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• v.28; Jan-Dec 2021

Cancer Biology, Epidemiology, and Treatment in the 21st Century: Current Status and Future Challenges From a Biomedical Perspective

Patricia piña-sánchez.

1 Oncology Research Unit, Oncology Hospital, Mexican Institute of Social Security, Mexico

Antonieta Chávez-González

Martha ruiz-tachiquín, eduardo vadillo, alberto monroy-garcía, juan josé montesinos, rocío grajales.

2 Department of Medical Oncology, Oncology Hospital, Mexican Institute of Social Security, Mexico

Marcos Gutiérrez de la Barrera

3 Clinical Research Division, Oncology Hospital, Mexican Institute of Social Security, Mexico

Hector Mayani

Since the second half of the 20th century, our knowledge about the biology of cancer has made extraordinary progress. Today, we understand cancer at the genomic and epigenomic levels, and we have identified the cell that starts neoplastic transformation and characterized the mechanisms for the invasion of other tissues. This knowledge has allowed novel drugs to be designed that act on specific molecular targets, the immune system to be trained and manipulated to increase its efficiency, and ever more effective therapeutic strategies to be developed. Nevertheless, we are still far from winning the war against cancer, and thus biomedical research in oncology must continue to be a global priority. Likewise, there is a need to reduce unequal access to medical services and improve prevention programs, especially in countries with a low human development index.

Introduction

During the last one hundred years, our understanding of the biology of cancer increased in an extraordinary way. 1 - 4 Such a progress has been particularly prompted during the last few decades because of technological and conceptual progress in a variety of fields, including massive next-generation sequencing, inclusion of “omic” sciences, high-resolution microscopy, molecular immunology, flow cytometry, analysis and sequencing of individual cells, new cell culture techniques, and the development of animal models, among others. Nevertheless, there are many questions yet to be answered and many problems to be solved regarding this disease. As a consequence, oncological research must be considered imperative.

Currently, cancer is one of the illnesses that causes more deaths worldwide. 5 According to data reported in 2020 by the World Health Organization (WHO), cancer is the second cause of death throughout the world, with 10 million deaths. 6 Clearly, cancer is still a leading problem worldwide. With this in mind, the objective of this article is to present a multidisciplinary and comprehensive overview of the disease. We will begin by analyzing cancer as a process, focusing on the current state of our knowledge on 4 specific aspects of its biology. Then, we will look at cancer as a global health problem, considering some epidemiological aspects, and discussing treatment, with a special focus on novel therapies. Finally, we present our vision on some of the challenges and perspectives of cancer in the 21 st century.

The Biology of Cancer

Cancer is a disease that begins with genetic and epigenetic alterations occurring in specific cells, some of which can spread and migrate to other tissues. 4 Although the biological processes affected in carcinogenesis and the evolution of neoplasms are many and widely different, we will focus on 4 aspects that are particularly relevant in tumor biology: genomic and epigenomic alterations that lead to cell transformation, the cells where these changes occur, and the processes of invasion and metastasis that, to an important degree, determine tumor aggressiveness.

Cancer Genomics

The genomics of cancer can be defined as the study of the complete sequence of DNA and its expression in tumor cells. Evidently, this study only becomes meaningful when compared to normal cells. The sequencing of the human genome, completed in 2003, was not only groundbreaking with respect to the knowledge of our gene pool, but also changed the way we study cancer. In the post-genomic era, various worldwide endeavors, such as the Human Cancer Genome Project , the Cancer Genome ATLAS (TCGA), the International Cancer Genome Consortium, and the Pan-Cancer Analysis Working Group (PCAWG), have contributed to the characterization of thousands of primary tumors from different neoplasias, generating more than 2.5 petabytes (10 15 ) of genomic, epigenomic, and proteomic information. This has led to the building of databases and analytical tools that are available for the study of cancer from an “omic” perspective, 7 , 8 and it has helped to modify classification and treatment of various neoplasms.

Studies in the past decade, including the work by the PCAWG, have shown that cancer generally begins with a small number of driving mutations (4 or 5 mutations) in particular genes, including oncogenes and tumor-suppressor genes. Mutations in TP53, a tumor-suppressor gene, for example, are found in more than half of all cancer types as an early event, and they are a hallmark of precancerous lesions. 9 - 12 From that point on, the evolution of tumors may take decades, throughout which the mutational spectrum of tumor cells changes significantly. Mutational analysis of more than 19 000 exomes revealed a collection of genomic signatures, some associated with defects in the mechanism of DNA repair. These studies also revealed the importance of alterations in non-coding regions of DNA. Thus, for example, it has been observed that various pathways of cell proliferation and chromatin remodeling are altered by mutations in coding regions, while pathways, such as WNT and NOTCH, can be disrupted by coding and non-coding mutations. To the present date, 19 955 genes that codify for proteins and 25 511 genes for non-coding RNAs have been identified ( https://www.gencodegenes.org/human/stats.html ). Based on this genomic catalogue, the COSMIC (Catalogue Of Somatic Mutations In Cancer) repository, the most robust database to date, has registered 37 288 077 coding mutations, 19 396 fusions, 1 207 190 copy number variants, and 15 642 672 non-coding variants reported up to August 2020 (v92) ( https://cosmic-blog.sanger.ac.uk/cosmic-release-v92/ ).

The genomic approach has accelerated the development of new cancer drugs. Indeed, two of the most relevant initiatives in recent years are ATOM (Accelerating Therapeutics for Opportunities in Medicine), which groups industry, government and academia, with the objective of accelerating the identification of drugs, 13 and the Connectivity Map (CMAP), a collection of transcriptional data obtained from cell lines treated with drugs for the discovery of functional connections between genes, diseases, and drugs. The CMAP 1.0 covered 1300 small molecules and more than 6000 signatures; meanwhile, the CMAP 2.0 with L1000 assay profiled more than 1.3 million samples and approximately 400 000 signatures. 14

The genomic study of tumors has had 2 fundamental contributions. On the one hand, it has allowed the confirmation and expansion of the concept of intratumor heterogeneity 15 , 16 ; and on the other, it has given rise to new classification systems for cancer. Based on the molecular classification developed by expression profiles, together with mutational and epigenomic profiles, a variety of molecular signatures have been identified, leading to the production of various commercial multigene panels. In breast cancer, for example, different panels have been developed, such as Pam50/Prosigna , Blue Print , OncotypeDX , MammaPrint , Prosigna , Endopredict , Breast Cancer Index , Mammostrat, and IHC4 . 17

Currently, the genomic/molecular study of cancer is more closely integrated with clinical practice, from the classification of neoplasms, as in tumors of the nervous system, 18 to its use in prediction, as in breast cancer. 17 Improvement in molecular methods and techniques has allowed the use of smaller amounts of biological material, as well as paraffin-embedded samples for genomic studies, both of which provide a wealth of information. 19 In addition, non-invasive methods, such as liquid biopsies, represent a great opportunity not only for the diagnosis of cancer, but also for follow-up, especially for unresectable tumors. 20

Research for the production of genomic information on cancer is presently dominated by several consortia, which has allowed the generation of a great quantity of data. However, most of these consortia and studies are performed in countries with a high human development index (HDI), and countries with a low HDI are not well represented in these large genomic studies. This is why initiatives such as Human Heredity and Health in Africa (H3Africa) for genomic research in Africa are essential. 21 Generation of new information and technological developments, such as third-generation sequencing, will undoubtedly continue to move forward in a multidisciplinary and complex systems context. However, the existing disparities in access to genomic tools for diagnosis, prognosis, and treatment of cancer will continue to be a pressing challenge at regional and social levels.

Cancer Epigenetics

Epigenetics studies the molecular mechanisms that produce hereditable changes in gene expression, without causing alterations in the DNA sequence. Epigenetic events are of 3 types: methylation of DNA and RNA, histone modification (acetylation, methylation, and phosphorylation), and the expression of non-coding RNA. Epigenetic aberrations can drive carcinogenesis when they alter chromosome conformation and the access to transcriptional machinery and to various regulatory elements (promoters, enhancers, and anchors for interaction with chromatin, for example). These changes may activate oncogenesis and silence tumor-suppressor mechanisms when they modulate coding and non-coding sequences (such as micro-RNAs and long-RNAs). This can then lead to uncontrolled growth, as well as the invasion and metastasis of cancer cells.

While genetic mutations are stable and irreversible, epigenetic alterations are dynamic and reversible; that is, there are several epigenomes, determined by space and time, which cause heterogeneity of the “epigenetic status” of tumors during their development and make them susceptible to environmental stimuli or chemotherapeutic treatment. 22 Epigenomic variability creates differences between cells, and this creates the need to analyze cells at the individual level. In the past, epigenetic analyses measured “average states” of cell populations. These studies revealed general mechanisms, such as the role of epigenetic marks on active or repressed transcriptional states, and established maps of epigenetic composition in a variety of cell types in normal and cancerous tissue. However, these approaches are difficult to use to examine events occurring in heterogeneous cell populations or in uncommon cell types. This has led to the development of new techniques that permit marking of a sequence on the epigenome and improvement in the recovery yield of epigenetic material from individual cells. This has helped to determine changes in DNA, RNA, and histones, chromatin accessibility, and chromosome conformation in a variety of neoplasms. 23 , 24

In cancer, DNA hypomethylation occurs on a global scale, while hypermethylation occurs in specific genomic loci, associated with abnormal nucleosome positioning and chromatin modifications. This information has allowed epigenomic profiles to be established in different types of neoplasms. In turn, these profiles have served as the basis to identify new neoplasm subgroups. For example, in triple negative breast cancer (TNBC), 25 and in hepatocellular carcinoma, 26 DNA methylation profiles have helped to the identification of distinct subgroups with clinical relevance. Epigenetic approaches have also helped to the development of prognostic tests to assess the sensitivity of cancer cells to specific drugs. 27

Epigenetic traits could be used to characterize intratumoral heterogeneity and determine the relevance of such a heterogeneity in clonal evolution and sensitivity to drugs. However, it is clear that heterogeneity is not only determined by genetic and epigenetic diversity resulting from clonal evolution of tumor cells, but also by the various cell populations that form the tumor microenvironment (TME). 28 Consequently, the epigenome of cancer cells is continually remodeled throughout tumorigenesis, during resistance to the activity of drugs, and in metastasis. 29 This makes therapeutic action based on epigenomic profiles difficult, although significant advances in this area have been reported. 30

During carcinogenesis and tumor progression, epigenetic modifications are categorized by their mechanisms of regulation ( Figure 1A ) and the various levels of structural complexity ( Figure 1B ). In addition, the epigenome can be modified by environmental stimuli, stochastic events, and genetic variations that impact the phenotype ( Figure 1C ). 31 , 32 The molecules that take part in these mechanisms/events/variations are therapeutic targets of interest with potential impact on clinical practice. There are studies on a wide variety of epidrugs, either alone or in combination, which improve antitumor efficacy. 33 However, the problems with these drugs must not be underestimated. For a considerable number of epigenetic compounds still being under study, the main challenge is to translate in vitro efficacy of nanomolar (nM) concentrations into well-tolerated and efficient clinical use. 34 The mechanisms of action of epidrugs may not be sufficiently controlled and could lead to diversion of the therapeutic target. 35 It is known that certain epidrugs, such as valproic acid, produce unwanted epigenetic changes 36 ; thus the need for a well-established safety profile before these drugs can be used in clinical therapy. Finally, resistance to certain epidrugs is another relevant problem. 37 , 38

Epigenetics of cancer. (A) Molecular mechanisms. (B) Structural hierarchy of epigenomics. (C) Factors affecting the epigenome. Modified from Refs. 31 and 32 .

As we learn about the epigenome of specific cell populations in cancer patients, a door opens to the evaluation of sensitivity tests and the search for new molecular markers for detection, prognosis, follow-up, and/or response to treatment at various levels of molecular regulation. Likewise, the horizon expands for therapeutic alternatives in oncology with the use of epidrugs, such as pharmacoepigenomic modulators for genes and key pathways, including methylation of promoters and regulation of micro-RNAs involved in chemoresponse and immune response in cancer. 39 There is no doubt that integrated approaches identifying stable pharmagenomic and epigenomic patterns and their relation with expression profiles and genetic functions will be more and more valuable in our fight against cancer.

Cancer Stem Cells

Tumors consist of different populations of neoplastic cells and a variety of elements that form part of the TME, including stromal cells and molecules of the extracellular matrix. 40 Such intratumoral heterogeneity becomes even more complex during clonal variation of transformed cells, as well as influence the elements of the TME have on these cells throughout specific times and places. 41 To explain the origin of cancer cell heterogeneity, 2 models have been put forward. The first proposes that mutations occur at random during development of the tumor in individual neoplastic cells, and this promotes the production of various tumor populations, which acquire specific growth and survival traits that lead them to evolve according to intratumor mechanisms of natural selection. 42 The second model proposes that each tumor begins as a single cell that possess 2 functional properties: it can self-renew and it can produce several types of terminal cells. As these 2 properties are characteristics of somatic stem cells, 43 the cells have been called cancer stem cells (CSCs). 44 According to this model, tumors must have a hierarchical organization, where self-renewing stem cells produce highly proliferating progenitor cells, unable to self-renew but with a high proliferation potential. The latter, in turn, give rise to terminal cells. 45 Current evidence indicates that both models may coexist in tumor progression. In agreement with this idea, new subclones could be produced as a result of a lack of genetic stability and mutational changes, in addition to the heterogeneity derived from the initial CSC and its descendants. Thus, in each tumor, a set of neoplastic cells with different genetic and epigenetic traits may be found, which would provide different phenotypic properties. 46

The CSC concept was originally presented in a model of acute myeloid leukemia. 47 The presence of CSCs was later proved in chronic myeloid leukemia, breast cancer, tumors of the central nervous system, lung cancer, colon cancer, liver cancer, prostate cancer, pancreatic cancer, melanoma, and cancer of the head and neck, amongst others. In all of these cases, detection of CSCs was based on separation of several cell populations according to expression of specific surface markers, such as CD133, CD44, CD24, CD117, and CD15. 48 It is noteworthy that in some solid tumors, and even in some hematopoietic ones, a combination of specific markers that allow the isolation of CSCs has not been found. Interestingly, in such tumors, a high percentage of cells with the capacity to start secondary tumors has been observed; thus, the terms Tumor Initiating Cells (TIC) or Leukemia Initiating Cells (LIC) have been adopted. 46

A relevant aspect of the biology of CSCs is that, just like normal stem cells, they can self-renew. Such self-renewal guarantees the maintenance or expansion of the tumor stem cell population. Another trait CSCs share with normal stem cells is their quiescence, first described in chronic myeloid leukemia. 49 The persistence of quiescent CSCs in solid tumors has been recently described in colorectal cancer, where quiescent clones can become dominant after therapy with oxaliplatin. 50 In non-hierarchical tumors, such as melanoma, the existence of slow-cycling cells that are resistant to antimitogenic agents has also been proved. 51 Such experimental evidence supports the idea that quiescent CSCs or TICs are responsible for both tumor resistance to antineoplastic drugs and clinical relapse after initial therapeutic success.

In addition to quiescence, CSCs use other mechanisms to resist the action of chemotherapeutic drugs. One of these is their increased numbers: upon diagnosis, a high number of CSCs are observed in most analyzed tumors, making treatment unable to destroy all of them. On the other hand, CSCs have a high number of molecular pumps that expulse drugs, as well as high numbers of antiapoptotic molecules. In addition, they have very efficient mechanisms to repair DNA damage. In general, these cells show changes in a variety of signaling pathways involved in proliferation, survival, differentiation, and self-renewal. It is worth highlighting that in recent years, many of these pathways have become potential therapeutic targets in the elimination of CSCs. 52 Another aspect that is highly relevant in understanding the biological behavior of CSCs is that they require a specific site for their development within the tissue where they are found that can provide whatever is needed for their survival and growth. These sites, known as niches, are made of various cells, both tumor and non-tumor, as well as a variety of non-cellular elements (extracellular matrix [ECM], soluble cytokines, ion concentration gradients, etc.), capable of regulating the physiology of CSCs in order to promote their expansion, the invasion of adjacent tissues, and metastasis. 53

It is important to consider that although a large number of surface markers have been identified that allow us to enrich and prospectively follow tumor stem cell populations, to this day there is no combination of markers that allows us to find these populations in all tumors, and it is yet unclear if all tumors present them. In this regard, it is necessary to develop new purification strategies based on the gene expression profiles of these cells, so that tumor heterogeneity is taken into account, as it is evident that a tumor can include multiple clones of CSCs that, in spite of being functional, are genetically different, and that these clones can vary throughout space (occupying different microenvironments and niches) and time (during the progression of a range of tumor stages). Such strategies, in addition to new in vitro and in vivo assays, will allow the development of new and improved CSC elimination strategies. This will certainly have an impact on the development of more efficient therapeutic alternatives.

Invasion and Metastasis

Nearly 90% of the mortality associated with cancer is related to metastasis. 54 This consists of a cascade of events ( Figure 2 ) that begins with the local invasion of a tumor into surrounding tissues, followed by intravasation of tumor cells into the blood stream or lymphatic circulation. Extravasation of neoplastic cells in areas distant from the primary tumor then leads to the formation of one or more micrometastatic lesions which subsequently proliferate to form clinically detectable lesions. 4 The cells that are able to produce metastasis must acquire migratory characteristics, which occur by a process known as epithelial–mesenchymal transition (EMT), that is, the partial loss of epithelial characteristics and the acquirement of mesenchymal traits. 55

Invasion and metastasis cascade. Invasion and metastasis can occur early or late during tumor progression. In either case, invasion to adjacent tissues is driven by stem-like cells (cancer stem cells) that acquire the epithelial–mesenchymal transition (EMT) (1). Once they reach sites adjacent to blood vessels, tumor cells (individually or in clusters) enter the blood (2). Tumor cells in circulation can adhere to endothelium and extravasation takes place (3). Other mechanisms alternative to extravasation can exist, such as angiopelosis, in which clusters of tumor cells are internalized by the endothelium. Furthermore, at certain sites, tumor cells can obstruct microvasculature and initiate a metastatic lesion right there. Sometimes, a tumor cells that has just exit circulation goes into an MET in order to become quiescent (4). Inflammatory signals can activate quiescent metastatic cells that will proliferate and generate a clinically detectable lesion (5).

Although several of the factors involved in this process are currently known, many issues are still unsolved. For instance, it has not yet been possible to monitor in vivo the specific moment when it occurs 54 ; the microenvironmental factors of the primary tumor that promote such a transition are not known with precision; and the exact moment during tumor evolution in which one cell or a cluster of cells begin to migrate to distant areas, is also unknown. The wide range of possibilities offered by intra- and inter-tumoral heterogeneity 56 stands in the way of suggesting a generalized strategy that could resolve this complication.

It was previously believed that metastasis was only produced in late stages of tumor progression; however, recent studies indicate that EMT and metastasis can occur during the early course of the disease. In pancreatic cancer, for example, cells going through EMT are able to colonize and form metastatic lesions in the liver in the first stages of the disease. 52 , 57 Metastatic cell clusters circulating in peripheral blood (PB) are prone to generate a metastatic site, compared to individual tumor cells. 58 , 59 In this regard, novel strategies, such as the use of micro-RNAs, are being assessed in order to diminish induction of EMT. 60 It must be mentioned, however, that the metastatic process seems to be even more complex, with alternative pathways that do not involve EMT. 61 , 62

A crucial stage in the process of metastasis is the intravasation of tumor cells (alone or in clusters) towards the blood stream and/or lymphatic circulation. 63 These mechanisms are also under intensive research because blocking them could allow the control of spreading of the primary tumor. In PB or lymphatic circulation, tumor cells travel to distant parts for the potential formation of a metastatic lesion. During their journey, these cells must stand the pressure of blood flow and escape interaction with natural killer (NK) cells . 64 To avoid them, tumor cells often cover themselves with thrombocytes and also produce factors such as VEGF, angiopoietin-2, angiopoietin-4, and CCL2 that are involved in the induction of vascular permeability. 54 , 65 Neutrophils also contribute to lung metastasis in the bloodstream by secreting IL-1β and metalloproteases to facilitate extravasation of tumor cells. 64

The next step in the process of metastasis is extravasation, for which tumor cells, alone or in clusters, can use various mechanisms, including a recently described process known as angiopellosis that involves restructuring the endothelial barrier to internalize one or several cells into a tissue. 66 The study of leukocyte extravasation has contributed to a more detailed knowledge of this process, in such a way that some of the proposed strategies to avoid extravasation include the use of integrin inhibitors, molecules that are vital for rolling, adhesion, and extravasation of tumor cells. 67 , 68 Another strategy that has therapeutic potential is the use of antibodies that strengthen vascular integrity to obstruct transendothelial migration of tumor cells and aid in their destruction in PB. 69

Following extravasation, tumor cells can return to an epithelial phenotype, a process known as mesenchymal–epithelial transition and may remain inactive for several years. They do this by competing for specialized niches, like those in the bone marrow, brain, and intestinal mucosa, which provide signals through the Notch and Wnt pathways. 70 Through the action of the Wnt pathway, tumor cells enter a slow state of the cell cycle and induce the expression of molecules that inhibit the cytotoxic function of NK cells. 71 The extravasated tumor cell that is in a quiescent state must comply with 2 traits typical of stem cells: they must have the capacity to self-renew and to generate all of the cells that form the secondary tumor.

There are still several questions regarding the metastatic process. One of the persisting debates at present is if EMT is essential for metastasis or if it plays a more important role in chemoresistance. 61 , 62 It is equally important to know if there is a pattern in each tumor for the production of cells with the capacity to carry out EMT. In order to control metastasis, it is fundamental to know what triggers acquisition of the migratory phenotype and the intrinsic factors determining this transition. Furthermore, it is essential to know if mutations associated with the primary tumor or the variety of epigenetic changes are involved in this process. 55 It is clear that metastatic cells have affinity for certain tissues, depending on the nature of the primary tumor (seed and soil hypothesis). This may be caused by factors such as the location and the direction of the bloodstream or lymphatic fluid, but also by conditioning of premetastatic niches at a distance (due to the large number of soluble factors secreted by the tumor and the recruitment of cells of the immune system to those sites). 72 We have yet to identify and characterize all of the elements that participate in this process. Deciphering them will be of upmost importance from a therapeutic point of view.

Epidemiology of Cancer

Cancer is the second cause of death worldwide; today one of every 6 deaths is due to a type of cancer. According to the International Agency for Research on Cancer (IARC), in 2020 there were approximately 19.3 million new cases of cancer, and 10 million deaths by this disease, 6 while 23.8 million cases and 13.0 million deaths are projected to occur by 2030. 73 In this regard, it is clear the increasing role that environmental factors—including environmental pollutants and processed food—play as cancer inducers and promoters. 74 The types of cancer that produce the greatest numbers of cases and deaths worldwide are indicated in Table 1 . 6

Total Numbers of Cancer Cases and Deaths Worldwide in 2020 by Cancer Type (According to the Global Cancer Observatory, IARC).

Data presented on this table were obtained from Ref. 6.

As shown in Figure 3 , lung, breast, prostate, and colorectal cancer are the most common throughout the world, and they are mostly concentrated in countries of high to very high human development index (HDI). Although breast, prostate, and colorectal cancer have a high incidence, the number of deaths they cause is proportionally low, mostly reflecting the great progress made in their control. However, these data also reveal the types of cancer that require further effort in prevention, precise early detection avoiding overdiagnosis, and efficient treatment. This is the case of liver, lung, esophageal, and pancreatic cancer, where the difference between the number of cases and deaths is smaller ( Figure 3B ). Social and economic transition in several countries has had an impact on reducing the incidence of neoplasms associated with infection and simultaneously produced an increase in the types related to reproductive, dietary, and hormonal factors. 75

Incidence and mortality for some types of cancer in the world. (A) Estimated number of cases and deaths in 2020 for the most frequent cancer types worldwide. (B) Incidence and mortality rates, normalized according to age, for the most frequent cancer types in countries with very high/& high (VH&H; blue) and/low and middle (L&M; red) Human Development Index (HDI). Data include both genders and all ages. Data according to https://gco.iarc.fr/today , as of June 10, 2021.

In the past 3 decades, cancer mortality rates have fallen in high HDI countries, with the exception of pancreatic cancer, and lung cancer in women. Nevertheless, changes in the incidence of cancer do not show the same consistency, possibly due to variables such as the possibility of early detection, exposure to risk factors, or genetic predisposition. 76 , 77 Countries such as Australia, Canada, Denmark, Ireland, New Zealand, Norway, and the United Kingdom have reported a reduction in incidence and mortality in cancer of the stomach, colon, lung, and ovary, as well as an increase in survival. 78 Changes in modifiable risk factors, such as the use of tobacco, have played an important role in prevention. In this respect, it has been estimated that decline in tobacco use can explain between 35% and 45% of the reduction in cancer mortality rates, 79 while the fall in incidence and mortality due to stomach cancer can be attributed partly to the control of Helicobacter pylori infection. 80 Another key factor in the fall of mortality rates in developed countries has been an increase in early detection as a result of screening programs, as in breast and prostate cancer, which have had their mortality rates decreased dramatically in spite of an increase in their incidence. 76

Another important improvement observed in recent decades is the increase in survival rates, particularly in high HDI countries. In the USA, for example, survival rates for patients with prostate cancer at 5 years after initial diagnosis was 28% during 1947–1951; 69% during 1975–1977, and 100% during 2003–2009. Something similar occurred with breast cancer, with a 5-year survival rate of 54% in 1947–1951, 75% in 1975–1977, and 90% in 2003–2009. 81 In the CONCORD 3 version, age-standardize 5-year survival for patients with breast cancer in the USA during 2010–2014 was 90%, and 97% for prostate cancer patients. 82 Importantly, even among high HDI countries, significant differences have been identified in survival rates, being stage of disease at diagnosis, time for access to effective treatment, and comorbidities, the main factors influencing survival in these nations. 78 Unfortunately, survival rates in low HDI countries are significantly lower due to several factors, including lack of information, deficient screening and early detection programs, limited access to treatment, and suboptimal cancer registration. 82 It should be noted that in countries with low to middle HDI, neoplasms with the greatest incidence are those affecting women (breast and cervical cancer), which reflects not only a problem with access to health services, but also a serious inequality issue that involves social, cultural, and even religious obstacles. 83

Up to 42% of incident cases and 47% of deaths by cancer in the USA are due to potentially modifiable risk factors such as use of tobacco, physical activity, diet, and infection. 84 It has been calculated that 2.4 million deaths by cancer, mostly of the lung, can be attributed to tobacco. 73 In 2020, the incidence rate of lung cancer in Western Africa was 2.2, whereas in Polynesia and Eastern Asia was 37.3 and 34.4, respectively. 6 In contrast, the global burden of cancer associated with infection was 15.4%, but in Sub-Saharan Africa it was 30%. 85 Likewise, the incidence of cervical cancer in Eastern Africa was 40.1, in contrast with the USA and Canada that have a rate of 6.2. This makes it clear that one of the challenges we face is the reduction of the risk factors that are potentially modifiable and associated with specific types of cancer.

Improvement of survival rates and its disparities worldwide are also important challenges. Five-year survival for breast cancer—diagnosed during 2010-2014— in the USA, for example, was 90%, whereas in countries like South Africa it was 40%. 82 Childhood leukemia in the USA and several European countries shows a 5-year survival of 90%, while in Latin-American countries it is 50–76%. 86 Interestingly, there are neoplasms, such as pancreatic cancer, for which there has been no significant increase in survival, which remains low (5–15%) both in developed and developing countries. 82

Although data reported on global incidence and mortality gives a general overview on the epidemiology of cancer, it is important to note that there are great differences in coverage of cancer registries worldwide. To date, only 1 out of every 3 countries reports high quality data on the incidence of cancer. 87 For the past 50 years, the IARC has supported population-based cancer registries; however, more than one-third of the countries belonging to the WHO, mainly countries of low and middle income (LMIC), have no data on more than half of the 18 indicators of sustainable development goals. 88 High quality cancer registries only cover 4% of the population in Africa, 8% in Asia, and 7% in Latin America, contrasting with 83% in the USA and Canada, and 33% in Europe. 89 In response to this situation, the Global Initiative for Cancer Registry Development was created in 2012 to generate improved infrastructure to permit greater coverage and better quality registries, especially in countries with low and middle HDI. 88 It is expected that initiatives of this sort in the coming years will allow more and better information to guide strategies for the control of cancer worldwide, especially in developing regions. This will enable survival to be measured over longer periods of time (10, 15, or 20 years), as an effective measure in the control of cancer. The WHO has established as a target for 2025 to reduce deaths by cancer and other non-transmissible diseases by 25% in the population between the ages of 30–69; such an effort requires not only effective prevention measures to reduce incidence, but also more efficient health systems to diminish mortality and increase survival. At the moment, it is an even greater challenge because of the effects of the COVID-19 pandemic which has negatively impacted cancer prevention and health services. 90

Oncologic Treatments

A general perspective.

At the beginning of the 20th century, cancer treatment, specifically treatment of solid tumors, was based fundamentally on surgical resection of tumors, which together with other methods for local control, such as cauterization, had been used since ancient times. 91 At that time, there was an ongoing burst of clinical observations along with interventions sustained on fundamental knowledge about physics, chemistry, and biology. In the final years of the 19 th century and the first half of the 20th, these technological developments gave rise to radiotherapy, hormone therapy, and chemotherapy. 92 - 94 Simultaneously, immunotherapy was also developed, although usually on a smaller scale, in light of the overwhelming progress of chemotherapy and radiotherapy. 95

Thus began the development and expansion of disciplines based on these approaches (surgery, radiotherapy, chemotherapy, hormone therapy, and immunotherapy), with their application evolving ever more rapidly up to their current uses. Today, there is a wide range of therapeutic tools for the care of cancer patients. These include elements that emerged empirically, arising from observations of their effects in various medical fields, as well as drugs that were designed to block processes and pathways that form part of the physiopathology of one or more neoplasms according to knowledge of specific molecular alterations. A classic example of the first sort of tool is mustard gas, originally used as a weapon in war, 96 but when applied for medical purposes, marked the beginning of the use of chemicals in the treatment of malignant neoplasms, that is, chemotherapy. 94 A clear example of the second case is imatinib, designed specifically to selectively inhibit a molecular alteration in chronic myeloid leukemia: the Bcr-Abl oncoprotein. 97

It is on this foundation that today the 5 areas mentioned previously coexist and complement one another. The general framework that motivates this amalgam and guides its development is precision medicine, founded on the interaction of basic and clinical science. In the forecasts for development in each of these fields, surgery is expected to continue to be the fundamental approach for primary tumors in the foreseeable future, as well as when neoplastic disease in the patient is limited, or can be limited by applying systemic or regional elements, before and/or after surgical resection, and it can be reasonably anticipated for the patient to have a significant period free from disease or even to be cured. With regards to technology, intensive exploration of robotic surgery is contemplated. 98

The technological possibilities for radiotherapy have progressed in such a way that it is now possible to radiate neoplastic tissue with an extraordinary level of precision, and therefore avoid damage to healthy tissue. 99 This allows administration of large doses of ionizing radiation in one or a few fractions, what is known as “radiosurgery.” The greatest challenges to the efficacy of this approach are related to radio-resistance in certain neoplasms. Most efforts regarding research in this field are concentrated on understanding the underlying biological mechanisms of the phenomenon and their potential control through radiosensitizers. 100

“Traditional” chemotherapy, based on the use of compounds obtained from plants and other natural products, acting in a non-specific manner on both neoplastic and healthy tissues with a high proliferation rate, continues to prevail. 101 The family of chemotherapeutic drugs currently includes alkylating agents, antimetabolites, anti-topoisomerase agents, and anti-microtubules. Within the pharmacologic perspective, the objective is to attain a high concentration or activity of such molecules in specific tissues while avoiding their accumulation in others, in order to achieve an increase in effectiveness and a reduction in toxicity. This has been possible with the use of viral vectors, for example, that are able to limit their replication in neoplastic tissues, and activate prodrugs of normally nonspecific agents, like cyclophosphamide, exclusively in those specific areas. 102 More broadly, chemotherapy also includes a subgroup of substances, known as molecular targeted therapy, that affect processes in a more direct and specific manner, which will be mentioned later.

There is no doubt that immunotherapy—to be explored next—is one of the therapeutic fields where development has been greatest in recent decades and one that has produced enormous expectation in cancer treatment. 103 Likewise, cell therapy, based on the use of immune cells or stem cells, has come to complement the oncologic therapeutic arsenal. 43 Each and every one of the therapeutic fields that have arisen in oncology to this day continue to prevail and evolve. Interestingly, the foreseeable future for the development of cancer treatment contemplates these approaches in a joint and complementary manner, within the general framework of precision medicine, 104 and sustained by knowledge of the biological mechanisms involved in the appearance and progression of neoplasms. 105 , 106

Immunotherapy

Stimulating the immune system to treat cancer patients has been a historical objective in the field of oncology. Since the early work of William Coley 107 to the achievements reached at the end of the 20 th century, scientific findings and technological developments paved the way to searching for new immunotherapeutic strategies. Recombinant DNA technology allowed the synthesis of cytokines, such as interferon-alpha (IFN-α) and interleukin 2 (IL-2), which were authorized by the US Food and Drug Administration (FDA) for the treatment of hairy cell leukemia in 1986, 108 as well as kidney cancer and metastatic melanoma in 1992 and 1998, respectively. 109

The first therapeutic vaccine against cancer, based on the use of autologous dendritic cells (DCs), was approved by the FDA against prostate cancer in 2010. However, progress in the field of immunotherapy against cancer was stalled in the first decade of the present century, mostly due to failure of several vaccines in clinical trials. In many cases, application of these vaccines was detained by the complexity and cost involved in their production. Nevertheless, with the coming of the concept of immune checkpoint control, and the demonstration of the relevance of molecules such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), and programmed cell death molecule-1 (PD-1), immunotherapy against cancer recovered its global relevance. In 2011, the monoclonal antibody (mAb) ipilimumab, specific to the CTLA-4 molecule, was the first checkpoint inhibitor (CPI) approved for the treatment of advanced melanoma. 110 Later, inhibitory mAbs for PD-1, or for the PD-1 ligand (PD-L1), 111 as well as the production of T cells with chimeric receptors for antigen recognition (CAR-T), 112 which have been approved to treat various types of cancer, including melanoma, non-small cell lung cancer (NSCLC), head and neck cancer, bladder cancer, renal cell carcinoma (RCC), and hepatocellular carcinoma, among others, have changed the paradigm of cancer treatment.

In spite of the current use of anti-CTLA-4 and anti-PD-L1 mAbs, only a subgroup of patients has responded favorably to these CPIs, and the number of patients achieving clinical benefit is still small. It has been estimated that more than 70% of patients with solid tumors do not respond to CPI immunotherapy because either they show primary resistance, or after responding favorably, develop resistance to treatment. 113 In this regard, it is important to mention that in recent years very important steps have been taken to identify the intrinsic and extrinsic mechanisms that mediate resistance to CPI immunotherapy. 114 Intrinsic mechanisms include changes in the antitumor immune response pathways, such as faulty processing and presentation of antigens by APCs, activation of T cells for tumor cell destruction, and changes in tumor cells that lead to an immunosuppressive TME. Extrinsic factors include the presence of immunosuppressive cells in the local TME, such as regulatory T cells, myeloid-derived suppressor cells (MDSC), mesenchymal stem/stromal cells (MSCs), and type 2 macrophages (M2), in addition to immunosuppressive cytokines.

On the other hand, classification of solid tumors as “hot,” “cold,” or “excluded,” depending on T cell infiltrates and the contact of such infiltrates with tumor cells, as well as those that present high tumor mutation burden (TMB), have redirected immunotherapy towards 3 main strategies 115 ( Table 2 ): (1) Making T-cell antitumor response more effective, using checkpoint inhibitors complementary to anti-CTLA-4 and anti-PD-L1, such as LAG3, Tim-3, and TIGT, as well as using CAR-T cells against tumor antigens. (2) Activating tumor-associated myeloid cells including monocytes, granulocytes, macrophages, and DC lineages, found at several frequencies within human solid tumors. (3) Regulating the biochemical pathways in TME that produce high concentrations of immunosuppressive molecules, such as kynurenine, a product of tryptophan metabolism, through the activity of indoleamine 2,3 dioxygenase; or adenosine, a product of ATP hydrolysis by the activity of the enzyme 5’nucleotidase (CD73). 116

Current Strategies to Stimulate the Immune Response for Antitumor Immunotherapy.

Abbreviations: TME, tumor microenvironment; IL, interleukin; TNF, Tumor Necrosis Factor; TNFR, TNF-receptor; CD137, receptor–co-stimulator of the TNFR family; OX40, member number 4 of the TNFR superfamily; CD27/CD70, member of the TNFR superfamily; CD40/CD40L, antigen-presenting cells (APC) co-stimulator and its ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; STING, IFN genes-stimulator; RIG-I, retinoic acid inducible gene-I; MDA5, melanoma differentiation-associated protein 5; CDN, cyclic dinucleotide; ATP, adenosine triphosphate; HMGB1, high mobility group B1 protein; TLR, Toll-like receptor; HVEM, Herpes virus entry mediator; GITR, glucocorticoid-induced TNFR family-related gene; CTLA4, cytotoxic T lymphocyte antigen 4; PD-L1, programmed death ligand-1; TIGIT, T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibition motives; CSF1/CSF1R, colony-stimulating factor-1 and its receptor; CCR2, Type 2 chemokine receptor; PI3Kγ, Phosphoinositide 3-Kinase γ; CXCL/CCL, chemokine ligands; LFA1, lymphocyte function-associated antigen 1; ICAM1, intercellular adhesion molecule 1; VEGF, vascular endothelial growth factor; IDO, indolamine 2,3-dioxigenase; TGF, transforming growth factor; LAG-3, lymphocyte-activation gene 3 protein; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; CD73, 5´nucleotidase; ARs, adenosine receptors; Selectins, cell adhesion molecules; CAR-T, chimeric antigen receptor T cell; TCR-T, T-cell receptor engineered T cell.

Apart from the problems associated with its efficacy (only a small group of patients respond to it), immunotherapy faces several challenges related to its safety. In other words, immunotherapy can induce adverse events in patients, such as autoimmunity, where healthy tissues are attacked, or cytokine release syndrome and vascular leak syndrome, as observed with the use of IL-2, both of which lead to serious hypotension, fever, renal failure, and other adverse events that are potentially lethal. The main challenges to be faced by immunotherapy in the future will require the combined efforts of basic and clinical scientists, with the objective of accelerating the understanding of the complex interactions between cancer and the immune system, and improve treatment options for patients. Better comprehension of immune phenotypes in tumors, beyond the state of PD-L1 and TME, will be relevant to increase immunotherapy efficacy. In this context, the identification of precise tumor antigenicity biomarkers by means of new technologies, such as complete genome sequencing, single cell sequencing, and epigenetic analysis to identify sites or subclones typical in drug resistance, as well as activation, traffic and infiltration of effector cells of the immune response, and regulation of TME mechanisms, may help define patient populations that are good candidates for specific therapies and therapeutic combinations. 117 , 118 Likewise, the use of agents that can induce specific activation and modulation of the response of T cells in tumor tissue, will help improve efficacy and safety profiles that can lead to better clinical results.

Molecular Targeted Therapy

For over 30 years, and based on the progress in our knowledge of tumor biology and its mechanisms, there has been a search for therapeutic alternatives that would allow spread and growth of tumors to be slowed down by blocking specific molecules. This approach is known as molecular targeted therapy. 119 Among the elements generally used as molecular targets there are transcription factors, cytokines, membrane receptors, molecules involved in a variety of signaling pathways, apoptosis modulators, promoters of angiogenesis, and cell cycle regulators. 120

Imatinib, a tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia, became the first targeted therapy in the final years of the 1990s. 97 From then on, new drugs have been developed by design, and today more than 60 targeted therapies have been approved by the FDA for the treatment of a variety of cancers ( Table 3 ). 121 This has had a significant impact on progression-free survival and global survival in neoplasms such as non-small cell lung cancer, breast cancer, renal cancer, and melanoma.

FDA Approved Molecular Targeted Therapies for the Treatment of Solid Tumors.

Abbreviations: mAb, monoclonal antibody; ALK, anaplastic lymphoma kinase; CDK, cyclin-dependent kinase; CTLA-4, cytotoxic lymphocyte antigen-4; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; GIST, gastrointestinal stroma tumor; mTOR, target of rapamycine in mammal cells; NSCLC, non-small cell lung carcinoma; PARP, poli (ADP-ribose) polimerase; PD-1, programmed death protein-1; PDGFR, platelet-derived growth factor receptor; PD-L1, programmed death ligand-1; ER, estrogen receptor; PR, progesterone receptor; TKR, tyrosine kinase receptors; SERM, selective estrogen receptor modulator; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor. Modified from Ref. [ 127 ].

Most drugs classified as targeted therapies form part of 2 large groups: small molecules and mAbs. The former are defined as compounds of low molecular weight (<900 Daltons) that act upon entering the cell. 120 Targets of these compounds are cell cycle regulatory proteins, proapoptotic proteins, or DNA repair proteins. These drugs are indicated based on histological diagnosis, as well as molecular tests. In this group there are multi-kinase inhibitors (RTKs) and tyrosine kinase inhibitors (TKIs), like sunitinib, sorafenib, and imatinib; cyclin-dependent kinase (CDK) inhibitors, such as palbociclib, ribociclib and abemaciclib; poli (ADP-ribose) polimerase inhibitors (PARPs), like olaparib and talazoparib; and selective small-molecule inhibitors, like ALK and ROS1. 122

As for mAbs, they are protein molecules that act on membrane receptors or extracellular proteins by interrupting the interaction between ligands and receptors, in such a way that they reduce cell replication and induce cytostasis. Among the most widely used mAbs in oncology we have: trastuzumab, a drug directed against the receptor for human epidermal growth factor-2 (HER2), which is overexpressed in a subgroup of patients with breast and gastric cancer; and bevacizumab, that blocks vascular endothelial growth factor and is used in patients with colorectal cancer, cervical cancer, and ovarian cancer. Other mAbs approved by the FDA include pembolizumab, atezolizumab, nivolumab, avelumab, ipilimumab, durvalumab, and cemiplimab. These drugs require expression of response biomarkers, such as PD-1 and PD-L1, and must also have several resistance biomarkers, such as the expression of EGFR, the loss of PTEN, and alterations in beta-catenin. 123

Because cancer is such a diverse disease, it is fundamental to have precise diagnostic methods that allow us to identify the most adequate therapy. Currently, basic immunohistochemistry is complemented with neoplastic molecular profiles to determine a more accurate diagnosis, and it is probable that in the near future cancer treatments will be based exclusively on molecular profiles. In this regard, it is worth mentioning that the use of targeted therapy depends on the existence of specific biomarkers that indicate if the patient will be susceptible to the effects of the drug or not. Thus, the importance of underlining that not all patients are susceptible to receive targeted therapy. In certain neoplasms, therapeutic targets are expressed in less than 5% of the diagnosed population, hindering a more extended use of certain drugs.

The identification of biomarkers and the use of new generation sequencing on tumor cells has shown predictive and prognostic relevance. Likewise, mutation analysis has allowed monitoring of tumor clone evolution, providing information on changes in canonic gene sequences, such as TP53, GATA3, PIK3CA, AKT1, and ERBB2; infrequent somatic mutations developed after primary treatments, like SWI-SNF and JAK2-STAT3; or acquired drug resistance mutations such as ESR1. 124 The study of mutations is vital; in fact, many of them already have specific therapeutic indications, which have helped select adequate treatments. 125

There is no doubt that molecular targeted therapy is one of the main pillars of precision medicine. However, it faces significant problems that often hinder obtaining better results. Among these, there is intratumor heterogeneity and differences between the primary tumor and metastatic sites, as well as intrinsic and acquired resistance to these therapies, the mechanisms of which include the presence of heterogeneous subclones, DNA hypermethylation, histone acetylation, and interruption of mRNA degradation and translation processes. 126 Nonetheless, beyond the obstacles facing molecular targeted therapy from a biological and methodological point of view, in the real world, access to genomic testing and specific drugs continues to be an enormous limitation, in such a way that strategies must be designed in the future for precision medicine to be possible on a global scale.

Cell Therapy

Another improvement in cancer treatment is the use of cell therapy, that is, the use of specific cells as therapeutic agents. This clinical procedure has 2 modalities: the first consists of replacing and regenerating functional cells in a specific tissue by means of stem/progenitor cells of a certain kind, 43 while the second uses immune cells as effectors to eliminate malignant cells. 127

Regarding the first type, we must emphasize the development of cell therapy based on hematopoietic stem and progenitor cells. 128 For over 50 years, hematopoietic cell transplants have been used to treat a variety of hematologic neoplasms (different forms of leukemia and lymphoma). Today, it is one of the most successful examples of cell therapy, including innovative modalities, such as haploidentical transplants, 129 as well as application of stem cells expanded ex vivo . 130 There are also therapies that have used immature cells that form part of the TME, such as MSCs. The replication potential and cytokine secretion capacity of these cells make them an excellent option for this type of treatment. 131 Neural stem cells can also be manipulated to produce and secrete apoptotic factors, and when these cells are incorporated into primary neural tumors, they cause a certain degree of regression. They can even be transfected with genes that encode for oncolytic enzymes capable of inducing regression of glioblastomas. 132

With respect to cell therapy using immune cells, several research groups have manipulated cells associated with tumors to make them effector cells and thus improve the efficacy and specificity of the antitumor treatment. PB leckocytes cultured in the presence of IL-2 to obtain activated lymphocytes, in combination with IL-2 administration, have been used in antitumor clinical protocols. Similarly, infiltrating lymphocytes from tumors with antitumor activity have been used and can be expanded ex vivo with IL-2. These lymphocyte populations have been used in immunomodulatory therapies in melanoma, and pancreatic and kidney tumors, producing a favorable response in treated patients. 133 NK cells and macrophages have also been used in immunotherapy, although with limited results. 134 , 135

One of the cell therapies with better projection today is the use of CAR-T cells. This strategy combines 2 forms of advanced therapy: cell therapy and gene therapy. It involves the extraction of T cells from the cancer patient, which are genetically modified in vitro to express cell surface receptors that will recognize antigens on the surface of tumor cells. The modified T cells are then reintroduced in the patient to aid in an exacerbated immune response that leads to eradication of the tumor cells ( Figure 4 ). Therapy with CAR-T cells has been used successfully in the treatment of some types of leukemia, lymphoma, and myeloma, producing complete responses in patients. 136

CAR-T cell therapy. (A) T lymphocytes obtained from cancer patients are genetically manipulated to produce CAR-T cells that recognize tumor cells in a very specific manner. (B) Interaction between CAR molecule and tumor antigen. CAR molecule is a receptor that results from the fusion between single-chain variable fragments (scFv) from a monoclonal antibody and one or more intracellular signaling domains from the T-cell receptor. CD3ζ, CD28 and 4-1BB correspond to signaling domains on the CAR molecule.

Undoubtedly, CAR-T cell therapy has been truly efficient in the treatment of various types of neoplasms. However, this therapeutic strategy can also have serious side effects, such as release of cytokines into the bloodstream, which can cause different symptoms, from high fever to multiorgan failure, and even neurotoxicity, leading to cerebral edema in many cases. 137 Adequate control of these side effects is an important medical challenge. Several research groups are trying to improve CAR-T cell therapy through various approaches, including production of CAR-T cells directed against a wider variety of tumor cell-specific antigens that are able to attack different types of tumors, and the identification of more efficient types of T lymphocytes. Furthermore, producing CAR-T cells from a single donor that may be used in the treatment of several patients would reduce the cost of this sort of personalized cell therapy. 136

Achieving wider use of cell therapy in oncologic diseases is an important challenge that requires solving various issues. 138 One is intratumor cell heterogeneity, including malignant subclones and the various components of the TME, which results in a wide profile of membrane protein expression that complicates finding an ideal tumor antigen that allows specific identification (and elimination) of malignant cells. Likewise, structural organization of the TME challenges the use of cell therapy, as administration of cell vehicles capable of recognizing malignant cells might not be able to infiltrate the tumor. This results from low expression of chemokines in tumors and the presence of a dense fibrotic matrix that compacts the inner tumor mass and avoids antitumor cells from infiltrating and finding malignant target cells.

Further Challenges in the 21st Century

Beyond the challenges regarding oncologic biomedical research, the 21 st century is facing important issues that must be solved as soon as possible if we truly wish to gain significant ground in our fight against cancer. Three of the most important have to do with prevention, early diagnosis, and access to oncologic medication and treatment.

Prevention and Early Diagnosis

Prevention is the most cost-effective strategy in the long term, both in low and high HDI nations. Data from countries like the USA indicate that between 40-50% of all types of cancer are preventable through potentially modifiable factors (primary prevention), such as use of tobacco and alcohol, diet, physical activity, exposure to ionizing radiation, as well as prevention of infection through access to vaccination, and by reducing exposure to environmental pollutants, such as pesticides, diesel exhaust particles, solvents, etc. 74 , 84 Screening, on the other hand, has shown great effectiveness as secondary prevention. Once population-based screening programs are implemented, there is generally an initial increase in incidence; however, in the long term, a significant reduction occurs not only in incidence rates, but also in mortality rates due to detection of early lesions and timely and adequate treatment.

A good example is colon cancer. There are several options for colon cancer screening, such as detection of fecal occult blood, fecal immunohistochemistry, flexible sigmoidoscopy, and colonoscopy, 139 , 140 which identify precursor lesions (polyp adenomas) and allow their removal. Such screening has allowed us to observe 3 patterns of incidence and mortality for colon cancer between the years 2000 and 2010: on one hand, an increase in incidence and mortality in countries with low to middle HDI, mainly countries in Asia, South America, and Eastern Europe; on the other hand, an increase in incidence and a fall in mortality in countries with very high HDI, such as Canada, the United Kingdom, Denmark, and Singapore; and finally a fall in incidence and mortality in countries like the USA, Japan, and France. The situation in South America and Asia seems to reflect limitations in medical infrastructure and a lack of access to early detection, 141 while the patterns observed in developed countries reveal the success, even if it may be partial, of that which can be achieved by well-structured prevention programs.

Another example of success, but also of strong contrast, is cervical cancer. The discovery of the human papilloma virus (HPV) as the causal agent of cervical cancer brought about the development of vaccines and tests to detect oncogenic genotypes, which modified screening recommendations and guidelines, and allowed several developed countries to include the HPV vaccine in their national vaccination programs. Nevertheless, the outlook is quite different in other areas of the world. Eighty percent of the deaths by cervical cancer reported in 2018 occurred in low-income nations. This reveals the urgency of guaranteeing access to primary and secondary prevention (vaccination and screening, respectively) in these countries, or else it will continue to be a serious public health problem in spite of its preventability.

Screening programs for other neoplasms, such as breast, prostate, lung, and thyroid cancer have shown outlooks that differ from those just described, because, among other reasons, these neoplasms are highly diverse both biologically and clinically. Another relevant issue is the overdiagnosis of these neoplasms, that is, the diagnosis of disease that would not cause symptoms or death in the patient. 142 It has been calculated that 25% of breast cancer (determined by mammogram), 50–60% of prostate cancer (determined by PSA), and 13–25% of lung cancer (determined by CT) are overdiagnosed. 142 Thus, it is necessary to improve the sensitivity and specificity of screening tests. In this respect, knowledge provided by the biology of cancer and “omic” sciences offers a great opportunity to improve screening and prevention strategies. All of the above shows that prevention and early diagnosis are the foundations in the fight against cancer, and it is essential to continue to implement broader screening programs and better detection methods.

Global Equity in Oncologic Treatment

Progress in cancer treatment has considerably increased the number of cancer survivors. Nevertheless, this tendency is evident only in countries with a very solid economy. Indeed, during the past 30 years, cancer mortality rates have increased 30% worldwide. 143 Global studies indicate that close to 70% of cancer deaths in the world occur in nations of low to middle income. But even in high-income countries, there are sectors of society that are more vulnerable and have less access to cancer treatments. 144 Cancer continues to be a disease of great social inequality.

In Europe, the differences in access to cancer treatment are highly marked. These treatments are more accessible in Western Europe than in its Eastern counterpart. 145 Furthermore, highly noticeable differences between high-income countries have been detected in the cost of cancer drugs. 146 It is interesting to note that in many of these cases, treatment is too costly and the clinical benefit only marginal. Thus, the importance of these problems being approached by competent national, regional, and global authorities, because if these new drugs and therapeutic programs are not accessible to the majority, progress in biomedical, clinical and epidemiological research will have a limited impact in our fight against cancer. We must not forget that health is a universal right, from which low HDI countries must not be excluded, nor vulnerable populations in nations with high HDI. The participation of a well-informed society will also be fundamental to achieve a global impact, as today we must fight not only against the disease, but also against movements and ideas (such as the anti-vaccine movement and the so-called miracle therapies) that can block the medical battle against cancer.

Final Comments

From the second half of the 20th century to the present day, progress in our knowledge about the origin and development of cancer has been extraordinary. We now understand cancer in detail in genomic, molecular, cellular, and physiological terms, and this knowledge has had a significant impact in the clinic. There is no doubt that a patient who is diagnosed today with a type of cancer has a better prospect than a patient diagnosed 20 or 50 years ago. However, we are still far from winning the war against cancer. The challenges are still numerous. For this reason, oncologic biomedical research must be a worldwide priority. Likewise, one of the fundamental challenges for the coming decades must be to reduce unequal access to health services in areas of low- to middle income, and in populations that are especially vulnerable, as well as continue improving prevention programs, including public health programs to reduce exposure to environmental chemicals and improve diet and physical activity in the general population. 74 , 84 Fostering research and incorporation of new technological resources, particularly in less privileged nations, will play a key role in our global fight against cancer.

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

Hector Mayani https://orcid.org/0000-0002-2483-3782

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Cancer Biology Research

Breast cancer cells

The Importance of Cancer Biology Research

Research on the biology of cancer starts with the simplest of questions: What is—and isn’t—normal? To understand how cancer develops and progresses, researchers first need to investigate the biological differences between normal cells and cancer cells. This work focuses on the mechanisms that underlie fundamental processes such as cell growth, the transformation of normal cells to cancer cells, and the spread ( metastasis ) of cancer cells.

Virtually all major advances against cancer originated with discoveries in basic science . Basic research can reveal new ideas about the causes of cancer and how it develops, progresses, and responds to therapy.

Knowledge gained from such studies deepens our understanding of cancer and produces insights that could lead to new clinical interventions. For example, studies of cell signaling pathways  in normal cells and cancer cells have contributed greatly to our knowledge about the disease, revealing molecular alterations that are shared among different types of cancer and pointing to possible treatment strategies.

Decades of basic research in cancer biology have created a broad base of knowledge that has been critical to progress against the disease.

Selected NCI Activities in Cancer Biology Research

NCI Research and the National Cancer Plan

NCI supports a broad variety of research that aligns with the goals of the National Cancer Plan. Read about the plan and explore each goal.

Federal funding for cancer biology is essential because this area of research receives relatively little funding from entities that are driven by profit. NCI supports and directs cancer biology research through a variety of programs and approaches. For example:

• The Metastasis Research Network (MetNet) supports research to improve our understanding of how cancer spreads. Cancer metastasis is a complex, dynamic, nonlinear process. The network supports several specialized centers working collaboratively on multidisciplinary projects focused on several themes of the metastatic process, including mechanisms of early dissemination, cellular and physical microenvironment crosstalk, dormancy, and mechanisms of responses to therapy by metastatic cells.
• The Translational and Basic Science Research in Early Lesions (TBEL) Program is advancing the understanding of the mechanisms driving, or restraining, the development of precancers and early cancers, as well as informing the development of precision prevention approaches. The program supports multidisciplinary research centers that are integrating basic and translational research to investigate the interactions of an early lesion, its microenvironment, and host factors as “co-organizers” of tumor initiation and the development of cancer.
• The Human Tumor Atlas Network is constructing 3-dimensional atlases of the cellular, morphological, and molecular features of human cancers as they evolve from precancerous lesions to advanced disease. The atlases, which represent a diverse patient population, will also be used to study how tumors respond to treatment and develop resistance to drugs.
• The Cancer Tissue Engineering Collaborative (TEC) supports the development and characterization of state-of-the-art biomimetic tissue-engineered technologies for cancer research. This program advances innovative, well-characterized in vitro and ex vivo systems available for cancer research, expands the breadth of these systems to several cancer types, and promotes investigations of cancer with tissue-engineered systems.

NCI Fiscal Year 2025 Professional Judgment Budget Proposal

Each year, NCI prepares a professional judgment budget to lead progress against cancer.

• The consortium of tumor glycomics laboratories and their research partners that make up the Alliance of Glycobiologists for Cancer Research are investigating the cancer-related dynamics of complex carbohydrates. The alliance, which NCI sponsors with the National Institute of General Medical Sciences and the National Heart, Lung, and Blood Institute, aims to study the structure and function of glycans in relation to cancer.
• The NCI RNA Biology Initiative facilitates the exchange of information and expertise among investigator studying the structure, function, and biological roles of RNA for the purpose of developing new cancer diagnostics and therapies.
• NCI’s Centers of Excellence bring together the institute’s intramural researchers to collaborate on new projects and initiatives in various areas of cancer biology, including Chromosome Biology and Genitourinary Malignancies .

Recent Research Findings in Cancer Biology

• Loss of Y Chromosome in Men Makes Bladder Cancer More Aggressive
• Cells’ decision to divide is reversible
• How Fatty Liver Disease Helps Cancer Thrive in the Liver
• No Glucose? Pancreatic Cancer May Have a Ready Energy Alternative
• How Some Brain Tumors Hijack the Mind to Grow
• Researchers discover the multiple shapes of RNA, a boon for drug design
• Vulnerability in Brain Tumors May Open Door to New Treatments
• Preventing Chemo Brain? Study Identifies Potential Approach for Common Problem

Chromatin openness sheds new light on prostate cancer plasticity

Treatment resistance caused by cancer cell plasticity constitutes a major challenge in the treatment of prostate cancer. Published in Nucleic Acids Research , a recent study from the University of Eastern Finland Institute of Biomedicine suggests that the SIX2 protein may be a possible factor underlying increased plasticity of prostate cancer cells and treatment resistance.

Prostate cancer is the most common cancer in men and the second most common cause of cancer mortality in Western countries. Prostate cancer growth is promoted by androgens and can be treated with androgen receptor inhibition therapies, especially as regards aggressive or advanced prostate cancer. However, cancer cells can develop resistance to these therapies, resulting in castration-resistant prostate cancer.

One mechanism underlying treatment resistance may be the plasticity of cancer cells: they can change their degree of differentiation and revert to a stem cell-like state, which helps them avoid the effects of hormonal therapies. However, factors contributing to cell plasticity and the development of treatment resistance remain unclear.

"It is important to identify the key factors contributing to treatment resistance in prostate cancer and how cancer cells change their degree of differentiation to find new targets for therapies. This could even lead to the discovery of a cure for these currently lethal types of cancer," Academy Research Fellow, Adjunct Professor (Docent) Kirsi Ketola of the University of Eastern Finland says.

Inhibition of the androgen receptor opens up new genomic regions

The new study by the Ketola Lab explored new potential factors contributing to treatment resistance in prostate cancer.

In cells, DNA is packed into chromatin. In regions where gene expression is active, this packing is looser, meaning that chromatin is more open. The Ketola Lab studied chromatin openness in androgen-dependent prostate cancer cells, which were treated with enzalutamide, an inhibitor of the androgen receptor used for treating prostate cancer. The researchers found that following exposure to enzalutamide, the number of new opened chromatin sites was greater than that of new closed chromatin sites. These new opened sites occurred especially in DNA regions containing binding site of the SIX2 protein. The increased activity of the SIX2 protein may contribute to the increased plasticity of cells following drug therapy.

In other words, inhibiting the function of the androgen receptor alters the regulation of genes within cells, allowing for the expression of genes that are normally silenced and the alteration of the cell state.

SIX2 is necessary for embryogenesis, but increases cell plasticity and malignancy in prostate cancer cells

The SIX2 protein is normally active during embryogenesis, where it maintains cells as undifferentiated stem cells, preserving their ability to differentiate.

The study found that the SIX2 protein can regulate the degree of differentiation of even prostate cancer cells that do not have an androgen receptor. The activity of the SIX2 gene increased in cancer cells after exposure to enzalutamide. In particular, the expression of the SIX2 protein has increased in cancer cells that do not express the androgen receptor.

"Silencing of the SIX2 gene, on the other hand, significantly reduced the malignancy of cancer cells that are resistant to hormonal therapies," Doctoral Researcher Noora Leppänen of the University of Eastern Finland notes.

The stem cell-like state of cancer cells that do not express the androgen receptor, as well as their ability to migrate, invade and metastasize, were significantly reduced following the silencing of the SIX2 gene. Reduced cell division and cancer spread were also observed in experiments conducted on zebrafish. Therefore, inhibiting the activity of the SIX2 protein could be a potential target for drug development to treat or prevent the development of metastatic, hormone therapy-resistant types of cancer.

• Prostate Cancer
• Men's Health
• Lung Cancer
• Skin Cancer
• Brain Tumor
• Breast Cancer
• Prostate cancer
• Pernicious anemia
• Breast cancer
• Stomach cancer
• Malignant melanoma
• Embryonic stem cell

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11 new breakthroughs in the fight against cancer

Medical advances are continuing to help the world fight cancer. Image:  Unsplash/National Cancer Institute

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Madeleine north.

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This article was originally published in May 2022, and most recently updated in June 2024 .

• Cancer is one of the world’s biggest killers, with around 10 million deaths per year due to the disease.
• Scientists are using artificial intelligence, DNA sequencing, precision oncology and other technologies to improve treatment and diagnosis.
• The Centre for the Fourth Industrial Revolution India, a collaboration with the World Economic Forum, hopes to accelerate 18 cancer interventions.

Cancer kills around 10 million people a year and is a leading cause of death globally, according to the World Health Organization.

Breast, lung and colon cancer are among the most common. Death rates from cancer were falling before the pandemic . But COVID-19 caused a big backlog in diagnosis and treatment .

There is some good news, however. Medical advances are accelerating the battle against cancer. Here are 11 recent developments.

Personalized cancer vaccines

Thousands of NHS cancer patients in England could soon access trials of a new vaccine treatment. It's designed to prime the immune system to target cancer cells and reduce recurrence risk . These vaccines are also hoped to produce fewer side effects than conventional chemotherapy. Thirty hospitals have joined the Cancer Vaccine Launch Pad , which matches patients with upcoming trials using the same mRNA technology found in current COVID-19 jabs. Over 200 patients from the UK, Germany, Belgium, Spain and Sweden will receive up to 15 doses of the personalized vaccine, with the study expected to complete by 2027.

Test to identify 18 early-stage cancers

Researchers in the US have developed a test they say can identify 18 early-stage cancers. Instead of the usual invasive and costly methods, Novelna's test works by analyzing a patient's blood protein. In a screening of 440 people already diagnosed with cancer, the test correctly identified 93% of stage 1 cancers in men and 84% in women. The researchers believe the findings "pave the way for a cost-effective, highly accurate, multi-cancer screening test that can be implemented on a population-wide scale". It's early days, however. With such a small sample screening and a lack of information on co-existing conditions, the test is currently more of "a starting point for developing a new generation of screening tests for the early detection of cancer".

Seven-minute cancer treatment jab

England's National Health Service (NHS) is to be the first in the world to make use of a cancer treatment injection , which takes just seven minutes to administer, rather than the current time of up to an hour to have the same drug via intravenous infusion. This will not only speed up the treatment process for patients, but also free up time for medical professionals. The drug, Atezolizumab or Tecentriq, treats cancers including lung and breast, and it's expected most of the 3,600 NHS patients in England currently receiving it intravenously will now switch to the jab.

Precision oncology

Precision oncology is the “ best new weapon to defeat cancer ”, the chief executive of Genetron Health, Sizhen Wang, says in a blog for the World Economic Forum. This involves studying the genetic makeup and molecular characteristics of cancer tumours in individual patients. The precision oncology approach identifies changes in cells that might be causing the cancer to grow and spread. Personalized treatments can then be developed. The 100,000 Genomes Project, a National Health Service initiative, studied more than 13,000 tumour samples from UK cancer patients , successfully integrating genomic data to more accurately pin-point effective treatment. Because precision oncology treatments are targeted – as opposed to general treatments like chemotherapy – it can mean less harm to healthy cells and fewer side effects as a result.

Artificial intelligence fights cancer

In India, World Economic Forum partners are using emerging technologies like artificial intelligence (AI) and machine learning to transform cancer care. For example, AI-based risk profiling can help screen for common cancers like breast cancer, leading to early diagnosis. AI technology can also be used to analyze X-rays to identify cancers in places where imaging experts might not be available. These are two of 18 cancer interventions that The Centre for the Fourth Industrial Revolution India, a collaboration with the Forum , hopes to accelerate.

Greater prediction capabilities

Lung cancer kills more people in the US yearly than the next three deadliest cancers combined. It's notoriously hard to detect the early stages of the disease with X-rays and scans alone. However, MIT scientists have developed an AI learning model to predict a person's likelihood of developing lung cancer up to six years in advance via a low-dose CT scan. Trained using complex imaging data, 'Sybil' can forecast both short- and long-term lung cancer risk, according to a recent study. "We found that while we as humans couldn't quite see where the cancer was, the model could still have some predictive power as to which lung would eventually develop cancer," said co-author Jeremy Wohlwend.

Clues in the DNA of cancer

At Cambridge University Hospitals in England, the DNA of cancer tumours from 12,000 patients is revealing new clues about the causes of cancer, scientists say. By analyzing genomic data, oncologists are identifying different mutations that have contributed to each person’s cancer. For example, exposure to smoking or UV light, or internal malfunctions in cells. These are like “fingerprints in a crime scene”, the scientists say – and more of them are being found. “We uncovered 58 new mutational signatures and broadened our knowledge of cancer,” says study author Dr Andrea Degasperi, from Cambridge’s Department of Oncology.

Liquid and synthetic biopsies

Biopsies are the main way doctors diagnose cancer – but the process is invasive and involves removing a section of tissue from the body, sometimes surgically, so it can be examined in a laboratory. Liquid biopsies are an easier and less invasive solution where blood samples can be tested for signs of cancer. Synthetic biopsies are another innovation that can force cancer cells to reveal themselves during the earliest stages of the disease.

The application of “precision medicine” to save and improve lives relies on good-quality, easily-accessible data on everything from our DNA to lifestyle and environmental factors. The opposite to a one-size-fits-all healthcare system, it has vast, untapped potential to transform the treatment and prediction of rare diseases—and disease in general.

But there is no global governance framework for such data and no common data portal. This is a problem that contributes to the premature deaths of hundreds of millions of rare-disease patients worldwide.

The World Economic Forum’s Breaking Barriers to Health Data Governance initiative is focused on creating, testing and growing a framework to support effective and responsible access – across borders – to sensitive health data for the treatment and diagnosis of rare diseases.

The data will be shared via a “federated data system”: a decentralized approach that allows different institutions to access each other’s data without that data ever leaving the organization it originated from. This is done via an application programming interface and strikes a balance between simply pooling data (posing security concerns) and limiting access completely.

The project is a collaboration between entities in the UK (Genomics England), Australia (Australian Genomics Health Alliance), Canada (Genomics4RD), and the US (Intermountain Healthcare).

CAR-T-cell therapy

A treatment that makes immune cells hunt down and kill cancer cells was declared a success for leukaemia patients in 2022. Known as CAR-T-cell therapy, it involves removing and genetically altering immune cells, called T cells, from cancer patients. The altered cells then produce proteins called chimeric antigen receptors (CARs), which can recognize and destroy cancer cells. In the journal Nature , scientists at the University of Pennsylvania announced that two of the first people treated with CAR-T-cell therapy were still in remission 12 years on.

However, the US Food and Drug Administration is currently investigating whether the process can in fact cause cancer , after 33 cases of secondary cancer were observed in patients receiving CAR-T therapies. The jury is still out as to whether the therapy is to blame but, as a precaution, the drug packaging now carries a warning.

Fighting pancreatic cancer

Pancreatic cancer is one of the deadliest cancers. It is rarely diagnosed before it starts to spread and has a survival rate of less than 5% over five years. At the University of California San Diego School of Medicine, scientists developed a test that identified 95% of early pancreatic cancers in a study. The research, published in Nature Communications Medicine , explains how biomarkers in extracellular vesicles – particles that regulate communication between cells – were used to detect pancreatic, ovarian and bladder cancer at stages I and II.

Have you read?

Cancer: how to stop the next global health crisis, how to improve access to cancer medicines in low and middle-income countries, why is cancer becoming more common among millennials, a tablet to cut breast cancer risk.

A drug that could halve the chance of women developing breast cancer is being tested out by England's National Health Service (NHS). It will be made available to almost 300,000 women seen as being at most risk of developing breast cancer, which is the most common type of cancer in the UK . The drug, named anastrozole, cuts the level of oestrogen women produce by blocking the enzyme aromatase . It has already been used for many years as a breast cancer treatment but has now been repurposed as a preventive medicine. “This is the first drug to be repurposed through a world-leading new programme to help us realize the full potential of existing medicines in new uses to save and improve more lives on the NHS," says NHS Chief Executive Amanda Pritchard.

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World Economic Forum articles may be republished in accordance with the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Public License, and in accordance with our Terms of Use.

The views expressed in this article are those of the author alone and not the World Economic Forum.

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Collection  10 March 2022

Top 100 in Cancer

This collection highlights our most downloaded* cancer papers published in 2021. Featuring authors from aroud the world, these papers showcase valuable research from an international community.

*Data obtained from SN Insights which is based on Digital Science's Dimensions.

Radiotherapy for brain metastasis and long-term survival

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• Jaehun Jung

The Angelina Jolie effect: Contralateral risk-reducing mastectomy trends in patients at increased risk of breast cancer

• Narendra Nath Basu
• James Hodson
• D. Gareth Evans

Deep learning classification of lung cancer histology using CT images

• Tafadzwa L. Chaunzwa
• Ahmed Hosny
• Hugo J. W. L. Aerts

Pancancer survival analysis of cancer hallmark genes

• Gyöngyi Munkácsy
• Balázs Győrffy

Anti-estrogenic and anti-aromatase activities of citrus peels major compounds in breast cancer

• Dina M. El-Kersh
• Shahira M. Ezzat
• Mohey M. Elmazar

Arsenic exposure in Indo Gangetic plains of Bihar causing increased cancer risk

• Mohammad Ali
• Ashok Kumar Ghosh

CIBERSORT analysis of TCGA and METABRIC identifies subgroups with better outcomes in triple negative breast cancer

• Kelly E. Craven
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The incidence and clinical analysis of non-melanoma skin cancer

• Magdalena Ciążyńska
• Grażyna Kamińska-Winciorek
• Aleksandra Lesiak

Real-world outcomes versus clinical trial results of immunotherapy in stage IV non-small cell lung cancer (NSCLC) in the Netherlands

• Christine M. Cramer-van der Welle
• Marjon V. Verschueren
• The Santeon NSCLC Study Group

Anti-tumour activity of deer growing antlers and its potential applications in the treatment of malignant gliomas

• Louis Chonco
• Tomás Landete-Castillejos
• Tomás Segura

Risk of cancer development in patients with keloids

• Hung-Pin Tu
• Chih-Hung Lee

Neutrophil to lymphocyte ratio influences impact of steroids on efficacy of immune checkpoint inhibitors in lung cancer brain metastases

• Bicky Thapa
• Manmeet S. Ahluwalia

Prediction of survival in patients with advanced, refractory colorectal cancer in treatment with trifluridine/tipiracil: real-world vs clinical trial data

• Ana Fernández Montes
• Alberto Carmona-Bayonas
• Teresa Garcia García

Hyperbaric oxygen suppressed tumor progression through the improvement of tumor hypoxia and induction of tumor apoptosis in A549-cell-transferred lung cancer

• Shao-Yuan Chen
• Koichi Tsuneyama
• Shih-Ming Huang

Histopathological analysis of mucinous breast cancer subtypes and comparison with invasive carcinoma of no special type

• Michał Piotr Budzik
• Marta Magdalena Fudalej
• Anna Maria Badowska-Kozakiewicz

Copper-67 radioimmunotheranostics for simultaneous immunotherapy and immuno-SPECT

• Guiyang Hao
• Tara Mastren
• Xiankai Sun

Associations between the gut microbiome and fatigue in cancer patients

• Joud Hajjar
• Tito Mendoza

cGAS–STING cytosolic DNA sensing pathway is suppressed by JAK2-STAT3 in tumor cells

• Manuel Adrian Suter
• Nikki Y. Tan
• Y. L. Zhang

Iodine containing porous organosilica nanoparticles trigger tumor spheroids destruction upon monochromatic X-ray irradiation: DNA breaks and K-edge energy X-ray

• Yuya Higashi
• Kotaro Matsumoto
• Fuyuhiko Tamanoi

COVID-19 engages clinical markers for the management of cancer and cancer-relevant regulators of cell proliferation, death, migration, and immune response

• Serhiy Souchelnytskyi
• Andriy Nera
• Nazariy Souchelnytskyi

High-dose methotrexate-based regimens and post-remission consolidation for treatment of newly diagnosed primary CNS lymphoma: meta-analysis of clinical trials

• Haowen Xiao

Sensitivity, specificity, and accuracy of a liquid biopsy approach utilizing molecular amplification pools

• Jessica Garcia
• Nick Kamps-Hughes
• Cristian Ionescu-Zanetti

A survival analysis of surgically treated incidental low-grade glioma patients

• Lingcheng Zeng

Integrated multi-omics analysis of ovarian cancer using variational autoencoders

• Muta Tah Hira
• M. A. Razzaque
• Mosharraf Sarker

Cell-free DNA concentration and fragment size as a biomarker for prostate cancer

• Emmalyn Chen
• Clinton L. Cario
• John S. Witte

Real-world outcomes of first-line pembrolizumab plus pemetrexed-carboplatin for metastatic nonsquamous NSCLC at US oncology practices

• Vamsidhar Velcheti
• Thomas Burke

Graphene oxide loaded with tumor-targeted peptide and anti-cancer drugs for cancer target therapy

Comprehensive analysis of metastatic gastric cancer tumour cells using single-cell RNA-seq

• Yingyi Zhang
• Xianbao Zhan

Ex vivo culture of intact human patient derived pancreatic tumour tissue

• John Kokkinos
• George Sharbeen
• Phoebe A. Phillips

A phase 2a clinical study on the safety and efficacy of individualized dosed mebendazole in patients with advanced gastrointestinal cancer

• S. Mansoori

Palliative radiation therapy for symptomatic advance breast cancer

• Galia Jacobson
• Orit Kaidar-Person
• Merav Akiva Ben-David

Deep learning identifies morphological features in breast cancer predictive of cancer ERBB2 status and trastuzumab treatment efficacy

• Dmitrii Bychkov
• Nina Linder
• Johan Lundin

A prostate-specific membrane antigen (PSMA)-targeted prodrug with a favorable in vivo toxicity profile

• Srikanth Boinapally
• Hye-Hyun Ahn
• Martin G. Pomper

Comparison of microsatellite instability detection by immunohistochemistry and molecular techniques in colorectal and endometrial cancer

• Franceska Dedeurwaerdere
• Kathleen BM Claes
• Geert Martens

Valerian and valeric acid inhibit growth of breast cancer cells possibly by mediating epigenetic modifications

• Fengqin Shi

Efficacy and safety of new anti-CD20 monoclonal antibodies versus rituximab for induction therapy of CD20 + B-cell non-Hodgkin lymphomas: a systematic review and meta-analysis

• Chengxin Luo

Morphofunctional analysis of human pancreatic cancer cell lines in 2- and 3-dimensional cultures

• Fuuka Minami
• Norihiko Sasaki
• Toshiyuki Ishiwata

Potentiality of multiple modalities for single-cell analyses to evaluate the tumor microenvironment in clinical specimens

• Yukie Kashima
• Yosuke Togashi
• Toshihiko Doi

Polysaccharide hydrogel based 3D printed tumor models for chemotherapeutic drug screening

• Aragaw Gebeyehu
• Sunil Kumar Surapaneni
• Mandip Singh

PTEN loss promotes oncogenic function of STMN1 via PI3K/AKT pathway in lung cancer

• Guangsu Xun

Co-culture model of B-cell acute lymphoblastic leukemia recapitulates a transcription signature of chemotherapy-refractory minimal residual disease

• Stephanie L. Rellick
• Gangqing Hu
• Laura F. Gibson

Effect of SSRI exposure on the proliferation rate and glucose uptake in breast and ovary cancer cell lines

• Britta Stapel
• Catharina Melzer

Impact of tumor-parenchyma biomechanics on liver metastatic progression: a multi-model approach

• Erik Brodin
• Paul Macklin

Pembrolizumab in vaginal and vulvar squamous cell carcinoma: a case series from a phase II basket trial

• Jeffrey A. How
• Amir A. Jazaeri

Relationship of breast volume, obesity and central obesity with different prognostic factors of breast cancer

• Daniel María Lubián López
• Carmen Aisha Butrón Hinojo
• Ernesto González Mesa

Meta-analysis of host transcriptional responses to SARS-CoV-2 infection reveals their manifestation in human tumors

• Fengju Chen
• Yiqun Zhang
• Chad J. Creighton

Selection and characterisation of Affimers specific for CEA recognition

• Shazana Hilda Shamsuddin
• David G. Jayne
• Paul A. Millner

Epidemiology and prognosis in young lung cancer patients aged under 45 years old in northern China

Real-world data of fulvestrant as first-line treatment of postmenopausal women with estrogen receptor-positive metastatic breast cancer

• M. Ruiz-Borrego

Classification of paediatric brain tumours by diffusion weighted imaging and machine learning

• Niloufar Zarinabad
• Andrew Peet

Metagenomic analysis of formalin-fixed paraffin-embedded tumor and normal mucosa reveals differences in the microbiome of colorectal cancer patients

• Gabriela Debesa-Tur
• Vicente Pérez-Brocal
• Andrés Moya

A novel proteomics approach to epigenetic profiling of circulating nucleosomes

• Priscilla Van den Ackerveken
• Alison Lobbens
• Marielle Herzog

A review and comparison of breast tumor cell nuclei segmentation performances using deep convolutional neural networks

• Andrew Lagree
• Majidreza Mohebpour
• William T. Tran

Comparative analysis of machine learning approaches to classify tumor mutation burden in lung adenocarcinoma using histopathology images

• Apaar Sadhwani
• Huang-Wei Chang
• Peter Cimermancic

Alteration of DNA mismatch repair capacity underlying the co-occurrence of non-small-cell lung cancer and nonmedullary thyroid cancer

• Shiro Fujita
• Katsuhiro Masago

Anticancer potential of rhizome extract and a labdane diterpenoid from Curcuma mutabilis plant endemic to Western Ghats of India

• T. Lakshmipriya
• P. R. Manish Kumar

Serum-derived exosomal PD-L1 expression to predict anti-PD-1 response and in patients with non-small cell lung cancer

• Yoshihisa Shimada
• Jun Matsubayashi
• Norihiko Ikeda

Transcript levels of keratin 1/5/6/14/15/16/17 as potential prognostic indicators in melanoma patients

• Guo-Liang Shen

Enhancing the landscape of colorectal cancer using targeted deep sequencing

• Chul Seung Lee
• In Hye Song
• Sung Hak Lee

PGMD/curcumin nanoparticles for the treatment of breast cancer

• Mankamna Kumari
• Nikita Sharma
• Surendra Nimesh

GATA3 somatic mutations are associated with clinicopathological features and expression profile in TCGA breast cancer patients

• Fahimeh Afzaljavan
• Ayeh Sadat Sadr
• Alireza Pasdar

Explainable drug sensitivity prediction through cancer pathway enrichment

• Yi-Ching Tang
• Assaf Gottlieb

A novel biosensor for the ultrasensitive detection of the lncRNA biomarker MALAT1 in non-small cell lung cancer

• Dongming Wu

Neuroendocrine prostate cancer has distinctive, non-prostatic HOX code that is represented by the loss of HOXB13 expression

• Siyuan Cheng

New combination chemotherapy of cisplatin with an electron-donating compound for treatment of multiple cancers

• Qinrong Zhang
• Qing-Bin Lu

Lung adenocarcinoma and lung squamous cell carcinoma cancer classification, biomarker identification, and gene expression analysis using overlapping feature selection methods

• Joe W. Chen
• Joseph Dhahbi

Similarities between pandemics and cancer in growth and risk models

• Lode K. J. Vandamme
• Ignace H. J. T. de Hingh
• Paulo R. F. Rocha

Flavonoids increase melanin production and reduce proliferation, migration and invasion of melanoma cells by blocking endolysosomal/melanosomal TPC2

• Ponsawan Netcharoensirisuk
• Carla Abrahamian
• Christian Grimm

Convolutional autoencoder based model HistoCAE for segmentation of viable tumor regions in liver whole-slide images

• Mousumi Roy
• Vandana Mukherjee

Low temperature plasma irradiation products of sodium lactate solution that induce cell death on U251SP glioblastoma cells were identified

• Hiromasa Tanaka
• Masaru Hori

CAD systems for colorectal cancer from WSI are still not ready for clinical acceptance

• Sara P. Oliveira
• Pedro C. Neto
• Jaime S. Cardoso

Applicability of pan-TRK immunohistochemistry for identification of NTRK fusions in lung carcinoma

• Simon Strohmeier

Sulforaphane induces S-phase arrest and apoptosis via p53-dependent manner in gastric cancer cells

• Huazhang Wu

Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment

• L. E. Anselmino
• M. V. Baglioni
• M. Menacho Márquez

Evaluation of wavelength ranges and tissue depth probed by diffuse reflectance spectroscopy for colorectal cancer detection

• Marcelo Saito Nogueira
• Siddra Maryam
• Stefan Andersson-Engels

C. elegans -based chemosensation strategy for the early detection of cancer metabolites in urine samples

• Enrico Lanza
• Martina Di Rocco
• Viola Folli

Detection of colorectal cancer in urine using DNA methylation analysis

• R. D. M. Steenbergen

Learning deep features for dead and living breast cancer cell classification without staining

• Gisela Pattarone
• Laura Acion
• Emmanuel Iarussi

Epidemiological overview of multidimensional chromosomal and genome toxicity of cannabis exposure in congenital anomalies and cancer development

• Albert Stuart Reece
• Gary Kenneth Hulse

Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model

• Yoshihiro Miyazaki
• Tatsuya Oda
• Yasuyuki S. Kida

Loss of Parkinson’s susceptibility gene LRRK2 promotes carcinogen-induced lung tumorigenesis

• Chandra Lebovitz
• Nicole Wretham
• Sharon M. Gorski

Enhanced anti-cancer activity of andrographis with oligomeric proanthocyanidins through activation of metabolic and ferroptosis pathways in colorectal cancer

• Tadanobu Shimura
• Priyanka Sharma

Differential expression of PD-L1 between primary and metastatic epithelial ovarian cancer and its clinico-pathological correlation

• Sandeep Kumar Parvathareddy
• Abdul K. Siraj
• Khawla S. Al-Kuraya

Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer

• Ryoichi Katsube
• Kazuhiro Noma
• Toshiyoshi Fujiwara

Prognostic gene expression signatures of breast cancer are lacking a sensible biological meaning

• Kalifa Manjang
• Shailesh Tripathi
• Frank Emmert-Streib

Activity of docetaxel, carboplatin, and doxorubicin in patient-derived triple-negative breast cancer xenografts

• Miguel Martin
• Rocio Ramos-Medina
• Sara Lopez-Tarruella

Evidence for improved prognosis of colorectal cancer diagnosed following the detection of iron deficiency anaemia

• Orouba Almilaji
• Sally D. Parry
• Jonathon Snook

CDC2-like (CLK) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer

• Sean R. Porazinski
• Michael R. Ladomery

Prognostic value of prostate volume in non-muscle invasive bladder cancer

• Won Sik Ham
• Jee Soo Park
• Jongchan Kim

Histamine H1 receptor antagonists selectively kill cisplatin-resistant human cancer cells

• Nobuki Matsumoto
• Miku Ebihara
• Toru Imamura

A prognostic model for colorectal cancer based on CEA and a 48-multiplex serum biomarker panel

• Kajsa Björkman
• Sirpa Jalkanen
• Caj Haglund

Breath biopsy of breast cancer using sensor array signals and machine learning analysis

• Hsiao-Yu Yang
• Yi-Chia Wang
• Chi-Hsiang Huang

Targeting the DNA replication stress phenotype of KRAS mutant cancer cells

• Tara Al Zubaidi
• O. H. Fiete Gehrisch
• Henning Willers

CD73 facilitates EMT progression and promotes lung metastases in triple-negative breast cancer

• Nataliia Petruk
• Sanni Tuominen
• Katri S. Selander

Targeting galectin-3 with a high-affinity antibody for inhibition of high-grade serous ovarian cancer and other MUC16/CA-125-expressing malignancies

• Marina Stasenko
• David R. Spriggs

The clinical significance of microvascular invasion in the surgical planning and postoperative sequential treatment in hepatocellular carcinoma

• Wentao Wang

Elevated levels of mitochondrial CoQ 10 induce ROS-mediated apoptosis in pancreatic cancer

• Tulin Dadali
• Anne R. Diers
• Rangaprasad Sarangarajan

Evaluation of dose-volume histogram prediction for organ-at risk and planning target volume based on machine learning

• Sheng xiu Jiao
• Ming li Wang
• Xiao-wei Liu

Parvimonas micra , Peptostreptococcus stomatis, Fusobacterium nucleatum and Akkermansia muciniphila as a four-bacteria biomarker panel of colorectal cancer

• Muhammad Afiq Osman
• Hui-min Neoh
• Rahman Jamal

Abiraterone acetate versus bicalutamide in combination with gonadotropin releasing hormone antagonist therapy for high risk metastatic hormone sensitive prostate cancer

• Takashi Ueda
• Takumi Shiraishi
• Osamu Ukimura

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Jill Barnholtz-Sloan Named CBIIT’s Acting Director

June 6, 2024 , by NCI CBIIT Staff

Dr. Jill Barnholtz-Sloan  is now the acting director for  NCI Center for Biomedical Informatics and Information Technology  (CBIIT). She takes this role after Dr. Tony Kerlavage, the previous director for seven years, retired on May 31, 2024.

Dr. Barnholtz-Sloan, who has been with CBIIT for the past three years, shows an extensive involvement in and a profound understanding of data. She has strong relationships with CBIIT and NCI staff, and possesses clear knowledge of NCI research programs. As both an active researcher and administrator, she has insight into how to translate data into real-world solutions to help diagnose, prevent, and treat cancer.

Along with her new acting director responsibilities, Jill will maintain her position as associate director for the  Informatics and Data Science Program  within CBIIT. In this capacity, she spearheads initiatives to formulate informatics and  data science  strategies while supporting collaboration throughout NCI, NIH, and beyond. She’ll also continue her role as senior investigator in the  Division of Cancer Epidemiology and Genetics Trans-Divisional Research Program .

Dr. Barnholtz-Sloan is a sought-out expert in informatics and data science. She finds and addresses new ways for ensuring that CBIIT’s rich data tools are available to investigators globally.

“I am thrilled to have this opportunity to ensure CBIIT’s excellence in data science,  data sharing , and technology; I’ll continue to innovate in these areas that impact the cancer research community,” notes Dr. Barnholtz-Sloan.

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