Multidisciplinary therapy strategy of precision medicine in clinical practice

Abstract The application of precision medicine concept in clinical work needs a period of practice and experience accumulation. The present article introduced an example of functioning approach named “multidisciplinary therapy strategy of precision medicine” (MDTS‐PM), clinical practice and process, decision‐making, and therapies. The MDTS‐PM integrates multidisciplinary experts and develops real‐time therapeutic strategy based on clinical phenomes and gene sequencing of tissue DNA and circulating DNA. The strength of MDTS‐PM is the combination of dynamical clinical phenomes, genetic information, diagnosis, and treatment to make the therapy more targeted and specific. MDTS‐PM provides comprehensive, whole‐process, and personalized diagnosis and treatment services for patients with complex cancer or complex drug resistance progression; provides guidance for further adjustment of drug use; and establishes a multidisciplinary cooperative team, improves the quality of clinical diagnosis and treatment, and optimizes the process of medical services.


INTRODUCTION
Precision medicine is an emerging discipline of prevention and treatment strategies to translate the molecular approach into precise target therapy for inherited genetic disorders and cancers. 1 Using clinical trans-omics to integrate clinical phenomes with molecular multi-omics, disease-specific biomarkers and therapeutic targets can be identified and validated to This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics find the causes of diseases and improve precise diagnosis, treatment, and prevention for specific patients. 2 Based on comprehensive molecular phenomes and characterizations of lung cancer (eg hereditary and somatic gene changes, mutation, and heterogeneity), we developed target-driven therapies and strategies and proposed the precise self-validation system named "Zhongshan strategy of precision medicine" as one of precision medicine approaches. 3 The proposed strategy suggested to treat patients according to cancer gene mutations and heterogeneity, after the validation of target therapy in the patient's own cancer cells or in patient-derived xenografts using their own cancer cells. The current article presents an approach of clinical precision medicine named "multidisciplinary therapy strategy of precision medicine" (MDTS-PM) to provide comprehensive, whole-process, and personalized diagnosis and treatment services for patients with cancer, and improve the level of clinical diagnosis and treatment as well as the quality of medical services.
The clinical practice of MDTS-PM is fully dependent upon the needs of patients in disease diagnosis and treatment. The MDTS-PM team includes the experts from different disciplines, for example, oncology, general medicine, radiology, pathology, biochemistry, genetics, bioinformatics, surgery, and pharmacology, to combine multidimensional specialties and provide diagnosis and treatment together. More precision medical analysts help to interpret gene data, and assist doctors to formulate treatment plans. Therapeutic strategy of precision medicine was designated and discussed on the basis of clinical phenomic profiles, including patient complaints, signs, pathological imaging, biochemical measurements, radiomic profiles, and gene heterogeneity, copy number, and mutations. The present article introduced an example of MDTS-PM functioning approach, clinical practice and process, decision-making, and therapies.

COLLECTION OF CLINICAL AND MOLECULAR PHENOMES
According to the MDTS-PM approach, the expert group received requests by doctors from different departments (such as departments of oncology, respiration, hepatobiliary surgery, etc) to recommend patients with gene sequencing reports. The important variant genes of patients were analyzed by the expert group to provide the suggestions about targeted drugs, chemotherapeutic drugs, and other appropriate therapies. The MDTS-PM team established a real-time function of data sharing and mining to collect clinical and molecular phenomes.
For example, a patient, 51-year-old male, was suffering from the onset of lower back pain for 2 weeks and had the first visit at the clinic in September of 2018. Multiple metastatic tumors in the thoracic 11-sac1 intervertebral were demonstrated by magnetic resonance imaging (MRI). The patient smoked for more than 20 years, 20 cigarettes per day. His father had a kidney transplant for chronic nephritis and uremia, took oral immunosuppressants, and developed bladder cancer 10 years later. The Eastern Cooperative Oncology Group (ECOG) score was 1, body mass index 24.5 kg/m 2 , and numeric rating scale score 3. The image of positron emission tomography (PET)/computed tomography (CT) scan demon- strated multiple tumors in the dorsal segment of the lower lobe of the right lung, multiple lymph node metastases in the mediastinum and the right hilum, multiple glassy nodules in the upper lobe of the right lung, tumor in the brain, bilateral pleural effusion, thickened gastric wall in the pylorus of the stomach, and increased metabolism and multiple bone metastases in the whole body. Thoracolumbar resection and reconstruction of internal fixation were performed and pathology demonstrated metastatic large-cell neuroendocrine carcinoma 1 month after onset, as detailed in Table 1. Epidermal growth factor receptor L858R mutation was defined by gene sequencing 2 months after onset, then gefitinib-targeted therapy at a dose of 250 mg/day was started, and zoledronic acid bone repair therapy at 4 mg per time was given regularly. Patient felt a significant improvement of lower back pain and CT image showed the lesion was smaller in 3 months after onset. Nine days later, the patient's cough and pain in the ribs and hip bone became worse and cranial enhanced MRI showed multiple intracranial metastatic tumors. Four months after onset, the cough and bone pain of the patient aggravated. At this time, PET/CT images of the patient showed that the metastasis increased in multiple bones, liver, brain, left submaxillary lymph nodes, spleen, and left adrenal gland, during which the patient was diagnosed as a progressive disease. The overview of PET/CT images of the brain, pelvic, and chest are shown in Figure 1. PET/CT images of the chest and abdomen are shown in Figure 2.

DISCUSSION OF MDTS-PM TEAM
The meeting of MDTS-PM was held 4 months after the onset to discuss whether the patient had resistant genes against tyrosine kinase inhibitors (TKI), L858R can be used as a therapeutic target in this particular tumor, the chemotherapy regimen for non-small cell lung cancer (NSCLC) or chemotherapy regimen for small cell lung cancer (SCLC) should be combined with targeted therapy, as well as radial and lumbar radiotherapy is required. The special concern was whether there was the most precise treatment for the patient with large-cell neuroendocrine carcinoma. In this case, the neuroendocrine carcinoma was mixed with adenocarcinoma, more dangerous than adenocarcinoma alone and more difficult to be treated. The patient had the EGFR L858R mutation of adenocarcinoma, and developed the rapid drug resistance against TKI probably due to the combination of neuroendocrine carcinoma and adenocarcinoma. RB1 mutation is common in SCLC, while neuroendocrine cancer also has certain biological characteristics of SCLC. 4 With the progression of the disease, mutations of EGFR L858R, PIK3CA H1047R, and ERBB2 S310F were detected in punctured lumbar tissues, and EGFR L858R and PIK3CA H1047R in ctDNA, consistent with the pathological characteristics of adenocarcinoma. It was proposed that the neuroendocrine carcinoma in the patient might be the type II pulmonary largecell neuroendocrine carcinoma, which is enriched for biallelic inactivation of TP53 and RB1, different from type I with biallelic TP53 and STK11/KEAP1 alterations. 5 Mutations of EGFR and PIK3CA H1047R were considered to be associated with the rapid development of drug resistance and disease progression, as TKI treatment is not effective for patients with such mutation. 6,7 The patient also had HER2 mutations, which may also contribute to the rapid tumor cell growth by activating HER2-encoded growth factor receptor-related protein.
Considering the molecular mechanism, The PIK3CA inhibitor may improve PIK3CA mutation-induced TKI resistance, as the patient had PIK3CA exon 20 mutation. However, the PIK3CA inhibitor is still in the clinical trials and is mostly used in breast cancer, so the clinical evidence for other tumors needs to be furthermore confirmed. 8 The missense mutation of c.3140A>G;p.H1047R at 1047 of exon 21 of PIK3CA gene was detected in the patient, which was recorded for 2852 times in the Catalogue of Somatic Mutations in Cancer database, including 1632 times for breast cancer, 434 times for colorectal cancer, 183 times for endometrial cancer, 110 times for ovarian cancer, and 72 times for soft tissue sarcoma. PIK3CA as an isoform member of the PI3K family is a common somatic mutant oncogene with a high mutation rate in various tumors, such as 32% in colon cancer, 4-25% in stomach cancer, 8-40% in breast cancer, 5-27% in meningeal cancer, 4-25% in ovarian cancer, 11% in head and neck tumor, T A B L E 2 Categories of functional clusters, number and characteristics of altered genes, potential correlations with therapies, and list of key findings in the patient  6,7 Common mutations of PIK3CA, for example, E542K, E545K, and H1047R, could increase lipid kinase activity, activate the downstream AKT signaling pathway, and enhance tumorigenicity. 6 It is challenging to define roles of PIK3CA mutations in the patients due to the complexity and specificity of PI3K isoform genes in transcriptional regulations and interactions during cell growth and proliferation. 9 It is hard to clarify passive and negative regulations among PI3K-associated target signal factors and select PI3K function-specific inhibitors. For example, EGFR-vIII mutation was found to negatively regulate gene expression of H2AZK4/7AC, H3K27AC, and ubiquitin-specific protease 11 through the PI3K/AKT-histone deacetylase2 axis. 10 RB1, a tumor-suppressor gene and negative regulator of cell cycle, regulates phosphoprotein in the nucleus through PB1-encoded protein that contains n-terminal, A/B pocket, and c-terminal domains. Of those, the n-terminal  domain plays a key role in the inhibition of tumor growth through the P16/CyclinD/CDK4/RB/E2F pathway, during which dephosphorylation or hypophosphorylation of RB binds to intracellular transcription factor (E2F) and inhibits gene transcription. 11 Mutation in RB1 gene losses the activation, prevents cells from S phase, and leads to the occur-rence of lung cancer. There is no effective drug treatment for patients with RB1 gene mutation clinically. p53 Mutations exist in most of the cancers, responsible for cancer cell resistance to drugs, which depends upon properties of anticancer drugs, biological functions of therapeutic targets, and mechanisms of interactions between drugs and targets. It was suggested that p53 mutations could alter molecular networks, dysregulate p53-associated signal pathways, and cause drug resistance-associated clinical manifestations. 12 We noticed that the degree of p53 mutation in the patient increased with the development of target drug resistance, indicating the urgent need of new targeted antitumor drugs and strategies, to improve the efficacy of the therapy. The experimental evidence showed that p53 mutation per se could cause probably the secondary changes in chemical structures and properties of PI3K subunit proteins or in interactions and intercommunications between p53 and PI3K isoform genes. 13 The p53-dependent cell sensitivity varied among target specificities, drug chemical properties, mechanism-specific signal pathways, and drug efficacies. In this patient, we found that drugs induced the occurrence of new p53 mutations and increased the number of p53 F I G U R E 4 Imaging phenomes of positron emission tomography/computed tomography (PET/CT) 9 months after onset. Compared with the PET/CT images of 4 months after onset, the lesions in the lower lobe of the right lung were smaller than before. The glucose metabolism in the lymph nodes of the right upper mediastinal increased. The remaining diseased lymph nodes and left adrenal metastases were significantly reduced and glucose metabolism was significantly decreased. The tumor activity of brain, liver, and spleen metastases was inhibited. Multiple bone metastases all over the body were improved, the second lumbar tumor metabolism was active, and the glucose metabolism in residual bone disease foci was significantly decreased compared with the previous one. A, Overview of PET/CT images. B, PET/CT images of the brain. C-F, PET/CT images of the chest F I G U R E 5 Changes of PET/CT results. The changes of PET/CT results including brain, neck, chest, abdomen, and pelvic are shown in the graph. After treatment, the images of 4 months after onset compared with the results of 9 months after onset, most lesions were smaller than before, or even not detected F I G U R E 6 Changes of inflammatory and tumor markers. A, Changes of inflammatory markers including CRP, ESR, PCT, and lymphocyte% after 4/5/6/7/8/9/10 months after onset. B, Changes of tumor markers including CEA, CA199, NSE, CYFRA21-1, HE4, and SCC after 4/5/6/7/8/9/10 months after onset mutation, probably leading to the real-time occurrence of cancer cell resistance to a period treatment with drugs. We believe that comutations of p53, PIK3CA, and PB1 may play an important role in the development of drug resistance in the patients and be a new breakthrough point for new therapeutic strategy.

NOVEL TREATMENTS RECOMMENDED BY THE MDTS-PM TEAM
One of the critical missions from MDTS-PM team provides the recommendation of the new therapeutic strategy in clinical practice. For example, RB1 gene mutation was detected in the patient with neuroendocrine carcinoma and adenocarcinoma by gene sequencing, indicating the biological characteristics of small-cell lung cancer. Etoposide and cisplatin (EP) chemotherapy was recommended in this stage. On basis of the high abundances and co-existence of EGFR L858R and HER2 mutation as one of the adenocarcinoma properties in the patient, the combination of dual inhibitors targeting EGFR and HER2 tyrosine kinases was recommended. The targeted therapy of second-line afatinib (40 mg/day) was also applied, as accompanied with local radiotherapy and analgesic treatment. Dynamic monitoring of ctDNA sequencing, especially those mutated genes detected, for example. EGFR and HER2 genes, was highly recommended. Since the gene sequencing reports are always complicated, for example, the team received another patient with EGFR L858R detected in tissue while not detected in blood, then how to choose the next

Term Definition
Clinical phenomes A series of abnormal changes in the body of a patient that include general signs, pathological manifestations, imaging manifestations, inflammatory indicators, and tumor markers.

Molecular phenomes
A series of changes in genes that include hereditary and somatic gene changes, mutation, and heterogeneity.

Precision medicine
Precision medicine is based on the internal biological information and clinical symptoms and signs of the patient to implement personal health care and clinical decision-making for patients.

Target therapy
Treatment at the cellular and molecular level for known carcinogenic sites.