Equivalence Ratio for Daunorubicin to Doxorubicin in Relation to Late Heart Failure in Survivors of Childhood Cancer

Feijin A (2015), Journal of Clinical Oncology (Link to abstract)

The differential risk for cardiotoxicity between daunorubicin and doxorubicin has not been rigorously evaluated among childhood cancer survivors but based on hematologic toxicity has been assumed to be approximately equivalent.  Here the authors report data from 7,387 survivors; 5,144 who received doxorubicin and 2,243 who received daunorubicin, with a median follow up of 17.3 years and a cumulative incidence of heart failure at age 40 years of 3.2 %.  They found the average ratio of HRs for daunorubicin to doxorubicin to be 0.45 (95% CI, 0.23 to 0.73).

* Compared with doxorubicin, daunorubicin is less cardiotoxic among childhhod cancer survivors than most current guidelines suggest. This has implications for treatment protocols in terms of reducing cardiotoxicity as well as follow up guidelines

RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics

Best J, 2015, Cancer Cell (Link to abstract)        

It has been previously established that mRNA expression and splicing in platelets is affected by their interactions with other cells. This group hypothesized that they could detect cancer by examining platelet mRNA. Using next generation sequencing they found a high (>97%) sensitivity and specificity for detecting cancer in general using platelet mRNA. With less accuracy they were also able to discriminate between different carcinoma types. There is also some ability to detect canonical mutations using this method such as KRAS mutations in colorectal cancer.

* “Liquid biopsies” are going to be a clinical thing in the near future. Whether they come in the form of plasma “cell free DNA” tests, circulating tumor cells, or this technique using platelet mRNA, you will see likely see them in your practice soon.

Relapse After Localized Rhabdomyosarcoma: Evaluation of the Efficacy of Second-Line Chemotherapy

Winter, S (2015), Pediatric Blood & Cancer (Link to abstract)

This is a retrospective multi-centre analysis performed in France, analyzing the efficacy of various second line regimens in children with relapsed locoregional RMS. 49 children were included who were treated between 1995 and 2013. At relapse, the chemotherapy regimen was at the physician’s discretion.  Overall response rate to second line chemo was 39.1%, 5 year OS was 49%. Response rates to various regimens are as follows: CEV/IVE: 11/15 patients: 73.3%, VI[T]: given to 7 patients: 42.9%, IVA/VAC: 0%.  Receipt of doxorubicin upfront is associated with poorer outcomes at relapse.  Local control was the most important factor in survival.

* It is important to note that salvage rates in Europe may appear higher than in North America because radiotherapy is sometimes used as salvage treatment rather than upfront. Alternatives like oral etoposide can also be used, and in practice sometimes patients receive maintenance chemotherapy with cyclophosphamide/vinorelbine after initial therapy. There is still no standard and local control remains vital.

Poly-ADP-Ribose Polymerase as a Therapeutic Target in Pediatric Diffuse Intrinsic Pontine Glioma and Pediatric High-Grade Astrocytoma

Chornenkyy, Y  (2015) Molecular Cancer Therapeutics  (Link to Abstract)

This is a preclinical study (from HSC) looking at PARP (poly-ADP-ribose polymerase) expression and inhibition in DIPG and pHGA.  Using cell culture, tissue microarray, immunohistochemistry and Western Blotting, they found that PARP1 protein is expressed in pHGA and DIPG patient samples and cell lines - 85% of pHGAs and 76% of DIPG tissue microarray samples expressed PARP.  Also they found that Niraparib (an oral PARP inhibitor that has been tested in adult cancer phase 3 trials) is more effective at reducing tumor cell growth than veliparib or olaparib using cell viability kits and colony forming assays.  Niraparib was also shown to cause DNA damage and reduce cell proliferation. Pretreatment with this prior to 2 Gy ionizing radiation decreased DNA damage repair and relative cell count.  In mice xenografts, Niraparib inhibited PARP1 activity and extended the survival of mice pre-treated with Niraparib before IR by 60% (40 vs. 25 days). 

*PARP is demonstrated to be a therapeutic target in DIPG and pHGA.  This study is preclinical rationale for Niraparib, an oral PARP inhibitor, to be further investigated as a radiosensitizer prior to radiation in patients with DIPG and pediatric high-grade astrocytoma.

Inhibition of MEK confers hypersensitivity to X‐radiation in the context of BRAF mutation in a model of childhood astrocytoma

Studebaker, A. Pediatric Blood and Cancer (2015) (Link to abstract)

This study explores the use of a MEK inhibitor in combination with ionizing radiation (XRT) in a model of BRAF- mutant anaplastic astrocytoma. The effect of MEK inhibition (selumetinib), XRT or the combination of both was evaluated in subcutaneous BRAF mutant xenografts. Inhibition of MEK signaling in BRAF mutant cells or in xenografts lead to complete suppression of FANCD2 and conferred hypersensitivity to XRT in BRAF mutant xenografts without increasing local skin toxicity.

*In the context of mutant BRAF in recurrent gliomas of childhood or anaplastic astrocytoma there is a possibility of potentiating XRT effects selectively in tumour cells by using MEK inhibition. This may allow reduced dosing of XRT and consequently reduced late effects.

Secreted Frizzled-Related Protein 3 (SFRP3) is Required for Tumorigenesis of PAX3-FOX01-Positive Alveolar Rhabdomyosarcoma

Kephart (2015) Clin Can Research (Link to abstract)            

In this study, negative regulators of the Wnt pathway were found to be upregulated in an expression array of myoblasts expressing the PAX3-FOXO1 fusion transcript. In particular, a gene called SFRP3 was upregulated and appears to play a key role. In several functional tests this protein was confirmed to be important both for proliferation of alveolar rhabdomyosarcoma (aRMS) cells and for downregulation of the Wnt pathway within those cells. An aRMS xenograft with a suppressible SFRP3 overexpression was established in mice. 5/7 of these mice showed no detectable tumor at necropsy when SFRP3 was suppressed and treatment with vincristine was also given.

*This study establishes the Wnt pathway and upreguation of SFRP3 in particular as a potential key process in translocation positive aRMS. This may open the door for a targeted treatment in this difficult disease.


Different outcomes for relapsed versus refractory neuroblastoma after therapy with 131I-metaiodobenzylguanidine (131I-MIBG)

Zhou MJ, Eur J Cancer (2015) (Link to Abstract)

Retrospective cohort analysis of 218 patients with refractory or relapsed neuroblastoma treated with 131I-MIBG at UCSF, San Francisco between 1996 and 2014. No significant difference in overall response rates to 131I-MIBG between patients with relapsed versus refractory neuroblastoma was seen. However, in terms of site, residual soft tissue disease a significantly have better response to 131 I-MIBG on univariate analysis compared to other sites like bone and bone marrow.

Patients with prior relapse had higher rates of progressive disease and had lower 2-year overall survival after 131I-MIBG compared to patients with refractory disease. Results showed that with 131I-MIBG, 24% of relapsed patients had progressive disease compared to only 9% of refractory patients, and 39% of relapsed patients had stable disease compared to 59% of refractory patients (p = 0.02). The 24-month OS for refractory patients was significantly higher with 65.3% compared to 38.7% for relapsed patients (p < 0.001).

*No firm conclusion can be drawn, however early start of MIBG therapy in refractory cases especially with soft tissue residual disease had better short term survival rates compared to relapsed cases in this cohort.

Dual Targeting of the Autophagic Regulatory Circuitry in Gliomas with Repurposed Drugs Elicits Cell-Lethal Autophagy and Therapeutic Benefit

Shchors K, 2015, Cancer Cell (Link to Abstract)

This publication outlines multiple related and progressive experiments. Firstly, the authors found that tricyclic antidepressants (TCA) can reduce the progression of low grade gliomas to GBM in a mouse model but does not change the progression or survival in mice who present with GBM. Then, an in-vitro assay measuring proteins generally degraded by autophagy found that TCAs promote autophagy in glioma cells. A high-throughput screen was then done to find a complementary drug that could accentuate the regulatory effect of TCAs on autophagy. Ticlopidine – an anti-platelet agent – had the best activity in this screen through its inhibition of P2Y12 which upregulates cAMP and promotes autophagy. They finally tested the combination of these drugs in various in-vitro and in-vivo model finding positive effects on autophagy and increased tumor killing and animal survival.

*Since GBM is so notoriously difficult to treat, inventive studies are needed. Approaches such as this one that target relatively uninvestigated biological pathways using drugs with already-established safety profiles that are off-patent is a promising way to get new effective treatments to clinic quickly.

Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein

Salanti A, 2015, Cancer Cell (Link to abstract)

Malaria forces erythrocytes to express a protein that binds to a proteoglycan found specifically on placenta which helps to avoid clearance in the spleen. This group found that most carcinomas and sarcomas have this same placental proteoglycan on their surface but that it is rarely found in other normal tissue. The group engineered a recombinant version of the malarial protein and it effectively targeted malignant cells with this surface marker. They then fused this protein to diphtheria toxin and found significant tumor killing effect in a variety of tumors. They have now developed a drug based on this concept called VDC886 that they have tested in mice.

*This is a totally new approach to targeting more than one cancer type. There is now a new promising drug that is yet to enter the trial pipeline. We now also know about a surface marker specific to malignancy that can be stained for diagnostic purposes.

Germ cell cancer and multiple relapses: toxicity and survival

Lauritsen J, 2015, Journal of Clinical Oncology (Link to abstract)

This paper looks at the toxicities experienced by the small number of adult patients with extracranial GCTs who receive more than one line of treatment for disseminated disease as well as their overall survival.  It is a retrospective cohort study of 268 patients from Denmark.  The comparator group were patients with GCT who were treated with only one line of therapy or with surgery only. 

The authors report that approximately half of patients requiring more than one line of therapy die of their disease and that for the survivors there is significant increased risk of second cancer, major cardiovascular disease, renal impairment, neurological disorders and death as a result of other causes at median follow up of only 10.8 years.

*There is a high risk of subsequent relapse, secondary malignancy, and other late effects in patients treated for refractory GCT. These results could also apply to our adolescent population.

High Prevalence of Hereditary Cancer Syndromes in Adolescents and Young Adults with Colorectal Cancer

Mark M, 2015, Journal of Clinical Oncology (Link to abstract)

This retrospective cohort study from MD Anderson evaluated 193 patients with colorectal cancer who underwent genetic counselling over a 5 year period.  They identified 35 % of these patients to have an identifiable hereditary cancer syndrome.  Whilst patients with a cancer syndrome were more likely to present at earlier stages and have a family history of cancer, 19 % of the hereditary syndromes were found in individuals with no family history.

*Refer ALL adolescents with colorectal cancer for genetic counselling regardless of family history or phenotype!

Cardiovascular mortality after chemotherapy or surgery for testicular nonseminoma: A population based study

Fung C, 2015, Journal of Clinical Oncology (Link to abstract)

This European population-based study quantifies the CVD mortality amongst 15,006 men with testicular non-seminoma over a 30 year period (1980-2010) when cisplatin-based chemotherapy became widely adopted.  The authors report a significantly increased CVD mortality after chemotherapy (Standardized Mortality Ratio 1.36) but not surgery.  In particular they note a significant excess of deaths in the first year after diagnosis (SMR 5.31) and included cerebrovascular disease (SMR 3.45) and heart disease (SMR 3.45), with distant disease and older age being identified as risk factors.

*Think about possibility of CVD in our TYA population with metastatic testicular GCTs even early post chemotherapy, particularly those with identifiable risk factors.  Remember VTE prophylaxis.

Review: Renal Medullary Carcinoma and Sickle Cell Trait: A Systematic Review Alvarez, O. Pediatr Blood Cancer 2015 (Link to abstract) This is a review of RMC which occurs almost exclusively in people with sickle cell trait or sickle cell disease. Whilst

Alvarez, O. Pediatr Blood Cancer 2015 (Link to abstract)

This is a review of RMC which occurs almost exclusively in people with sickle cell trait or sickle cell disease. Whilst the majority of the time hematuria does not represent RMC in these patients, they should be counselled that this is a symptom that warrants further investigation. Mortality may be as high as 95%.

Diagnostic and prognostic value of 18F-DOPA PET and 1H-MR spectroscopy in pediatric supratentorial infiltrative gliomas: a comparative study

Morana, G (2015), Neuro-Oncology (Link to abstract)

Retrospective review of pediatric patients with supratentorial gliomas or non-neoplastic lesions suspected to be gliomas based on initial MRI. Pts had MRI spectroscopy (MRS) and 18F-DOPA PET within 2 weeks. (Spectroscopy estimates levels of different metabolites, DOPA chosen as uptake of amino acid analogs less in normal brain and uniform in tumor whether enhancing component or not).  Twenty-seven patients enrolled aged 4-17 years, 21 with gliomas and 6 with non-neoplastic lesions.  Median follow up was 19 months. For PET, sensitivity was 78% (5 false negatives), specificity 83% (1 false positive), accuracy 78%.  For MRS, sensitivity was 95% (1 false negative), specificity 83% (1 false positive), accuracy 93%.  False negatives for PET and MRS were LGG, and false positive were encephalitis. Statistically significant difference in uptake of DOPA found between HGG and LGG, also seen with choline peaks on MRS, but the difference was lower with MRS. DOPA uptake was also found to be an independent predictor of survival on multivariate analysis. Authors concluded that MRS was better for distinguishing glioma from non-neoplastic lesions as it is more widely available, cheaper and does not involve radiation. DOPA-PET was best for distinguishing low-grade from high-grade lesion.

* In the future, non-invasive imaging techniques such as PET and MR spectroscopy may be able to predict pathology and prognosis of brain tumors, specifically gliomas. Biopsy may still be required though, as molecular information to inform potential targeted therapy is becoming more important.

Spatiotemporal Evolution of the Primary Glioblastoma Genome

Kim et al, 2015 Cancer Cell                         

Link to abstract: http://www.cell.com/cancer-cell/abstract/S1535-6108(15)00265-2

Kim et al examined 38 pairs of primary and relapsed GBMs using CGH-array, whole exome sequencing, and RNA Seq. They found that distant relapses had a much more divergent mutation profile compared to local relapses. It has also been previously known that IDH1 mutant tumors (usually progressed from LGG) have a hypermutation profile at relapse if initially treated with temozolamide. Kim et al confirmed this finding but also found that it does not hold true for IDH1 wild type tumors.

*You can read an excellent summary of this paper in the same issue by Vijay Ramaswamy and Michael Taylor (see http://www.cell.com/cancer-cell/abstract/S1535-6108(15)00301-3).

ABCG2 Transporter Expression Impacts Group 3 Medulloblastoma Response to Chemotherapy

Morfuace et al, 2015 Cancer Research                   

Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/26199091

ABC membrane transporters have been implicated in several tumors as conferring chemotherapy-resistance by expelling the drug from the cell. Group 3 medulloblastoma is known to be particularly difficult to treat with current therapy. This group showed that ABC group 2 transporters have increased expression in both human and mouse group 3 medulloblastoma cells and this expression decreased in vitro response to 11/12 chemotherapeutic agents.

*In a mouse model they showed that blockade of ABCG2 using Ko143 increased tumor susceptibility to topotecan and the combination of these two drugs produced the longest survival time (compared to each individually).

Real-time Imaging of the Resection Bed Using a Handheld Probe to Reduce Incidence of Microscopic Positive Margins in Cancer Surgery

Erickson-Bhatt et al, 2015 Cancer Research                        

Link to abstract: http://www.ncbi.nlm.nih.gov/pubmed/26374464

This group developed a handheld probe that uses Optical Coherence Tomography (OCT) to try to differentiate between malignant and normal tissue in a surgical bed and a resection specimen (based on how organized the tissue appears) in an attempt to guide the surgeon as to the extent of resection. They tested the device in 35 breast surgery cases but did not suggest a change in management based on the findings. Histological assessment of the resection specimen was used as the gold standard.

*The sensitivity and specificity of this device for detecting positive margins were 91.7% (62.5% - 100%) and 92.1% (78.4% - 98%) respectively.

Durability of Kinase-Directed Therapies—A Network Perspective on Response and Resistance

Murray et al, 2015 Molecular Cancer Therapeutics                                          

Link to abstract: http://mct.aacrjournals.org/content/14/9/1975.abstract?sid=b737b689-2fe8-4813-95b7-d36f1bafd756

Protein kinase directed cancer therapies are being used more and more, but have issues with poor clinical response (“innate resistance”) or disease relapse (“acquired or secondary resistance).  Examples of these drugs are: sunitinib, dabrafenib, erlotinib, crizotinib and imatinib. 

*This is a review of intrinsic and extrinsic mechanisms of resistance to these drugs and how drug combination therapy can be used to improve outcomes.  

Phase 1 study of Birinapant, a novel SMAC mimetic. Inhibitors of apoptosis (IAP) proteins suppress apoptosis and activate TNF. Overexpression of IAP contributes to tumor chemotherapy resistance. SMAC binds to IAP causing them to degrade and apoptosis to

Amaravadi et al, 2015 Molecular Cancer Therapeutics                                  

Link to abstract: http://mct.aacrjournals.org/content/early/2015/09/02/1535-7163.MCT-15-0475.abstract?sid=a5c93016-4afe-43a8-9272-369a40095dc3

Phase 1 study of Birinapant, a novel SMAC mimetic.  Inhibitors of apoptosis (IAP) proteins suppress apoptosis and activate TNF. Overexpression of IAP contributes to tumor chemotherapy resistance.  SMAC binds to IAP causing them to degrade and apoptosis to occur in tumor cells.

This is the first human study of birinapant. In 50 adults this drug was well tolerated with main side effects of headache, nausea and vomiting. These were patients with relapsed or refractory colorectal, head and neck, lung, and pancreatic cancers, soft tissue sarcomas and melanomas aged 31-58.  The regimen was given iv q 3 weeks, with good PK and PD profile. Transient cytokine release syndrome seen at doses which exceeded the MTD.  Stable disease and anti-tumor activity was noted.

*Further studies will look at combination with other chemotherapy (particularly as it can overcome resistance), and is in phase 2 trials for MDS and ovarian cancer.

Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial

Sandmann T et al, 2015 Journal of Clinical Oncology                                      

Link to abstract: http://jco.ascopubs.org/content/early/2015/06/24/JCO.2015.61.5005.abstract

The previously reported AVAglio (Avastin in Glioblastoma) trial found prolonged progression-free survival (but not overall survival) in adult patients with GBM who had bevacizumab added to radiotherapy plus temozolomide.  This paper is a follow up from that study and looks to determine if certain sub-groups may actually have an OS benefit from adding avastin to first line standard of care.  The authors retrospectively grouped pre-treatment specimens from just over a third of patients enrolled in the study (349/921) using gene expression analysis and IDH1 mutation status.  They found that bevacizumab conferred an OS advantage versus placebo in patients with proneural IDH1 wild-type tumors (17.1 v 12.8 months, respectively; hazard ratio, 0.43; 95% CI, 0.26 to 0.73; P = .002).

*Take home message: With IDH1 mutations seen in 7 of 43 pediatric primary malignant gliomas treated on the Children’s Oncology Group ACNS0423 study (and therefore 36 of 43 WT) it will be interesting/important for us to see if this is validated when the results of the HERBY study are reported (see https://clinicaltrials.gov/ct2/show/NCT01390948).