Genomics and policy news - March 2016 (UK)

March 2016
 

open access: Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer

open access : 
Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer : British Journal of Cancer 

Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer

Abstract : 
Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer : British Journal of Cancer

Background:

Rucaparib is an orally available potent selective small-molecule inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2. Rucaparib induces synthetic lethality in cancer cells defective in the homologous recombination repair pathway including BRCA-1/2. We investigated the efficacy and safety of single-agent rucaparib in germline (g) BRCA mutation carriers with advanced breast and ovarian cancers.

Methods:

Phase II, open-label, multicentre trial of rucaparib in proven BRCA-1/2 mutation carriers with advanced breast and or ovarian cancer, WHO PS 0–1 and normal organ function. Intravenous (i.v.) and subsequently oral rucaparib were assessed, using a range of dosing schedules, to determine the safety, tolerability, dose-limiting toxic effects and pharmacodynamic (PD) and pharmacokinetic (PK) profiles.

British Journal of Cancer - PARP inhibitors: the race is on

PARP inhibitors: the race is on

 A number of other critical questions remain in terms of optimising and widening the clinical efficacy and utility of PARP inhibitors, respectively. Although benefits are observed following PARP inhibitor treatment in patients with a range of tumour types with germline BRCA1/2 mutations (Kaufman et al., 2015), it is now clear that clinical efficacy is not restricted to this niche population of patients.

Table 1 - Table showing the response rates and predominant toxicities for different PARP inhibitors in patients with advanced ovarian cancer.

Genetic testing for Lynch syndrome in the province of Ontario

abstract
 

BACKGROUND

In November 2001, genetic testing for Lynch syndrome (LS) was introduced by the Ministry of Health and Long-Term Care (MOH) in Ontario for individuals at high risk for LS cancers according to either tumor immunohistochemistry staining or their family history. This article describes the outcomes of the program and makes recommendations for improving it and informing other public health care programs.

METHODS

Subjects were referred for molecular testing of the mismatch repair (MMR) genes MutL homolog 1, MutS homolog 2, and MutS homolog 6 if they met 1 of 7 MOH criteria. Testing was conducted from January 2001 to March 2015 at the Molecular Diagnostic Laboratory of Mount Sinai Hospital in Toronto.

RESULTS

A total of 1452 subjects were tested. Of the 662 subjects referred for testing because their tumor was immunodeficient for 1 or more of the MMR genes, 251 (37.9%) carried a germline mutation. In addition, 597 subjects were tested for a known family mutation, and 298 (49.9%) were positive; 189 of these 298 subjects (63.4%) were affected with cancer at the time of testing. An additional 193 subjects were referred because of a family history of LS, and 34 of these (17.6%) had a mutation identified.

CONCLUSIONS

These results indicate that the provincial criteria are useful in identifying LS carriers after an MMR-deficient tumor is identified. Placing greater emphasis on testing unaffected relatives in families with a known mutation may identify more unaffected carriers and facilitate primary prevention in those individuals. 

What is the Asian Consensus Statement on NCCN clinical practice guidelines in oncology (NCCN-ACS)?

abstract

Cancer treatment guidelines are compiled on the basis of established evidence. Such evidence is obtained from epidemiological, pathological and pharmacological study and, most importantly of all, the information gained from clinical trials. However, very little of the kind of evidence that is required for the compilation of treatment guidelines is actually obtained from Asian countries. When one considers the ethnic differences and disparities in medical care, coupled with the tremendous cultural diversity that characterize the Asian region, it would be difficult to conclude that there is currently sufficient evidence that could form the basis for the formulation of guidelines that would be relevant and applicable to all Asian countries. An urgent issue that needs to be addressed in order to achieve a breakthrough in this difficult situation is to build up a body of evidence at an advanced level that is specific to the Asian region and Asian ethnicities. For the interim, however, it is also necessary to efficiently incorporate evidence that has been obtained in Western countries. Furthermore, an effective method of utilizing guidelines that have already been compiled in Western countries is considered to be not by simply translating them into local languages, but rather to engage in a process of adaptation, whereby the guidelines are adjusted or modified to match the circumstances of a particular country or region. The NCCN Clinical Practice Guidelines-Asian Consensus Statement (NCCN-ACS) documents have been compiled with this intention in mind, utilizing the NCCN guidelines that are widely used internationally. 

Wide Variation Found In Consumer Blood Tests (science news)

sciences news and update

JCI - Evaluation of direct-to-consumer low-volume lab tests in healthy adults

JCI - open access



.....Direct-to-consumer service models now provide means for individuals to obtain laboratory testing outside traditional health care settings (4, 5). One company implementing this new model is Theranos, which offers a blood testing service that uses capillary tube collection and promises several advantages over traditional venipuncture: lower collection volumes (typically ≤150 μl versus ≥1.5 ml), convenience, and reduced cost — on average about 5-fold less than the 2 largest testing laboratories in the USA (Quest and LabCorp) (8). However, availability of these services varies by state, where access to offerings may be more or less restrictive according to state-level health care regulations. Furthermore, Theranos is a private company, and the technical details of their test procedures and processes are not available to the public.
Despite its commercial availability and technological promise, the Theranos collection system has not yet been evaluated through independent, rigorous, and publicly disclosed peer-review (9). To encourage transparency and rigorous scientific review of clinical laboratory testing procedures, we conducted a cohort study of 60 individuals from July 27, 2015, to July 31, 2015, to compare the accuracy and equivalency of clinical laboratory test blood collected via finger prick and tested at Theranos against traditional venipuncture, followed by laboratory testing offered through Quest Diagnostics and LabCorp.....

Paradigm Shift in Ovarian Cancer Points to Fallopian Tube as Site of Origin

article

.....The decade-long paradigm shift in decoding ovarian cancer is only now beginning to make its way from research journals into clinical practice.
These changes will have a tremendous effect on the management of ovarian cancer, which is still treated as a single disease.
That's the conclusion of Ronny Drapkin, MD, PhD, the Franklin Payne Chair in Gynecologic Oncology and director of the Penn Ovarian Cancer Research Center at the University of Pennsylvania Perelman School of Medicine in Philadelphia......

....Pointing out that only 59% of cases of ovarian cancer are detected by screening plus ultrasound, “we must and can focus on mechanisms of early cancer detection,” René H M Verheijen and Ronald P. Zweemer, of the Department of Gynaecological Oncology, Division of Surgical Oncology, UMC Utrecht Cancer Center, Utrecht, Netherlands, commented in The Lancet regarding the UKCTOCS trial.³
However, “awareness and symptom recognition for diagnosis of ovarian cancer at an early stage will be difficult to improve upon,” they wrote, adding that “screening will not be warranted until the UKCTOCS outcome has been validated in daily practice.”

References

1. Jacobs IJ, Menon U, Ryan A, et al. Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet. 2016;387(10022):945-956.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30.
3. Verheijen RHM, Zweemer RP. Screening to improve ovarian cancer prognosis? Lancet. 2016;387(10022):921-923.

Cancer drugs and the FDA: Safety vs. saving lives (media/ovarian cancer/moonshot)

Miami Herald

  All the cancer doctors interviewed feel encouraged about the Obama administration’s $1 billion “moonshot” to cure cancer — although they’re not sure how much it will mean.

“For the last 10 years, the field has been starved for resources,” DeVita said.

Nimer at Sylvester welcomes the discussion, but “most doctors aren’t going to refer to cures for cancer,” since researchers know cancer is really many diseases with myriad treatment options, and no silver bullet is going to permanently fix all these diseases. In such a context, $1 billion doesn’t go far.
DeVita said that when he referred to 100,000 more people who he believed could be cured each year, he was citing American Cancer Society reports that include all of those who don’t now get proper treatment.
One example: Nimer pointed to a recent New York Times report that less than half of patients with ovarian cancer are getting the recommended care.
Still, Nimer added: “The one message to take away is this: “We’re making incredible progress against cancer.”

Read more here: http://www.miamiherald.com/living/health-fitness/article68177247.html#storylink=cpy

Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations

pdf

  In the present study, we have sequenced 13 additional genes that
have been deemed HBOC susceptibility loci (BARD1, EPCAM,
MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PMS2, PTEN,
RAD51B, STK11, and XRCC2 [Minion et al., 2015]). These genes
encode proteins with roles in DNA repair, surveillance, and cell
cycle regulation (Fig. 1; for further evidence supporting this gene
set see Supp. Table S1 [Apostolou and Fostira, 2013; Al Bakir and
Gabra, 2014]), and are associated with specific disease syndromes
that confer an increased risk of BC and OC, as well as many other
types of cancer (Supp. Table S2).

 EPCAM, MLH1, MSH2, MSH6, and PMS2 have also been
proposed to harbor high-risk BC alleles, but the RR (relative risk) is still controversial
[Maxwell and Domchek, 2013].

 ABSTRACT: 
BRCA1 and BRCA2 testing for hereditary breast and ovarian cancer (HBOC) does not identify all pathogenic variants. Sequencing of 20 complete genes in HBOC patients with uninformative test results (N = 287), including noncoding and flanking sequences of ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, EPCAM, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51B, STK11, TP53,
and XRCC2, identified 38,372 unique variants. We apply information theory (IT) to predict and prioritize noncoding variants of uncertain significance in regulatory,
coding, and intronic regions based on changes in binding sites in these genes. .........When combined with pedigree information, complete gene sequence analysis can focus attention on a limited set of variants in a wide spectrum of functional mutation types for downstream functional and cosegregation analysis.
Hum Mutat 00:1–13, 2016

The Cost-Effectiveness of Bevacizumab in Advanced Ovarian Cancer Using Evidence from the ICON7 Trial - NICE

abstract

Background

Bevacizumab is used extensively in the treatment of cancer, including advanced ovarian cancer, for which results of the International Collaborative Ovarian Neoplasm (ICON) 7 trial have been recently reported. The National Institute for Health and Care Excellence’s (NICE’s) recent decision not to recommend bevacizumab for advanced ovarian cancer was not based on evidence related to the unlicensed lower dosage (7.5 mg/kg) of the drug despite its use in the English National Health Service (NHS) and the ICON7 trial.

Objective

To report on the findings of an analysis that considered whether the lower dose is cost-effective.

The 2nd annual conference of Intl ovarian cancer consortium & symposium on tumor microenvironment & therapeutic resistance

open access
The second annual conference of International ovarian cancer consortium and the symposium on tumor microenvironment and therapeutic resistance
  

Abstract

The second Annual Meeting of the International Ovarian Cancer Consortium (IOCC) was held in conjunction with the Symposium on Tumor Microenvironment and Therapeutic Resistance at the Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, and USA. A brief welcoming event along with the banquet on Aug 16th was followed by the eight thematic scientific sessions from August 16 to 18, 2015. Forty-three lectures, organized in eight sessions, were discussed in front of an audience of more than hundred attendees. Emphasis was put on oncogene signaling in cancer genesis and progression, new approaches in Precision Medicine and therapy of ovarian cancer, the role of tumor microenvironment in carcinogenesis, and preventive/curative potential of natural products. In this meeting-report, we highlight the findings and the perspectives in cancer biology and therapeutic strategies that emerged during the conference.

 

INTRODUCTION

 1. Ovarian Carcinogenesis: Signaling and Stem Cells

 2. Chemoresistance and Cancer Targeted Therapy

 3. Role of Tumor Microenvironment in Cancer Progression

 4. Bioinformatic and Xenograft Technology for Personalized Treatments

 5. Chemoprevention with Natural Products

 CONCLUSION

The conference promoted the gathering of cancer researchers from more than thirty different institutions from nine different countries, thereby offering the participants with a cooperative network environment for future collaboration. The latest advances in the understanding of the biology of cancer and the possible translational impact on the clinical practice of this knowledge for a better management of cancer patients were successfully discussed among the participants. The conference was adjourned with the resolution that the next annual consortium meeting will be held in Oklahoma City while a satellite meeting will be held in South Korea.

SGO Conference Coverage from Medpage (sundry articles)

SGO 

Latest SGO Coverage

SGO: Reduced Opioid Use With Liposomal Bupivacaine in Surgery

3/28/2016

Nausea, ileus also reduced with same pain control more

SGO: No CIN3 Regression With COX-2 Inhibitor

3/27/2016

Some evidence of benefit in patients with high VEGF levels  more

Seeking Predictor of Survival in Ovarian Cancer

3/24/2016

Studies examine pCR to speed up trials, approvals  more

1 comment

SGO: Paclitaxel Prevails in Ovarian Cancer Trials

3/23/2016

Targeted agent, oncolytic virus fall short in recurrent disease more

SGO: Optimal Chemo for Ovarian Cancer Fails to Emerge

3/22/2016

No PFS difference among three regimens evaluated in key trial more

SGO: Studies Hone Prediction of Ovarian Ca Outcomes

3/21/2016

Mutations, markers of homologous recombination deficiency portend better survival more

SGO: Optimal Chemo for Ovarian Cancer Fails to Emerge (gyn oncs "dissapointed"

Medpage Today

Clinical Context 03.22.2016

Action Points

• Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
• Results of a long-awaited ovarian cancer trial failed to show an advantage for any of three chemotherapy regimens.
• Note that the regimens -- involving combinations of intraperitoneal (IP) and intravenous (IV) chemotherapy plus bevacizumab (Avastin) -- led to a median progression-free survival of 27 to 29 months in patients with optimally debulked stage II-III disease.

SAN DIEGO -- A roomful of gynecologic oncologists walked away disappointed after results of a long-awaited ovarian cancer trial failed to show an advantage for any of three chemotherapy regimens.

Targeted agents in epithelial ovarian cancer: review on emerging therapies and future developments

open access
Targeted agents in epithelial ovarian cancer: review on emerging therapies and future developments. ecancermedicalscience - The open access journal from the European Institute of Oncology and the OCEI
 

Abstract

 Introduction

 Targeting angiogenesis in ovarian cancer

 Exploring beyond VEGF ligand in angiogenesis pathway

 Inhibiting beyond VEGF pathway

 Newer possible targets explored in ovarian cancer

 Conclusion

BRCA testing, treatment patterns and survival in platinum-sensitive recurrent ovarian cancer – an observational cohort study

open access

 Owing to the enhanced susceptibility of platinum-containing agents in BRCAm platinum-sensitive recurrent ovarian cancer and the prevalence of BRCAm in recurrent disease, it is important to evaluate BRCA testing, treatment patterns and survival in patients who may benefit most from platinum therapy. The purpose of this study was to assess BRCA testing patterns, treatment patterns, and survival in patients with platinum-sensitive recurrent ovarian cancer.

 

Conclusion

This study demonstrates in an academic oncology center with extensive genetic services support that BRCA testing rates increased during the study period and that the likelihood of BRCA testing increased with lower age, positive family history, and presenting time. However, wider BRCA testing may have identified additional BRCA carriers. Patients tested for BRCAm had greater median overall survival rates versus untested patients and a corresponding greater number of systemic treatment lines. BRCAwt patients had similar outcomes to BRCAm patients. Overall, this study continues to demonstrate the distinct clinical behavior of BRCA-mutated ovarian cancer and underscores the importance of appropriate genetic risk assessment and BRCA testing.

alternate open access: link

Initiation of a formalized precision medicine program in gyn oncology (single institution study)

abstract

OBJECTIVE:

In an effort to better incorporate precision medicine into clinical practice, we initiated a pilot project to screen, discuss, and genetically characterize patients with metastatic or recurrent gynecologic malignancies for whom no curative standard of care exists.

METHODS:

In 7/2014, we initiated a multi-disciplinary Precision Medicine Board (PMB) whose purpose was to apply molecular profiling to select and prioritize early phase clinical trial enrollment for high-risk gynecologic malignancies. Additional objectives were to record outcomes and enable scientific discussions of mutations which may foster local translational research. FoundationOne was the preferred genomic platform; results were reviewed by a team comprised of disease site specialists, phase I trialists, and basic and translational scientists affiliated with the Gynecologic Cancer Program. A detailed database for each patient was created and is followed prospectively for treatment use and resultant outcomes.

RESULTS:

To date, we have presented 62 cases with interpretable FoundationOne testing on 60 tumor samples (31 ovarian, 18 uterine, 9 cervical, and 4 other female genital tract). Significant genomic alterations were commonly found in all tumor types (median: 3); TP53 (45%) and PIK3CA (27%) were the most frequently noted mutations; however, molecular profiling resulted in identification of few actionable mutations (6%). To date, we have matched 4 patients on therapies based on actionable mutations.

CONCLUSIONS:

The predominant function of our PMB is establishment of a forum to enhance research while providing clinical care for refractory malignancies. We have matched patients with specific mutations to ongoing trials and are developing investigator-initiated studies based on trends within genomic profiling results. Longer-term follow up will be required to determine the success of this strategy.

Cancer(s), Benign Gynecology, and Sexual Function—Issues and Answers

open access

 Article outline

• Abstract
• Introduction
• Aims
• Methods
• Main Outcomes Measures
• Results
• Conclusion
• Key Words
• Introduction
• Prostate cancer
• Active Surveillance
• Surgical Therapy
• Radiotherapy
• Bladder cancer
• Intravesical Treatment
• Pelvic Radiotherapy
• Radical Cystectomy and Nerve Sparing to Preserve Erectile Function
• Types of Urinary Diversion
• Treatment of Bladder Cancer in Women
• Penile cancer
• Testicular cancer
• Breast cancer
• Surgical Considerations
• Radiation, Chemotherapy, and Hormonal Considerations
• Psychological Considerations
• Sexual Pain Syndromes
• Benign gynecologic disease
• Laser therapy for vaginal atrophy
• Treatment for Introital Vaginal Laxity
• Colorectal and anal cancer
• Conclusions
• Statement of authorship
• References

Drug makers inconsistently report side effects in the US, Europe

medical news

Editorial: Another Breast Cancer Entity Confirmed: Genomics of Invasive Lobular Breast Cancer

open access

 The article that accompanies this editorial by Desmedt et al² reinforces and extends this understanding.

 Metastatic ILC also has unusual patterns of spread to sites such as the ovaries, lining of the GI tract, and peritoneum.^1,8 All these features are consistent with a unique biology.

A SNaPshot of potentially personalized care: Molecular diagnostics in gynecologic cancer

Abstract
 

Highlights

•

Genotyping with SNaPshot identified few drugable targets in serous cancers.

•

SNaPshot may have merit in endometrial cancer where PI3kinase signaling is important.

•

Genotyping platforms should be chosen to reflect disease and histology.

---

Abstract

Background

Genetic abnormalities underlie the development and progression of cancer, and represent potential opportunities for personalized cancer therapy in Gyn malignancies.

Methods

We identified Gyn oncology patients at the MGH Cancer Center with tumors genotyped for a panel of mutations by SNaPshot, a CLIA approved assay, validated in lung cancer, that uses SNP genotyping in degraded DNA from FFPE tissue to identify 160 described mutations across 15 cancer genes (AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, IDH1, KIT, KRAS, MAP2KI, NOTCH1, NRAS, PIK3CA, PTEN, TP53).

Results

Between 5/17/10 and 8/8/13, 249 pts consented to SNaPshot analysis. Median age 60 (29–84) yrs. Tumors were ovarian 123 (49%), uterine 74(30%), cervical 14(6%), fallopian 9(4%), primary peritoneal 13(5%), or rare 16(6%) with the incidence of testing high grade serous ovarian cancer (HGSOC) halving over time. SNaPshot was positive in 75 (30%), with 18 of these (24%) having 2 or 3 (n = 5) mutations identified. TP53 mutations are most common in high-grade serous cancers yet a low detection rate (17%) was likely related to the assay. However, 4 of the 7 purely endometrioid ovarian tumors (57%) harbored a p53 mutation. Of the 38 endometrioid uterine tumors, 18 mutations (47%) in the PI3Kinase pathway were identified. Only 9 of 122 purely serous (7%) tumors across all tumor types harbored a ‘drugable’ mutation, compared with 20 of 45 (44%) of endometrioid tumors (p < 0.0001). 17 pts subsequently enrolled on a clinical trial; all but 4 of whom had PIK3CA pathway mutations. Eight of 14 (47%) cervical tumors harbored a ‘drugable’ mutation.

Conclusion

Although SNaPshot can identify potentially important therapeutic targets, the incidence of ‘drugable’ targets in ovarian cancer is low. In this cohort, only 7% of subjects eventually were treated on a relevant clinical trial. Geneotyping should be used judiciously and reflect histologic subtype and available platform.

Leveraging immunotherapy for the treatment of gynecologic cancers in the era of precision medicine

abstract

Highlights

•

Cancers evolve mechanisms for evading and suppressing the immune system

•

A number of different immunotherapy approaches have been used and show promise in gynecologic cancers

•

Emerging data reveal durable responses in some patients with gynecologic cancers

---

Abstract

During the past decade significant progress in the understanding of stimulatory and inhibitory signaling pathways in immune cells has reinvigorated the field of immuno-oncology. In this review we outline the current immunotherapy based approaches for the treatment of gynecological cancers, and focus on the emerging clinical data on immune checkpoint inhibitors, adoptive cell therapies, and vaccines. It is anticipated that in the coming years biomarker-guided clinical trials, will provide for a better understanding of the mechanisms of response and resistance to immunotherapy, and guide combination treatment strategies that will extend the benefit from immunotherapy to patients with gynecologic cancers.

Rational selection of biomarker driven therapies for gynecologic cancers: The more we know, the more we know we don't know

Rational selection of biomarker driven therapies for gynecologic cancers: The more we know, the more we know we don't know
 

Highlights

•

Applications for targeted therapy in gynecologic cancers are growing rapidly.

•

Resistance to targeted therapy may be innate, acquired, or adaptive.

•

Translational endpoints will be essential to maximize response to targeted therapy.

---

Abstract

Precision medicine is a rapidly evolving area in the treatment of gynecologic malignancies. Advances in sequencing technology have resulted in an increasing wealth of data regarding the genomic characteristics of ovarian, endometrial, and cervical cancers. These vast new datasets of information have led to novel insights into potential vulnerabilities and therapeutic targets for these cancers. However, unraveling the complex molecular changes within cancer cells to determine how best to attack these targets and to identify effective biomarkers of response remains a significant challenge. In this article, we review the current status of biomarker-driven targeted therapy in gynecologic malignancies.

Copy number deletion of RAD50 as predictive marker of BRCAness and PARP inhibitor response.....

abstract:Copy number deletion of RAD50 as predictive marker of BRCAness and PARP inhibitor response in BRCA wild type ovarian cancer
 

Highlights

•

Whole-exome analysis identifies BRCAness OvCa tumors.

•

BRCAness OvCa tumors resemble BRCA deficient OvCa tumors by in similar genome instability.

•

RAD50 deletion predicts BRCAness and augments OvCa cell's drug sensitivity.

Conclusion

Our study identified the copy number deletion of RAD50 as a candidate marker for survival and response to PARPis in BRCAwt OvCa tumors.

---

Use of “big data” in drug discovery and clinical trials

abstract

Oncology is undergoing a data-driven metamorphosis. Armed with new and ever more efficient molecular and information technologies, we have entered an era where data is helping us spearhead the fight against cancer. This technology driven data explosion, often referred to as “big data”, is not only expediting biomedical discovery, but it is also rapidly transforming the practice of oncology into an information science. This evolution is critical, as results to-date have revealed the immense complexity and genetic heterogeneity of patients and their tumors, a sobering reminder of the challenge facing every patient and their oncologist. This can only be addressed through development of clinico-molecular data analytics that provide a deeper understanding of the mechanisms controlling the biological and clinical response to available therapeutic options. Beyond the exciting implications for improved patient care, such advancements in predictive and evidence-based analytics stand to profoundly affect the processes of cancer drug discovery and associated clinical trials.

Use of “big data” in drug discovery and clinical trials

abstract

Oncology is undergoing a data-driven metamorphosis. Armed with new and ever more efficient molecular and information technologies, we have entered an era where data is helping us spearhead the fight against cancer. This technology driven data explosion, often referred to as “big data”, is not only expediting biomedical discovery, but it is also rapidly transforming the practice of oncology into an information science. This evolution is critical, as results to-date have revealed the immense complexity and genetic heterogeneity of patients and their tumors, a sobering reminder of the challenge facing every patient and their oncologist. This can only be addressed through development of clinico-molecular data analytics that provide a deeper understanding of the mechanisms controlling the biological and clinical response to available therapeutic options. Beyond the exciting implications for improved patient care, such advancements in predictive and evidence-based analytics stand to profoundly affect the processes of cancer drug discovery and associated clinical trials.

The genetic prediction of risk for gynecologic cancers

abstract

 Keywords

• precision medicine;
• ovarian cancer;
• uterine cancer;
• BRCA;
• Lynch syndrome;
• risk-reduction

Highlights

•

Hereditary cancer syndromes are an important precision medicine opportunity.

•

Homologous recombination mutations including BRCA contribute to ovarian cancer.

•

DNA mismatch repair defects increase risk for both ovarian and uterine cancers.

•

Risks can be significantly reduced with prophylactic surgery or surveillance.

•

These mutations can predict response to novel molecular therapies.

---

Abstract

Salient to the intent of personalized medicine, hereditary cancer syndromes present significant opportunities in the treatment and prevention of some gynecologic cancers. Mutations in BRCA1, BRCA2, and DNA mismatch repair genes: MLH1, MSH2, MSH6, and PMS2 are important causal agents in hereditary breast and ovarian cancer (HBOC) and Lynch syndromes. Though they only account for an estimated 10-18% of ovarian, tubal, peritoneal, and endometrial cancer cases, inherited cancers are imminently preventable if mutation carriers are identified in a timely manner. Population level screening is currently impractical due to low prevalence of disease, cost of testing, and ethical issues associated with testing, so diagnosis of these mutations is limited. Being affected by one of the heritable gynecologic malignancies is a logical entry point into the genetic counseling and testing pipeline for the patient and her family members. Thus, gynecologic cancer providers are uniquely positioned to diagnose germline mutations that can inform prognosis and treatment for their patients in addition to enabling prevention for patients’ cancer-unaffected blood relatives, or “previvors”. The purpose of this review is to describe our current perspective on testing for and implications of heritable cancer syndromes in the women with ovarian, tubal, peritoneal, and endometrial cancers.

Use of comprehensive genomic profiling to direct point-of-care management of patients with gynecologic cancers (trial ongoing)

abstract

Highlights

•

Few effective standard options available for patients with refractory disease

•

Identification of genomic alterations can inform treatment decisions.

•

Point-of-care management using this approach is feasible.

•

A molecular tumor board (MTB) is an important component of point-of-care management.

•

Implementation barriers of MTB-based therapeutic recommendations are discussed.

---

Abstract

Objective

To determine the feasibility and clinical utility of using comprehensive genomic profiling (CGP) in the course of clinical care to identify clinically relevant tumor genomic alterations for patients with either rare or refractory gynecologic cancers to facilitate point-of-care management. Use of an expert, multidisciplinary, institutional molecular tumor board (MTB) assessment is discussed regarding input on putative targeted options for individualized therapy.

Methods

A prospective clinical trial is ongoing. We report on the initial 69 patients with gynecologic cancers that were either rare or refractory to standard therapy. CGP was performed by Foundation Medicine, Inc. Genomic alterations were reviewed by members of an MTB. Consensus recommendations on genomically targeted, FDA-approved, on- and off-label therapies and clinical trials were sent to the treating physician, and decisions and outcomes were assessed.

Results

Study outcomes were available for 64 patients. The mean number of genes altered per tumor was 4.97 (median = 4; range, 1–26), and the average turnaround time from testing laboratory report to generation of formal recommendations was approximately three weeks. Evaluation of genomic and clinical data by the MTB led to generation of targeted treatment options in all 64 patients, and the percentage of patients for whom one or more of these recommendations were implemented by the treating physician was 39%. Sixty-four percent of the patients receiving targeted therapy based on a CGP result experienced radiologic response or showed evidence of clinical benefit or stable disease.

Conclusion

These data suggest that an institutional MTB is a feasible venue for reviewing tumor genomic profiling results and generating clinical recommendations. These data also support the need for further studies and guidelines on clinical decision making with greater availability of broad genomically based diagnostics.

(U.S.) State Cancer Profiles (and quick profiles)

State Cancer Profiles
 About State Cancer Profiles
State Cancer Profiles characterizes the cancer burden in a standardized manner to motivate action, integrate surveillance into cancer control planning, characterize areas and demographic groups, and expose health disparities. The focus is on cancer sites with evidence based control interventions. Interactive graphics and maps provide support for deciding where to focus cancer control efforts. State Cancer Profiles is one tool of the Cancer Control P.L.A.N.E.T. portal which provides access to Web-based resources.

eg. Florida

Quick Profiles: Florida

• Demographics
• Screening & Risk Factors
• Incidence
• Prevalence
• Mortality

Happy Easter!

Gatekeeper role of gastroenterologists and surgeons in recognising and discussing familial colorectal cancer

open access

 Despite the relatively high frequency of familial and hereditary CRC syndromes and the proven benefit of screening, referral for genetic counselling appears to be suboptimal leading to under-diagnosis of hereditary CRC [4]. Furthermore, referral is often patient-initiated leading to under-representation of patient....

 Contrary to our expectations, the checklist did not increase the discussion of cancer in the family during the first consultation, as reported by the patients.(ceiling effect)

 

Index: Apr 2016 Familial Cancer journal

Familial Cancer

Metastatic Carcinoma of the Urinary Bladder in a 67-year-old Female with Underlying Triple Primary Cancers (worth reading see notes)

Blogger's Note: worth reading regarding recap of numerous genetic syndromes/related biology

open access

Frequent mismatch-repair defects link prostate cancer to Lynch syndrome | BMC Urology | Full Text

open access

 Background

Lynch syndrome is a multi-tumor syndrome with the highest risks for colorectal cancer and endometrial cancer though a number of other tumor types, e.g. cancer of the urinary tract, the small bowel and the ventricle, ovarian cancer, brain tumors and skin tumors develop at increased incidence [1, 2]. Other tumor types assumed to represent sporadic tumors in families with hereditary cancer, e.g. breast cancer, pancreatic cancer and sarcoma may indeed develop as part of the syndrome. This is suggested based on identification of mismatch repair (MMR) defective tumors of these subtypes and demonstration of an increased risk of these tumor types in mutation carriers [3–10].

Prostate cancer is the most common tumor type in men in the Western world with an estimated lifetime risk of 18 % and a median age at diagnosis of 67 years [1]. Worldwide, prostate cancer is the sixth common tumor with more than 250,000 deaths annually [11]. In Denmark, prostate cancer constitutes 23 % of all male cancers with an estimated risk of 10 % for disease development before age 75 [12]. The role of prostate cancer in Lynch syndrome is unresolved though molecular investigations and epidemiologic studies have suggested a potential link to the syndrome [1, 8, 13]. The MMR system has been suggested to influence prostate carcinogenesis e.g. through an increased risk of prostate cancer linked to single nucleotide polymorphisms in MLH1 and MSH3, and a role for complex structural rearrangements in MSH2 and MSH6 as a mechanism underlying the hypermutation in aggressive prostate cancer [14–20]. We assessed the role of prostate cancer in the Danish Lynch syndrome cohort with characterization of MMR status and risk estimates.....

 Conclusions

The Danish Lynch syndrome cohort contains 28 prostate cancers that developed at a median age of 63 years, showed high Gleason scores and frequent TILs. The tumors were predominantly linked to MSH2 mutations. Frequent MMR defects consistent with the underlying germline defects suggest that prostate cancer is included in Lynch syndrome tumor spectrum and should be considered during genetic counseling.

An Individual with Both MUTYH-Associated Polyposis and Lynch Syndrome Identified by Multi-Gene Hereditary Cancer Panel Testing: A Case Report | Cancer Genetics

open access
 An Individual with Both MUTYH-Associated Polyposis and Lynch Syndrome Identified by Multi-Gene Hereditary Cancer Panel Testing

..... Although the cancer risk in individuals who carry multiple pathogenic variants has not been established for combined biallelic MUTYH-associated polyposis and Lynch syndrome, the identification of multiple pathogenic variants does allow for screening for cancers associated with both syndromes and has implications for cancer risk for family members. In particular, this has significant impact on those who test negative for a known familial pathogenic variant, yet could be still be at risk for cancer due to a second pathogenic variant in a family. More information is needed on the frequency of occurrence of multiple pathogenic variants, as well as the phenotypic spectrum when multiple pathogenic variants are present....

Identification of Ovarian Cancer Metastatic miRNAs (serous/omental mets)

Open access

 Abstract
Serous epithelial ovarian cancer (EOC) patients often succumb to aggressive metastatic disease, yet little is known about the behavior and genetics of ovarian cancer metastasis. Here, we aim to understand how omental metastases differ from primary tumors and how these differences may influence chemotherapy. We analyzed the miRNA expression profiles of primary EOC tumors and their respective omental metastases from 9 patients using miRNA Taqman qPCR arrays. We find 17 miRNAs with differential expression in omental lesions compared to primary tumors. miR-21, miR-150, and miR-146a have low expression in most primary tumors with significantly increased expression in omental lesions, with concomitant decreased expression of predicted mRNA targets based on mRNA expression. We find that miR-150 and miR-146a mediate spheroid size. Both miR-146a and miR-150 increase the number of residual surviving cells by 2–4 fold when challenged with lethal cisplatin concentrations. These observations suggest that at least two of the miRNAs, miR-146a and miR-150, up-regulated in omental lesions, stimulate survival and increase drug tolerance. Our observations suggest that cancer cells in omental tumors express key miRNAs differently than primary tumors, and that at least some of these microRNAs may be critical regulators of the emergence of drug resistant disease.

 Metastases can be enriched for a distinct mutational spectrum compared to primary tumors [2], [3], [4]. Comparing primary and metastatic tumors has generated important insights into disease progression in both animal models [5] and in patients [2]. To improve treatment of metastatic disease, it is vital to understand the genes and pathways emerging in metastases that may not be present in primary tumors. Although metastatic potential can be predicted based on the primary tumor [6], [7], this observation is not mutually exclusive with the possibility that key features emerge in metastases that are not observed in primary tumors.

Triple peptide vaccination as consolidation treatment in women affected by ovarian and breast cancer: phase I/II clinical trial

open access
Triple peptide vaccination as consolidation treatment in women affected by ovarian and breast cancer: Clinical and immunological data of a phase I/II clinical trial

 ovarian cancer Histology, n7
Serous adenocarcinoma 4
Endometrioid 1
Mucinous 2
 

In particular OC patients appear to show a higher response rate compared to BC patients. 

quick search: ovarian cancer received on or after 01/01/2016

List Results - ClinicalTrials.gov

 39 studies found for:    Open Studies | ovarian cancer | received on or after 01/01/2016

Mucinous ovarian cancer: A therapeutic review

abstract

 Highlights

•

Mucinous epithelial ovarian cancer (mEOC) is a rare chemo-resistant subtype of ovarian cancer with distinct epidemiology, pathology and natural history.

•

MEOC can often masquerade as metastatic mucinous tumours from the gastrointestinal (GI) tract.

•

Molecularly, in contrast to high-grade serous ovarian cancer (HGSOC), mEOC are far less defined by p53 mutations and instead commonly harbour KRAS and HER 2 mutations.

•

The current gold standard of 1st line platinum/taxane doublet chemotherapy, is more tailored towards HGSOC and generally ineffective for mEOC.

•

This review summarises the limited evidence for using GI style chemotherapeutic agents in treating mEOC and explores novel therapeutic possibilities such as targeting HER2, VEGF and Src.

 Mucinous ovarian cancer represents approximately 3% of epithelial ovarian cancers (EOC). Despite this seemingly low prevalence, it remains a diagnostic and therapeutic conundrum that has resulted in numerous attempts to adopt novel strategies in managing this disease. Anecdotally, there has been a prevailing notion that established gold standard systemic regimens should be substituted for those utilised in cancers such as gastrointestinal (GI) malignancies; tumours that share more biological similarities than other EOC subtypes. This review summarises the plethora of small studies which have adopted this philosophy and influenced the design of the multinational GOG142 study, which was ultimately terminated due to poor accrual. To date, there is a paucity of evidence to support delivering ‘GI style’ chemotherapy for mucinous ovarian cancer over and above carboplatin-paclitaxel doublet therapy. Hence there is an urge to develop studies focused on targeted therapeutic agents driven by refined mutational analysis and conducted within the context of harmonised international collaborations.

Opinion (Markman)
 

Provocative Perspectives in Oncology Blog

MARCH 21, 2016

Separating Quality Clinical Research From a Philosophy of Life

A questionable study is compounded by a questionable invited commentary 

...Surely, there can be no argument with the conclusion of this editorial that oncologists should “not contribute to the suffering cancer and other associated therapy brings, particularly at the end.”² However, to equate these meaningful words with the unequivocal statement that essentially says physicians should either strongly encourage, or directly tell, patients to not undergo active treatment raises the serious ethical concern that a physician is not simply providing clear and objective data but rather is mandating that patients accept the physician’s personal philosophical view of life.

 References:

1. Prigerson HG, Bao Y, Shah MA, et al. Chemotherapy use, performance status, and quality of life at the end of life.JAMA Oncol. 2015;1(6):778-784, PMID: 26203912.
2. Blanke CD, Fromme EK. Chemotherapy near the end of life. First—and third and fourth (line)—Do no harm.JAMA Oncol. 2015;1(6):785-786, PMID: 26203585.

Seeking Predictor of Survival in Ovarian Cancer

Medpage

Many targeted cancer therapies suppress T cell immune responses....

medical news:
Many targeted cancer therapies suppress T cell immune responses: New 'superagonist' can help overcome these immunosuppressive effects while preserving the powerful anti-cancer benefits of these drugs

Upper tract urothelial carcinoma: epidemiology, high risk populations, and detection (Lynch Syndrome/MD Anderson))

abstract

 Upper tract urothelial carcinoma (UTUC) is a rare but highly morbid genitourinary malignancy. In 2014 approximately 15000 new cases were diagnosed in the United States. It accounts for approximately 5-10% of all urothelial cell carcinomas, and 10% of renal tumors. Recent research has increased understanding of the epidemiology of this disease, including several high-risk populations. Environmental exposure to tobacco as well as aristolochic acid, and other carcinogens significantly increase the development of UTUC. Additionally, the genetic condition of hereditary nonpolyposis colorectal carcinoma (HNPCC), also known as Lynch Syndrome (LS) is linked to development of UTUC. Advances in imaging, ureteroscopy, cytological techniques and pathological recognition have allowed for improved detection of primary tumors and recurrent disease. Non-invasive imaging with computed tomography (CT) and magnetic resonance imaging (MRI) now represent the gold standard in imaging detection and surveillance, while technological advances in ureteroscopy allow for minimally invasive approaches to obtain pathologic diagnosis anywhere within the upper tracts. This review will highlight these recent improvements to allow better understanding of who is affected by this rare and morbid disease, as well as the latest developments in detection and surveillance.

Molecular classification of high grade endometrioid and clear cell ovarian cancer using TCGA gene expression signatures

abstract

Background

It is unclear whether the transcriptional subtypes of high grade serous ovarian cancer (HGSOC) apply to high grade clear cell (HGCCOC) or high grade endometrioid ovarian cancer (HGEOC). We aim to delineate transcriptional profiles of HGCCOCs and HGEOCs.

Methods

We used Agilent microarrays to determine gene expression profiles of 276 well annotated ovarian cancers (OCs) including 37 HGCCOCs and 66 HGEOCs. We excluded low grade OCs as these are known to be distinct molecular entities. We applied the prespecified TCGA and CLOVAR gene signatures using consensus non-negative matrix factorization (NMF).

Results

We confirm the presence of four TCGA transcriptional subtypes and their significant prognostic relevance (p < 0.001) across all three histological subtypes (HGSOC, HGCCOC and HGEOCs). However, we also demonstrate that 22/37 (59%) HGCCOCs and 30/67 (45%) HGEOCs form 2 additional separate clusters with distinct gene signatures. Importantly, of the HGCCOC and HGEOCs that clustered separately 62% and 65% were early stage (FIGO I/II), respectively. These finding were confirmed using the reduced CLOVAR gene set for classification where most early stage HGCCOCs and HGEOCs formed a distinct cluster of their own. When restricting the analysis to the four TCGA signatures (ssGSEA or NMF with CLOVAR genes) most early stage HGCCOCs and HGEOC were assigned to the differentiated subtype.

Conclusions

Using transcriptional profiling the current study suggests that HGCCOCs and HGEOCs of advanced stage group together with HGSOCs. However, HGCCOCs and HGEOCs of early disease stages may have distinct transcriptional signatures similar to those seen in their low grade counterparts.

How to (seriously) read a scientific paper

 AAAS (opinions)

Special Supplement: Use of Cannabinoids in Cancer Care

open access Vol 23 (2016)

Current Oncology, Vol 23, Supplement 2 - Now Published!

Use of Cannabinoids in Cancer Care

Multimed Inc. is pleased to announce that Current Oncology has published a supplement dedicated to the use of cannabinoids in cancer care.

Edited by Dr. Mark Ware, this issue brings together the work of some of the leading minds around the world who have dedicated themselves and their laboratories to understanding the role of cannabis and cannabinoids in the pathophysiology and management of cancer. This collection of papers takes us on a journey from bedside to bench and back, and provides a series of important signposts that will help to chart a path to better cancer care.

Table of Contents

Editorial(s)

Cannabis and cancer: towards a new understanding M.A. Ware

PDF HTML S5-S6

Cancer Narratives: Words Beyond Disease

Why I chose to use cannabis L. Perrier

PDF HTML S7

Original Article(s)

Integrative Oncology

Integrating cannabis into clinical cancer care D.I. Abrams

PDF HTML S8-S14

Pediatric Oncology

In vitro and in vivo efficacy of non-psychoactive cannabidiol in neuroblastoma T. Fisher, H. Golan, G. Schiby, S. PriChen, R. Smoum, I. Moshe, N. Peshes-Yaloz, A. Castiel, D. Waldman, R. Gallily, R. Mechoulam, A. Toren

PDF HTML S15-S22

Review Article(s)

Anticancer mechanisms of cannabinoids G. Velasco, C. Sánchez, M. Guzmán

PDF HTML S23-S32

Commentary(ies)

Use of cannabinoids in cancer care: palliative care S.K. Aggarwal

PDF HTML S33-S36

Journal Gynecologic Oncology Index April 2016

Index 
(not an open access publication)

Advanced Ovarian Cancer: Primary or Interval Debulking? 5 Categories of Patients in View of the Results of RCTs and Tumor Biology

abstract
Advanced Ovarian Cancer: Primary or Interval Debulking? Five Categories of Patients in View of the Results of Randomized Trials and Tumor Biology: the Oncologist

HIPEC in Ovarian Cancer: Where Do We Go From Here? - theoncologist.2015-0486.full.pdf

Commentary: open access

 This commentator challenges the gynecologic cancer research community to develop rational alternative methods to objectively evaluate the multiple new approaches that will surely be proposed in the future to favorably impact both the quantity and quality of the lives of our patients. The increasingly hollow and objectively unsustainable mantra of the randomized phase III trial as the answer to all questions in oncology must end.