On September 3, the 2022 MGTO (Molecular Guided Treatment Option) Academy II Symposium was hosted by the Taiwan Oncology Society and co-organized by Roche. Looking back and looking forward. During the meeting, the disease categories covered breast cancer, lung cancer, colorectal cancer, etc., and the Molecular Tumor Board (MTB) played a key role in guiding and decision-making in tumor clinical practice. It is hoped that in the future, personalized cancer medicine will lead to more accurate diagnosis. Treatment advances.
Create the prospect of accurate detection, diagnosis and treatment of cancer medicine
Yang Zhixin, director of National Taiwan University Cancer Hospital and chairman of the Cancer Society of the Republic of China, said in his speech that the great leap forward in cancer medicine is to obtain genetic testing information of cancer patients through next-generation sequencing (NGS), helping physicians to promote individual This is not only the mainstream strategy of international cancer medicine, but also the direction of Taiwan’s cancer medicine’s active efforts.
Shi Chongliang, deputy minister of the Ministry of Health and Welfare, said that “precision medicine” not only covers medical aspects, but also includes precise detection and precise diagnosis. Accurate detection technologies such as NGS have gradually improved to lower the price threshold, but genetic testing results are often not interpretable by a single physician, and how to interpret them is critical to subsequent drug selection and treatment plans. The MTB team, which gathers professional experts from multiple fields, can select the appropriate drugs for patients more deeply and comprehensively. The accumulation of relevant information in the biobank will also facilitate new drug development processes, accelerate the drug approval process, and build a good cancer treatment ecosystem as a whole. patients benefit.
CGP flips genetic data-based cancer treatment
Devmanyu Singh, Roche’s Personalized Healthcare division, will focus on Comprehensive Genomic Profiling (CGP). The situation is that the diagnosis is not confirmed until the late stage, which makes it difficult to implement precision medicine.
Compared with traditional detection techniques, the advantage of NGS is that it has a wider detection range and can detect a single oncogene mutation site. With the progress of genetic database information, such as the two major cancers: breast cancer and lung cancer, the known mutated gene types continue to increase, and now approved targeted drugs have been designed for more than 5 biomarkers, so the technology for a single gene mutation is time-consuming. It also wastes specimen resources. In contrast, CGP using NGS can detect large-scale genomic copy number variation (CNV) and tumor mutational burden (TMB). Biopsy (liquid biopsy) technology can effectively distinguish early-stage cancer and predict the effect of immunotherapy.
The emergence of CGP and targeted therapy has accelerated the explosive growth of tumor-related clinical information, but in clinical practice, translating genetic information into actual medical decisions requires the intervention of a multi-professional MTB team to assist in the use of gene mutation-specific therapeutic drugs (molecular guided treatment options, MGTO). In addition to this, Singh also mentioned that the MGTO strategy has greatly contributed to the establishment of innovative clinical trial models, integrating CGP results with real-world data (RWD) to form a clinical-genomic database. It will serve as an effective and comprehensive treatment guide.
Chief Strategy Officer Singh concluded that cancer personalized medicine has laid a solid foundation for CGP testing. For patients, MTB analysis results can be used to establish early diagnosis, and then give immunotherapy and targeted therapy that meet individual genetic characteristics. For drug research and development units, it is beneficial to conduct clinical trials with cancer biomarkers as the research core. In addition, genetic big data can also accelerate the entry of new anti-cancer drugs into the market, such as tumor agnostic therapy, which emerges as the times require. The use is not limited to the tumor type, but makes the treatment more popular and effective by targeting the specific genotype of the tumor.
Cancer Emerging Biomarker Continues to Advance Drug Development
Dr. Jiang Nai-Rong, President of Taipei Rong, gave the topic of “Drug Development Prospects of Emerging Biomarkers”. By analyzing the approval status of cancer drugs using biomarkers in the United States, she took lung cancer, thyroid cancer, and bile duct cancer as examples to introduce common tumors. RET Gene fusion/mutation (RET fusion mutation）、IDH Mutation-related advances in clinical trials, drug development strategies and future treatment trends.
Looking back at the number of approved cancer drugs in recent years, about 65% of the drugs approved by the US FDA and EMA from 2015 to 2019 targeted at least one biomarker, and common variants include ALK, BRCA, EGFR, FGFR, NTRK, PIK3CA, ROS1, so the treatment guidelines specifically recommend that it be confirmed by NGS. Dr. Jiang mentioned that as the number of cancer clinical trials centered on genomic data increases, there will also be a key increase in the number of cancer drug approvals for specific biomarkers within five years.
Dr. Jiang for the common non-small cell lung cancer (NSCLC), thyroid cancer RET Gene variation is explained.of cancer patients RET About 70% of the variation is in the form of mutation and fusion. LIBRETTO-001, ARROW clinical trials show that with selective RET Inhibitors Selpercatinib, Pralsetinib treatment RET In the fusion NSCLC population, the response rate (RR) was 64 and 69%. The two drugs also have the ability to penetrate the blood-brain barrier, so they are effective for patients with central nervous system (CNS) metastasis.rather than selective RET Inhibitors’ efficacy in lung cancer treatment is not selective RET Good inhibitor.
Another example of genetic variation IDHdue to excessive DNA methylation can cause abnormal proliferation of tumor cells.IDH1/2 The subtype is most common in cholangiocarcinoma, blood cancer AML (acute myeloid leukemia), and this gene variant is more prevalent in the United States than in Asians, if the patient has IDH Usually the prognosis is better. Ivosidenib is the first FDA-approved treatment for cholangiocarcinoma in 2021 IDH1 drug. The phase III clinical trial ClarlDHy used Ivosidenib as the second-line treatment for cholangiocarcinoma, with a progression-free survival (PFS) of 2.7 months and a stable safety profile.It should be noted that IDH Mutations have the risk of inducing the production of the tumor metabolite 2-hydroxyglutaric (2HG), so long-term monitoring of 2HG concentrations in patients should be done to ensure efficacy.
Dr. Jiang concluded,RET Variants are many of the causative tumor driver genes responsible for cancer, and targeting RET Fusion/mutated NSCLC, thyroid cancer patients,RET-TKI drugs have demonstrated therapeutic benefit.IDH1 It is one of the most common metabolic mutation genes in cancer cells. IDH1/2 Dual-inhibitor drug trials are being conducted to treat brain and blood cancers.
Application scenarios of MTB in various cancers
In order to explore the application of MTB in different cancer types, the second half of the seminar was conducted in the form of case discussions. Physicians from major medical centers such as Taipei Rong Zong, Chengda Hospital, Kaohsiung Rong Zong, etc. In-depth communication on the comparison of detection tools and the process of MTB-guided treatment planning.
In genitourinary cancer, an increasing number of drug targets for prostate cancer mutations are now known, such as PTEN Tumor suppressor genes, which are relatively slow in application TP53 Genes, and androgen receptor (AR) inhibitors are also important targets for prostate cancer drugs.In patients with metastatic prostate cancer, NGS sequencing results can help physicians decide which targeted therapy option to pursue, regardless of PARP、AKT、CDK4/6 Inhibitors of various genes, androgen receptor (AR) inhibitors to achieve the principle of precise treatment. At the same time, it should be noted in clinical practice that some elderly patients are accompanied by clonal hematopoiesis without clinical manifestations, which may affect the choice of therapeutic drugs. In such cases, liquid biopsy detection tools should be included in the evaluation. To rule out false positive results from blood cell mutations.
Lung cancer treatment is currently one of the most widely used cancers combined with genetic testing. Common known targets include EGFR、ALK、 ROS1、 NTRK、MET、KRASisogenic. However, TCM practitioners also pointed out that there are still more than 30% of patients with no functional oncogenic driver gene (oncogenic driver) in the test results. Therefore, it is specially reminded that special attention should be paid to the impact of unknown gene mutations.Finally, gastrointestinal cancer is a cancer category that has rarely been discussed in MTB in the past, but with the development of cholangiocarcinoma IDH The drug will be approved for marketing for the first time in 2021, and the treatment of specific gene mutation has attracted more and more attention, except for the reference for colorectal cancer in the past.KRAS、 BRAF、MSI and other biomarkers, gastrointestinal cancer also has new FGFR Inhibitors are all reference options for selecting target drugs.
Taking breast cancer as an example, in the past 10 years, more than 15 drugs for specific gene mutation therapy (molecular guided treatment) have been approved for marketing, including BRCA1/2 of PARP inhibitor drugs, and PIK3CA of PIK3CA inhibitors, etc.However, breast cancer is not included in the cancer categories recommended by ESMO guidelines for NGS detection, resulting in a small number of HER2 The characteristics of mutation groups are ignored in diagnosis and treatment, which is the direction for continuous improvement in the future. In addition, TCM physicians agree that with the evolution of NGS technology and the downward trend of price thresholds, the earlier the patient undergoes genetic testing, the tissue integrity of the specimen will be preserved, and it will also help to formulate a precise treatment plan as soon as possible without having to look for a needle in a haystack in the past.
Join forces to advance the precision medicine future of cancer MGTO!
The panel discussion at the end of the symposium was chaired by Dr. Yang Muhua, President of Taipei Rong. Physicians at the meeting mentioned that CGP test results can effectively guide tumor histology and follow-up drug administration, which could not be achieved by pathological tissue analysis alone in the past. As for the interpretation and analysis of the data after output, it is related to the fact that many hospitals adopt outsourcing companies to send inspection services, and face the problem of inconsistent interpretation quality of various manufacturers. Therefore, the physician speaker suggested that the ability of multi-specialty teams in the hospital to interpret initial data should be strengthened, and even self-developed platforms should be developed for detection and interpretation, so as to implement molecular pathology and molecular biology for more use in cancer clinical situations.
In addition to inter-professional cooperation, the promotion of personalized medicine is also related to the scale and characteristics of the data database for comparison of test results. For example, the genetic characteristics of Asian, European and American ethnic groups are different, which affects the expression of genes in different diseases. and subsequent treatment effects. In addition to the existing analysis of known gene loci, the future enhancement of the database for predicting unknown mutation sites, as well as drug simulation drug effectiveness, will accelerate the transformation of the existing paradigm of cancer treatment with the MGTO approach and create more possibilities for new drug development. It is quite worth looking forward to the development direction.
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