Tuesday, June 02, 2015
Precision Medicine — Personalized, Problematic, and Promising — NEJM
open access
The growing recognition of precision medicine by clinicians, health systems, and the pharmaceutical industry, as well as by patients and policymakers,1 reflects the emergence of a field that is accelerating rapidly and will leave a major imprint on the practice of medicine. In this article, we summarize the forces accelerating precision medicine, the challenges to its implementation, and the implications for clinical practice......
Disappointing NICE decision on olaparib for ovarian cancer (UK)
In the news
......The preliminary guidance is now open for consultation, and members of the public can respond directly. Target Ovarian Cancer will also be responding to the NICE consultation on your behalf and have been invited by NICE to attend the next appraisal meeting following this consultation. You can read the consultation documents, and send your consultation response by emailing Dr Simon Newman, our Head of Research.
Unanimity on Death with Dignity — Legalizing Physician-Assisted Dying in Canada + comments
open access - Dying in Canada (Perspective)
....These developments will trouble people who instinctively find legalized physician-assisted dying repellent. But increasingly, society is acknowledging that denying people the right to die with dignity and safety is even more repellent.
Gene-Panel Sequencing and the Prediction of Breast-Cancer Risk — NEJM
open access
Advances in sequencing technology have made multigene testing, or “panel testing,” a practical option when looking for genetic variants that may be associated with a risk of breast cancer. In June 2013, the U.S. Supreme Court1 invalidated specific claims made by Myriad Genetics with respect to the patenting of the genomic DNA sequence of BRCA1 and BRCA2. Other companies immediately began to offer panel tests for breast cancer genes that included BRCA1 and BRCA2. The subsequent flourishing of gene-panel testing services (Table 1Table 1Examples of Multigene Testing Panels for Breast Cancer., and Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org) has generated much interest both within the clinical genetics community and in the popular press.2 These panels cover a total of more than 100 genes, and breast cancer is specifically mentioned as an indication for 21 of these genes. However, the fact that the technology is available does not necessarily mean that such tests are appropriate or desirable........
.... Mutations in three other DNA repair genes, RAD51C, RAD51D, and BRIP1, have shown clear evidence of an association with ovarian cancer.49-53 However, in each case, the evidence for association with breast cancer is limited. Recent exome studies and targeted sequencing studies have suggested that breast cancer is associated with deleterious variants in FANCC,54 FANCM,55 and XRCC2.56 In none of these instances, however, does the evidence reach the threshold level (P<0.0001) that we propose for DNA-repair genes. The recent findings of deleterious mutations in RECQL in women with a strong family history of breast cancer, however, suggests that this gene confers susceptibility to breast cancer.57,58.....
Other Genes
The panels currently marketed for the prediction of risk of cancer contain many other genes, most of which have been included by virtue of their relevance to rare mendelian cancer syndromes. Variants in some of these genes may also be associated with breast cancer. Mutations in DNA mismatch-repair genes (MLH1, MSH2, MSH6, and PMS2) may be associated with breast cancer, but in a recent review, Win et al.59 concluded that the evidence was equivocal. It has also been suggested that MUTYH variants that confer a predisposition to polyposis colorectal cancer may confer a predisposition to breast cancer, but a recent case–control study reported no association.60 Another recent study suggested that carriers of MEN1 mutations may be at increased risk for breast cancer.61 A recent case–control study has reported an association between rare variants in PPM1D and breast cancer.62 However, this association does not reach our proposed significance threshold, and, in addition, the sequence variants are observed as mosaics in lymphocytes and are not inherited. There is currently no clear evidence of an association between breast cancer and any other gene.........Monday, June 01, 2015
Risk Algorithm Using Serial Biomarker Measurements Doubles the Number of Screen-Detected Cancers Compared With a Single-Threshold Rule in the United Kingdom Collaborative Trial of Ovarian Cancer Screening
open access
In conclusion, our data support use of velocity-based algorithms as opposed to a predefined single-threshold rule in cancer screening strategies that use blood biomarkers.
Is it Unethical to 'Look Up' ED Patients on Social Media?
medscape
Conclusion
Our findings suggest that although some emergency physicians and trainees use OSM and Google to research their patients, many consider it unethical. Furthermore, we found no age or training-level differences in the likelihood of using Facebook to research patients. Future work should focus on exploring patients' views on whether this act is desirable and permissible. Research should also explore the nature and content of online searches performed on patients, and the usefulness of information obtained. As the prevalence of social media use by patients increases steadily, individuals, institutions, and professional bodies will need to ethically integrate social media into patient care and medical education.[33] Autonomy and beneficence should be guiding principles so that we benefit, rather than harm, our patients and profession.NCI-MATCH trial will link targeted cancer drugs to gene abnormalities
NCI-MATCH trial
... Adults 18 years of age and older with solid tumors or lymphomas that have advanced following at least one line of standard systemic therapy, or with tumors for which there is no standard treatment, will be eligible. Each arm of the trial will enroll up to 35 patients. The trial’s design calls for at least a quarter of the 1,000-patients enrolled to involve people with rare types of cancer.....
The National Cancer Institute leads the National Cancer Program and the NIH’s efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER.
Childhood cancers in families with/without Lynch syndrome
abstract
Inheritance of a germline mutation in one of the DNA mismatch repair (MMR) genes or the EPCAM gene is associated with an increased risk of colorectal cancer, endometrial cancer, and other adult malignancies (Lynch syndrome). The risk of childhood cancers in Lynch syndrome families, however, is not well studied. Using data from the Colon Cancer Family Registry, we compared the proportion of childhood cancers (diagnosed before 18 years of age) in the first-, second-, and third-degree relatives of 781 probands with a pathogenic mutation in one of the MMR genes; MLH1 (n = 275), MSH2 (n = 342), MSH6 (n = 99), or PMS2 (n = 55) or in EPCAM (n = 10) (Lynch syndrome families), with that of 5073 probands with MMR-deficient colorectal cancer (non-Lynch syndrome families). There was no evidence of a difference in the proportion of relatives with a childhood cancer between Lynch syndrome families (41/17,230; 0.24 %) and non-Lynch syndrome families (179/94,302; 0.19 %; p = 0.19). Incidence rate of all childhood cancers was estimated to be 147 (95 % CI 107-206) per million population per year in Lynch syndrome families and 115 (95 % CI 99.1-134) per million population per year in non-Lynch syndrome families. There was no evidence for a significant increase in the risk of all childhood cancers, hematologic cancers, brain and central nervous system cancers, Lynch syndrome-associated cancers, or other cancers in Lynch syndrome families compared with non-Lynch syndrome families. Larger studies, however, are required to more accurately define the risk of specific individual childhood cancers in Lynch syndrome families
Role of Red Meat and Resistant Starch in Promutagenic Adduct Formation, MGMT Repair......
abstract
J Nutrigenet Nutrigenomics. 2015 May 27;7(4-6):299-313. [Epub ahead of print]
Role of Red Meat and Resistant Starch in Promutagenic Adduct Formation, MGMT Repair, Thymic Lymphoma and Intestinal Tumourigenesis in Msh2 -Deficient Mice.
...No link between red meat-induced promutagenic adducts and risk for colorectal cancer was observed after 6 months' feeding (mice). Colonic epithelial changes after red meat and RS consumption with MMR deficiency will differ from normal epithelial cells.
Minor changes in expression of the mismatch repair protein MSH2 exert a major impact on glioblastoma response to temozolomide
abstract
Glioblastoma (GBM) is often treated with the cytotoxic drug temozolomide (TMZ) but the disease inevitably recurs in a drug-resistant form after initial treatment. Here we report that in GBM cells even a modest decrease in the mismatch repair (MMR) components MSH2 and MSH6 have profound effects on TMZ sensitivity. RNAi-mediated attenuation of MSH2 and MSH6 showed that such modest decreases provided an unexpectedly strong mechanism of TMZ resistance. In a mouse xenograft model of human GBM, small changes in MSH2 were sufficient to suppress TMZ-induced tumor regression. Using the Cancer Genome Atlas to analyze mRNA expression patterns in tumors from TMZ-treated GBM patients, we found that MSH2 transcripts in primary GBM could predict patient responses to initial TMZ therapy. In recurrent disease, the absence of microsatellite instability (the standard marker for MMR deficiency) suggests a lack of involvement of MMR in the resistant phenotype of recurrent disease. However, more recent studies reveal that decreased MMR protein levels occur often in recurrent GBM. In accordance with our findings, these reported decreases may constitute a mechanism by which GBM evades TMZ sensitivity while maintaining microsatellite stability. Overall, our results highlight the powerful effects of MSH2 attenuation as a potent mediator of TMZ resistance, and argue that MMR activity offers a predictive marker for initial therapeutic response to TMZ treatment.
Getting It Right with Lynch Syndrome Genetic and Phenotypic Diagnosis
Commentary
However, the more data public mutation databases can amass, from researchers and clinicians, on mutations that are interpretable or not, the closer we will come to understanding causal relationships between genotypes and disease.
In reference to: (open access)
Lynch Syndrome Associated with Two MLH1 Promoter Variants and Allelic Imbalance of MLH1 Expression
A risk prediction algorithm for ovarian cancer incorporating BRCA1/2, common alleles & other familial effects
open access
Risk models that incorporate both BRCA1 and BRCA2 mutations and other sources of variation are required to provide accurate estimates of mutation carrier probabilities and cancer risk for use in genetic counselling. Existing risk-prediction models for familial OvC such as Breast and Ovarian Analysis of Disease Incidence and Carrrier Estimation Algorithm (BOADICEA) or BRCAPRO3 ,4 assume that all familial aggregation to OvC is due to BRCA1 and BRCA2 mutations but this does not reflect our understanding of OvC genetic susceptibility. As a consequence, these models may underestimate OvC risks in women without mutations in these genes. Therefore, how to counsel women with family history of OvC but without BRCA1 or BRCA2 mutations has remained a major unresolved question in clinical cancer genetics.....
Willingness of Japanese patients with breast cancer to have genetic testing of BRCA without burden of expenses
abstract
CONCLUSIONS:
These data indicate that the currently available preventive measures and/or counseling system may not be sufficient enough to convince the high risk population to receive the genetic testing or to overcome the prejudice in non-urban area in Japan, even if served free.Sunday, May 31, 2015
Ten modifiers of BRCA1 penetrance validated in a Norwegian series
open access
....BRCA1-associated cancer is age-dependent, and whether or not this is stochastic or influenced by other factors (modifiers of penetrance) is a question that has not been fully explored: Both stochastic elements and modifying factors may be instrumental in diseases causation. Modifying factors may be genetic, environmental, or both. This study was designed to validate previous reports of normal genetic variants that contribute to modifying BRCA1 penetrance.....
Background Common genetic variants have been shown to modify BRCA1 penetrance. The
aim of this study was to validate these reports in a special cohort of Norwegian BRCA1
mutation carriers that were selected for their extreme age of onset of disease.
Methods
The ten variants rs13387042, rs3803662, rs8170, rs9397435, rs700518, rs10046, rs3834129,
rs1045485, rs2363956 and rs16942 were selected to be tested on samples from our biobank.
We selected female BRCA1 mutation carriers having had a diagnosis of breast or ovarian
cancer below 40 years of age (young cancer group, N = 40), and mutation carriers having
had neither breast nor ovarian cancer above 60 years of age (i.e., old no cancer group,
N = 38). Relative risks and odd ratios of belonging to the young cancer versus old
no cancer groups were calculated as a function of having or not having the SNPs in
question.
Results Five of the ten variants were found to be significantly associated
with early onset cancer. Some of the variation between our results and those previously
reported may be ascribed to stochastic effects in our limited number of patient studies,
and/or genetic drift in linkage disequilibrium in the genetically isolated Norwegian
population. This is in accordance with the understanding that the SNPs are markers
in linkage disequilibrium with their respective disease-causing genetic variants,
and that this may vary between different populations.
Conclusions The results confirmed
associations previously reported, with the notion that the degree of association may
differ between other populations, which must be considered when discussing the clinical
use of the associations described.
Evaluation of in vitro chemoresponse profiles in women with Type I and Type II epithelial ovarian cancers: An observational study ancillary analysis
abstract
Conclusion(s)
The majority of women
with Type I EOC displayed assay sensitivity to at least one agent.
Given the small sample size these findings need to be evaluated further.
Highlights
- •
- Multi-drug resistance was more likely in women with Type I compared to Type II cancers.
- •
- The majority of women with Type I epithelial ovarian cancer displayed assay sensitivity to at least one chemotherapeutic agent in a chemoresponse assay.
- •
- PFS was significantly worse in women with Type II EOC with resistant compared to non-resistant chemoresponse assay results for carboplatin.
Ovarian Cancer Competition Accelerates With Clovis Drug Data - Rucaparib
media
....In a midstage study of 204 patients, rucaparib shrunk tumors in 32 of 39 patients with BRCA mutations. Four women in that group had their tumors disappear, known as a complete response. The study data was released Saturday at the American Society of Clinical Oncology’s meeting in Chicago.....
Saturday, May 30, 2015
Profiling of actionable gene alterations in ovarian cancer by targeted deep sequencing
abstract
Affiliations: Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan, Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo 105-8471, Japan, Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan, Division of Genetics, National Cancer Center Research Institute, Tokyo 104-0045, Japan
To construct a profile of therapeutically actionable gene alterations in the major histological types of ovarian cancer, 72 Japanese patients with surgically resected ovarian cancers were selected from an original cohort consisting of 267 patients who had not received pre-treatment before surgery. Somatic mutations and copy number alterations at 740 hotspots in 46 cancer-related genes were detected by deep sequencing of genomic DNAs obtained from snap-frozen tumor tissues using a next generation sequencer. The alterations were verified by Sanger sequencing and quantitative genomic PCR. Mutations and/or copy number aberrations which will make tumors respond to molecular targeting drugs were detected in nine genes of 35/72 (48.6%) patients; PIK3CA (25.0%), KRAS (13.9%), ERBB2 (4.3%), PTEN (2.8%), RB1 (2.8%), CDKN2A (2.8%), AKT1 (1.4%), CTNNB1 (1.4%) and NRAS (1.4%). These mutations tended to occur in a mutually exclusive manner. Non-serous histological type tumors showed such actionable gene alterations frequently (32/47; 68.1%). Therefore, ovarian cancers, particularly of non-serous types, frequently carry gene aberrations that link to therapy using molecular targeting drugs.
Reduced accumulation of platinum drugs is not observed in drug-resistant OC cell lines derived from cisplatin-treated pts
abstract
The resistance of ovarian cancer towards front-line chemotherapy, usually cisplatin or carboplatin in combination with paclitaxel or docetaxel, remains a major clinical challenge. Resistance to these agents has been largely studied using cell lines selected for resistance to agents in vitro. We examined a series of paired cell lines derived from patients with ovarian cancer prior to chemotherapy (PEO1, PEO4, PEO14 and PEA1), and following the acquisition of resistance to a platinum-based chemotherapy regimen (PEO6, PEO23 and PEA2, respectively). All resistant patient lines showed resistance to cisplatin (2-5-fold), but this did not correspond with lowered accumulation. No general cross-resistance was observed for oxaliplatin, paclitaxel or docetaxel, and paclitaxel accumulation was not affected. PEO1 cells carrying BRCA2 mutations were hypersensitive to the PARP inhibitors olaparib and velaparib, but all other cell lines expressing functional forms of BRCA2 were less sensitive. While reduced drug accumulation was not observed, we believe these pairs of lines are of use to researchers studying Pt drug resistance and experimental therapeutics against drug-resistant ovarian cancer.
Friday, May 29, 2015
Editorial: Novel Methods for Measuring Global Cancer Burden: Implications for Global Cancer Control
JAMA Oncology
"Because cancer can occur in young people and creates significant disability prior to death, the social impact as measured by disability-adjusted life-years (DALYs) is staggering."
....In
oncology, diagnostic accuracy is a critical issue for developing cancer
treatment strategies. Cancer registries are linked to surgical
pathology assessments. While some cancers may be amenable to accurate
diagnosis through clinical evaluation or simple diagnostic testing, most
cancers can be difficult to specify in the absence of tissue diagnosis.
The GBD investigators provide estimates of years of life lost for
different cancers, some of which showed little change in ranking over
the study years (eg, lung, colon, breast, esophagus, ovarian, uterine,
melanoma), whereas others had marked variation in rank order (eg,
pancreatic, bladder, gall bladder, Hodgkin lymphoma, myeloma). These
variations in the latter group could reflect differences in cancer
prevalence, biology, and/or treatment but may alternatively relate to
diagnostic inaccuracy, because all of the cancers with variations in
rank order require higher-quality imaging studies and/or pathology
assessment for definitive diagnosis. Histologically different cancers
that present in adjacent anatomic locations and/or with similar signs
and symptoms could easily be confused. Without histologic evidence
confirming malignant tissue diagnosis, mortality causation assessment
tools cannot reliably differentiate between primary liver cancer, gall
bladder cancer, pancreatic cancer, and cancer metastatic to liver, all
of which have similar clinical presentations. Because accurate tissue
diagnosis is fundamental to cancer registry methodology but is not
required in GBD analysis, the GBD approach developed by IHME seems
unlikely to achieve the diagnostic precision of a pure cancer
registry–based method. These findings highlight the importance for
strengthening global pathology and imaging services in conjunction with
expanding cancer registration data systems throughout the world, which
could benefit both GLOBOCAN and GBD estimates........
Explaining variation in cancer survival between 11 jurisdictions in the Intl Cancer Benchmarking Partnership: a primary care vignette survey
open access
Strengths and limitations of this study
-
A novel, large and logistically complicated study using a validated survey.
-
Data were analysed from 2795 primary care physicians (PCPs) across 11 jurisdictions.
-
Response rates were suboptimal (ranging from 5.5% in England and British Columbia to 45.6% in Manitoba) and respondents were not totally representative of the PCPs in all jurisdictions.
-
It is difficult to assess the effect of these weaknesses on the interpretation of results but sensitivity analyses and the literature suggest it would not be large.
Principal findings
Using an online survey in 11 jurisdictions, we have demonstrated a correlation that suggests a relationship between the readiness of PCPs to investigate or refer for suspected cancer and cancer survival in each jurisdiction. This is the first time that readiness to investigate cancer—either directly or by referral to secondary care—has been shown to correlate with cancer survival. Evidence suggests that variations between healthcare systems have an impact on health outcomes.24 There is significant variation between jurisdictions in PCP's access to diagnostic tests. Whether greater access to tests improves outcomes depends on the sensitivity of the test and how the waiting time for test results compares with the waiting time if a referral is made. PCPs may not be aware of the fastest way to diagnose cancer: referral or primary care investigation. Our data indicate significantly long waits in some jurisdictions for the results of tests undertaken in primary care. However, access to tests was not associated with readiness to investigate or refer. Further research is required in this complex area.
Thursday, May 28, 2015
What Can You Do to Improve Your Odds Against Cancer? |
Dr. Robert A. Nagourney - Rational Therapeutics - Blog
I sometimes joke with my patients that a new diagnosis of cancer rarely provides them enough time to get an MD or PhD. Yet it is that level of preparation that may be required to answer the myriad questions that lie ahead.
Although it’s a joke, it is only partly in jest. Unlike buying a house or a car for which one’s life experiences can prepare you, medicine is opaque, complicated and ever changing. At the bleeding edge of medical complexity sits medical oncology and its dizzying array of genomics, transcriptomics, proteomics, epigenomics and metabolomics. Not only is it difficult for patients to keep up with all the changes, it is increasingly beyond the ken of their doctors who have spent entire careers training in the specialty, many of whom may have an MD and a PhD........
Anti-Angiogenesis Therapy in Gynecologic Malignancies - open access
open access
The purpose of this paper is to provide a review of site-specific treatment options that involve the targeting of angiogenesis in gynecologic malignancies.
Toxicities of Immunotherapy for the Practitioner
abstract and articles plus editorial
The
toxicities of immunotherapy for cancer are as diverse as the type of
treatments that have been devised. These range from
cytokine therapies that induce capillary leakage to
vaccines associated with low levels of autoimmunity to cell therapies
that can induce damaging cross-reactivity with
normal tissue to checkpoint protein inhibitors that induce
immune-related adverse
events that are autoinflammatory in nature. The
thread that ties these toxicities together is their mechanism-based
immune
nature and the T-cell–mediated adverse events seen.
The basis for the majority of these adverse events is a hyperactivated
T-cell response with reactivity directed against
normal tissue, resulting in the generation of high levels of CD4
T-helper
cell cytokines or increased migration of cytolytic
CD8 T cells within normal tissues. The T-cell immune response is not
tissue
specific and may reflect a diffuse expansion of the
T-cell repertoire that induces cross-reactivity with normal tissue,
effectively
breaking tolerance that is active with cytokines,
vaccines, and checkpoint protein inhibitors and passive in the case of
adoptive
cell therapy. Cytokines seem to generate diffuse
and nonspecific T-cell reactivity, whereas checkpoint protein
inhibition,
vaccines, and adoptive cell therapy seem to
activate more specific T cells that interact directly with normal
tissues, potentially
causing specific organ damage. In this review, we
summarize the toxicities that are unique to immunotherapies, emphasizing
the need to familiarize the oncology practitioner
with the spectrum of adverse events seen with newly approved and
emerging
modalities.
Footnotes
-
See accompanying articles doi: 10.1200/JCO.2014.58.3708 and doi: 10.1200/JCO.2014.58.1041 and editorial doi: 10.1200/JCO.2015.61.4172
Editorial: Recognizing the Financial Burden of Cancer Patients in Clinical Trials
"Clinical trials often represent an increasingly important option for patients
with cancer, thus oncologists participating in clinical research need to consider and address the financial burden associated with trial participation."
Mutated Fanconi anemia pathway in non-Fanconi anemia cancers
abstract
An extremely high cancer incidence and the hypersensitivity to DNA crosslinking agents associated with Fanconi Anemia (FA) have marked it to be a unique genetic model system to study human cancer etiology and treatment, which has emerged an intense area of investigation in cancer research. However, there is limited information about the relationship between the mutated FA pathway and the cancer development or/and treatment in patients without FA. Here we analyzed the mutation rates of the seventeen FA genes in 68 DNA sequence datasets. We found that the FA pathway is frequently mutated across a variety of human cancers, with a rate mostly in the range of 15 to 35 % in human lung, brain, bladder, ovarian, breast cancers, or others. Furthermore, we found a statistically significant correlation (p < 0.05) between the mutated FA pathway and the development of human bladder cancer that we only further analyzed. Together, our study demonstrates a previously unknown fact that the mutated FA pathway frequently occurs during the development of non-FA human cancers, holding profound implications directly in advancing our understanding of human tumorigenesis as well as tumor sensitivity/resistance to crosslinking drug-relevant chemotherapy.
Pharmacoethnicity in Paclitaxel-Induced Sensory Peripheral Neuropathy
Sensory Peripheral Neuropathy
PURPOSE:
Paclitaxel is used worldwide in the treatment of breast, lung, ovarian and other cancers. Sensory peripheral neuropathy is an associated adverse effect that cannot be predicted, prevented or mitigated. To better understand the contribution of germline genetic variation to paclitaxel-induced peripheral neuropathy, we undertook an integrative approach that combines genome-wide association study (GWAS) data generated from HapMap lymphoblastoid cell lines (LCLs) and Asian patients.METHODS:
GWAS was performed with paclitaxel-induced cytotoxicity generated in 363 LCLs and with paclitaxel-induced neuropathy from 145 Asian patients. A gene-based approach was used to identify overlapping genes and compare to a European clinical cohort of paclitaxel-induced neuropathy. Neurons derived from human induced pluripotent stem cells were used for functional validation of candidate genes.RESULTS:
SNPs near AIPL1 were significantly associated with paclitaxel-induced cytotoxicity in Asian LCLs (P < 10-6). Decreased expression of AIPL1 resulted in decreased sensitivity of neurons to paclitaxel by inducing neurite morphological changes as measured by increased relative total outgrowth, number of processes and mean process length. Using a gene-based analysis, there were 32 genes that overlapped between Asian LCL cytotoxicity and Asian patient neuropathy (P < 0.05) including BCR. Upon BCR knockdown, there was an increase in neuronal sensitivity to paclitaxel as measured by neurite morphological characteristics.CONCLUSION:
We identified genetic variants associated with Asian paclitaxel-induced cytotoxicity and functionally validated the AIPL1 and BCR in a neuronal cell model. Furthermore, the integrative pharmacogenomics approach of LCL/patient GWAS may help prioritize target genes associated with chemotherapeutic-induced peripheral neuropathy.Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications....
abstract
Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs
BACKGROUND:
Ovarian
and triple-negative breast cancers with BRCA1 or BRCA2 loss are highly
sensitive to treatment with PARP inhibitors and platinum-based cytotoxic
agents and show an accumulation of genomic scars in the form of gross
DNA copy number aberrations. Cancers without BRCA1 or BRCA2 loss but
with accumulation of similar genomic scars also show increased
sensitivity to platinum-based chemotherapy. Therefore, reliable
biomarkers to identify DNA repair-deficient cancers prior to treatment
may be useful for directing patients to platinum chemotherapy and
possibly PARP inhibitors. Recently, three SNP array-based signatures of
chromosomal instability were published that each quantitate a distinct
type of genomic scar considered likely to be caused by improper DNA
repair. They measure telomeric allelic imbalance (named NtAI), large
scale transition (named LST), and loss of heterozygosity (named
HRD-LOH), and it is suggested that these signatures may act as
biomarkers for the state of DNA repair deficiency in a given cancer.
RESULTS:
We explored the pan-cancer distribution of scores of the three signatures utilizing a panel of 5371 tumors representing 15 cancer types from The Cancer Genome Atlas, and found a good correlation between scores of the three signatures (Spearman's ρ 0.73-0.87). In addition we found that cancer types ordinarily receiving platinum as standard of care have higher median scores of all three signatures. Interestingly, we also found that smaller subpopulations of high-scoring tumors exist in most cancer types, including those for which platinum chemotherapy is not standard therapy.CONCLUSIONS:
Within several cancer types that are not ordinarily treated with platinum chemotherapy, we identified tumors with high levels of the three genomic biomarkers. These tumors represent identifiable subtypes of patients which may be strong candidates for clinical trials with PARP inhibitors or platinum-based chemotherapeutic regimens.KEYWORDS:
Cancer; Genomic scars; Homologous recombination deficiencyWednesday, May 27, 2015
Primary Chemo Good Option in Advanced Ovarian Cancer ?
Cancer Network
..... These results raise two questions, Kang wrote: whether the CHORUS findings apply to expert surgeons, and which patients would benefit most from this treatment strategy.
“Concerns are also increasing that neoadjuvant chemotherapy could be used as an excuse for neglecting maximum surgical efforts or improvement of competent surgical skills,” Kang wrote. “Despite these questions and concerns, Kehoe and colleagues are to be congratulated on their research showing that neoadjuvant chemotherapy lowers treatment-related morbidity without sacrificing treatment efficacy. However, efforts should now be directed towards identifying and resolving the remaining uncertainties.”
Olaparib not being funded by the NHS
Behind the headlines
Posted by Simon Newman, Head of Research on Tuesday 26 May 2015
Olaparib is a treatment for women with relapsed platinum sensitive ovarian cancer with a BRCA gene mutation (around 400 women a year in England). It had been submitted for funding to the Cancer Drugs Fund, which announced on Friday that it won’t be funded by NHS England.....
Risk Factors for Surgical Complications in Ovarian Cancer | Cancer Network
Risk Factors
..... A woman’s preoperative albumin level and the number of extended cytoreductive procedures performed were found to be the strongest predictors of perioperative morbidity when undergoing surgery for ovarian cancer, according to the results of a retrospective analysis published in Gynecologic Oncology.....
Ovarian cancer's tricks discovered, new hope for better treatment
comparison costs differing cancers-Clinical Oncology News - Lofty Goals Being Set For Reimbursement Reform
Clinical Oncology News
Figure. Trends in cancer costs.
Source:National Cancer Institute (http://costprojections.cancer.gov/expenditures.html)
Tuesday, May 26, 2015
(EGFR) Pathway Biomarkers Phase III Trial of Erlotinib Vs Observation in Ovarian Cancer Patients
abstract
Epidermal Growth Factor Receptor (EGFR) Pathway Biomarkers in the Randomized Phase III Trial of Erlotinib Versus Observation in Ovarian Cancer Patients with No Evidence of Disease Progression after First-Line Platinum-Based Chemotherapy
BACKGROUND:
In
this work, we aimed to identify molecular epidermal growth factor
receptor (EGFR) tissue biomarkers in patients with ovarian cancer who
were treated within the phase III randomized European Organisation for
Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG)
55041 study comparing erlotinib with observation in patients with no
evidence of disease progression after first-line platinum-based
chemotherapy.
METHODS:
Somatic mutations in KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN were determined in 318 (38 %) and expression of EGFR, pAkt, pMAPK, E-cadherin and Vimentin, and EGFR and HER2 gene copy numbers in 218 (26 %) of a total of 835 randomized patients. Biomarker data were correlated with progression-free survival (PFS) and overall survival (OS).RESULTS:
Only 28 mutations were observed among KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN (in 7.5 % of patients), of which the most frequent were in KRAS and PIK3CA. EGFR mutations occurred in only three patients. When all mutations were pooled, patients with at least one mutation in KRAS, NRAS, BRAF, PIK3CA, or EGFR had longer PFS (33.1 versus 12.3 months; HR 0.57; 95 % CI 0.33 to 0.99; P = 0.042) compared to those with wild-type tumors. EGFR overexpression was detected in 93 of 218 patients (42.7 %), and 66 of 180 patients (36.7 %) had EGFR gene amplification or high levels of copy number gain. Fifty-eight of 128 patients had positive pMAPK expression (45.3 %), which was associated with inferior OS (38.9 versus 67.0 months; HR 1.81; 95 % CI 1.11 to 2.97; P = 0.016). Patients with positive EGFR fluorescence in situ hybridization (FISH) status had worse OS (46.1 months) than those with negative status (67.0 months; HR 1.56; 95 % CI 1.01 to 2.40; P = 0.044) and shorter PFS (9.6 versus 16.1 months; HR 1.57; 95 % CI 1.11 to 2.22; P = 0.010). None of the investigated biomarkers correlated with responsiveness to erlotinib.CONCLUSIONS:
In this phase III study, increased EGFR gene copy number was associated with worse OS and PFS in patients with ovarian cancer. It remains to be determined whether this association is purely prognostic or is also predictive.Epidemiology in ovarian carcinoma: lessons from autopsy
abstract
OBJECTIVE:
We challenge epidemiologic knowledge regarding ovarian carcinoma (OC) by bridging the gap between clinical and autopsy data.
METHODS:
Autopsy reports, histological slides and clinical files from 660 patients in whom OC was diagnosed from 1975-2005 were studied (autopsy cohort, n=233; Clinical Cancer Registry from the local gyneco-oncologic center, n=427).RESULTS:
Out of the autopsy cohort, we identified four distinct subgroups of patients: 1) OC was diagnosed before autopsy, n=156 (67.0%). 2) OC was an incidental finding, n=16 (6.8%). 3) The ovarian tumors were not primary OC but rather metastases from other primary tumors; this revised diagnosis was first made by using current histopathological knowledge/techniques, n=24 (10.3%). 4) Death was directly due to OC in its final stage and OC was first diagnosed by autopsy, n=37 (15.9%); when these cases were added to the Clinical Cancer Registry to an adjusted OC incidence model, the autopsy cases comprised 8.8% of the adjusted cohort and almost doubled the percentage of oldest patients (≥80 years at diagnosis) from 4.9% to 9.3% (p=0.013).CONCLUSIONS:
Epidemiological data from the 1970s-1990s may overestimate true incidence because up to 10% of carcinomas in the ovary were not properly classified. Patients who were first diagnosed with OC by autopsy comprise a distinct subgroup. These are patients who have not been seen by specialized oncologists and thus play no role in their perception of the disease. Nevertheless, these cases have impact on prevalence and incidence data of OC and in an era of reduced autopsy rates will probably be overlooked.Monday, May 25, 2015
Committee Opinion No. 634: Hereditary Cancer Syndromes & Risk Assessment
open access
ABSTRACT:
A hereditary cancer syndrome is a genetic predisposition to certain types of cancer, often with onset at an early age, caused by inherited mutations in one or more genes. Cases of cancer commonly encountered by obstetrician–gynecologists or other obstetric–gynecologic providers––such as breast cancer, ovarian cancer, and endometrial cancer––are features of specific hereditary cancer syndromes. The most common hereditary cancer syndromes related to gynecologic cancer include hereditary breast and ovarian cancer syndrome, Lynch syndrome, Li–Fraumeni syndrome, Cowden syndrome, and Peutz–Jeghers syndrome. A hereditary cancer risk assessment is the key to identifying patients and families who may be at increased risk of developing certain types of cancer. Screening should include, at minimum, a personal cancer history and a first- and second-degree relative cancer history that includes a description of the type of primary cancer, the age of onset, and the lineage (paternal versus maternal) of the family member. In addition, a patient’s ethnic background can influence her genetic risk. If a hereditary cancer risk assessment suggests an increased risk of a hereditary cancer syndrome, referral to a specialist in cancer genetics or a health care provider with expertise in genetics is recommended for expanded gathering of family history information, risk assessment, education, and counseling, which may lead to genetic testing.
Effectiveness of the RMI & ROMA Algorithm - Cohort of Women With OC: Does Histotype and Stage Matter?
abstract
Objective: To examine the performance of the Risk of
Malignancy Index (RMI) and Risk of Ovarian Malignancy Algorithm (ROMA)
by histologic subtype and stage of disease in a cohort of women with
ovarian cancer.
Methods: All patients with confirmed ovarian cancer at
the Princess Margaret Hospital between February 2011 and January 2013
were eligible for study inclusion. Preoperative cancer antigen 125,
human epididymis protein 4, and ultrasound findings were reviewed, and
the sensitivity and false-negative rates of the RMI and ROMA were
determined by stage of disease and tumor histology.
Results: A total of 131 patients with ovarian cancer
were identified. High-grade serous (HGS) histology was most frequently
associated with stage III/IV disease (n = 46 [72% of stage III/IV]) vs
stage I (n = 5 [11% of stage I]; P < 0.0001). Clear cell
(CC) and endometrioid (EC) histology presented most commonly with stage I
disease (n = 9 [20%] and n = 13 [29% of stage I cases], respectively).
Median cancer antigen 125 and human epididymis protein 4 values were
significantly higher for HGS than for EC or CC histology. Risk of
Malignancy Index II demonstrated the highest sensitivity of the 3 RMI
algorithms. All RMIs and ROMA were significantly more sensitive in
predicting malignancy in patients with HGS than EC or CC histology. Risk
of Malignancy Index II (n = 38) and ROMA (n = 35) exhibited
sensitivities of 68% and 54% and false-negative rates of 32% and 46%,
respectively, for patients with stage I disease vs sensitivities of 94%
and 93% and false-negative rates of 6% and 7% for patients with stage
III/IV disease.
Conclusion: Both RMI and ROMA performed well for the
detection of advanced ovarian cancer and HGS histology. These triaging
algorithms do not perform well in patients with stage I disease where EC
and CC histologies predominate. Clinicians should be cautious using RMI
or ROMA scoring tools to triage isolated adnexal masses because many
patients with stage I malignancies would be missed.
Index: Intl Journal of Gynecological Cancer June 2015
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