Association of serine/threonine kinase 11 mutations and response to programmed cell death 1 inhibitors in metastatic gastric cancer

Programmed cell death 1 (PD-1) inhibitors have shown therapeutic efficacy in metastatic gastric cancer (mGC). However, no predictive biomarkers have been established in mGC. Inactivating mutations in serine/threonine kinase 11 (STK11) are associated with poor response to PD-1 inhibitors in KRAS-mutant lung adenocarcinoma. Therefore, we hypothesized that STK11 inactivating mutations would be associated with inferior clinical response to PD-1 inhibitors in mGC. We analyzed 59 mGC patients who had been treated with PD-1 inhibitors and whose tumors had been analyzed by targeted high-throughput sequencing. STK11 mutations were identified in 30 (50.8%) patients, and were all missense mutations. Three patients (5.1%) had STK11 gene amplification and mutation, simultaneously. Patients with STK11 mutations had prolonged overall survival (median: 19.0 vs 11.6 months, p = 0.15), and progression-free survival (4.2 vs 1.9 months, p = 0.06) when treated with PD-1 inhibitors, but these differences were not statistically significant. Patients with STK11 inactivating mutations without STK11 gene amplification had significantly prolonged progression-free survival compared to patients with wild type STK11 or STK11 gene amplification (4.8 vs 1.0 months, p = 0.04). However, in multivariate Cox regression analysis with high microsatellite instability (MSI-H), the number of tumor mutations, PD Ligand-1 (PD-L1)+, Epstein-Barr virus positivity (EBV)+, and type of PD-1 inhibitor used (pembrolizumab vs nivolumab), only MSI-H and PD-L1+ were significantly associated with longer progression-free survival. In mGC, the presence of STK11 mutation was not predictive of the response to PD-1 inhibitors. Instead, patients with MSI-H or PD-L1+ tumors displayed superior clinical responses to PD-1 inhibitors.     

急性心肌梗死患者血清sLOX-1、CK-MB水平及意义

目的探讨急性心肌梗死(AMI)患者血清可溶性凝集素样氧化型低密度脂蛋白受体-1(sLOX-1)和心肌型肌酸激酶同工酶(CK-MB)水平及意义。方法选取AMI患者120例(AMI组),同时选取健康体检者120例作为对照组,检测血清sLOX-1、CK-MB水平。结果AMI组患者血清sLOX-1、CK-MB水平明显高于对照组(P<0.05);AMI组左室舒张末期容积指数(LVEDVI)、左室收缩末期容积指数(LVESVI)和左室射血分数(LVEF)分别为(73.39±2.29)mL/m^2、(38.83±9.28)mL/m^2和(47.88±8.29)%;血清sLOX-1、CK-MB与LVEDVI、LVESVI和LVEF未见明显相关性(P>0.05);AMI组重度狭窄患者血清sLOX-1、CK-MB明显高于轻度和中度狭窄患者(P<0.05);中度狭窄患者血清sLOX-1、CK-MB明显高于轻度狭窄患者(P<0.05);血清sLOX-1、CK-MB与Gensini评分呈正相关(G=0.339和0.252,P<0.05),血清sLOX-1与CK-MB呈正相关(r=0.301,P<0.05)。结论急性心肌梗死患者血清SLOX-1、CK-MB水平升高,与冠状动脉狭窄程度有一定相关性。     

Can cyclin-dependent kinase 4/6 inhibitors convert inoperable breast cancer relapse to operability? A case report

BACKGROUND Pathological complete response(pCR) is rare in hormone receptor-positive(HR+)HER2-negative breast cancer(BC) treated with either endocrine therapy(ET) or chemotherapy. Radical resection of locoregional relapse, although potentially curative in some cases, is challenging when the tumor invades critical structures.The oral cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with ET has obtained a significant increase in objective response rates and progression-free survival in patients with advanced BC and is now being evaluated in the neoadjuvant setting. We present a clinical case of a patient with an inoperable locoregional relapse of HR+ HER2-negative BC who experienced p CR after treatment with palbociclib.CASE SUMMARY We report the clinical case of a 60-year-old patient who presented with an inoperable locoregional relapse of HR+, HER2-negative BC 10 years after the diagnosis of the primary tumor. During a routine follow-up visit, breast magnetic resonance imaging and positron emission tomography/computed tomography revealed a 4-cm lesion in the right subclavicular region, infiltrating the chest wall and extending to the subclavian vessels, but without bone or visceral involvement. Treatment was begun with palbociclib plus letrozole, converting the disease to operability over a period of 6 mo. Surgery was performed and a p CR achieved. Of note, during treatment the patient experienced a very uncommon toxicity characterized by burning tongue and glossodynia associated with dysgeusia, paresthesia, dysesthesia, and xerostomia. A reduction in the dose of palbociclib did not provide relief and treatment with the inhibitor was thus discontinued, resolving the tongue symptoms. Laboratory exams were unremarkable. Given that this was a late relapse, the tumor was classified asendocrine-sensitive, a condition associated with high sensitivity to palbociclib.CONCLUSION This case highlights the potential of the cyclin-dependent kinase 4/6 inhibitor plus ET combination to achieve pCR in locoregional relapse of BC, enabling surgical resection of a lesion initially considered inoperable.     

Interactions médicamenteuses des inhibiteurs de tyrosine kinase dans le traitement du cancer bronchique non à petites cellules

The development of tyrosine kinase inhibitors has revolutionized the treatment strategy in patients with non-small cell lung cancer with activating EGFR mutations, ALK or ROS-1 gene rearrangements. The Food and Drug Administration and European Medicines Agency have approved several inhibitors for the treatment of non-small cell lung cancer : five tyrosine kinase inhibitors targeting EGFR (erlotinib, gefitinib, afatinib, osimertinib and dacomitinib) and six tyrosine kinase inhibitors targeting ALK (crizotinib, céritinib, alectinib, brigatinib, lorlatinib and entrectinib). Interestingly, these tyrosine kinase inhibitor treatments are administered orally. While this route of administration improves the treatment flexibility and provides a comfortable and preferable option for patients, it also increases the risk of drug-drug interactions. The latter may result in changes in pharmacokinetics or pharmacodynamics of the tyrosine kinase inhibitors or their concomitant treatments, with subsequent risks of increasing their toxicity and/or reducing their effectiveness. This review provides an overview of drug-drug interactions with tyrosine kinase inhibitors targeting EGFR and ALK, as well as practical recommendations to guide oncologists and clinical pharmacists in the process of managing drug-drug interactions during the treatment of non-small cell lung cancer with tyrosine kinase inhibitors.     

表皮生长因子受体酪氨酸激酶抑制剂治疗晚期非小细胞肺癌的效果及对免疫功能的调节作用

目的探讨表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)治疗晚期非小细胞肺癌(NSCLC)患者的效果及对免疫功能的调节作用。方法选取2017年1月至2019年12月山西省肿瘤医院呼吸二科收治的100例经病理诊断为晚期(ⅢA~Ⅳ期)NSCLC的患者,男60例,女40例,年龄(58.94±12.33)岁,年龄范围为35~72岁。根据基因检测结果,依据患者基因突变情况分为EGFR-TKI组(n=48)、克唑替尼组(n=7)与联合治疗组(n=45),EGFR-TKI组采用EGFR-TKI治疗,克唑替尼组采用克唑替尼治疗,联合治疗组采用多西他赛联合顺铂治疗。比较三组患者的治疗效果、不良反应发生情况、淋巴细胞亚群[表面抗原分化簇3(CD3⁺)、表面抗原分化簇4(CD4⁺)、表面抗原分化簇8(CD8⁺)、CD4⁺/CD8⁺]和生活质量[健康调查简表(SF-36)评分、卡氏行为能力状况量表(KPS)评分]。结果 EGFR-TKI组的有效率(68.8%)、疾病控制率(87.5%)和克唑替尼组的有效率(71.4%)、疾病控制率(85.7%)高于联合治疗组[(31.1%)、(44.4%)],差异有统计学意义(P<0.05)。三组患者不良反应发生率比较,差异无统计学意义(P>0.05)。治疗后,EGFR-TKI组CD3⁺[(49.67±7.35)%]、CD4⁺[(42.00±5.17)%]、CD4⁺/CD8⁺(1.97±0.51)高于治疗前[(28.73±4.92)%]、[(24.16±3.90)%、(1.30±0.49)],克唑替尼组CD3⁺[(51.21±7.72)%]、CD4⁺[(40.79±4.37)%]、CD4⁺/CD8⁺(2.01±0.48)高于治疗前[(28.42±4.52)%]、[(23.85±3.73)%、(1.30±0.52)],联合治疗组CD3⁺[(41.05±6.37)%]、CD4⁺[(34.52±4.41)%]、CD4⁺/CD8⁺(1.67±0.45)高于治疗前[(28.62±5.36)%]、[(23.65±3.66)%、(1.28±0.53)],三组患者的CD8⁺[(16.71±1.79)%、(15.90±1.93)%、(21.28±2.40)%]均低于治疗前[(26.44±3.20)%、(26.42±3.11)%、(26.32±3.05)%];治疗后,EGFR-TKI组的SF-36评分[(84.26±6.70)分]、卡氏评分[(86.29±7.92)分]和克唑替尼组的SF-36评分[(82.85±5.72)分]、卡氏评分[(87.84±7.28)分]均高于联合治疗组[(67.19±6.33)分、(73.56±8.16)分],差异均有统计学意义(P<0.05)。结论靶向药物在晚期非小细胞肺癌患者治疗中具有较为显著的效果,不良反应发生率低,可改善患者免疫功能,值得临床推广。