早期乳腺小叶癌患者复发死亡风险预测的临床病理因素和分子因素尚不明确。

　　2020年2月3日，欧洲乳腺癌专科医师学会《乳腺》在线发表意大利罗马圣心天主教大学、维罗纳大学、罗马国家癌症研究所、帕多瓦大学、那不勒斯腓特烈二世大学、威尼托肿瘤研究所的研究报告，建立并验证了乳腺小叶癌的生存结局预测模型，还根据生存结局分析了分子异常（尤其细胞周期蛋白依赖型激酶CDK4/6改变）分布情况。

　　该多中心研究对773例早期乳腺小叶癌患者的临床病理数据进行分析，将其中491例作为模型演算组，其余282例作为模型验算组。根据无病生存结局多因素分析，建立列线图将患者风险分为低、中、高三类，并进行外部验证。对预后不良或良好的患者，通过大规模并行测序，进行突变、拷贝数变异、转录组学分析，并通过定量聚合酶链反应进行验证。

　　结果，该列线图预测风险低、中、高三类患者的10年无病生存率分别为：

• 演算组：76.3%、67.6%、39.8%（P<0.0001）

• 验算组：81.5%、53.4%、44.0%（P<0.0001）

　　对于34例亚组患者的分子分析表明，CDK4增高仅存在于高风险患者（35.0%，P=0.03；比值比：7.98，95%置信区间：1.51～42.1，P=0.014）。

　　此外，CDK4/6过表达患者预后不良比例较高：

• CDK4过表达患者预后不良比例高2.7倍（95%置信区间：0.4～18.1，P=0.3）

• CDK6过表达患者预后不良比例高3.29倍（95%置信区间：0.56～19.25，P=0.18）

　　因此，该研究结果表明，该风险分层列线图能够根据临床病理因素将早期乳腺小叶癌患者的预后准确分为不同风险类别，从而可以通过大规模并行测序对潜在的生物学预后标志进行分析，建议将CDK4增加作为乳腺小叶癌患者的生物学预后标志和潜在治疗指征进行验证。

Breast. 2020 Feb 3;49:56-63. [Epub ahead of print]

Targeted next-generation sequencing identifies genomic abnormalities potentially driving the prognosis of early-stage invasive lobular breast carcinoma patients stratified according to a validated clinico-pathological model.

Luisa Carbognin, Michele Simbolo, Anna Caliò, Caterina Vicentini, Pietro Delfino, Isabella Sperduti, Matteo Fassan, Francesco Schettini, Maria Vittoria Dieci, Gaia Griguolo, Sara Pilotto, Elena Fiorio, Grazia Arpino, Valentina Guarneri, Sabino De Placido, Pierfranco Conte, Erminia Manfrin, Matteo Brunelli, Giovanni Scambia, Aldo Scarpa, Giampaolo Tortora, Emilio Bria.

University of Verona, Verona, Italy; Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy; Azienda Ospedaliera Universitaria Integrata, Verona, Italy; Regina Elena National Cancer Institute, Roma, Italy; University of Padova, Padova, Italy; Federico II University, Napoli, Italy; Istituto Oncologico Veneto, IRCCS, Padova, Italy; Università Cattolica Del Sacro Cuore, Roma, Italy.

HIGHLIGHTS

• The current multicenter analysis developed and validated a prognostic nomogram for early stage ILC.

• A next-generation sequencing analysis was performed in prognostic 'outlier' patients.

• CDK4 gain emerges as a potential negative prognostic factor in ILC patients.

INTRODUCTION: The clinico-pathological and molecular factors that drive the prognosis of invasive lobular breast carcinoma (ILC) are not entirely explored. In this regard, the development and validation of a prognostic model for ILC and the investigation of the distribution of molecular abnormalities (focusing on CDK4/6 alterations) according to prognosis were the aims of this study.

PATIENTS AND METHODS: Two clinico-pathological multi-center data-sets of early-stage ILC patients (Training/Validation Set, TS/VS) were gathered. A 3-class model was developed according to the multivariate analysis for disease-free-survival (DFS) and externally validated. Mutational, copy number variation and transcriptomic analyses by targeted next generation sequencing (NGS) were performed (and validated with quantitative PCR) in an explorative cohort of patients with poor and good prognosis.

RESULTS: Data from overall 773 patients (TS/VS: 491/282) were gathered. The developed model significantly discriminated low/intermediate/high risk in the TS (10-years DFS: 76.3%/67.6%/39.8%, respectively, p<0.0001) and in the VS (p<0.0001). In the explorative cohort for molecular analysis (34 patients), CDK4 gain was present exclusively in the poor prognosis group (35.0%, p = 0.03; OR 7.98, 95%CI 1.51-42.1, p = 0.014). Moreover, CDK4 and 6 overexpression showed a trend toward an association with poor prognosis (OR 2.7, 95%CI 0.4-18.1, p = 0.3; OR 3.29, 95%CI 0.56-19.25, p = 0.18).

CONCLUSIONS: A risk stratification model, able to accurately separate early-stage ILC patients' prognosis into different risk classes according to clinico-pathological variables, allowed to investigate potential biomarkers of prognosis with targeted NGS. CDK4 gain is suggested for future validation as a prognostic biomarker and a potential therapeutic opportunity in ILC patients.

KEYWORDS: Breast cancer; Lobular; Prognosis; Next-generation sequencing; Transcriptome analysis; CDK4

DOI: 10.1016/j.breast.2020.01.034