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Adapting to change and seeing the opportunities in breast cancer management

2012; Future Medicine; Volume: 1; Issue: 1 Linguagem: Inglês

10.2217/bmt.12.1

1758-1931

V. Craig Jordan, J. Michael Dixon,

Global Cancer Incidence and Screening

Breast Cancer ManagementVol. 1, No. 1 ForewordFree AccessAdapting to change and seeing the opportunities in breast cancer managementV Craig Jordan & J Michael DixonV Craig Jordan* Author for correspondenceSenior Editor; Georgetown University Medical Center, 3970 Reservoir Rd, NW Research Building, Suite E501, Washington, DC 20057, USA. & J Michael DixonSenior Editor; Edinburgh Breast Unit, Western General Hospital, Edinburgh EH4 2XU, UKPublished Online:3 May 2012https://doi.org/10.2217/bmt.12.1AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail The management of breast cancer has entered a new era: personalized medicine; but what does that mean, both for the patient, and the medical practitioner? Doctors will no longer treat patients with surgery, radiation and drug therapy with the expectation of treatment success for only a proportion of patients in their care – one size will no longer fit all. That is the good news; however, the treatment approach for each individual patient and their cancer will ultimately be different.Some 40 years ago, there were no practical tests available capable of determining the effectiveness and outcome of cancer therapy [1]. This contrasts dramatically with the early days of the antibiotic revolution in the 1940s and 1950s when the appropriate antibiotic could be identified rapidly in the laboratory, targeting the infection affecting an individual patient. It was personalized medicine and it worked. Increasingly in the future, a new spectrum of diagnostic tests will identify which cancers express a series of targets, and tumors will be treated individually based on the targets they express; both should dramatically enhance the chances of a successful outcome for the patient. The launch of this new journal Breast Cancer Management is, therefore, timely.The aim of this new journal is to provide clarity for the medical practitioner in an age when the publicity pendulum swings dramatically from 'triumphant breakthrough' to 'drug approval withdrawn by the US FDA'. Our outstanding multidisciplinary Editorial Board was selected specifically to ensure a balanced range of expertise that covers all clinical disciplines, as well as translational researchers involved in breast cancer management.As we move forward, it is reasonable to reflect on the changes that have occurred over the last 40 years. In America, the National Cancer Act was signed by President Richard Nixon on 23 December 1971. This was a unique document that proposed a National Cancer Institute to provide funding for peer-reviewed research and the creation of local cancer centers to foster translational research, conduct clinical trials and bring 'best-practice' medical treatment to cancer patients; noble goals that remain in place today. Currently in the UK, six national partners have joined a government initiative to build the Francis Crick Institute, which will open in 2015 in premises behind Kings Cross, London, UK. Here, talented investigators will create knowledge that will catalyze innovations in medicine, including breast cancer.Over these last 40 years we can see that many advances have been achieved, and there has been a subsequent fall in mortality in numerous cancers, including breast cancer. The anticipation is that changes in breast cancer management will continue with our increased understanding of molecular biology. Since the 1970s (a time when there was no molecular biology), molecular biology has evolved dramatically and is being incorporated into our management protocols for breast cancer (Box 1). The first oncogene to be identified, src, was identified in 1970. It is now known that 70% of breast cancers contain src. Shortly after, a host of other oncogenes were identified and Michael Bishop and Harold Varmus were awarded the Nobel Prize for Physiology and Medicine in 1989 for their pioneering work on oncogenes and cancer. However, molecular biology is not about oncogenes, it relates to a technology that can cut and recombine genes in DNA. This technology began to appear in the mid 1970s and the entrepreneurs Stanley Cohen and Herbert Boyer, the founders of Genentech, were pioneers of the technology and its practical applications.Molecular science has emerged slowly, but how has knowledge of molecular biology influenced therapeutic research and clinical care in breast cancer? In 1970, few were recommending careers for pharmacologists in cancer therapeutics and the pharmaceutical industry, which is risk adverse, avoided investments in cancer-drug discovery. All focus was on tranquilizers and cardiac drugs, a situation which can be demonstrated by looking at research into endocrinological aspects of breast cancer over the last 40 years (Box 2).Endocrine research was slowing down after the explosion of work to produce the oral contraceptive, which was the first medicine to be developed for something that was not a disease. However, the benefit for breast cancer therapy was that tamoxifen was identified as a consequence of pharmaceutical research on potential antifertility drugs. Tamoxifen was perfect as a morning after pill in rats, but had the opposite effect in humans; it enhanced ovulation. This failed contraceptive was reinvented as the most widely used adjuvant endocrine therapy for breast cancer and has been shown to extend the lives of millions of patients with estrogen receptor (ER)-positive breast cancer [2]. In the 1970s, trials of adjuvant combination cytotoxic chemotherapy started, with mastectomy and radiation becoming the standard of care. Therapy for recurrences and a diagnosis of stage IV breast cancer were abysmal and endocrine therapy was palliative. There was no ER testing of cancers to assess likely sensitivity to endocrine therapy and great hopes were pinned on combinations of cytotoxic chemotherapy as a result of encouraging early studies. 'Chemoprevention' did not even exist as a word; however, the concept of chemoprevention was first raised in 1923. Studies in mice demonstrated that early ovariectomy prevented mouse mammary cancer. There was, however, no practical way forward, as there were no anti-estrogens.The milestones illustrated in Box 2 reflect the significant progress made through cooperative group clinical trials and overviews of large randomized trials, which occur every 5 years at Oxford, UK. This has resulted in major advances in patient care and survivorship over the past 40 years; however, these advantages are largely for populations and not for individuals. Taking the impact of tamoxifen alone there has been a 30% decrease in mortality; however, significant numbers of patients still continue to die [3]. Chemoprevention has become a reality with both tamoxifen and raloxifene being approved in the USA for high-risk populations. Nonetheless, few breast cancers are prevented in the thousands of high-risk women who are treated [4].The symbiotic relationship between the people and science to produce a better life for us all requires accountability and demands progress from invested resources. This is a reality for governments as it has been true for the pharmaceutical industry. With dwindling resources, dramatic reductions in research budgets and an uncertain pharmaceutical industry, delivering personalized medicine will be a challenge. A new era of strategic clinical trials cooperation by industry and academia needs to be embraced by the pharmaceutical giants. It can work, but so far it has only proven successful in specific areas. Clinical trials of new AIDS combination therapies were funded principally by government because combination therapy of individual patented drugs was required for success. The various partners each had to be convinced that success in a clinical trial would lead to a secure and expanding marketing, and a satisfactory profitability model. The hope is, just as this approach has worked in AIDS, the same approach may succeed in pushing forward personalized medicine in cancer.It may be that numerous different targeted small molecules and antibodies will need to be used to subvert cancer cell-survival mechanisms and to selectively target apoptosis. In addition, patent laws may need to be re-thought as survival outcomes in breast cancer trials may take so long to demonstrate that patents have expired before drugs are fully marketed. This is true especially for chemoprevention trials in huge populations, and explains why the pharmaceutical industry is not interested – it cannot find an adequate financial model to recover investment.The challenges are great, but effective solutions will benefit us all. The current economic crisis may in fact create an environment to exploit these opportunities. The new journal Breast Cancer Management presents a new platform in which advances in understanding can be converted to improvement in management and outcomes. It provides a forum for presenting results from the new generation of trials of the many small targeted molecules in clinical development. Furthermore, it is a new journal for a new approach in which therapies are targeted to those who will benefit, rather than those who are just at risk of relapse.Box 1. Origin of 'molecular biology'.William Thomas Astbury of Leeds University, UK, was among the first to realize the tremendous potential of x-ray pattern analysis of proteins to understand biology. In 1945, he was invited to lead a new department at Leeds, which he proposed should be named the 'Department of Molecular Biology'. Others decided it should be named the 'Department of Biomolecular Structure' (today, it is the Astbury Department of Biophysics). Nevertheless, Astbury, it is claimed, popularized the term 'molecular biology' from the time of his Harvey Lecture in 1950 entitled 'Adventures in Molecular Biology'.Box 2. What was the situation in breast cancer research and treatment in 1970?▪ Reproductive endocrinology was the fashion for research, because the oral contraceptive became available clinically in 1957▪ Nonsteroidal anti-estrogens failed as contraceptives▪ Mastectomy and radiation alone were the standard care in breast cancer▪ Combination cytotoxic chemotherapy had the potential to cure metastatic breast cancer (e.g., Cooper's Cocktail 1963; no adjuvant chemotherapy trials by cooperative oncology groups)▪ High-dose hormone therapy (e.g., diethylstilboestrol) was the standard endocrine therapy for postmenopausal patients (one in three responded for 1 year)▪ Chemoprevention was a concept (proposed at American Association for Cancer Research [AACR] 1936), but of no practical valueFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Haddow A, David A. Karnofsky memorial lecture. Thoughts on chemical therapy. Cancer26,737–754 (1970).Crossref, Medline, CAS, Google Scholar2 Jordan VC. Tamoxifen: catalyst for the change to targeted therapy. Eur. J. Cancer44,30–38 (2008).Crossref, Medline, CAS, Google Scholar3 Davies C, Godwin J, Gray R et al.; Early Breast Cancer Trialists' Collaborative Group. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet378,771–784 (2011).Crossref, Medline, CAS, Google Scholar4 Vogel VG, Costantino JP, Wickerham DL et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: preventing breast cancer. Cancer Prev. Res. (Phila.)3,696–706 (2010).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetails Vol. 1, No. 1 STAY CONNECTED Metrics History Published online 3 May 2012 Published in print May 2012 Information© Future Medicine LtdFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download