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Cancer

Cancer is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells in the body, which can invade nearby tissues and metastasize to distant sites. These malignant cells differ from normal cells by ignoring growth signals, evading , and forming new blood vessels to sustain their . If left untreated, cancer can lead to severe health complications and death, making it one of the leading causes of mortality worldwide. Globally, cancer imposes a significant burden on systems and populations. In , an estimated 20 million new cases were diagnosed, resulting in 9.7 million deaths, with projections indicating a 77% increase in the cancer burden by 2050 due to , aging, and factors. In the United States alone, approximately 2,041,910 new cases and 618,120 deaths are expected in 2025, with , , , and colorectal cancers among the most common types. There are over 100 distinct types of cancer, broadly classified by the tissue of origin—such as carcinomas (from epithelial cells), sarcomas (from connective tissues), leukemias (from blood-forming tissues), and lymphomas (from the )—with carcinomas accounting for about 80-90% of cases. Cancer arises from genetic mutations that disrupt normal cell regulation, often triggered by a combination of inherited predispositions, environmental exposures (like , ultraviolet , and certain chemicals), and factors (including , physical inactivity, and consumption). Benign tumors, in contrast, do not invade or spread and are generally non-life-threatening, whereas malignant tumors exhibit aggressive behavior and require intervention. typically involves , from localized (stages I-II) to advanced metastatic disease (stage IV), guiding treatment options such as , , , , and targeted therapies, which have improved survival rates over time. Prevention strategies, including against cancer-causing viruses (e.g., HPV for ) and screening programs, play a crucial role in reducing incidence and enabling early detection.

Background

Etymology

The term "cancer" originates from the word karkinos (καρκίνος), meaning "," a term first applied to tumors by the physician around 400 BCE. Hippocrates and his followers used karkinos to describe non-ulcerated tumors and karkinoma for ulcerated ones, likening the swollen veins extending from the tumor to the legs of a crab grasping its prey. This terminology evolved through Roman medicine when , in the 1st century CE, translated the Greek karkinos directly into the Latin cancer, preserving the crab imagery in his medical encyclopedia De Medicina. Later, the Greek physician in the 2nd century CE refined the distinction, employing carcinoma specifically for malignant growths that spread aggressively, while reserving oncos (meaning "swelling") for more general tumors and differentiating them from benign conditions. In contemporary medical usage, "cancer" denotes a malignant characterized by uncontrolled and potential , explicitly contrasting with benign tumors that do not invade surrounding tissues. This precise delineation emerged with advancements in during the , solidifying the term's focus on over mere swelling or ulceration. Etymologically, the word also names the zodiac sign Cancer, derived from the same Latin root, symbolizing the summer solstice in ancient astronomy. Beyond medicine, "cancer" has permeated literature and culture as a metaphor for insidious corruption or unrelenting destruction, as seen in works from early modern Europe where it evoked social or moral decay.

Definitions

Cancer is a generic term for a large group of diseases characterized by the uncontrolled proliferation of abnormal cells that can invade adjacent tissues and metastasize to distant sites in the body. These malignant neoplasms arise from the transformation of normal cells into cancerous ones, leading to the formation of tumors or abnormal proliferations of cells that disrupt normal physiological functions. Unlike benign conditions, cancer's hallmark ability to spread distinguishes it as a potentially lethal disease if untreated. Central to the biological behavior of cancer cells are acquired capabilities that enable their survival and proliferation, as outlined in the seminal framework of cancer hallmarks. These include autonomy from exogenous growth signals, allowing self-sustained proliferation; evasion of , or ; induction of sustained to ensure nutrient supply; and attainment of replicative immortality through mechanisms like telomere maintenance. This framework, originally proposed in and updated in to incorporate emerging insights such as metabolic reprogramming and immune evasion, was further expanded in 2022 to include additional dimensions like unlocking and influences from polymorphic microbiomes, providing a conceptual foundation for understanding cancer's core attributes across diverse types. Cancer must be differentiated from non-malignant proliferative conditions to guide accurate and . Benign tumors consist of non-invasive cells that grow slowly, remain localized, and do not metastasize, posing risks primarily through rather than dissemination. In contrast, involves an increase in the number of normal-appearing cells due to excessive division, often reversible and non-neoplastic, while features abnormal cellular maturation, architectural disorganization, and , representing a precancerous state that may progress to if unchecked. These distinctions underscore cancer's unique malignant potential, rooted in genetic and epigenetic alterations that confer invasive properties. Neoplastic diseases, encompassing both benign and malignant forms, are systematically classified for clinical, epidemiological, and research purposes. The (WHO) Classification of Tumours series provides detailed, organ-specific histological and molecular criteria for tumor types, serving as the international standard for pathology-based diagnosis. Complementing this, the (, Chapter 2: Neoplasms) categorizes neoplasms by behavior—malignant (primarily 2A00–2E0Z), (integrated within malignant categories), benign (2E80–2F3Z), and uncertain or unknown (2D10–2E7Z and 2F00–2F9Z)—facilitating data standardization and coding for morbidity and mortality statistics (as of 2025). These systems ensure precise identification and tracking of cancer entities, supporting advances in precision medicine.

Clinical Presentation

Local Symptoms

Local symptoms of cancer refer to manifestations that arise directly from the presence and growth of the at its original site, often resulting from mechanical effects such as of surrounding tissues, obstruction of nearby structures, or ulceration of the surface . These symptoms vary depending on the tumor's and size but typically reflect the tumor's local impact rather than distant spread. For instance, in head and neck squamous cell carcinomas, well-localized at the primary site is a common early presentation due to the tumor mass exerting pressure on nerves and tissues. Site-specific examples illustrate how primary tumors produce distinct local signs. In , a common early symptom is a new lump or thickening in the breast tissue, often painless and firm, which may be accompanied by skin dimpling or nipple inversion as the tumor grows and distorts local anatomy. For , changes in existing moles or the appearance of new lesions, such as asymmetrical growths with irregular borders, varied colors, or evolving shapes (often summarized by the ABCDE criteria), signal the primary tumor's disruption of normal architecture. In , or blood in the stool arises from tumor ulceration or erosion into the intestinal mucosa, while changes in bowel habits like persistent or result from partial obstruction by the mass. Mechanisms underlying these symptoms include the tumor's , which causes pain or functional impairment through compression; obstruction, leading to blockages in hollow organs; and ulceration, resulting in bleeding or . In esophageal cancer, early local signs may be subtle, but as the tumor advances, it produces (difficulty swallowing) due to luminal narrowing from the mass or mucosal invasion. Similarly, in , a persistent often emerges early from or partial airway obstruction by the primary bronchial tumor, potentially progressing to (coughing up blood) with ulceration. Recognizing these non-specific yet persistent local changes is crucial for early detection, as they can mimic benign conditions but prompt timely investigation when enduring. For example, ongoing cough in or unexplained in may indicate the primary tumor's presence before more severe obstruction develops. Early intervention based on such signs can improve outcomes by addressing the tumor at its primary site.

Systemic Symptoms

Systemic symptoms in cancer arise from the disease's widespread effects on the body, often resulting from tumor-secreted factors, inflammatory responses, or metabolic disruptions rather than direct tumor invasion. These manifestations can precede or accompany local signs and may affect patients across various cancer types, signaling advanced disease or significant physiological burden. Fatigue is one of the most prevalent systemic symptoms, reported in up to 90% of cancer patients, stemming from anemia, cytokine-mediated inflammation, or deconditioning due to the illness. It manifests as profound tiredness not relieved by rest and can impair daily functioning, with studies linking it to elevated levels of pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α). Weight loss, often as part of cancer cachexia syndrome, affects approximately 80% of patients with advanced malignancies and involves involuntary loss of more than 5% of body weight over six months, driven by increased metabolic rate and appetite suppression via factors such as proteolysis-inducing factor (PIF). Cachexia contributes to muscle wasting and weakness, worsening prognosis, as evidenced by research showing it independently predicts mortality in lung and pancreatic cancers. Fever and night sweats, known as B symptoms in lymphomas, occur in about 20-30% of cases and result from tumor-induced pyrogenic cytokines or tumor necrosis, with interleukin-1 (IL-1) and IL-6 playing key roles in hypothalamic temperature regulation. Paraneoplastic syndromes represent remote effects of cancer mediated by humoral or immune mechanisms, occurring in 10-20% of patients and often preceding tumor . Hypercalcemia, induced by (PTHrP) secretion from tumors like squamous cell carcinomas, affects up to 30% of patients with solid tumors and leads to symptoms such as , confusion, and due to elevated serum calcium levels above 10.5 mg/dL. from ectopic (ACTH) production, seen in in about 2-5% of cases, causes , , and through excess. These syndromes highlight cancer's ability to disrupt endocrine balance without direct . Anemia complicates 30-90% of cancer cases depending on the type, arising from infiltration by tumor cells, effects, or chronic inflammation suppressing . In chronic disease , upregulation inhibits iron availability, leading to with levels below 12 g/dL in women and 13 g/dL in men, exacerbating and dyspnea. This is particularly common in inflammatory cancers like , where it correlates with disease stage and survival. Underlying many systemic symptoms is the release of cytokines from tumor cells and the host , with IL-6 promoting and fever by activating the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in muscle and liver tissues. This inflammatory milieu fosters a catabolic state, reducing and increasing energy expenditure, as demonstrated in preclinical models of colon cancer where IL-6 blockade ameliorated .

Metastatic Manifestations

Metastatic manifestations refer to the clinical symptoms and signs that arise when cancer cells spread from the to distant organs or tissues, forming secondary tumors that disrupt normal function. These effects are distinct from local or systemic symptoms of the primary cancer and often indicate advanced disease stage IV. Common metastatic sites include the bones, liver, lungs, and , where the presence of secondary tumors can lead to organ-specific complaints. In skeletal metastases, which frequently occur in cancers such as , , and , patients commonly experience persistent , often described as deep and aching, localized to the affected area like the back or hips. This pain results from tumor of , periosteal stretching, or microfractures, and may worsen at night or with movement. Fractures can occur spontaneously due to weakened structure, leading to sudden severe pain and mobility issues. Liver involvement, a frequent site for colorectal, breast, and pancreatic cancers, manifests as —a yellowing of and eyes—due to biliary obstruction from tumor or . Abdominal swelling or may accompany this, along with early and , as secondary tumors impair liver function and cause from portal vein obstruction. Brain metastases, common in , breast, and cases, produce neurological deficits such as headaches, seizures, confusion, or focal weaknesses, stemming from increased or direct of brain tissue by growing tumors. These symptoms can progress rapidly, affecting , , or . Pulmonary metastases, often from primary tumors in , colon, or , lead to , persistent , or as secondary tumors lung parenchyma or compress airways and blood vessels, reducing respiratory capacity. The of these metastatic symptoms generally involves three mechanisms: direct of tumor cells into surrounding tissues, causing local destruction and ; compression of adjacent structures like nerves, vessels, or ducts by expanding tumor masses; and the formation of secondary tumors that secrete factors leading to paraneoplastic effects or . For instance, metastases may trigger hypercalcemia through osteolytic activity, exacerbating and . In patients with a known cancer , the onset of new, unexplained symptoms—such as unexplained or sudden neurological changes—raises high suspicion for and necessitates prompt diagnostic workup, including imaging like , MRI, or scans, and possibly , to confirm spread and guide targeted therapies. Early recognition of these manifestations can improve symptom and through interventions like or systemic treatments.

Causes and Risk Factors

Chemical Carcinogens

Chemical carcinogens are exogenous substances that can initiate or promote cancer development by interacting with cellular processes, particularly through genotoxic effects on DNA. These agents are diverse, including components of , industrial pollutants, and naturally occurring toxins, and their carcinogenicity is evaluated based on epidemiological, experimental, and mechanistic evidence. Exposure often occurs via inhalation, ingestion, or dermal contact, leading to dose-dependent risks that vary by chemical potency and individual susceptibility factors. Tobacco smoke contains over 70 known carcinogens, with polycyclic aromatic hydrocarbons (PAHs) such as benzopyrene and tobacco-specific nitrosamines like 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) being among the most potent contributors to lung and bladder cancers. PAHs in cigarette smoke arise from incomplete combustion of tobacco and additives, while nitrosamines form during curing and processing; epidemiological studies link chronic exposure to a 15- to 30-fold increased risk of lung cancer in smokers. These compounds are classified as Group 1 carcinogens by the International Agency for Research on Cancer (IARC), indicating sufficient evidence of carcinogenicity in humans. Industrial and occupational chemicals represent another major class of carcinogens, with (a fibrous ) strongly associated with and due to its in , , and settings. , a volatile aromatic used in production and as a solvent, is linked to through bone marrow toxicity and chromosomal damage. Naturally produced aflatoxins, mycotoxins from fungi contaminating foodstuffs like peanuts and corn, primarily cause , especially in regions with high dietary exposure. All three—asbestos, benzene, and aflatoxins—are agents, with global bans or regulations implemented to mitigate risks, such as the U.S. EPA's phase-out of asbestos use. The primary mechanism of chemical carcinogenesis involves metabolic activation to reactive electrophiles that form covalent DNA adducts, leading to mutations in oncogenes and tumor suppressor genes. For instance, benzopyrene from tobacco smoke is oxidized by cytochrome P450 enzymes to the ultimate carcinogen benzopyrene-7,8-diol epoxide (BPDE), which binds preferentially to guanine bases in DNA, forming stable adducts that, if unrepaired, cause G-to-T transversions during replication. This process, first elucidated in seminal studies on PAH metabolism, underlies the initiation phase of tumorigenesis and is a key biomarker for exposure assessment in molecular epidemiology. Adduct formation is modulated by detoxification pathways like glutathione S-transferase, but overload can overwhelm repair mechanisms, promoting clonal expansion of mutated cells. The IARC Monographs program systematically classifies chemicals into groups based on carcinogenic hazard: (carcinogenic to humans, e.g., , ), Group 2A (probably carcinogenic, e.g., some PAHs), and Group 2B (possibly carcinogenic). As of , 135 agents are in Group 1, guiding international regulations like the EU's REACH framework and WHO's measures to reduce exposure. These evaluations integrate human studies, bioassays, and mechanistic data, emphasizing prevention through substitution and exposure limits.
ChemicalIARC GroupAssociated CancersPrimary Exposure Sources
1Lung, bladder,
1, lungOccupational (construction, mining)
1Industrial solvents, fuels
Aflatoxins1LiverContaminated foods (nuts, grains)

Lifestyle and Environmental Factors

and environmental factors play a significant role in cancer development, as certain modifiable behaviors and exposures can substantially influence risk through mechanisms such as , hormonal disruption, and DNA damage. These factors are distinct from inherent genetic predispositions or infectious causes, emphasizing the potential for prevention through behavioral changes. Among the most studied are dietary patterns, physical inactivity, consumption, and , each contributing to elevated risks for specific cancers like colorectal, , and liver types. Dietary habits, particularly high consumption of red and , are linked to increased risk primarily due to iron, a component that promotes and cellular damage in the colon. Epidemiological studies indicate that daily intake of 120 grams of elevates this risk by approximately 24%, while processed meats show a stronger association at 36% for 30 grams per day. Conversely, diets rich in from , , and whole grains offer protective effects against by facilitating bowel regularity, binding potential carcinogens, and supporting a healthy gut ; meta-analyses show that an additional 10 grams of daily intake reduces risk by about 10%. Both soluble and insoluble fibers contribute to this benefit, with insoluble types particularly aiding in reducing transit time for harmful compounds. A independently heightens cancer risk, with prolonged sitting or low associated with 20-30% increased incidence for and colon cancers compared to active individuals. Regular exercise mitigates this by improving insulin sensitivity, reducing , and regulating levels, with meta-analyses confirming a 24% lower colon cancer risk among physically active populations. This protective effect is evident across multiple studies, underscoring the importance of at least moderate activity to counteract the harms of inactivity. Alcohol consumption poses a dose-dependent for several cancers, with its metabolite directly damaging DNA and proteins while generating that promote . Even moderate intake elevates risk, while heavier use strongly correlates with through chronic and ; the risk rises linearly with grams consumed daily, affecting upper aerodigestive tract sites foremost. , characterized by excess , drives cancer via chronic low-grade and altered hormone production, particularly excess from in fat cells, which fuels hormone-sensitive tumors like those in the breast and . Inflamed releases pro-inflammatory cytokines such as interleukin-6 and , alongside elevated , linking to up to 13 cancer types with increased incidence and poorer prognosis in postmenopausal women.

Infectious Agents

Infections by certain viruses, bacteria, and parasites are established causes of various cancers, primarily through mechanisms involving chronic , direct cellular transformation, and immune evasion. These infectious agents are classified as Group 1 carcinogens by the International Agency for Research on Cancer (IARC), indicating sufficient evidence of carcinogenicity in humans. Among viruses, human papillomavirus (HPV), particularly high-risk types such as HPV-16 and HPV-18, is a major cause of . The viral oncoproteins and E7 play central roles by binding and degrading the tumor suppressor protein (via E6) and inactivating the pRb (via E7), thereby disrupting control and promoting uncontrolled proliferation. (HBV) and (HCV) are primary etiological agents of (HCC), the most common type of . Chronic infection with these viruses leads to persistent hepatic , , and , creating a microenvironment conducive to oncogenic mutations; HBV additionally integrates its DNA into host genomes, directly altering cellular genes. Epstein-Barr virus (EBV), a herpesvirus, is associated with several lymphomas, including , , and post-transplant . EBV immortalizes B lymphocytes through latent membrane proteins (e.g., LMP1) that mimic CD40 signaling, activating pathways and inhibiting , particularly in immunocompromised individuals. Bacterial infections also contribute to , with being the leading cause of gastric cancer, responsible for the majority of non-cardia adenocarcinomas. This Gram-negative bacterium colonizes the , inducing chronic that progresses to atrophy, , and . The CagA, delivered via a type IV secretion system, is translocated into epithelial cells where it phosphorylates and activates signaling cascades such as Src and PI3K, promoting cell motility, inflammation, and eventual . Parasitic infections, though less common globally, are significant in endemic areas. Schistosoma haematobium, a trematode prevalent in and the , causes of the through chronic urinary tract inflammation and irritation from egg deposition, leading to epithelial hyperplasia, , and genotoxic damage from nitrosamines produced by bacterial superinfections. Similarly, the Opisthorchis viverrini, found in , induces by provoking chronic inflammation, , and periductal ; parasite secretions and immune responses generate that damage DNA in cholangiocytes. Globally, infectious agents account for approximately 12% of all new cancer cases, equating to about 2.4 million incident cases in 2022, with a disproportionate burden in low- and middle-income countries where the proportion can reach up to 25% in some regions of and due to limited and coverage.

Radiation and Physical Agents

Ionizing radiation, which includes (UV) light and X-rays, is a well-established physical that induces DNA damage leading to cancer. UV radiation, particularly UVB wavelengths, penetrates the skin and causes the formation of cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts in DNA, which are highly mutagenic and primarily responsible for skin cancers such as , , and . These lesions, if unrepaired, lead to characteristic C>T transition mutations in oncogenes and tumor suppressor genes like TP53, driving photocarcinogenesis. Diagnostic imaging procedures involving X-rays and computed tomography (CT) scans expose bone marrow to ionizing radiation, elevating the risk of leukemia, especially in children. Studies of pediatric CT exposures have shown a dose-dependent increase in leukemia incidence, with estimated red bone marrow doses as low as 5-10 mGy associated with a detectable excess risk of acute lymphoblastic and myeloid leukemias. This risk arises from radiation-induced mutations in hematopoietic stem cells within the bone marrow, with cumulative exposures from multiple scans amplifying the effect. The relationship between exposure and cancer risk is described by the linear no-threshold (LNT) model, which posits that carcinogenic effects occur proportionally to dose without a safe threshold, even at low levels. This model originated from early experiments on in fruit flies and was formalized for human protection based on epidemiological data from high-dose exposures, such as atomic bomb survivors, extrapolated linearly to low doses. The LNT framework underpins radiation safety standards, assuming that risks from low-dose exposures, like those from , are small but nonzero and cumulative over lifetime. Beyond radiation, mechanical physical agents, such as chronic friction and irritation, can promote carcinogenesis through persistent tissue damage and inflammation. For instance, habitual pipe smoking causes localized mechanical irritation and thermal injury to the lower lip, establishing a causal link to squamous cell carcinoma of the lip via epithelial hyperplasia and eventual malignant transformation. Asbestos fibers represent another key physical carcinogen, acting through direct mechanical disruption and indirect inflammatory pathways to induce lung cancer and mesothelioma. Upon inhalation, durable asbestos fibers, particularly amphibole types like crocidolite, embed in lung parenchyma and pleural tissues, triggering frustrated phagocytosis by macrophages, which releases reactive oxygen species (ROS) and pro-inflammatory cytokines. This chronic inflammation leads to DNA strand breaks, epigenetic alterations, and activation of oncogenes like NF-κB, with fiber length and biopersistence determining potency—longer fibers (>5 μm) being more carcinogenic due to impaired clearance. Occupational exposure to gas, an alpha-emitting product of , is a major cause of among underground miners. Radon progeny deposit on lung , delivering high localized doses that induce DNA double-strand breaks and mutations, with cohort studies of uranium miners showing a linear excess of lung cancer at 1.7% per 100 working level months (WLM) of exposure. This risk is multiplicative with but persists independently in nonsmokers, underscoring radon's role as a potent physical in mining environments.

Genetic and Hereditary Factors

Approximately 5% to 10% of all cancers are attributable to inherited changes passed from a parent. These hereditary factors primarily involve mutations in specific genes that predispose individuals to certain cancer types, often following an autosomal dominant inheritance pattern with incomplete . While most cancers arise sporadically, understanding these genetic predispositions enables targeted screening and preventive measures for at-risk families. Hereditary syndromes exemplify high-penetrance genetic risks, such as mutations in the BRCA1 and BRCA2 genes, which account for 5% to 10% of breast cancer cases and a significant proportion of ovarian cancers. Individuals carrying pathogenic variants in BRCA1 or BRCA2 face lifetime breast cancer risks of 55% to 72% and ovarian cancer risks of 39% to 44%, respectively, highlighting the substantial impact of these mutations on familial cancer burden. Similarly, Lynch syndrome, caused by germline defects in DNA mismatch repair genes including MLH1, MSH2, MSH6, and PMS2, is responsible for about 3% of colorectal cancers and increases the lifetime risk of colorectal cancer to 52% to 82%. This syndrome also elevates risks for endometrial, ovarian, and other cancers due to impaired DNA repair mechanisms that lead to microsatellite instability. In contrast, the majority of cancers develop through the accumulation of mutations in non-inherited cells, as described by Knudson's originally proposed for . This model posits that both hereditary and sporadic forms of require inactivation of both alleles of the RB1 : in familial cases, one mutation is and the second is , while sporadic cases necessitate two hits. The hypothesis has broader implications, explaining how mutations drive the onset of many common cancers without a hereditary component. Additionally, genome-wide association studies (GWAS) have identified numerous low-penetrance common variants that contribute to cancer risk, which can be aggregated into polygenic risk scores (PRS) to estimate an individual's overall genetic susceptibility. These PRS, incorporating hundreds of variants, refine risk prediction beyond high-penetrance genes and interact with environmental factors to modulate cancer incidence.

Hormonal and Autoimmune Influences

Hormonal imbalances significantly contribute to cancer by promoting uncontrolled in hormone-sensitive tissues. Prolonged exposure to is a key for hormone-receptor-positive , which accounts for approximately 70-75% of cases, as binds to (ERα) on breast epithelial cells, stimulating proliferation and inhibiting . Women with extended endogenous exposure, such as those experiencing early or late , face a 20-50% higher of developing this subtype compared to those with shorter exposure periods. Similarly, elevated insulin and (IGF-1) levels, often associated with and , increase endometrial cancer by activating IGF-1 receptor signaling, which enhances endometrial cell proliferation and survival. can upregulate local production in , further exacerbating this in postmenopausal women. Autoimmune diseases elevate cancer risk primarily through chronic inflammation and immune system dysregulation, which foster a microenvironment conducive to . In primary Sjögren's syndrome (pSS), patients exhibit an 8- to 10-fold increased standardized incidence ratio (SIR) for , driven by persistent B-cell hyperactivity and ectopic lymphoid structures in salivary glands. This risk is further heightened by factors like and use, with lymphoma often manifesting as mucosa-associated lymphoid tissue (MALT) type. Systemic (SLE) is linked to a 12- to 27-fold elevated SIR for hematologic malignancies, including and , owing to impaired immune surveillance and recurrent infections that promote lymphoproliferation. Older age at SLE onset independently doubles the odds of these malignancies compared to younger-onset cases. The underlying mechanisms involve hormone-driven proliferation, where ligands like and IGF-1 bind nuclear receptors to activate transcription programs that upregulate cyclins and growth factors, leading to sustained in and endometrial tissues. In autoimmune contexts, immune evasion arises from dysregulated tolerance, where chronic autoantigen stimulation exhausts cytotoxic T cells and promotes regulatory T-cell dominance, impairing anti-tumor immunity and allowing nascent cancers to escape detection. A representative example is oral contraceptive use, which reduces risk by 30-50% after 5 or more years of use through suppression and decreased exposure, but increases risk by 20-60% in human papillomavirus-infected women due to progestin-enhanced viral persistence and epithelial changes.

Pathophysiology

Genetic Mutations

Genetic mutations play a central role in the initiation and progression of cancer by altering DNA sequences that disrupt normal cellular regulation. These somatic alterations accumulate in the genome of cancer cells, leading to uncontrolled proliferation, evasion of cell death, and other hallmarks of malignancy. Unlike germline mutations that may predispose individuals to cancer, somatic mutations arise sporadically within tumors and drive oncogenesis through specific genetic changes. Oncogenes arise from mutations that activate proto-oncogenes, promoting excessive cell growth and division. For instance, mutations in genes, which encode involved in , occur in approximately 19% of all human cancers and constitutively activate downstream pathways like MAPK, thereby enhancing . In , deregulation via of the oncogene, a that regulates genes, drives aggressive B-cell and is associated with poor prognosis in some cases. Tumor suppressor genes, conversely, normally inhibit cell growth, and their inactivation through mutations allows unchecked tumor development. The TP53 gene, encoding the protein that induces in response to DNA damage, is mutated in over 50% of human cancers, leading to loss of this protective mechanism and genomic instability. A notable example is Li-Fraumeni syndrome, where germline TP53 mutations confer a lifetime cancer approaching 90%, predisposing carriers to multiple tumor types including sarcomas, breast cancers, and brain tumors due to impaired and . Within tumors, mutations are classified as driver or based on their functional impact. Driver mutations confer a selective growth advantage to cancer cells, while passenger mutations are neutral byproducts of genomic instability that do not directly contribute to tumorigenesis. This distinction underlies clonal evolution in cancer, where driver mutations enable Darwinian selection of fitter subclones, leading to intratumor heterogeneity and disease progression. Mutational signatures provide insights into the mutational processes shaping cancer genomes, reflecting specific patterns of DNA alterations. In , enzymes induce cytosine-to-thymine mutations at TC dinucleotides, contributing to tumor evolution and therapy resistance. Similarly, ultraviolet radiation exposure generates a signature of C>T transitions at dipyrimidine sites, predominantly observed in skin cancers like , highlighting the environmental of these mutations.

Epigenetic Modifications

Epigenetic modifications in cancer involve heritable changes in gene expression without alterations to the underlying DNA sequence, playing a critical role in tumorigenesis by silencing tumor suppressor genes and activating oncogenes. These changes include DNA methylation, histone modifications, and regulation by non-coding RNAs, which collectively disrupt normal cellular control mechanisms. Unlike genetic mutations, which permanently alter DNA and are covered elsewhere, epigenetic alterations can interact with mutations to enhance cancer progression but are often reversible, offering therapeutic opportunities. DNA methylation, primarily occurring at CpG islands in gene promoters, leads to through the addition of methyl groups to bases, a process mediated by DNA methyltransferases. In cancer, aberrant hypermethylation frequently inactivates tumor suppressor ; for instance, hypermethylation of the O6-methylguanine-DNA methyltransferase () promoter in gliomas silences this , impairing the cell's ability to counteract alkylating agents and promoting genomic . This modification is observed in approximately 40-50% of cases and serves as a prognostic for improved response to chemotherapy. Histone modifications, such as and deacetylation, regulate structure and accessibility for transcription factors, thereby influencing . Histone deacetylases (HDACs) remove acetyl groups from residues on tails, leading to condensation and repression of transcription; overexpression of HDACs in cancers contributes to tumorigenesis primarily by repressing tumor suppressor genes, such as those involved in control and , thereby promoting activity and . For example, and HDAC2 are upregulated in various solid tumors, where they repress genes like p21, enhancing cell growth. HDAC inhibitors, such as , exploit this mechanism to restore acetylation and reactivate silenced genes. Non-coding RNAs, particularly microRNAs (miRNAs), post-transcriptionally regulate by binding to messenger RNAs, leading to their degradation or translational repression. In multiple cancers, miR-21 is overexpressed and acts as an by targeting the tumor suppressor PTEN, which normally inhibits the PI3K/AKT signaling pathway to prevent uncontrolled cell growth. This repression of PTEN by miR-21 has been documented in , non-small cell , and , where elevated miR-21 levels correlate with increased invasion and poor prognosis.00817-3/fulltext) The reversibility of epigenetic modifications distinguishes them from genetic changes and underpins targeted therapies that restore normal gene expression patterns. DNA methyltransferase inhibitors like azacitidine, approved by the FDA in 2004 for myelodysplastic syndromes (MDS), incorporate into RNA and DNA to deplete methyltransferases, leading to hypomethylation and re-expression of silenced genes such as p15 and p16. Clinical trials, including the AZA-001 study, demonstrated that azacitidine extends overall survival in higher-risk MDS patients by 9.4 months compared to conventional care, highlighting its role in epigenetic reprogramming.70001-8/fulltext)

Metastatic Mechanisms

Metastasis, the spread of cancer cells from the to distant sites, is a complex, multi-step process that enables the formation of secondary tumors. This dissemination begins with the acquisition of invasive properties by cancer cells, allowing them to breach tissue barriers and enter the , followed by their survival during transit, arrest at distant organs, and eventual colonization. Central to these events is the epithelial-mesenchymal transition (), a reversible program that transforms adherent epithelial cells into motile mesenchymal cells, enhancing their migratory and invasive capabilities. During EMT, transcription factors such as and play pivotal roles in repressing epithelial markers like E-cadherin while upregulating mesenchymal genes such as and N-cadherin, thereby promoting cell motility and resistance to . , for instance, induces EMT by directly suppressing E-cadherin expression and activating pathways that facilitate tumor cell invasion into surrounding . Similarly, drives EMT through similar transcriptional repression and is associated with increased metastatic potential in various carcinomas. These factors are often upregulated by signals from the , such as transforming growth factor-β (TGF-β), underscoring their context-dependent activation in . Following , cancer cells undergo intravasation, the entry into blood or lymphatic vessels, and later , their exit at distant sites, both processes heavily reliant on the degradation of the (). Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, are key effectors in these steps; for example, MMP-2 and MMP-9 remodel the to create breaches in the , enabling tumor cell intravasation into the bloodstream. During , MMPs facilitate adhesion to endothelial cells and penetration through vessel walls, with MMP-9 particularly implicated in promoting transendothelial migration in experimental models of . Dysregulated MMP activity not only aids physical invasion but also releases bioactive fragments that further stimulate tumor progression. Prior to the arrival of circulating tumor cells, primary tumors establish a pre-metastatic niche at future metastatic sites through secreted factors that prime the microenvironment for . The CXCL12, produced by stromal cells in target organs, interacts with its receptor on cancer cells to direct their homing and survival, creating a supportive niche via signaling that enhances and proliferation. This CXCL12/ axis recruits bone marrow-derived cells to the niche, fostering and , as demonstrated in models where blockade disrupts pre-metastatic conditioning and reduces incidence. Such signaling exemplifies how tumors orchestrate distant site preparation to favor seeding. The non-random distribution of metastases, known as organ tropism, is elegantly captured by Stephen Paget's 1889 "seed and soil" hypothesis, which posits that viable tumor cells (seeds) preferentially metastasize to compatible organ microenvironments (soils) rather than disseminating randomly. For instance, cells exhibit a strong tropism for due to the supportive niche rich in growth factors like TGF-β, which activates osteoclasts and promotes osteolytic lesions upon seeding. This hypothesis has been validated through clinical observations and experimental data showing that tropism arises from molecular compatibilities, such as expression guiding cells to CXCL12-abundant bones. Modern extensions incorporate dynamic interactions between seed properties and soil factors, explaining patterns like prostate cancer's affinity for .

Tumor Metabolism

Cancer cells exhibit distinct metabolic reprogramming compared to normal cells, enabling rapid proliferation and survival in nutrient-limited environments. This adaptation, often termed the metabolic hallmarks of cancer, prioritizes biosynthetic pathways over efficient energy production, diverting resources toward biomass generation such as nucleotides, amino acids, and lipids.01066-0) A hallmark of this reprogramming is the Warburg effect, where cancer cells preferentially utilize aerobic glycolysis even in the presence of oxygen, leading to increased glucose uptake and lactate production rather than complete oxidation in mitochondria. This shift, first observed by Otto Warburg in the 1920s, supports rapid ATP generation and provides glycolytic intermediates for biosynthesis, with lactate dehydrogenase (LDH) upregulated to convert pyruvate to lactate, maintaining NAD+ levels for sustained glycolysis. In many tumors, such as those in breast and lung cancers, this results in elevated lactate levels that acidify the tumor microenvironment, promoting invasion and immune evasion.01066-0) Many cancers also display glutamine addiction, relying heavily on as a carbon and source for . In MYC-driven cancers, like lymphomas and neuroblastomas, the glutaminase enzyme (GLS) is upregulated, facilitating conversion to glutamate and entry into the tricarboxylic acid () cycle for and . This dependency arises from MYC's transcriptional activation of glutaminolytic genes, making depletion a potential therapeutic vulnerability in these tumors.00366-8) Metabolic vulnerabilities in cancer include in 1 and 2 (IDH1/2), prevalent in gliomas and acute myeloid leukemias, which produce the oncometabolite 2-hydroxyglutarate (2-HG) instead of α-ketoglutarate. This neomorphic activity inhibits α-ketoglutarate-dependent dioxygenases, disrupting epigenetic regulation and promoting tumorigenesis by altering DNA and patterns.00527-1) In gliomas, IDH1/2 mutations occur in over 70% of low-grade cases, with 2-HG levels reaching millimolar concentrations that mimic hypoxia-inducible factors. Therapeutic strategies target these metabolic alterations, such as metformin, a used for , which inhibits mitochondrial complex I and downstream signaling to suppress cancer cell growth. Epidemiological data link metformin use in diabetics to reduced cancer incidence, including colorectal and breast cancers, by up to 30-50%, attributed to its role in lowering insulin levels and directly impairing tumor bioenergetics.00441-0) Clinical trials are exploring metformin in combination therapies to exploit these vulnerabilities, particularly in metabolic-dependent tumors.

Diagnosis

Clinical Evaluation

Clinical evaluation begins with a thorough assessment of the patient's history and physical findings to identify signs suggestive of cancer and guide subsequent diagnostic steps. This initial evaluation is crucial for determining the urgency of further investigation and establishing a for the patient's overall health status. It integrates patient-reported information with objective clinical observations to contextualize symptoms within the broader risk profile. History taking forms the cornerstone of clinical evaluation, focusing on the patient's , family history, risk factors, and symptom characteristics. A detailed family history is obtained by constructing a three-generation pedigree that includes cancers in first-, second-, and third-degree relatives, noting the age at diagnosis, tumor types, and any hereditary patterns to assess for inherited syndromes such as Lynch or . Risk factors are systematically reviewed, encompassing lifestyle elements like tobacco and alcohol use, environmental exposures, and personal medical history such as prior cancers or ethnic predispositions (e.g., Ashkenazi Jewish heritage increasing BRCA-related risks). Symptom duration and progression are carefully documented using a chronological timeline, including onset, aggravating or relieving factors, and any delays in seeking care, which can influence prognosis and inform the likelihood of advanced disease. The complements history taking by providing objective evidence of potential through systematic inspection and . Key maneuvers include of the for masses, noting their size, location, fixation, and tenderness, as well as assessment for such as or indicative of underlying tumors or metastases. evaluation involves palpating , axillary, and inguinal regions for enlarged, firm, or matted nodes, which may signal from primary cancers or . Additional targeted exams, such as digital for prostate irregularities or for abnormalities, are performed based on symptoms to detect palpable lesions. Performance status scales are employed to quantify the patient's functional capacity and predict tolerance to potential treatments. The Eastern Cooperative Oncology Group (ECOG) scale categorizes patients from 0 (fully active, able to carry on all pre-disease activities without restriction) to 5 (dead), assessing ambulatory ability, , and daily activity levels to stratify and eligibility for clinical trials. Similarly, the Karnofsky scale rates function from 100 (normal, no complaints, no evidence of disease) to 0 (dead), evaluating the need for assistance in daily living and medical care requirements, which aids in comparing therapy effectiveness and forecasting survival in advanced cancer. Certain findings during evaluation warrant immediate concern as red flags for occult malignancy. Unexplained , particularly exceeding 10% of body weight over six months, signals possible from underlying cancer and necessitates prompt investigation. Persistent, unexplained —such as ongoing back, abdominal, or joint discomfort not attributable to —represents another critical indicator, often reflecting tumor or metastatic spread, and should prompt expedited referral.

Imaging Techniques

Imaging techniques play a crucial role in the detection, localization, and characterization of tumors in cancer patients by providing non-invasive visualization of anatomical structures and functional processes. and are primary modalities for assessing anatomical details, such as tumor size, location, and involvement of surrounding tissues. CT scans utilize X-rays to generate cross-sectional images, offering high-resolution views of dense structures like bones and lungs, which is particularly useful for thoracic and abdominal malignancies. MRI, employing magnetic fields and radio waves, excels in contrast, making it ideal for evaluating brain, liver, and musculoskeletal tumors without exposure. Positron emission tomography combined with CT (PET-CT) integrates metabolic and anatomical information, enhancing tumor detection through the uptake of fluorodeoxyglucose (FDG), a radioactive glucose analog that accumulates in hypermetabolic cancer cells. This modality is widely used for identifying metabolically active lesions in lymphomas, lung cancers, and colorectal metastases, with sensitivity often exceeding 90% for FDG-avid tumors. In comparison, PET-MRI offers superior resolution and reduced radiation compared to PET-CT, showing comparable or better performance in head and neck, , and cancers. Specific imaging methods are tailored to organ systems for optimal tumor detection. , a low-dose technique, is the standard for , detecting microcalcifications and masses with a of 85-90% in women aged 40-74, as recommended by major guidelines for annual or biennial use in average-risk populations. serves as the initial imaging for nodules, distinguishing solid from cystic lesions and identifying suspicious features like microcalcifications or irregular margins, with high specificity for guiding in nodules over 1 cm. For gastrointestinal cancers, provides direct visualization of the esophageal, , and colorectal mucosa, enabling early detection of precancerous lesions like or adenomas through high-definition optics and capabilities. Recent advances in (AI) have improved the accuracy of imaging for early cancer detection, particularly in identifying subtle lung nodules on low-dose CT scans. AI algorithms, such as deep learning models, achieve sensitivities of 70-93% for nodule detection, outperforming or matching radiologists in reducing false negatives and prioritizing high-risk findings in screening programs. Transformer-based AI systems further enhance segmentation and of nodules, facilitating earlier intervention in high-risk smokers. Despite these benefits, from and PET-CT scans poses s, particularly with cumulative doses from serial imaging in cancer follow-up. Effective doses from a single chest range from 5-7 mSv, and cumulative exposures exceeding 100 mSv in patients with multiple scans are associated with a 1-2% increased lifetime attributable cancer , varying by , , and scanned . Guidelines emphasize dose optimization, such as using low-dose protocols and alternating with non-ionizing modalities like MRI or , to minimize long-term effects.

Biopsy and Laboratory Tests

Biopsy procedures are essential for obtaining tissue samples to confirm the presence of cancer cells and determine their characteristics. These methods allow pathologists to examine cellular morphology and molecular features directly from the tumor site. Common biopsy techniques include fine-needle aspiration (FNA), core needle biopsy (CNB), and surgical biopsy, each selected based on the tumor's location, size, and accessibility. FNA involves using a thin needle to extract cells from a lump or mass, providing rapid results but often limited to cytological analysis rather than full tissue architecture. CNB employs a larger needle to obtain a cylindrical core of tissue, enabling more accurate histopathological diagnosis compared to FNA, with higher rates of definitive benign or malignant classification. Surgical biopsy, including excisional or incisional approaches, removes a larger portion or the entire suspicious area and is typically reserved for cases where less invasive methods are inconclusive or when comprehensive sampling is needed. Many biopsies are performed under imaging guidance, such as ultrasound or CT, to precisely target the lesion. Liquid biopsy represents a non-invasive alternative or complement to tissue sampling, particularly for ongoing monitoring. It analyzes (ctDNA) shed into the bloodstream by tumor cells, allowing detection of genetic alterations without repeated invasive procedures. ctDNA-based liquid biopsies are valuable for tracking treatment response, identifying , and detecting emerging resistance mutations in . This approach has shown promise in various cancers, though challenges remain in sensitivity for low-burden disease and standardization across platforms. Laboratory tests often include the measurement of tumor markers, which are substances produced by cancer cells or the body in response to , aiding in and surveillance. () is a widely used blood-based marker for , where elevated levels may prompt further investigation, though its specificity is limited by elevations in benign conditions like . Similarly, cancer antigen 125 (CA-125) serves as a marker for , with a of approximately 79% for detection, but it lacks specificity due to elevations in non-malignant states such as or . These markers are not diagnostic alone and must be interpreted alongside clinical findings, as false positives can lead to unnecessary procedures. Pathological examination of biopsy samples typically begins with hematoxylin and eosin (H&E) staining, the standard method for visualizing structure and identifying malignant features like irregular nuclei and mitotic activity. (IHC) builds on this by using antibodies to detect specific proteins, providing insights into tumor biology; for instance, IHC assesses human epidermal growth factor receptor 2 (HER2) expression in , where overexpression (scored 3+) indicates eligibility for targeted therapies. IHC for HER2 offers high efficiency in metastatic cases, with around 95-96%, though equivocal results (score 2+) often require confirmatory testing. Molecular testing on biopsy material has advanced with next-generation sequencing (NGS), a high-throughput technique that profiles multiple genetic alterations simultaneously. In non-small cell lung cancer (NSCLC), NGS detects (EGFR) mutations, such as exon 19 deletions or L858R substitutions, which occur in about 10-15% of cases and guide targeted inhibitor use. NGS surpasses traditional methods like in identifying complex or rare variants, with advantages in sensitivity for low-frequency mutations in heterogeneous tumors. This approach enables comprehensive genomic profiling, informing personalized diagnostic strategies.

Classification

Histopathological Types

Histopathological classification of cancer relies on the microscopic examination of tumor to identify the cell of origin and characteristic morphological features, enabling categorization into distinct types that guide and . This approach, standardized by organizations such as the (WHO), emphasizes architecture, , and patterns observed under light microscopy following or surgical resection. Carcinomas, the most prevalent histopathological type accounting for 80-90% of all human cancers, arise from lining organs, glands, or body surfaces. They are subdivided based on the type of involved: originate from glandular and exhibit microscopic features such as glandular structures or production, commonly affecting sites like the , , colon, and ; in contrast, squamous carcinomas develop from squamous and display pearls, intercellular bridges, and flattened s, frequently occurring in the skin, , , and . For instance, in non-small (NSCLC), the WHO recognizes as the predominant subtype, characterized by lepidic, acinar, or papillary growth patterns. Sarcomas originate from mesenchymal cells of connective tissues, including , muscle, , and , and represent a rarer category comprising about 1% of adult malignancies but up to 15% in children. Microscopically, they often appear as spindle-shaped or pleomorphic cells resembling the native , forming whorled or fascicular patterns. Osteosarcomas, for example, produce and affect , showing malignant osteoblasts under , while leiomyosarcomas derive from and feature intersecting fascicles of spindle cells with cigar-shaped nuclei and varying degrees of atypia. Leukemias and lymphomas emerge from hematopoietic and lymphoid tissues, classified by and maturity under microscopic and flow cytometric analysis. Leukemias involve the and , with overproduction of immature blasts; shows myeloblasts with , while displays small mature lymphocytes. Lymphomas form solid tumors in lymph nodes or extranodal sites, with subtypes like featuring Reed-Sternberg cells amid inflammatory backgrounds, and non-Hodgkin lymphomas encompassing diverse B- or T-cell proliferations with follicular or diffuse architectures. The WHO delineates over 80 lymphoma subtypes based on these features. Germ cell tumors develop from primordial germ cells, typically in the gonads or midline structures like the , and are identified microscopically by primitive elements mimicking embryonic development. They include seminomas with uniform cells and lymphocytic infiltrates, tumors showing Schiller-Duval bodies, and mixed forms combining multiple components like embryonal carcinoma and . The WHO system codes these under specific histological groups for ovarian and testicular sites, emphasizing their totipotent potential.

Staging Systems

Staging systems in provide a standardized method to assess the extent of cancer spread, guiding decisions and prognostic estimates. The most widely adopted is the TNM classification, which categorizes tumors based on three key components: the (T), regional involvement (N), and distant (M). Developed by Pierre Denoix in the 1940s and first formalized in the 1950s, the TNM has become the global standard for solid tumors, enabling consistent communication among healthcare professionals worldwide. In the TNM framework, the T category describes the size and extent of the , ranging from (primary tumor cannot be assessed) to T4 (tumor invades adjacent structures extensively), with intermediate categories like T1 for small, localized tumors and Tis for . The N category evaluates involvement, from N0 (no regional metastasis) to N3 (extensive regional spread), while the M category indicates distant as M0 (none) or M1 (present). These categories are site-specific, with criteria varying by cancer type to reflect anatomical differences, such as tumor invasion depth in versus size in . The American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) collaboratively maintain and update the TNM system, with the AJCC Version 9 released starting in 2024 and the UICC 9th edition released in 2025 to incorporate refined criteria based on survival data from international registries. TNM categories are combined into stage groupings from 0 to IV to simplify clinical application and provide prognostic stratification. Stage 0 represents disease, confined to the without ; stage I indicates localized cancer with low risk; stage II involves local extension but no nodal or distant spread; stage III denotes regional spread to lymph nodes; and stage IV signifies distant , typically associated with advanced disease. These groupings, often subdivided (e.g., IVA, IVB), are tailored per cancer site in the AJCC Cancer Staging Manual and UICC TNM , ensuring they align with evidence from large-scale databases like the Surveillance, Epidemiology, and End Results () program. requires histological confirmation of malignancy, typically via , to validate the anatomical findings. For certain cancers, site-specific systems supplement or replace TNM to better capture disease behavior. The International Federation of Gynecology and Obstetrics (FIGO) staging is used for gynecologic malignancies, such as , , and ovarian cancers, emphasizing pelvic organ involvement, status, and peritoneal spread rather than strict tumor size metrics. For example, the 2023 FIGO update for integrates myometrial invasion and involvement into stages I-IV, incorporates molecular subtyping to further stratify stages based on prognostic molecular profiles such as abnormal (p53abn) and POLE ultramutated (POLEmut), harmonizing with TNM where possible but prioritizing gynecologic . Similarly, lymphomas employ the Ann Arbor system, modified as the classification, which divides disease into stages I-IV based on the number of regions affected, diaphragmatic involvement, and extranodal sites, with modifiers for bulky disease (X) or systemic symptoms (A/B). This approach differs from TNM by focusing on lymphatic distribution rather than solid tumor dimensions. Despite its utility, the TNM system has limitations, primarily its reliance on anatomical extent without integrating molecular or biological factors, which can lead to heterogeneous prognoses within the same stage. For instance, advances in reveal that tumors with similar T, N, and M profiles may differ significantly in aggressiveness due to unaccounted variables like expression, complicating personalized treatment. The system's periodic updates help address evolving data, but its anatomical focus remains a constraint in the era of precision oncology.

Molecular and Genomic Classification

Molecular and genomic classification of cancer involves analyzing genetic mutations, patterns, and proteomic profiles to delineate tumor subtypes that inform , therapeutic response, and personalized strategies. This approach has revolutionized by moving beyond traditional histopathological methods to identify biologically distinct subgroups with varying clinical behaviors. (TCGA) project has been instrumental in this domain, providing comprehensive multi-omics data that enable robust subtype definitions across various cancers. In , TCGA analyses have identified four primary molecular subtypes—proneural, neural, classical, and mesenchymal—based on integrated genomic, transcriptomic, and epigenomic features. The proneural subtype is characterized by in (IDH1), platelet-derived growth factor receptor alpha (PDGFRA) amplifications, and expression of genes associated with neural progenitor s, often showing better response to therapies targeting these pathways. In contrast, the mesenchymal subtype exhibits NF1 , higher immune infiltration, and upregulation of mesenchymal transition genes, correlating with more aggressive and poorer outcomes. These classifications highlight intratumoral heterogeneity and guide targeted interventions, such as those exploiting mesenchymal vulnerabilities in . Breast cancer exemplifies the application of genomic tools in subtyping, with the PAM50 gene signature—a 50-gene expression panel—stratifying tumors into luminal A, luminal B, HER2-enriched, basal-like, and normal-like categories to predict recurrence risk and tailor endocrine or targeted therapies. (TNBC), corresponding largely to the basal-like subtype, lacks expression of (ER), (PR), and human epidermal growth factor receptor 2 (HER2), comprising about 15-20% of cases and exhibiting high genomic instability with frequent BRCA1/2 mutations, leading to aggressive disease and limited targeted options. Conversely, the HER2-enriched subtype features HER2 amplification and overexpression, often with ER/PR negativity, and responds robustly to anti-HER2 agents like , underscoring the prognostic and therapeutic divergence between these profiles. The PAM50 assay, validated in clinical settings, integrates with these subtypes to refine risk assessment in hormone receptor-positive cases, enabling by identifying low-risk patients who may avoid . In , genomic classification centers on driver mutations, with BRAF-mutant tumors—present in approximately 40-50% of cutaneous melanomas—defining a subtype responsive to BRAF and MEK inhibitors like and trametinib. These mutations, predominantly , activate the MAPK pathway, promoting uncontrolled proliferation, and TCGA frameworks further subclassify melanomas into BRAF-mutant, NRAS-mutant, NF1-mutant, and triple-wild-type groups based on mutually exclusive alterations, influencing metastatic potential and efficacy. BRAF-mutant melanomas often arise in younger patients with intermittent sun exposure and show distinct transcriptomic profiles compared to UV-signature-driven subtypes. A key prognostic implication of genomic classification is seen in , where microsatellite instability-high (MSI-H) tumors—arising from deficient mismatch repair (dMMR) and comprising 15% of cases—exhibit hypermutation and high , predicting superior responses to inhibitors like . MSI-H status identifies patients with durable clinical benefits, including objective response rates exceeding 40% in metastatic settings, contrasting with microsatellite stable (MSS) tumors that rarely respond to . This integrates molecular insights with systems to prioritize in advanced disease.

Prevention

Lifestyle Interventions

Lifestyle interventions play a crucial role in reducing cancer incidence by modifying modifiable risk factors. These behavioral changes, supported by extensive epidemiological evidence, target key contributors to such as , , and hormonal imbalances. Adopting these habits can significantly lower the risk of various cancers, with benefits accruing over time through sustained practice. Tobacco cessation is one of the most impactful lifestyle changes for , particularly for . Quitting reduces the risk of lung cancer by 30% to 50% after 10 years compared to continued smoking, as former smokers' risk approaches that of never-smokers over longer periods. This reduction occurs because cessation halts exposure to carcinogens like polycyclic aromatic hydrocarbons and nitrosamines, allowing cellular repair mechanisms to mitigate accumulated DNA damage. The emphasizes that within 10 years of quitting, lung cancer risk falls to about half that of a current smoker. Limiting alcohol consumption is another essential intervention, as alcohol is a known carcinogen associated with increased risk of breast, colorectal, esophageal, liver, and other cancers. Guidelines recommend no more than one drink per day for women and two for men, or abstinence for optimal prevention; even moderate intake raises breast cancer risk by 7-10%. Mechanisms include acetaldehyde-induced DNA damage and altered hormone levels. Maintaining a healthy body weight through balanced and regular activity is critical, as and are linked to at least 13 types of cancer, including endometrial, postmenopausal , and colorectal. Achieving and sustaining a (BMI) of 18.5-24.9 kg/m² can reduce cancer risk by 10-40% depending on the type, by lowering , , and levels. Dietary modifications, such as adhering to a Mediterranean diet, have been linked to decreased colorectal cancer risk through its emphasis on antioxidant-rich foods. High adherence to this diet, which includes fruits, vegetables, whole grains, and olive oil, is associated with a 16% reduction in colorectal cancer incidence, attributed to polyphenols, flavonoids, and other antioxidants that combat oxidative stress and inflammation in the colonic mucosa. Additionally, avoiding processed meats is recommended, as their consumption increases colorectal cancer risk by 18% per 50 grams daily due to compounds like N-nitroso chemicals formed during processing. Limiting such meats helps prevent heme iron-induced DNA damage and heterocyclic amine formation during cooking. Regular is another evidence-based , with guidelines recommending at least 150 minutes of moderate-intensity exercise per week to lower cancer risk. This level of activity is associated with a 12-21% reduction in risk among women, likely through mechanisms including reduced levels, improved insulin sensitivity, and decreased . The protective effect is consistent across pre- and postmenopausal women, highlighting exercise's role in modulating adiposity-related pathways that promote mammary carcinogenesis. Sun protection measures, including consistent use of broad-spectrum sunscreen with SPF 15 or higher, are essential for preventing melanoma. Daily application of such sunscreen reduces melanoma risk by up to 50%, as demonstrated in randomized trials, by blocking ultraviolet B radiation that causes DNA mutations in melanocytes. The U.S. Food and Drug Administration supports this, noting that proper sunscreen use, combined with seeking shade and wearing protective clothing, significantly mitigates UV-induced skin damage.

Chemopreventive Agents

Chemopreventive agents are pharmaceutical compounds used to inhibit or reverse the process of , primarily for primary prevention in high-risk individuals or secondary prevention to halt progression from precancerous lesions to invasive cancer. These agents target specific molecular pathways involved in tumor initiation and promotion, offering a targeted approach distinct from modifications. Key examples include selective estrogen receptor modulators (SERMs) for and nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin for , with efficacy demonstrated in large-scale clinical trials and meta-analyses. Tamoxifen, a prototypical SERM, is approved for reducing incidence in women at high risk, such as those with a 5-year Gail model risk greater than 1.7%. In the Breast Cancer Prevention Trial, reduced the incidence of invasive by approximately 50% over 5 years in high-risk postmenopausal women. This risk reduction is primarily observed for estrogen receptor-positive tumors, with a 69% decrease in such cases. Similarly, raloxifene, another SERM, provides comparable but slightly less potent protection, reducing risk by about 38% in the STAR trial. For , low-dose aspirin has emerged as an effective chemopreventive agent, particularly in individuals with elevated risk due to factors like or prior adenomas. Meta-analyses of randomized controlled trials indicate that regular aspirin use reduces incidence by 20-30%, with a 27% in observational studies encompassing over 150,000 cases. High-dose regimens (≥325 mg daily) for at least 2 years show more pronounced effects, lowering risk by up to 40% in high-risk cohorts. The mechanisms of these agents involve interference with key oncogenic pathways. and other SERMs exert their effects by competitively binding to receptors in breast tissue, thereby blocking -driven and reducing the promotional effects of hormonal signaling on mammary . In contrast, aspirin's chemopreventive action stems from irreversible inhibition of (COX-2), an enzyme overexpressed in colorectal adenomas that promotes , , and tumor growth through synthesis; this inhibition disrupts these pro-carcinogenic processes without fully suppressing the housekeeping COX-1 isoform at low doses. Despite their benefits, chemopreventive agents carry notable risks that necessitate individualized assessment. increases the risk of venous thromboembolism, including deep vein thrombosis and , by 1.5- to 3-fold, with an absolute 5-year risk rising from 0.5% to 1.2% in treated women; this thrombotic potential is linked to its pro-estrogenic effects on vascular . Aspirin, while generally safer, elevates risk, particularly at higher doses. The U.S. Preventive Services Task Force (USPSTF) recommends offering , raloxifene, or aromatase inhibitors to women at increased risk after discussing benefits and harms, but advises against routine use in average-risk populations due to adverse effects. For , USPSTF guidelines on aspirin focus on cardiovascular prevention but acknowledge its risk reduction in select older adults, emphasizing shared decision-making for those aged 50-59 with elevated cardiovascular risk.

Vaccinations and Public Health Measures

Vaccinations play a crucial role in preventing certain cancers linked to viral s. The quadrivalent papillomavirus ( targets HPV types 6, 11, 16, and 18, which are responsible for approximately 70% of cancers worldwide. Clinical trials and real-world studies have demonstrated near 100% efficacy in preventing persistent s and precancerous lesions caused by these vaccine-targeted HPV types when administered before exposure. Similarly, the (HBV) vaccine has significantly reduced the incidence of in endemic regions, such as parts of and , where HBV accounts for up to 80% of cases. Universal infant programs, like those implemented in since 1984, have led to a 75-90% decline in childhood rates over subsequent decades. Public health measures, including fiscal and educational strategies, complement vaccination efforts by addressing modifiable risk factors. Increasing taxes is one of the most effective interventions, with a 10% price hike leading to a 4% reduction in consumption in high-income countries and up to 8% in low- and middle-income countries. These policies have contributed to declining smoking prevalence and averted millions of tobacco-related cancer deaths globally. anti-smoking campaigns, such as the U.S. Centers for Disease Control and Prevention's Tips From Former Smokers initiative, have prompted over 1 million quit attempts and prevented an estimated 129,000 premature deaths between 2012 and 2018, while saving $7.3 billion in healthcare costs. International eradication efforts emphasize high vaccination coverage to achieve cancer elimination targets. The World Health Organization's global strategy for elimination sets a goal of 90% HPV coverage among girls by age 15 by 2030, alongside 70% screening and 90% treatment access, to reduce new cases by over 90% in high-burden regions. For HBV, the WHO's Agenda 2030 aims for 90% coverage of the birth dose in endemic areas to further curb incidence. These targets build on evidence from high-coverage programs that have already averted over 1.3 million cases through HPV since 2006. Despite these advances, poses a significant challenge to efficacy, driven by , cultural barriers, and access issues, which have limited global HPV coverage to just 31% for the first dose as of 2024. In regions with low uptake, such as parts of , hesitancy has delayed progress toward elimination goals and sustained preventable cancer burdens. Addressing hesitancy through and policy incentives is essential to maximize impact.

Screening

General Screening Guidelines

Cancer screening programs seek to detect precancerous lesions or early-stage malignancies in individuals to reduce morbidity and mortality, guided by evidence from randomized controlled trials that weigh benefits against potential harms. Key principles include addressing lead-time bias, where earlier detection prolongs the time from diagnosis to death without altering overall survival, and , the identification of indolent tumors that would not cause harm if undetected, potentially leading to unnecessary treatments and psychological distress. These risks are mitigated through rigorous trial designs that compare screened and unscreened cohorts over extended follow-up periods to assess true net benefits, such as reductions in cancer-specific mortality. The Preventive Services (USPSTF) evaluates screening based on such , assigning grades A or B to interventions with high certainty of substantial net benefit or moderate certainty of moderate net benefit, respectively, and recommending their routine provision in . For instance, USPSTF Grade A recommendations stem from consistent results across multiple well-designed RCTs demonstrating significant improvements, while Grade B reflects solid but somewhat limited . These gradings inform broad implementation, emphasizing screenings proven effective in diverse populations through trials like those for and colorectal cancers. Common examples of recommended screenings include for and or stool-based tests for . The USPSTF recommends biennial screening for women aged 40 to 74 years (Grade B), with a 2024 update affirming routine screening starting at age 40 rather than individualizing for ages 40-49, supported by meta-analyses of randomized trials showing reductions in mortality ranging from 12% (ages 39-49) to 33% (ages 60-69). For , the USPSTF advises screening for adults aged 50 to 75 years (Grade A) and 45 to 49 years (Grade B) using options such as every 10 years or annual fecal immunochemical testing (FIT), with evidence from four large RCTs of flexible indicating a 26% reduction in mortality (mortality rate ratio 0.74, 95% CI 0.68-0.80). Cost-effectiveness analyses further support these guidelines, often using quality-adjusted life years (QALYs) to quantify benefits relative to costs. Modeling studies show that , such as blood-based multitarget tests, are cost-effective with incremental cost-effectiveness ratios of $25,600 to $43,700 per QALY gained compared to no screening. Similarly, breast cancer screening programs demonstrate favorable , averting deaths at costs below common willingness-to-pay thresholds like $100,000 per QALY in long-term projections. Despite these established benefits, equity challenges undermine screening effectiveness, particularly in low-resource settings where access disparities result in lower uptake among socioeconomically disadvantaged and rural populations. , screening rates for , , and colorectal cancers have risen overall since 1997, but persistent regional gaps—such as lower prevalence in the Southwest compared to the Northeast—highlight barriers like limited healthcare and in underserved areas. Addressing these inequities requires targeted interventions to ensure broad implementation of evidence-based guidelines.

Population-Specific Recommendations

Screening recommendations for cancer vary significantly by age, gender, and other demographic factors to balance benefits and risks. For prostate cancer, the U.S. Preventive Services Task Force (USPSTF) assigns a Grade D recommendation against routine prostate-specific antigen (PSA) screening in men aged 70 years and older, citing limited benefits and potential harms from overdiagnosis and overtreatment. In contrast, for men aged 55 to 69 years, the USPSTF recommends individualized decision-making after discussing potential benefits and harms with a clinician, reflecting ongoing debate about PSA's net value in this group. For cervical cancer, the USPSTF advises screening with cervical cytology (Pap test) every three years for women aged 21 to 29 years, transitioning to primary high-risk human papillomavirus (HPV) testing every five years or co-testing (HPV and cytology) every five years for those aged 30 to 65 years, with screening cessation after age 65 for those with adequate prior negative results. Regional variations in screening protocols account for differences in cancer incidence and population-specific risks. In , where breast cancer incidence is rising but mortality remains lower than in Western countries, the national breast cancer screening program recommends biennial starting at age 40 for women up to age 69, with no strict upper age limit but active encouragement through age 74 to address prevalence in Asian populations. For gastric cancer, which has high incidence in East Asian countries like , , and parts of , guidelines from the European Society of Gastrointestinal (ESGE) and others recommend population-based endoscopic screening in high-risk regions, typically starting at age 40 to 50 and performed every 2 to 3 years, as allows direct visualization and biopsy of precancerous lesions like . The Gastroenterological Association (AGA) similarly endorses endoscopic screening for immigrants from high-incidence areas or those with relevant risk factors, emphasizing its superiority over non-invasive tests like in detecting early-stage disease. Individuals at elevated risk due to family history require tailored, earlier interventions. For in those with a family history suggestive of Lynch syndrome (), the AGA recommends initiating screening every one to two years beginning at age 20 to 25 years, or two to five years before the earliest diagnosed family member's age, to detect and remove premalignant polyps given the syndrome's accelerated . This approach has been shown to significantly reduce incidence and mortality in affected families through vigilant . The USPSTF maintains its recommendation for annual low-dose computed tomography (LDCT) screening in adults aged 50 to 80 years with a 20-pack-year history who currently smoke or quit within the past 15 years. Emerging 2025 research, such as the LC-SHIELD study presented at the (ASCO) annual meeting, demonstrates the potential of (AI) to enhance screening efficiency, with AI software serving as the initial reader to prioritize suspicious nodules and reduce radiologist workload without compromising sensitivity in high-risk never-smokers. This AI integration aims to improve early detection rates, potentially lowering mortality by facilitating faster in resource-limited settings.

Genetic Testing for Risk Assessment

Genetic testing for cancer risk assessment involves analyzing an individual's germline DNA to identify inherited variants that predispose to cancer development, enabling personalized prevention strategies. This process typically begins with genetic counseling to evaluate family and personal history, followed by targeted or comprehensive testing. Multigene panel tests, which sequence multiple cancer susceptibility genes simultaneously using next-generation sequencing, have become standard for assessing hereditary risks, particularly for breast, ovarian, colorectal, and other cancers. These panels often include genes such as BRCA1, BRCA2, and TP53, where pathogenic variants confer significantly elevated lifetime risks—for instance, BRCA1/2 variants increase breast cancer risk to 55-72% and ovarian cancer risk to 39-44%. Direct-to-consumer (DTC) genetic testing kits, such as those offered by , provide an accessible entry point for risk assessment by screening for select variants in genes like /2, though they are limited in scope and do not cover all known pathogenic mutations. These tests report on a subset of variants (e.g., up to 44 in /2 for certain populations), potentially missing up to 90% of risk-associated changes in diverse groups, and results should be confirmed through clinical-grade testing. Following identification of a pathogenic variant in a (the first family member tested), cascade testing extends screening to at-risk relatives, systematically offering targeted testing to first-degree family members and beyond, which can identify carriers at a population level and facilitate early interventions. Ethical considerations in genetic testing include potential psychological impacts, such as anxiety or distress from learning one's risk, which may affect and family dynamics, necessitating pre- and post-test counseling. Concerns about insurance discrimination persist despite protections under the (GINA) of 2008, which prohibits health insurers from using genetic information for coverage decisions or premiums and employers from based on genetics, though gaps remain for life and . In high-risk families meeting criteria like those from the , the yield of positive pathogenic variants ranges from 10-20%, informing decisions on prophylactic measures such as risk-reducing surgeries (e.g., for BRCA carriers) or enhanced screening protocols.

Treatment

Surgical Interventions

Surgical interventions remain a of , primarily aimed at removing malignant tumors and achieving local control of the disease. These procedures are most effective when the cancer is localized and can be completely excised, serving both curative and palliative purposes depending on the stage and type of . The choice of surgical approach is influenced by factors such as tumor , , and health status, with the goal of maximizing oncologic outcomes while minimizing morbidity. Curative resection involves the complete removal of the along with a margin of healthy tissue to eliminate all detectable cancer cells, often applied in early-stage solid tumors like or . For instance, is a common curative procedure for , where the entire tissue is excised to prevent recurrence. Debulking surgery, in contrast, reduces the bulk of an inoperable tumor to alleviate symptoms or facilitate subsequent therapies, particularly in advanced ovarian or pancreatic cancers where full resection is not feasible. is a targeted diagnostic and technique that identifies the first draining the tumor site, allowing for selective removal and avoiding unnecessary full ; it is widely used in and cases to assess risk. Minimally invasive techniques, such as , have revolutionized cancer by employing small incisions and endoscopic tools to access and excise tumors, leading to reduced postoperative pain, shorter hospital stays, and faster recovery times compared to open . In procedures, laparoscopic approaches have demonstrated equivalent oncologic outcomes to traditional methods while decreasing recovery time by several days. These techniques are particularly beneficial in abdominal and pelvic cancers, though they require specialized training and may not suit all tumor anatomies. Despite advancements, surgical interventions carry risks of complications, including infections at the surgical site, which can occur in up to 5-10% of cases and are exacerbated by factors like or poor wound care. , a chronic swelling due to lymphatic disruption, is a notable following axillary dissection in surgery, affecting in approximately 20% of patients. Other potential issues include bleeding, injury, and delayed , with overall complication rates varying by procedure complexity. In , often integrates with other treatments; for example, neoadjuvant following preoperative can downstage rectal cancer, enabling sphincter-preserving resections and improving local control rates. assessments, such as or biopsies, inform the surgical plan by delineating tumor extent and guiding the scope of intervention.

involves the use of cytotoxic drugs designed to target and kill rapidly dividing cancer cells by interfering with essential cellular processes such as and . These agents are administered systemically, often intravenously or orally, and are a cornerstone of for many malignancies, either as primary , to , or in with other modalities. While effective in reducing tumor burden, chemotherapy's non-specific action can also affect healthy proliferating cells, leading to a range of toxicities. Chemotherapeutic drugs are classified into several major categories based on their mechanisms of action. Alkylating agents, such as , work by adding alkyl groups to DNA, causing cross-links that prevent strand separation and halt replication; they are particularly active in the of the and are used against a broad spectrum of cancers including lymphomas and . Antimetabolites, exemplified by 5-fluorouracil (5-FU), mimic natural metabolites to incorporate into DNA or , disrupting synthesis and primarily affecting cells in the S phase; 5-FU is commonly employed in colorectal and s. Topoisomerase inhibitors, like , block the enzymes that relieve during replication, leading to DNA breaks and , with activity across phases but maximal in S and ; is a key agent in treating and lymphomas. Standard regimens combine multiple agents to enhance efficacy and overcome resistance through synergistic effects. The CHOP regimen, consisting of , , , and , is a widely used combination for , typically administered in cycles every 21 days for 4-6 courses, achieving cure rates exceeding 60% in when combined with rituximab as R-CHOP. For breast cancer, the neoadjuvant AC-T regimen— and followed by —is employed to shrink tumors prior to , improving rates of breast-conserving procedures and pathologic complete response in up to 20-30% of patients with triple-negative or HER2-positive disease. Common side effects of chemotherapy include myelosuppression, which manifests as reduced of blood cells leading to , , and , increasing risk; this is most pronounced 7-14 days post-treatment with agents like . and affect up to 70% of patients, often triggered by drugs such as , and can be acute or delayed. Management strategies include (G-CSF) analogs like , which stimulate and reduce incidence by 50% when given prophylactically in high-risk regimens. Antiemetics such as are standard for control, alongside supportive care like and dietary adjustments. Drug resistance poses a major challenge to efficacy, with multidrug resistance protein 1 (MDR1, or ) acting as an ATP-dependent that expels chemotherapeutic agents from cancer cells, reducing intracellular drug accumulation and contributing to failure in up to 50% of advanced cases. Overexpression of MDR1, often induced by prior exposure or genetic factors, confers cross-resistance to multiple drugs including and taxanes. Recent advances in 2024-2025 have focused on nanoparticle-based delivery systems to circumvent resistance; these carriers, such as lipid nanoparticles encapsulating , enhance tumor penetration via the , improve drug bioavailability, and reduce efflux by MDR1 through surface modifications like , showing up to 2-3 fold increased efficacy in preclinical models of resistant and cancers. Clinical trials in 2025 are evaluating these systems to minimize systemic while targeting residual disease post-surgery.

Radiation Therapy

Radiation therapy, also known as radiotherapy, utilizes high-energy rays or particles, such as X-rays, gamma rays, or protons, to damage the DNA of cancer cells, thereby inhibiting their growth and division or inducing cell death. This localized treatment targets specific areas of the body, minimizing exposure to surrounding healthy tissues when advanced techniques are employed. It is commonly used as a primary treatment, adjuvant therapy following surgery, or palliative measure to alleviate symptoms in various cancers, including those of the breast, prostate, head and neck, and cervix. The two primary types of are external beam radiation therapy (EBRT) and . EBRT delivers from an external machine that directs beams toward the tumor, with intensity-modulated (IMRT) representing a precise form that uses computer-controlled adjustments to vary beam intensity and shape, allowing higher doses to the tumor while sparing adjacent normal tissues. For instance, IMRT employs thin, computer-generated beams based on tumor to conform the dose closely to the tumor's contours. , in contrast, involves placing radioactive sources directly inside or near the tumor; low-dose-rate (LDR) implants, such as permanent radioactive seeds in the , provide continuous low-level over months, effectively treating localized with reduced impact on surrounding structures. Dosing in radiation therapy is measured in gray (Gy), the unit of absorbed radiation, and typically delivered in fractions over multiple sessions to balance efficacy and toxicity. A common regimen for breast cancer following lumpectomy involves whole-breast irradiation of 45-50 administered in 25 daily fractions over five weeks, often with an optional tumor bed of 10-16 in additional fractions to enhance local control. These fractionated schedules allow normal tissues time to repair between treatments, improving the therapeutic ratio. Side effects of radiation therapy arise from damage to nearby healthy cells and are categorized as acute (occurring during or shortly after treatment) or late (developing months to years later). Acute effects include skin irritation resembling sunburn, , and temporary in the treated area, while late effects may involve (scarring and tissue stiffening), , or such as in head and neck treatments. Image-guided radiation therapy (IGRT) enhances precision by using real-time imaging, such as X-rays or scans, to verify tumor position before each , thereby reducing doses to critical organs like the heart or lungs and mitigating both acute and late toxicities. Radiation therapy is sometimes combined with to improve tumor response in certain cancers, though this section focuses on radiation modalities. Recent advances include , which uses protons rather than photons (X-rays) to deliver with a sharp dose fall-off beyond the tumor, minimizing exposure to distal tissues. In pediatric patients, proton therapy has demonstrated a lower incidence of severe side effects and secondary malignancies compared to traditional photon-based EBRT, with cohort studies showing reduced risks of second cancers due to decreased radiation scatter and integral dose to healthy tissues. This is particularly beneficial for children with brain tumors or sarcomas, where long-term survival amplifies the importance of avoiding treatment-induced cancers.

Immunotherapy

Immunotherapy represents a transformative approach in by leveraging the patient's to recognize and destroy malignant cells. Unlike conventional therapies, it enhances natural immune responses rather than directly targeting tumor cells, leading to durable remissions in subsets of patients across various cancer types. This modality has revolutionized , particularly for hematologic malignancies and certain solid tumors, with ongoing research expanding its applications. Checkpoint inhibitors, a cornerstone of immunotherapy, block inhibitory signals that tumors exploit to evade immune detection, thereby "releasing the brakes" on T-cells to mount an effective antitumor response. For instance, inhibitors like prevent the interaction between programmed death-1 (PD-1) on T-cells and PD-L1 on tumor cells, restoring T-cell . The U.S. (FDA) approved in for unresectable or metastatic in patients who progressed on prior therapies, demonstrating objective response rates of approximately 33% in clinical trials. Chimeric antigen receptor (CAR) T-cell therapy involves genetically engineering a patient's T-cells to express receptors targeting specific tumor antigens, enabling precise immune attack. , a CD19-directed CAR-T product, redirects T-cells against s, achieving complete remission rates of up to 54% in relapsed or refractory large B-cell lymphoma. The FDA granted approval for in 2017 for adults after two or more lines of , with subsequent expansions in 2022 for second-line use. CAR-T mechanisms trigger rapid T-cell activation and proliferation upon antigen binding, but this can lead to (CRS), a potentially severe managed primarily with , an IL-6 , which resolves symptoms in most cases without compromising efficacy. By 2025, immunotherapy approvals have broadened, including expansions for microsatellite instability-high (MSI-high) solid tumors; for example, the FDA approved the combination of nivolumab and in April 2025 as first-line therapy for unresectable or metastatic MSI-high or mismatch repair-deficient , building on prior single-agent uses. Response to is often predicted by (TMB), where tumors with TMB greater than 10 mutations per megabase (mut/Mb) generate more neoantigens, correlating with higher objective response rates to checkpoint inhibitors across solid tumors. can complement targeted therapies by amplifying immune-mediated effects alongside molecular inhibition.

Targeted Therapies

Targeted therapies represent a cornerstone of precision , utilizing drugs or other agents designed to interfere with specific molecular targets that drive , , or , thereby minimizing damage to healthy cells compared to traditional treatments. These therapies exploit genetic alterations or overexpressed proteins unique to , such as mutated kinases or deficiencies, to selectively inhibit tumor growth. For instance, small-molecule inhibitors and monoclonal antibodies are the primary classes, with the former penetrating cell membranes to block intracellular targets and the latter binding extracellularly to flag or disrupt signaling. A seminal example is (Gleevec), a that specifically targets the BCR-ABL resulting from the translocation in (CML), dramatically improving patient outcomes since its approval in 2001 by transforming a once-fatal disease into a manageable with response rates exceeding 90% in early-stage patients. Similarly, like (Lynparza) exploit in cancers with BRCA1/2 mutations, which impair repair; by inhibiting PARP enzymes involved in alternative pathways, leads to unrepaired DNA damage and , earning FDA approval in 2014 for maintenance therapy in BRCA-mutated advanced , where it extended by over 7 months in clinical trials. Precision in targeted therapy relies on companion diagnostics to identify eligible patients, such as (FISH) assays detecting ALK gene rearrangements in non-small cell lung cancer (NSCLC), which guide the use of like ; FDA-approved FISH probes confirm ALK fusions in approximately 3-7% of NSCLC cases, enabling personalized treatment that improves median survival by up to 20 months. However, resistance often emerges through secondary mutations or pathway bypasses, exemplified by the T790M mutation in the gene, which confers resistance to first- and second-generation EGFR tyrosine kinase inhibitors in about 50-60% of NSCLC patients; third-generation inhibitors like , approved in 2015, overcome this by selectively targeting T790M-mutated EGFR while sparing wild-type forms, thereby restoring sensitivity in resistant cases. As of 2025, advancements include bispecific antibodies that simultaneously engage tumor-specific antigens and immune effector cells or dual signaling pathways in solid tumors, enhancing tumor cell lysis with reduced off-target effects; for example, , approved in 2021 for EGFR exon 20 insertion-mutated NSCLC, bispecifically targets and MET to address resistance , while ongoing trials explore broader applications in colorectal and pancreatic cancers, showing response rates of 20-40% in solid tumors. These developments underscore the evolving integration of targeted therapies with biomarker-driven strategies to combat heterogeneity and resistance in diverse cancers.

Palliative Care

in cancer focuses on alleviating symptoms and enhancing for patients with advanced disease, emphasizing comfort and support rather than cure. It addresses physical, emotional, and spiritual needs through a multidisciplinary approach, integrating medical, psychological, and social interventions tailored to the individual's stage of illness. Early involvement of teams can occur alongside active treatment, while in later stages, it transitions to comprehensive end-of-life support. Key components of palliative care include effective , often guided by the (WHO) analgesic ladder, which provides a stepwise framework for escalating treatment based on severity. The ladder starts with non-opioids such as acetaminophen or nonsteroidal anti-inflammatory drugs for mild , progresses to weak opioids like for moderate , and advances to strong opioids such as for severe , with adjunct therapies like antidepressants or anticonvulsants as needed. This approach has been widely adopted for relief, ensuring prompt and regular reassessment to maintain efficacy. Nausea and , common in advanced cancer due to disease progression or treatments, are managed with antiemetics like , a selective serotonin antagonist. effectively prevents by blocking serotonin release in the gut and , typically administered at 8 mg doses before emetogenic stimuli. Clinical guidelines recommend it as a first-line agent for moderate to high emetic risk scenarios in cancer patients. Psychosocial support forms a cornerstone of palliative care, addressing emotional distress, anxiety, , and family dynamics through counseling, support groups, and spiritual guidance. Interventions such as individual and peer-led groups help patients with existential concerns and improve mood, while support mitigates burden and enhances family . Integrated care has been shown to reduce symptoms and foster better adjustment to illness. For patients with end-stage cancer, care integrates seamlessly into palliative services, providing holistic comfort-focused support in the final months of life. emphasizes symptom control, emotional care, and dignity, often delivered at home or in specialized facilities, with interdisciplinary teams including nurses, social workers, and chaplains. This model reduces aggressive interventions and promotes peaceful transitions, improving outcomes for both patients and families. Integrating early in the course of advanced cancer yields significant benefits, including improved and mood, as demonstrated in randomized trials. Landmark studies, such as the 2010 trial in metastatic , reported a median survival extension of approximately 2.7 months with early compared to standard care alone. More recent evidence confirms these gains, attributing them to better symptom management, prognostic understanding, and reduced . Cultural variations influence preferences, particularly regarding location of , with many patients favoring home-based support to align with family-oriented values. In diverse populations, such as those in low- and middle-income countries, a express a for dying at home over hospital settings, though access barriers like resource limitations can shift outcomes toward institutional care. These differences underscore the need for culturally sensitive discussions to honor individual and communal priorities in care planning.

Prognosis

Prognostic Factors

Prognostic factors in cancer refer to characteristics that help predict the likely course and outcome of the disease for an individual patient, guiding clinical decision-making and personalized care. These factors encompass tumor biology, patient demographics, molecular markers, and external influences, often integrated into predictive models to estimate survival probabilities. systems, such as the TNM , serve as a foundational prognostic element by assessing tumor extent, node involvement, and . Tumor-related factors are among the most established predictors of cancer outcomes. Tumor grade evaluates the degree of abnormality in cancer cells under a , with higher s (indicating more aggressive, poorly differentiated cells) associated with faster growth and poorer across various cancers, such as and malignancies. Stage at remains a dominant factor, where early-stage cancers (localized without spread) generally yield better survival rates compared to advanced stages involving . Surgical margins, the edges of tissue removed during resection, also influence ; negative margins (no cancer cells at the edge) correlate with lower recurrence risk, while positive margins increase the likelihood of local , particularly in and colorectal cancers. Patient-specific factors significantly modulate by reflecting overall health and resilience to . is a key determinant, with older patients often facing worse outcomes due to reduced physiological reserve and higher vulnerability to therapy side effects, as evidenced in and pancreatic cancers. Comorbidities, quantified by tools like the (CCI), further refine predictions; a higher CCI score, incorporating conditions such as or , is linked to increased mortality risk in cancer patients, independent of tumor characteristics. Molecular and genetic markers provide deeper insights into tumor behavior and treatment response. In colorectal cancer, KRAS wild-type status is a favorable prognostic indicator, associated with improved survival and better responsiveness to therapies like anti-EGFR antibodies, compared to KRAS-mutated tumors that exhibit more aggressive progression. Socioeconomic factors indirectly shape prognosis by affecting timely access to care. Limited healthcare access, often tied to lower socioeconomic status, can delay diagnosis and lead to presentation at more advanced stages, thereby worsening overall outcomes in cancers like cervical and breast. To integrate these diverse factors, nomograms are widely used as graphical tools for individualized . These models combine variables like , , age, and molecular markers to generate personalized probability estimates for outcomes such as recurrence or , enhancing precision in prognostication for cancers including and .

Survival Statistics and Outcomes

for cancer vary widely depending on the type, at , and access to . The 5-year relative , which compares the of cancer patients to that of the general population, serves as a key metric for assessing outcomes. For instance, has a high 5-year relative of 97.9%, largely due to effective early detection and localized treatments. In contrast, has a much lower rate of 13.3%, reflecting challenges in early and limited therapeutic options. Female falls in between, with a 91.7% 5-year relative , benefiting from advances in screening and targeted therapies. These figures, based on U.S. data from 2015–2021, illustrate the spectrum of outcomes across cancer types, where early-stage detection often correlates with exceeding 90% for many solid tumors. Global trends in cancer survival have shown steady improvements since 1990, driven by enhanced screening programs, reduced use, and innovations in treatment. In high-income countries like the , the overall 5-year relative survival rate for all cancers combined rose from approximately 50% in the early 1990s to around 70% by 2020, representing a significant gain attributed to better prevention and multimodal therapies. Worldwide, age-standardized cancer mortality rates have declined by about one-third from 1990 to 2021, reflecting broader progress in early intervention and care, though aggregate 5-year survival data remain heterogeneous due to varying across regions. These advancements have particularly benefited common cancers such as and colorectal, where survival increases of 10–20 percentage points have been observed in many developed nations over this period.33326-3/fulltext) Disparities in survival outcomes persist between high-income and low-income countries, exacerbating global inequities in cancer care. For , the 5-year net survival rate reaches 68% but drops to as low as 19–23% in low-income settings like and , primarily due to limited access to screening, , and timely treatment. In low- and middle-income countries, overall cancer survival is often 20–30% lower than in high-income counterparts, stemming from infrastructure gaps, delayed diagnoses, and fewer resources for advanced therapies. These gaps highlight the need for targeted international efforts to improve . Recent developments, particularly in , have notably enhanced outcomes for specific cancers like . By 2025, combination immunotherapy regimens, such as nivolumab plus ipilimumab, have boosted the 5-year survival rate for advanced to approximately 50%, with about half of responders remaining cancer-free at 10 years. This marks a dramatic shift from historical rates below 20% for metastatic disease, underscoring the transformative impact of inhibitors on long-term survival.

Epidemiology

Global Incidence and Prevalence

In 2022, an estimated 20 million new cancer cases were diagnosed worldwide, excluding non-melanoma cancers, marking a significant challenge. was the most commonly diagnosed, accounting for approximately 2.5 million cases or 12.4% of the total, followed closely by with about 2.3 million cases or 11.6%. Other prevalent types included colorectal (1.9 million), (1.5 million), and (nearly 1 million) cancers. These figures highlight the diverse burden across cancer sites, with incidence rates varying substantially by region; for instance, incidence is notably high in Eastern due to endemic infection, while predominates in owing to human papillomavirus prevalence and limited screening. The global of cancer, defined as the number of individuals alive within five years of , reached approximately 53.5 million in , reflecting improved rates in high-income countries alongside rising elsewhere. This underscores the long-term societal impact, as many survivors require ongoing care for treatment side effects or recurrence risks. Projections indicate a sharp escalation in incidence, with an estimated 35 million new cases by 2050—a 77% increase from levels—driven primarily by and aging demographics. Key drivers of this rising incidence include the aging global population, which amplifies age-related cancer risks, and increasing use in low- and middle-income countries, where over 80% of the projected case increase is anticipated. Additional contributors encompass rising rates of , physical inactivity, and environmental exposures, particularly in transitioning economies. These patterns emphasize the need for targeted prevention strategies to mitigate the expanding burden in vulnerable regions.

Mortality Trends and Disparities

Cancer mortality remains a significant challenge, with an estimated 9.7 million deaths attributed to the disease in 2022. This figure underscores the burden, particularly as accounted for 1.8 million deaths, representing the leading cause, followed by with approximately 900,000 deaths. These statistics highlight how tobacco-related and diet-influenced cancers dominate fatalities, with projections indicating a rise to approximately 18.5 million annual deaths by 2050, a 90% increase from 2022 levels, if current trends persist without intensified interventions. In high-income countries, such as the , age-standardized cancer mortality rates have declined by about 34% from 1991 to 2022, driven by improvements in early detection, treatment efficacy, and measures. For instance, , overall cancer death rates fell by 34% from their 1991 peak through 2022, averting over 4.5 million deaths. Similar declines are observed in other high-income countries. Conversely, in low- and middle-income countries, mortality rates are increasing, with cancer deaths expected to rise by 146% in low (HDI) nations by 2050 compared to a 57% increase in very high HDI countries, reflecting growing incidence and resource constraints. Cancer mortality closely ties to global incidence patterns, where rising cases in transitioning economies exacerbate fatalities. Disparities in cancer mortality are pronounced, particularly along racial and geographic lines. In the United States, face approximately 20% higher overall cancer mortality rates than , a gap persisting despite declines in death rates for both groups—49% for men and 33% for from 1991 to 2022. This inequity stems from barriers in screening, access, and socioeconomic factors, with individuals showing 16% higher mortality than in recent years despite similar or lower incidence for some cancers. Rural-urban divides further compound these issues, as rural residents experience higher mortality rates—such as 14% elevated deaths compared to areas—due to limited healthcare , transportation challenges, and delayed diagnoses. Key interventions, notably tobacco control policies, have substantially mitigated mortality by targeting a risk factor responsible for about 25% of cancer deaths worldwide. Comprehensive strategies, including smoking cessation programs and regulations, have averted nearly 4 million deaths in the United States alone since 1990, accounting for over 50% of the overall decline in cancer mortality. Such efforts demonstrate the potential for public health measures to narrow global and domestic disparities when equitably implemented.

History

Early Concepts and Discoveries

The earliest documented descriptions of cancer appear in ancient medical texts, particularly the , which dates to around 3000 BCE and details eight cases of tumors characterized as "bulging masses" that were cool to the touch and untreatable, with no effective interventions proposed beyond observation. This papyrus, likely a copy of even older writings, reflects an empirical approach to through visual and manual but offers no curative measures, viewing such tumors as grave and inevitable. In , circa 400 BCE, advanced early concepts of cancer within his humoral theory, positing that the disease arose from an imbalance of the body's four humors—, , yellow bile, and black bile—with excess black bile leading to the formation of hard, invasive tumors. He coined the term "" (from the Greek karkinos, meaning crab) to describe the crab-like extensions of veins surrounding these growths, distinguishing benign from malignant forms and rejecting causes in favor of natural imbalances treatable through diet, purgatives, and cautery. This framework dominated medical thought for centuries, influencing perceptions of cancer as a systemic disorder rather than a localized affliction. During the , Islamic physician (Ibn Sina) built upon humoral ideas in his influential (completed around 1025 CE), classifying cancer as an "atrabilious" swelling rooted in corrupted black bile and recommending surgical excision for accessible, non-ulcerated tumors to prevent spread, while cautioning against operations on advanced cases due to risks of dissemination. His text emphasized preoperative assessment and postoperative care, marking a shift toward more systematic surgical approaches in pre-modern . The 18th and 19th centuries saw folk remedies persist alongside emerging scientific inquiry, with common treatments including herbal poultices made from plants like or applied to tumors to draw out supposed poisons, often combined with incantations in traditional practices. Surgical interventions, such as mastectomies for , were performed without using crude tools like knives and cauterizing irons, as exemplified by procedures in the early 1800s that caused excruciating pain and high mortality from . These methods highlighted the era's limitations in and antisepsis. A pivotal shift occurred in 1858 when published Cellular Pathology, using to demonstrate that cancer originates from the abnormal proliferation of normal s rather than humoral imbalances, establishing the cellular basis of the disease and laying groundwork for modern . Virchow's observation that "every comes from a " (omnis cellula e cellula) applied directly to tumors, transforming cancer from a mystical or fluid-based entity into a pathological process rooted in tissue derangement.

Modern Developments and Milestones

In the mid-20th century, the discovery of marked a pivotal shift in . During , researchers observed that exposure to , a chemical warfare agent, suppressed white blood cell production, leading to its experimental use against s in the . In 1942, pharmacologists Louis Goodman and Alfred Gilman at administered the first dose of to a with advanced , achieving tumor regression and establishing the proof-of-concept for systemic . This breakthrough, formalized with FDA approval of mechlorethamine in 1949, laid the foundation for modern chemotherapeutic regimens. Sidney Farber, often called the father of modern , advanced these efforts in pediatric oncology. In the late 1940s, Farber pioneered the use of folic acid antagonists like to treat childhood (ALL), achieving the first temporary remissions in 10 of 16 severely ill children by November 1947. His work at Children's Hospital Boston not only demonstrated chemotherapy's potential in but also spurred the creation of in 1948 to support such research. Another landmark in the was the U.S. government's intensified commitment to . On December 23, 1971, President signed the National Cancer Act, declaring a "war on cancer" that expanded the National Cancer Institute's authority, increased funding to $100 million annually, and fostered interdisciplinary collaborations. This legislation accelerated progress in , , and prevention, influencing global efforts. In the 1970s and 1980s, cytogenetic discoveries illuminated cancer's genetic basis. In 1973, Janet Rowley demonstrated that the in chronic myeloid leukemia (CML), first identified in 1960, results from a consistent translocation between chromosomes 9 and 22. Her subsequent work uncovered additional translocations, such as t(8;21) in (AML) and t(15;17) in , demonstrating how these rearrangements drive oncogenesis and enabling targeted diagnostics. The link between human papillomavirus (HPV) and emerged in the 1980s through Harald zur Hausen's research. In 1983, zur Hausen and colleagues isolated HPV-16 from biopsies, followed by HPV-18 in 1984, proving these high-risk types integrate into host DNA to cause most cervical carcinomas. This discovery, awarded the 2008 in or , paved the way for prophylactic vaccines approved in 2006. The 1990s brought breakthroughs in hereditary cancer risks with the identification of BRCA genes. In 1994, researchers cloned and sequenced BRCA1 on chromosome 17, linking mutations to elevated breast and ovarian cancer susceptibility. BRCA2, mapped to chromosome 13, was identified in 1995, revealing similar risks and enabling genetic screening for high-risk families. These findings revolutionized preventive strategies, including prophylactic surgeries and targeted therapies like PARP inhibitors. Entering the , targeted therapies transformed outcomes for specific cancers. (Gleevec), a , received FDA approval on May 10, 2001, for Philadelphia chromosome-positive CML, achieving complete cytogenetic responses in over 80% of chronic-phase patients and converting a fatal disease into a manageable one. This approval, based on rapid clinical trials, exemplified precision medicine by blocking the identified by Rowley's translocation work. Genome editing tools further accelerated cancer research in the 2010s. The 2012 development of by , , and colleagues provided a precise method for and modification, enabling of cancer drivers and modeling of tumor suppressors like TP53 in cell lines. By facilitating loss-of-function studies, CRISPR has elucidated dependencies and supported designs. By 2025, chimeric antigen receptor (CAR)-T cell therapy has seen widespread clinical adoption for hematologic malignancies. Approved products like and have treated over 20,000 patients globally since 2017, with complete remission rates exceeding 50% in relapsed B-cell lymphomas; manufacturing expansions and reduced costs have broadened access, projecting a market surpassing $7 billion annually. Advancements in (AI) have also reshaped cancer by 2025. AI algorithms now analyze digital slides to detect micrometastases in and cancers with accuracy comparable to expert pathologists, reducing diagnostic times by up to 30% and identifying biomarkers like PD-L1 expression for selection. Tools integrated into routine workflows, such as those from Paige.AI, enhance precision in over 100 U.S. labs, improving equity in underserved regions.

Societal Impact

Economic and Healthcare Burden

The economic burden of cancer encompasses both direct medical costs, such as and healthcare services, and , primarily lost from morbidity, premature mortality, and caregiving. A comprehensive 2023 analysis estimated the global economic cost of 29 major cancers from 2020 to 2050 at $25.2 trillion in international dollars (constant prices), equivalent to an annual tax of 0.55% on global . This projection highlights the escalating fiscal strain, with losses due to premature mortality comprising the largest share—over 70% in high-income countries—while direct health expenditures and informal care costs account for the remainder. Cancer mortality trends, as detailed in epidemiological data, drive a substantial portion of these by reducing participation and economic output. In terms of cost breakdown, direct medical expenses for cancer care, including diagnostics, , , and supportive services, represented approximately 49% of the total global burden in 2020, while lost accounted for around 33% and informal care for 18%, based on the . For instance, in 2020, global from health expenditures were estimated at $152 billion, with productivity losses adding $103 billion and informal care $55 billion, underscoring how treatment demands strain care systems while mortality impacts long-term economic vitality. More recent data indicate global spending on cancer medicines reached $223 billion in 2023, projected to increase to $409 billion by 2028 due to innovative therapies. In the United States, the annual economic cost of cancer exceeded $200 billion in 2020, encompassing both direct medical spending and indirect losses, with projections indicating a rise to over $245 billion by 2030 due to aging populations and advancing therapies. High-cost innovative therapies exemplify the challenges in managing these expenses. Chimeric antigen receptor T-cell (CAR-T) therapy, approved for certain blood cancers, typically costs $400,000 or more per patient, excluding additional hospitalization and follow-up care that can push totals beyond $1 million. Such prices reflect manufacturing complexities and limited scalability, contributing disproportionately to overall treatment expenditures despite their potential for durable remissions. Efforts to mitigate this burden include adopting value-based care models, which tie reimbursements to clinical outcomes and patient rather than service volume, as advocated by frameworks to optimize . Additionally, the increased availability of and drugs has reduced costs for essential chemotherapies and supportive agents by up to 80% in some markets, easing financial pressures on healthcare systems and patients. These strategies aim to balance innovation with affordability, potentially curbing the projected growth in global cancer expenditures.

Cultural and Social Dimensions

Cancer often manifests as a fear of , despite the disease's non-infectious nature, leading to and withdrawal from support networks among patients. Studies have shown a positive between perceived and subjective , with contributing to feelings of and that exacerbate in cancer survivors. For instance, in cancer patients, levels were significantly associated with higher (β = 0.843, p < 0.001). portrayals frequently reinforce these stigmas through narratives that depict cancer as a tragic or fatal condition, such as in films like , which emphasize young patients' untimely deaths and may foster fatalistic attitudes toward the disease. However, positive survivor narratives in shows like highlight resilience and full lives post-diagnosis, potentially normalizing experiences and reducing . Cancer diagnosis places considerable strain on dynamics, often resulting in spousal tension and higher rates of marital , particularly for patients. indicates that women with serious illnesses, including cancer, face a or separation rate of 20.8%, compared to 2.9% for men, representing over a sixfold increased (P < .001). This gender disparity underscores broader relational challenges, where partners may struggle with caregiving roles, emotional burdens, and changes in intimacy, leading to overall marital stress similar to general rates of about 11.6% but amplified by the illness's demands. Cultural variations significantly influence structures for cancer patients, with collectivist societies prioritizing family-based practical assistance over individualistic emphases on emotional autonomy. In collectivist cultures, such as those in and , extended family networks provide tangible aid like meals and financial help, but caregivers may suppress their own emotional needs to avoid burdening the group. Conversely, individualistic societies like those in the United States focus on personal emotional disclosure, fostering empathy and reciprocal support but often limiting broader community involvement in daily care. Among Chinese American survivors, for example, emotional restraint is common to prevent worry among relatives, contrasting with ' preference for open discussions that strengthen bonds. Advocacy movements have played a pivotal role in raising cancer awareness, exemplified by the pink ribbon campaign, which originated in 1991 when the Susan G. Komen Foundation distributed ribbons at its Race for the Cure event and evolved into a global symbol through efforts like Estée Lauder's 1992 distribution of 1.5 million ribbons alongside petitions for funding. These initiatives have heightened public visibility and encouraged early detection, yet they face criticism for "pinkwashing," where companies exploit the symbol for profit without substantial contributions to prevention or , such as marketing products containing potential carcinogens. Groups like Action, which coined the term in 2002, advocate for transparency to ensure campaigns prioritize meaningful action over superficial marketing.

Research Directions

Advances in Therapies

In 2025, antibody-drug conjugates () have emerged as a pivotal advancement in targeted cancer therapy, particularly for (). , an ADC targeting TROP2, demonstrated significant efficacy in frontline treatment for advanced in the phase III ASCENT-03 trial, reducing the risk of disease progression or death by 38% compared to alone, with a progression-free survival of 9.7 months versus 6.9 months. This approval by the FDA in late 2025 expanded its use to PD-1/PD- ineligible patients, addressing a high-need where traditional often falls short. Similarly, oncolytic viruses like (T-VEC), an engineered , continue to show promise in treatment, with studies highlighting its role in regimens to overcome resistance, achieving sustained responses in advanced cases. Combination therapies integrating (IO) with targeted agents have gained traction through ongoing trials, enhancing response rates in genetically defined cancers. For instance, sequential treatment starting with plus followed by has improved in BRAF V600-mutant , with the phase II ImmunoCobiVem trial reporting a of 0.55 for early switching from targeted to IO therapy, minimizing resistance development. These approaches, presented at ESMO 2025, underscore the synergy between immune activation and molecular targeting, though optimal sequencing remains under investigation. Personalized medicine has advanced through tumor s, three-dimensional models derived from patient biopsies that enable drug testing to predict therapeutic responses. In 2025, platforms have facilitated precision oncology by screening ADCs and IO agents, with studies showing high concordance between organoid predictions and clinical outcomes in and colorectal cancers, allowing tailored regimens that avoid ineffective treatments. This technology addresses tumor heterogeneity, as organoids recapitulate microenvironmental resistance mechanisms, accelerating the shift from empirical to individualized therapies. In November 2025, researchers at UCSF reported a breakthrough in targeting mutations, responsible for about 25% of all cancers, using a new approach that restores drug sensitivity and slows tumor growth by exploiting previously undruggable pathways. Additionally, Duke Health announced promising results from a vaccine trial, demonstrating enhanced immune responses against tumor cells in early-stage patients, potentially reducing recurrence rates. Despite these innovations, challenges persist in translating advances to clinical success, including and profiles that limit broad applicability. Resistance mechanisms, such as adaptive signaling in targeted therapies, often emerge within months, necessitating sequential or adaptive trial designs. from combinations, like immune-related adverse events and off-target effects of ADCs, affects up to 40% of patients, requiring vigilant management. Overall, phase III trials succeed in approximately 50% of cases, highlighting the need for better biomarkers to improve efficacy and reduce failure rates.

Innovations in Detection and Prevention

Innovations in multi-cancer early detection have advanced through blood-based tests that analyze cell-free DNA for epigenetic markers, such as methylation patterns, enabling the identification of over 50 cancer types with high sensitivity for many deadly forms in early stages. The Galleri test, developed by GRAIL, exemplifies this approach by detecting cancer signals in plasma and predicting their anatomical origin, with real-world data from approximately 35,000 individuals showing its potential to increase detection rates more than seven-fold when added to standard screenings. These tests address the limitations of organ-specific screenings by offering a non-invasive, pan-cancer strategy that could shift diagnosis toward earlier intervention. In prevention, gene editing technologies like / are being explored to target oncogenic viruses, particularly human papillomavirus (HPV), which drives and other cancers. Clinical trials, such as one evaluating BD114 for HPV , assess the and efficacy of / in editing HPV genes to clear persistent infections and regress precancerous lesions. Preclinical studies have demonstrated that CRISPR-mediated knockout of HPV E6 and E7 oncogenes can effectively halt carcinogenesis , paving the way for therapeutic clearance in high-risk populations. Additionally, modulation emerges as a strategy for prevention by reversing through , prebiotics, and fecal transplantation, which suppress epithelial proliferation and reduce DNA-damaging toxins. Gut interventions, including natural product-derived modulators, have shown promise in preclinical models by altering inflammation and metabolic pathways to lower incidence. Artificial intelligence and big data analytics are enhancing cancer risk stratification by integrating wearable device data, such as activity and physiological metrics, into predictive models that identify at-risk individuals before symptoms arise. algorithms applied to wearable sensors enable real-time monitoring of lifestyle factors and biomarkers, improving personalized for cancers like and colorectal. For instance, AI-driven models using data from fitness trackers and electronic health records have demonstrated high accuracy in forecasting cancer susceptibility by combining genetic and environmental variables, supporting proactive prevention in . Ongoing 2025 clinical trials are advancing liquid biopsy applications for detecting (MRD) post-treatment, using (ctDNA) to monitor recurrence in early-stage cancers. Trials at institutions like are evaluating ctDNA-based MRD assays, such as Haystack MRD, to guide decisions in colorectal and cancers, with breakthrough designations highlighting their sensitivity in stage II disease. These efforts, including presentations at ASCO 2025, underscore liquid biopsy's role in precision by enabling dynamic surveillance and reducing through molecular-level tumor detection.

Cancer in Special Contexts

Cancer During Pregnancy

Cancer during pregnancy, also known as pregnancy-associated cancer, occurs in approximately 1 in 1,000 pregnancies, with the incidence estimated at around 84 per 100,000 deliveries based on large-scale meta-analyses. The most common malignancies include , accounting for about 1 in 3,000 pregnancies, as well as and malignant melanoma, which together represent over half of all cases. Diagnosis typically involves and biopsies adapted to minimize fetal exposure, such as or MRI without , while avoiding unnecessary radiation-based scans unless essential. Management requires a multidisciplinary approach involving oncologists, obstetricians, and neonatologists to balance maternal treatment needs with fetal safety. Surgery is generally safe across all trimesters, though it is preferably performed in the second or third trimester to reduce risks of miscarriage or preterm labor associated with anesthesia in the first trimester. Chemotherapy is typically avoided during the first trimester due to high risks of congenital malformations but can be administered after 14 weeks gestation, using standard regimens like anthracyclines and taxanes, with discontinuation 3 to 4 weeks before delivery to allow maternal bone marrow recovery and minimize neonatal toxicity. Radiation therapy is feasible with appropriate shielding to limit fetal exposure below 50 mGy, particularly for localized tumors away from the pelvis, and is often deferred if possible until postpartum. Fetal risks from cancer treatments vary by gestational age and modality. Teratogenic effects from chemotherapy are low after the first trimester, with primary concerns being intrauterine growth restriction and low birth weight rather than structural anomalies; long-term follow-up shows no increased risk of childhood cancer in exposed offspring. Radiation poses risks of intellectual disability if exposure exceeds safe thresholds during organogenesis, but shielding mitigates this effectively. Regarding breastfeeding, it is contraindicated during active chemotherapy due to potential drug transfer into breast milk, but may resume after a washout period of 2 to 3 weeks post-treatment, depending on the agent, or from the unaffected breast in cases like unilateral breast cancer. With multidisciplinary care, maternal outcomes are comparable to those in non-pregnant women of similar age and cancer stage, with overall survival rates exceeding 70% across common types like (around 90% at 5 years) and when treated promptly. Fetal and neonatal outcomes, while carrying elevated risks of and growth issues (up to 40% incidence), achieve viability rates over 90% with close monitoring and timely interventions like antenatal corticosteroids. Delays in or treatment, occurring in up to 65% of cases historically, underscore the need for heightened awareness to optimize both maternal and perinatal survival.

Cancer in Non-Human Animals

Cancer occurs naturally across a wide range of non-human animals, including vertebrates and . A comprehensive of 16,049 necropsy records from 292 species (mammals, , reptiles, and amphibians) revealed a neoplasia of 4.89% (ranging from 0% to 62.86%) and of 3.20% (ranging from 0% to 40.95%). Mammals showed the highest rates, with 12% neoplasia and 7% , compared to 4% and 1.6% in sauropsids ( and reptiles) and 1.2% and 0% in amphibians. These variations correlate positively with (2.1% increase in neoplasia per log₁₀ gram) and rates (47.26% increase per substitution per year), while longer periods are associated with reduced (−5.65% per log₁₀ month). In domestic and companion animals, cancer is a leading , particularly in pets like and , and serves as a cornerstone of comparative oncology to advance human research. Approximately 6 million are affected by cancer each year, with a 25% lifetime risk and half of over 10 years old developing the disease. Common cancers include , , mammary tumors, , and , which exhibit molecular parallels to human forms, such as TP53 mutations in 38–50% of cases and PIK3CA alterations (e.g., A3140G) in about 30% of mammary tumors. provide a naturally occurring, immunocompetent model with shared environmental exposures, enabling faster evaluation of therapies like anti-PD-L1 antibodies, which have shown efficacy against metastatic in both species. Breed-specific risks, such as higher incidence in Golden Retrievers, further enhance genomic studies due to across over 100 breeds. Certain species demonstrate exceptional cancer resistance, offering evolutionary insights that challenge —the expectation that larger, longer-lived animals should have higher cancer rates due to more divisions. carry up to 40 copies of the TP53 , compared to two in humans, which amplifies DNA damage response and to suppress tumorigenesis despite their massive size. Naked mole rats (Heterocephalus glaber) produce high-molecular-weight that enforces stringent contact inhibition in cells, preventing uncontrolled proliferation, and they rarely develop cancer even in captivity. These mechanisms, identified through comparative genomic analyses across 223 mammalian species reporting neoplasia, inform human strategies like enhancing TP53 function or hyaluronan-based therapies. In wild animals, cancer influences and , often intensified by human-induced environmental changes such as , , and shifts. Transmissible cancers, like the devil facial tumor disease in Tasmanian devils (Sarcophilus harrisii), have caused over 80% population decline since the 1990s by evading immune recognition and spreading via bites. Pollution-driven cases include elevated cancer rates in St. Lawrence beluga whales (Delphinapterus leucas), linked to contaminants like polycyclic aromatic hydrocarbons, and fibropapillomatosis in green sea turtles (Chelonia mydas), associated with viral infections in degraded habitats. These oncogenic pressures can reduce reproductive success, alter behaviors, and drive evolutionary adaptations, such as faster life histories, underscoring the need for wildlife monitoring and mitigation to preserve .