History of Breast Cancer Identification and Treatment

History of Breast pubic louse Identification and wordA City of StringsIn the late 1970s, researchers at Standford and UCSF had invented a engineering kn induce as recombinant DNA. They founded a biotech company cal take Genentech in 1976 to leverage on this technology to develop untested drugs. Genentech used Recombinant DNA technology to synthesize merciful proteins in bacteria cells instead of extracting proteins from animal and human organs. From 1982 to 1985, Genentech had manufactured many important drugs such as human insulin, a clotting factor to treat hemophilia, and a human growth endocrine gland all engineered and produced in bacterial cells.In 1984, a team of researchers led by a German scientist named Axel Ullrich from Genentech detect the human homolog of the neu agent, an onco element previously discovered by Weinberg. In the summer of 1986, Ullrich told the story of the isolation of Her-2 at a UCLA seminar. Among the audience was a UCLA oncologist named Dennis Slamon. Slamon had a collection of genus Cancer tissues from patients at UCLA. He proposed a simple collaboration to Ullrich. If Ullrich direct him the Her-2 DNA probes, Slamon could analyze his collection for malignant neop finalic disease cells with hyperactive Her-2 genes. Ullrich maked.Slamon screened Her-2 with his collection of cancer cells. He discovered that disparager cancers could be divided into dickens types Her-2 positive and Her-2 negative, depending on whether or not the cancer cells amplify Her-2 by making sextuple copies. Her-2 positive tumors are more aggressive, more metastatic, and more likely to cut down than Her-2 negative tumors.The association of Her-2 with an aggressive knocker cancer prompted Ullrich to look for a drug to shut off the Her-2 function. In 1988, Genentech produced a mouse antibody that could inactivated Her-2 and sent it to Slamon. Slamon tested the antibody with cancer cells in a dish, the cancer cells stopped growing and died. W hen he injected the antibody into mice with Her-2 positive tumors, the tumors also disappeared. He concluded that the Her-2 inhibition worked in an animal model.Both Slamon and Ullrich expected Genentech to leap at the opportunity. besides Genentech got coldness feet and wanted to focus on simpler and more profitable drugs. Feeling dejected, Ullrich left over(p) Genentech, leaving Slamon alone at UCLA trying to hold in the Her-2 project alive(predicate) at Genentech. Eventually, Slamon and Art Levinson, a molecular biologist at Genentech, convinced(p) a tiny entrepreneurial team to push ahead with the Her-2 project. In the summer of 1990, Genentech produced a human Her-2 antibody ready for clinical visitations. They called it Herceptin.Fifteen women enrolled in Slamons streak at UCLA in 1992. The drug was combined with a archetype chemotherapy drug, both delivered intravenously. Only five of the original cohort continued the trial to its six-month end point. One of them is Barbara Bradfield. She had told Slamon that she was at the end of the road and had accepted what seemed inevitable, when Slamon essay to enroll her in the trial in the summer of 1991. She survives today.Drugs, Bodies, and ProofBy the summer of 1993, news of the Herceptin early bod trial had spread by the community. Her-2 positive breast cancer is one of the most fatal variants of the disease, and patients lead try any therapy that could produce a positive answer. Cancer activist urged the release of the drug to patients who had failed other therapies. These patients, they argued, could not wait for the drug to permit the long periods of clinical trial they wanted a life parsimoniousness medicine now. For Genentech, Herceptin had not been approved by the FDA. Genentech wanted carefully execute early phase trials.Marti Nelson, a gynecologist in California, had breast cancer when she was 33 in 1987. In 1993, six kind classs after her initial surgery, her cancer had relapsed. She wanted to test the tumor for Her-2 sensitivity, but her HMO insisted that the test was useless because Herceptin was in investigational trials. In the summer of 1993, she contacted the Breast Cancer fulfil (BCA) project for help. Working through its activist networks, BCA asked several laboratories to test Nelsons tumor. In October 1994, the tumor was found to be Her-2 positive. She would be an ideal candidate for the drug. But the news came too late. She died nine days later.On December 4, 1994, a group of women from the BCA staged a funeral procession for Nelson through the Genentech campus. Unable to clam up the activists, Genentech joined them. In 1995, Genentech agreed to provide an expanded access class for Herceptin, allowing oncologist to treat patients outside clinical trials.Trial ResultsOn May 17, 1998, Slamon account the results of the clinical trial at the 34th meetings of the American Society of clinical Oncology in Los Angeles. In the pivotal 648 study, 469 wo men had puzzled standard chemotherapy and were randomized to receive either Herceptin or a placebo. Women hard-boiled with Herceptin had shown a clear a measurable benefit. Response rates had increased by 150 percent, wither more tumors, and extending lives by four to five months compared to the control arm.In 2003, two studies were launched to test Herceptin in early stage breast cancer. When the trials were combined, overall survival of the fittest in women do by with Herceptin was increased by 33 percent.A Four-Minute milliliterIn 1973, Janet Rowley identified a unique chromosomal aberration in chronic myeloid leukemia (CML) cells. The ab regulationity, the so-called Philadelphia chromosome, resulted from a translocation in which the head of chromosome 22 and the tail of chromosome 9 had been fused to create a new gene. A team of Dutch researchers isolated the gene on Chromosome 9 in 1982. They called it abl. And in 1984, they isolated abls partner on chromosome 22 a gene called Bcr. In normal cells, Bcr and abl are dissever genes living on separate chromosomes. But in CML cells, the fusion of the two genes created a new chimaera called Bcr-abl which coded a hyperactive kinase that causes cells to divide without control.In the mid-1980s, a team of chemists at Ciba-Geigy was trying to develop selective kinase inhibitors. Ciba-Geigy was a pharmaceutical company in Basel, Switzerland. The team was headed by a Swiss physician named Alex Matter, and an English biochemist named break off Lydon.In 1986, Matter and Lydon discovered a simple skeletal chemical that could bind a kinase and inhibit its function. By the early 1990s. Matter and Lydon had created scores of new molecules with similar structures. When Lydon tested these molecules on various kinases, he discovered that they were kinase inhibitors with extraordinary specificity. What Matter and Lydon indispensabilityed now was a disease in which to apply this collection of chemicals.In the late 1 980s, Nick Lydon met Brian Druker at the Dana-Farber Cancer Institute. Druker, a young faculty member at the institute, was interested in CML the cancer driven by the Bcr-abl kinase. He proposed an ambitious collaboration suit to test the kinase inhibitors on the patients at the institute. But the project was tabled because the lawyers could not agree to terms.In 1993, Druker reconnected with Lydon after he left Boston to start his own laboratory in Portland at the Oregon Health and Science University (OHSU). Lydon inform Druker that the Ciba-Geigy team had found a molecule called CGP57148 that might inhibit Bcr-abl with uplifted specificity. Revealing little about the potentials of the chemicals, Druker got a collaboration agreement sign between OHSU and Ciba-Geigy.In the summer of 1993, Druker added the drug from Lydon to CML cells in a petri dish. Overnight, the CML cells were dead. He induced CML tumors into mice and then treated the mice with the drug. The tumors regressed in days, leaving behind the normal blood cells. He drew out samples of bone midpoint from a few patients with CML and applied the drug to the cells in a petri dish. The leukemia cells in the marrow died immediately, leaving behind the normal blood cells. He had remediationd leukemia in the dish.Druker expected Ciba-Geigy to be excited about these results. But in Basel, Ciba-Geigy has clean merged with its arch rival into a pharmaceutical behemoth called Novartis. The picture of spending millions on a drug to benefit thousands gave Novartis cold feet.Novartis in conclusion relented in early 1998. They changed the name of the drug to Gleevec.In the initial phase of the study, 53 out of 54 patients receiving the drug showed a complete response within days. The remissions extended into weeks and months as the patients continued the medicine. The initial phase of the trial was a success.The Red promote RaceIn the fifth year of their Gleevec trial, Charles Sawyer and Mashe Talpaz f ound the vast proportion of CML patients maintained deep remissions on the drug. But occasionally, a patients leukemia became Gleevec- loathsome and stopped responding to Gleevec. Sawyers discovered that the CML cells become Gleevec-resistant by modify the structure of the molecule.In 2005, Sawyerss team generated another kinase inhibitor, called dasatinib, to target Gleevec-resistant Bcr-abl. The effect of this new drug on Gleevec-resistant patients was remarkable the leukemia cells disappeared again.Even targeted therapy was a cat-and-mouse game. When the cancer becomes resistant to the drug, we would need a different molecular variant. And when it becomes resistant to the new drug, you would need the next generation drug. Like the Red Queens race, we suffer to keep running to remain still.In the decade since the discovery of Gleevec, 24 legend cancer-targeted drugs keep been introduced and dozens more are in development. The 24 drugs have been effective against lung, breast, and prostate cancers, lymphomas, leukemias and sarcomas. Some inactivate oncogenes, others target oncogene-activated pathways.The Red Queens race applies to cancer binding and cancer prevention. Circles of relationships are powerful predictors of mortal behaviors. The tobacco epidemic originated as a form of metastatic social behavior. Successful cancer-prevention strategies can lapse swiftly when social behavior changes. xiii MountainsThe Human Genome Project was completed in 2003. It exit be followed by the Cancer Genome Atlas project a compendium of every gene mutation in the most common form of cancer. Mutations in the cancer genome, Bert Vogelstein believes, come in two forms. Some are passenger mutations that have no impact on the biology of the cancer cell. Others are number one wood mutations that play a crucial role in the biology of a cancer cell.The mountains in the cancer genome, the most frequent mutations in a particular form of cancer, have another property. They can be unionized into between eleven and fifteen key cancer pathways. The dysregulation of these core pathways poses an considerable challenge for cancer therapists.These changes provoke three directions for cancer medicine erst we have identified the crucial driver mutations in any cancer, we will need to hunt for targeted therapies against these genes.We need to integrate the insights of cancer biology into cancer prevention to preempt the need for a million-person association study. Cancer screening can also be fortified by the molecular reasonableness of cancer.We need to integrate our understanding of abnormal genes and pathways to explain the behavior of cancer, alteration the circle of knowledge, discovery, and therapeutic intervention.Atossas WarImagine Atossa, the Persian queen who had breast cancer in 500 BC, traveling through time, appearing and reappearing in one age after the next. How would her treatment and prognosis changed in the last four millennia, and what ha ppens to her later in the new millennium?In 2500 BC at Imhoteps clinic in Egypt, Imhotep provides a diagnosis, but there is no treatment, he says.In 500 BC, her Greek slave cuts her tumor out a primitive form of a mastectomy.In 400 BC, in Thrace, Hippocrates identifies her tumor as a karkinos.In AD 168, Claudius Galen says its a systemic overdose of black bile cutting the tumor out would not cure it.Medieval surgeons cut her cancer away with knives and scalpels. Some offer stern dung, lead plates, crab paste, and holy water as treatments.In 1778, at John Hunters clinic in London, her cancer is assigned a stage. If the tumor is local, he recommends surgery. For advanced cancers, he advises remote sympathy.In 1890, at Halsteds clinic in Baltimore, her breast cancer is treated with radical mastectomy.In the early twentieth century, ray of light oncologists try to destroy the tumor using X-rays. By the 1950s, her cancer is treated with a lumpectomy followed by radiation.In the 1970s , her surgery is followed by adjuvant conclave chemotherapy to diminish the chance of a relapse.In the 1980s, besides surgery, radiation, and adjuvant chemotherapy, she is treated with hormonal and targeted therapy.In the mid-1990s, Atossas genome was sequenced and found positive for BRCA-1. She is offered several targeted therapies to treat the illness.In 2050, Atossa will arrive at her oncologists clinic with a thumb drive containing the total sequence of her cancers genome. The computer would identify the mutations and pathways that are causing the cancer. Therapies will be targeted against these mutations and pathways. She will start with one combination of targeted drugs, expect to switch to a second one when her cancer mutates, and switch again when the cancer mutates again.