Inova Schar Cancer Institute.
Foundation Medicine.
Cancer Treat Res Commun. 2022;32:100569. doi: 10.1016/j.ctarc.2022.100569. Epub 2022 Apr 30.
BRAF V600E+ microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients comprise up to 10% of advanced CRC. They have a poor prognosis with a median survival typically <1 year. Despite use of multi-agent 1 line chemotherapy regimens and combination targeted therapies, outcomes are still poor. In our Institutional Molecular Tumor Board (MTB) database, we identified 3 mCRC patients with MSS/BRAF V600E who also had a BRCA1 or BRCA2 co-mutation and had relatively long overall survivals. Prior studies suggested that BRCA mutations are uncommon in CRC and we queried the Foundation Medicine (FM) genomic database to evaluate the prevalence of these cases as well as those with co-mutations in other homologous recombination genes.
36,966 CRC pts were sequenced by FMI using hybrid capture comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA) for pathogenic BRAF mutations and/or a mutation in BRCA1/2 or a co-mutation in other homologous recombination (HR) genes (BARD1, CDK12, FANCL, PALB2, ATM, RAD54L, CHEK2, BRAF, BRIP1, RAD51D, RAD51C, RAD51B, CHEK1). Selected cohort analysis of BRAF V600E co-mutated with BRCA1 and BRCA2 were separated into MSI-H and MSS cohorts. The clinicopathological features and genomic loss of heterozygosity (gLOH) of those with a BRAF V600E and a BRCA1/BRCA2 mutation were collected and analyzed. We also describe 3 consecutive cases of mCRC patients, identified through the Inova Schar Cancer Institute (ISCI) MTB registry, whom had prolonged OS.
Of 36,966 colorectal cancer pts, 6.6% were BRAF V600E+ and 1.5% had any co-occurring HR gene mutation(s) with 0.6% of the total mCRC population having co-ocurring BRAF V600E and BRCA1/2 alterations. BRCA co-mutations were higher in MSI-High BRAF V600E, however 24.1% of co-occurrences were observed in MSS samples. BRCA1 co-mutation was more commonly associated with MSS BRAF V600E and was associated with a higher gLOH than MSI-H BRAF V600E (18.7% vs 2.8%; p <0.001). In our institutional MTB database, (3/241;1.2%) CRC patients were MSS, BRAF V600E+ with BRCA1 or BRCA2 co-mutations, all somatic in origin, with an average gLOH of 21.4% and overall survivals of 72+(alive), 17+(alive), and 30 months, respectively.
Co-existence of BRAF V600E/BRCA1/2 may represent a unique subset of advanced MSS CRC that may have a better prognosis and represent an opportunity to test novel targeted therapies. The elevated gLOH in these cases may also be a valuable biomarker for these pts. Larger prospective clinical validation trials in this subset is warranted.
BRAF V600E+微卫星稳定（MSS）转移性结直肠癌（mCRC）患者占晚期 CRC 的 10%。他们的预后较差，中位生存期通常<1 年。尽管使用了多药一线化疗方案和联合靶向治疗，但结果仍然不佳。在我们的机构分子肿瘤委员会（MTB）数据库中，我们鉴定了 3 名 MSS/BRAF V600E 且具有 BRCA1 或 BRCA2 共突变的 mCRC 患者，且他们的总生存期相对较长。先前的研究表明，BRCA 突变在 CRC 中并不常见，我们查询了 Foundation Medicine（FM）基因组数据库，以评估这些病例以及其他同源重组基因共突变的发生率。
使用杂交捕获综合基因组分析（CGP），通过 FMI 对 36966 例 CRC 患者进行测序，以评估致病性 BRAF 突变和/或 BRCA1/2 突变或其他同源重组（HR）基因（BARD1、CDK12、FANCL、PALB2、ATM、RAD54L、CHEK2、BRAF、BRIP1、RAD51D、RAD51C、RAD51B、CHEK1）的所有基因突变。对 BRAF V600E 与 BRCA1 和 BRCA2 共突变的选定队列进行分析，分为 MSI-H 和 MSS 队列。收集并分析了那些具有 BRAF V600E 和 BRCA1/BRCA2 突变的患者的临床病理特征和基因组杂合性缺失（gLOH）。我们还描述了 3 例连续的 mCRC 患者，这些患者通过 Inova Schar 癌症研究所（ISCI）MTB 登记处被鉴定出来，他们的总生存期延长。
在 36966 例结直肠癌患者中，6.6%为 BRAF V600E+，1.5%存在任何同时发生的 HR 基因突变，总 mCRC 人群中有 0.6%存在同时发生的 BRAF V600E 和 BRCA1/2 改变。MSI-High BRAF V600E 中 BRCA 共突变发生率较高，但在 MSS 样本中也观察到 24.1%的共发生。BRCA1 共突变与 MSS BRAF V600E 更常见相关，与 MSI-H BRAF V600E 相比，其 gLOH 更高（18.7% vs 2.8%；p<0.001）。在我们的机构 MTB 数据库中，（3/241；1.2%）CRC 患者为 MSS、BRAF V600E+且具有 BRCA1 或 BRCA2 共突变，均为体细胞起源，平均 gLOH 为 21.4%，总生存期分别为 72+（存活）、17+（存活）和 30 个月。
BRAF V600E/BRCA1/2 的共存可能代表了一种独特的 MSS CRC 晚期亚群，可能具有更好的预后，并为测试新的靶向治疗提供了机会。这些病例中升高的 gLOH 也可能是这些患者的一个有价值的生物标志物。在这个亚群中需要进行更大规模的前瞻性临床验证试验。
