Target Cancer

[Michael Scally MD]

Najari BB, Rink M, Li PS, et al. Sex disparities in cancer mortality: The risks of being a man in the U.S. The Journal of urology. Elsevier

Purpose - In the United States, more men are diagnosed with cancer than women. We sought to quantify the differential mortality rate between the sexes from non-sex specific cancers, and compare their cancer stage distribution.

Materials and Methods - In this descriptive epidemiologic study, incidence of new cancer cases, cancer deaths, and stage distributions for the past ten years in the United States were obtained from Surveillance Epidemiology and End Results (SEER) program results. Sexspecific cancers were excluded. We compared male to female relative mortality rate for all cancers, as well as average male to female relative mortality rate weighted by cancer incidence over the past ten years. Sex specific stage distributions were also compared using Kendall’s tau-c test.

Results - The male to female relative mortality rate for any cancer was 1.060 (95% CI: 1.055-1.065). The average male to female relative mortality rate for the same cancer was 1.126 (1.086-1.168). The discrepancy in incidence and mortality rates has been stable for the last 10 years. Of the top ten most common cancers, men had an unfavorable stage distribution in all but colorectal, urinary bladder, and brain cancers.

Conclusions - Men are more likely to develop non-sex specific cancers than women, and are more likely to die from their cancer, even after controlling for the incidence. This discrepancy has been stable for the last decade. In seven of the 10 most commonly occurring non-sex specific cancers (78% of all incident cancers), men are more likely to be diagnosed with advanced stage.

 

[Michael Scally MD]

Ertel A, Tsirigos A, Whitaker-Menezes D, et al. Is cancer a metabolic rebellion against host aging? In the quest for immortality, tumor cells try to save themselves by boosting mitochondrial metabolism. Cell Cycle 2012;11(2):253-63. Landes Bioscience Journals: Cell Cycle

Aging drives large systemic reductions in oxidative mitochondrial function, shifting the entire body metabolically towards aerobic glycolysis, a.k.a, the Warburg effect. Aging is also one of the most significant risk factors for the development of human cancers, including breast tumors. How are these two findings connected? One simplistic idea is that cancer cells rebel against the aging process by increasing their capacity for oxidative mitochondrial metabolism (OXPHOS). Then, local and systemic aerobic glycolysis in the aging host would provide energy-rich mitochondrial fuels (such as L-lactate and ketones) to directly “fuel” tumor cell growth and metastasis. This would establish a type of parasite-host relationship or “two-compartment tumor metabolism”, with glycolytic/oxidative metabolic-coupling. The cancer cells (“the seeds”) would flourish in this nutrient-rich microenvironment (“the soil”), which has been fertilized by host aging. In this scenario, cancer cells are only trying to save themselves from the consequences of aging, by engineering a metabolic mutiny, through the amplification of mitochondrial metabolism. We discuss the recent findings of Drs. Ron DePinho (MD Anderson) and Craig Thomspson (Sloan-Kettering) that are also consistent with this new hypothesis, linking cancer progression with metabolic aging. Using data mining and bioinformatics approaches, we also provide key evidence of a role for PGC1a/NRF1 signaling in the pathogenesis of (1) two-compartment tumor metabolism, and (2) mitochondrial biogenesis in human breast cancer cells.

 

[Michael Scally MD]

Searchable Database

ASCO Abstracts 2013 Abstracts - ASCO

 

[Michael Scally MD]

[ame=http://www.youtube.com/watch?v=Cj2flGL2MVY]Mutation Based Resistance to TKI Therapy - by Frank G. Haluska, MD, PhD - YouTube[/ame]

 

[Michael Scally MD]

Beck AH, Knoblauch NW, Hefti MM, et al. Significance Analysis of Prognostic Signatures. PLoS Comput Biol 2013;9(1):e1002875. PLOS Computational Biology: Significance Analysis of Prognostic Signatures

A major goal in translational cancer research is to identify biological signatures driving cancer progression and metastasis. A common technique applied in genomics research is to cluster patients using gene expression data from a candidate prognostic gene set, and if the resulting clusters show statistically significant outcome stratification, to associate the gene set with prognosis, suggesting its biological and clinical importance. Recent work has questioned the validity of this approach by showing in several breast cancer data sets that “random” gene sets tend to cluster patients into prognostically variable subgroups. This work suggests that new rigorous statistical methods are needed to identify biologically informative prognostic gene sets. To address this problem, we developed Significance Analysis of Prognostic Signatures (SAPS) which integrates standard prognostic tests with a new prognostic significance test based on stratifying patients into prognostic subtypes with random gene sets. SAPS ensures that a significant gene set is not only able to stratify patients into prognostically variable groups, but is also enriched for genes showing strong univariate associations with patient prognosis, and performs significantly better than random gene sets. We use SAPS to perform a large meta-analysis (the largest completed to date) of prognostic pathways in breast and ovarian cancer and their molecular subtypes. Our analyses show that only a small subset of the gene sets found statistically significant using standard measures achieve significance by SAPS. We identify new prognostic signatures in breast and ovarian cancer and their corresponding molecular subtypes, and we show that prognostic signatures in ER negative breast cancer are more similar to prognostic signatures in ovarian cancer than to prognostic signatures in ER positive breast cancer. SAPS is a powerful new method for deriving robust prognostic biological signatures from clinically annotated genomic datasets.

 

[Michael Scally MD]

Excess Sugar Linked to Cancer

Highlights
• High-glucose amplification of Wnt signaling ties a cancer-related pathway to diabetes
• High glucose induces p300 and inhibits SIRT1
• High glucose increases ?-catenin acetylation and requires ?-catenin lysine 354
• High glucose increases nuclear accumulation and transcriptional activity of ?-catenin

Chocarro-Calvo A, García-Martínez Jose M, Ardila-González S, De la Vieja A, García-Jiménez C. Glucose-Induced ?-Catenin Acetylation Enhances Wnt Signaling in Cancer. Molecular cell. Molecular Cell - Glucose-Induced ?-Catenin Acetylation Enhances Wnt Signaling in Cancer

Nuclear accumulation of ?-catenin, a widely recognized marker of poor cancer prognosis, drives cancer cell proliferation and senescence bypass and regulates incretins, critical regulators of fat and glucose metabolism. Diabetes, characterized by elevated blood glucose levels, is associated with increased cancer risk, partly because of increased insulin growth factor 1 signaling, but whether elevated glucose directly impacts cancer-associated signal-transduction pathways is unknown. Here, we show that high glucose is essential for nuclear localization of ?-catenin in response to Wnt signaling. Glucose-dependent ?-catenin nuclear retention requires lysine 354 and is mediated by alteration of the balance between p300 and sirtuins that trigger ?-catenin acetylation. Consequently ?-catenin accumulates in the nucleus and activates target promoters under combined glucose and Wnt stimulation, but not with either stimulus alone. Our results reveal a mechanism by which high glucose enhances signaling through the cancer-associated Wnt/?-catenin pathway and may explain the increased frequency of cancer associated with obesity and diabetes.

 

[Michael Scally MD]

Strohmaier S, Edlinger M, Manjer J, et al. Total Serum Cholesterol and Cancer Incidence in the Metabolic Syndrome and Cancer Project (Me-Can). PLoS One 2013;8(1):e54242. PLOS ONE: Total Serum Cholesterol and Cancer Incidence in the Metabolic Syndrome and Cancer Project (Me-Can)

OBJECTIVE: To investigate the association between total serum cholesterol (TSC) and cancer incidence in the Metabolic syndrome and Cancer project (Me-Can).

METHODS: Me-Can consists of seven cohorts from Norway, Austria, and Sweden including 289,273 male and 288,057 female participants prospectively followed up for cancer incidence (n = 38,978) with a mean follow-up of 11.7 years. Cox regression models with age as the underlying time metric were used to estimate hazard ratios (HR) and their 95% confidence intervals (CI) for quintiles of cholesterol levels and per 1 mmol/l, adjusting for age at first measurement, body mass index (BMI), and smoking status. Estimates were corrected for regression dilution bias. Furthermore, we performed lag time analyses, excluding different times of follow-up, in order to check for reverse causation.

RESULTS: In men, compared with the 1st quintile, TSC concentrations in the 5th quintile were borderline significantly associated with decreasing risk of total cancer (HR = 0.94; 95%CI: 0.88, 1.00). Significant inverse associations were observed for cancers of the liver/intrahepatic bile duct (HR = 0.14; 95%CI: 0.07, 0.29), pancreas cancer (HR = 0.52, 95% CI: 0.33, 0.81), non-melanoma of skin (HR = 0.67; 95%CI: 0.46, 0.95), and cancers of the lymph-/hematopoietic tissue (HR = 0.68, 95%CI: 0.54, 0.87). In women, hazard ratios for the 5th quintile were associated with decreasing risk of total cancer (HR = 0.86, 95%CI: 0.79, 0.93) and for cancers of the gallbladder (HR = 0.23, 95%CI: 0.08, 0.62), breast (HR = 0.70, 95%CI: 0.61, 0.81), melanoma of skin (HR = 0.61, 95%CI: 0.42, 0.88), and cancers of the lymph-/hematopoietic tissue (HR = 0.61, 95%CI: 0.44, 0.83).

CONCLUSION: TSC was negatively associated with risk of cancer overall in females and risk of cancer at several sites in both males and females. In lag time analyses some associations persisted, suggesting that for these cancer sites reverse causation did not apply.

 

[Michael Scally MD]

Clinical Cancer Advances 2012: ASCO’s Annual Report on Progress Against Cancer
http://www.cancerprogress.net/pdf/CCA_2012.pdf

Cancer reviews the year’s most important clinical cancer research. This unique report describes the most significant advances of the year, showcasing the achievements, trends and challenges in oncology today.

 

[Michael Scally MD]

Blood test tracks cancer
Monitoring tumour DNA shows promise for following progress of disease.
Blood test tracks cancer : Nature News & Comment


Dawson S-J, Tsui DWY, Murtaza M, et al. Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer. New England Journal of Medicine. MMS: Error

BACKGROUND - The management of metastatic breast cancer requires monitoring of the tumor burden to determine the response to treatment, and improved biomarkers are needed. Biomarkers such as cancer antigen 15-3 (CA 15-3) and circulating tumor cells have been widely studied. However, circulating cell-free DNA carrying tumor-specific alterations (circulating tumor DNA) has not been extensively investigated or compared with other circulating biomarkers in breast cancer.

METHODS - We compared the radiographic imaging of tumors with the assay of circulating tumor DNA, CA 15-3, and circulating tumor cells in 30 women with metastatic breast cancer who were receiving systemic therapy. We used targeted or whole-genome sequencing to identify somatic genomic alterations and designed personalized assays to quantify circulating tumor DNA in serially collected plasma specimens. CA 15-3 levels and numbers of circulating tumor cells were measured at identical time points.

RESULTS - Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) in whom somatic genomic alterations were identified; CA 15-3 and circulating tumor cells were detected in 21 of 27 women (78%) and 26 of 30 women (87%), respectively. Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%).

CONCLUSIONS - This proof-of-concept analysis showed that circulating tumor DNA is an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer.

 

[Michael Scally MD]

Arcaro A. Targeting the insulin-like growth factor-1 receptor in human cancer. Front Pharmacol 2013;4:30. Frontiers | Targeting the insulin-like growth factor-1 receptor in human cancer | Frontiers in Pharmacology of Anti-Cancer Drugs

The insulin-like growth factor (IGF) signaling system plays a crucial role in human cancer and the IGF-1 receptor (IGF-1R) is an attractive drug target against which a variety of novel anti-tumor agents are being developed. Deregulation of the IGF signaling pathway frequently occurs in human cancer and involves the establishment of autocrine loops comprising IGF-1 or IGF-2 and/or IGF-1R over-expression. Epidemiologic studies have documented a link between elevated IGF levels and the development of solid tumors, such as breast, colon, and prostate cancer. Anti-cancer strategies targeting the IGF signaling system involve two main approaches, namely neutralizing antibodies and small molecule inhibitors of the IGF-1R kinase activity. There are numerous reports describing anti-tumor activity of these agents in pre-clinical models of major human cancers. In addition, multiple clinical trials have started to evaluate the safety and efficacy of selected IGF-1R inhibitors, in combination with standard chemotherapeutic regimens or other targeted agents in cancer patients. In this mini review, I will discuss the role of the IGF signaling system in human cancer and the main strategies which have been so far evaluated to target the IGF-1R.

 

[Michael Scally MD]

The Wild Story Behind A Promising Experimental Cancer Drug
The Wild Story Behind A Promising Experimental Cancer Drug - Forbes

 

[Michael Scally MD]

Loven J, Hoke HA, Lin CY, et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 2013;153(2):320-34. Cell - Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers

Chromatin regulators have become attractive targets for cancer therapy, but it is unclear why inhibition of these ubiquitous regulators should have gene-specific effects in tumor cells. Here, we investigate how inhibition of the widely expressed transcriptional coactivator BRD4 leads to selective inhibition of the MYC oncogene in multiple myeloma (MM). BRD4 and Mediator were found to co-occupy thousands of enhancers associated with active genes. They also co-occupied a small set of exceptionally large super-enhancers associated with genes that feature prominently in MM biology, including the MYC oncogene. Treatment of MM tumor cells with the BET-bromodomain inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent transcription elongation defects that preferentially impacted genes with super-enhancers, including MYC. Super-enhancers were found at key oncogenic drivers in many other tumor cells. These observations have implications for the discovery of cancer therapeutics directed at components of super-enhancers in diverse tumor types.


Floyd SR, Pacold ME, Huang Q, et al. The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. Nature 2013;498(7453):246-50. http://www.nature.com/nature/journal/v498/n7453/full/nature12147.html

DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation-induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage.


Anand P, Brown Jonathan D, Lin Charles Y, et al. BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure. Cell 2013;154(3):569-82. Cell - BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure

Heart failure (HF) is driven by the interplay between regulatory transcription factors and dynamic alterations in chromatin structure. Pathologic gene transactivation in HF is associated with recruitment of histone acetyl-transferases and local chromatin hyperacetylation. We therefore assessed the role of acetyl-lysine reader proteins, or bromodomains, in HF. Using a chemical genetic approach, we establish a central role for BET family bromodomain proteins in gene control during HF pathogenesis. BET inhibition potently suppresses cardiomyocyte hypertrophy in vitro and pathologic cardiac remodeling in vivo. Integrative transcriptional and epigenomic analyses reveal that BET proteins function mechanistically as pause-release factors critical to expression of genes that are central to HF pathogenesis and relevant to the pathobiology of failing human hearts. This study implicates epigenetic readers as essential effectors of transcriptional pause release during HF pathogenesis and identifies BET coactivator proteins as therapeutic targets in the heart.

 

[Michael Scally MD]

Highlights
• High dietary sugar enhances Ras/Src-mediated transformation in Drosophila
• Ras/Src-activated tumors evade diet-mediated insulin resistance
• Insulin resistance evasion is due to Wingless-mediated insulin receptor upregulation
• Rational targeting of multiple pathways can reduce diet-enhanced tumors

Hirabayashi S, Baranski Thomas J, Cagan Ross L. Transformed Drosophila Cells Evade Diet-Mediated Insulin Resistance through Wingless Signaling. Cell 2013;154(3):664-75. Cell - Transformed Drosophila Cells Evade Diet-Mediated Insulin Resistance through Wingless Signaling

The risk of specific cancers increases in patients with metabolic dysfunction, including obesity and diabetes.

Here, we use Drosophila as a model to explore the effects of diet on tumor progression. Feeding Drosophila a diet high in carbohydrates was previously demonstrated to direct metabolic dysfunction, including hyperglycemia, hyperinsulinemia, and insulin resistance.

We demonstrate that high dietary sugar also converts Ras/Src-transformed tissue from localized growths to aggressive tumors with emergent metastases. Whereas most tissues displayed insulin resistance, Ras/Src tumors retained insulin pathway sensitivity, increased the ability to import glucose, and resisted apoptosis. High dietary sugar increased canonical Wingless/Wnt pathway activity, which upregulated insulin receptor gene expression to promote insulin sensitivity.

The result is a feed-forward circuit that amplified diet-mediated malignant phenotypes within Ras/Src-transformed tumors. By targeting multiple steps in this circuit with rationally applied drug combinations, we demonstrate the potential of combinatorial drug intervention to treat diet-enhanced malignant tumors.

 

[Michael Scally MD]

Looking for lessons in cancer's 'miracle' responders
http://www.reuters.com/article/2013/09/15/us-cancer-superresponders-idUSBRE98E07420130915

 

[Michael Scally MD]

American Association for Cancer Research Progress Report 2013

Cancer will soon surpass heart disease as the Number One disease-related killer in the U.S. soon unless research is able to churn out more cures, the American Association for Cancer Research said Tuesday.

With 75% of cancer diagnoses occurring in those age 55 and over and with this segment of the population increasing, the number of cancer-related deaths will increase dramatically as baby boomers age.

The global incidence of cancer is expected to increase from 12.8 million in 2008 to 22.2 million in 2030, the report stated.

The rise in cancer prevalence is also tied to troublesome lifestyle issues such as tobacco use, obesity, diet, lack of physical activity, and tanning beds. AACR said half of cancer deaths are related to these preventable causes.

American Association for Cancer Research. AACR Cancer Progress Report 2013. Clin Cancer Res 2013;19(Supplement 1):S1-S86. http://cancerprogressreport.org/2013/Documents/2013_AACR_CPR_FINAL.pdf

 

[Michael Scally MD]

Heritability and Familial Risk of Cancer: An Update from The Nordic Twin Registry Of Cancer (NorTwinCan).
http://www.ashg.org/2013meeting/abstracts/fulltext/f130123547.htm

Background. The landmark study by Lichtenstein et al in 2000 estimated cancer heritability using unique twin cohorts from the Nordic countries. We updated analyses within the Nordic Twin Registry of Cancer (NorTwinCan), expanding the original cohort, adding 10 years of follow-up and increasing number of cancer cases 3-fold to provide precise estimates of heritability and familial cancer risk.

Methods. NorTwinCan includes 133,689 monozygotic (MZ) and dizygotic (DZ) twin pairs (N=267,378 total) from nationwide registries in Denmark, Finland, Norway and Sweden. We incorporate novel time-to-event analyses to estimate the concordance risk and heritability (95%; Confidence Intervals, CI) for 23 unique malignancies, with follow-up from cancer registration and accounting for censoring and competing risks of death through 2009.

Results. During a median 40 year follow-up, 29,599 cancer cases were diagnosed.

The heritability (95% CI) for prostate cancer was 58% (52-63%), the highest of any malignancy. The risk of prostate cancer in a twin given his cotwin also had prostate cancer (concordance risk) was 32%; in MZ and 16%; in DZ twins.

For breast cancer among women, the difference in concordance between MZ (29%) and DZ (21%) twins was smaller, and heritability was 28%; (12-52%).

There were notable differences in findings for colon and rectal cancer: the data supported a significant genetic component to colon cancer (16%, 2-63%) but not for rectal cancer.

For testicular cancer, with a cumulative incidence of 0.4% in the population, the concordance risk was substantial amongst MZ (23%) and DZ (11%) twins, with heritability of 36% (2-95%).

Estimates of heritability (95% CI) were also significant for kidney (23%, 11-42%), lung (25%, 12-44%), melanoma (39%, 8-81%), ovarian cancer (28%, 15-47%), stomach (24%, 5-65%), and uterine cancer (24%, 14-87%).

Discussion. This expanded analysis in NorTwinCan provides more precise estimates of familial risk and heritability in cancer. Estimates of heritability for prostate cancer are even greater than previously estimated. For rare cancers such as testicular, the concordance risk was substantial and provides an accurate estimate for familial risk prediction. Twin studies can also provide context for genome wide association studies.

 

[Michael Scally MD]

What is the price of a happy marriage, a secure family, and a network of well-connected friends within our communities today?

Researchers present noteworthy findings in the article that accompanies this editorial, which suggest that being single, separated, divorced, or widowed significantly increases the risk of oncologic presentation with already metastatic cancer, reduced adherence to state-of-the-art treatment, and greater likelihood of earlier death from this cancer.

On the basis of the National Cancer Institute's SEER Medicare data from 734,889 contemporary Americans (2004 to 2008), these incontrovertible data come from the 10 leading cancers, apply to both men and women, and create profound implications for our models of cancer care.

Strikingly, the benefits of marriage are comparable to or greater than anticancer treatment with chemotherapy.

Kissane DW. Marriage Is As Protective As Chemotherapy in Cancer Care. Journal of Clinical Oncology 2013;31(31):3852-3. http://jco.ascopubs.org/content/31/31/3852.full


Aizer AA, Chen M-H, McCarthy EP, et al. Marital Status and Survival in Patients With Cancer. Journal of Clinical Oncology 2013;31(31):3869-76. http://jco.ascopubs.org/content/31/31/3869.full

Purpose To examine the impact of marital status on stage at diagnosis, use of definitive therapy, and cancer-specific mortality among each of the 10 leading causes of cancer-related death in the United States.

Methods We used the Surveillance, Epidemiology and End Results program to identify 1,260,898 patients diagnosed in 2004 through 2008 with lung, colorectal, breast, pancreatic, prostate, liver/intrahepatic bile duct, non-Hodgkin lymphoma, head/neck, ovarian, or esophageal cancer. We used multivariable logistic and Cox regression to analyze the 734,889 patients who had clinical and follow-up information available.

Results Married patients were less likely to present with metastatic disease (adjusted odds ratio [OR], 0.83; 95% CI, 0.82 to 0.84; P < .001), more likely to receive definitive therapy (adjusted OR, 1.53; 95% CI, 1.51 to 1.56; P < .001), and less likely to die as a result of their cancer after adjusting for demographics, stage, and treatment (adjusted hazard ratio, 0.80; 95% CI, 0.79 to 0.81; P < .001) than unmarried patients. These associations remained significant when each individual cancer was analyzed (P < .05 for all end points for each malignancy). The benefit associated with marriage was greater in males than females for all outcome measures analyzed (P < .001 in all cases). For prostate, breast, colorectal, esophageal, and head/neck cancers, the survival benefit associated with marriage was larger than the published survival benefit of chemotherapy.

Conclusion Even after adjusting for known confounders, unmarried patients are at significantly higher risk of presentation with metastatic cancer, undertreatment, and death resulting from their cancer. This study highlights the potentially significant impact that social support can have on cancer detection, treatment, and survival.

 

[Michael Scally MD]

In cancer science, many "discoveries" don't hold up
http://www.reuters.com/article/2012/03/28/us-science-cancer-idUSBRE82R12P20120328

(Reuters) - A former researcher at Amgen Inc has found that many basic studies on cancer -- a high proportion of them from university labs -- are unreliable, with grim consequences for producing new medicines in the future.

During a decade as head of global cancer research at Amgen, C. Glenn Begley identified 53 "landmark" publications -- papers in top journals, from reputable labs -- for his team to reproduce. Begley sought to double-check the findings before trying to build on them for drug development.

Result: 47 of the 53 could not be replicated. He described his findings in a commentary piece published on Wednesday in the journal Nature.

 

[Michael Scally MD]

A Blood Test for Cancer

A blood test that detects tiny amounts of DNA shed by tumors could be used to screen for cancer. The test spotted tumor DNA in many of more than 600 cancer patients, although it worked better for some types of cancer and more advanced disease.

Cancer evolves over time, without any warning signs. Similarly, the development of resistance to therapy generally becomes apparent only when there are obvious signs of tumor growth, at which point the patient may have lost valuable time. Although a repeat biopsy may be able to identify drug-resistant mutations before the tumor has a chance to regrow, it is usually not feasible to do many repeat biopsies.

Researchers showed that sampling a patient’s blood may be sufficient to yield information about the tumor’s genetic makeup, even for many early-stage cancers, without a need for an invasive procedure to collect tumor tissue, such as surgery or endoscopy. The authors demonstrated the presence of circulating DNA from many types of tumors that had not yet metastasized or released detectable cells into the circulation.

They could detect more than 50% of patients across 14 tumor types at the earliest stages, when these cancers may still be curable, suggesting that a blood draw could be a viable screening approach to detecting most cancers. They also showed that in patients with colorectal cancer, the information derived from circulating tumor DNA could be used to determine the optimal course of treatment and identify resistance to epidermal growth factor receptor (EGFR) blockade.

Thus study shows the effectiveness of analyzing circulating DNA from a variety of tumors and highlight the potential investigational and clinical applications of this novel technology for early detection, monitoring resistance, and devising treatment plans to overcome resistance.

Bettegowda C, Sausen M, Leary RJ, et al. Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies. Science Translational Medicine 2014;6(224):224ra24. http://stm.sciencemag.org/content/6/224/224ra24.abstract

The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction–based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types.

We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities.

In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%.

Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway.

Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.