Editorial: Tumor Heterogeneity and Personalized Medicine — NEJM

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Editorial

Tumor Heterogeneity and Personalized Medicine

This article has no abstract; the first 100 words appear below.

"In the past 10 years, the number of tools available to treat cancer has increased, as has our understanding of what makes some cancers tick. The standard old-time cancer treatments were largely predicated on attacking DNA, an approach fueled by the belief that tumor cells divide more rapidly than normal cells. However, with the notable exception of Burkitt's lymphoma, only a small percentage of tumor cells in a patient are dividing at any given time. As we have learned more about DNA repair mechanisms and epigenetic alterations in cancers, DNA remains a viable target for new cancer therapies, but DNA . . ."

abstract: Editorial: Whole-Genome Sequencing, April 20, 2011 JAMA

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Whole-Genome Sequencing

Since this article does not have an abstract, we have provided the first 150 words of the full text.

KEYWORDS:
• EARLY DIAGNOSIS,
• GENETIC PREDISPOSITION TO DISEASE,
• GENOME, HUMAN,
• LEUKEMIA, MYELOID, ACUTE,
• LEUKEMIA, PROMYELOCYTIC, ACUTE,
• MUTATION,
• NEOPLASMS,
• ONCOGENE PROTEINS, FUSION,
• ONCOGENES,
• SEQUENCE ANALYSIS, DNA,
• TIME FACTORS,
• TP53 GENES,
• TP53 PROTEIN, HUMAN.

The past 60 years have witnessed remarkable progress in genetics and genomics from the description of the DNA double helix by Watson and Crick ¹ to the release of the first draft sequence of the human genome in 2001 ^{2, 3} and the successful completion of the human genome project in 2003. ⁴ From that time, there has been increasing hope and expectation that, as soon as the cost of sequencing the whole genome could become affordable, the promise of personalized medicine would be fulfilled.

No field of medicine has benefited more from advances in genomics and the application of genetic testing than oncology. These advances have had a substantial influence on cancer risk assessment, determination of prognosis, and choice of treatment. Clinical applications of novel genetic tools include sequencing and analysis of germline genomic rearrangements at key cancer genes like BRCA1, BRCA2, and TP53 ⁵; …

NCI Cancer Bulletin: Whole-Genome Sequencing Improves Cancer Diagnoses (including some good links eg Li-Fraumeni Syndrome, BRCA, Editorial)

Whole-Genome Sequencing Improves Cancer Diagnoses

Although whole-genome sequencing is not yet ready for routine clinical use, two studies show how the approach could improve the diagnosis and, potentially, the treatment of cancer. The reports, in the April 20 Journal of the American Medical Association, describe how researchers at Washington University School of Medicine in St. Louis and their colleagues used whole-genome sequencing to investigate the cases of two patients.
The first study focused on a 42-year-old woman who died from leukemia that was probably related to previous treatment for breast and ovarian cancers. The woman did not have a known family history of cancer, and tests for mutations in the breast cancer-associated genes BRCA1 and BRCA2 were negative. But a comparison of the genomes of her cancer cells and normal cells revealed a novel mutation in the TP53 gene that altered the function of the encoded protein. TP53 gene mutations have been implicated in a number of cancers, including some early-onset breast and ovarian cancers, as well as Li-Fraumeni syndrome.
The TP53 mutation does not appear to have been inherited from one of the patient’s parents. But because the mutation was seen in both normal and cancer cells, it had to have occurred very early in the patient’s life, possibly at conception. Thus, the mutation could have been present in her germline DNA and been passed on to her children, the researchers noted.
As specified by the study protocol, the researchers contacted the woman’s primary care physician, who then discussed the issue with the patient’s family members and encouraged them to seek genetic counseling. “Even though the patient died, her contribution to this study yielded new knowledge that might one day save the lives of her children,” study co-author Dan Koboldt of the Genome Institute at Washington University wrote in a post about the studies on his blog, MassGenomics.
The second study involved a 39-year-old woman with a form of acute myeloid leukemia (AML). A comparison of DNA from her tumor and normal cells revealed a fusion of two genes in her blood cells that was not detected through routine cytogenetic testing. The presence of this gene fusion is associated with good outcomes after chemotherapy. Consequently, the patient’s doctors recommended chemotherapy rather than stem cell transplantation, the treatment that had been indicated by the standard diagnostic testing results.
At the time of publication, the woman had been in remission for 15 months. The sequencing, analysis, and validation of the fusion gene were completed in just 7 weeks, which was quick enough that doctors could use the information to choose the most effective treatment for the patient, the researchers noted.
“These cases of personalized genomic medicine are just some of the first examples of what will likely be commonplace in the near future,” wrote the authors of an accompanying editorial.
“Clearly, the technology will no longer be the major impediment to widespread clinical use of these tools, and the main challenges will soon move to the clinical implementation and interpretation of genomic data,” the authors added.

Editorial (excerpt) Short-term Use of Unopposed Estrogen, April 6, 2011

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JCO March 7. 2011: Editorial Big Costs for Little Gain in Ovarian Cancer

Editorial: Big Costs for Little Gain in Ovarian Cancer

• Martee L. Hensley

JCO published online on March 7, 2011; DOI:10.1200/JCO.2010.34.0489.

• [PDF]
• [JCO Podcast]

Editorial: Cancer: the revolution has begun : The Lancet

Editorial - Current Opinion in Oncology Sept 2010 issue (ovarian cancer/gyn)

In this issue, we present two generic themes: the first relates to managing patients with ovarian cancer and Glenn McCluggage presents an excellent review of the difficult area of diagnosing and categorizing borderline tumours of the ovary. No multidisciplinary meeting is complete without clinicians asking their pathologist difficult questions relating to the significance of the different appearances that can occur in this group of tumours and whether patients should receive further staging and treatment and how they should be followed up. Glenn McCluggage describes the clinical significance of the different subtypes and appearances and he presents a very clear exposition of the field which will be extremely helpful to clinicians. In this issue, we also take a broad look at ovarian cancer in terms of a review of current thoughts on first-line therapy from Dr D'Hondt and colleagues and an article focused on relapsed disease. The era of targeted therapies in oncology is well and truly upon us and ovarian cancer is very much part of this therapeutic revolution with the development of PARP inhibitors for patients with BRACA mutations and defects. Data are emerging very quickly on the usefulness of PARP inhibition and Stan Kaye and colleagues give an excellent summary of the current position.

Gordon Rustin sets the results of his trial on early versus late treatment of relapsed disease in the wider context of follow-up strategies. The debate relating to the follow-up of patients with ovarian cancer has always been one that has simmered in the background but with the release of the data from Professor Rustin's trial the whole issue of the management of patients following the completion of first-line therapy, has become an area of great interest and much argument. As a companion article, we have an excellent update presented by Drs Moore and MacLaughlan on biomarkers in epithelial ovarian cancer. This sets into context some of the recent data on new biomarkers and their possible usefulness in the important area of ovarian cancer screening.

Many of the most hotly argued controversies in cancer relate to the treatment of patients with early disease. The balance between not compromising potentially curative therapy and causing unnecessary long-term morbidity in cured patients is one that can be very difficult to ascertain because often the data are not mature or available due to the lengthy follow-up required before definitive answers emerge. We present controversies in three areas of gynaecological malignancy relating to the management of early stage disease namely vulva cancer, cervical cancer and endometrial cancer. Professor van der Zee and colleagues describe the current status of sentinel node biopsy for early stage vulva cancer and Drs Al-Mansour and Verschraegen give a very complete review of the data relating to locally advanced cervical cancer and give clinicians clear recommendations. Finally, the issue of the management of lymph nodes in uterine cancer is excellently discussed by Drs Delpech and Barranger.

This issue is very full with a lot of data presented but the authors have described often very complex areas with real clarity and the conclusions that they draw will help all of us who are practising physicians in the area of gynaecological oncology manage our patients better.

Challenges to the Paclitaxel/Carboplatin Algorithm in Ovarian Cancer Treatment - Cancer Network

ONCOLOGY. Vol. 24 No. 8

THE LIU/MATULONIS ARTICLE REVIEWED

Challenges to the Paclitaxel/Carboplatin Algorithm in Ovarian Cancer Treatment

By
Kristin K. Zorn, MD
Gynecologic Cancer Program
Magee-Womens Hospital of UPMC
Pittsburgh, Pennsylvania
| July 22, 2010

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Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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After years of maintaining the status quo in ovarian cancer treatment, a number of recent advances have challenged the paradigm based on intravenous (IV) taxane and platinum as the therapy of choice for advanced ovarian cancer. These new data are summarized concisely by Liu and Matulonis in this issue.[1]
Interestingly, a review of recent history reveals that a major milestone in ovarian cancer chemotherapy is reached about every 10 years. The publication of Gynecologic Oncology Group (GOG) protocol 47 in 1986 provided randomized evidence of a 4-month improvement in overall survival with the addition of cisplatin to the previous standard of doxorubicin and cyclophosphamide.[2] In 1996, GOG 111 was published, documenting a 14-month improvement in overall survival with the addition of paclitaxel to cisplatin.[3] GOG 172 was published in 2006, becoming the third in a series of GOG trials to demonstrate a survival advantage with the use of combined IV and intraperitoneal (IP) chemotherapy.[4] Despite a 17-month improvement in overall survival that triggered an NCI alert commenting on the results, combined IV/IP therapy has yet to be broadly accepted as a new standard of care.[5] Widespread acceptance of the GOG 172 regimen has been limited by the relative complexity of the treatment (especially when compared to IV paclitaxel/carboplatin); the increased potential for toxicity; the requirement for IP port placement and maintenance; and the relative lack of experience in community centers with IP chemotherapy administration. Perhaps the most challenging part about incorporating IV/IP treatment into routine management of ovarian cancer is the idea that a route of administration—rather than a particular drug, such as cisplatin in the 1980s and then paclitaxel in the 1990s—appears to be the advance.
Concurrent with the evolution of the IP chemotherapy story has been the development of targeted or biologic therapy, particularly the antiangiogenic agent bevacizumab. Results from a phase II trial in women with recurrent ovarian cancer were published in 2007 and revealed a response rate of 21%, made more remarkable by a 51.6% stable disease rate.[6] This level of activity in recurrent disease led to a randomized phase III trial in the frontline setting, GOG 218, which tested the inclusion of bevacizumab both with IV paclitaxel/carboplatin and as a maintenance strategy. Preliminary results from GOG 218 were presented at ASCO 2010, showing a significant improvement in progression-free survival in the arm where patients received bevacizumab maintenance after their initial six cycles of chemotherapy plus bevacizumab, but not in the arm where patients received bevacizumab only during their initial chemotherapy.[7] The improvement was somewhat disappointing at 3.8 months, however, making it a difficult question of whether, despite the added toxicity and expense, bevacizumab merits inclusion in frontline regimens. The overall survival data from GOG 218, when mature, as well as the results from the ongoing ICON study with a comparable design, will help inform that question. In the meantime, oncologists caring for women with ovarian cancer have been left with the decision of whether to prioritize IV/IP therapy or bevacizumab in treatment plans.
Liu and Matulonis point to the GOG's attempt to incorporate both of these treatment advances in the current phase III trial, GOG 252. An additional confounder has been introduced by recent Japanese results, which showed a benefit from weekly IV paclitaxel compared to the traditional IV dose given every 3 weeks.[8] GOG 252 incorporates bevacizumab into IV/IP therapy, while also trying to address the toxicity issue by comparing a modified GOG 172 regimen to an IP carboplatin regimen. It also addresses the dose-density issue by utilizing weekly paclitaxel in the IV arm.
Besides the renewed hope for meaningful improvement in outcomes with advanced ovarian cancer that these trials have provided, we are witnessing another development that has the potential to advance ovarian cancer care on an even more fundamental level. The pathogenesis of ovarian cancer has been exhaustively investigated but never fully elucidated. The identification of the BRCA1 and BRCA2 genes in the early 1990s, however, has allowed a population at high risk for the development of ovarian cancer to be clearly defined. These women, in turn, have been able to undergo risk-reducing bilateral salpingo-oophorectomy to manage their risk. Studies of the specimens collected at the time of prophylactic surgeries have identified an unexpectedly high rate of tubal cancers.[9] Further study of serous cancers thought to be ovarian in origin has shown the unexpectedly frequent presence of fallopian tube dysplasia (termed tubal intraepithelial neoplasia or TIC).[10] Although larger-scale confirmation of these studies is needed, the high-risk population has provided a potential insight into the development of sporadic ovarian cancer. As we move to a more mechanistic understanding of cancer therapy and its targets, these insights into the BRCA pathway may well provide the next big advance in ovarian cancer care through manipulation with agents such as PARP inhibitors. For a disease that saw only halting advances for too long, ovarian cancer is now on the verge of being better understood and more effectively treated than ever before.
—Kristin K. Zorn, MD

The Elusive Goal of Maintaining Population Cancer Screening: It Is Time for a New Paradigm -- Editorial (full free access)

Note: focus on breast cancer/not specific to ovarian cancer; discusses high risk (BRCA's) "In this issue of the Journal, Vernon et al. conducted a methodologically rigorous review of the literature on controlled behavioral interventions to increase repeat mammography screening among women at average risk for the disease.......The promise of breast cancer screening has fallen short of its goals because of its imprecision, failure to screen those at highest risk, lack of compliance with screening continuance over recommended periods of time, and gaps in access to or quality of diagnostic follow-up and treatment (20). It is no longer enough to simply conduct more interventions to understand which work best in motivating individuals to undergo repeat cancer screening. New paradigms, guided by evidence from modeling, novel trials, and new scientific discovery, will be needed to realize the promise of eliminating the burden of cancer."

Putting research into context—revisited : The Lancet - Editorial

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"In July, 2005, Lancet editors wrote that “we will require authors of clinical trials submitted to The Lancet to include a clear summary of previous research findings, and to explain how their trial's findings affect this summary.
They called for the relation between existing and new evidence to be referenced to a published systematic review or meta-analysis. The CONSORT statement2 first required in 1996 that findings should be interpreted to take into account the totality of the evidence.
Michael Clarke and colleagues have been monitoring since then how the five high-impact journals (Annals of Internal Medicine, BMJ, JAMA, The Lancet, and The New England Journal of Medicine) have been doing. They report in The Lancet today their latest results for May, 2009.
Their findings are discouraging: only one of 24 reports that were not first trials placed the results in the context of an updated systematic review in the Discussion.
They conclude that there is no evidence of progress since 1997, and that editors and authors are not informing sufficiently those who have to make decisions about health care."
Clearly, clinicians and others in health care need to know what the results of research mean for patients.
Authors and editors can help them by doing exactly what CONSORT4 and Clarke and colleagues call for. 
Authors need to spell out what their study adds to other work and what that means for clinical practice...."cont'd

Editorial: The cancer of bureaucracy: How it will destroy science, medicine, education; and eventually everything else

Editorial

The cancer of bureaucracy: How it will destroy science, medicine, education; and eventually everything else

References and further reading may be available for this article. To view references and further reading you must purchase this article.

Summary

Everyone living in modernizing ‘Western’ societies will have noticed the long-term, progressive growth and spread of bureaucracy infiltrating all forms of social organization: nobody loves it, many loathe it, yet it keeps expanding. Such unrelenting growth implies that bureaucracy is parasitic and its growth uncontrollable – in other words it is a cancer that eludes the host immune system. Old-fashioned functional, ‘rational’ bureaucracy that incorporated individual decision-making is now all-but extinct, rendered obsolete by computerization. But modern bureaucracy evolved from it, the key ‘parasitic’ mutation being the introduction of committees for major decision-making or decision-ratification. Committees are a fundamentally irrational, incoherent, unpredictable decision-making procedure; which has the twin advantages that it cannot be formalized and replaced by computerization, and that it generates random variation or ‘noise’ which provides the basis for natural selection processes. Modern bureaucracies have simultaneously grown and spread in a positive feedback cycle; such that interlinking bureaucracies now constitute the major environmental feature of human society which affects organizational survival and reproduction. Individual bureaucracies must become useless parasites which ignore the ‘real-world’ in order to adapt to rapidly-changing ‘bureaucratic reality’. Within science, the major manifestation of bureaucracy is peer review, which – cancer-like – has expanded to obliterate individual authority and autonomy. There has been local elaboration of peer review and metastatic spread of peer review to include all major functions such as admissions, appointments, promotions, grant review, project management, research evaluation, journal and book refereeing and the award of prizes. Peer review eludes the immune system of science since it has now been accepted by other bureaucracies as intrinsically valid, such that any residual individual decision-making (no matter how effective in real-world terms) is regarded as intrinsically unreliable (self-interested and corrupt). Thus the endemic failures of peer review merely trigger demands for ever-more elaborate and widespread peer review. Just as peer review is killing science with its inefficiency and ineffectiveness, so parasitic bureaucracy is an un-containable phenomenon; dangerous to the extent that it cannot be allowed to exist unmolested, but must be utterly extirpated. Or else modernizing societies will themselves be destroyed by sclerosis, resource misallocation, incorrigibly-wrong decisions and the distortions of ‘bureaucratic reality’. However, unfortunately, social collapse is the more probable outcome, since parasites can evolve more rapidly than host immune systems.

Editorial: Dietary Assessment and the Reliability of Nutritional Epidemiology Research Reports

".......The fact that Dahm et al. could not correct the fiber consumption odds ratios for these types of systematic biases casts a shadow over the interpretation of their reported inverse association.

Unfortunately, this shadow extends to virtually the entire body of the existing nutritional epidemiology literature and may well contribute to the fact that few associations between diet and cancer are regarded as established or probable (8).

The explicit use of biomarkers to correct nutritional epidemiology associations for systematic and random measurement error in dietary assessment seems a logical next step in the nutritional epidemiology research agenda..." cont'd

Editorial: Solving the Overdiagnosis Dilemma

Note: worth reading

Lung Cancer Risks Rise With Nanoparticles, Lung Cancer

Editorial comment (mine):
I had written concerning this issue before, but new info/repeat for newer members. Some years ago, I had spoken with a well known researcher while discussing family histories of ovarian cancer because in a small non-scientific study we had done, it seemed certain cancers were very prevelant and outside of what might be considered the norm. Lung cancer was one. The researcher at the time said that they believed there is was/is a genetic component between ovarian and lung cancer, aside from both being epithelial (the lining of an organ) cancers. It seems, although not specific, this article is starting to document these concerns/advances. Anyway, a FYI, but mostly it is because over years I have witnessed lung cancer patients being ostracized not only by the public by others. I hope some now take a reflective look when judging those most in need. Anyway, a bit off topic but I think it important not only for cancer communities but for all.
....................................................................................

http://www.emaxhealth.com/1075/99/31666/lung-cancer-risks-rise-nanoparticles.html

> More recent studies point to the cause of lung cancer as possibly genetic. While researchers insist environmental factors, such as smoking, asbestos exposure, etc., play a role in the development of the disease, there is growing evidence that the answer to the question is at the gene level.




Lung Cancer Risks Rise With Nanoparticles, Lung Cancer: "More recent studies point to the cause of lung cancer as possibly genetic. While researchers insist environmental factors, such as smoking, asbestos exposure, etc., play a role in the development of the disease, there is growing evidence that the answer to the question is at the gene level."