From the past: Professor Li Ning talks about rare tumors

Lung cancer, number one killer; lung sarcoma-like cancer, lung-infused mucus adenocarcinoma? Hepatocellular carcinoma, the king of cancer; Not to mention a lot of soft tissue sarcoma, Juve sarcoma, transverse muscular tumors... Some tumors are defined as "rare" tumors because of their low incidence, low tissue type, or rare molecular type.
Although there are not many patients with certain types of rare tumors, the overall incidence of rare tumors as a whole is as high as 20%, which means that one in five newly diagnosed tumor patients in our country is a rare tumor patient.
like common tumors such as lung cancer and breast cancer, rare tumors deserve the attention of oncologists.
sources of tissue and molecular biology lead to significant differences in clinical manifestations and treatment responses for rare tumors.
compared with common tumors, the routine diagnosis and treatment of rare tumors and clinical trials are difficult.
years, with the development of precision medicine, researchers have gradually deepened their understanding of rare tumors and have new expectations for their treatment prospects.
In September 2020, the Official Public Number of the Drug Clinical Trial Research Center (GCP) of the Oncology Hospital of the Chinese Academy of Medical Sciences opened a special "Rare Tumors, Where are the Drugs" column, which aims to raise the industry's attention to rare tumors, and to study doctors and pharmacists to share information, treatment status and (potential) therapeutic drugs on several rare tumors.
the past and know the past, this paper especially reviews the definition of rare tumors, the status quo, bottlenecks, and on the context of precision medicine in the context of a new research opportunities to explain, to peer reference.
Introduction: Professor Li Ning, M.D., Chief Physician of Thoracic Surgery, Assistant To the President of the Oncology Hospital of the Chinese Academy of Medical Sciences, Director of the Party and Government Office of the National Cancer Center, Director of the Office of the Cancer Hospital of the National Cancer Center/Chinese Academy of Medical Sciences, Deputy Chairman of the Youth Committee of the Thoracic Cardiovascular Surgery Branch of the Chinese Medical Association, Deputy Secretary-General of the Beijing Oncology Society, Member of the Clinical Drug Evaluation Committee of the Chinese Pharmaceutical Society, And editorial board of the Clinical Journal of Thoracic Cardiovascular Surgery of China.
first author and correspondent has published more than 20 articles in publications such as Lancet Oncology, JTO, Journal of Genetics and Genomics, and Frontiers in Oncology.
As the national 973 major project sub-topic leader, the national key research and development program precision medicine special, the National Natural Science Foundation of China, clinical trial capacity-building (GCP) platform construction and genotype guidance precision treatment of Rare Tumor Platform research project leaders in China to undertake a number of research topics, committed to lung cancer surgery minimally invasive treatment standardization, immunotherapy and clinical research standards set.
changing cognitive boundaries: from rare diseases to rare tumors Today, so-called rare tumors are based on a concept of the tumor population, where as a category of rare diseases were 30 or 40 years ago.
The Oncology Hospital of the Chinese Academy of Medical Sciences was founded in 1958, formerly created as the Suntan Hospital, and when the Oncology Department was added in 1959, there were only seven beds.
, tumor incidence was not only low, but also a "nightmare" that no one wanted to talk about.
many general hospitals did not establish their own departments of oncology until the beginning of this century, before which the treatment of tumors was carried out in the mode of respiratory and stomach cancer in the digestive department.
, with the increasing incidence, tumors have become a risk factor of 20% to 25% of the causes of death in the Chinese group, and are therefore no longer referred to as "rare diseases".
based on an average life expectancy of 77 years, each person has a one-third chance of developing a tumor in their lifetime, equivalent to every household having a tumor patient.
tumor is a generalization of a large category of diseases, heterogeneity is strong.
the current clinical understanding of the tumor is still in the shallowest stage, the tumor is still basically named according to the growth site classification, can not be based on the pathogenic causes of the "fundamental" classification.
"rare" tumor, which is naturally more difficult to define as a special type of tumor that is rare and low-interested.
, the biggest question that needs to be answered now is: What kind of disease is a rare tumor or group of diseases? What kind of tumor is a rare tumor? The concept of a rare tumor sounds simple, but it's actually very complex.
In the United States, "orphan drugs", as a specific drug for rare diseases, have become a "must-win" for some bidders because of a series of policy supports in the development of new drugs, including priority review, 7-year patent protection, and return of review fees.
, however, the definition of orphan medicine and rare diseases is still not a fixed concept, there are still many places worth thinking about.
For example, lung cancer accounts for 30%-40% of the incidence of malignant tumors, which is not uncommon, but the APK gene fusion of lung cancer accounts for only about 4% of all lung cancer, this molecular type of lung cancer is a rare disease, rare tumor? Can genotypes be used to assess and define rare diseases and tumors? This is still a big controversy in the field of tumor.
there is currently no uniform international definition of rare tumors.
The European Society of Oncology (ESMO) defines rare tumors as tumors with an annual incidence of less than 6/10,000, and the National Cancer Institute, NCI, and the U.S. Food and Drug Administration (FDA) as tumors with an annual incidence of less than 15/10,000.
in the International Classification of Diseases (ICD), there are 100 types of tumors coded from C00-C99 that are defined according to the site of onset of the tumor.
According to the analysis of incidence in China, the top 18 common tumors accounted for 85.8%, while the number of new cases of less than 40,000 patients in the year a total of 76 tumors, a total of 527,410 people, accounting for 13.3% of all tumor patients.
Referring to the definitions and standards of Europe and the United States, combined with China's specific national conditions and cancer incidence, we define an organ/system tumor with an independent ICD code or its specific pathological subspecies (including an unknown tumor of the primary lesions) as a rare tumor in the study of the Rare Tumor Platform.
overall, although the incidence of individual tumors is very low, but the overall incidence of all rare tumors as high as 20%, and the incidence of colorectal cancer in China is comparable.
The forgotten "death cycle": no large number of patients, no clinical experience, no clinical research, no diagnosis and treatment guidelines China's annual number of new tumors about 3.9 million, the total number of new cases of rare tumors as many as 780,000! Overall, "rare tumors" are not uncommon.
, however, the low incidence of specific tumors, on the one hand, results in a lack of clinical experience of clinicians, on the other hand, it leads to a small corresponding market, low industry attention, it is difficult to attract pharmaceutical companies to invest in research and development.
subjective and objective factors make it difficult to carry out clinical trials of rare tumors, and the corresponding normative guidelines cannot be formed, which aggravates the difficulty of diagnosis and treatment of rare tumors, and further pushes them into the abyss of drug incurable drugs.
An solution to the "dead cycle" of rare tumors - low concern - more difficult to treat, improve the status quo of diagnosis and treatment of rare tumors, will be a systematic project, requiring the common attention of all parties, a large amount of investment and support of different resources.
, the prevention and treatment of rare tumors need the attention and attention of clinicians.
tumor from everyone "avoid" the rare disease development to today's degree, the objective incidence rate is only to promote one side, the more important factor is the continued attention of generations of medical workers and years of research to pay.
, some tumors do not have as high incidence, such as neuroendocrine tumors and melanomas, but also have relatively good doctors.
Therefore, only clinicians who do not let go of each patient, aware that every tumor patient, regardless of the incidence of tumors, should have access to appropriate medical resources, and that rare tumors need to be paid attention to, worthy of study, and must be overcome, can other participants be driven to make the necessary objective inputs.
attention to the thought and action of clinicians is the driving factor and fundamental factor to promote the development of rare tumors.
, diagnosis of rare tumors requires the support of a professional pathology team.
pathologist is a doctor's doctor, if the pathology can not be in the initial diagnosis stage of rare tumors from the huge team of common tumors, the corresponding differences, targeted treatment is impossible to talk about.
, a strong pathology team is key to supporting the exploration of rare tumors.
, the diagnosis and treatment of rare tumors requires the joint attention of the sponsors and researchers.
, clinical trials often block out rare types of large tumors in order to maintain consistency among patients in the group.
such as liver cancer research are liver cell carcinoma, kidney cancer only for renal transparent cell carcinoma, sarcoma-like cancer, papilloma cancer and other rare types were excluded.
such a trial design is not a scientific flaw, but in clinical practice, it may be a pity.
patients with rare tumors of rare pathological types often want to participate in clinical trials without, and if each trial excludes rare tumors, the exact efficacy of the drug in rare tumors will never be systematically understood.
, drug development for rare tumors requires strong policy support.
reality, the expansion of drug-adaptive disorders needs to take into account the potential space and risk-benefit ratio of the market.
clinical trials of rare tumors in pharmaceutical companies are at great risk from a variety of sources.
For example, in a targeted treatment clinical trial for FGFR bit variation in bile tube cell carcinoma, the candidates and researchers experienced difficulties with an average group rate of 0.1 patients per center per month.
, without policy support for similar orphan drugs and relatively strong research and development capabilities, the vast majority of clinical studies of rare tumors may not be possible.
It is worth mentioning that China's attention to rare diseases is quite high, there are many policy tilts, such as rare disease drugs can be imported in special batches, without the approval of the Drug Enforcement Administration can be imported directly into a specific population for use, but also prove that the national level has never given up any one patient.
platform research is on the rise: a new opportunity in the context of precision medicine to think about the clinical needs of the real world to be met, deep-seated academic innovation, in order to go faster and farther.
with the widening of cognitive boundaries and the new era of immunity and targeting of tumor therapy, new treatment methods have also achieved some efficacy in some rare tumors.
2019, the American Society of Clinical Oncology (ASCO) released its 14th annual report on cancer progress, making the progress of the treatment of rare tumors the largest advance in the 2018 cancer session.
On April 15, 2020, Canser, the official journal of the American Cancer Society (ACS), published a special issue of Rare Tumors in China online on its official website, which includes a review and six original studies covering clinical experience and exploration of rare tumors such as gastrointestinal mesothelioma, renal cell carcinoma, neuroendocrine tumors, and soft tissue tumors.
Medical College Oncology Hospital has also carried out a lot of clinical studies on tumor types with relatively low incidence, such as the anti-angiogenic drug atrogenesis developed by Zhengda Tianqing, the research and development phase opened a total of about 15 adaptations, including the relatively rare soft tissue sarcoma, Phase I studies observed patients reached SD, Based on this timely adjustment of research direction, anchoring this rare disease, the researchers successfully promoted soft tissue sarcoma to become the third adaptive disease approved after NSCLC and SCLC, and atrotinib also became the first approved targeted treatment drug in the field of soft tissue sarcoma in China.
Joyingly, with the spread of precision medicine concepts and the transformation of clinical trial design models for the same-disease treatment and hetero-treatment, the GCP Center is also planning to conduct a Platform (Plateau) study that combines basket and umbrella trials in the hope of exploring the effectiveness of existing drugs for targeted treatment of rare tumors.
Wang Shuhang conducted a study that compared the occurrence of rare tumor treatable targets in the defined cBioPortal database and the Chinese-group database, and found that the Chinese groups were significantly higher than the overall population (53.43% 701/1312 vs. 20.40% 1000/4901), and the occurrence rate of variations in groups Chinese is more than three times (32.4%) of the world population in groups of CBioPortal that are currently targeted by targeted drugs approved for adaptation (ALK, BRAF, BRCA2, CDKN2A, EGFR, HER2, KIT, MET, ROS1).
follow-up studies suggest that this option is feasible, it is equivalent to finding potential treatment options for this group of forgotten people under existing conditions.
1: Actionable target variation rate in cBioPortal and Chinese groups Figure 2: China's head and neck glandular adenocarcinoma action target variation rate of 20.2% (including FGFR2, BRAF, FGFR1, ERBB2, EGFR, CDKN2A, BRCA1, etc.)