Rare tumors: a blue ocean of investigation

Abstract

Advances in novel drugs, therapies, and genetic techniques have revolutionized the diagnosis and treatment of cancers, substantially improving cancer patients’ prognosis. Although rare tumors account for a non-negligible number, the practice of precision medicine and development of novel therapies are largely hampered by many obstacles. Their low incidence and drastic regional disparities result in the difficulty of informative evidence-based diagnosis and subtyping. Sample exhaustion due to difficulty in diagnosis also leads to a lack of recommended therapeutic strategies in clinical guidelines, insufficient biomarkers for prognosis/efficacy, and inability to identify potential novel therapies in clinical trials. Herein, by reviewing the epidemiological data of Chinese solid tumors and publications defining rare tumors in other areas, we proposed a definition of rare tumor in China, including 515 tumor types with incidences of less than 2.5/100 000 per year. We also summarized the current diagnosis process, treatment recommendations, and global developmental progress of targeted drugs and immunotherapy agents on the status quo. Lastly, we pinpointed the current recommendation chance for patients with rare tumors to be involved in a clinical trial by NCCN. With this informative report, we aimed to raise awareness on the importance of rare tumor investigations and guarantee a bright future for rare tumor patients.

Keywords

rare tumors / diagnosis flowchart / treatment strategy / clinical trials recommendation

1 Introduction

With the development of cutting-edge sequencing techniques and novel therapies, the survival of cancer patients has been substantially prolonged over the past decades. However, rare tumors have always been the Achilles’ heel of modern medical practice. The definition of rare tumors was the first issue encountered. To accurately define rare tumors, most countries adopt incidence rates rather than the prevalence, which is commonly used to define rare diseases. However, due to the drastic differences in genetic background, living environment, and lifestyle across populations, the incidence and molecular underpinnings of rare tumors vary substantially. Consequently, regional disparities in rare-tumor lists arise across countries, and a unanimous definition of rare tumor that can be accepted worldwide is lacking [1–4]. In the US, according to the Food and Drug Administration (FDA) and National Cancer Institute [5], rare tumors are defined as those with an incidence of less than 15/100 000 per year [1]. In Europe, the European Society for Medical Oncology and European Medicines Agency defined cancers with an annual incidence of less than 6/100 000 as rare tumors [2]. In China, as defined previously by our group, the threshold of rare tumors incidence is 2.5/100 000 per year after a comprehensive analysis based on the epidemiological data and the current availability of standardized treatments in China [3].

Rare tumors are few in number, but they have investigation value. Biologically or medically significant discoveries have been made through research on rare tumors, thereby further deepening our understanding of the mechanisms of tumorigenesis. The best-known example is that the study of retinoblastoma has led to the discovery of RB1 and the double-hit hypothesis [6]. However, knowledge on rare tumors is being gained slowly due to several reasons. Inadequate experience in most medical centers due to limited patient number constrains the clinicians’ knowledge of rare tumors, leading to misdiagnosis and delayed or improper treatment of patients. The hesitation of drug industries and researchers has further constricted the development of diagnosis, treatment, and management of rare tumors based on evidence from translational studies and randomized controlled trials (RCTs). Nowadays, rare tumors are gaining increased attention, but an underlying unmet need for clinical trials is a challenge faced by rare-tumor research, such as the shortage of centers of excellence for rare-tumor enrollment, an updated consensus for treatment, proper recommendations for participation in clinical trials, appropriate preclinical research models, funding agencies, public awareness, attention of policymakers, and an overall knowledge base.

Herein, we summarized the current status of rare-tumor research and management in China and worldwide. Guideline recommendations were proposed for the diagnosis and treatment of listed rare tumors, and appropriate ways for clinical-trial consultation were clarified. We aimed to inspire more potential multilateral trials for developing novel therapies, solving the problems faced by traditional rare-tumor studies.

2 Definitions of rare tumors

Currently, although no commonly accepted definition exists for rare tumors, three different types of cancer can be considered as “rare.” First, cancers that arise from uncommon anatomic sites or of unusual histological types are conventionally considered rare. Examples include cancers of the small intestine, anus, gallbladder, chondrosarcoma, osteosarcoma, retinoblastoma, and liposarcoma, as well as neuroendocrinal tumors of the colorectum, etc. Second, certain common cancers having a drastically low incidence in specific populations can be considered as rare. For instance, breast cancer, the most prevalent cancer among females, is considered to be a rare cancer in males due to its considerably low incidence. Other examples include renal cell carcinoma and hematological malignancies such as multiple myeloma/plasmacytoma and diffuse B cell lymphoma, which are considered rare in Europe but common in the US [4,7]. Lastly, cancers with unknown primary sites (CUPs) can also be characterized as rare tumors, and they also require specialized attention and treatments. Nevertheless, due to the limited authorized data and the lack of a gold standard in determining molecular subtypes in most cancers, recent nationwide studies in Western countries that categorize rare tumors are primarily based on traditional anatomical and histological methods. Considering the substantial heterogeneity of rare tumors across populations and geographic regions, sorting out country-specific rare-tumor catalogs has great significance in laying a solid foundation for practicing precision medicine and performing regionally specific clinical trials.

Current definitions for rare tumors have been established based on incidence instead of prevalence in most countries. The reason why prevalence, an extensively used indicator for defining rare diseases, is not applicable for rare tumors is that prevalence is determined by incidence and survival, yet life expectancy across cancer patients tends to vary dramatically. In the US and Europe, the National Cancer Institute and RARECARE consortium define rare tumors by adopting different cutoff values of annual incidence (15/100 000 and 6/100 000, respectively). Some even further define cancers with a prevalence of less than 2000 or an incidence of fewer than 2 cases per 100 000 individuals as ultrarare tumors [8]. Notably, the cutoff incidence value for defining rare tumors should vary depending on specific populations because this value is set manually to serve as a reference. In particular, the cutoff values should be set based on the epidemiological data collected locally. These values are influenced by various factors such as population base, ethnic structure, and local environment. Thus, they are associated with the carcinogen exposure experienced by patients and show significant regional disparities.

In the case of testicular cancer, statistics from the UK suggest that testicular cancers are common among men aged 20–34 years with an incidence rate of 20/100 000. However, this type of cancer is defined as rare because in the entire population, its incidence rate is only 3.3/100 000 [9,10]. Cancer types are also unevenly distributed across countries and regions. Certain cancers are considered rare in one country but common in another, such as nasopharyngeal cancers. Therefore, investigating the country-wide epidemiological data of different cancer types and classifications is necessary before establishing local definitions for rare tumors.

For rare tumors in China, after consulting with the Registration Office of the China National Cancer Center, an annual incidence of 2.5/100 000 is selected as the cutoff incidence value for “rare tumors” for cancers with unique ICD codes listed within systems or organs. Accordingly, we searched OncoTrees to further investigate the subtypes of common cancers either with a distinct ICD code or an annual incidence > 2.5/100 000 in China. Conversely, subtypes of cancers with an annual incidence of ≤ 2.5/100 000 in China were included after further confirming the incidence by searching the PubMed database and the China National Knowledge Infrastructure database. CUPs were also included because their incidences met our cutoff value and no consensus or guidelines for treatment are available for them in China [3]. Finally, 515 rare tumor types were collected in total. Similar to the European rare-tumor list built by RARECARE, we classified the Chinese rare-tumor list into three layers based on a combinatory characterization of ICD-O morphology and topography (Table S1) [11]. In particular, the second layer, which provides a reference for clinical management and the development of therapeutic drugs, comprised 133 rare tumor types exhibiting the great potential to serve as the targets for clinical trials and novel therapies. Establishing a bibliography for rare tumors in China can produce an authentic source for clinical diagnosis and treatment and provide the groundwork for further trial-based investigations.

Notably, according to the above definition, most pediatric cancers fell into the category of rare tumors in China [12].

3 Current state of rare-tumor diagnosis and treatment in China and worldwide

Numerous patients suffer from rare tumors globally. Although considered “rare,” rare tumors collectively account for around 24% of all cancer diagnoses in Europe [7] and 20% in the US [4]. Unfortunately, the five-year survival rates of such tumors range from 15% to 20%, lower than those of common cancers [4]. Simple categorization of rare tumors based on epidemic statistics is insufficient to reflect their high heterogeneity and fails to accommodate sufficient clinical and pathological information, which is critical for diagnosis, subtyping, and making treatment recommendations for these diseases. With the advancements in sequencing and computing technologies, molecular tools are becoming increasingly important for facilitating pathology confirmations and for identifying potential target genes. Herein, we created a flowchart for the diagnosis of newly identified rare-tumor patients based on the consensus in rare-tumor investigations (Fig.1). As emphasized in the flowchart, pathologic and molecular examinations should be utilized essentially, along with supportive genome-wide sequencing technologies, when necessary, to report rare tumors with abundant information to support further differential diagnosis and guide specific therapies. The degree of malignancy could always be indicative of the necessity for further pathology and molecular examinations. Based on the estimated 5-year relative survival rate for rare tumors from the National Cancer Centre, we summarized the distribution of rare-tumor survival rates and emphasized the tumors with the worst prognosis (Fig.2). Notably, rare tumor from digestive, hematopoietic, genital, or other origins had worse outcomes than the rest. Ten rare diseases having less than 20% 5-year relative survival rates are also listed in Tab.1.

After making precise diagnoses on the eligibility and class of rare tumors, selecting effective treatment strategies for rare tumors appears to be more critical, representing another difficulty in the field of rare-tumor management. Based on our review, < 40% of rare tumor types are covered by the National Comprehensive Cancer Network Clinical Practice Guidelines (NCCN Guidelines) for oncology or the Chinese Society of Clinical Oncology diagnosis and treatment guidelines. Further analysis of these recommendations showed that most treatments focused on patients at earlier stages (1st line (539/965, 55.9%), 2nd line (363/965, 37%), 3rd line or later stages (63/965, 6.5%) in the NCCN Guidelines; 87/142 (61%), 55/142 (38.7%), and 10/142 (7.0%), respectively, in the CSCO guidelines). Among the 133 types of cancer included in the rare-tumor list of China, up to 60 lacked treatment guidelines recommended by NCCN or CSCO. Even for those covered by the guidelines, most recommendations fell into Category 2A (Fig.3). Examples included the recommendation of using cisplatin to treat undifferentiated carcinoma of nasal cavity and sinuses [13–19], prostate small-cell carcinoma, carcinoid of the lung, and epithelial tumors of major salivary glands [9,20–33]. By contrast, breast and prostate cancers, the most common cancers affecting women and men, respectively, had over 20 Category 1 interventions in the NCCN Guidelines [34].

We further looked into the current representative treatments supported by their recommendation levels (level 1) in rare tumors (Fig.4). Chemotherapy was the mainstream option to treat rare tumors, and the major classes of chemo-drugs were those utilized frequently (e.g., G, gemcitabine; P, platinum; and E, etoposide). Targeted therapies primarily focused on actionable mutations in MET, NTRK, and other genes in lung tissues. For immunotherapy, MSI-H/dMMR and a high PD-L1 CPS score were considered the prerequisites. Detailed information on recommended treatments for rare tumors and their efficacies tested in clinical trials are summarized in Table S2 based on updated NCCN and CSCO guidelines. The numbers of recommendations from NCCN and CSCO for rare tumors that had treatment guidelines were limited. The recommendations supported by high-quality evidence were even sparser. This problem was more serious in China, highlighting the need for more attention and trial-based data.

4 Challenges in rare tumors: the treatment strategies are also “rare”

For the majority of rare tumors lacking treatment recommendations, clinical practitioners tend to resort to standardized treatment options or use the solutions for their more common counterparts. However, the unique characteristics of rare tumors may prevent the standard therapies from producing a satisfying efficacy. For a minority of rare tumors, the discovery of their treatment strategies manifests a “byproduct” pattern, i.e., clinical trials for common cancers may have enrolled patients with wider and vague pathological classifications, thereby covering some uncommon cancer subtypes [34]. Given the absence of high-quality evidence-based interventions, a pressing need exists for more comprehensive, precise translational and clinical investigations that specifically focus on rare tumors, such as genetic-sequencing studies and drug trials. These investigations can fill the gap in current clinical guidelines and improve the situations faced by rare-tumor patients, especially in China.

For most rare tumors, sufficient evidence supporting the use of targeted therapies and immunotherapies is lacking (Fig.3 and Table S2). Among 76 cancer types in the Chinese rare-tumor list with treatment guidelines recommended by the NCCN, targeted therapy was recommended as the first-line treatment for only 38 tumor types (50%) and the second- or third-line treatment for 30 tumor types (39.5%). Taken together, among 133 rare tumors, 84 lacked recommended targeted therapies (63.2%). Taking the targeted-therapy recommendations for 49 cancers as an example, most of them fell into the 2A category (73% in NCCN and 35% in CSCO). We summarized the currently approved targeted therapies (Tab.2 and S3). Notably, most of these recommendations were indeed extrapolated from the clinical evidence obtained from common cancers. Taking lung sarcomatous carcinoma, a typical rare tumor originating from the lung, as an example, current NCCN guidelines recommend first-line therapies of osimertinib, dacomitinib, and erlotinib. These recommendations are essentially made based on clinical evidence from drug trials for non-small-cell lung cancer [35–37]. Two other therapies for lung sarcomatous carcinoma, afatinib and gefitinib, are actually candidate drugs for lung adenocarcinoma [38–41]. Given that the pathogenesis of several rare tumors is driven by specific genes, developing targeted therapies to treat these diseases especially soft tissue sarcomas is reasonable. For example, given that more than 70% of medullary thyroid cancer (MTC) cases are driven by alterations in the proto-oncogene rearranged during transfection (RET), a trial LIBRETTO-001 testing the efficacy and safety of selpelcatinib, an oral MET inhibitor, for MTC treatment was conducted. Results show that the MTC subgroup treated with selpelcatinib has an objective response rate (ORR) of 64% and a one-year disease-free survival (DFS) rate of 82%, whereas pemetrexed-based chemotherapy has only 40%–50% ORR and PFS around 4–9 months [42,43]. Another success has been witnessed in a basket trial for crizotinib, an inhibitor of multiple kinases (ALK, MET, ROS1, and RON) in patients with inflammatory myofibroblastic tumor. Crizotinib achieves an ORR of 66.7% in the ALK-positive group compared with 14.3% in the ALK-negative group, and the 3-year overall survival (OS) rates are 83.3% versus 34.3%, respectively, in these groups [44,45]. These encouraging results seen in rare tumors with druggable mutations enlighten the exploration of precise therapies with limited accruals. In our previous study, we have comprehensively analyzed the genomic profiles of rare tumors in Chinese population and compared them with data from foreign studies deposited in cBioPortal. Results show that the prevalence of targetable genomic alterations in rare tumors is considerably high worldwide and even higher in Chinese population [3]. Combining this information with novel trial design, we have initiated an open label, multi-arm PLATFORM trial for patients with advanced rare-solid tumors (NCT04423185). Therapies have been given to patients involved in this trial based on their targetable genome mutations [3]. Similar trials have been opened in other countries (Japan, USA, Denmark, etc.), suggesting an actionable tactic in developing efficacious treatments for patients with rare tumors (Fig.5).

As for immunotherapies of rare tumors, although immunotherapies blocking PD-1/PD-L1 have benefited many cancer types and shown promising efficacies in rare tumors as well, evidence from clinical trials guiding the use of immunotherapy remains scarce (Table S4) and originates mostly from trials of drugs with wide-ranging indications. For example, pembrolizumab has been approved for the treatment of patients with unresectable or metastatic tumor mutational burden-high (TMB-H) (≥ 10 mutations/mega base (mut/Mb)) or MSI-H/dMMR solid tumors that have progressed following prior treatments and no satisfactory alternative treatment options. Additionally, some phase I/II studies also suggest that immune checkpoint inhibitors (ICIs) could achieve objective responses in some rare tumors. Recently, a phase II clinical trial evaluating the effectiveness and safety of Keytruda (pembrolizumab) in advanced rare tumors (squamous cell carcinoma of the skin; two types of cancer that arise in the adrenal glands above the kidneys, namely, adrenocortical carcinoma and paraganglioma-pheochromocytoma; and carcinoma of unknown primary, which may affect various organs) has exhibited favorable outcomes in patients recruited based on an interim analysis. This finding suggests a much-needed and ideal clinical treatment option for this patient population [46]. A similar attempt has been made in soft-tissue sarcomas (myxofibrosarcoma, undifferentiated pleomorphic sarcoma, cutaneous angiosarcoma, and undifferentiated) and has been approved based on this small-sample-size, phase-II-trial data, in patients with advanced/metastatic soft tissue sarcoma (STS) who failed first-line therapy [47,48]. Due to the heterogeneity of rare tumors, evaluating potential markers such as PD-L1 expression, tumor mutational loads, expression of neoantigens, and tumor immune microenvironment in rare tumors is necessary for the selection of candidate tumor types and prediction of treatment efficacy. Sporadic reports based on samples with small sizes have addressed these issues, but the conclusions remain ambiguous. One study has shown that NY-ESO-1 antigen is aberrantly expressed on metastatic synovial sarcoma cells, and these patients have an objective partial response after receiving the treatment of tumor-infiltrating lymphocytes. However, the poor statistical power caused by the small sample size weakens the evidence of that study [49]. Another work by our group has summarized data from 852 rare tumor patients in China and found that the PD-L1 expression and rates of TMB-H, MSI-H, and HLA-I-heterozygous are relatively high (47.8%, 15.5%, 7.4%, and 78.9%) [3]. These studies provide a strong rationale for adopting immunotherapies (mostly PD-1/PD-L1 blockades) in treating rare tumors at a large population scale. Meanwhile, the development of precise biomarkers is needed to predict an advantageous patient population that could benefit most from ICI treatments. Combination of immune checkpoint blocker with targeted drugs, primarily angiogenesis blocker, shows preliminary results in rare tumor such as alveolar soft-part sarcoma (axitinib plus pembrolizumab) [50], indicating the potential syngeneic effect of “improving tumor microenvironment” and worthy of further validation.

5 Clinical trials are recommended inclusively in guidelines as a treatment option

With the lack of high-quality evidence-based treatment plans, the importance of clinical trials as a practical solution has been emphasized. Aside from a general recommendation for clinical-trial enrollment noted in NCCN, patients with rare tumors are encouraged to participate in clinical trials with an elaborate design to improve their chances of survival. A total of 97 entries of recommendations for 61 rare tumors of 23 categories were mentioned with or without specific terms in the corresponding guidelines. Different levels of recommendation were observed: the highest priority was presented in 36.1% of the entries, 33.0% were recommended along with other treatments, and the rest had no current recommendation. Moreover, 71.1% of the total recommendations were proposed for the perioperative period, among which the strongest recommendations were available for preoperation or systemic therapies, especially for tumor metastasis (17 of 35 entries). Clinical trials should be considered as a later-line therapy under the circumstance of recurrent or refractory tumors, with other treatments recommended in combination.

For now, data from clinical trials are limited primarily due to the difficulty in patient enrollment, which reflects the current challenge faced in clinics, especially when providing specific recommendations for patients with rare tumors. For the majority of rare tumors that lack powerful evidence, we provided clinical-trial consultation at proper time points under specified treatment conditions with corresponding recommendation levels according to relevant NCCN guidelines (Fig.6). The aim was to provide essential information that could enable smooth clinical-trial enrollment and ultimately benefit patients.

To this end, real-world data may be able to provide a potential solution. Compared with traditional RCTs, real-world integrated data from uncontrolled trials and observational studies can circumvent the common problems of limited sample sizes. To date, valuable real-world data offering reference for making rare-tumor treatment decision have been integrated from a considerable number of research and clinical centers equipped with expertized and specialized facilities, such as those from the Stafford Fox Rare Tumor Program launched by the Walter and Eliza Hall Institute of Medical Research [51]. More large-scale programs supported by expertized centers and multicenter collaborations could intensively deepen our understanding of rare tumors and make room for the development of rare tumor therapies. Such studies are actually underway.

6 Conclusions

Taken together, numerous challenges are faced by rare-tumor researchers and clinicians, including a lack of clear definition and therapeutic guidelines, limited evidence for scientific diagnosis, treatment, and prognosis prediction, few novel therapeutic strategies, and insufficient samples for innovative investigations. Herein, we categorized 515 cancer types as rare tumors in China and summarized their current treatment strategies, ongoing studies, and proper time points for clinical trial enrollment. We aimed to provide an explicit protocol for rare-tumor diagnosis and treatment, inspire the enrollment of rare tumor patients for clinical trials, and update the innovative design of targeted therapies and immunotherapies based on genome sequencing techniques, hopefully improving the situations for rare tumor patients in a precise and efficient manner.

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