Precision cancer medicine in China: the Fudan University Shanghai Cancer Center experience

Introduction

Cancer is one of the major causes of death worldwide (1). In China, the incidence and mortality of cancer have also been increasing rapidly with the development of the country in recent decades (2). Founded in 1931, Fudan University Shanghai Cancer Center (FUSCC) was the first cancer center in China. Since its establishment, FUSCC has witnessed the development of oncology in China. And currently, FUSCC is one of the leading entities in the field of precision cancer medicine.

Clinicians have been seeking treatments to cure cancer for centuries. However, therapies for cancer may not only benefit patients but also result in concerning side effects. Chemotherapy, which still outperforms all other systematic medications in the management of cancer, is a representative treatment. As a less precise therapy, chemotherapy has demonstrated its efficacy but also produces unfavorable toxicity. Currently, clinicians are pursuing chemotherapy-free management for cancer patients to improve the therapeutic effect while reducing adverse events. Nevertheless, the lack of a thorough understanding of cancer and disjointedness between research and industry are still restricting this aspiration.

Modern cancer care has entered the era of precision cancer medicine, which has been one of the common views among oncologists. Many specific interpretations of precision cancer medicine exist, but precision cancer medicine is universally acknowledged to consider the optimal medication for patients (3,4). However, the heterogeneity of cancer constantly challenges its diagnosis and treatment. The combination of genetics, environment and lifestyle that induces cancer is unique for each patient (5-8). Among these three aspects, genetics is the most pivotal in tumor biology and the most targetable by clinical treatment. Thus, narrowly speaking, precision cancer medicine focuses on revealing the genetics of cancer and then treating it with targeted drugs (3,4).

Broad application of precision cancer medicine has demonstrated its clinical value in improving survival and reducing untoward effects. Taking breast cancer as an example, ERBB2 (erb-b2 receptor tyrosine kinase 2) is one of the major genes amplified in breast cancer, which indicates an unfavored prognosis (9,10). Before the development of monoclonal antibodies, patients with ERBB2 amplifications could only receive chemotherapy for systemic treatment, and the outcome was rather poor. Currently, with the establishment of a diagnostic system combining immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), these patients can be identified and benefit from targeted therapy such as Herceptin (11,12). With further research, more treatments targeting ERBB2, such as tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs), have been developed (13), which can further improve the prognosis of patients. Similar findings have also been reported in other malignancies, thus benefiting more patients (14-16).

As one of the major cancer centers across the country and the leading center in eastern China, FUSCC was one of the first to introduce the idea of precision cancer medicine in China. Since the new century, especially in the last 10 years, precision cancer medicine at FUSCC has entered a new stage, receiving acknowledgment both domestically and internationally. With continuous efforts, FUSCC has established a mature layout of precision cancer medicine covering some major kinds of cancers and has accumulated abundant practical experience that might substantially benefit our peers.

Focusing on the Chinese population

Nationality and race are both important factors in oncology research because they are related to populations’ different genetic backgrounds and unique behaviors (17).

For a long time, we have noticed a potential disparity in cancer patients’ genetics between China and the Western world, and we have been exerting constant effects in the Chinese population. BRIP1/BACH1 mutation is an important mechanism in disordered BRCA1-mediated DNA double-strand break repair in breast cancer among Western populations (18). In 2009, after analyzing genetic data collected from 357 Chinese breast cancer patients and 864 normal controls, we revealed that germline mutations in BRIP1/BACH1 were so rare in the Chinese population that, unlike in Western populations, BRIP1/BACH1 testing is not recommended (19). Then, we launched a larger program to screen BRCA mutations in 2,991 patients and 1,043 controls by next-generation sequencing (NGS) and ultimately established a comprehensive spectrum of BRCA1/2 mutations in the Chinese population. Based on this spectrum, we further proposed that breast cancer patients in China who are at high and moderate risk are strongly advised to undergo BRCA1/2 mutation testing (20).

Solid work has also been completed in the field of prostate cancer. The difference in the incidence of prostate cancer between Asia and the Western world is massive. In Europe and the US, prostate cancer accounts for nearly one-third of solid tumors in humans (21). In China, although the past two decades have witnessed a surge in its incidence, prostate cancer is still widely considered a low-incidence malignancy (22). This discrepancy indicates the disparity in innate characteristics of prostate cancer between Asian patients and Western patients (23). Based on data collected from the Chinese population, our Department of Urology has established a stromal immunotype suitable for Chinese muscle-invasive bladder cancer patients to predict their prognosis and chemotherapy response (24).

Sequencing techniques represented by NSG are core tools in precision cancer medicine research (25). The large-scale practice of precision cancer medicine relies on a series of sequencing products with high reliability, feasibility and practicability. However, mainstream sequencing tools such as MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) are rarely adopted for the Chinese population (26,27). To support precision medicine research and application in Chinese patients, FUSCC and CHGC (Chinese National Human Genome Center at Shanghai) cooperatively established the Precision Cancer Medicine Center (PCMC) in 2018. Based on the genetics of the Chinese population, the PCMC has developed diverse gene testing panels for prevailing malignancies, which show outstanding technical performance and impressive cost performance and are subject to independent intellectual property rights. Currently, PCMC is one of the leading providers in genetic testing, aiming to boost the translation of research advances and industrialize precision cancer medicine.

The establishment of the PCMC first facilitated our research in breast cancer, which has topped the list of women’s cancers in terms of incidence in major cities of China such as Shanghai (27). Breast cancer is highly heterogeneous and can be coarsely divided into several molecular subtypes (28). For a long time, no large-scale domestic genetic profiles were available for research, and we had to rely on foreign datasets. Thus, we categorized 484 genes closely related to precision therapy for breast cancer and established the first large-scale mutation landscape of Chinese breast cancer patients with more than 1,000 paired samples (29). Furthermore, we focused on TNBC (triple-negative breast cancer), which accounts for 15% of all breast cancer cases and has a poor prognosis due to a lack of specific targets, and established the world’s largest single-center multiomic cohort of TNBC patients (30).

From bench to bedside

We insist that research in precision cancer medicine should be a closed-loop system starting from patients (clinical problems) and ending with patients (clinical practice). A promising research system of precision cancer medicine should be renewable and constantly accommodate new scientific discoveries.

Based on our multiomic TNBC cohort, we proposed the Fudan Subtyping System to subdivide TNBC into four distinct molecular subtypes: luminal androgen receptor (LAR), immunomodulatory (IM), basal-like immune-suppressed (BLIS), and mesenchymal-like (MES) (30). To verify potential targets identified by data mining in each subtype, we launched a phase Ib/II, open-label, umbrella study named FUTURE to evaluate the efficacy and safety of multiple targeted treatments in patients with refractory metastatic TNBC. The outcomes of the study showed an impressive response of patients to the designated treatment (31).

During the follow-up of the FUTURE trial, we discovered that heavily pretreated patients in the C arm or the IM arm who received anti-PD-1 with nab-paclitaxel showed a significant increase in the ORR (objective response rate) compared with those who received traditional chemotherapy (31). Thus, we further tried to introduce the same medication as a first-line treatment for patients with unresectable locally advanced or metastatic IM TNBC (FUTURE-C-PLUS trial) (32). Additionally, we found that famitinib, a multitarget small-molecule inhibitor, was able to promote the infiltration of CD8⁺ cells and enhance PD-L1 expression without further increasing adverse events in a preclinical model (unpublished result). Thus, famitinib was also added to the treatment regimen. Recently, the FUTURE-C-PLUS trial reported exciting confirmed ORRs of 81.3% in the intention-to-treat population (n=48) and 84.8% in the per-protocol population (n=46) (32).

We are also investigating our largest original multiomics dataset of TNBC from more diverse perspectives to create a well-rounded system. The tumor microenvironment was reported to exert a profound effect on prognosis and immunotherapy (33). Therefore, we conducted an extensive immunogenomic analysis to explore the heterogeneity and prognostic significance of the microenvironment (34). We also sought to interpret TNBC metabolically. We investigated TNBC from a metabolic-pathway-based view and found that TNBC actually consists of three heterogeneous subtypes with distinct metabolic features (35). Of course, these preclinical results require further clinical verification, which is our current research objective.

Precision cancer medicine beyond genomics

Although genomics plays an essential role in precision cancer medicine, precision cancer medicine can never be restricted to pure genomics (3). Through extensive efforts, FUSCC has established several precise management systems for cancer patients.

Pancreatic cancer is widely considered “the king of carcinoma” due to its poor prognosis (36). Our Department of Pancreas Surgery has made constant efforts to revolutionize the management of pancreatic cancer patients requiring surgical therapy. The contradiction between the staging systems of European Neuroendocrine Tumor Society (ENETS) and American Joint Committee on Cancer (AJCC) once caused chaos in the field of pancreatic neuroendocrine tumors. In addition, we discovered loop holes in the AJCC and ENETS staging systems. Thus, we proposed our own staging system for pancreatic cancer, which was assessed as the Best of Journal of Clinical Oncology (JCO) and was among JCO’s Most-Accessed Articles (37,38). To solve the inability of the single biomarker CA19-9 to identify Lewis-negative patients, we established the triple CA19-9/CA125/CEA serum tumor marker system, which can discriminate patients who would have been missed. In addition, this system can help us identify patients who cannot benefit from surgery, which promotes personalized management of pancreatic cancer patients (39). We also explored mechanisms in patients unable to benefit from surgery from diverse molecular aspects, including the essential role of the KRAS/MEK/ERK axis (40-43), abnormal glucose metabolism (44-46) and the structure of caveolae (47,48). Through collective efforts, the PFS of pancreatic cancer patients after surgery in FUSCC has markedly improved from 14.4 to 23.6 months.

Lung cancer has long been the leading cause of death among all tumors (1). Ground-glass opacity (GGO), a hazy cloudiness observed on computed tomography (CT) images that does not obscure underlying bronchial structures or pulmonary vessels, is considered a possible sign of lung adenocarcinoma (49). With the increasing popularity of low-dose CT in lung cancer screening, proper management of GGO is rather challenging. Our Department of Thoracic Surgery developed a versatile system to address GGO comprehensively. We first proposed “minimally invasive thoracic surgery 3.0” worldwide, which pointed out the necessity of reducing systemic damage through comprehensive efforts (50). For instance, we demonstrated that facilitated by interoperative fresh-frozen pathology examination, not all peripheral small-sized lung adenocarcinomas require radical treatment (51,52). In 2017, this momentous result was introduced into the guidelines released by the European Society for Medical Oncology (ESMO) (53). Furthermore, we established “surgical strategies for pre- and minimally invasive lung adenocarcinoma 3.0” for the selection of optimal surgical timing, which include three rules, namely, (I) benign disease should not be treated as malignancy, (II) pre- and minimally invasive disease should not be treated as invasive disease, and (III) indolent malignancy should not be treated as aggressive malignancy (54). Guided by these strategies, we recommend a minimum follow-up of 4–6 months to avoid overtreatment for newly identified GGOs (55). We also demonstrated that lung adenocarcinoma with GGO cannot benefit from conventionally recommended examinations such as bronchoscopy, PET/CT, bone scanning or brain MRI, which can alleviate unfavorable physical, mental and economic impacts on patients (56-59).

Future development of precision cancer medicine at FUSCC

Guided by the idea of precision cancer medicine, FUSCC has substantially promoted the diagnosis and treatment of cancer. However, further efforts are required improve our practice and benefit a larger population.

More effective integration of industry, education and research is needed to boost precision cancer medicine. Our PCMC has had a good start, but we need to do more. Collaboration mechanisms must be established to facilitate the sharing of all kinds of medical datasets, which will facilitate the thorough utilization of such information. In addition, greater collaboration with pharmaceutical enterprises can realize rapid translation of scientific discovery into clinical application.

Precision cancer medicine should cover the stages of the human life cycle, including cancer consultation, prevention, diagnosis, treatment, recovery and hospitalization. For a long time, we limited precision cancer medicine to cancer diagnosis and treatment, which is not sufficient. For instance, with increasing attention from both physicians and patients and decreasing screening costs, precision cancer prevention (e.g., predictive genetic testing) will likely be more prevalent or even routine in the near future.

As the leading cancer center in eastern China and one of the pioneers of precision cancer medicine in the country, FUSCC is obliged to advocate this idea among other oncologists and cancer centers in China.

In China, the practice of precision cancer medicine still faces some setbacks. Although precision cancer medicine is a future trend, not all clinicians have realized the tremendous hit that it will cause to the current cancer management system. Meanwhile, with no systemic theories for reference, some entities diverged in the research and application of precision cancer medicine, causing colossal waste. Additionally, the disparity in health care levels among different regions and institutions is another major predicament. In top cancer centers such as FUSCC, where precision cancer medicine resources are more abundant, the prognoses of patients have approximately equaled international advanced standards. However, in some districts or regional hospitals, precision care is less accessible due to restrictions in testing equipment, and sometimes, even standard treatment guidelines are not sufficiently followed.

Collective efforts must be made to advance precision cancer medicine across the country. We will create platforms on which clinicians can communicate their practices and experiences, such as promoting the operation of the journal Precision Cancer Medicine, holding symposiums, and organizing visiting programs. In addition, we aim to provide public gene diagnostic tools and evidence-based guidelines to standardize the practice of precision cancer medicine. Finally, we hope to launch more large-scale multicenter studies to put precision cancer medicine into practice and cure more cancer patients.

Acknowledgments

Funding: This work was sponsored by Shanghai Sailing Program for Youth S&T Talents (20YF1408700).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Precision Cancer Medicine, for the series “Eastern and Western Perspectives on Precision Cancer Medicine”. The article has undergone external peer review.

Peer Review File: Available at: https://dx.doi.org/10.21037/pcm-21-26

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at: https://dx.doi.org/10.21037/pcm-21-26). The series “Eastern and Western Perspectives on Precision Cancer Medicine” was commissioned by the editorial office without any funding or sponsorship. Dr. ZMS serves as an unpaid Executive Editor-in-Chief of Precision Cancer Medicine and served as unpaid Guest Editor of the series. Dr. DM received sponsorship from Shanghai Sailing Program for Youth S&T Talents (20YF1408700). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects for the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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