【原】乳腺肿瘤高突变发生率与突变决定因素

　　肿瘤突变负荷（肿瘤基因突变数量）越多，越有利于肿瘤的免疫治疗。不过，乳腺癌的肿瘤高突变发生率与突变决定因素尚不明确。

　　2020年1月13日，欧洲肿瘤内科学会《肿瘤学报》在线发表美国达纳法伯癌症研究所、麻省理工学院、哈佛大学医学院、布罗德研究所、布莱根医院和波士顿妇女医院的研究报告，探讨了高突变乳腺癌的发生率、突变形式和基因特征。

　　该研究利用6项基因组研究可公开获得的原发性或转移性乳腺癌患者去身份数据，对其中3969例进行过全外显子组测序或基因组测序的患者标本进行分析，以确定高突变乳腺癌的发生率。如果标本每百万碱基的突变≥10个，那么将其归类为高突变。此外，另外8例来自达纳法伯癌症研究的雌激素受体阳性转移性乳腺癌患者被归入高突变。对高突变患者，确定突变形式和基因组特征。对免疫检查点PD-1抑制剂帕博利珠单抗治疗的患者进行亚组分析。

　　结果，全部乳腺癌的肿瘤基因突变数量为每百万碱基0.2～290.8个突变（中位2.63个突变）

• 三阴性乳腺癌：每百万碱基中位1.8个突变

• HER2阳性乳腺癌：每百万碱基中位1.3个突变（P=0.003）

• 激素受体阳性乳腺癌：每百万碱基中位1.1个突变（P=2.8×10-8）

• 转移性乳腺癌：每百万碱基中位3.8个突变

• 原发性乳腺癌：每百万碱基中位2.0个突变（P=2.2×10-16）

　　高突变乳腺癌患者198例（5%），其中：

• 转移性乳腺癌：8.4%

• 原发性乳腺癌：2.9%（P=6.5×10-14）

　　高突变乳腺癌发生率最高的突变为APOBEC活性突变（59.2%），其次为DNA碱基错配修复缺陷（36.4%）。

　　对于帕博利珠单抗治疗的3例高突变乳腺癌患者，包括2例APOBEC活性突变、1例DNA碱基错配修复缺陷，帕博利珠单抗治疗带来了客观而持久的缓解。

　　因此，该研究结果表明，乳腺癌的肿瘤基因高突变发生率大约为5%，并且较多发生于转移性乳腺癌，该人群存在不同的突变特征，其中APOBEC活性是发生率最高的突变表现形式。亚组分析初步数据表明，PD-1抑制剂治疗高突变乳腺癌的获益可能较大，并且与突变表现形式无关。

Ann Oncol. 2020 Jan 13. [Epub ahead of print]

Prevalence and mutational determinants of high tumor mutation burden in breast cancer.

R. Barroso-Sousa, E. Jain, O. Cohen, D. Kim, J. Buendia-Buendia, E. Winer, N. Lin, S.M. Tolaney, N. Wagle.

Dana-Farber Cancer Institute, Boston, USA; Broad Institute of MIT and Harvard, Cambridge, USA; Harvard Medical School, Boston, USA; Brigham and Women's Hospital, Boston, USA.

HIGHLIGHTS

• High tumor mutation burden is found in 5% of all breast cancers and is more common in metastatic tumors.

• While different mutational signatures are present in hypermutated tumors, APOBEC activity is the most common process.

• Patients with hypermutated breast cancers may represent a subgroup more likely to benefit from PD-1 inhibitors.

• The response to PD-1 inhibitors in hypermutated breast cancer may be independent of underlying mutational process.

BACKGROUND: High tumor mutation burden (TMB) can benefit immunotherapy for multiple tumor types, but the prevalence of hypermutated breast cancer is not well described. The aim of this study was to evaluate the frequency, mutational patterns, and genomic profile of hypermutated breast cancer.

PATIENTS AND METHODS: We used de-identified data from individuals with primary or metastatic breast cancer from six different publicly available genomic studies. The prevalence of hypermutated breast cancer was determined among 3969 patients' samples that underwent whole exome sequencing or gene panel sequencing. The samples were classified as having high TMB if they had ≥10 mutations per megabase (mut/Mb). An additional eight patients were identified from a Dana-Farber Cancer Institute cohort for inclusion in the hypermutated cohort. Among the patients with high TMB, the mutational patterns and genomic profiles were determined. A subset of patients was treated with regimens containing PD-1 inhibitors.

RESULTS: The median TMB was 2.63 mut/Mb. The median TMB significantly varied according to the tumor subtype (HR-/HER2- >HER2+ >HR+/HER2-, P < 0.05) and sample type (metastatic > primary, P = 2.2 × 10-16). Hypermutated tumors were found in 198 patients (5%), with enrichment in metastatic versus primary tumors (8.4% versus 2.9%, P = 6.5 × 10-14). APOBEC activity (59.2%), followed by mismatch repair deficiency (MMRd; 36.4%), were the most common mutational processes among hypermutated tumors. Three patients with hypermutated breast cancer—including two with a dominant APOBEC activity signature and one with a dominant MMRd signature—treated with pembrolizumab-based therapies derived an objective and durable response to therapy.

CONCLUSION: Hypermutation occurs in 5% of all breast cancers with enrichment in metastatic tumors. Different mutational signatures are present in this population with APOBEC activity being the most common dominant process. Preliminary data suggest that hypermutated breast cancers are more likely to benefit from PD-1 inhibitors.

KEYWORDS: breast cancer, tumor mutational burden, APOBEC, mutational signatures, immunotherapy, mismatch repair deficiency

DOI: 10.1016/j.annonc.2019.11.010