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Tuesday, December 06, 2016

Practical guidance on the use of olaparib capsules as maintenance therapy for women with BRCA mutations and platinum-sensitive recurrent ovarian carcinoma



abstract

Affiliations: UK/Australia
 
Olaparib is the first oral poly(ADP-ribose) polymerase inhibitor to be approved as maintenance monotherapy for treatment of patients with platinum-sensitive relapsed BRCA-mutated (BRCAm) serous ovarian cancer. This review provides practical guidance on the use of olaparib (capsule formulation) in the maintenance setting. The article focuses on the key toxicities that can arise with olaparib therapy and recommendations for their management. Nausea, vomiting, fatigue and anemia are the most commonly reported adverse events in olaparib clinical trials and are generally mild to moderate and transient in nature in most patients. Implementation of an effective and timely management plan can control many of the side effects. It is vital that health care providers effectively communicate the potential side effects of olaparib, as well as educate patients on management strategies to combat these symptoms. To this end, realistic expectations regarding the potential side effects need to be set, with an understanding that dose interruptions and modifications may be required to allow patients to continue receiving treatment.

OA: Debated Role of Ovarian Protection With Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Women With Cancer: Journal of Clinical Oncology: Vol 0, No 0



Correspondence/References: Debated Role of Ovarian Protection With Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Women With Cancer: Journal of Clinical Oncology

Senate committee calls for ban on surgeons doing simultaneous operations



The Boston Globe

OA: Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: ASCO Guideline



Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline: Journal of Clinical Oncology
December 5th, 2016 (open access)



 

Canada needs 'defined model' of universal pharmacare, citizen panel urges



Health - CBC News
 
 There isn't a lot of political momentum to introduce universal pharmacare because most Canadians think they're covered, says Prof. Colleen Flood. (EvidenceNetwork.ca)
 Colleen Flood, director of the Centre for Health Law, Policy and Ethics at the University of Ottawa, is one of the experts who presented to the panel. She supports the idea of a Canada-wide pharmacare plan.
"Essentially for pharmaceuticals needed outside the hospital, we pretty much have a U.S.-style system," Flood said.

Monday, December 05, 2016

December 05, 2016 Diluted chemo survivors call settlement offer ‘insulting’ (Ontario) media



Diluted chemo survivors call settlement offer ‘insulting’ | Talk Radio AM640



 

MRI as an Adjunct to Mammography for Breast Cancer Screening in Women at Less Than High Risk for Breast Cancer = NO



Magnetic Resonance Imaging as an Adjunct to Mammography for Breast Cancer Screening in Women at Less Than High Risk for Breast Cancer - Health Quality Ontario (HQO)

Help wanted: Canada begins search for chief science adviser deadline Jan 27th, 2017



Help wanted: Canada begins search for chief science adviser : Nature News & Comment

 applications for the job until 27 January 2017

press release: Tina’s Wish to Fund $1.6M in Grants for Eight Early Detection Ovarian Cancer Research Projects




http://www.tinaswish.orgna's Wish will fund $1.6M in grants for eight early detection ovarian cancer research projects in 2017/18.                     ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Tina’s Wish to Fund $1.6M in Grants for Eight Early Detection Ovarian Cancer Research Projects
 
NEW YORK, Dec. 5, 2016 /PRNewswire/ -- Tina's Wish, the only nonprofit organization dedicated exclusively to funding scientific research for the early detection of ovarian cancer has announced its eight 2017/18 individual grant recipients after soliciting proposals nationally for the first time. Researchers from Dana-Farber Cancer Institute, Johns Hopkins Medicine, Memorial Sloan Kettering Cancer Center, NYU School of Medicine, Penn Medicine, University of Michigan, University of Virginia and Yale Cancer Center will receive funding.
The Foundation utilized a team of expert external reviewers in addition to the Tina's Wish Scientific Advisory Board for the nine-month selection process. Only 13 percent of applicants received funding.
Tina's Wish will fund $1.6M in grants for eight early detection ovarian cancer research projects in 2017/18.

It's time to overhaul the secretive peer review process (opinion)



It's time to overhaul the secretive peer review process

.... Communicating the results of basic science, clinical trials, observational studies, case reports, and the like is essential to the forward movement of science. The peer review system is at the core of this process. It works like this: a journal editor asks outside experts to critique a manuscript and assess its suitability for publication, with or without modifications. Editors use these peer reviews to help determine whether or not to publish a report.....

Oral arguments in CRISPR patent case expected to be 'fight to the death'



Oral arguments in CRISPR patent case expected to be 'fight to the death'

 University of California against the Broad Institute of Harvard and MIT

21st Century Cures Act produces winners and losers (eg. clinical trials etc)



21st Century Cures Act produces winners and losers - political news

 But this is Washington, so even this bipartisan bill, which the House of Representatives approved in a landslide and which the Senate is expected to pass Tuesday, leaves a trail of winners and losers.

SGO annual meeting: Call for Scientific Abstracts & Surgical Films



Call for Scientific Abstracts & Surgical Films
 Visit Sgo Website

All for one, and one for all! Patient power at ESMO 16 | The Cancer Blog



All for one, and one for all! Patient power at ESMO 16 | The Cancer Blog

 
....There was overflow needed for most Patient Track sessions, and those that were attending to listen were not just Patient Advocates, but the Oncologists, the Researchers, and the Pharma representatives. That’s because what we have to say is important and well informed – this is not our job it is our lives, so what could be more important to us?
Often the general public don’t understand the complexities of difference in cancer until you get one. It’s not a topic one reads up on for fun, most only keep up if they are personally connected. Also, all cancers are not created equal – it can become all too apparent that maybe you didn’t get the one with the most support or media air time or the most funding attached to researching it. But at the ESMO patient’s track this year I didn’t feel any of that. I felt instead part of a movement, a revolution of sorts that brought us all together bound by the one thing we have in common: a deep rooted desire to achieve the best for patients no matter what type of cancer they have. We are all in the same boat, there was no paddling your own canoe at ESMO.....

OA: Genomics of (sporadic serous) Ovarian Cancer Progression Reveals Diverse Metastatic Trajectories Including Intraepithelial Metastasis to the Fallopian Tube



open access: Genomics of Ovarian Cancer Progression Reveals Diverse Metastatic Trajectories Including Intraepithelial Metastasis to the Fallopian Tube | Cancer Discovery
 
The data presented herein may lead us to develop our perception of STIC further: STIC in HGSOC could be primary or metastatic. Previous studies observed precursor lesions exclusively in the fallopian tube of BRCA mutation carriers undergoing prophylactic salpingo-oophorectomy (32), whereas our study focused on sporadic HGSOC. As clinical studies have begun to investigate the utility and safety of salpingectomy in high-risk patients (33–35), it will be imperative to understand if metastasis to the fallopian tube occurs in the context of germline BRCA mutations. Lastly, the frequent observation of STIC detected after neoadjuvant treatment (occurring in 50% of all cases) could represent a late metastasis to a chemoresistant niche (36). Therefore, a better understanding of the cross-talk between cell types unique to intraepithelial fallopian tube metastases could be both relevant clinically and important biologically.
 

Culprit or Bystander? The Role of the Fallopian Tube in “Ovarian” High-Grade Serous Carcinoma | Cancer Discovery



Culprit or Bystander? The Role of the Fallopian Tube in “Ovarian” High-Grade Serous Carcinoma | Cancer Discovery

 Abstract

Summary: The concurrence of intraepithelial high-grade neoplasia in the fallopian tube with metastatic implants has been taken as evidence of a tubal origin for high-grade serous pelvic carcinomas. In the current issue, Eckert and colleagues perform detailed genomic phylogenetic analyses and demonstrate that some cases of high-grade serous intraepithelial tubal neoplasia are metastatic implants and not precursor lesions.

 See related article by Eckert and colleagues, p. 1342.

Worldwide comparison of ovarian cancer survival: Histological group and stage at diagnosis (CONCORD-2)



 BioMed Research International
Volume 2014 (2014), Article ID 934261, 11 pages
http://dx.doi.org/10.1155/2014/934261

Review ArticleRecent Concepts of Ovarian Carcinogenesis: Type I and Type II

 Type I ovarian tumors, where precursor lesions in the ovary have clearly been described, include endometrioid, clear cell, mucinous, low grade serous, and transitional cell carcinomas, while type II tumors, where such lesions have not been described clearly and tumors may develop de novo from the tubal and/or ovarian surface epithelium, comprise high grade serous carcinomas, undifferentiated carcinomas, and carcinosarcomas.
                 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Worldwide comparison of ovarian cancer survival: Histological group and stage at diagnosis (CONCORD-2)

Highlights

Survival from ovarian cancer depends on the morphological subtype of the tumour.
Type I epithelial tumours have much higher survival than type II tumours.
Survival from sex cord-stromal tumours is the highest of the subtypes.

Objective

Ovarian cancer comprises several histological groups with widely differing levels of survival. We aimed to explore international variation in survival for each group to help interpret international differences in survival from all ovarian cancers combined. We also examined differences in stage-specific survival.

Methods

The CONCORD programme is the largest population-based study of global trends in cancer survival, including data from 60 countries for 695,932 women (aged 15–99 years) diagnosed with ovarian cancer during 1995–2009. We defined six histological groups: type I epithelial, type II epithelial, germ cell, sex cord-stromal, other specific non-epithelial and non-specific morphology, and estimated age-standardised 5-year net survival for each country by histological group. We also analysed data from 67 cancer registries for 233,659 women diagnosed from 2001 to 2009, for whom information on stage at diagnosis was available. We estimated age-standardised 5-year net survival by stage at diagnosis (localised or advanced).

Results

Survival from type I epithelial ovarian tumours for women diagnosed during 2005–09 ranged from 40 to 70%. Survival from type II epithelial tumours was much lower (20–45%). Survival from germ cell tumours was higher than that of type II epithelial tumours, but also varied widely between countries. Survival for sex-cord stromal tumours was higher than for the five other groups. Survival from localised tumours was much higher than for advanced disease (80% vs. 30%).

Conclusions

There is wide variation in survival between histological groups, and stage at diagnosis remains an important factor in ovarian cancer survival. International comparisons of ovarian cancer survival should incorporate histology.

(see comment) A prospective algorithm to reduce anastomotic leaks after rectosigmoid resection for gynecologic malignancies



Blogger's Note: abstract does not detail adverse event/s of adhesions based on abdominal/pelvic surgeries
                   ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
A prospective algorithm to reduce anastomotic leaks after rectosigmoid resection for gynecologic malignancies

Abstract
 Highlights
Criteria-based temporary bowel diversion following rectosigmoid resection may reduce anastomotic leak rate and morbidity.
No anastomotic leaks were observed among diversions.
Prophylactic bowel diversion carries acceptable morbidity, but requires an additional surgery.
Bowel diversion reversal rates were high even after debulking surgery for gynecologic malignancies.

Objective

Determine whether a standardized protocol for temporary bowel diversion after rectosigmoid resection (RSR) for cytoreduction can reduce the rate of anastomotic leak (AL).

Methods

A prospective quality improvement project for patients undergoing RSR during debulking surgery from 07/2013 to 01/2016 was conducted. Patients with any of the following underwent temporary diversion: preoperative albumin ≤ 3.0 g/dL, prior pelvic radiation, RSR plus additional large bowel resection (LBR), anastomosis (AS) ≤ 6 cm from the anal verge, failed leak test or contamination of the pelvis with stool. The AL rate was compared to the historic AL rate from 01/04–06/11.

Results

Seventy-seven patients underwent RSR, with 27 (35.1%) receiving diverting stomas vs. 25/309 (8.1%) in the historic cohort. Additional LBR (33.3%) and AS at ≤ 6 cm from anal verge (26.3%) were the most common indications for diversion. No AL was observed among diverted patients. If one AL which occurred following protocol violation (failed leak test but not diverted) is excluded, the theoretical AL rate is 1.3% (1/77) vs. 7.8% (24/309; P = 0.039) in the historic cohort. Not excluding this case, the AL rate was 2.6% (2/77) vs. 7.8% (P = 0.11). Short-term outcomes following primary surgery were not different between diverted and non-diverted patients. Stoma-related complications were observed in 7/27 (25.9%) patients, primarily related to dehydration. Reversal surgery was successfully performed in 24/75 (88.9%) patients.

Conclusions

Criteria-based temporary bowel diversion for patients undergoing RSR for gynecologic cancer reduced the AL rate. Diversion was associated with acceptable morbidity and high reversal rate.

Diagnostic accuracy of Cancer Antigen 125 (CA125) for endometriosis in symptomatic women: A multi-center study.



Diagnostic accuracy of Cancer Antigen 125 (CA125) for endometriosis in symptomatic women: A multi-center study

Abstract

Study Objective

To assess the diagnostic accuracy of serum Cancer Antigen 125 (CA 125) ≥30 units/milliliter (u/ml) for diagnosing endometriosis in symptomatic women.

Study Design

Prospective observational cohort study including patients with symptoms of pelvic pain or subfertility undergoing elective diagnostic laparoscopy at two tertiary referral hospitals. We excluded patients suspected to have other gynecological pathology. We evaluated the accuracy of serum CA 125 (index test) with histologically confirmed endometriosis (reference standard).

Main Results

Fifty-eight consecutive women recruited between October 2013 to March 2015. Women with endometriosis had a higher CA 125 level than those without endometriosis (mean 54.7 +/−71.6 vs 16.2 +/− 8.0). The specificity of CA 125 ≥30 u/ml was 96% and sensitivity was 57%. The positive likelihood ratio for the histological presence of endometriosis with a CA 125 ≥ 30 u/ml was 15.8  providing a post-test probability of 94% in women with pelvic pain or subfertility. The area under the curve, 0.85 indicates high test accuracy.

Conclusions

CA 125 ≥30 u/ml is highly predictive of endometriosis in women with symptoms of pain and/or subfertility. CA 125 should be considered as a rule-in test for expediting the diagnosis and management of endometriosis, CA 125 <30 u/ml is, however, unable to rule out endometriosis.

(eg. BRCA......) Genetic screening: The battle to raise awareness of life-threatening conditions



The Jewish Chronicle

OA: Germline mutations in BRCA1 and BRCA2 in epithelial ovarian cancer patients in Brazil



Full Text

 Abstract
 Background
Approximately 8–15% epithelial ovarian cancer patients are BRCA1 or BRCA2 germline mutation carriers. Brazilian inhabitants may have peculiar genetic characteristics associated with ethnic diversity, and studies focusing on the entire BRCA1/BRCA2 gene sequencing in Brazilian ovarian cancer patients are still lacking. The aim of this study was to evaluate BRCA1/2 mutations, through entire gene sequencing, in a Brazilian population of women with epithelial ovarian cancer.

Methods

In a cross sectional study performed in one reference centre for cancer treatment in São Paulo, Brazil, 100 patients diagnosed with epithelial ovarian cancer unselected for family history of breast and/or ovarian cancer were included. The complete coding sequence of BRCA1/2 genes was evaluated through Next-Generation or capillary sequencing. Large deletions were investigated through Multiplex Ligation-dependent Probe Amplification (MLPA).

Results

Nineteen pathogenic mutations (BRCA1: n = 17 and BRCA2: n = 2) featuring 14 different mutations, including two large deletions in BRCA1 (exon 1–2 deleted and exon 5–7 deleted) were identified. Three mutations were detected more than once (c.3331_3334delCAAG, c.5266dupC and c.4484G > T). Two novel frameshift mutations were identified, one in BRCA1 (c.961_962delTG) and one in BRCA2 (c.1963_1963delC). BRCA1/2 mutations were seen in 35.5% of the patients with first and/or second-degree relatives with breast and/or ovarian cancer. Nineteen variants of uncertain significance (VUS) were detected (BRCA1: n = 2 and BRCA2: n = 17), including five distinct missense variants (BRCA1: c.5348 T > C; BRCA2: c.2350A > G, c.3515C > T, c.7534C > T, and c.8351G > A).

Conclusions

Among epithelial ovarian cancer patients unselected for family history of cancer, 19% were BRCA1/2 germline mutation carriers. Almost ¾ of the BRCA mutations, including two large deletions, were detected only once. Our work emphasizes the need of entire gene sequencing and MLPA screening in Brazil.

Background

Among the gynaecological malignancies, ovarian cancer has the highest mortality rate in developed countries and is the second leading cause of mortality in developing countries. In Brazil, 6150 new cases of ovarian cancer are expected in 2016, and in 2013, ovarian cancer accounted for 3283 deaths, indicating its importance in public health [1].....

Screening frail patients before surgery: JAMA release clearly lays out benefits of intervention - HealthNewsReview.org



HealthNewsReview.org

Women dissatisfied with long process to diagnose polycystic ovary syndrome



ScienceDaily

 Endocrine Society
Summary:
A large international survey of women with a common condition called polycystic ovary syndrome (PCOS), which is characterized by reproductive and metabolic problems, found nearly two in three were dissatisfied with the length of time they waited and the number of healthcare professionals they had to see before they received a diagnosis, according to a new study. 
 Respondents lived in 32 countries.
 Nearly half of the 1,385 women surveyed internationally saw three or more healthcare providers before they were diagnosed. The diagnostic process took more than two years for a third of the survey respondents.

Journal Reference:
  1. Melanie Gibson-Helm, Helena Teede, Andrea Dunaif, Anuja Dokras. Delayed diagnosis and a lack of information associated with dissatisfaction in women with polycystic ovary syndrome. The Journal of Clinical Endocrinology & Metabolism, 2016; jc.2016-2963 DOI: 10.1210/jc.2016-2963

(PD1 and CTLA-4) Disabling critical 'node' revs up attack when cancer immunotherapies fall short



ScienceDaily
  
Disabling critical 'node' revs up attack when cancer immunotherapies fall short

Preclinical study shows blocking tumor interferon pathway antagonizes resistance

Date: December 1, 2016

Sunday, December 04, 2016

Immune System, Unleashed by Cancer Therapies, Can Attack Organs - The New York Times



Immune System, Unleashed by Cancer Therapies, Can Attack Organs - The New York Times

New insights and evolving role of pegylated liposomal doxorubicin in cancer therapy (vs doxorubicin)



New insights and evolving role of pegylated liposomal doxorubicin in cancer therapy
http://www.drupjournal.com/pb/assets/raw/Health%20Advance/journals/ydrup/logo.gif
Abstract
 We herein review various pharmacological and clinical aspects of pegylated liposomal doxorubicin (PLD), the first nanomedicine to be approved for cancer therapy, and discuss the gap between its potent antitumor activity in preclinical studies and its comparatively modest achievements in clinical studies and limited use in clinical practice. PLD is a complex formulation of doxorubicin based on pharmaceutical nanotechnology with unique pharmacokinetic and pharmacodynamic properties. Its long circulation time with stable retention of the payload and its accumulation in tumors with high vascular permeability both result in important advantages over conventional chemotherapy. The ability of PLD to buffer a number of undesirable side effects of doxorubicin, including a major risk reduction in cardiac toxicity, is now well-established and confers a major added value in a number of disease conditions. PLD is approved for the treatment of ovarian cancer, breast cancer, multiple myeloma, and Kaposi sarcoma. In addition, clinically significant antitumor activity of PLD has been reported in a number of other cancer types, including lymphomas and soft tissue sarcomas. In spite of this, PLD has not replaced conventional doxorubicin in common applications such as the adjuvant and neoadjuvant treatment of breast cancer, and its use in the clinic has not become as widespread as one may have predicted. Exploiting the unique pharmacology of PLD, analyzing its selective biodistribution and homing to tumors in cancer patients with proper theranostic tools, and harnessing its complex interaction with the immune system, will lead to a more selective and rational use of PLD that may have great impact on future clinical results and may help realize its largely untapped potential.

The Role of Vitamin D and VDR in carcinogenesis: through Epidemiology and Basic Sciences



THE ROLE OF VITAMIN D AND VDR IN CARCINOGENESIS: THROUGH EPIDEMIOLOGY AND BASIC SCIENCES
 

Abstract

In the last two decades vitamin D (VD) research has demonstrated new extraskeletal actions of this pre-hormone, suggesting a protective role of this secosteroid in the onset, progression and prognosis of several chronic noncommunicable diseases, such as cardiovascular disease, diabetes mellitus or cancer. Regarding carcinogenesis, both preclinical and epidemiological evidence available show oncoprotective actions of VD and its receptor, the VDR. However, in late neoplastic stages the VD system (VDS) seems to be less functional, which appears to be due to an epigenetic silencing of the system. In preclinical experimental studies, VD presents oncoprotective actions through modulation of inflammation, cell proliferation, cell differentiation, angiogenesis, invasive and metastatic potential, apoptosis, miRNA expression regulation and modulation of the Hedgehog signalling pathway. Moreover, epidemiological evidence points towards an oncoprotective role of vitamin D and VDR in colorectal cancer. This association is more controversial with breast, ovarian and prostate cancers, although with a few adverse effects. Nonetheless, we should consider other factors to determine the benefit of increased serum concentration of VD. Much of the epidemiological evidence is still inconclusive, and we will have to wait for new, better-designed ongoing RCTs and their results to discern the real effect of vitamin D in cancer risk reduction and therapy. The objective of this literature review is to offer an up-to-date analysis of the role of the VD and VDR, in the onset, progression and prognosis of all types of cancer. We further discuss the available literature and suggest new hypotheses and future challenges in the field of VD research.

The number of cycles of neoadjuvant chemotherapy is associated with prognosis of stage IIIc–IV high-grade serous ovarian cancer



The number of cycles of neoadjuvant chemotherapy is associated with prognosis of stage IIIc–IV high-grade serous ovarian cancer

Abstract

Conclusion

NAC cycles, CA-125 decreasing kinetics, and optimal debulking are independently associated with the prognosis of patients with advanced stage HG-SOC who underwent NAC/IDS and achieved CCR. The number of administered NAC cycles should not exceed 4.

Objective

No consensus exists on the number of chemotherapy cycles to be administered before and after interval debulking surgery (IDS) in patients with advanced stage epithelial ovarian cancer. The present study aims to explore the optimal number of cycles of neoadjuvant chemotherapy (NAC) and post-operation chemotherapy to treat the International Federation of Gynecology and Obstetrics stage IIIc–IV high-grade serous ovarian cancer (HG-SOC).

Materials and Methods

A total of 129 IIIc–IV stage HG-SOC cases were retrospectively analyzed. Cases were comprised of patients who underwent NAC followed by IDS and who achieved clinical complete response (CCR) at the end of primary therapy. Patients were recruited from the Jiangsu Institute of Cancer Research between 1993 and 2013. Optimal IDS-associated factors were explored with logistic regression. The association between progression-free survival (PFS), overall survival (OS) duration, and covariates was assessed by Cox proportional hazards model and log-rank test.

Results

The median number of NAC cycle was 3 (range 1–8). CA-125 decreasing kinetics (p = 0.01) was independently associated with optimal IDS. CA-125 decreasing kinetics, optimal IDS, and NAC cycles was independently associated with OS (p < 0.01, p < 0.01, p = 0.03, respectively) and PFS (p < 0.01, p < 0.01, p = 0.04, respectively). The PFS of patients who underwent ≥5 NAC cycles was shorter than those of patients who underwent <5 NAC cycles (12.3 versus 17.2 months). The PFS and OS of patients who underwent <5 cycles of adjuvant chemotherapy post-IDS were shorter than those of patients who underwent ≥5 cycles (14.2 and 20.3 versus 21.2 and 28.8 months).

Conclusion

NAC cycles, CA-125 decreasing kinetics, and optimal debulking are independently associated with the prognosis of patients with advanced stage HG-SOC who underwent NAC/IDS and achieved CCR. The number of administered NAC cycles should not exceed 4.

Almost 2% of Spanish breast cancer families are associated to germline pathogenic mutations in the ATM gene



 ATM gene
Research suggests that people who carry one mutated copy of the ATM gene in each cell may have an increased risk of developing several other types of cancer. In particular, some studies have shown that cancers of the breast, stomach, bladder, pancreas, lung, and ovaries occur more frequently in ATM mutation carriers than in people who do not carry these mutations. The results of similar studies, however, have been conflicting. Additional research is needed to clarify which other types of cancer, if any, are associated with ATM mutations.
                  ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Almost 2% of Spanish breast cancer families are associated to germline pathogenic mutations in the ATM gene

 Abstract

PURPOSE:

There is still a considerable percentage of hereditary breast and ovarian cancer (HBOC) cases not explained by BRCA1 and BRCA2 genes. In this report, next-generation sequencing (NGS) techniques were applied to identify novel variants and/or genes involved in HBOC susceptibility.

METHODS:

Using whole exome sequencing, we identified a novel germline mutation in the moderate-risk gene ATM (c.5441delT; p.Leu1814Trpfs*14) in a family negative for mutations in BRCA1/2 (BRCAX). A case-control association study was performed to establish its prevalence in Spanish population, in a series of 1477 BRCAX families and 589 controls further screened, and NGS panels were used for ATM mutational screening in a cohort of 392 HBOC Spanish BRCAX families and 350 patients affected with diseases not related to breast cancer.

RESULTS:

Although the interrogated mutation was not prevalent in case-control association study, a comprehensive mutational analysis of the ATM gene revealed 1.78% prevalence of mutations in the ATM gene in HBOC and 1.94% in breast cancer-only BRCAX families in Spanish population, where data about ATM mutations were very limited.

CONCLUSION:

ATM mutation prevalence in Spanish population highlights the importance of considering ATM pathogenic variants linked to breast cancer susceptibility.

Saturday, December 03, 2016

top 10 most read articles (by you) this week/other stats: Ovarian Cancer and Us (blog)



 
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OA: Diagnosis of Lynch syndrome before colorectal resection: does it matter?



Diagnosis of Lynch syndrome before colorectal resection: does it matter?

Ovarian metastasis from uveal melanoma with MLH1/PMS2 protein loss in a patient with germline MLH1 mutated Lynch syndrome: consequence or coincidence?



 uveal tract
YOO-vee-ul trakt)
The middle layer of the wall of the eye. The uveal tract has 3 main parts: (1) the choroid (the tissue layer filled with blood vessels); (2) the ciliary body (the ring of muscle tissue that changes the size of the pupil and the shape of the lens); and (3) the iris (the colored part of the eye). Also called uvea.
                     ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Ovarian metastasis from uveal melanoma with MLH1/PMS2 protein loss in a patient with germline MLH1 mutated Lynch syndrome: consequence or coincidence? 

Abstract
Currently, uveal melanoma is not considered within the Lynch syndrome tumor spectrum. However, there are studies suggesting a contribution of microsatellite instability in sporadic uveal melanoma tumorigenesis. We report a 45-year-old woman who was referred for genetic counseling due to a family history of Lynch syndrome caused by a MLH1 mutation. She originally underwent enucleation (removal) of the right eye secondary to a uveal spindle cell melanoma diagnosed at age 25. The tumor recurred 22 years later presenting as an ovarian metastasis and concurrently a microscopic endometrial endometrioid carcinoma, grade 1/3 was diagnosed. Subsequent studies highlighted that the uveal melanoma showed high microsatellite instability and loss of MLH1 and PMS2 protein expression, with no MLH1 promoter methylation or BRAF mutation. Additionally, a GNAQ mutation was found. We conclude that our patient’s uveal melanoma is most likely related to MLH1 germline mutation and thus Lynch syndrome related. To the best of our knowledge, this is the first report of uveal melanoma showing MLH1/PMS2 protein loss in the context of Lynch syndrome.

Fighting for the ‘right to try’: Terminally ill Canadians want legal right to access unproven treatments



National Post

New data on risk vs benefit for potent CAR-T cancer drugs | Reuters



Reuters

Ovarian Cancer : Articles



Ovarian Cancer : Articles (recent from RightRelevance.com)

Overspending Under Scrutiny | TVO.org re: Auditor General report video 23:05 min



Overspending Under Scrutiny | TVO.org
 
Air Date: 
Dec 02, 2016
Length: 
23:05
 
About this Video
The Auditor General of Ontario, Bonnie Lysyk, speaks with Steve Paikin about some of the key findings in her 2016 annual report. From overbilling by doctors and hospital wait times, to poor quality road repair and problems with contractors at Metrolinx, the report uncovers issues that cost taxpayers millions of dollars and also suggests solutions.

Prognostic significance of lymphadenectomy and prevalence of lymph node metastasis in clinically-apparent stage I endometrioid and mucinous ovarian carcinoma



Prognostic significance of lymphadenectomy and prevalence of lymph node metastasis in clinically-apparent stage I endometrioid and mucinous ovarian... 

 Abstract

OBJECTIVE:

The aim of the present study was to investigate the prevalence of lymph node (LN) metastasis in women with apparent stage I ovarian carcinoma of endometrioid or mucinous histology and to examine the prognostic significance of LN sampling/dissection (LND) on patient survival.

METHODS:

The National Cancer Institute's Surveillance, Epidemiology, and End Results database was accessed and a cohort of surgically-staged women, diagnosed between 1988 and 2013, with apparent stage I ovarian carcinoma of mucinous or endometrioid histology was selected. Information derived from the histopathology report was employed to determine whether LND was performed and the status of harvested LNs. Five-year cancer-specific survival (CSS) rate was calculated following generation of Kaplan-Meier curves. Comparisons were made using the log-rank test. Cox proportional hazard models were constructed to evaluate the effect of LND on survival.

RESULTS:

A total of 3354 and 2855 women with endometrioid and mucinous tumors who met the inclusion criteria were identified. LND was performed in 2307 (68.8%) and 1602 (56.1%) of them (p<0.001), respectively. The rate of histopathologically confirmed LN metastasis was 2.1% and 1.7%, respectively. By multivariate analysis LND was associated with superior cancer-specific mortality only for women with endometrioid carcinoma.

CONCLUSIONS:

Lymph node involvement in women with mucinous and endometrioid ovarian carcinoma grossly confined to the ovary is infrequent. LND is associated with a survival advantage for those with endometrioid carcinoma.

Metachronous Uterine Endometrioid Adenocarcinoma and Peritoneal Mesothelioma in Lynch Syndrome



Metachronous Uterine Endometrioid Adenocarcinoma and Peritoneal Mesothelioma in Lynch Syndrome

Abstract
 Lynch syndrome is a hereditary disease with germline mutation in a DNA mismatch repair gene, most often presenting with colorectal and/or endometrial carcinomas; however, the spectrum of Lynch syndrome–associated tumors is expanding. In this article, we report a case of a primary peritoneal epithelioid mesothelioma that developed in a Lynch syndrome patient 10 months after diagnosis of uterine endometrioid adenocarcinoma. To our knowledge, this is the first reported case of a Lynch syndrome patient with metachronous uterine endometrioid adenocarcinoma and primary peritoneal mesothelioma.

Incidence and survival rates of ovarian cancer in low-income women in Sudan



abstract: Incidence and survival rates of ovarian cancer in low-income women in Sudan


Abstract

Ovarian cancer is the second most common gynecological cancer worldwide. Little is known about the disease in Sudan. The objective of the present study was to evaluate the incidence rate, age and stage at diagnosis, and median survival time of patients presenting at the National Cancer Institute‑University of Gezira (NCI-UG), Sudan. Data were collected in a prospective study of women with ovarian cancer over a period of eleven years of follow‑up (between 2000 and 2011). Descriptive statistics were used to summarize the distribution of the demographics of the sample. The direct method was used to compute the age‑standardized rate (ASR) using data from the 1966 and 2000 World Standard Populations (WSPs). The Kaplan-Meier method was used to estimate survival functions and the median survival time. Log‑rank tests were used to statistically compare between the survival functions. There were steady increases in ovarian cancer incidence rates between 2000 and 2009, with a slight decline noted in 2010 and 2011. The patients' age range was 9‑90. The age‑specific incidence rate increased greatly in women aged 55 years or older. The majority of the patients had stage III or IV disease. The annual ASR using WSPs 1966 and 2000 as standard populations were 3.3 and 3.7 per 100,000 women, respectively. The median survival time was 31 months (95% confidence interval, 19‑43). The 5‑year cumulative survival rate was 38%. In Sudan, ovarian cancer affects postmenopausal women, akin to what is reported in the developed world with high incidence rates. Presenting with advanced stage disease is the predominant factor that results in a short survival time for women.

OA: Validation of the myBRCA HiRisk Hereditary Breast and Ovarian Cancer Test for Population Screening



Validation of the myBRCA HiRisk Hereditary Breast and Ovarian Cancer Test for Population Screening 

authors:  ¶Veritas Genetics, Danvers, MA 01923, §Massachusetts General Hospital, Boston, MA 02114 and & Harvard Medical School, Boston, MA 02115 

 Abstract
 
The myBRCA HiRisk test is a clinical est detecting mutations in 26 genes
associated with increased risk for breast and ovarian cancer. The test is based on next-generation sequencing and multiplex PCR del/dup detection and is performed in Veritas Genetics’ CLIA approved clinical laboratory. The test utilizes saliva or whole blood and was carefully validated on a diverse set of samples with variants representing both rare and relatively common pathogenic mutations. Validation
results are described.

 The analysis was performed blinded to exclude interpretation bias. All
positives counted were pathogenic, i.e., this analysis was not “padded” by including benign polymorphisms as true positives.

Genes tested in myBRCA HiRisk
 
ATM BARD1 BLM BRCA1
BRCA2 BRIP1 CDH1 CHEK2
EPCAM* FAM175A MEN1 MLH1
MRE11A MSH2 MSH6 MUTYH
NBN PALB2 PSM2 PTEN
RAD50 RAD51C RAD51D STK11
TP53 XRCC2
*del/dup analysis only

A Validation Study of Administrative Claims Data to Measure Ovarian Cancer Recurrence and Secondary Debulking Surgery



pdf

text version

A Validation Study of Administrative Claims Data to Measure Ovarian Cancer Recurrence and Secondary Debulking Surgery

(small study)  Abstract

Objective:

Administrative claims data offer an alternative to chart abstraction to assess ovarian cancer recurrence, treatment and outcomes. Such analyses have been hindered by lack of valid recurrence and treatment algorithms. In this study, we sought to develop claims-based algorithms to identify ovarian cancer recurrence and secondary debulking surgery, and to validate them against the gold-standard of chart abstraction.

Conclusions:

A recurrence algorithm based on treatment timing accurately identified ovarian cancer =recurrence. If validated in other populations, such an algorithm can provide a tool to compare effectiveness of recurrent ovarian cancer treatments.
                    ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

 Conclusions

Algorithms based on timing and utilization of select administrative billing codes for secondary treatment may be used to identify ovarian cancer recurrence and secondary debulking procedures. Applying these algorithms to existing sources of administrative
data can enable comparisons of treatment effects on recurrent ovarian cancer morbidity and mortality that can inform treatment decision-making in the
absence of clinical trial results.

70-Gene Signature in Early-Stage Breast Cancer — Comments (eg. QOL...)



70-Gene Signature in Early-Stage Breast Cancer — NEJM

The authors reply:

.....We agree that evaluating health-related quality of life is extremely important. However, patients in our study could potentially have been asked to sign four informed-consent documents, depending on their group assignment, and all the study patients had to comprehend the complexities of the trial, including information on genomic testing. We decided that the addition of quality-of-life questionnaires to the overall study would be too burdensome for the patients, a decision that was supported by patient advocates. At the time of the study, there existed no validated instrument to evaluate the psychological effects of genomic testing on patients, although we agree that such evaluation is important.

Friday, December 02, 2016

(Canada) Genetic discrimination bill headed back to Senate, Liberals deny it reopens possibility for government changes



Genetic discrimination bill headed back to Senate, Liberals deny it reopens possibility for government changes - The Hill Times - The Hill Times

https://www.hilltimes.com/2016/12/01/genetic-discrimination-bill-headed-back-senate-liberals-deny-reopens-possibility-government-changes/89756
While the substance of the bill was untouched, the House Justice Committee passed a coordinating amendment regarding the trans rights bill C-16 that could delay S-201’s passage.
PUBLISHED : Thursday, Dec. 1, 2016 3:12 PM
PARLIAMENT HILL—The bill that pit Liberal backbenchers against cabinet is headed back to the Senate, but not for the reason Justice Minister Jody Wilson-Raybould had hoped.
During Thursday’s clause-by-clause by the Justice and Human Rights Committee, the Senate public bill, S-201, Genetic Non-Discrimination Act passed as it was proposed, untouched, but on the suggestion of Liberal MP Colin Fraser (West Nova, N.S.), a coordinating amendment that will send the controversial, long-fought bill back to the Senate was also passed.
During the brief clause-by-clause on the bill, which was sponsored by Senate Liberal James Cowan, the 10 clauses of the bill as it was proposed passed the committee almost unanimously, but as the bill neared the end of receiving all the approvals needed to pass committee, Mr. Fraser, proposed adding a clause 11.
This clause, as proposed and passed, was aimed at protecting the intent of both Bill S-201 and Bill C-16, the government’s trans rights bill, because they propose to amend the same section of the Canadian Human Rights Act. The technical change added on to the bill makes it so that whichever bill passes second doesn’t override the wording of the first.

HESA - Development of a National Pharmacare Program (federal - Canada)



HESA - Development of a National Pharmacare Program

42nd Parliament, 1st Session
(December 3, 2015 - Present)

Development of a National Pharmacare Program

Last meeting: Thursday, December 1, 2016

Meetings

OA: (Comment) Precision medicine to precision care: managing multimorbidity - The Lancet



Precision medicine to precision care: managing multimorbidity - The Lancet

 Guidance for management of multimorbidity in clinical practice is insufficient.

(interview/video/text) Molecular Testing to Determine Gastric Cancer Treatment



 Molecular Testing to Determine Gastric Cancer Treatment

Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Yelena Y. Janjigian, MD, Memorial Sloan Kettering Cancer Center; Manish Shah, MD, Weill Cornell Medical College; Ian Chau, MD, Royal Marsden Hospital
Published Online: Monday, Nov 28, 2016
Other hereditary syndromes, Lynch syndrome, is associated with gastric cancer. And also FAP is associated with gastric cancer, and that’s actually really quite interesting. A mutation in the APC gene, it affects beta-catenin signaling, and not only is it important in colon cancer, which we all know about, but it’s also important in gastric cancer. It gives you a 10-fold risk. There are things to be wary about, so I always ask my patients about their family history because it comes up not too infrequently.g to Determine Gastric Cancer Treatment

FDA Grants Priority Review to Pembrolizumab for MSI-H Cancer (including non-CRC)



FDA Grants Priority Review to Pembrolizumab for MSI-H Cancer

 In the 3-arm study that was the basis for the new designation, pembrolizumab was administered at 10 mg/kg every 2 weeks to patients with CRC who were MMR-deficient (n = 13) and MMR-proficient (n = 25). Additionally, a separate arm looked at pembrolizumab in patients with MMR-deficient non-CRC malignancies (n = 10). MMR and microsatellite instability testing was conducted using PCR and IHC, which are standard tests conducted for patients with CRC in order to detect Lynch syndrome.

 In the 48 patients analyzed from the study for the ASCO presentation, those with MMR-deficient CRC experienced a DCR of 92% compared with 16% in MMR-proficient tumors. After a median treatment duration of 5.9 months, no patients in the MMR-deficient group who responded had progressed. In patients with MMR-deficient non-CRC tumors, the ORR was 60% and the DCR was 70%.
OS and PFS were not reached in the MMR-deficient group versus a median PFS of 2.3 months (HR, 0.10; 95% CI, 0.03-0.37; P <.001) and an OS of 7.6 months in the MMR-proficient group (HR, 0.22; 95% CI, 0.05-1.00; P = .05)......

 The phase II study enrolled 3 patient cohorts. The first 2 cohorts were patients with CRC, while the third cohort included 21 patients with any solid gastrointestinal tumor that had mismatch repair deficiency.

...This Data from 17 patients with non-CRC GI cancers deficient in mismatch repair were available for analysis: 4 patients with ampullary cancer, 4 with pancreatic cancer, 3 with biliary cancer, 3 with small bowel cancer, and 3 with gastric cancer. Their median age was 60 years; 29% were female, 29% had an ECOG performance score of 0, and 100% had metastatic disease. The median number of prior regimens was 2.cohort was subsequently expanded by 50 patients.....Clinical benefit was observed across tumors with mismatch repair deficiency including cancers of the colon, stomach, duodenum, pancreas, ampulla, and bile ducts.

Novel Agent Moves Into Ovarian Cancer Combinations (fosbretabulin tromethamine)



Novel Agent Moves Into Ovarian Cancer Combinations


A recently launched clinical trial is exploring a new agent to treat patients with advanced, recurrent, platinum-resistant ovarian cancer. 
 
A clinical trial is looking to develop new therapeutic options for women with advanced, recurrent, platinum-resistant ovarian cancer by using a multipronged attack on the tumor vasculature network.

The novel agent fosbretabulin tromethamine is being combined with Avastin (bevacizumab) and physician’s choice of either paclitaxel or pegylated liposomal doxorubicin in the experimental arm of the phase 2/3 FOCUS study (NCT02641639). The regimen will be compared with Avastin plus chemotherapy, which is one option for this patient population.....

Dr Douglas A. Levine: Treatment Continues to Advance in Ovarian Cancer and Other Gynecologic Malignancies



Treatment Continues to Advance in Ovarian Cancer and Other Gynecologic Malignancies

 In an interview with CURE at the recent 2016 Chemotherapy Foundation Symposium, Levine, professor, Department of Obstetrics and Gynecology, director, Division of Gynecologic Oncology, NYU Langone Medical Center, discussed these agents and other advances toward precision medicine in the treatment of patients with gynecologic malignances.
 There has been major progress in treating gynecologic malignancies in recent years, especially for ovarian cancer, says Douglas A. Levine, M.D.
 Rucaparib was granted a priority review by the FDA in August 2016 for patients with BRCA-positive advanced ovarian cancer who have received two or more prior lines of chemotherapy. A final decision is expected by Feb. 23, 2017.

 And in November 2016, a new drug application to the FDA was completed for niraparib as a maintenance treatment for women with recurrent platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer.....

Watson: A Glorified Search Engine?



Comment: Progress in PARP inhibitors beyond BRCA mutant recurrent ovarian cancer? - The Lancet Oncology



Progress in PARP inhibitors beyond BRCA mutant recurrent ovarian cancer? - The Lancet Oncology
 (not open access)
Up to half of newly diagnosed patients with high-grade serous ovarian cancer have a deficit in the homologous recombination system, which repairs double-strand breaks in DNA. Mutations in BRCA1 or BRCA2, which occur in roughly 20% of patients (16% germline and 4% somatic), are the most common cause of homologous recombination deficiency.1 Patients with BRCA mutations have longer overall survival than do patients without such mutations, and their tumours are extremely sensitive to platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors.

References 


References

  1. Nielsen, FC, van Overeem Hansen, T, and Sørensen, CS. Hereditary breast and ovarian cancer: new genes in confined pathways. Nat Rev Cancer. 2016; 16: 599–612
  2. Konstantinopoulos, PA, Ceccaldi, R, Shapiro, GI, and D'Andrea, AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015; 5: 1137–1154
  3. Ledermann, J, Harter, P, Gourley, C et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014; 15: 852–861
  4. Kaufman, B, Shapira-Frommer, R, Schmutzler, RK et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015; 33: 244–250
  5. Gelmon, KA, Tischkowitz, M, Mackay, H et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011; 12: 852–861
  6. Abkevich, V, Timms, KM, Hennessy, BT et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer. 2012; 107: 1776–1782
  7. Watkins, JA, Irshad, S, Grigoriadis, A, and Tutt, AN. Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. Breast Cancer Res. 2014; 16: 211
  8. Swisher, EM, Lin, KK, Oza, AM et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncology. 2016; (published online Nov 28.)http://dx.doi.org/10.1016/S1470-2045(16)30559-9.
  9. Coleman, RL, Swisher, EM, and Oza, AM. Refinement of prespecified cutoff for genomic loss of heterozygosity in ARIEL2 part 1: a phase II study of rucaparib in patients (pts) with high grade ovarian carcinoma. Proc Am Soc Clin Oncol. 2016; 34 (abstr 5540.)
  10. Mirza, MR, Monk, BJ, Herrstedt, J et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016; (published online Oct 7.)