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

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

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.

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

Pageviews all time history     868,035 (2004 - ytd)

		(top 10) By Country (high - low) United States Germany Canada Portugal Romania India United Kingdom Russia Bulgaria France #1: Medscape Ethics Report 2016: Money, Romance, and P... #2: FDA Grants Priority Review to Pembrolizumab for MS... #3: JAMA: Investigation/Comment: Vaginal Mesh (erosion... #4: Watson: A Glorified Search Engine? #5: The Journal of Urology, December 2016 Index #6: OA: Basket Trials in Oncology: A Trade-Off Between... #7: Information Deficits and 2nd Opinion Seeking – A S... #8: ACOG: How to Apply New Guidelines for Evaluating A... #9: Primary Resistance to PD-1 Blockade Mediated by JA... #10: (interview/video/text) Molecular Testing to Determ...

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.

The Agenda with Steve Paikin

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

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.

(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

HESA

Standing Committee on Health

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42nd Parliament, 1st Session

(December 3, 2015 - Present)

Development of a National Pharmacare Program

Last meeting: Thursday, December 1, 2016

Information

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Tuesday, December 6, 2016

Meeting 35

8:45 a.m. - 10:45 a.m. (EST)

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Meeting 34

8:45 a.m. - 10:37 a.m. (EST)

Tuesday, November 29, 2016

Meeting 33

8:46 a.m. - 10:36 a.m. (EST)

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?

Cancer Therapy Advisor 

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)

Published: 28 November 2016

 

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

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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;
    DOI: http://dx.doi.org/10.1056/NEJMoa1611310
    (published online Oct 7.)
    • Crossref

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial - The Lancet Oncology

  This trial is registered with ClinicalTrials.gov, number NCT01891344. Enrolment into ARIEL2 Part 1 is complete, although an extension (Part 2) is ongoing.

 ARIEL2 is an international, multicentre, two-part, phase 2, open-label study done at 49 hospitals and cancer centres in Australia, Canada, France, Spain, the UK, and the USA. In ARIEL2 Part 1, patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma.....

 Interpretation
In patients with BRCA mutant or BRCA wild-type and LOH high platinum-sensitive ovarian carcinomas treated with rucaparib, progression-free survival was longer than in patients with BRCA wild-type LOH low carcinomas. Our results suggest that assessment of tumour LOH can be used to identify patients with BRCA wild-type platinum-sensitive ovarian cancers who might benefit from rucaparib. These results extend the potential usefulness of PARP inhibitors in the treatment setting beyond BRCA mutant tumours.

Rucaparib Prolongs PFS in Ovarian Cancer

Rucaparib Prolongs PFS in Ovarian Cancer - Cancer Therapy Advisor

  The findings suggest that evaluation of tumor LOH can help to identify patients with BRCA wild-type platinum-sensitive ovarian carcinomas who might benefit from treatment with rucaparib.
Reference

1. 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 Oncol. 2016 Nov 28. doi: 10.1016/S1470-2045(16)30559-9 [Epub ahead of print]

Reducing research waste – messages from the Cochrane community

Reducing research waste – messages from the Cochrane community | Cochrane Community


Key messages from the survey and the Special Session include:

• Support priority setting processes for systematic reviews. All Cochrane Review Groups are already encouraged to engage in a formal prioritization process, and many Cochrane Review Groups are already defining their priorities and examples are being documented. However, the processes followed to define the priorities vary, and it also remains a challenge to include priorities of disadvantaged groups and low and middle income countries. Not surprisingly, about 60% of survey respondents indicated Cochrane could do more in priority setting, for example by being more inclusive and by developing a clearer and more consistent process.
• Advocate for systematic reviews with funding organizations: 86% of respondents to the survey felt that Cochrane could do more in working with research funders in advocating systematic reviews be conducted prior to funding new research.
• Speed up the ‘empty review’ process: 62% of survey respondents indicated that ‘empty reviews’ (reviews that have no studies eligible for inclusion or only included a single small RCT) are very to extremely important. “Empty reviews are important but they ought to take weeks not months, at least once the search is complete. As soon as you see the review is empty, getting that out should be very, very quick.” In response to this concern, Cochrane will change the focus of ‘empty reviews’ from guiding clinical practices to identifying research gaps and stimulating further research in relevant areas. A pilot to change the editorial process for empty reviews will take place in 2017.
• Work with partners to strengthen reporting of research: 60% of survey respondents felt that Cochrane should do more in ensuring better reporting of research and research results, among other in clinical trial registries, especially through working with strategic partners such as AllTrials and WHO ICTRP.
• Automate the review process: The production of more rapid reviews is important and automation tools are a means to do this. Project Transform is an important step in this direction, but will need continued contribution from the Cochrane community and beyond to succeed.

OA: Cancer-associated thrombosis and palliative care: an interview with Simon Noble

Cancer-associated thrombosis and palliative care: an interview with Simon Noble, Future Oncology, Future Medicine

 Q CAT is a condition that is not normally discussed, despite it being one of the leading causes of death in cancer patients. Can you tell our readers more about the condition & the risk factors involved?

 Another thing that is very important to note is that 52% of people that get CAT will do so in the first 3 months of diagnosis of cancer. So you have people who are still reeling from their diagnosis of a life-threatening condition and then usually within 3 months of that, usually as they have just started their treatment for it, they will then have another life-threatening condition that is either a deep vein thrombosis or a pulmonary embolus; so the psychological impact of that cannot be underestimated.

...Interestingly, we have done some other research in noncancer patients, which shows that patients who have experienced a clot will develop ongoing anxiety and distress, and proportion of them will develop post-traumatic stress disorder. One of the reasons that triggers post-traumatic stress disorder is an unexpected threat to life and then living with the unknowing of whether that threat is likely to return so it is that uncertainty which causes a lot of the distress....

Q Can you tell our readers about your current research & other ongoing studies?

First of all I am continuing the PELICAN study. We have analyzed data from Spain, which we are writing up at the moment and we are also analyzing data from Canada. We have still got data from France coming in and we have opened recently in New Zealand. We have also got other countries that are opening such as Manila, Singapore and also The Netherlands. We have now got quite a few countries still going so that will be very interesting.....
 (Patient Experience of LIving with CANcer associated thrombosis)

OA: Which BRCA genetic testing programs are ready for implementation in health care? A systematic review of economic evaluations

Which BRCA genetic testing programs are ready for implementation in health care? A systematic review of economic evaluations : Genetics in Medicine

 The main challenge in conducting a systematic review of economic evaluations derives from their high degree of heterogeneity, meaning that results cannot be pooled across studies by meta-analysis or other quantitative synthesis methods.^12,13 Consequently, the majority of such reviews have presented the results obtained in a narrative format.¹¹

   Our survey of the literature found only nine full economic evaluations of BRCA genetic testing. Most of these were of acceptable quality, although some methodological limitations should be mentioned. For example, the included costs were frequently inadequate. Thus, although the societal perspective is the most appropriate for the analysis of health-care programs and five economic evaluations adopted this perspective, none of the authors included social costs.

In conclusion, the results of this systematic review indicate that, although BRCA1/2 population-based screening is currently an inefficient use of health-care resources, population-based screening of the AJ (Ashkenazi Jewish) community appears to be a good value for the money. Furthermore, it is highly likely that FH-based (family-history) screening will prove cost-effective, although further economic evaluations that include the costs of identifying high-risk women are needed to fully justify this conclusion. This point is crucial because counseling strategies to detect at-risk individuals could involve primary-care physicians, and currently physicians seem to be not yet adequately prepared about hereditary breast cancer and BRCA1/2 testing.^47,48 Finally, in contrast to genetic testing for hereditary colorectal cancer (i.e., Lynch syndrome),^49,50,51 there is no evidence for the cost-effectiveness of screening for BRCA1/2 of newly diagnosed cases of breast and ovarian cancers, followed by cascade testing of relatives. However, cancer-based genetic screening programs for BRCA1/2 that includes tools for identifying women at higher risk for inherited forms are very promising in terms of cost-effectiveness. On the contrary, more high-quality studies are needed to prove the cost-effectiveness of BRCA genetic testing as an instrument of secondary prevention in affected women with predisposing gene mutation.

In any case, the price of BRCA1/2 testing is of paramount importance in determining the cost-effectiveness of BRCA1/2 testing programs.⁴⁴ If the cost of testing falls significantly, then all BRCA1/2 testing strategies analyzed in this review—perhaps including population-based screening—are likely to become highly cost-effective interventions.

Excess weight as a risk factor common to many cancer sites: words of caution when interpreting meta-analytic evidence

Excess weight as a risk factor common to many cancer sites: words of caution when interpreting meta-analytic evidence | Cancer Epidemiology, Biomarkers & Prevention

Abstract
 For over a decade, excess body weight, commonly categorized as overweight (body mass index, BMI: 25.0 to 29.9 kg/m2) and obesity (BMI: ≥ 30 kg/m2) has been an established incidence risk factor for several adult cancers (1). For 2012, the burden of disease attributed to elevated BMI was estimated as nearly half-million new cancers worldwide, making this the third highest ranked cancer risk factor globally after smoking and infections (ranked second in most western populations) and an important public health problem (2, 3). In recent years, scientific evidence on BMI-cancer associations has continued to accumulate and reveal positive associations for even more and more cancer sites. Among the most comprehensive and systematic evaluations undertaken on these associations have been through the World Cancer Research Fund (WCRF) continuous update project, which now links excess weight or body fatness to 11 cancers (4).

In 2016, an expert working group of 21 scientists from eight countries, gathered under the auspices of the International Agency for Research on Cancer (IARC), to evaluate the preventive effects of avoidance of excess body fatness on cancer risk. This group extended the list of obesity-related cancers, for which sufficient evidence exists, to thirteen as follows: cancers of the colon and rectum, esophagus (adenocarcinoma), kidney (renal cell), breast (post-menopausal), endometrium, gastric cardia, liver, gallbladder, pancreas, ovary, thyroid, multiple myeloma and meningioma. Considering that excess body adiposity is related to a vast array of metabolic and physiological dysfunctions, underlying biological mechanisms have been identified explaining many of these associations.

Primary Resistance to PD-1 Blockade Mediated by JAK½ Mutations

Primary Resistance to PD-1 Blockade Mediated by JAK½ Mutations |abstract

 Loss of function mutations in JAK½ can lead to acquired resistance to anti-programmed death protein 1 (PD-1) therapy. We reasoned they may also be involved in primary resistance to anti-PD-1 therapy. JAK½ inactivating mutations were noted in tumor biopsies of 1 of 23 patients with melanoma and in 1 of 16 patients with mismatch repair deficient colon cancer treated with PD-1 blockade. Both cases had a high mutational load but did not respond to anti-PD-1 therapy. Two out of 48 human melanoma cell lines had JAK½ mutations, which led to lack of PD-L1 expression upon interferon gamma exposure mediated by inability to signal through the interferon gamma receptor pathway. JAK½ loss-of-function alterations in TCGA confer adverse outcomes in patients. We propose that JAK½ loss-of-function mutations are a genetic mechanism of lack of reactive PD-L1 expression and response to interferon gamma, leading to primary resistance to PD-1 blockade therapy.

(aka. the reality of some lawsuit/settlements) Jarvis: $1,500 for a lifetime of worry and fear (media/diluted chemo/lawsuits)

Jarvis: $1,500 for a lifetime of worry and fear

Should research volunteers get to see their medical tests?

Should research volunteers get to see their medical tests?