雪松西奈述评:乳腺癌分期体系的进化

09-12 05:48 首页 SIBCS


  2017年9月8日,美国乳腺外科医师学会、外科肿瘤学会《外科肿瘤学年鉴》在线发表洛杉矶西达赛奈(雪松西奈)医疗中心肿瘤外科述评:乳腺癌分期体系的进化。


  肿瘤的生物学特性可高度影响乳腺癌的预后和治疗,例如激素受体状态、HER2/Neu受体过表达可指导治疗,并与疾病的复发和生存相关。仅仅根据肿瘤大小、淋巴结状态、转移病变与否(TNM分期)的解剖学分期无法精准获知某些肿瘤的行为、患者预后、肿瘤对靶向疗法的反应。解剖学分期的这些局限已被美国癌症联合委员会(AJCC)专家组分期体系既往版本承认,并且已使雌激素受体(ER)状态、HER2状态、分级、肿瘤分子学特征被纳入2016年11月公布经过修订的第8版,并于2018年实施【1】。不幸的是,由于缺乏强有力数据支持较复杂分期体系的预后价值,编写第8版的专家组对于将生物学因素纳入AJCC分期体系存在广泛争论。


  生物学评分(Bioscore)和新辅助生物学评分(Neo-Bioscore)是将肿瘤生物学因素纳入分期的两个评分体系,可对个体预后进行更细致入微的了解并提出现代化治疗策略。这些体系通过ER状态和HER2过表达以及解剖学因素,更精准地反映了我们如何理解并治疗当前的乳腺癌患者。


  Mittendorf等【2】利用病理学肿瘤大小、淋巴结状态、分级、ER、HER2,将未经治疗的患者分为7个不同亚组,根据2007~2013年在MD安德森癌症中心接受治疗的3327例患者基线组多变量分析,得出疾病相关生存风险比,对各个肿瘤特征进行数值评分,通过对个体预测因素评分相加计算出1~7分的最终“生物学评分”。该体系被确立后,即被用于加利福尼亚癌症登记中心大样本队列(6万7944例患者)并与传统的AJCC分期体系第7版进行比较。虽然AJCC第7版分期组估算5年疾病相关生存范围为79.5~99.1%,但是生物学评分分期体系更好地区分出结局(转归)并且队列跨越范围更大(33.3~100%)。生物学评分模型与单用解剖学分期相比,一致指数较高。对于生物学评分较高的患者,分层改善最为明显,尽管在加利福尼亚癌症登记中心大样本队列中,生物学评分较低队列的分层也很明确。Mittendorf等的生物学评分被AJCC第8版专家组作为体现生物学标志重要性的证据。


  由于AJCC分期手册第8版并不包括新辅助治疗后分期,故Bergquist等【3】将上述原则应用于新辅助化疗后患者,该量表共7分,此前已在单机构2377例新辅助化疗患者数据组中进行验证【4】。作者将该新辅助生物学评分应用于从国家癌症数据库(NCDB)获取的4万3420例患者队列,由于NCDB自2010年才开始收集HER2状态,故其中仅1万2002例(27.7%)有HER2数据可用。结果发现,新辅助生物学评分优于解剖学的AJCC病理学和临床分期体系,可提高分期辨别力和分期质量,尤其当随访时间较短时更为显著。


  无论生物学评分,还是新辅助生物学评分,都符合癌症医疗更个体化的大趋势,同时也对肿瘤生物学复杂性的理解更深入,有助于AJCC第8版从单纯解剖学分期体系转化为包括生物学因素的分期体系。无论患者是否接受新辅助化疗,纳入肿瘤生物学特征均优于单独使用解剖学分期。当考虑肿瘤生物学时,分期可被改进。


  上述两项研究存在某些局限,并且中位随访分别为5年和35.8个月,需要长期随访。由于该肿瘤亚型患者的无病生存较长、复发较晚,故短期随访可能无法获得ER阳性患者的所有死亡事件。对于新辅助HER2靶向治疗患者,由于HER2阳性状态仅记录于2010年之后的NCDB患者,中位随访时间仅为36个月,故也需要长期随访。


  此外,生物学评分分期体系将ER阳性肿瘤患者作为单一人群进行处理,然而,在临床实践中,根据基因组特征,ER阳性患者的预后不同。将基因组风险评估纳入分期体系,可能有助于更好地对生物学评分较低的肿瘤进行分层。上述研究作者无法纳入基因组信息,因为数据无法普遍获得。随着这些信息被常规收集,其将增入现有的认知,可能有助于区分某些ER阳性肿瘤。例如,AJCC分期体系第8版将21基因检测低风险评分纳入了某些分期较低的期ER阳性肿瘤。


  分期体系正在不断适应,以反映对乳腺癌异质性的深入理解,以及个体肿瘤因素对预后和治疗的影响。随着治疗方法改变,分期必须适应反映当前的临床实践。当基因组和分子学检测被更深入地理解时,可被进一步加入分期体系。结果将使临床医师和个体患者对治疗和预后更加深入理解。后果无法预期,分期体系可能更加复杂、也许更难掌握。这些复杂的方法将被如何纳入临床实践以改善医疗仍有待观察,但是显而易见单用解剖学分期不足以完全解释肿瘤行为。


雪松西奈

  • 西达赛奈(雪松西奈)医疗中心最初建于1902年,经过不断发展,1961年由黎巴嫩西达(雪松)医院赛奈(西奈)山医院合并而成,现位于洛杉矶比佛利大道,是美国西海岸最大的非营利医院、洛杉矶加利福尼亚大学(UCLA)和南加利福尼亚大学(USC)的教学医院。在美国国家研究协会(NRC)大洛杉矶地区综合医疗质量排名中连续19年蝉联第一,心脏、神经、肿瘤等优势学科皆处于全美国领导地位。

  • 西达(雪松)又称香柏,原产于喜玛拉雅山和地中海沿岸(黎巴嫩、土耳其、塞浦路斯、阿尔及利亚、摩洛哥)山区,《圣经》把黎巴嫩雪松称颂为植物之王、上帝之树,有75处经文提及黎巴嫩雪松

  • 赛奈(西奈)山即月亮山,根据古代闪米特民族神话的月亮老人(Sin)而命名,位于地中海与红海之间,此山在犹太历史中是上帝发出启示的主要地点,根据《圣经》上帝在此向摩西显灵并赐给他十诫,在基督教和伊斯兰教的传说中也是圣地。


参考文献

  1. Hortobagyi GN, Connolly JL, DOrsi CJ, et al. Breast. In: Amin MB, editor. AJCC cancer staging manual. 8th Ed. New York: Springer; 2017:589-628.

  2. Mittendorf E, Chavez-MacGregor M, Vila J, et al. Bioscore: a staging system for breast cancer patients that reflects the prognostic significance of underlying tumor biology. Ann Surg Oncol. 2017 Jul 19. DOI: 10.1245/s10434-017-6009-x [Epub ahead of print]

  3. Bergquist J, Murphy B, Storlie C, et al. Incorporation of tumor grade and receptor status improves staging quality in breast cancer patients treated with neoadjuvant chemotherapy. Ann Surg Oncol. 2017 Aug 21. DOI: 10.1245/s10434-017-6010-4 [Epub ahead of print]

  4. Mittendorf EA, Vila J, Tucker SL, et al. The neo-bioscore update for staging breast cancer treated with neoadjuvant chemotherapy: incorporation of prognostic biologic factors into staging after treatment. JAMA Oncol. 2016;2(7):929-936.


Ann Surg Oncol. 2017 Sep 8. [Epub ahead of print]


Evolution of the Staging System in Breast Cancer.


Donovan CA, Giuliano AE.


Department of Surgical Oncology, Cedars-Sinai Medical Center, Los Angeles, USA.


Tumor biology strongly influences the prognosis and treatment of breast cancer. Hormone receptor status and HER2/Neu (HER2) receptor overexpression guide treatment and are related to disease recurrence and survival. Anatomic staging based solely on tumor size, nodal status and the presence or absence of metastatic disease (TNM staging) fails to accurately capture the behavior of some tumors, patient prognosis, and tumor response to targeted therapy. This limitation of anatomic staging has been acknowledged by the American Joint Committee on Cancer (AJCC) Expert Panels in past editions of the staging system, and has resulted in the incorporation of estrogen receptor (ER) status, HER2 status, grade, and molecular tumor characteristics into the 8th Edition Revision published in November 2016 and set for adoption in 2018.[1] Unfortunately, since there are no robust data to support the prognostic value of a more complex staging system, the Expert Panel writing the 8th edition extensively debated the incorporation of biologic factors into the AJCC staging system.


The Bioscore and the Neo-Bioscore are two scoring systems that incorporate aspects of tumor biology into staging to produce a more nuanced understanding of individual prognosis and to address modern treatment strategies. By including ER status and overexpression of HER2 alongside anatomic factors, these systems more accurately mirror how we understand and treat contemporary breast cancer patients. Mittendorf et al. used pathologic tumor size, nodal status, grade, ER and HER2 to stratify untreated patients into seven distinct subgroups.[2] Each tumor characteristic was given a numeric score based on the hazard ratio for disease-specific survival derived from multivariable analysis of a baseline group of 3327 patients treated at MD Anderson Cancer Center from 2007 to 2013. A final Bioscore from 1 to 7 is calculated by summing the scores of individual predictors. Once developed, this system was applied to a large cohort (67,944 patients) from the California Cancer Registry and compared favorably with the traditional 7th edition AJCC staging system. While the AJCC 7th edition stage groups estimated 5-year disease-specific survival ranging from 79.5 to 99.1, the Bioscore staging system better separated outcomes and had cohorts spanning a broader range, from 33.3-100%. The Bioscore model had a higher concordance index than anatomical staging alone. The improved stratification was most pronounced in patients with higher Bioscores, although in the larger cohort from the California Cancer Registry there was also clear stratification of the cohorts with lower Bioscores. The Bioscore of Mittendorf and colleagues was considered by the Expert Panel for the 8th edition as evidence of the importance of biomarkers.


Bergquist et al. applied similar principles to patients following treatment with neoadjuvant chemotherapy.[3] Staging after neoadjuvant treatment is not included in the 8th edition of the AJCC staging manual. The Neo-Bioscore allocates numerical points for pretreatment clinical stage and pathologic stage after neoadjuvant chemotherapy, as well as tumor grade, ER status, and HER2 status. This 7-point scale was validated in a single institutional dataset involving 2377 patients treated with neoadjuvant chemotherapy.[4] The authors applied this Neo-Bioscore to a much broader cohort of 43,320 patients obtained through the National Cancer Data Base (NCDB). Of these, only 12,002 (27.7%) had HER2 data available since the NCDB did not begin the collection of HER2 status until 2010. Neo-Bioscore outperformed the anatomic AJCC pathologic and clinical staging systems, providing improved stage discrimination and quality of staging. This was most significant when staging systems were compared at shorter follow-up times.


Both Bioscore and Neo-Bioscore are part of an overall movement towards more individualized cancer care that accompanies an improved understanding of the complexity of tumor biology. They support the transition of the AJCC 8th edition from a purely anatomic staging system to one that incorporates biologic factors. In patients treated with and without neoadjuvant chemotherapy, the inclusion of tumor biologic features is superior to the use of anatomic stage alone. Staging is improved when tumor biology is considered.


There are some limitations to the above two studies and longer-term follow-up is required. In these studies, the median follow-up was 5 years and 35.8 months, respectively. This is likely not sufficient to capture all mortality events in ER+ patients, given the long disease-free survival and late recurrences for patients with this tumor subtype. Longer-term follow-up is also needed for the patients treated with neoadjuvant HER2-targeted therapy as HER2-positive status was only recorded in NCDB patients after 2010, and the resultant median follow-up time was only 36 months.


Additionally, the Bioscore staging system treated patients with ER + tumors as a monolithic group, while, in clinical practice, ER+ patients can have different prognoses based on genomic profiles. Incorporating genomic risk evaluation into a staging system might help to better stratify tumors with lower Bioscores. The authors were unable to include genomic information as the data were not widely available. As this information is routinely collected, it will add to current knowledge and may help distinguish among some ER+ tumors. The 8th edition of the AJCC staging system incorporates Oncotype DX low-risk score to lower stage for some ER+ tumors.


The staging system is adapting to reflect a better understanding of the heterogeneity of breast cancers and the implications of individual tumor factors on prognosis and treatment. As treatment approaches change, staging must adapt to reflect current clinical practice. As genomic and molecular assays are better understood, they may become further incorporated into the staging system. The result will be a richer understanding of treatment and prognosis for the individual patient and the clinician. The unintended consequence may be an increasingly complex and perhaps more difficult-to-manage staging system. It remains to be seen how these complex algorithms will be incorporated into clinical practice to improve care, but it is clear that anatomic staging alone is inadequate to fully explain tumor behavior.


References

  1. Hortobagyi GN, Connolly JL, DOrsi CJ, et al. Breast. In: Amin MB, editor. AJCC cancer staging manual. 8th Ed. New York: Springer; 2017:589-628.

  2. Mittendorf E, Chavez-MacGregor M, Vila J, et al. Bioscore: a staging system for breast cancer patients that reflects the prognostic significance of underlying tumor biology. Ann Surg Oncol. 2017 Jul 19. DOI: 10.1245/s10434-017-6009-x [Epub ahead of print]

  3. Bergquist J, Murphy B, Storlie C, et al. Incorporation of tumor grade and receptor status improves staging quality in breast cancer patients treated with neoadjuvant chemotherapy. Ann Surg Oncol. 2017 Aug 21. DOI: 10.1245/s10434-017-6010-4 [Epub ahead of print]

  4. Mittendorf EA, Vila J, Tucker SL, et al. The neo-bioscore update for staging breast cancer treated with neoadjuvant chemotherapy: incorporation of prognostic biologic factors into staging after treatment. JAMA Oncol. 2016;2(7):929-936.


PMID: 28887762


DOI: 10.1245/s10434-017-6035-8





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