夜读札记（五）

一、EGFR和P53突变，不能只针对EGFR治疗

《Meta-analysis of the prognostic impact of TP53 co-mutations in EGFR-mutant advanced non-small-cell lung cancer treated with tyrosine kinase inhibitors》

“Methods: Studies exploring the clinical outcomes of EGFR mutant/TP53 wild-type versus EGFR/TP53 co-mutant patients treated with TKIs were selected. Data were cumulated by adopting a fixed and random-effect model.
Results: Overall, 29 trials were eligible. The PFS analysis showed that TP53 co-mutant group has shorter PFS versus EGFR mutant/TP53 wild-type group (HR = 1.67, 95% CI 1.51-1.83, heterogeneity I2 =20%, p = 0.18). Patients affected by EGFR/TP53 co-mutant NSCLC have a higher chance of shorter OS versus EGFR mutant/TP53 wild type (HR= 1.89, 95% CI 1.67-2.14, heterogeneity I2 = 21%; p = 0.19). The subgroup analysis showed no significant difference between first-second versus third-generation TKIs in both PFS and OS (p = 0.31, p = 0.08).
Conclusions: TP53 mutations represent a clinically relevant mechanism of resistance to EGFR-TKIs, regardless of their generation.”


二、病例报告：EGFR L858R、p53、ERBB2共突变的非小细胞肺癌脑膜转移患者，用奥拉帕尼+达克替尼有效

《Successful treatment of a patient with Li-Fraumeni syndrome and metastatic lung adenocarcinoma harboring synchronous EGFR L858R and ERBB2 extracellular domain S310F mutations with the pan-HER inhibitor afatinib》

“We report the case of a young, never-smoker woman with Li-Fraumeni syndrome and advanced lung adenocarcinoma refractory to multiple lines of conventional chemotherapy and negative for actionable alterations by routine testing. Comprehensive genomic profiling by clinical-grade next generation sequencing was performed on 3320 exons of 184 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer. The tumor was found to harbor both EGFR L858R and ERBB2 S310F alterations and also tested positive for a known TP53 germline mutation. The presence of the EGFR mutation was further validated by direct sequencing. Based on these results, a dual EGFR/ERBB2 inhibitor, afatinib, was chosen for treatment. The patient achieved a rapid, complete, and durable response to afatinib monotherapy, both clinically and radiographically. The treatment was very well tolerated. This unique case raises practical questions as to the challenges of molecular testing and highlights the potential association of p53 mutations with concurrent EGFR and ERBB2 aberrations. As this case powerfully illustrates, the combination of broad genomic profiling and targeted therapy guided by mutational analysis offers the possibility of precision management of refractory advanced adenocarcinoma in the background of neoplastic syndromes.”

三、高压氧对脑瘤脑转移瘤的辅助治疗作用

1、《高压氧联合放疗和单纯放疗对脑瘤术后治疗的临床效果比较》

“方法选取中国医科大学附属第一医院鞍山医院神经外科2014-07—2015-07收治的108例脑瘤术后患者,将其按照随机数字法随机分为联合治疗组和单纯放疗组,每组54例,联合治疗组患者给予高压氧联合放疗治疗,单纯放疗组仅给予放疗,所有患者均在术后24周开始常规放疗,联合治疗组患者在每次高压氧治疗后1530 min内给予放疗。结果经过治疗后联合治疗组的完全缓解率、部分缓解率及总有效率均显著性高于单纯放疗组(均P<0.05)。治疗2年、3年后,联合治疗组的生存率分别为83.3%、79.6%均显著性高于单纯放疗组的66.7%和61.1%(均P<0.05)。结论高压氧联合放疗治疗脑瘤术后患者疗效显著。”

2、《手术后高压氧加放疗治疗脑瘤的疗效》

“方法选取2009年12月至2013年12月间收治的126例术后脑瘤患者,采用抽签法分为对照组和治疗组,每组63例,对照组患者予以单纯放射疗法治疗,治疗组患者予以高压氧加放疗治疗,比较两组患者的治疗效果和临床症状改善情况。结果治疗组患者疾病控制率为96.8%,对照组患者疾病控制率为85.7%,组间差异有统计学意义(P<0.05)。治疗组患者的临床改善情况显著优于对照组,差异有统计学意义(P<0.05)。治疗组3年生存率为54.0%,明显高于对照组的33.3%,差异有统计学意义(P<0.05)。结论术后高压氧加放疗治疗脑瘤疗效显著,可降低治疗后期并发症发生率,改善患者生存质量,具有临床使用和推广价值。”

3、《脑瘤术后高压氧加放疗治疗的临床观察》

“方法在我院接受手术治疗的脑瘤患者中抽取72例,将其分为2组,参考组(n=34)患者术后2周左右应用放射疗法,观察组(n=38)患者同时应用高压氧联合放疗治疗。结果观察组患者疾病控制率为97.37%,参考组组患者疾病控制率为82.35%,2组疾病控制率差异有统计学意义(χ2=3.0575,P=0.0363),观察组37例患者病情得到控制,1例患者病情进展,参考组28例患者病情得到控制,6例患者病情进展。结论脑瘤患者术后应用高压氧联合放疗能够使临床疗效得到提高。”


四、KRAS G12C 抑制剂耐药的机制

《Acquired Resistance to KRAS G12C Inhibition in Cance》

“A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRASG12C allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRASG12C inhibitors.”


五、braf突变分成三类，braf抑制剂和mek抑制剂对这三类突变体有不同的药效

《BRAF Mutation Class and Clinical Outcomes—Response》

“We appreciate the interest generated by our study on the impact of BRAF functional class on clinical outcomes in patients with NSCLC. In our analysis, responses to standard first-line chemotherapy were not durable for patients with class II and III BRAF mutations. We therefore agree that it is essential to develop alternative therapeutic strategies for this molecular subgroup. Inhibition of BRAF and coinhibition of BRAF/MEK have proven effective for lung cancers harboring class I mutations. Given the shared dependence on activation of the MAPK pathway, it is important to determine whether patients with class II and III tumors derive similar benefit from targeting MAPK signaling. Data demonstrating clinical activity of MAPK-directed therapies in class II and III BRAF-mutant lung cancers are lacking. In a small retrospective series that included 5 patients with class II or III BRAF-mutant (G466V, G469A, G469L, G596V, or K601E) NSCLC, only one patient responded to monotherapy with a BRAF inhibitor (1). These findings are consistent with preclinical studies suggesting limited efficacy of BRAF monomer inhibitors (e.g., vemurafenib and dabrafenib) against dimer-promoting BRAF variants (2, 3). These preclinical observations are supported by multiple clinical reports in melanoma demonstrating that resistance to BRAF inhibitors can result from acquired genetic alterations that facilitate RAF dimerization (4, 5). In our study, one patient with a class II K601E BRAF mutation received vemurafenib. The patient succumbed to his cancer within one week of initiating treatment.

In contrast to the limited activity of BRAF inhibitors, MEK inhibitors may be effective against class II and III BRAF mutants, at least based on preclinical studies (3, 6). Three patients in our study cohort—all with class III BRAF G466 mutations—received a MEK inhibitor (n = 1 trametinib and n = 2 selumetinib). Two patients achieved a best response of progressive disease and were taken off therapy within 1 month, one of which had cooccurring BRAF G466V and KRAS G12C mutations. The remaining patient achieved disease stabilization lasting 4 months. This suggests that while this strategy may not be broadly effective for lung cancers with class III BRAF mutations, it may provide short-term benefit for a subset of patients. Recently, efforts have turned away from repurposing existing drugs toward exploring the activity of novel RAF dimer inhibitors (7), pan-RAF inhibitors, or ERK inhibitors in a variety of MAPK-activated tumors (8), including those driven by non-V600E BRAF mutations. Two patients with class II BRAF mutations (K601E and L597Q) in our study cohort were enrolled in a phase I study of ulixertinib, an investigational ERK inhibitor (8). Both patients discontinued therapy due to early toxicity and were not evaluable for response.”