).

Women with BI-RADS 1 density had an elevated risk for breast cancer death (HR, 1.36), and that risk was further increased among those with tumors of at least 2.0 cm (HR, 1.55), and those with high-grade tumors (HR, 1.45), the investigators reported (J. Natl. Cancer Inst. 2012 Aug. 20 [doi: 10.1093/jnci/djs327]).

BMI was found to modify the relationship between breast density and risk of breast cancer death (P for interaction = .007). The investigators reported a hazard ratio of 2.02 in obese women with "almost entirely fatty" breasts, and noted that it remained apparent even if morbidly obese women with BMI greater than 40 were excluded.

Although the study is limited by "moderate interobserver reliability" with respect to BI-RADS density assessment, and by the fact that that detailed, cumulative information on treatment, comorbidities, and changes in weight after diagnosis was limited, the findings raise additional questions about possible interactions between breast density, other patient characteristics, and subsequent treatment, the investigators said.

"It is reassuring that elevated breast density, a prevalent and strong breast cancer risk factor, was not associated with risk of breast cancer death or death from any cause in this large, prospective study," they said.

"However, we identified subsets of women with breast cancer for whom low density was associated with adverse prognoses, highlighting the possibility of integrating breast density with epidemiological data and other measurements to understand mechanisms of breast carcinogenesis and to identify women who are likely to develop aggressive cancers, which might be preventable or detectable through specific interventions," they said.

The findings underscore the need for improved understanding of the biological characteristics of, and the relationships between breast tissue components responsible for inter-individual variations in breast density, they added.

This study was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute (NCI), and the NCI-funded BCSC.