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Cross-cancer

Foundations

The discoveries every cancer timeline rests on: how cancer was first described, how its causes and biology were found, and how surgery, radiation, chemotherapy and immunotherapy became possible.

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Antiquity & classical

  1. c. 1.7 million years ago · Origin · UnderstandingEarliest likely cancer in a human ancestor: Swartkrans foot boneA fossil foot bone from Swartkrans Cave in South Africa, between roughly 1.6 and 1.8 million years old, carries a bony growth. In 2016 researchers used micro-CT scans to diagnose osteosarcoma, a bone cancer, which they call the earliest identifiable malignancy in a human ancestor. It is one bone, diagnosed from its structure.Case report re-analysing SK 7923, a hominin left fifth metatarsal (genus and species indeterminate) from the Swartkrans Member 1 Hanging Remnant, South Africa, dated 1.8-1.6 million years. Micro-CT showed a 5.2 mm x 4.7 mm surface mass with a Codman triangle, subperiosteal invasion and medullary infilling. The authors diagnose osteosarcoma, possibly the parosteal variant, from morphology and differential diagnosis, and call it the earliest identifiable malignant neoplasm in a hominin.
  2. c. 1600 BCE · Origin · UnderstandingEdwin Smith Papyrus: Case 45, bulging tumours of the breastAn Egyptian surgical text, copied around 1600 BCE, describes a man with cool, bulging swellings on the breast. Its 1930 translator reads the treatment line as 'there is no treatment', with the word supplied in brackets. The text does not name the condition, so calling it cancer is an interpretation.Case 45 of Breasted's 1930 translation of the Edwin Smith Surgical Papyrus describes a man with bulging tumours spreading over the breast: very cool, no fever, no granulation, no fluid or secretions. The verdict is 'an ailment with which I will contend' (doubtful). The treatment line reads 'There is no [treatment]', the bracket being Breasted's. Breasted dates the copy to the seventeenth century BCE and does not state that the disease is cancer.
  3. 5th-4th century BCE · Origin · UnderstandingHippocratic writings: karkinos and the first cancer vocabularyWritings in the Hippocratic collection, from ancient Greece, use the word karkinos, Greek for crab, for non-healing swellings and ulcers, including tumours of the breast. They describe burning a throat tumour and advise leaving deep cancers untreated. The collection has many authors, and the word covered more conditions than cancer as defined today.The Hippocratic Corpus uses karkinos and karkinoma for tumours; Papavramidou notes karkinos covered any non-healing swelling or ulcer, with karkinoma reserved for non-healing cancer. Retsas cites a woman from Abdera with breast cancer and a bloody nipple discharge, cautery of a pharyngeal carcinoma, fatal cancers in the elderly, and advice that deep cancers are better left untreated. No detailed surgical technique survives.
  4. 1st century CE · Understanding · UnderstandingCelsus: carcinoma, its stages and a warning against treating itThe Roman writer Celsus, in the first century CE, described carcinoma as a fixed, uneven swelling with swollen veins, found mostly on the face and in women's breasts. He named stages from an early removable form to ulcerated and wart-like disease, and warned that treating the later stages made them worse.In De Medicina (Book V, Loeb translation), Celsus describes carcinoma mostly of the face, lips and women's breasts: a fixed irregular swelling with dilated veins, progressing from cacoethes to non-ulcerated carcinoma, ulceration and a wart-like stage. Only cacoethes could be removed; later stages worsened with caustics, cautery or excision, and recurrence followed excision, while many patients with mild treatment lived to old age. He uses Latin cancer for a separate spreading ulcer.
  5. 2nd century CE · Understanding · UnderstandingGalen: tumours against nature and the black-bile theory of cancerIn the second century CE the physician Galen wrote about tumours 'against nature'. He explained cancer as a build-up of residues of black bile, one of the four humours, and compared the swollen veins around breast tumours to the legs of a crab. The black-bile explanation is a historical theory, not a documented cause.Galen (2nd century CE) wrote On Tumours Against Nature. Papavramidou summarises his humoral view: residues of black bile, left by a weak liver and spleen, accumulate to cause cancer. Retsas quotes his definition of carcinoma as a malignant, indurated tumour, ulcerated or not, named after the animal 'cancer' (crab), from distended veins around breast tumours. He saw cancer most often in the breast, treated early disease, and advised circular excision with cautery.
  6. 1700 · Understanding · UnderstandingRamazzini links breast cancer in nuns to celibacyThe Italian physician Bernardino Ramazzini, in his 1700 book on diseases of workers, noted that cancerous breast tumours seemed more frequent in nuns than in other women and suggested their celibate life as the reason. It was an observation without counts. Later writers read it as an early hint that childbearing affects breast cancer risk.In De Morbis Artificum Diatriba (Modena, 1700), chapter XX on the diseases of wet-nurses, Ramazzini writes of a sympathy between the breasts and the uterus and says cancerous breast tumours are seen more often in nuns than in other women, attributing this not to absent menstruation but, as he thinks, to the celibate life. Horn and Vatten note he made no direct link between sexual inactivity and childbearing; later readers treated it as the first hint of a parity association.

Anatomists & surgeons

  1. 1775 · Understanding · UnderstandingPott links chimney sweeps' scrotal cancer to sootIn 1775 the London surgeon Percivall Pott described scrotal cancer in chimney sweeps, many of them young, and attributed it to soot. It is generally counted as the first described occupational cancer, and later laboratory work on coal tar and soot built on it.In Chirurgical Observations (1775), Pott described scrotal cancer in chimney sweeps and attributed it to soot, making scrotal cancer the first described occupational cancer; Bassius had described the disease in 1731. Doll writes that Pott's observation began the chain leading to the first experimental production of cancer, the first synthesis of a carcinogen and the first isolation of one from a natural substance. Experimental evidence of carcinogens in soot came from Passey in 1922.
  2. 1838 · Understanding · UnderstandingJohannes Müller applies the microscope to tumours (1838)In 1838 Johannes Müller published in Berlin the first part of a book on the fine structure of tumours. Using a microscope, he described cells, nuclei and nucleoli in cancers and told tumour types apart. A catalogue note says he saw that cell theory was needed to understand cancer.Müller's Ueber den feinern Bau und die Formen der krankhaften Geschwülste (Berlin: G. Reimer, 1838) applied the microscope to tumours; only the first part (Lieferung 1) appeared, and C. West translated it into English in 1840. The translation describes cells, nuclei and nucleoli in tumours and cites Schwann's cell theory; Garrison-Morton adds that he distinguished tumour types microscopically. Virchow was among his students.
  3. 1842 · Understanding · UnderstandingRigoni-Stern compares cancer deaths by marital status (1842)In 1842 the Italian surgeon Domenico Rigoni-Stern used death registers from the Verona region to compare cancer deaths in married and unmarried women. He found more breast cancer deaths in nuns and fewer uterine cancer deaths in nuns and other unmarried women. Historians see an early clue to infection in cervical cancer, though the nun finding has been questioned.Per Horn and Vatten, Rigoni-Stern (1842) used death registers in the Verona region to compare uterine and breast cancer mortality in married and unmarried women. Nuns had higher breast cancer mortality; nuns and other unmarried women had lower uterine cancer risk (cervix and corpus not yet separated). Griffiths questions a very low cervical cancer risk in nuns, estimating their risk of death is little different from the general female population.
  4. 1846 · Treatment · SurgeryEther anaesthesia at Massachusetts General Hospital (1846)On 16 October 1846 in Boston a dentist, William Morton, gave ether during an operation by surgeon John Collins Warren, a demonstration seen as the first public demonstration of anaesthesia. Surgical volume at the hospital rose afterwards. The patient's swelling was a vascular malformation, not a cancer, but later cancer surgery relied on anaesthesia.On 16 October 1846 at Massachusetts General Hospital, Morton administered ether during Warren's operation on Edward Gilbert Abbott. Firth's review of the hospital records finds a congenital vascular malformation treated by attempted ligation under incomplete anaesthesia, not the tumour removal described on the commemorative plaque. Andrew and colleagues report that surgical volume rose after ether and the share of female patients doubled. Wyld and colleagues state that before anaesthesia and antisepsis cancer surgery carried high morbidity and mortality.
  5. 1858 · Understanding · UnderstandingVirchow's Cellular Pathology applies cell theory to diseaseIn 1858 Rudolf Virchow published Cellular Pathology, arguing that disease arises in cells and that every cell comes from another cell. This turned pathology toward the microscope and shaped how tumours were studied. He also held that chronic irritation or inflammation could predispose to cancer, an idea later tested in animal experiments.Virchow's Die Cellularpathologie (1858) gave Schwann's cell theory clinical significance; Breathnach describes his aim of a pathological physiology founded on omnis cellula e cellula, and notes that advances in microscopy dictated the growth of histopathology. Schmidt and Weber call it the basis of his oncology; he recognised inflammation as predisposing to tumours. Fujiki dates his irritation theory (Reiztheorie) of cancer to 1858.
  6. 1867 · Treatment · SurgeryLister publishes the antiseptic principle in surgery (1867)In 1867 the surgeon Joseph Lister published his antiseptic method, using carbolic acid to prevent wound infection, drawing on Pasteur's work on germs. A biography says that as many as 80 in 100 operations of that era led to infection. His results were debated for years, but reviews date the growth of cancer surgery from anaesthesia and antisepsis.From 1867 Lister published a series of papers in the Lancet and British Medical Journal on carbolic acid treatment of wounds, drawing on Pasteur; the BMJ paper cited here is 'On the Antiseptic Principle in the Practice of Surgery'. Tröhler: the first paper reported 11 patients with compound fractures, two of whom died; the effect of Listerism was controversial for over a decade in Britain. Jessney: as many as 80% of 1800s operations resulted in infection.

The age of rays

  1. 1895 · Origin · RadiationRöntgen discovers X-rays (1895)Wilhelm Röntgen discovered X-rays on 8 November 1895 and described them in a paper dated 28 December 1895. Within months physicians tried the new rays on patients, and a history of cancer says the discoveries of Röntgen and the Curies changed how cancers were diagnosed and treated.Röntgen discovered X-rays on 8 November 1895 and published 'On a new kind of rays' in the proceedings of the Würzburg physical-medical society on 28 December 1895, the date taken as the discovery. Cosset notes that scientists tried the rays on patients within months. Hajdu's history of cancer counts the discoveries of Röntgen and the Curies among developments that transformed the diagnosis and treatment of cancers.
  2. 1896 · Treatment · RadiationFirst X-ray treatments of tumours (1896): priority disputedIn 1896, within months of Röntgen's discovery, several physicians tried X-rays on patients, and who first treated a cancer is disputed. A 2016 French review calls Victor Despeignes, who treated an abdominal tumour in July 1896, the most serious candidate; accounts differ on whether it was stomach cancer. Many early radiation workers were harmed.Cosset (2016) reviews who first used X-rays therapeutically: Freund of Vienna treated a benign skin lesion; Grubbé of Chicago, often named first, seems to have been disqualified; Despeignes, who in 1896 treated what Cosset calls a gastric cancer with marked regression, appears the most serious candidate. Foray dates Despeignes's treatment 4-23 July 1896 and one abstract says the neighbour did not have stomach cancer; El Nachef reports death by the end of July.
  3. 1898 · Origin · RadiationPierre and Marie Curie announce radium (1898)On 26 December 1898 Henri Becquerel presented to the Paris Academy of Sciences the discovery of radium by Pierre and Marie Curie. Radium sources became the basis of early brachytherapy, and a French review says radium treated thousands of patients over about eighty years before safety concerns ended its use.Mazeron and Gerbaulet: Becquerel presented the discovery of radium by Pierre and Marie Curie to the Paris Academie des Sciences on 26 December 1898. They write that modern brachytherapy is likely the successor of techniques designed for radium sources, and that radium treated thousands of patients over about 80 years before being abandoned mainly for radiation-safety reasons. Hajdu counts the Curies' discovery among developments that transformed cancer diagnosis and treatment.
  4. c. 1906 · Understanding · Chemotherapy⚑ needs reviewEhrlich and 'chemotherapy': a term and a concept (circa 1906)The German physician Paul Ehrlich, who worked on dyes, trypanosomes and syphilis, is credited with coining the word chemotherapy for treating disease with chemicals. His own successes were against infections, not cancer. Attempts to treat cancer with chemicals, using transplanted tumours in rodents, began early in the twentieth century.Williams states that Ehrlich coined the terms chemotherapy and magic bullet while working on arsenical compounds against trypanosomes and syphilis, which led to arsphenamine; no year is given. Kasten lists chemotherapy and cancer research among his accomplishments. DeVita and Chu date the use of chemotherapy against cancer to the start of the 20th century, with screening of chemicals in transplantable rodent tumours, and write that four World War II-related programmes led to the 1955 national drug development effort.
  5. 1911 · Understanding · UnderstandingRous: a chicken sarcoma transmitted by a cell-free filtrateIn 1911 Peyton Rous at the Rockefeller Institute reported that a sarcoma of the chicken could be passed to healthy chickens by a filtered, cell-free extract, pointing to a transmissible agent. It became known as the first tumour virus. Many scientists doubted it for decades, and Rous received the Nobel Prize in 1966.Rous (J Exp Med, 1911) showed that a spontaneous spindle-cell sarcoma from a Plymouth Rock chicken could be transmitted to healthy chickens with filtered cell-free tumour extracts (Javier and Butel). It was later called Rous sarcoma virus, the first known tumour virus and first RNA tumour virus. Critics argued it was an infectious granuloma or that filtrates contained cell fragments; Rous stopped this work after about four years and received the Nobel Prize in 1966, 55 years later.
  6. 1914 · Understanding · UnderstandingBoveri proposes a chromosomal origin of malignant tumoursIn 1914 the German biologist Theodor Boveri proposed that a tumour begins in one cell that has an abnormal combination of chromosomes, perhaps after a faulty cell division. He also reasoned about inherited predisposition. Many of his predictions waited decades for confirmation, and his wife's English translation of 1929 helped bring the theory to wider notice.Boveri's monograph Zur Frage der Entstehung maligner Tumoren (1914; English translation by Marcella Boveri, 1929) proposed that a tumour originates from a single cell with an incorrect combination of chromosomes, for example after abnormal mitosis. Hansford and Huntsman credit predictions of chromosomal instability, loss of key cellular attributes now called tumour suppressor functions, and heritable predisposition. Hardy and Zacharias note he drew on Hansemann's 1890 observation of asymmetric mitoses; Potter notes that many predictions awaited the 1950s-1960s.
  7. 1915 · Understanding · UnderstandingYamagiwa and Ichikawa induce cancer with coal tar (1915)In 1915 the Japanese pathologists Katsusaburo Yamagiwa and Koichi Ichikawa reported that painting coal tar on rabbit ears for months produced skin tumours, including cancer. It has been called the first artificial production of cancer in experimental animals. It gave experimental support to the idea that chronic irritation can lead to cancer.Yamagiwa and Ichikawa reported in 1915 that prolonged coal-tar painting of rabbit ears produced folliculoepithelioma (papilloma) and, in some animals, carcinoma; Sekiya calls it the world's first artificial cancer in experimental animals. In Fujiki's English summary, the first three carcinoma cases had no metastasis, and the second report found two lymph node metastases among eight malignant lesions. They attributed the effect to chronic chemical-mechanical irritation. The first English paper appeared in 1918.
  8. 1941 · Detection · UnderstandingPapanicolaou and Traut: vaginal smear cytology for uterine cancerIn 1941 George Papanicolaou and Herbert Traut reported that cancer cells shed from the uterus can be recognised in vaginal smears under the microscope. Papanicolaou had first seen cancer cells in a human specimen in 1928. Their work became the basis of the Pap test used for cervical cancer screening.Papanicolaou and Traut's 'The diagnostic value of vaginal smears in carcinoma of the uterus' (1941; reprinted Arch Pathol Lab Med 1997) described cytological diagnosis of uterine cancer. Papanicolaou had encountered cancer cells in a human specimen in 1928 (van Gijn); his 1928 report made little impact until the collaboration with the gynaecologist Traut (Swailes). Their 1943 book on diagnosis of uterine cancer by the vaginal smear followed (Elgert). The 1941 results were not read.

Chemotherapy

  1. 1946 · Treatment · ChemotherapyNitrogen mustard: first chemotherapy for lymphoma, reported 1946In August 1942 doctors at Yale gave a patient with lymphoma an injectable drug related to mustard gas. His tumours shrank, then returned, and he died that December. Wartime secrecy shrouded the work, and the first medical reports appeared in 1946, describing the drug for Hodgkin disease, lymphoma and leukemia.Patient JD, with lymphosarcoma refractory to radiotherapy and surgery, received intravenous nitrogen mustard at Yale from 27 August 1942: 0.1 mg/kg, 10 daily injections. Biopsy afterwards showed no tumour; counts then fell, tumours recurred by day 49, and he died on 1 December 1942 (day 96); autopsy showed marrow aplasia. First reports followed in 1946 (Science; JAMA). Single-patient chart review, no comparison group.
  2. 1948 · Treatment · Chemotherapy⚑ needs reviewAminopterin produces temporary remissions in childhood leukemiaIn 1948 Sidney Farber and colleagues reported that aminopterin, a drug that blocks folic acid, brought temporary remissions to some children with acute leukemia. The remissions were short and the drug was toxic, but the report showed that a chemical could drive leukemia back, and methotrexate, a close relative, is still used today.Uncontrolled clinical series of children with acute leukemia given the folic acid antagonist aminopterin (NEJM, 3 June 1948). Later accounts (Spain and Kadan-Lottick 2012; Izraeli 2022) describe 16 children studied, 10 with remissions that were temporary, and five documented in detail in the paper; main toxicity severe stomatitis with oral ulceration. These counts come from the later accounts and were not checked against the full 1948 text.
  3. 1950 · Understanding · UnderstandingHospital case-control study links smoking to lung carcinoma (1950)In 1950 Richard Doll and A. Bradford Hill compared the smoking habits of London hospital patients with and without lung cancer. Almost all the men with lung cancer had smoked, and heavier smokers were over-represented. The authors concluded that smoking is an important factor; later follow-up of British doctors strengthened the case.Hospital case-control study in 20 London-region hospitals: 649 men and 60 women with carcinoma of the lung, compared with patients with other cancers and with non-cancer controls. Non-smokers were 0.3% of men and 31.7% of women with lung carcinoma versus 4.2% and 53.3% of controls. The authors concluded that smoking is an important factor. A 1951 to 2001 cohort of 34,439 male doctors followed (Doll 2004).
  4. 1952 · Understanding · Understanding⚑ needs reviewTNM: Denoix's anatomic extent classification takes shape (1943-1954)Working from a French cancer registry begun in 1943, the surgeon Pierre Denoix and colleagues developed one common scheme for recording how far each cancer had spread. It grew into the tumour, node and metastasis (TNM) system, which the international cancer union adopted and still publishes as a shared language for describing cancer extent.Clinical classification of anatomic tumour extent developed by Pierre Denoix at the Institut Gustave Roussy, Paris. Registration began in 1943; a unified classification was proposed in 1947; a 1952 report added a metastasis component; a 1954 article set out local, regional and distant extent. UICC first recommendations 1958, brochures from 1960, TNM pocket book 1968; first AJCC manual 1977.
  5. 1956 · Treatment · Chemotherapy⚑ needs reviewMethotrexate reported active against choriocarcinoma (1956)In 1956 Min Chiu Li, Roy Hertz and Donald Spencer reported methotrexate treatment of three patients with metastatic choriocarcinoma or a related tumour, all of whom improved. A later biography credits Hertz and Li with the first medical cure of a solid cancer. A 2011 review puts the cure rate for these tumours today above nine in ten.Proc Soc Exp Biol Med 1956 (Li, Hertz, Spencer): three patients with progressive metastases (two choriocarcinoma, one chorioadenoma destruens) received repeated courses of methotrexate; gonadotropin fell towards normal and all improved clinically, with radiological regression of lung metastases; the authors called for more observations. Am J Obstet Gynecol 1961: five years' experience (no abstract). 2003 biography: first medical cure of a solid cancer. 2011 review: overall cure rate above 90%.
  6. 1960 · Understanding · Understanding⚑ needs reviewA minute chromosome found in chronic myeloid leukemia (1960)In 1960 Peter Nowell and David Hungerford noticed an unusually small chromosome in leukemia cells from patients with chronic myeloid leukemia. It was later named the Philadelphia chromosome, shown to come from an exchange of material between chromosomes 9 and 22, and became the target of the drug imatinib.A characteristic small chromosome in leukemic cells, first reported in two chronic cases (JNCI, July 1960); a 1961 JNCI paper reports 10 patients, 9 with a similar abnormality. Accounts of the 1960 Science abstract and of the naming differ (Nowell 2007; Radich 2022). Rowley (Nature 1973): in nine consecutive patients, a 22q deletion with extra material on 9q, suggesting a 9;22 translocation. BCR-ABL is targeted by imatinib.
  7. 1969 · Treatment · ChemotherapyPlatinum compounds found to be antitumour agents: path to cisplatinA 1965 experiment found that products from a platinum electrode stopped bacteria from dividing, and a 1969 paper reported platinum compounds as a new class of antitumour agents. Cisplatin reached the clinic in the 1970s; a 1977 series of patients with disseminated testicular cancer treated with cisplatin, vinblastine and bleomycin reported complete remission in nearly three of four.1965 (Nature): platinum electrolysis products inhibited E. coli division. 1969 (Nature): platinum compounds inhibited mouse sarcoma 180 and leukaemia L1210. 1977 (Ann Intern Med): 50 patients with disseminated testicular cancer received cisplatin, vinblastine and bleomycin; 3 inevaluable; 74% complete and 26% partial remission; 85% disease-free after surgery for residual disease; 2 drug-related deaths; 38 alive, 32 disease-free at 6+ to 30+ months. Single-arm series.
  8. 1970 · Treatment · ChemotherapyMOPP combination chemotherapy for advanced Hodgkin disease (1970)In 1970 DeVita, Serpick and Carbone reported combination chemotherapy for advanced Hodgkin disease, the four-drug regimen later called MOPP. Follow-up of patients treated at the US National Cancer Institute showed that most reached complete remission and about two in three of them stayed free of disease for over ten years, so advanced Hodgkin disease came to be seen as curable.National Cancer Institute series of 198 patients with advanced Hodgkin disease treated with MOPP (mechlorethamine, vincristine, procarbazine, prednisone). 1980 analysis: 80% complete remission; 68% of complete responders disease-free beyond 10 years. 1986 update, median follow-up 14 years: of 188 patients with confirmed Hodgkin disease, 157 (84%) achieved complete response and 101 (66%) stayed disease-free beyond 10 years. Uncontrolled single-institution series.
  9. 1971 · Understanding · UnderstandingTwo-hit hypothesis: retinoblastoma as a two-mutation cancer (1971)In 1971 A. G. Knudson analysed 48 cases of retinoblastoma, a childhood eye cancer, and proposed that it arises after two mutational events. In the inherited form one is present from birth; in the non-inherited form both happen in the same cell. The model explained why some carriers have no tumour and others have tumours in both eyes.Statistical model based on observations on 48 retinoblastoma cases and published reports. Hypothesis: retinoblastoma is caused by two mutational events; in the dominantly inherited form the first is germinal and the second somatic, in the nonhereditary form both are somatic. Poisson statistics with a mean of three tumours per carrier accounted for carriers without tumour, unilateral and bilateral disease and multiple tumours in one eye. Mutation rates were estimated as approximately equal.
  10. 1971 · Understanding · UnderstandingNational Cancer Act of 1971 creates the National Cancer ProgramOn 23 December 1971 US President Richard Nixon signed the National Cancer Act. It gave the director of the National Cancer Institute wide powers to plan a national cancer programme and sent the institute's budget proposal straight to the President and Congress. Nixon described the effort as the 'war on cancer', language of that time.Legislative milestone, not a clinical study. Public Law 92-218 (Senate Bill 1828), enacted 23 December 1971, created the National Cancer Program under the NCI director; established an 18-member National Cancer Advisory Board and a three-member President's Cancer Panel; sent the NCI budget proposal directly to the President; funded 15 new cancer research centres, local control programmes and an international cancer research data bank.
  11. 1975 · Understanding · UnderstandingHybridoma technique makes monoclonal antibodies possible (1975)In 1975 Georges Köhler and César Milstein fused antibody-producing cells with tumour cells to create cell lines that make identical antibodies of a chosen specificity in unlimited amounts. The Nobel Committee later called the method one of the most important methodological advances in biomedicine of the 1970s, and a route to precise diagnosis and treatment of disease.Laboratory method (Nature 1975): fusion of antibody-producing cells with tumour cells gives continuous cultures of fused cells secreting antibody of predefined specificity. The Nobel Committee (1984) states that the method allows unlimited production of monoclonal antibodies with predetermined specificity and opens new fields of research and precise diagnosis and treatment of disease. Köhler and Milstein shared the 1984 Nobel Prize in Physiology or Medicine with Niels Jerne.

Molecular origins

  1. 1976 · Understanding · UnderstandingViral oncogene traced to a normal cellular gene (1976)In 1976 Stehelin, Varmus, Bishop and Vogt reported that DNA related to the cancer-causing gene of avian sarcoma viruses is present in normal bird DNA. The result showed that such viral genes were copies of normal cellular genes that control growth, and it started a wider search for similar genes.Nucleic-acid probe study (Nature 1976): DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. The Nobel Committee (1989) states that Bishop and Varmus concluded that the viral oncogene is a normal cellular gene acquired by the virus; oncogene-like sequences were found throughout the animal kingdom; more than 40 oncogenes had been identified by 1989. Bishop and Varmus received the 1989 Nobel Prize in Physiology or Medicine.
  2. 1979 · Understanding · Understandingp53 discovered, then shown to be a tumour suppressor geneIn 1979 two groups reported a cellular protein, later called p53, associated with a tumour virus protein in transformed cells. It was first thought to promote cancer. Studies a decade later showed that p53 is a tumour suppressor: its gene was mutated in colorectal tumours and in families with the inherited Li-Fraumeni syndrome.1979 (Lane and Crawford, Nature; Linzer and Levine, Cell): a 54K dalton host protein associated with SV40 T antigen in transformed cells; Linzer and Levine also found it in uninfected embryonal carcinoma cells. 1989: 17p deletions in over 75% of colorectal carcinomas; the remaining p53 allele was mutated in both tumours sequenced (codons 143, 175). 1990: germ line p53 mutations in all five Li-Fraumeni families analysed. p53 is a tumour suppressor, not an oncogene (Levine and Oren 2009).
  3. 1983 · Understanding · UnderstandingHPV 16 and 18 found in cervical cancer (zur Hausen, 1983-1984)In 1983 and 1984 Harald zur Hausen's team found two new human papillomavirus types, HPV 16 and HPV 18, in biopsies of cervical cancer. Later work showed that HPV DNA is present in virtually all cervical cancers, which led to vaccines against the virus. zur Hausen received half of the 2008 Nobel Prize for the discovery.Dürst et al. (PNAS 1983): HPV 16 cloned from a cervical carcinoma; sequences found in 61.1% (11/18) of German and 34.8% (8/23) of Kenyan and Brazilian cervical cancer biopsies, and in 2 of 33 condylomata. Boshart et al. (EMBO J 1984): HPV 18 found in 9/36 cervical carcinomas from Africa and Brazil and 2/13 from Germany, not in benign lesions tested. Reanalysis (Walboomers 1999): HPV prevalence in cervical carcinoma 99.7%.
  4. 1986 · Detection · Detection & preventionOrganised cervical cytology screening linked to falling mortalityStudies in the 1980s compared cervical screening programmes. Organised programmes protected women better than uncoordinated testing, screening every three years protected about as well as yearly screening, and Nordic countries with wide organised screening, such as Iceland, saw the largest falls in cervical cancer deaths.IARC collaborative study (1986, eight countries): relative protection higher after two or more negative smears; little difference between yearly and 3-yearly screening; screening only every 5 or 10 years appreciably less protective; organised programmes more effective than uncoordinated screening. Nordic trends (1987): cumulative mortality age 0-74 fell between 1965 and 1982, by 80% in Iceland (widest programme), 50% Finland, 34% Sweden, 25% Denmark (40% covered), 10% Norway (5% covered). Observational data.
  5. 1992 · Understanding · UnderstandingPD-1 gene found in dying cells; later shown to be a T-cell brakeIn 1992 Y. Ishida, Tasuku Honjo and colleagues identified a new gene, PD-1, switched on in mouse cells undergoing programmed cell death. Honjo then spent years working out its role. The Nobel Committee describes how PD-1 turned out to act as a brake on T cells, and blocking it became a cancer treatment.Gene discovery in mouse cell lines (EMBO J 1992): PD-1, a novel member of the immunoglobulin gene superfamily, isolated by subtractive hybridisation from a T-cell hybridoma and a haematopoietic progenitor line undergoing programmed cell death; mouse expression restricted to thymus. The authors suggested involvement in programmed cell death. The Nobel Committee (2018) states that Honjo's later work showed PD-1 acts as a T-cell brake and cites a key clinical study in 2012.
  6. 1996 · Understanding · ImmunotherapyCTLA-4 blockade enhances antitumour immunity in mice (1996)In 1996 James Allison's group showed that antibodies blocking a T-cell protein called CTLA-4 made mice reject tumours, including established ones. A 2010 trial of an anti-CTLA-4 antibody, ipilimumab, in previously treated metastatic melanoma lengthened survival, and Allison shared the 2018 Nobel Prize with Tasuku Honjo.Preclinical study (Science 1996): antibodies to CTLA-4 given in vivo caused rejection of tumours, including preestablished tumours, and immunity to a secondary exposure. Phase 3 follow-on (Hodi, NEJM 2010; 676 previously treated patients with metastatic melanoma): median OS 10.0 months with ipilimumab plus gp100 vs 6.4 months with gp100 alone (HR 0.68; P<0.001); 10.1 months with ipilimumab alone (HR 0.66; P=0.003); grade 3 or 4 immune-related adverse events 10 to 15% vs 3%; 14 study-drug deaths (2.1%).
  7. 1997 · Detection · Detection & preventionTaiwan hepatitis B vaccination programme and childhood liver cancerTaiwan began vaccinating infants against hepatitis B in July 1984. A 1997 registry study found that liver cancer became less common in children aged 6 to 14, and a 2009 follow-up found the lower rate held into early adulthood. The remaining cases were mostly linked to children of highly infectious mothers.Registry-based comparison of birth cohorts after Taiwan's July 1984 universal programme. 1997 (NEJM): hepatocellular carcinoma incidence in children aged 6 to 14 fell from 0.70 per 100,000 (1981-1986) to 0.57 (1986-1990) and 0.36 (1990-1994), P<0.01. 2009 (JNCI; 1958 cases aged 6 to 29, 1983-2004): relative risk 0.31 (P<.001) at ages 6 to 19 for persons vaccinated at birth; incomplete vaccination OR 4.32 (95% CI 2.34 to 7.91); maternal HBsAg seropositivity OR 29.50 (13.98 to 62.60).

Targeted therapy

  1. 2000 · Understanding · UnderstandingThe Hallmarks of Cancer: a framework (2000, 2011, 2022)In 2000 D. Hanahan and R. A. Weinberg proposed that the many forms of cancer share a small set of acquired capabilities, which they called hallmarks. They revised the list in 2011, and Hanahan proposed further additions in 2022, such as cell plasticity and the microbiome. It is a way of organising knowledge, not a clinical result.Conceptual review series (Cell 2000; Cell 2011; Cancer Discovery 2022). The 2011 paper lists six biological capabilities, with genome instability and inflammation as enabling characteristics, adds two emerging hallmarks (reprogramming of energy metabolism; evading immune destruction) and the tumour microenvironment. The 2022 paper proposes phenotypic plasticity and disrupted differentiation as a hallmark, epigenetic reprogramming and polymorphic microbiomes as enabling characteristics, and senescent cells. A 2026 Cell review synthesises 25 years. No data.
  2. 2003 · Understanding · UnderstandingHuman Genome Project completed: first sequence of the human genomeThe Human Genome Project, an international effort launched in October 1990, was completed in April 2003 and produced the first sequence of the human genome. A draft appeared in 2001, and a finishing report in 2004 described a sequence covering about 99% of the euchromatic genome. It is a foundation for later programmes that read the genomes of tumours.Not a cancer study. Draft sequence reported in Nature, February 2001. Finishing report (Nature, October 2004): Build 35, 2.85 billion nucleotides with 341 gaps, covering about 99% of the euchromatic genome with an error rate of about 1 event per 100,000 bases; 20,000 to 25,000 protein-coding genes. The NHGRI dates the project from October 1990 to April 2003.
  3. 2006 · Detection · Detection & preventionFirst US-licensed HPV vaccine; later data show fewer cervical cancersOn 8 June 2006 the US regulator licensed Gardasil, which it called the first vaccine developed to prevent cervical cancer, for girls and women aged 9 to 26. A large randomised trial found it prevented nearly all HPV 16 and 18 high-grade cervical lesions in women not already infected; a Swedish study later found fewer cervical cancers in vaccinated women.FUTURE II (placebo-controlled RCT, 12,167 women aged 15 to 26, three doses): vaccine efficacy against HPV 16/18-related CIN 2/3, adenocarcinoma in situ or cervical cancer 98% (95.89% CI 86 to 100) in the per-protocol susceptible population; 44% (95% CI 26 to 58) in ITT. Swedish register cohort (1,672,983 females aged 10 to 30): cervical cancer in 19 vaccinated and 538 unvaccinated women; adjusted incidence rate ratio 0.37 (0.21 to 0.57); 0.12 (0.00 to 0.34) if vaccinated before 17.
  4. 2008 · Understanding · UnderstandingTCGA: first tumour atlas report (glioblastoma, 2008)The Cancer Genome Atlas began in 2006 as a joint effort of two US institutes. Its first report, in 2008, mapped changes in the DNA of 206 glioblastomas. Over the next dozen years the programme profiled over 20,000 tumour and matched normal samples spanning 33 cancer types, and made the data public.TCGA pilot, interim analysis (Nature 2008): integrative analysis of DNA copy number, gene expression and methylation in 206 glioblastomas, with sequencing of 91; new roles for ERBB2, NF1 and TP53, frequent PIK3R1 mutations, and a link between MGMT promoter methylation and a hypermutator phenotype from mismatch repair deficiency in treated tumours. Programme (NCI): began 2006, over 20,000 primary cancer and matched normal samples, 33 cancer types, over 2.5 petabytes.

Immunotherapy

  1. 2017 · Treatment · ImmunotherapyFirst tissue-agnostic approval: pembrolizumab for MSI-H/dMMR tumoursOn 23 May 2017 the US regulator approved pembrolizumab for advanced solid tumours whose cells have a repair defect called MSI-H or dMMR, whatever organ the cancer began in. The regulator describes it as its first approval based on a tumour feature rather than a tumour site. It rested on 149 patients in five single-arm studies with no comparison group.FDA accelerated approval for adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumours that progressed after prior treatment with no satisfactory alternative, and for MSI-H or dMMR colorectal cancer after fluoropyrimidine, oxaliplatin and irinotecan. Basis: 149 patients in five uncontrolled single-arm trials (90 colorectal, 59 other): ORR 39.6% (95% CI 31.7 to 47.9), CR 7.4%, PR 32.2%; 78% of responses lasted 6 months or longer.
  2. 2017 · Treatment · Cell therapy & transplantFirst CAR T-cell therapy approved in the US: tisagenlecleucel for ALLOn 30 August 2017 the US regulator approved tisagenlecleucel, made from a patient's own T cells, for people up to age 25 with B-cell acute lymphoblastic leukemia that had resisted treatment or relapsed twice or more. Most patients in the pivotal single-arm study had a remission, but serious immune side effects were common.Single-arm phase 2 (ELIANA). FDA efficacy set, 63 patients: overall remission rate within 3 months 82.5% (95% CI 70.9 to 91.0), CR 63.5%, CRi 19.0%, all MRD-negative; median follow-up 4.8 months; median duration of response not reached. Published analysis (NEJM 2018, 75 patients): remission rate 81%; EFS 73% at 6 and 50% at 12 months; cytokine release syndrome 77%, neurologic events 40%. FDA review: CRS 79%, neurologic toxicity 65%.

Pioneers

References

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1915UnderstandingUnderstanding

majorAny setting

Yamagiwa and Ichikawa induce cancer with coal tar (1915)

In 1915 the Japanese pathologists Katsusaburo Yamagiwa and Koichi Ichikawa reported that painting coal tar on rabbit ears for months produced skin tumours, including cancer. It has been called the first artificial production of cancer in experimental animals. It gave experimental support to the idea that chronic irritation can lead to cancer.

Yamagiwa and Ichikawa reported in 1915 that prolonged coal-tar painting of rabbit ears produced folliculoepithelioma (papilloma) and, in some animals, carcinoma; Sekiya calls it the world's first artificial cancer in experimental animals. In Fujiki's English summary, the first three carcinoma cases had no metastasis, and the second report found two lymph node metastases among eight malignant lesions. They attributed the effect to chronic chemical-mechanical irritation. The first English paper appeared in 1918.

Standard before

Transplantation of mouse tumours was widespread, but real malignant epithelial tumours had not been induced artificially, apart from Fibiger's 1913 gastric lesions in rats.

What changed

Cancer could be induced in animals by a chemical mixture, opening experimental carcinogenesis; mouse skin painting became a standard tool.

Why it mattered

Showed experimentally that a chemical exposure could cause cancer, supporting Pott's observation and Virchow's irritation theory and starting experimental carcinogenesis in animals.

Caveats

  • Yamagiwa and Ichikawa interpreted the effect as chronic chemical-mechanical irritation; the carcinogenic hydrocarbons in coal tar were identified in later work not covered here. Doll describes the first synthesis and isolation of carcinogens as following Pott's observation.
  • In Fujiki's summary the first three rabbit carcinomas did not metastasise and transplantation experiments were negative, so the authors themselves discussed whether the lesions were fully carcinomatous.
  • Priority is described differently in sources: Fujiki says Fibiger's 1913 rat gastric lesions came first and were later reinterpreted by a journal reviewer as granulomas, a point not independently confirmed here.
  • The work became known late in Europe because it was first published in Japan during the First World War (Fujiki, citing Henschen).
  • Fujiki lists a preliminary paper of 1914 (Gann) before the 1915 reports; the year 1915 is that of the first reports of artificial production of papilloma and tumours (September 1915) and of the first comprehensive report in German. Fujiki gives 1918 for the first English paper (Journal of Cancer Research) in one passage and 1916 in another; 1918 is used here.