Acidemia, Isovaleric

导读 从遗传学的突破到精准医学的崛起，基因科学引领科学家们不断解开生命的奥秘。“因知·真见，基因组学点亮肿瘤精准医学未来一一肿瘤基因月”专栏，在2024 CSCO大会召开之际，分享基因组学与肿瘤精准医学研究前沿动态，与您共绘肿瘤精准医学的未来蓝图。 在肿瘤精准医学的探索之路上，基因测序技术的快速发展推动了精准医学进入全新的篇章。其中以下一代测序（NGS）为代表的基因测序技术正逐渐从实验室走向临床，为肿瘤精准治疗奠定了坚实基础。然而从测序平台选择到复杂生物标志物解读，再到如何实现标准化和规范化应用，为临床实践中使用NGS带来诸多挑战。本期我们将以“NGS检测的肿瘤精准医学临床实践”为主题，分享NGS技术在肿瘤精准医疗中的临床意义，探讨推动临床NGS标准化和规范化发展过程中所面临的机遇与挑战。 科技的进步推动肿瘤精准医学逐渐成熟并走向临床应用，分子诊断也逐渐成为肿瘤体外诊断（IVD）的关键，特别是在NGS技术的推动下，肿瘤基因分析的效率和准确性得到了极大地提高。今年，ESMO精准医学工作组更新了ESMO NGS检测指南，较2020版扩大了NGS推荐建议范围，在更多晚期癌种中推荐了更广泛的NGS检测。目前根据2024版ESMO NGS检测指南推荐，建议在晚期的非鳞状非小细胞肺癌、前列腺癌、结直肠癌、胆管癌、卵巢癌、乳腺癌（新增）和罕见肿瘤（新增，包括胃肠道间质瘤、肉瘤、甲状腺癌和原发不明肿瘤）患者中进行NGS检测[1]。同时还建议晚期癌症患者可进行泛癌种NGS检测，以寻找泛实体瘤用药的可能性[1]。 表1：2024版ESMO NGS检测指南推荐检测的泛癌种变异基因 随着NGS技术的进步，近年来美国食品药品监督管理局（FDA）批准的NGS伴随诊断产品逐渐增多，回顾FDA批准的肿瘤分子诊断产品，可发现一次性覆盖更多标志物、可兼容丰富样本类型的NGS成为肿瘤分子诊断的主流。特别是近日FDA批准的首个泛癌种全景变异分析（CGP）NGS伴随诊断IVD试剂盒——TruSight Oncology Comprehensive（TSO COMP），其单次检测可覆盖500多个基因，报告DNA和RNA样本中的基因突变以及肿瘤突变负荷（TMB），也具备NTRK（实体瘤）和RET（非小细胞肺癌）伴随诊断功能。以TSO COMP为代表的CGP NGS检测，大大提高了的肿瘤精准诊疗的临床可及性和检测效率，为癌症患者提供了更多治疗机会。 在肿瘤精准诊疗实践中，为患者选择合适的NGS检测是确保精准治疗成功的关键。不同NGS平台的算法、阈值设定和数据解读方式各异，这使得临床医生在面对多种可供选择的检测时，如何为肿瘤患者选择最合适的NGS检测，成为当前精准医疗实践中的一大难题。 01 CGP NGS可检测广泛的靶点基因， 增加患者靶向治疗机会 传统基因检测（即单基因序贯检测）是逐一检测生物标志物，因此部分患者并不会接受所有推荐的治疗生物标志物检测。一项真实世界研究提示，接受单基因序贯检测的患者中，只有≤20%接受了RET、MET的检测，＜10%接受了ERBB2和NTRK的检测；而接受CGP NGS检测的患者中有超过79%接受了所有生物标记物的检测[2]。除常见靶点外，CGP NGS也可检测出少见/罕见变异，可实现对生物标志物的更全面覆盖[2,3]。以EGFR检测为例，EGFR突变含有众多可影响治疗疗效的突变亚型，传统单基因测序可能无法满足对EGFR少见突变的检测需求，而CGP NGS可实现对常见/少见变异的全面覆盖，进一步指导靶向治疗选择[4]。CGP NGS也可能发现其他与肿瘤发生相关的基因，比如前文提及的近日获FDA批准的TSO COMP作为泛癌种CGP NGS IVD试剂盒，涵盖了超过28种实体瘤的临床相关生物标志物，涉及64项临床指南、111个药物标签和超过615项临床研究。由此可见，CGP NGS不仅提升了肿瘤患者接受靶向治疗或免疫治疗的比例，也为更多患者提供更多参与临床试验用药和潜在跨适应症用药的机会[5–8]。 除此以外，多项研究表明与接受传统单基因序贯检测相比，CGP NGS也可节约检测周转时间（从检测订单到报告时间，10天 vs 12天）、节省临床样本，且并没有显著增加检测费用[2,8,9]。基于此，目前多项国内外指南均推荐晚期肿瘤患者开展CGP NGS，进一步指导肿瘤精准治疗策略[10]。 02 基于RNA的融合基因检测 可提高检测准确性 基因融合是肿瘤中一类重要的分子变异，其在癌症中的发生率约为20%[11]。近年来针对融合基因的靶向治疗进展迅速，目前已获批的靶向药物中涉及的融合基因包括ALK、ROS1、RET、FGFR1/2/3和NTRK1/2/3，为特定融合基因阳性的患者带来了显著临床获益。然而基因融合的形成机制多样，在临床中的分子检测也相对复杂。根据2024版ESMO NGS检测指南推荐，目前融合基因NGS检测可基于DNA和RNA水平进行测序，虽然DNA比RNA更稳定，但相比DNA水平，RNA水平上融合基因表现为前后两个基因外显子之间的衔接，融合点相对固定，因此在RNA水平上检测融合基因比DNA水平更易实现，也更加准确[1,12]。《非小细胞肺癌融合基因检测临床实践中国专家共识（2023版）》也建议对于DNA水平检测为阴性的病例，推荐必要时可在RNA水平进一步明确[13]。近日，FDA已批准TSO COMP用于检测鉴别RET和NTRK。据悉，TSO COMP可检测出RNA中的23个基因的融合，这也进一步为未来融合基因阳性的实体瘤领域新药研发和精准治疗提供了技术保障。 03 复杂肿瘤标志物检测的选择 同源重组修复缺陷（HRD）、TMB等复杂生物标志物近年来逐渐成为肿瘤精准治疗中的重要靶点和疗效预测工具。目前国内外指南推荐的评估HRD、TMB等复杂肿瘤标志物的检测产品包括Myriad myChoice CDx、FoundationOne CDx等，不过目前这些检测产品在国内可及性较差。对于有临床需求的患者来说，可能会选择其它HRD、TMB的检测产品，但不同HRD、TMB的检测技术是非等效的，在疗效预测效能、检测结果一致性上存在差异。并且大多HRD、TMB的检测技术并未进行一致性评估，因此其是否可用于指导临床用药、精准预测疗效仍有待商榷。由因美纳推出的用于HRD、TMB等复杂生物标志物检测的标准化CGP试剂盒TruSight Oncology 500（TSO 500），可与目前全球公认的HRD、TMB的评估方法保持高度一致。 在HRD检测方面，因美纳和Myriad共同推出了融合TSO 500和Myriad myChoice CDx技术优点的TSO 500 HRD检测试剂盒。一项对比了不同HRD检测技术一致性的研究提示，TSO 500 HRD可与目前获FDA批准且已经临床验证的Myriad myChoice CDx的检测结果保持高度一致，与其它检测方法相比TSO 500 HRD与Myriad myChoice CDx的相关系数最高，为0.92和0.93（来自2家实验室）[14]。并且TSO 500 HRD能保证检测结果在不同实验室、不同操作者间的准确性、可重复性、可比性。 图1：不同HRD检测产品与Myriad myChoice CDx评估HRD的相关性分析 在TMB检测方面，TSO 500与全球公认的TMB评估方法（FoundationOne CDx和全外显子检测[WES]）可保持高度一致，并且具有较高的可重复性[15]。在利用TSO 500检测样本的既往临床数据分析时发现，TSO 500提示的TMB值高低也与帕博利珠单抗疗效显著相关，其对帕博利珠单抗的疗效预测也与FoundationOne CDx和WES相似[15]。 图2：TSO 500与FoundationOne CDx和WES的评估TMB的相关性 图3：TSO 500、FoundationOne CDx、WES评估TMB对疗效的预测情况 04 兼容丰富样本类型的 NGS平台可满足不同临床需求 在肿瘤精准治疗中，样本类型和样本质量也是确保NGS检测结果准确性和可靠性的关键因素。目前NGS检测样本可包含肿瘤组织样本和液体活检样本。肿瘤组织样本通常被认为是准确性更高的选择，但肿瘤组织样本的基因检测在临床实践中往往存在诸多限制。目前循环肿瘤DNA（ctDNA）NGS检测已被国内外专家共识或指南建议作为多种晚期恶性肿瘤组织基因检测的替代方式。因此随着肿瘤精准治疗的发展，可满足多样化临床需求、兼容不同样本类型的NGS测序平台正逐渐成为主流。 05 NGS IVD和实验室自建项目 共同助力NGS标准化提升 在NGS IVD临床使用中，不能更改任何试剂组份和操作步骤，而目前国内已获国家药品监督管理局（NMPA）批准的NGS IVD产品来自不同的测序平台（截至2024年8月，NMPA共批准20款肿瘤NGS IVD试剂盒[15款是基于因美纳NGS测序平台]），这也为院内开展标准化NGS IVD检测提出了更高要求。不过目前获NMPA批准的NGS IVD仅适用于非小细胞肺癌、结直肠癌和上皮性卵巢癌3个癌种，远无法满足临床治疗需求。为进一步推动肿瘤精准诊疗的高质量发展，当前国内各地正在积极尝试推动实验室自建NGS检测的试点工作，以进一步满足日益增长的精准医疗需求[10]。 然而随着NGS、多组学技术的快速发展，越来越多的治疗靶点开始应用于新药研发和临床实践，众多新靶点和既往临床中难以检测到的变异对NGS检测与解读提出了更高的要求。 由于NGS报告包含大量生物信息数据，变异解读具有挑战，许多临床医生在解读NGS报告时面临困难。这也“催生”出了一种特殊的多学科协作模式——分子肿瘤专家委员会（MTB），与多学科会诊（MDT）模式主要侧重于肿瘤的综合治疗方案制定不同的是，MTB模式更加聚焦于基因测序数据的深度解读和临床应用，从分子层面讨论肿瘤患者的治疗问题，从而为临床治疗提供更加精准、科学的指导。此外，随着“AI+基因组大数据”的进一步发展，如PrimateAI-3D等基因变异AI解释工具已经在肿瘤精准医学研究中展现出巨大潜力，未来其也可能结合健康记录大数据，协助医生进行精准医疗决策。 一项对45万例患者的基因检测结果显示，约有21.6%的患者会携带一种或多种致病性变异，这些携带变异的患者中约有13.8%无法被常规NGS检测[16]。基于RNA水平NGS检测可提高部分复杂变异的检出率，比如在一项实体瘤研究中，基于DNA水平的NGS检测出MET 14号外显子跳跃突变的比例仅为1.3%，基于RNA水平的NGS检测出MET 14号外显子跳跃突变的比例为4.2%[17]。但与DNA相比，RNA稳定性较差、容易降解，这也导致临床实践中获得的RNA质量可能较低，导致假阴性结果。 全基因组测序（WGS）作为一种更全面的基因组分析技术，与常规NGS相比能够提供更为全面的基因组信息，是肿瘤特别是罕见肿瘤基因诊断的前沿方法。但WGS生成的数据量远超既往基因测序，数据处理和解读较常规NGS检测难度更大；其次，WGS的成本相对较高，在资源有限的医疗机构中难以普及。不过随着测序成本的下降和数据分析能力的提升，WGS有望在未来的肿瘤诊疗中发挥更大作用，可以为那些常规NGS难以检测出的基因变异提供更多线索。而MTB、AI等新模式、新技术的发展也将可能为临床解读WGS数据提供更多助力。 作为一项具有划时代意义的技术，NGS极大推动了精准医学的发展，为实现患者的个体化临床诊疗奠定了基础。新一代的CGP NGS进一步推动了肿瘤精准医学的高速发展，为患者带来更多的治疗机会。随着技术的不断发展与完善、相关应用指南与规范的逐步出台，相信NGS技术将更好地服务于精准医疗实践。今年CSCO 2024期间，因美纳全球肿瘤医学负责人John Jiang将分享WGS，CGP等NGS检测的全球临床肿瘤实践，另外来自梅奥诊所基因组学实验室的郑刚教授将聚焦液体活检技术分享肿瘤分子诊断趋势，和与会专家共同探讨精准医学时代NGS检测前沿。 下期预告 本栏目将在CSCO 2024期间隆重推出“第一直播间”线上直播活动。“第一直播间”汇聚来自肿瘤研究领域的顶尖专家，聚焦精准医学的最新研究策略与临床实践经验，实时分享肿瘤精准医学的前沿学术动态与临床应用心得。 因知·真见 | 栏目回顾 参考文献 [1]  Mosele M F, Westphalen C B, Stenzinger A, et al. Recommendations for the use of next-generation sequencing (NGS) for patients with advanced cancer in 2024: a report from the ESMO Precision Medicine Working Group[J]. Annals of Oncology, 2024, 35(7): 588-606. [2]  Subbiah V, Vasudevan A, Roos A, et al. Performance of comprehensive genomic profiling (CGP) versus single gene testing (SGT) in guideline-recommended biomarker selection in non-small cell lung cancer (NSCLC).[J]. Journal of Clinical Oncology, 2024, 42(16_suppl): 8640-8640. [3]  Nesline M K, Wallen Z D, Strickland K C, et al. Multi-specimen comprehensive genomic profiling for diagnostic disambiguation in advanced and metastatic solid tumors.[J]. Journal of Clinical Oncology, 2024, 42(16_suppl): e15166-e15166. [4]  Bai Y, Liu X, Zheng L, et al. Comprehensive profiling of EGFR mutation subtypes reveals genomic-clinical associations in non-small-cell lung cancer patients on first-generation EGFR inhibitors[J]. Neoplasia (New York, N.Y.), 2023, 38: 100888. [5]  Dowdell A K, Meng R, Weerasinghe R K, et al. CGP-based IO biomarker assessment and treatment utilization across a major US health system.[J]. Journal of Clinical Oncology, 2024, 42(16_suppl): e23109-e23109. [6]  Stockl K M, Morin P, Reyes C, et al. Differences in baseline characteristics and healthcare costs among insured patients with advanced cancer with vs without clinical trial participation.[J]. Journal of Clinical Oncology, 2024, 42(16_suppl): 11154-11154. [7]  Fox J L, Daniel S, Abrol M. NGS panels’ capture of biomarkers associated with targeted therapies in clinical trials.[J]. Journal of Clinical Oncology, 2024, 42(16_suppl): e13508-e13508. [8]  Tan A C, Lai G G Y, Tan G S, et al. Utility of incorporating next-generation sequencing (NGS) in an Asian non-small cell lung cancer (NSCLC) population: Incremental yield of actionable alterations and cost-effectiveness analysis[J]. Lung Cancer (Amsterdam, Netherlands), 2020, 139: 207-215. [9]  Nesline M K, Subbiah V, Previs R A, et al. The Impact of Prior Single-Gene Testing on Comprehensive Genomic Profiling Results for Patients with Non-Small Cell Lung Cancer[J]. Oncology and Therapy, 2024, 12(2): 329-343. [10]  中国抗癌协会肿瘤病理专业委员会分子病理协作组, 中华医学会病理学分会分子病理学组. 实验室自建肿瘤全景变异检测性能确认中国专家共识（2024版）[J]. 中华肿瘤杂志, 2024, 46(04): 274-284. [11]  Mitelman F, Johansson B, Mertens F. The impact of translocations and gene fusions on cancer causation[J]. Nature Reviews. Cancer, 2007, 7(4): 233-245. [12]  Guo W, Liang J, Zhang D, et al. Lung adenocarcinoma harboring complex EML4-ALK fusion and BRAF V600E co-mutation responded to alectinib[J]. Medicine, 2022, 101(40): e30913. [13]  中国抗癌协会肿瘤病理专业委员会, 中华医学会肿瘤学分会肺癌专家委员会, 国家病理质控中心. 非小细胞肺癌融合基因检测临床实践中国专家共识（2023版）[J]. 中华病理学杂志, 2023, 52(06): 565-573. [14]  Liu L, Roessler K, Bilke S, et al. 925P Analytical performance of a next-generation sequencing (NGS) assay kit for assessing homologous recombination deficiency (HRD) from solid tumor samples[J]. Annals of Oncology, 2022, 33: S969. [15]  B W, J K, M K, et al. Evaluation of the TruSight Oncology 500 Assay for Routine Clinical Testing of Tumor Mutational Burden and Clinical Utility for Predicting Response to Pembrolizumab[J]. The Journal of molecular diagnostics : JMD, 2022, 24(6). [16]  Lincoln S E, Hambuch T, Zook J M, et al. One in seven pathogenic variants can be challenging to detect by NGS: an analysis of 450,000 patients with implications for clinical sensitivity and genetic test implementation[J]. Genetics in Medicine: Official Journal of the American College of Medical Genetics, 2021, 23(9): 1673-1680. [17]  Socinski M A, Pennell N A, Davies K D. MET Exon 14 Skipping Mutations in Non-Small-Cell Lung Cancer: An Overview of Biology, Clinical Outcomes, and Testing Considerations[J]. JCO precision oncology, 2021, 5: PO.20.00516. 本文转自医脉通肿瘤公众号 .

Pictured: FDA signage at its office in Washington, DC/iStock, JHVEPhoto The FDA on Wednesday approved the use of UTILITY therapeutics’ oral antibiotic pivmecillinam, which will now carry the brand name Pivya, for the treatment of adult women with uncomplicated urinary tract infections. In its approval announcement, the FDA noted that uncomplicated urinary tract infections (UTIs) are bacterial infections of the bladder in females with no structural abnormalities of their urinary tract. The regulator added that approximately one-half of all women experience at least one UTI in their lifetime. Pivya is indicated for patients whose UTIs are caused by susceptible strains of Escherichia coli, Proteus mirabilis and Staphylococcus saprophyticus. UTILITY is working to make Pivya available in the U.S. in 2025, according to reporting from The New York Times. The antibiotic’s approval “will provide an additional treatment option for uncomplicated UTIs,” Peter Kim, director of the Division of Anti-Infectives at the FDA’s Center for Drugs Evaluation and Research, said in a statement. “Uncomplicated UTIs are a very common condition … and one of the most frequent reasons for antibiotic use.” The FDA’s approval on Wednesday was supported by data from three clinical trials, which compared Pivya to placebo, another oral antibacterial agent as well as to the anti-inflammatory drug ibuprofen. All three studies primarily evaluated Pivya’s composite response rate, which included clinical cure and microbiological response. In the placebo study, Pivya treatment elicited a 62% composite response rate at eight to 14 days after enrollment. Only 10% of placebo counterparts achieved the composite response endpoint. When compared with another antibacterial agent, Pivya elicited a 72% composite response rate versus 76% in those who received the other drug. In the third trial, 66% of patients treated with Pivya achieved composite response compared to only 22% of those who were given ibuprofen. In terms of safety, Pivya was overall well-tolerated and its most common side effects were nausea and diarrheas. The antibiotic carries warnings for hypersensitivity reactions, carnitine depletion, Clostridioides difficile-associated diarrhea and severe cutaneous adverse reactions. It should not be taken by patients with known histories of severe hypersensitivities against beta-lactam drugs. Pivya can also interfere with a newborn screening test for the rare metabolic disorder isovaleric acidemia. Pivya’s active ingredient pivmecillinam is an aminopenicillin, which is a specific subclass of beta-lactams that work by disrupting the synthesis of the bacterial cell wall. According to UTILITY’s website, pivmecillinam has already been commercially approved for more than 40 years outside the U.S. and has long been used to successfully treat UTIs. Pivmecillinam has also been recommended as the frontline treatment option in many countries. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Pivya is intended for treating UTIs. Credit: ANN PATCHANAN via Shutterstock. The US Food and Drug Administration (FDA) has approved Utility Therapeutics’ Pivya tablets, a new treatment for female adults with uncomplicated urinary tract infections (UTIs). This decision is based on the efficacy of Pivya in treating UTIs caused by susceptible Escherichia coli isolates , Staphylococcus saprophyticus and Proteus mirabilis. The approval was supported by three controlled clinical trials. These trials assessed the efficacy of Pivya in treating females aged 18 years or older with uncomplicated UTIs, comparing various dosing regimens of the drug to placebo, another oral antibacterial drug, and to anti-inflammatory drug ibuprofen. The trials’ primary efficacy measure was the composite response rate, which included both clinical cure and microbiological response. In the study comparing Pivya to placebo, 62% of the 137 participants receiving the therapy achieved the composite response, significantly higher than the 10% response rate in the placebo group. See Also: Mundipharma to acquire rezafungin assets from Cidara Therapeutics Novartis bags paediatric FDA label expansion for Lutathera When compared to another oral antibacterial drug, Pivya’s composite response rate was 72%, closely matching the comparator drug’s 76%. Against ibuprofen, Pivya showed a 66% response rate, compared to 22% for those who received the anti-inflammatory drug. Nausea and diarrhoea were the common side effects reported during the trials for Pivya. The FDA advises against the use of Pivya in patients with a history of severe hypersensitivity to beta-lactam antibacterial drugs, those with carnitine deficiency disorders, and individuals suffering from porphyria. Pivya carries warnings for potential hypersensitivity reactions, carnitine depletion, severe cutaneous adverse reactions, Clostridioides difficile-associated diarrhoea, and possible interference with newborn screening tests for metabolic disorder isovaleric acidemia. The FDA granted Pivya priority review and qualified infectious disease product designations. FDA Center for Drug Evaluation and Research Anti-Infectives division director Peter Kim said: “Uncomplicated UTIs are a very common condition impacting women and one of the most frequent reasons for antibiotic use. “The FDA is committed to fostering new antibiotic availability when they prove to be safe and effective, and Pivya will provide an additional treatment option for uncomplicated UTIs.”