Landmarks in Cancer Research: 1991-2010
- AACR publishes the first issue of the journal, Cancer Epidemiology, Biomarkers & Prevention.
- Fifteen U.S. departments and agencies join to create the Federal Policy for the Protection of Human Subjects, informally known as the “Common Rule.”
- Specific mutation in p53 in liver cancer is associated with exposure to the environmental carcinogen aflatoxin.
Mutations in codon 249 of p53 in hepatocellular carcinoma, a cancer endemic to locations in southern Africa and Asia, were shown to be associated with aflatoxin exposure. (179-181)
- American Cancer Society recommends widespread use of prostate-specific antigen test for prostate cancer.
- PD1 gene is discovered.
A gene encoding the protein PD-1 was discovered in a screen for proteins likely to be involved in controlling T-cell apoptosis. This protein has become a key cancer immunotherapy target since preventing it from binding to its ligands enhances T-cell anticancer activity. (182)
- Comparative genomic hybridization is developed.
A new technique allowed changes in genome copy number to be mapped onto normal representations of the human genome. Initial mapping representations were metaphase chromosomes, but these have now been supplanted by a wide range of microarray technologies, including some that allow allele-specific analysis. (183-185)
- The inaugural AACR-American Cancer Society Award for Research Excellence in Cancer Epidemiology and Prevention is presented to Pelayo Correa.
- First AACR Workshop, “Molecular Biology in Clinical Oncology,” is held in Aspen, Colorado.
- Mammography Quality Standards Act regulates mammography screening facilities, providers, and equipment.
- U.S. Department of Defense is mandated to fund the Breast Cancer Research Program.
- The first Joint Meeting of the Japanese Cancer Association and AACR is held.
- The Prostate Cancer Foundation is founded.
- Inaugural AACR-Gertrude B. Elion Cancer Research Award is presented to Benjamin G. Neel.
The award is intended to encourage and support tenure-eligible junior faculty by providing a one-year grant for expenses related to a research project.
- AACR membership passes 10,000.
- Carcinomas originate from normal stem cells that become cancer stem cells.
Investigations showed that a determined stem cell required for normal tissue renewal is the most likely cell of origin of carcinomas. (186)
- AACR publishes the first issue of the journal, Clinical Cancer Research.
- Microarray technology is developed for molecular profiling.
A chip that can assay the expression of thousands of genes from one sample rapidly expands the generation of data on molecular targets and diagnostics and drives the need for computational analysis methods. This hardware and software can be applied to gene expression, measuring genetic variation at single-nucleotide polymorphisms (SNPs) and gene copy number and examining alternative splicing to measure biomarkers for individual cancers, which ultimately can lead to personalized therapies. (187)
- Serial Analysis of Gene Expression (SAGE) technology is described as another method to analyze gene expression profiles.
SAGE was described in the same year as microarray technology and provides another method for gene expression analysis. Short nucleotide sequence tags (~9-14 bps) are designed to a unique portion of a transcript and are sufficient to identify this transcript with specificity from the sample mRNA pool. Sequence tags are linked together (concatemers), cloned, and sequenced. The number of times a particular tag is observed quantifies the expression level of that transcript in the original mRNA sample. For example, conducting SAGE on mRNA derived from tumor and normal adjacent tissue can evaluate differential gene expression, if any, in the transcript the sequence tags are designed to identify. (188)
- Computer-guided technology improves delivery of radiation therapy.
Computerized systems improve the accuracy of radiation therapy with better focusing on the tumor, reducing damage to surrounding healthy tissue. (189)
- First demonstration that blocking CTLA-4 could enhance antitumor immunity and lead to tumor elimination.
Antibodies preventing the immune checkpoint protein CTLA-4 from putting the brakes on T-cell activation were shown to cause tumor elimination in mice. This proof-of-principle preclinical study led directly to the first of a groundbreaking class of cancer immunotherapeutics called immune checkpoint inhibitors. (190)
- AACR in partnership with ASCO launches “Methods in Clinical Cancer Research: A Workshop,” held in Park City, Utah.
- Inaugural AACR-Joseph H. Burchenal Memorial Award for Outstanding Achievement in Clinical Cancer Research is presented to Samuel A. Wells, Jr.
- Inaugural AACR-DeWitt S. Goodman Memorial Lecture is delivered by David J. Mangelsdorf.
The lectureship is awarded for significant contributions to the field of nutrition and cancer and cancer prevention.
- AACR holds its first Special Conference on “DNA Methylation, Imprinting, and the Epigenetics of Cancer.”
- Rituximab (Rituxan) approved by FDA for the treatment of B-cell non-Hodgkin lymphoma resistant to other treatments.
Rituximab was the first monoclonal antibody FDA approved for the treatment of cancer. Rituximab, in combination with CHOP chemotherapy (RCHOP), is now standard of care in the treatment of diffuse large B-cell lymphoma and many other B-cell lymphomas. (191)
- Use of a monoclonal antibody (trastuzumab, Herceptin) significantly improves survival in advanced Her-2/neu breast cancer.
Patients with Her-2/neu-positive metastatic breast cancer who were treated with chemotherapy plus trastuzumab (Herceptin) lived longer and their tumors showed a greater decrease in size compared with those in patients who received chemotherapy alone. (192,193)
- Selective estrogen receptor modulators prevent breast cancer in high-risk women.
A study showed reduction of breast cancer incidence by 44% in women at high risk for developing breast cancer who were treated with selective estrogen receptor modulators. This led to FDA approval of tamoxifen for prevention of breast cancer in women at high risk of developing the disease. (194)
- PTEN is a lipid phosphatase.
This observation focused attention on the PI3K pathway in cancer development, which is currently an important area of drug development. (195,196)
- Inaugural AACR-Women in Cancer Research Charlotte Friend Memorial Lecture is delivered by Frances M. Visco.
The lecture is intended to give recognition to an outstanding female or male scientist who has made meritorious contributions to the field of cancer research and who has, through leadership or by example, furthered the advancement of women in science.
- One-quarter million people take part in “THE MARCH: Coming Together to Conquer Cancer,” a rally on the National Mall in Washington, DC, in support of increased cancer research funding.
THE MARCH Research Task Force Report was published in Cancer Research. (197)
- Inaugural Pezcoller Foundation-AACR International Award for Cancer Research is presented to Anthony J. Pawson.
- RNA Interference (RNAi) knockdown is demonstrated.
RNAi provides a method to switch off the actions of genes and can be performed in a high-throughput manner, unlike the creation of knockout mice, which is very time consuming. Researchers are using RNAi to identify genes that might be involved in cancer by switching them off and examining the consequences. It is hoped that therapies might one day be enhanced through RNAi, for example, by using RNAi to switch off genes involved in drug resistance to make chemotherapy more effective. (198)
- Master Settlement Agreement forces tobacco companies to pay $246 billion to U.S. states over the next 25 years as restitution for violating antitrust and consumer protection laws.
- Positron emission tomography (PET) scanner is approved for functional imaging.
PET uses an injected dye to view tissues that are highly metabolically active. PET can identify tumors that are fast growing and active. It is more sensitive at detecting small tumors and metastatic tumors than computed tomography (CT) or MRI and so may aid in early diagnosis. (199-201)
- Human embryonic stem cells are grown for the first time.
Embryonic stem cells have the capacity to become any cell type. Various possible applications have been suggested for how stem cells might be used to cure cancer, from generating host-identical replacement cells for tissues that have been surgically removed or destroyed by radiation therapy to generating immune cells that recognize tumors and can enhance the body’s own defense system to kill cancers. (202,203)
- U.S. Congress enacts a plan to double the 1998 NIH budget by 2003.
- Cancer-associated fibroblasts are found to promote tumorigenesis.
This study showed that CAFs can drive transformation of initiated epithelial cells. Research on CAFs has helped highlight that cancer is not a cell-autonomous illness and that the tumor microenvironment plays an important role in driving tumorigenesis. (204)
- AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics is launched.
This conference, which alternates between locations in the U.S. and Europe each year, has become the most important drug development meeting in the world and an important collaboration among the organizing bodies.
- AACR launches the Scientist↔Survivor Program® to unite scientific, cancer survivor, and patient advocacy communities worldwide.
- AACR Molecular Epidemiology Working Group is formed.
This first AACR Working Group (later renamed the Population Sciences Working Group) brings multiple disciplines together to foster advances in molecular epidemiology. Its success has motivated the formation of other Working Groups, all of which contribute in major ways to AACR programs, including the Annual Meeting.
- Pancreas Cancer Think Tank is held by AACR.
- Douglas Hanahan and Robert A. Weinberg publish their seminal review, “The Hallmarks of Cancer.”
The authors coalesced a framework around which tumorigenesis could be understood as the result of a finite number of underlying principles and acquired capabilities “. . . shared by most and perhaps all types of human cancer.” The goal of articulating these principles was to help cancer researchers more clearly understand and discuss the complexities of neoplastic disease. (205)
- Massively parallel signature sequencing method is published.
This method launched the development of a variety of “next-generation” sequencing platforms. (206,207)
- Da Vinci robotic surgical system is the first robotic surgery system approved by the FDA for general laparoscopic surgery.
The da Vinci robotic surgical system is less invasive than previous surgical techniques and is used to treat a number of cancers. (208)
- Minorities in Cancer Research (MICR) is established by the AACR to meet the professional needs and advance the careers of minority scientists.
The MICR Council acts as an advisory body to the AACR leadership on issues of concern to minority investigators and is also responsible for organizing the activities of MICR through its committees.
- AACR Foundation for the Prevention and Cure of Cancer (now renamed the American Association for Cancer Research Foundation) is launched.
- Breast and Cervical Cancer Treatment Act passes to provide treatment for low-income women diagnosed with cancer.
- AACR Journals Online first offers the full text of all AACR scientific publications.
- NCI establishes the Center to Reduce Cancer Health Disparities to help reduce the disproportionate impact of cancer on underserved populations.
- First commercial PET/CT scanner is developed.
The first prototype began clinical evaluation at the University of Pittsburgh in 1998. The results from over 300 cancer patients were published in peer-reviewed journals two years later. The impressive results of high-resolution structural, anatomic data coupled with functional data created a market for commercial design. The first commercial PET/CT scanner, Discovery LS, was announced in 2001. (209,210)
- FDA approves CyberKnife Robotic Radiosurgery System.
This noninvasive alternative to surgery allowed for more accurate targeting of radiation therapy to treat cancers, tumors, and other lesions. (208)
- Children’s Oncology Group is formed.
Formed from four of NCI’s pediatric cooperative groups (the National Wilms Tumor Study Group, the Children’s Cancer Group, the Pediatric Oncology Group, and the Intergroup Rhabdomyosarcoma Study Group), the Children’s Oncology Group directs most of the pediatric cancer clinical trials in the U.S. Fifty to 60 percent of eligible children participate in clinical trials.
- National Nanotechnology Initiative (NNI) is established.
The National Nanotechnology Initiative (NNI) is a research and development initiative of the U.S. government and comprises the individual and cooperative nanotechnology-related activities of 20 departments and federal agencies. NNI’s common goals are to: 1) advance a world-class nanotechnology research and development program; 2) foster the transfer of new technologies into products for commercial and public benefit; 3) develop and sustain educational resources, a skilled workforce, and a dynamic infrastructure and toolset to advance nanotechnology; and 4) support responsible development of nanotechnology. (211)
- Guidelines and recommendations for the implementation of intensity-modulated radiotherapy (IMRT) are published by the NCI Intensity Modulated Radiation Therapy Collaborative Working Group.
IMRT represents one of the most important developments in radiation therapy. It enables the delivery of high-dose radiation targeted to the tumor and minimal dose to the surrounding healthy tissue. IMRT is now how radiation therapy is most commonly delivered. (212)
- Two ligands for inhibitory PD-1 are identified.
Engagement of PD-1 by either of its two newly discovered ligands B7-H1 and B7-DC (PD-L1 and PD-L2, respectively) drastically inhibits T-cell receptor-mediated proliferation and cytokine production. Researchers believe this is a way to regulate T-cell responses as dysregulation of this pathway can lead to autoimmunity. This pathway will become a major target for cancer immunotherapy, as blocking PD-1 from binding either of its two immunomodulatory ligands can shift the balance toward heightened T-cell cytotoxicity activity, directing it toward the cancer. (213-216)
- AACR publishes the first issue of the journal, Molecular Cancer Therapeutics.
- Imatinib, the first FDA-approved small-molecule kinase inhibitor, is effective in treating chronic myelogenous leukemia.
Earlier work established that the Bcr-Abl fusion protein, a result of the Philadelphia chromosome translocation event, was characteristic and causative of chronic myelogenous leukemia. The kinase inhibitor imatinib (Gleevec) selectively shuts down Bcr-Abl signaling in leukemic cells resulting in remission. (217)
- Draft sequence of the human genome is published.
A public, free-access, complete human genomic sequence allows researchers to perform many experiments, including but not limited to studies of comparison with other organisms, predictions of gene functions, identification of new genes involved in cancer, and design of new diagnostics and therapeutics. The race to sequence the genome advanced technologies for sequencing and analysis, and it is believed that the $1000 genome sequence may be possible within a few years. This opens up the possibility that patients might sequence and store their full genetic information and that it might be used for personalized medicine, such as determining customized drug treatments and preventive measures. (218,219)
- AACR introduces two new categories of membership: Affiliate Membership, for health professionals working in support of cancer and biomedical research, and Student Membership, for high school and undergraduate students.
- I-SPY Trials are launched.
The I-SPY TRIALs are an adaptive approach to clinical trial design to accelerate the processes of identifying patients who would benefit from new drugs and to bring effective drugs to the market. The I-SPY Trials Program consists of three integrated and linked phases: phase I (I-SPY 1), phase II (I-SPY 2), and phase III (I-SPY 3). The I-SPY 1 study integrated patients’ clinical, imaging, and genomic data to evaluate whether response to therapy could predict recurrence-free survival. Additionally, the trial data were used to inform and enable decisions at earlier time points for the I-SPY 2 Trial. The adaptive design of the I-SPY 2 Trials allowed investigators to learn from study data as they were collected and adapt treatments to those that would be more likely to benefit the patient. Rather than waiting until the end of the trial, outcomes were assessed continually and data used to inform the ongoing trial. I-SPY 3 is designed to accelerate the phase III testing of agents.
- BRAF gene is mutated in human cancers.
Somatic missense mutations in BRAF, a gene encoding a kinase in the RAS–RAF–MEK–ERK–MAP pathway, are described as occurring in a variety of human cancers. Mutated BRAF proteins have elevated kinase activity capable of transforming NIH3T3 cells. BRAF mutations occur most frequently in malignant melanoma. This observation provided a new therapeutic target. (220)
- NSG mouse is an excellent model for engraftment of human tumors.
The NOD/SCID/gamma-deficient mouse model is functionally incompetent, lacking functional T, B, and natural killer (NK) cells, and is therefore a model recipient for xenotransplantation. This mouse model can be used to engraft human cancer cells so that researchers can study and understand features of patients’ tumors, such as progression and metastasis. (221)
- First clinical trials of checkpoint inhibitor antibody are held.
Immunosuppressive CTLA-4 on T cells acts as a brake on the immune system. A specific monoclonal antibody that recognizes CTLA-4 blocks it and unleashes the potential of the immune system to destroy cancerous cells, opening the door to a new approach to cancer immunotherapy. (190,222,223)
- International Agency for Research on Cancer (IARC) classifies secondhand smoke as carcinogenic to humans.
IARC, in its monograph, Tobacco Smoke and Involuntary Smoking, concluded that there is sufficient evidence that secondhand smoke, also referred to as involuntary or passive smoking, causes lung cancer in humans. (224)
- AACR holds first multidisciplinary Frontiers in Cancer Prevention Research conference.
- AACR publishes the first issue of the journal, Molecular Cancer Research (successor to Cell Growth & Differentiation).
- Inaugural IARC-Prevent Cancer Foundation Award for Excellence in Cancer Prevention research is presented to Michael B. Sporn.
In 2013, the award was renamed the AACR Award for Outstanding Achievement in Cancer Prevention Research.
- The Inaugural Kirk A. Landon-AACR Prize for Basic Cancer Research is presented to Robert N. Eisenman.
- The Inaugural Dorothy P. Landon-AACR Prize for Translational Cancer Research is presented to Elwood V. Jensen and V. Craig Jordan.
- FDA approves ibritumomab tiuxetan for the treatment of patients with relapsed or refractory, low-grade or follicular B-cell non-Hodgkin lymphoma.
Ibritumomab tiuxetan was the first radioimmunotherapy drug approved by FDA to treat cancer. It was approved for the treatment of patients with relapsed or refractory, low-grade or follicular B-cell non-Hodgkin lymphoma (NHL), including patients with rituximab refractory follicular NHL. (225)
- Obesity is associated with increased cancer death rates.
In a prospective study of more than 900,000 U.S. adults, the death rates from all cancers combined in men and women with a body-mass index (BMI) of 40 or above were 52% and 62% higher than in men and women with normal BMI, respectively. The study estimated that 90,000 cancer-related deaths could be prevented each year in the U.S. if men and women could maintain normal weight. (226)
- FDA approves the first EGFR inhibitor.
Gefitinib was approved by FDA in 2003 for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of both docetaxel- and platinum-based treatments. The surrogate endpoint for clinical efficacy was tumor response rate. Erlotinib, another EGFR inhibitor, was approved by FDA in 2004 for this same cohort, but clinical efficacy was based on improved overall survival. Two follow-up clinical trials with gefitinib did not demonstrate survival benefit. This led to FDA relabeling of gefinitib in 2005 for cancer patients who, in the opinion of their treating physicians, are currently benefiting or have previously benefited from gefitinib treatment. Approval of gefinitib as a first-line therapy was granted in 2015 for patients with metastatic NSCLC whose tumors express either of two specific EGFR mutations (exon 19 deletions or exon 21 L858R substitution gene mutations). Erlotinib received the same first-line therapy indication for the specific EGFR-mutant cohort in 2013. (227)
- Institute of Medicine (IOM) of the National Academies publishes report on disparities in health care.
In 1999 Congress requested an IOM study on the extent of disparities in health services received by U.S. racial and ethnic minorities. The report from that study, Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care, found that U.S. racial and ethnic minorities received lower quality health services and were less likely to receive routine medical procedures. The report recommended several policies to decrease these disparities, including raising awareness about health disparities, developing guidelines for providers, and increasing the numbers of minority health care providers and interpreters in clinics and hospitals. (228)
- Loss of function of some tumor suppressor genes occurs through hypermethylation.
Some genes that are frequently hypermethylated in cancer, but are not themselves mutated, can be important tumor suppressor genes. Tumor suppressor genes can be silenced through hypermethylation of their promoter regions, allowing cells to grow and reproduce uncontrollably. (229,230)
- Database of target genes responsive to Myc is developed.
The database serves as a warehouse for information about Myc-responsive genes. Genes are clustered based on their responsiveness to the transcription factor Myc and paired with phylogenetic sequence comparisons to predict the target-binding sites of c-Myc. The database also provides information and references on alterations of MYC genes in human cancers and links to a c-Myc protein-protein interaction database. (231)
- Large-scale mutation analysis of tyrosine kinome identifies mutations in genes, including NTRK and PIK3CA, implicated in cancer.
The large-scale sequencing-based approach helped identify previously unknown gene mutations providing potential targets for drug development. Therapies targeting NTRK fusions and PIK3CA mutations were developed subsequently. (232-234)
- AACR membership passes 20,000.
- Ubiquitin-proteasome pathway inhibitor bortezomib (Velcade) receives accelerated approval.
Bortezomib (Velcade), a member of a new class of anticancer drugs that target the ubiquitin protein degradation system, was shown to be active in patients with relapsed multiple myeloma that was refractory to conventional chemotherapy. (235)
- Inaugural AACR Distinguished Lecture is delivered by James E. Darnell, Jr.
In 2013, the lectureship was renamed the AACR-Irving Weinstein Foundation Distinguished Lecture.
- FDA approves bevacizumab (Avastin) for treating advanced colon cancer.
This the first FDA-approved antiangiogenic therapeutic; there are now 11. Building on earlier work identifying the need of new blood vessel networks to feed tumor growth, therapies were designed to antagonize VEGF, a key molecule in angiogenesis. The addition of bevacizumab to conventional fluorouracil-based combination chemotherapy resulted in improved survival in patients with metastatic colorectal cancer. (236)
- Radiotherapy is shown to induce antitumor immunity.
The ability of ionizing radiation to cause tumor regression outside the field of radiation was shown in this preclinical study to be a result of immune-cell activation and action at distant sites. (237)
- 5-Azacitidine (Vidaza), the first-in-class drug targeting an epigenetic mechanism, is approved.
5-Azacitidine targets an epigenetic mechanism in cancer. It is a hypomethylating agent and a chemical analogue of the nucleoside cytosine. It works by inhibiting DNA methyltransferase, leading to DNA hypomethylation. FDA approved this drug for the treatment of several subtypes of myelodysplastic syndrome. (238)
- According to the American Cancer Society, the absolute number of cancer deaths in the United States declines for the second year in a row, confirming a trend in cancer-related mortality.
- Vaccines against HPV are developed to prevent cervical cancer.
Vaccination against the most common oncogenic HPV types, HPV 16 and HPV 18, could prevent up to 70% of cervical cancer cases worldwide. (239,240)
- Inaugural AACR Award for Lifetime Achievement in Cancer Research is presented to Emil Frei III.
- First haplotype map of the human genome is published.
A large consortium published a database of one million SNPs in 269 DNA samples from four population groups. This resource allowed for the beginning of whole-genome association studies and the identification of susceptibility variants. (241)
- NCI Biorepositories and Biospecimen Research Branch of the Cancer Diagnosis Program is established.
- EGFR T790M mutation is reported.
Lung adenocarcinomas that contain a primary drugsensitive mutation in EGFR initially respond to the tyrosine kinase inhibitors gefitinib and erlotinib, but eventually progress by previously unknown mechanisms of acquired resistance. This study found that the tumors that progress due to acquired resistance contain, in addition to the primary mutation, a secondary mutation in exon 20, leading to the substitution of methionine for threonine at position 790 (T790M) in the kinase domain. This information provided a basis for the development of second-generation kinase inhibitors to treat NSCLC. (242)
- Proffered abstracts at the AACR Annual Meeting set a new record of over 6,000.
- Small noncoding RNAs have a role in oncogenesis.
Traditionally, much of the focus of genomic research had concentrated on genes that code for proteins. Several studies showing that small, noncoding RNAs may play a role in the development of cancer, including one published in Cancer Research, challenged the long-standing belief that proteins were the principal functional products of the genome. (243-245)
- AACR Chemistry in Cancer Research Working Group is formed.
- AACR Workshop on the Human Epigenome is held.
- The Cancer Genome Atlas (TCGA) is established to map cancer genes.
TCGA, a collaboration between the NCI and the National Human Genome Research Institute, seeks to identify the changes in each cancer’s complete set of DNA in the hope of understanding how such changes drive the disease.
- NCI TAILORx Breast Cancer Trial is launched.
TAILORx [Trial Assigning IndividuaLized Options for Treatment (Rx)] examined whether genes that are frequently associated with risk of recurrence for women with early-stage breast cancer can be used to assign patients to the most appropriate and effective treatment.
- U.S. Surgeon General’s report on secondhand smoke is released.
This Surgeon General’s report updated the evidence of the harmful effects of secondhand smoke. The previous comprehensive review of this evidence by the Department of Health and Human Services was released in 1986. (246)
- New method of adoptive T-cell transfer is introduced.
Genetic engineering of T cells to express T-cell receptor bypasses the need to expand tumor-specific T cells. Some cancer patients have few to no tumor-reactive T cells; genetically modifying normal circulating peripheral T cells overcomes this limitation to standard adoptive transfer. (247)
- Cancer is described as an evolutionary and ecological process, providing insight into its clonal heterogeneity.
In 1976, a landmark paper was published on the evolutionary theory of cancer. Advances in biology and sequencing facilitated the validation of this theory. A 2006 paper decribed each neoplasm as a complex, Darwinian, adaptive system made up of a “mosaic of mutant cells” that “compete for space and resources, evade predation by the immune system and can even cooperate to disperse and colonize new organs.” These papers provided insight into the clonal heterogeneity of tumors and described how resistant clones arise. (248,249)
- Protein-coding genes of breast and colon cancers are sequenced.
Genomic sequencing and analysis of the 13,023 genes in 11 breast and 11 colorectal cancers revealed that only a subset of the accumulated mutations in a tumor contribute to the neoplastic process. The comprehensive data and analysis helped researchers understand the genetic landscape of breast and colon cancers, while also providing clues for new targets for diagnostic and therapeutic intervention. (250)
- AACR publishes CR (relaunched in 2011 as Cancer Today), the association’s first magazine specifically for cancer patients, survivors, and their family members and friends.
- Inaugural AACR-Minorities in Cancer Research Jane Cooke Wright Memorial Lecture is delivered by Olufunmilayo I. Olopade.
- AACR Tumor Microenvironment Working Group is formed.
- AACR Council of Scientific Advisors is formed.
- The term “myeloid-derived suppressor cells” is coined. Myeloid-derived suppressor cells are a heterogeneous mixture of immunosuppressive cells of myeloid origin. These cells accumulate in several pathologic conditions, including many types of cancer, where they suppress antitumor immune responses, promote tumor immune evasion, and associate with poor prognosis. (251)
- ALK rearrangements in NSCLC are identified. Researchers identified a small inversion on chromosome 2p in NSCLC cells that results in a fusion gene of EML4 and ALK. Expression of the mutant EML4-ALK fusion transcript transformed foci in normal cells and resulted in subcutaneous tumors in nude mice. In this original study, the EML4-ALK mutant fusion transcript was identified in ~6.7% of the human NSCLC patients tested. Later studies identified additional ALK fusion gene variants that encode oncogenic kinases in NSCLC patients. In fact, these mutations are most often found in NSCLC patients who are younger, female, light/never smokers, or do not harbor EGFR or KRAS mutations. This finding in a subset of NSCLC patients provided a new therapeutic target based on cancer genotype and led to landmarks in both targeted therapy and precision medicine. (252-254)
- AACR celebrates 100 years of fostering research in cancer and related biomedical science; disseminating new research findings among scientists and others dedicated to the conquest of cancer; promoting science education and training; and advancing the understanding of cancer etiology, prevention, diagnosis, and treatment throughout the world.
- Inaugural AACR Team Science Award is presented to the University of Michigan-Brigham and Women’s Hospital Team.
- Inaugural AACR Award for Leadership and Extraordinary Achievements in Cancer Research is presented to AACR CEO Margaret Foti.
In 2008, the award was renamed the Margaret Foti Award.
- Inaugural AACR-Princess Takamatsu Memorial Lecture is delivered by Webster K. Cavenee.
- AACR holds its first Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved.
- Inaugural AACR Award for Outstanding Achievement in Chemistry in Cancer Research is presented to Samuel J. Danishefsky.
- AACR Office of Science Policy and Government Affairs opens in Washington, DC.
- AACR-FDA-NCI Cancer Biomarkers Collaborative is convened.
This body of more than 100 cancer researchers and advocates produced a definitive publication in the form of a consensus report that was published in Clinical Cancer Research. (255)
- AACR Translational Cancer Medicine Think Tank is held.
- Tumor burden is tracked using circulating DNA alterations in the blood.
Tumor cells can be found in the circulation of those with advanced cancers, and tumor-derived mutant DNA can be detected in the cell-free fraction of the blood. However, previous studies were unable to use sufficiently sensitive techniques to detect low levels of circulating tumor DNA (ctDNA). Modifications to the BEAMing technique (beads, emulsion, amplification, and magnetics) made it possible to detect low levels of circulating mutant DNA fragments, precisely measure the level of ctDNA, and track tumor burden in patients. This indicated that ctDNA could serve as a potential biomarker to noninvasively monitor many types of cancer and help inform clinical decision-making. (256)
- Whole-genome sequence of a human cancer is reported.
Treatment of acute myeloid leukemia has been particularly challenging since most of the genetic events that initiate the disease are unknown. Whole-genome sequencing of a typical acute myeloid leukemia genome and its matched normal counterpart found 10 genes with acquired mutations, eight of which were new mutations. This study established whole-genome sequencing as a method for discovering mutations that may respond to targeted therapies. (257)
- AACR publishes the first issue of the journal, Cancer Prevention Research.
- Stand Up To Cancer, a charitable program of the Entertainment Industry Foundation, holds its first fundraising telecast.
The AACR is the Scientific Partner of SU2C.
- AACR launches its collaboration with the Cancer Therapy & Research Center (CTRC) at UT Health Science Center San Antonio and Baylor College of Medicine to support the CTRC-AACR San Antonio Breast Cancer Symposium.
At this symposium, the Inaugural AACR Outstanding Investigator Award for Breast Cancer Research was presented to Douglas Easton, and the Inaugural AACR Distinguished Lecture in Breast Cancer Research was given by Joan Massagué.
- AACR-NCI Think Tank, “Charting the Future of Cancer Prevention,” is held.
- Cancer cells secrete exosomes that deliver genetic information and proteins to cells in the tumor environment.
This study showed that glioblastoma-derived exosomes can serve as a mechanism by which tumors can alter the microenvironment and make it more permissive to tumor growth and invasion. (258)
- Congress passes the American Recovery and Reinvestment Act, also known as the Stimulus.
The provisions of the Act support initiatives by the Division of Cancer Control and Population Sciences related to cancer prevention, screening, treatment, and genomics.
- Congress passes the Family Smoking Prevention and Tobacco Control Act.
The Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) was signed into law on June 22, 2009, giving the FDA authority to regulate the manufacture, distribution, and marketing of tobacco products. (259)
- AACR commemorates its 100th Annual Meeting in Denver, Colorado.
- AACR membership passes 30,000.
- Childhood cancer mortality rates decline by more than 50%.
Improved drugs, treatment strategies, and investments in clinical trials are some of the possible factors resulting in this decrease in childhood cancer mortality. (260)
- Patient-Centered Outcomes Research Institute (PCORI) is created.
As part of the Patient Protection and Affordable Care Act, PCORI was established as a nonprofit organization to put a focus on patient priorities for research. The goal of PCORI is to improve patient outcomes by using the best clinical technology, techniques, and medications, as determined by the best available research evidence. (261)
- Congress passes the Patient Protection and Affordable Care Act (ACA).
The ACA was designed to expand coverage, control health care costs, and improve the health care delivery system, including improving insurance coverage for preventative care, screening services, and tobacco cessation treatments. (262)
- Prostate cancer vaccine composed of the patient’s activated immune cells shows promise in clinical trial.
The vaccine, sipuleucel-T, composed of the patient’s dendritic cells, stimulates T cells to respond to prostatic acid phosphatase, an antigen found on most prostate cancer cells. (263)
- Dissemination of cells from primary tumors occurs early, often before primary tumor diagnosis.
Some patients with localized cancer subsequently develop metastatic disease years after complete primary tumor resection. Tumor cells were found to disseminate throughout the body early during tumor development, even before the primary tumor became clinically detectable, and late metastases arose from these early disseminated cells. (264)
- Inaugural AACR Distinguished Lecture on the Science of Cancer Health Disparities is given by Charles M. Perou at the AACR Cancer Disparities meeting (right).
- AACR is certified as a provider of Continuing Medical Education (CME).
- AACR forms the Cancer Immunology and the Behavioral Science in Cancer Research Working Groups.
- AACR launches Task Forces on the Cancer Epigenome, Survivorship Research, and Membership Development.
- Bressac B, Kew M, Wands J, Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 1991;350:429−31.
- Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC. Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 1991;350:427−8.
- Ozturk M. p53 mutation in hepatocellular carcinoma after aflatoxin exposure. Lancet 1991;338:1356−9.
- Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992;11:3887−95.
- Kallioniemi A, Kallioniemi OP, Sudar D, Rutovitz D, Gray JW, Waldman F, et al. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 1992;258:818−21.
- Solinas-Toldo S, Lampel S, Stilgenbauer S, Nickolenko J, Benner A, Dohner H, et al. Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes Chromosomes Cancer 1997;20:399−407.
- Pinkel D, Segraves R, Sudar D, Clark S, Poole I, Kowbel D, et al. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet 1998;20:207−11.
- Sell S, Pierce GB. Maturation arrest of stem cell differentiation is a common pathway for the cellular origin of teratocarcinomas and epithelial cancers. Lab Invest 1994;70:6−22.
- Schena M, Shalon D, Davis RW, Brown PO. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 1995;270:467−70.
- Velculescu VE, Zhang L, Vogelstein B, Kinzler KW. Serial analysis of gene expression. Science 1995;270:484−7.
- Lichter AS, Ten Haken RK. Three-dimensional treatment planning and conformal radiation dose delivery. Important Adv Oncol 1995:95−109.
- Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271:1734−6.
- Pierpont TM, Limper CB, Richards KL. Past, present, and future of rituximab—the world’s first oncology monoclonal antibody therapy. Front Oncol 2018;8:163.
- Pegram MD, Lipton A, Hayes DF, Weber BL, Baselga JM, Tripathy D, et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998;16:2659−71.
- Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783−92.
- Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371−88.
- Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998;273:13375−8.
- Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, et al. The lipid phosphatase activity of PTEN is critical for its tumor suppressor function. Proc Natl Acad Sci U S A 1998;95:13513−8.
- Sigal EV, Barker AD. Report from THE MARCH Research Task Force. September 25−26, 1998. Cancer Res 1998;58:5590−627.
- Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998;391:806−11.
- Schiepers C, Hoh CK. Positron emission tomography as a diagnostic tool in oncology. Eur Radiol 1998;8:1481−94.
- Brooks RA, Sank VJ, Di Chiro G, Friauf WS, Leighton SB. Design of a high resolution positron emission tomograph: the Neuro-PET. J Comput Assist Tomogr 1980;4:5−13.
- Rohren EM, Turkington TG, Coleman RE. Clinical applications of PET in oncology. Radiology 2004;231:305−32.
- Shamblott MJ, Axelman J, Wang S, Bugg EM, Littlefield JW, Donovan PJ, et al. Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc Natl Acad Sci U S A 1998;95:13726−31.
- Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science 1998;282:1145−7.
- Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 1999;59:5002−11.
- Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57−70.
- Brenner S, Johnson M, Bridgham J, Golda G, Lloyd DH, Johnson D, et al. Gene expression analysis by massively parallel signature sequencing (MPSS) on microbead arrays. Nat Biotechnol 2000;18:630−4.
- Reinartz J, Bruyns E, Lin JZ, Burcham T, Brenner S, Bowen B, et al. Massively parallel signature sequencing (MPSS) as a tool for in-depth quantitative gene expression profiling in all organisms. Brief Funct Genomic Proteomic 2002;1:95−104.
- Shah J, Vyas A, Vyas D. The history of robotics in surgical specialties. Am J Robot Surg 2014;1:12−20.
- Beyer T, Townsend DW, Brun T, Kinahan PE, Charron M, Roddy R, et al. A combined PET/CT scanner for clinical oncology. J Nucl Med 2000;41:1369−79.
- Townsend DW. Combined positron emission tomography-computed tomography: the historical perspective. Semin Ultrasound CT MR 2008;29:232−5.
- National Nanotechnology Initiative [cited 2022 Mar 14]. Available from: https://www.nano.gov/.
- Intensity Modulated Radiation Therapy Collaborative Working Group. Intensity-modulated radiotherapy: current status and issues of interest. Int J Radiat Oncol Biol Phys 2001;51:880−914.
- Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999;5:1365−9.
- Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192:1027−34.
- Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001;2:261−8.
- Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8:793−800.
- Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031−7.
- Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, et al. The sequence of the human genome. Science 2001;291:1304−51.
- Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing and analysis of the human genome. Nature 2001;409:860−921.
- Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949−54.
- Ito M, Hiramatsu H, Kobayashi K, Suzue K, Kawahata M, Hioki K, et al. NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood 2002;100:3175−82.
- Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 2003;100:8372−7.
- Fong L, Small EJ. Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment. J Clin Oncol 2008;26:5275−83.
- IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Tobacco smoke and involuntary smoking. Lyon, France: International Agency for Research on Cancer; 2004. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 83. Available from: https://www.ncbi.nlm.nih.gov/books/NBK316407/.
- Grillo-Lopez AJ. Zevalin: the first radioimmunotherapy approved for the treatment of lymphoma. Expert Rev Anticancer Ther 2002;2:485−93.
- Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348:1625−38.
- Cohen MH, Williams GA, Sridhara R, Chen G, McGuinn WD Jr, Morse D, et al. United States Food and Drug Administration Drug Approval summary: Gefitinib (ZD1839; Iressa) tablets. Clin Cancer Res 2004;10:1212−8.
- Institute of Medicine (US) Committee on Understanding and Eliminating Racial and Ethnic Disparities in Health Care; Smedley BD, Stith AY, Nelson AR, editors. Unequal treatment: confronting racial and ethnic disparities in health care. Washington, DC: The National Academies Press; 2003.
- Chen WY, Zeng X, Carter MG, Morrell CN, Chiu Yen RW, Esteller M, et al. Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. Nat Genet 2003;33:197−202.
- Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Chen WD, et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nat Genet 2004;36:417−22.
- Zeller KI, Jegga AG, Aronow BJ, O’Donnell KA, Dang CV. An integrated database of genes responsive to the Myc oncogenic transcription factor: identification of direct genomic targets. Genome Biol 2003;4:R69.
- Bardelli A, Parsons DW, Silliman N, Ptak J, Szabo S, Saha S, et al. Mutational analysis of the tyrosine kinome in colorectal cancers. Science 2003;300:949.
- Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554.
- Bardelli A, Velculescu VE. Mutational analysis of gene families in human cancer. Curr Opin Genet Dev 2005;15:5−12.
- Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003;348:2609−17.
- Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335−42.
- Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 2004;58:862−70.
- Kaminskas E, Farrell AT, Wang YC, Sridhara R, Pazdur R. FDA drug approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist 2005;10:176−82.
- Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A, et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 2004;364:1757−65.
- Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano AR, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 2005;6:271−8.
- International HapMap Consortium. A haplotype map of the human genome. Nature 2005;437:1299−320.
- Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:e73.
- He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, et al. A microRNA polycistron as a potential human oncogene. Nature 2005;435:828−33.
- Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. MicroRNA expression profiles classify human cancers. Nature 2005;435:834−8.
- Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res 2005;65:7065−70.
- Office of Smoking and Health (US). The health consequences of involuntary exposure to tobacco smoke: a report of the Surgeon General. Atlanta, GA: Centers for Disease Control and Prevention; 2006.
- Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006;314:126−9.
- Nowell PC. The clonal evolution of tumor cell populations. Science 1976;194:23−8.
- Merlo LM, Pepper JW, Reid BJ, Maley CC. Cancer as an evolutionary and ecological process. Nat Rev Cancer 2006;6:924−35.
- Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, et al. The consensus coding sequences of human breast and colorectal cancers. Science 2006;314:268−74.
- Gabrilovich DI, Bronte V, Chen SH, Colombo MP, Ochoa A, Ostrand-Rosenberg S, et al. The terminology issue for myeloid-derived suppressor cells. Cancer Res 2007;67:425.
- Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561−6.
- Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 2007;131:1190−203.
- Sullivan I, Planchard D. ALK inhibitors in non-small cell lung cancer: the latest evidence and developments. Ther Adv Med Oncol 2016;8:32−47.
- Khleif SN, Doroshow JH, Hait WN, AACR-FDA-NCI Cancer Biomarkers Collaborative. AACR-FDA-NCI Cancer Biomarkers Collaborative consensus report: advancing the use of biomarkers in cancer drug development. Clin Cancer Res 2010;16:3299−318.
- Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med 2008;14:985−90.
- Ley TJ, Mardis ER, Ding L, Fulton B, McLellan MD, Chen K, et al. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 2008;456:66−72.
- Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 2008;10:1470−6.
- Family Smoking Prevention and Tobacco Control Act of 2009, Pub. L. No. 111-31, 123 Stat. 1776 (Jun 22, 2009) [cited 2022 Mar 14]. Available from: https://www.congress.gov/bill/111th-congress/house-bill/1256.
- Smith MA, Seibel NL, Altekruse SF, Ries LA, Melbert DL, O’Leary M, et al. Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 2010;28:2625−34.
- Clancy C, Collins FS. Patient-Centered Outcomes Research Institute: the intersection of science and health care. Sci Transl Med 2010;2:37cm18.
- Patient Protection and Affordable Care Act of 2010, Pub. L. No. 111-148, 124 Stat. 119 (Mar 23, 2010) [cited 2022 Mar 14]. Available from: https://www.congress.gov/bill/111th-congress/house-bill/3590.
- Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363:411−22.
- Eyles J, Puaux AL, Wang X, Toh B, Prakash C, Hong M, et al. Tumor cells disseminate early, but immunosurveillance limits metastatic outgrowth, in a mouse model of melanoma. J Clin Invest 2010;120:2030−9.