Allelic dosage of RB1 drives CDK4/6 inhibitor treatment resistance in metastatic breast cancer.
Allelic dosage of RB1 drives CDK4/6 inhibitor treatment resistance in metastatic breast cancer.
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RB1 的等位基因剂量会导致转移性乳腺癌对 CDK4/6 抑制剂治疗产生耐药性。
DOI：
10.1200/jco.2022.40.16_suppl.1010
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发表时间：
2022
影响因子：
45.3
通讯作者：
P. Razavi
中科院分区：
文献类型：
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作者：
A. Safonov;C. Bandlamudi;P. Selenica;A. Marra;E. Ferraro;D. Mandelker;D. Solit;M. Berger;L. Norton;S. Powell;R. Shen;M. Robson;S. Chandarlapaty;J. Reis;P. Razavi
1010 背景：我们最近报道，在一组雌激素受体 (ER) 阳性乳腺癌中，与种系 BRCA2 (g BRCA2) 相关的 CDK4/6 抑制剂和内分泌治疗 (CDK4/6i-ET) 的结果较差。研究发现，gBRCA2 与邻近 RB1 杂合性缺失 (LOH) 的同时出现预示着特别糟糕的结果。在这里，我们试图通过分析扩大的转移性 ER+ 乳腺癌患者队列来确定治疗前 RB1 等位基因拷贝数状态对 CDK4/6i-ET 结果的影响，以及 CDK4/6i 上发生 RB1 功能丧失 (LOF) 突变的可能性。方法：纳入 2014 年 4 月至 2021 年 5 月在 MSK-IMPACT 上接受测序的患者。对于 CDK4/6i-ET 之前的每个样本，我们执行 FACETS 来推断 RB1 等位基因特定拷贝数、倍性、肿瘤纯度和基因组改变分数 (FGA)。根据 RB1 等位基因状态对患者进行分类：HetLoss（总共一个等位基因拷贝）、拷贝中性 LOH (CNLOH)、其他等位基因失衡（包括所有其他非整倍性状态）和二倍体。使用针对 ET 伴侣和 FGA 进行调整的单变量和多变量 Cox 比例风险模型评估无进展生存期 (PFS)。 Firth 惩罚逻辑回归用于研究配对 CDK4/6i 后样本中治疗前 RB1 状态与获得性 RB1 LOF 变异的关联。结果：在 2,630 名潜在合格患者中，279 名患者在一线 CDK4/6i-ET 之前进行了基因组测序。其中，75 例（26.8%）表现出 RB1 HetLoss，39 例（14.0%）表现出 RB1 的 CNLOH，111 例（39.7%）表现出二倍体 RB1 状态，而 54 例（19.4%）表现出 RB1 等位基因不平衡的其他模式。相对于二倍体，所有非二倍体 RB1 状态均与显着缩短的 PFS 相关（单变量 HetLoss HR：2.05，95% CI：1.42，2.97；CNLOH HR：2.08，95% CI：1.32，3.25；其他不平衡 HR：1.70，95% CI：1.11，2.58）。根据 FGA 调整后，只有 HetLoss 仍然显着（HR 1.61，95% CI：1.09、2.38，p = 0.017）。 RB1 LOF 在 CDK4/6i 之前的肿瘤中很少见 (< 1%)；排除这些情况并没有改变我们的结果。在具有配对的 CDK4/6i 前后样本的 176 名患者中，与二倍体相比（4.2%，OR 4.25，95% CI 1.02、17.7，p = 0.047），只有 CDK4/6i 前样本中的 RB1 HetLoss 与 CDK4/6i 后样本中 RB1 LOF 突变的发生显着相关（18.4%）。这些结果表明，具有一个功能性 RB1 拷贝的肿瘤更有可能在 CDK4/6i 上获得 RB1 LOF，从而实现双等位基因 RB1 丢失，作为 CDK4/6i 耐药的机制。结论：我们证明 LOH 和 RB1 等位基因失衡与 CDK4/6-ET 上较短的 PFS 相关。我们推测这可能部分是由于 CDK4/6i 的选择性压力下更频繁的获得性 RB1 LOF 突变所致。这些数据支持实施更精细的等位基因特异性拷贝数方法，并确定高风险人群以升级监测和治疗方法。
1010 Background: We recently reported inferior outcomes to CDK4/6 inhibitors and endocrine therapy (CDK4/6i-ET) associated with germline BRCA2 (g BRCA2) in a cohort of estrogen receptor (ER) positive breast cancers. Co-occurrence of gBRCA2 with loss of heterozygosity (LOH) of neighboring RB1 was found to portend particularly poor outcomes. Here, we sought to define the effects of pre-treatment RB1 allelic copy number status on outcomes of CDK4/6i-ET and the likelihood of developing RB1 loss-of-function (LOF) mutations on CDK4/6i through the analysis of an expanded cohort of metastatic ER+ breast cancer patients. Methods: Patients who underwent sequencing on MSK-IMPACT from April 2014 to May 2021 were included. For every sample preceding CDK4/6i-ET, we performed FACETS to infer RB1 allele specific copy number, ploidy, tumor purity and fraction genome altered (FGA). Patients were categorized based on RB1 allelic status: HetLoss (total of one allelic copy), copy neutral LOH (CNLOH), other allelic imbalance including all other aneuploidy states, and diploid. Progression free survival (PFS) was assessed using univariate and multivariate Cox proportional hazard models adjusted for ET partner and FGA. Firth penalized logistic regression was used to study association of pre-treatment RB1 status with acquired RB1 LOF variants in paired post-CDK4/6i samples. Results: Of 2,630 potentially eligible patients, 279 patients had genomic sequencing performed prior to 1st line CDK4/6i-ET. Of these, 75 (26.8%) exhibited RB1 HetLoss, 39 (14.0%) had CNLOH of RB1, 111 (39.7%) exhibited diploid RB1 state, while 54 (19.4%) had other patterns of RB1 allelic imbalance. All non-diploid RB1 states were associated with significantly shortened PFS relative to diploid (univariate HetLoss HR: 2.05, 95% CI: 1.42, 2.97; CNLOH HR: 2.08, 95% CI: 1.32, 3.25; other imbalance HR: 1.70, 95% CI: 1.11, 2.58). Only HetLoss remained significant when adjusted for FGA (HR 1.61, 95% CI: 1.09, 2.38, p = 0.017). RB1 LOF was rare in pre-CDK4/6i tumors (< 1%); excluding these cases did not change our results. Of the 176 patients with paired pre- and post-CDK4/6i samples, only RB1 HetLoss in pre-CDK4/6i sample was significantly associated with development of RB1 LOF mutations in post-CDK4/6i sample (18.4%) as compared to diploid (4.2%, OR 4.25, 95% CI 1.02, 17.7, p = 0.047). These results indicate that tumors with one functional copy of RB1 are more likely to acquire RB1 LOF on CDK4/6i to achieve biallelic RB1 loss as a mechanism of CDK4/6i resistance. Conclusions: We demonstrate that LOH and allelic imbalance of RB1 are associated with shorter PFS on CDK4/6-ET. We postulate this may occur partly as a result of more frequent acquired RB1 LOF mutations under selective pressure of CDK4/6i. These data supports the implementation of more refined allele-specific copy number methods and identifies a high-risk population for escalated monitoring and treatment approaches.