Key Points

• The cumulative incidence of breast cancer recurrence (BCR) continues to increase decades after a diagnosis of nonmetastatic female breast cancer.
• Factors that are independently associated with a greater risk of late recurrence include a diagnosis before the age of 40 years, estrogen receptor–positive tumors, treatment with breast-conserving surgery, 4 or more positive lymph nodes, and a primary tumor diameter of 20 mm or greater.

During the past several decades, the combination of improved treatment, increased detection of early disease, population growth, and population aging has led to a growing number of long-term breast cancer survivors. Although late recurrence in survivors of nonmetastatic female breast cancer has been documented in some small studies and case series, more current and detailed information on this phenomenon is needed for optimal follow-up care of these women. A new study from Denmark, published in the Journal of the National Cancer Institute (doi:10.1093/jnci/djab202), confirms an increasing body of literature showing BCR occurring more than 10 years after diagnosis. More importantly, the new study is the first to document an elevated risk of BCR persisting more than 25 years after primary surgery, and it also reports on demographic and clinical factors associated with the risk of BCR.

Study Details

The primary goals of the study were to investigate the incidence of late BCR, which the authors defined as breast cancer that recurred 10 or more years or more after the primary diagnosis, and to identify any associations with patient, tumor, and treatment characteristics. “As such, this study is the first to provide evidence that the risk of breast cancer recurrence remains elevated over a prolonged period,” says study senior author and principal investigator Deirdre Cronin Fenton, PhD, BSc, an associate professor in the Department of Clinical Epidemiology at Aarhus University in Aarhus, Denmark.

This nationwide cohort study is set in Denmark, which has a wealth of population-based registries and a tax-supported health care system guaranteeing access to medical care. The study combined data from the Danish Breast Cancer Cooperative Group clinical database and other national information sources, including the Danish National Patient Registry, the Danish Pathology Register, the Danish Cancer Registry, the Danish Register of Causes of Death, and the Danish Civil Registration System, as well as a database on contralateral breast cancer created for an earlier Danish study reported in 2014 (doi:10.1093/ije/dyu202).

Dr. Cronin Fenton says that the registry network can be linked on an individual level with a unique personal identifier number. “These resources facilitate large epidemiological studies with long-term and complete follow-up, minimizing the risk of selection bias. This was particularly valuable for studying long-term recurrence, which would not be feasible in clinical trials.”

From these databases, the researchers identified all women who were diagnosed with an operable, early breast cancer (T1-2, N0-3, M0) between January 1, 1987, and December 31, 2004. They limited this study to patients who survived for 10 years after their diagnosis without a recurrence, an additional primary cancer of the contralateral breast (contralateral breast cancer), or a new nonmammary primary cancer.

The researchers followed study participants from 10 years after the date of their primary cancer diagnosis until recurrence, death, emigration, the diagnosis of a second cancer, or December 31, 2018. They calculated the incidence rates per 1000 person-years and the cumulative incidences for late BCR overall and among subgroups defined by patient, tumor, and treatment characteristics. They used multivariable Cox regression to model adjusted hazard ratios for associations of these characteristics with late BCR.

Study Results

The researchers found that 16.6% (95% CI, 15.8%-17.5%) of 20,315 survivors of early breast cancer who were disease-free during the first 10 years developed BCR between 10 and 32 years after their primary diagnosis. The 10- to 25-year cumulative incidence of BCR ranged from 13.5% to 34.3% and depended on the extent of the disease at the time of the primary diagnosis. Although the risk of recurrence was highest 10 to 12 years after the primary diagnosis, recurrences continued to occur throughout the follow-up period. The incidence of late recurrence was highest among women who had primary tumors that were estrogen receptor–positive, were histological grade 1, were greater than 20 mm in diameter, or involved regional lymph nodes. The researchers concluded that the more involved the lymph nodes were at the primary diagnosis, the greater the risk of late recurrence was.

The researchers note that their results showing a higher incidence of late recurrence among patients with lower grade primary tumors appear to contradict some earlier studies. They believe that this discrepancy may be due to time period differences and associations of tumor grade with treatment decisions; that is, in the past, some low-grade tumors may have been treated less intensively.

The researchers also found that the cumulative incidence of late recurrence was higher in younger patients than in older patients and in those treated with breast-conserving surgery (relative to those who underwent mastectomy). They also found higher adjusted hazards of recurrence for women who were diagnosed before the age of 40 years, underwent breast-conserving surgery, had 4 or more positive lymph nodes, or had primary tumors that were 20 mm in diameter or greater.

Study Interpretation

“Late recurrence after primary breast cancer is not a new finding,” says Laura Makaroff, DO, senior vice president of prevention and early detection at the American Cancer Society in Atlanta, Georgia. “But distant recurrence, up to 32 years in this study, may offer new understanding of the need for ongoing surveillance and attention to new symptoms in patients with any history of breast cancer, no matter how distant.”

Dr. Cronin Fenton says that the findings in this study are important, particularly when one considers the growing population of cancer survivors. “Earlier diagnosis facilitated by population-based mammography screening, advances in breast cancer diagnostics, and increasingly effective breast cancer-directed treatments have contributed to an ever-increasing prevalence of breast cancer survivors,” she says.

Dr. Cronin Fenton notes that in Denmark, approximately 75% of women diagnosed with breast cancer today will survive the first 10 years after their diagnosis, with their survival depending on the severity and extent of their disease at the primary diagnosis. Furthermore, women with estrogen receptor–positive breast tumors are candidates for up to 10 years of endocrine therapy. “Endocrine therapy has associated side effects, so determining which women stand to benefit from these treatments is important,” she says. “Despite this, in most countries, there is a lack of infrastructure to monitor the long-term prognosis and risk of late recurrence in these women.”

Dr. Cronin Fenton adds that because there is limited evidence on the long-term health care needs of breast cancer survivors, addressing this knowledge gap could help direct strategies for the prevention and treatment of late recurrence and elucidate effective surveillance programs for women who are at risk of late recurrence. “Critically, research is needed on the biology underlying late recurrences—for example, what biological mechanisms prompt a tumor to emerge after such a long dormancy period?”

In an accompanying editorial to the study, Serban Negoita, MD, DrPH, chief of the Data Quality, Analysis, and Interpretation Branch at the National Institutes of Health in Bethesda, Maryland, and Esmeralda Ramirez-Peña, PhD, MPH, a fellow in the Breast and Gynecologic Cancer Research Group at the National Cancer Institute in Rockville, Maryland, wrote that this study is important because the Danish researchers were able to take advantage of their nation's coordinated system of universal health care to overcome “the logistical difficulties of studying recurrence.” They also wrote that better understanding of late BCR will require better data that support recurrence research. “This includes clinical data to elucidate the biology and tumor microenvironment conditions that influence dormancy, antitumor immune surveillance, which could prompt the development of treatments that maintain longer disease-free time.”

Dr. Makaroff says that she believes what cancer researchers and clinicians should take away from the study is a greater awareness of the risk of late and distant BCR. “This issue is important so that effective long-term follow-up strategies can help detect recurrence as early as possible for optimal treatment outcomes.” She also notes that many long-term breast cancer survivors are no longer followed by their oncology specialists, and clear communication among oncologists, primary care clinicians, and patients regarding follow-up is essential.

For further guidance on this topic, Dr. Makaroff suggests the American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline, which includes recommendations for surveillance for recurrence (https://www.cancer.org/health-care-professionals/american-cancer-society-survivorship-guidelines/breast-cancer-survivorship-care-guidelines.html).

Photo credit: Shutterstock/Peakstock

中文翻译：

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乳腺癌复发风险可维持 10 至 32 年

关键点

• 在诊断为非转移性女性乳腺癌几十年后，乳腺癌复发 (BCR) 的累积发病率继续增加。
• 与晚期复发风险增加独立相关的因素包括 40 岁之前的诊断、雌激素受体阳性肿瘤、保乳手术治疗、4 个或更多阳性淋巴结和原发肿瘤直径 20 mm或更大。

在过去的几十年里，改善治疗、增加早期疾病检测、人口增长和人口老龄化导致了越来越多的长期乳腺癌幸存者。尽管在一些小型研究和病例系列中记录了非转移性女性乳腺癌幸存者的晚期复发，但需要更多关于这一现象的最新和详细信息，以便对这些女性进行最佳后续护理。丹麦的一项新研究发表在《国家癌症研究所杂志》上(doi:10.1093/jnci/djab202)，证实越来越多的文献显示 BCR 在诊断后 10 年以上发生。更重要的是，这项新研究首次记录了初次手术后 BCR 风险升高持续超过 25 年，并且还报告了与 BCR 风险相关的人口统计学和临床​​因素。

学习详情

该研究的主要目标是调查晚期 BCR 的发生率，作者将其定义为在初次诊断后 10 年或更长时间复发的乳腺癌，并确定与患者、肿瘤和治疗特征的任何关联。“因此，这项研究首次提供证据表明乳腺癌复发的风险在很长一段时间内仍然升高，”该研究的资深作者和首席研究员 Deirdre Cronin Fenton 博士说，他是临床系副教授，理学士丹麦奥胡斯大学的流行病学。

这项全国性的队列研究设在丹麦，该国拥有大量基于人口的登记处和税收支持的医疗保健系统，可保证获得医疗服务。该研究结合了丹麦乳腺癌合作组临床数据库和其他国家信息来源的数据，包括丹麦国家患者登记处、丹麦病理学登记处、丹麦癌症登记处、丹麦死因登记处和丹麦民事登记系统，以及为 2014 年报告的丹麦早期研究创建的对侧乳腺癌数据库 (doi:10.1093/ije/dyu202)。

Cronin Fenton 博士说，注册网络可以在个人层面上与一个唯一的个人识别号联系起来。“这些资源促进了大型流行病学研究，并进行了长期和完整的随访，从而最大限度地降低了选择偏倚的风险。这对于研究长期复发特别有价值，这在临床试验中是不可行的。”

从这些数据库中，研究人员确定了在 1987 年 1 月 1 日至 2004 年 12 月 31 日期间被诊断出患有可手术的早期乳腺癌（T1-2、N0-3、M0）的所有女性。他们将这项研究限制在幸存的患者身上诊断后 10 年内未复发，对侧乳腺癌有额外的原发性癌症（对侧乳腺癌），或新的非乳腺原发性癌症。

研究人员从原发癌症诊断之日起 10 年跟踪研究参与者，直至复发、死亡、移民、诊断出第二种癌症或 2018 年 12 月 31 日。他们计算了每 1000 人年的发病率和累积发病率对于晚期 BCR 整体和在由患者、肿瘤和治疗特征定义的亚组中。他们使用多变量 Cox 回归来模拟这些特征与晚期 BCR 关联的调整后风险比。

研究结果

研究人员发现，在最初 10 年无病的 20,315 名早期乳腺癌幸存者中，有 16.6%（95% CI，15.8%-17.5%）在初次诊断后 10 至 32 年发生 BCR。BCR 的 10 至 25 年累积发病率范围为 13.5% 至 34.3%，取决于初次诊断时的疾病程度。尽管在初次诊断后 10 至 12 年复发风险最高，但在整个随访期间复发继续发生。原发肿瘤为雌激素受体阳性、组织学分级为 1 级、直径大于 20 mm 或累及区域淋巴结的女性，晚期复发的发生率最高。研究人员得出的结论是，淋巴结受累越多，在初步诊断时，

研究人员指出，他们的结果显示低级别原发性肿瘤患者的晚期复发率较高，这似乎与一些早期研究相矛盾。他们认为，这种差异可能是由于时间段差异以及肿瘤分级与治疗决策的关联。也就是说，在过去，一些低级别肿瘤的治疗强度可能较低。

研究人员还发现，年轻患者的晚期复发累积发生率高于老年患者和接受保乳手术的患者（相对于接受乳房切除术的患者）。他们还发现，对于在 40 岁之前被诊断出、接受过保乳手术、有 4 个或更多淋巴结阳性或原发肿瘤直径为 20 毫米或更大的女性，其复发风险更高。

学习解释

“原发性乳腺癌后的晚期复发并不是一个新发现，”佐治亚州亚特兰大的美国癌症协会预防和早期检测高级副总裁 Laura Makaroff 说。“但在这项研究中长达 32 年的远处复发可能会提供对持续监测和关注任何乳腺癌病史患者新症状的必要性的新认识，无论多远。”

Cronin Fenton 博士说，这项研究的结果很重要，尤其是考虑到癌症幸存者人数不断增长的情况。“基于人群的乳房 X 线摄影筛查促进了早期诊断、乳腺癌诊断的进步以及越来越有效的乳腺癌导向治疗，这些都导致乳腺癌幸存者的患病率不断增加，”她说。

Cronin Fenton 博士指出，在丹麦，今天大约 75% 的被诊断患有乳腺癌的女性在诊断后的头 10 年内都能存活下来，她们的存活率取决于初次诊断时疾病的严重程度和程度。此外，患有雌激素受体阳性乳腺肿瘤的女性可以接受长达 10 年的内分泌治疗。“内分泌治疗具有相关的副作用，因此确定哪些女性将从这些治疗中受益很重要，”她说。“尽管如此，在大多数国家，缺乏监测这些女性长期预后和晚期复发风险的基础设施。”

Cronin Fenton 博士补充说，由于关于乳腺癌幸存者长期医疗保健需求的证据有限，解决这一知识差距可能有助于指导预防和治疗晚期复发的策略，并为处于晚期复发的风险。“至关重要的是，需要对晚期复发背后的生物学进行研究——例如，什么生物学机制促使肿瘤在如此长的休眠期后出现？”

在该研究的随附社论中，马里兰州贝塞斯达国立卫生研究院数据质量、分析和解释部门负责人 Serban Negoita 医学博士和公共卫生硕士 Esmeralda Ramirez-Peña 博士、公共卫生硕士马里兰州罗克维尔国家癌症研究所的乳腺癌和妇科癌症研究小组写道，这项研究很重要，因为丹麦研究人员能够利用他们国家的全民医疗保健协调系统来克服“研究复发的后勤困难。” 他们还写道，更好地理解晚期 BCR 需要更好的数据来支持复发研究。“这包括阐明影响休眠、抗肿瘤免疫监视、

Makaroff 博士说，她认为癌症研究人员和临床医生应该从这项研究中获得的是对晚期和远期 BCR 风险的更高认识。“这个问题很重要，因此有效的长期随访策略可以帮助尽早发现复发以获得最佳治疗结果。” 她还指出，许多长期乳腺癌幸存者不再由他们的肿瘤学专家跟踪，肿瘤学家、初级保健临床医生和患者之间关于随访的明确沟通至关重要。

有关该主题的进一步指导，Makaroff 博士建议使用美国癌症协会/美国临床肿瘤学会乳腺癌幸存者护理指南，其中包括监测复发的建议 (https://www.cancer.org/health-care-professionals /american-cancer-society-survivorship-guidelines/breast-cancer-survivorship-care-guidelines.html）。

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