Comparative microRNA profiling of sporadic and BRCA1 associated basal-like breast cancers

Full text 

Background

While a number of studies have examined miRNA profiles across the molecular subtypes of breast cancer, it is unclear whether BRCA1 basal-like cancers have a specific miRNA profile. This study aims to compare grade independent miRNA expression in luminal cancers, sporadic and BRCA1 basal-type breast cancers. It also aims to ascertain an immunohistochemical profile regulated by BRCA1 specific miRNAs for potential diagnostic use.

Conclusion

In summary, our study demonstrates basal-like cancers have a grade independent miRNA expression profile. Furthermore miRNA driven differences in the expression of proteins by BRCA1 vs. sporadic basal cancers may be detected via immunohistochemical staining of paraffin embedded tissue. These findings may have important diagnostic implications, as immunohistochemical assessment of basal cancers, in addition to the patient’s family and clinical history, may potentially identify patients who may benefit from BRCA1 gene testing. Lastly, there is evidence to suggest BRCA1 deficient cancers may be sensitive to PARP inhibitors [47]. Hence stratification of basal-like cancers, based on the “BRCA1-ness” of their miRNA signature, generated from archival FFPE tissue, may be highly relevant to clinical trials investigating targeted therapies, such as PARP inhibitors [48]. Validation of these findings in larger patient cohorts, however, will be required to assess the diagnostic utility of such an approach.

Long-term follow-up of patients with an isolated ovarian recurrence after conservative treatment of epithelial ovarian cancer

abstract

 Long-term follow-up of patients with an isolated ovarian recurrence after conservative treatment of epithelial ovarian cancer: review of the results of a international multicenter study comprising 545 patients

OBJECTIVE:

To determine the long-term outcomes of patients with an isolated ovarian recurrence after fertility sparing surgery (FSS) for epithelial ovarian cancer (EOC) and to evaluate the recurrence rates (and location) according to the new 2014 International Federation of Gynecology and Obstetrics (FIGO) staging system.

DESIGN:

Retrospective multicenter study.

SETTING:

Teams having reported recurrence after FSS for EOC.

PATIENT(S):

Four series comprising 545 patients undergoing FSS and 63 (12%) recurrences.

INTERVENTION(S):

FSS (salpingo-oophorectomy for a majority of cases) for EOC.

MAIN OUTCOMES MEASURE(S):

Recurrences rates and characteristics of recurrent disease.

RESULT(S):

Among 63 recurrent patients, 24 (38%) recurrences were isolated on the spared ovary, and 39 (62%) arose at an extraovarian site. Among the patients with an isolated ovarian recurrence, three patients died after a median follow-up period of 186 months (range: 28-294 months). Among the patients with recurrent extraovarian disease, 24 died and 7 were alive with persistent disease after a median follow-up period of 34 months (range: 3-231 months). The overall rate of isolated ovarian and extrapelvic recurrences was higher for grade 3 tumors (compared with grades 1/2).

CONCLUSION(S):

The long-term survival of patients with an isolated ovarian recurrence after FSS for EOC remains favorable. The prognosis of patients with an extraovarian recurrence is poor compared with those who have an isolated recurrent ovarian tumor. Grade 3 tumors (compared to grades 1/2) give rise to a higher rate of extraovarian recurrences.

Malignant Pericardial Effusion in Ovarian Malignancy: A Treatable Oncologic Emergency

abstract

BACKGROUND:

Pericardial tamponade is a life-threatening condition that can occur, albeit rarely, in patients with ovarian cancer. Whether or not prolonged survival is possible after such an event is debatable. Our aim was to describe our experience with seven ovarian cancer patients who experienced malignant cardiac tamponade at tumor diagnosis or at recurrence.

CASE REPORT:

Six patients were treated with pericardiocentesis and one with pericardial fenestration. Survival after tamponade ranged from 3 to 72 weeks. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: We suggest that when pericardial effusion occurs in patients with recurrent ovarian cancer, timely diagnosis and proper management might allow palliation and prolongation of life.

Pleural metastasis of ovarian cancer. A price to pay for debulking the upper abdomen - Minerva Ginecologica 2015 August;67(4):384-5 - Minerva Medica - Journals

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Theorist's Toy: Equipoise - JNCCN

Theorist's Toy: Equipoise

Debbie is a real patient in crisis. She is poised, with her pen faltering at the end of the consent form, and says, ”You really are telling me that I'll just take the tablets and I won't know and you won't know whether it's the new wonder drug or placebo, and that there is a 1 in 3 chance it's placebo?” The 8 capsules of olaparib or placebo will be hard enough to swallow, but in this moment, she's choking on just how much dedication is required to be a participant in a randomized clinical trial (RCT). Debbie recently died and had quite literally laid down her life early in the pursuit of a greater good.....

....Although we often cite equipoise as the trump card in the overlap between clinical care and scientific research, the ethics of equipoise are complicated and controversial.¹ This played out on the front page of The New York Times² during the development of vemurafenib.³ Equipoise is not the main justification for an RCT being ethical and, in a pure form, rarely exists. Very rarely with the newer treatments can we explain randomization in RCTs with a coin flip of equitable allocation, or the illustration of 2 envelopes; you get to pick, and both contain equally good options (Gore M, personal communication)..... 

Clinical Sequencing Contributes to a BRCA-Associated Cancer Rediagnosis That Guides an Effective Therapeutic Course

NCCN: open access

Abstract
Cancer is currently classified and treated using an approach based on tissue of origin. Ambiguous or incorrect diagnoses, however, are common and often go unnoticed......

Case and Results

A 54-year-old woman presented to a community hospital with jaundice, anorexia, and 20-pound weight loss. An abdominal and pelvic CT showed a 5-cm mass at the head of the pancreas with intrahepatic and extrahepatic biliary dilatation and involvement of the celiac plexus with extensive retroperitoneal lymphadenopathy (Figure 1A and B). Results of a CT-guided biopsy of the pancreatic mass showed a poorly differentiated adenocarcinoma. Initial review of the specimen with immunohistochemistry indicated that it was positive for CK7 and CK19 and negative for CK20, TTF-1, ER, CGA, and synaptophysin, with these results interpreted as PDA (pancreatic). On external review, a tertiary medical center pathologist concurred with this diagnosis. The patient underwent decompressive bile duct stenting and was referred to our institution with a diagnosis of stage IV PDA.

On presentation, because of the patient's relatively young age at diagnosis of advanced-stage cancer, she was referred for genetic counseling, which revealed no family history of hereditable cancer. Plasma was sent for cell-free DNA (cfDNA) sequencing.⁷ A baseline staging CT scan was obtained before the planned initiation of gemcitabine and nanoparticle albumin-bound paclitaxel therapy.⁸ Results of this CT showed evolving findings, including ascites with peritoneal thickening, a complex 6.1-cm right adnexal lesion, and the absence of a discrete pancreatic mass, which was reinterpreted as a lymph node conglomerate (Figure 1B and C). Extensive celiac plexus retroperitoneal lymphadenopathy with bile duct compression remained. An examination of a repeat biopsy again showed poorly differentiated adenocarcinoma. However, immunohistochemistry staining at our institution suggested a pelvic serous carcinoma (Figure 1C, inset). These new CT results and disparate pathologic conclusions suggested the possibility that this patient was incorrectly diagnosed with PDA and instead had advanced serous ovarian cancer. However,.....

Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium : British Journal of Cancer

Abstract

 Background:

Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer.

Methods:

We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype.

Results:

Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30–34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99–1.23); BMI: 35, pHR: 1.12 (95% CI: 1.01–1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m⁻²) and endometrioid subtypes (pHR: 1.08 per 5 kg m⁻²), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m⁻²) subtype, but only the association with high-grade serous cancers was significant.

Conclusions:

Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.

Ludwig, CRI launch clinical trials to evaluate immunotherapies ...

medical news

.... The other trial, which Ludwig and CRI launched in 2013, is a Phase 1 nonrandomized multicenter trial evaluating the combination of durvalumab with another checkpoint blockade therapy (tremelimumab, anti-CTLA-4) for the treatment of a variety of advanced solid tumors including ovarian cancer, non-small cell lung cancer, colorectal cancer, head and neck cancer, cervical cancer and kidney cancer.
Both clinical trials, which are now under way, are part of a larger clinical research program supported by Ludwig and CRI to speed the evaluation of novel cancer immunotherapies, alone or in combination with other cancer drugs.....

Canadian HRT users can claim compensation from $13M fund

media

Female Hormonal Factors & Risk of Endometrial Cancer in Lynch Syndrome

JAMA Network

Importance  Apart from hysterectomy, there is no consensus recommendation for reducing endometrial cancer risk for women with a mismatch repair gene mutation (Lynch syndrome).

Objective  To investigate the association between hormonal factors and endometrial cancer risk in Lynch syndrome.

Design, Setting, and Participants  A retrospective cohort study included 1128 women with a mismatch repair gene mutation identified from the Colon Cancer Family Registry. Data were analyzed with a weighted cohort approach. Participants were recruited between 1997 and 2012 from centers across the United States, Australia, Canada, and New Zealand.

Exposures  Age at menarche, first and last live birth, and menopause; number of live births; hormonal contraceptive use; and postmenopausal hormone use.

Main Outcomes and Measures  Self-reported diagnosis of endometrial cancer.

Results  Endometrial cancer was diagnosed in 133 women (incidence rate per 100 person-years, 0.29; 95% CI, 0.24 to 0.34). Endometrial cancer was diagnosed in 11% (n = 70) of women with age at menarche greater than or equal to 13 years compared with 12.6% (n = 57) of women with age at menarche less than 13 years (incidence rate per 100 person-years, 0.27 vs 0.31; rate difference, −0.04 [95% CI, −0.15 to 0.05]; hazard ratio per year, 0.85 [95% CI, 0.73 to 0.99]; P = .04). Endometrial cancer was diagnosed in 10.8% (n = 88) of parous women compared with 14.4% (n = 40) of nulliparous women (incidence rate per 100 person-years, 0.25 vs 0.43; rate difference, −0.18 [95% CI, −0.32 to −0.04]; hazard ratio, 0.21 [95% CI, 0.10 to 0.42]; P < .001). Endometrial cancer was diagnosed in 8.7% (n = 70) of women who used hormonal contraceptives greater than or equal to 1 year compared with 19.2% (n = 57) of women who used contraceptives less than 1 year (incidence rate per 100 person-years, 0.22 vs 0.45; rate difference, −0.23 [95% CI, −0.36 to −0.11]; hazard ratio, 0.39 [95% CI, 0.23 to 0.64]; P < .001). There was no statistically significant association between endometrial cancer and age at first and last live birth, age at menopause, and postmenopausal hormone use.

Conclusions and Relevance  For women with a mismatch repair gene mutation, some endogenous and exogenous hormonal factors were associated with a lower risk of endometrial cancer. These directions and strengths of associations were similar to those for the general population. If replicated, these findings suggest that women with a mismatch repair gene mutation may be counseled like the general population in regard to hormonal influences on endometrial cancer risk.

Medical Facts versus Value Judgments — Toward Preference-Sensitive Guidelines — NEJM

 Perspective: NEJM (open access) + readers' comments

......  Good decision making requires familiarity with decision-relevant facts and recognition of the values relevant to weighing the pros and cons of the alternatives. If physicians or medical societies — in presenting treatment alternatives to patients or developing guidelines laying out the standard of care — fail to recognize when they have gone beyond the medical facts to make value judgments, they will harm patients by taking viable choices away from them.

New Articles in PLOS Journals Published between Jun 30 2015 - Jul 07 2015 (OC related)

New Articles in PLOS Journals

Published between Jun 30 2015 - Jul 07 2015

Ascites Increases Expression/Function of Multidrug Resistance Proteins in Ovarian Cancer Cells
Lihong Mo, Vendula Pospichalova, Zhiqing Huang, Susan K. Murphy, Sturgis Payne, Fang Wang, Margaret Kennedy, George J. Cianciolo, Vitezslav Bryja, Salvatore V. Pizzo, Robin E. Bachelder

Hsp90 Is a Novel Target Molecule of CDDO-Me in Inhibiting Proliferation of Ovarian Cancer Cells
Dong-Jun Qin, Cai-Xia Tang, Li Yang, Hu Lei, Wei Wei, Ying-Ying Wang, Chun-Min Ma, Feng-Hou Gao, Han-Zhang Xu, Ying-Li Wu

CDK5 Regulates Paclitaxel Sensitivity in Ovarian Cancer Cells by Modulating AKT Activation, p21Cip1- and p27Kip1-Mediated G1 Cell Cycle Arrest and Apoptosis
Shu Zhang, Zhen Lu, Weiqun Mao, Ahmed A. Ahmed, Hailing Yang, Jinhua Zhou, Nicholas Jennings, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Roberto Miranda, Wei Qiao, Veera Baladandayuthapani, Zongfang Li, Anil K. Sood, Jinsong Liu, Xiao-Feng Le, Robert C. Bast

Meta-Analysis of Public Microarray Datasets Reveals Voltage-Gated Calcium Gene Signatures in Clinical Cancer Patients
Chih-Yang Wang, Ming-Derg Lai, Nam Nhut Phan, Zhengda Sun, Yen-Chang Lin

Analytical Validation of AmpliChip p53 Research Test for Archival Human Ovarian FFPE Sections
Matthew J. Marton, Andrew R. McNamara, D. Michele Nikoloff, Aki Nakao, Jonathan Cheng
 
Molecular Analysis of Mixed Endometrioid and Serous Adenocarcinoma of the Endometrium
Kate Lawrenson, Elham Pakzamir, Biao Liu, Janet M. Lee, Melissa K. Delgado, Kara Duncan, Simon A. Gayther, Song Liu, Lynda Roman, Paulette Mhawech-Fauceglia
 
Cell Free DNA of Tumor Origin Induces a ‘Metastatic’ Expression Profile in HT-29 Cancer Cell Line
István Fűri, Alexandra Kalmár, Barnabás Wichmann, Sándor Spisák, Andrea Schöller, Barbara Barták, Zsolt Tulassay, Béla Molnár


Data Mining Approaches for Genomic Biomarker Development: Applications Using Drug Screening Data from the Cancer Genome Project and the Cancer Cell Line Encyclopedia
David G. Covell


The Use of Non-Variant Sites to Improve the Clinical Assessment of Whole-Genome Sequence Data
Alberto Ferrarini, Luciano Xumerle, Francesca Griggio, Marianna Garonzi, Chiara Cantaloni, Cesare Centomo, Sergio Marin Vargas, Patrick Descombes, Julien Marquis, Sebastiano Collino, Claudio Franceschi, Paolo Garagnani, Benjamin A. Salisbury, John Max Harvey, Massimo Delledonne

Office of the Health Ombudsman - Australia

Australia

 Our functions

• Receive and investigate complaints about health services and health service providers, including registered and unregistered health practitioners.
• Decide what action to take in relation to those complaints and, in certain instances, take immediate action to protect the safety of the public.
• Monitor the health, conduct and performance functions of the Australian Health Practitioner Regulation Agency and national health practitioner boards.
• Provide information about minimising and resolving health service complaints.
• Report publicly on the performance of our functions.

Ombudsman Saskatchewan - how it works in Sask.

Ombudsman Saskatchewan

 Ombudsman Saskatchewan has jurisdiction over many health entities in the province, including:

• the Saskatchewan Regional Health Authorities
• the Ministry of Health
• the Saskatchewan Cancer Agency
• many EMS and ambulance services
• many hospitals and health care centres
• many special care homes
• many addiction services and treatment centres

If you feel that an administrative or policy decision of one of these entities is unfair, try to resolve it by talking to the person who made the decision or to a director or manager. If you are still unable to resolve it, you are welcome to contact us.
Complaints or inquiries about services or access to those services provided by a Regional Health Authority should go to the Quality of Care Coordinator for the applicable Regional Health Authority. If the matter remains unresolved, you are welcome to contact us. For more information about our services in health care, see our health care publications page.

Health Firings: How Ombudsperson's Hands Could Be Tied (lessons for Ontario's new Health Ombudsman)

media

Excellent Care for All Act, 2010, S.O. 2010, c. 14 | Ontario.ca

Act, 2010, S.O. 2010, c. 14 | Ontario.ca

  Browse laws 
 

Français

Excellent Care for All Act, 2010

S.o. 2010, chapter 14

Consolidation Period: From December 11, 2014 to the e-Laws currency date.

Last amendment: 2014, c. 13, Sched. 5.

CONTENTS

Preamble
Interpretation
1.	Definitions
2.	Responsibility of health care organizations
Quality Committee
3.	Quality committee to be established
4.	Responsibilities of quality committees
Surveys
5.	Surveys
Patient Relations Process
6.	Patient relations process
Patient Declaration of Values
7.	Patient declaration of values
Annual Quality Improvement Plans
8.	Quality improvement plans
Performance based Compensation
9.	Performance based compensation
Council
10.	Council
11.	No personal liability
12.	Functions of Council
13.	Reports
Patient Ombudsman
13.1	Patient ombudsman
13.2	Complaints
13.3	Investigation
13.4	Recommendations
13.5	Reports by patient ombudsman
13.6	Personal health information and the patient ombudsman
13.7	Immunity
Offences
14.	Offences
Regulations
15.	Regulations — Minister
16.	Regulations — Lieutenant Governor in Council

  cont'd....

Help Ontario Recruit Its First Patient Ombudsman - share your feedback by Aug 31st

Blogger's Note:  Read this first before taking the survey:

 Excellent Care for All Act, 2010, S.O. 2010, c. 14

Versions

Regulations under this Act

current	December 11, 2014 – (e-Laws currency date)
	January 1, 2011 – December 10, 2014
	October 25, 2010 – December 31, 2010
	1 more

___________________________________________________________________

 
Government of Ontario Newsroom

 Backgrounder

Ontario's First Patient Ombudsman

July 7, 2015 10:45 A.M.

Ministry of Health and Long-Term Care (Ontario)

Ontario is taking steps toward appointing its first Patient Ombudsman to help people who have an unresolved complaint about their care at a hospital, long-term care home or Community Care Access Centre.

Background
The vast majority of complaints about health care quality are resolved by current patient relations processes.  There are, however, some complaints that are outside the scope of existing oversight bodies.  To close any gaps that may continue to exist, the Ministry of Health and Long-Term Care is establishing Ontario's first Patient Ombudsman.
The Patient Ombudsman position was created in December 2014 as part of Bill 8, the Public Sector and MPP Accountability and Transparency Act, 2014, which includes amendments to the Excellent Care for All Act, 2010.

The Role of the Patient Ombudsman
The Patient Ombudsman will help patients who have not had their concerns resolved through existing complaint mechanisms in a way that meets their needs.
As set out in the law, the Patient Ombudsman's powers and responsibilities will be specifically tailored to the health care system. Once appointed, the Patient Ombudsman will:

• Respond to unresolved complaints from patients, residents, clients - as well as their caregivers - about their health care experience at a hospital, long-term care home or Community Care Access Centre
• Investigate a health sector organization on his or her own initiative
• Make recommendations to a health sector organization that is the subject of an investigation, following the conclusion of that investigation
• Report to the Minister of Health and Long-Term Care on his or her activities and recommendations annually and provide reports to Local Health Integration Networks as appropriate

The Patient Ombudsman will not try to resolve or investigate complaints that are the responsibility of another person or body such as the Health Services Appeal and Review Board and the Information and Privacy Commissioner.

Selection and Appointment
The Patient Ombudsman will be selected via a three-stage process:

• Stage 1 - Identify key skills, competencies and training of a Patient Ombudsman. This stage will include a public consultation.
• Stage 2 - Assess, select and recommend a Patient Ombudsman.
• Stage 3 - Finalize appointment of a Patient Ombudsman.

The term of the Patient Ombudsman's appointment will be five years, with the possibility of reappointment for an additional five-year term.  The government cannot shorten that term, except under exceptional circumstances.
Once appointed by the Lieutenant Governor in Council, the Patient Ombudsman will be housed in Health Quality Ontario. This relationship will allow the Patient Ombudsman to build on Health Quality Ontario's expertise - as well as its responsibility for promoting quality improvement and enhancing patient relations across health care organizations.
All reports made by the Patient Ombudsman will be made available on Health Quality Ontario's website.

Strengthening the Patient Relations Process in Public Hospitals
The introduction of the Patient Ombudsman is one of two government initiatives to strengthen complaints management processes in the health care system. The second initiative - new regulations under the Excellent Care for All Act will strengthen the patient relations process in public hospitals.
Once in force on September 1, 2015, new regulations under the Excellent Care for All Act will require public hospitals to:

• Uphold minimum standards for how patient complaints are managed
• Engage patients and their caregivers in designing, reviewing and maintaining the hospital's complaint processes
• Have a staff member to oversee the patient-relations process; and present internal reports on patient relations to the hospital's Quality Committee at least twice a year
• Engage patients and their caregivers when developing Quality Improvement Plans.

Health Quality Ontario and the Ontario Hospital Association will support the hospital sector in the adoption of practices that reflect these requirements. While these new regulations will only apply to public hospitals, other sectors may choose to adopt the principles of the regulations as well.
Taken together, these two initiatives will help ensure that patients are at the centre of the health care system; and that patient concerns are addressed in a structured manner.

 Patient Ombudsman: share your feedback

Shut up and sip your coffee

Healthnewsreview

 Brian Palmer of Slate sounds like he’s as fed up with observational studies about coffee’s benefits and coffee’s harms as we are.
He published a piece, “Shut Up and Sip: Coffee is neither good nor bad for you.  Now you may go.”  It makes me think of the book (cover image at right) written by my friend, Robert Davis, PhD.  You should read Palmer’s entire Slate piece yourself, so I’ll only offer this one excerpt:

“A century’s worth of research proves that coffee’s effects on human health are marginal at most. Unless you belong to some particularly sensitive group, the choice to drink or abstain will neither shorten nor lengthen your life in a noticeable way. If there’s a lesson to be had from 100 years of studying this question, it is this: Look hard enough for something to worry about, and you’ll find it—even if it’s not there.”....

Patient Voices on Social Media - When patients speak – some hear golden tones and others noise

HealthNewsReview.org

  A Brookings Institute economics expert and a patient advocate argued with each other last week during a live Google chat. They disagreed about the voices of patients, and how much these voices should count. Their debate is just one of hundreds going on as to how and where and when to register patient feedback in health care. The two of them had spent almost a week in barbed exchanges on Twitter, but were relatively kind to each other at the live chat.....

"Cancer-fighting spices": news or nonsense?

HealthNewsReview.org

Women with ovarian cancer in England to have increased access to genetic testing | Target Ovarian Cancer

Target Ovarian Cancer

‘Navigators’ for cancer patients: A nice perk or something more? - The Washington Post

media
 
....In the end, many say, debating patient navigation may be asking the wrong question. Why not, they wonder, spend the money and energy needed to overhaul the entire cancer-treatment system?
“One question worth asking is why do [patient navigators] exist,” Ramsey said. “And the reason is the cancer community has done a very poor job of helping patients through the system. The fact that navigation exists is kind of an indictment of the cancer-care system.”

Use of Systemic Hormone Therapy After Age 65 - North American Menopause Society

medscape

....Provided that the woman has been advised of the increase in risks associated with continuing HT beyond age 60 and has clinical supervision, extending HT use with the lowest effective dose is acceptable under some circumstances, such as for the woman who has persistent bothersome menopausal symptoms and for whom her clinician has determined that the benefits of menopause symptom relief outweigh the risks. Use of HT should be individualized and not discontinued solely based on a woman's age.^[5] The decision to continue or discontinue HT should be made jointly by the woman and her healthcare provider.

 References

1. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause 2012;19:257-271.
2. Avis NE, Crawford SL, Greendale G, et al; Study of Women's Health Across the Nation (SWAN). Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med 2015;175:531-539.
3. Gartoulla P, Worsley R, Bell RJ, Davis SR. Moderate to severe vasomotor and sexual symptoms remain problematic for women aged 60 to 65 years. Menopause 2015;22:XXX-XXX.
4. Kaunitz AM. Extended duration use of menopausal hormone therapy. Menopause 2014;21:679-681.
5. ACOG Practice Bulletin No. 141: management of menopausal symptoms. Obstet Gynecol 2014;123:202-216.

Upper urinary tract disease: what we know today and unmet needs (Lynch syndrome patients)

open access

.....Several tissue, blood, genetic or urine based biomarkers, such as microsatellite instability (MSI) of the tumor, p53, E-cadherin, HIF1alpha, and ki-67 have been proposed to help in the prognostication of UTUC (15). Krabbe et al. reported in 475 patients treated with RNU that Ki-67 was an independent prognosticator of recurrence free survival (RFS) and CSS for high grade tumors (16). Bagrodia et al. similarly demonstrated that both PI3K and cyclin D, two mTOR biomarkers, were associated with adverse pathologic results and worse oncological outcomes in a cohort of 620 patients who underwent RNU or partial ureterectomy (17).
To date, none of these potential biomarkers have been integrated to clinical practice or predictive models.....

 Conclusions
Ten years of intense collaborative efforts in basic and clinical research have made the natural history of UTUC more comprehensible and predictable. Current management is based, however, on low level evidence and there are many challenges to face in the future. There is a need to clarify the role of KSP management, topical agents, LND, and perioperative chemotherapy. New further collaborative efforts are mandatory to propose ambitious multi-institutional studies with preferentially prospective design.

MSI is not an important feature in early onset pancreatic carcinoma (Lynch/EPCAM)

Abstract A37: AACR

Background and Aim: There is scant information on pancreatic cancer occurring at young age. About 5 to 10 percent of patients with pancreatic cancer have a family history of pancreatic cancer, which is partially due to defined hereditary syndromes like Lynch syndrome. Recently, we have identified deletions of the 3’ end of the EPCAM gene as a novel cause of this hereditary syndrome. In the cohort of patients with EPCAM deletions a relatively high number of pancreatic cancers and duodenal cancers were observed. We therefore aimed to assess whether development of pancreatic or duodenal cancer at young age might be an indication of EPCAM-associated Lynch syndrome. 

Conclusion: This nationwide study cohort suggests that early onset pancreatic cancer and ampulla of Vater cancer are at most rarely associated with (EPCAM-associated) Lynch syndrome, in contrast to early onset duodenal cancer.

Prevalence of germline BRCA & MMR gene mutations in pancreatic cancer

Abstract B113: AACR

AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA

Background: Germline mutations of BRCA1, BRCA2, MLH1, MSH2, and MSH6 are known to increase risk of pancreatic cancer. However, the prevalence of pathogenic germline mutations of these genes among pancreatic cancer patients is unknown. Accurately characterizing the frequencies of mutations of these genes will inform patient selection for future gene discovery studies and, clinically, foster screening strategies and tailored treatments.

Objective: To determine the prevalence of pathogenic germline mutations of BRCA1, BRCA2, MLH1, MSH2, and MSH6 in a cohort of pancreatic cancer patients, and to determine the association between mutation carrier status and personal and family history of cancer.

Methods: The Ontario Pancreas Cancer Study (OPCS) enrolls all consenting participants with a diagnosis of pancreatic cancer into a province-wide electronic pathology database. A cross-sectional sample of 300 patients from 715 OPCS probands enrolled between April 2003 and August 2012 were randomly selected from three strata based on a family history of pancreatic, breast, and ovarian cancer. Targeted next-generation sequencing was successfully performed on germline DNA from 291 of the 300 selected probands. Mutations were classified as benign, of unknown significance, or pathogenic by literature and database review. Pathogenic mutations were confirmed with Sanger sequencing. Prevalence estimates representing the whole OPCS were estimated using the Horvitz-Thompson estimator. Univariate analysis determined association between carrier status and clinical covariates, and regression analysis for overall survival.

Results: A total of 7 pathogenic germline mutations were identified: 1 BRCA1, 2 BRCA2, 1 MLH1, 2 MSH2, and 1 MSH6. The estimated prevalence of pathogenic mutations in BRCA1 and BRCA2 among probands in this OPCS series was 1.1% (95% confidence interval: 0.1-2.0%); in the mismatch repair genes MLH1, MSH2 , and MSH6 it was 1.5% (0.3-2.6%). Both a personal history of colorectal cancer and a first-degree relative with colorectal cancer, breast cancer, or melanoma were significantly associated (p<0.001 and p<0.01, respectively) with MMR mutations. There were no significant differences in tumor location within the pancreas (head/uncinate versus body/tail), clinical nodal status, rates of resection, age at diagnosis, BMI, history of smoking, history of pancreatitis, family history of pancreatic cancer, family history of colorectal cancer, or differences in survival between the MMR or sporadic cohorts.

Conclusion: This study is the first to quantify population-based prevalences of germline mutations of BRCA1, BRCA2, MLH1, MSH2, and MSH6 in pancreatic cancer. Surprisingly, the prevalence of pathogenic germline mutations of the MMR genes in pancreatic cancer is higher than expected, and is comparable to that of BRCA1 and BRCA2. The prevalence of the MMR germline mutations is also comparable to the prevalence of MMR germline mutations in colorectal cancer cohorts. Relatives who carry MMR gene mutations can benefit from tailored cancer prevention strategies; thus mutational analysis of MLH1 , MSH2, and MSH6 should be included in molecular genetic testing and counseling strategies for pancreatic cancer patients, especially those with a family history of malignancy. Translational studies will follow to determine if stratifying pancreatic cancer risk by familial susceptibility genes, as in colorectal cancer, fosters tailored and cost-effective primary and secondary prevention strategies for carriers. Moreover, unique chemotherapy sensitivity and resistance patterns would be expected for MMR-associated pancreatic cancer, as is emerging for BRCA-associated pancreatic cancer.

Monitoring performance of progression assessment criteria for cancer antigen 125 among patients with ovarian cancer compared by computer simulation

abstract

Background: Cancer antigen 125 (CA125) is used to monitor tumor burden among patients with advanced serous epithelial ovarian cancer. The purpose is to compare the monitoring performance of seven previously proposed criteria.  
Materials & methods: The CA125 assessment criteria were applied to simulated datasets. We investigated the ability to provide information on CA125 increments as well as their robustness against false positive signals.  
Results: For baseline concentrations above cut-off, the best performing criterion was based on a confirmed increment ≥2.5-times the nadir concentration. For baseline concentrations below cut-off, the best performing criterion was based on a confirmed increment from ≤ cut-off to >two-times cut-off.  
Discussion: Computer simulation models may be useful for a preclinical validation of criteria to be investigated in clinical trials.

Prognostic value of circulating tumor cells and disseminated tumor cells in patients with ovarian cancer

open access: Journal of Ovarian Research | Full text | Prognostic value of circulating tumor cells and disseminated tumor cells in patients with ovarian cancer: a systematic review and meta-analysis

Abstract

Recent studies have shown diagnostic and prognostic values of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) in various cancers, including ovarian cancer. We aimed to evaluate the association of CTCs and/or DTCs with the clinical outcomes of ovarian cancer. Clinical studies of CTCs/DTCs of ovarian cancer were included for systematic review and meta-analysis. A total of 236 studies were screened but only 16 qualified studies with 1623 subjects were included....

.... In total, there were 1623 patients, and the sample size of each study was ranged from 43 to 216. Most studies were published between 2002 and 2014, 4 studies from US, 11 studies from Europe and 1 study from Asia. There were 6 studies including 459 patients recorded the prognostic values of DTCs detected in bone marrow and 10 studies including 1164 patients recorded the prognostic values of CTCs detected in peripheral blood. Seven out of 16 studies had positive results of CTC/DTC effects on survival. Four out of 16 had negative results, remaining 5 studies had controversial conclusions....
 

Conclusion

In conclusion, available evidence supports that CTCs/DTCs were significantly associated with advanced tumor stage, residual diseases, and treatment response, but not with histological types and lymph node metastasis in patients with ovarian cancer. Moreover, CTCs also were significantly associated with a poorer survival. CTCs/DTCs could be a reliable non-invasive prognostic marker for ovarian cancer. Clinical management based on CTCs/DTCs could be useful for determining which patients would potentially benefit from adjuvant therapy.

A method to investigate the anti-metabolic activity of anti-cancer agents on ovarian cancer cells ....

open access: Journal of Ovarian Research

 Brief communication A method to investigate the anti-metabolic activity of anti-cancer agents on ovarian cancer cells cultured in a 96-well high throughput format
Published:4 July 2015

 Background

An early step of advanced ovarian cancer begins when floating cancerous cells as single cells or small clusters grow on the peritoneal surface. This surface is rich in extracellular matrix (ECM) proteins, which have profound effects on cellular behaviour and can facilitate cancer progression. Subsequently, this ECM may alter cellular metabolism making cancer cells susceptible to chemotherapeutic agents differently. Therefore, generating a cell culture tool in vitro that includes the interaction between ECM and cancer cells will facilitate our understanding of how cancer cells behave during cancer treatment.....

open access: No difference in time to diagnosis for Type I vs Type II invasive epithelial ovarian cancers

open access

Objective

To compare time to diagnosis of the typically slow-growing Type I (low-grade serous, low-grade endometrioid, mucinous, clear cell) and the more aggressive Type II (high-grade serous, high-grade endometrioid, undifferentiated, carcinosarcoma) invasive epithelial ovarian cancer (iEOC).

First symptom

The first symptom reported was similar for Type I and II cancers with the exception of more irregular vaginal bleeding (almost all postmenopausal) in Type I (Q: 15% versus 4%, P = 0.01) (see Table 2). Abdominal symptoms were the most common (Q: Type I 77% and Type II 65%), whereas gynaecological symptoms were the least common (Q: Type I 15% and Type II 4%). The reporting of bloating and increased abdominal size was three to four times higher on questionnaire than in primary-care records (e.g. Type II bloating 40% Q versus 9% GP)......

...If time to diagnosis was a significant contributor to stage at diagnosis, then patient and diagnostic intervals should be different between the biologically disparate Type I and Type II iEOC. Instead it seems that the link between symptoms and tumour biology in ovarian cancer is complex and that a symptom-based intervention may not result in earlier stage diagnosis of Type II iEOC.

Taxonomy of the burden of treatment: a multi-country web-based qualitative study of patients with chronic conditions

 Blogger's Note: cancer was included in 'chronic conditions' - 8% of respondents

open access

Background

Management strategies for patients with chronic conditions are becoming increasingly complex, which may result in a burden of treatment for patients. To develop a Minimally Disruptive Medicine designed to reduce the burden of treatment, clinicians need to understand which healthcare tasks and aggravating factors may be responsible for this burden. The objective of the present study was to describe and classify the components of the burden of treatment for patients with chronic conditions from the patient’s perspective.

Results

From June 22, 2013, to March 30, 2014, 5,492 people connected to the Internet tool, and 1,345 people (24 %) identified themselves as eligible for the study; 1,267 (94 %) completed the demographic and clinical part of the survey, and 1,053 (78 %) answered the open-ended questions about the burden of treatment (Fig. 1). The mean (SD) age was 46 years and 766 (73 %) were women (Table 1). In total, 671 patients resided in France (64 %), 140 in the United States (13 %), 66 in Canada (6.3 %), 56 in the United Kingdom (5.3 %), 34 in Spain (3.2 %), 30 in Australia (2.8 %), and 56 (5.3 %) in a different country. Self-reported chronic conditions included rheumatologic diseases (33 %), cancer (8 %), and well-controlled psychiatric illnesses (13 %). The mean (SD) number of chronic conditions was 2.4 (1.6, range 1–10). A total of 662 patients (63 %) had two or more chronic conditions.....

Table 1. Characteristics of participants (n = 1,053) 

Fig. 2. Taxonomy of the burden of treatment

 

 

Conclusions

Data from our qualitative study of patients with different chronic conditions, in different contexts and countries, provides a comprehensive taxonomy of the burden of treatment for such patients. Results could inform the development of cross-cultural instruments to assess the burden of treatment for patients with chronic conditions and new interventions to reduce the burden of treatment, ultimately moving towards minimally disruptive medicine [6].

The burden of bowel preparations in patients undergoing elective colonoscopy

open access

 In conclusion, the real-life burden of bowel preparations is substantial. This information should be openly discussed with patients to set clear expectations and to guide choice and outcome. Additional work is needed in order to develop a validated global score for the burden of bowel preparation and prospectively investigate the impact of informed and individualized patient selection of preparation regimen on satisfaction, adherence and quality of colon cleansing.

Ovarian Cancer Highlights from the SGO Annual Meeting (2 items)

 medical news

Ovarian Cancer Highlights from the SGO Annual Meeting on Women's Cancer

Kim, Meeri PhD

Several notable studies on innovative treatment options for patients with ovarian cancer were highlighted at this year's Society of Gynecologic Oncology (SGO) Annual Meeting on Women's Cancer, including two that are noted here.......

 

Secondary Surgery & Bevacizumab

Personalized Vaccine

 

Phase I study of combination of vorinostat, carboplatin, and gemcitabine in women with recurrent, platinum-sensitive epithelial ovarian, ft, or pp

abstract

 Conclusions

Combination of carboplatin, gemcitabine, and vorinostat has activity in relapsed platinum-sensitive ovarian cancer, but was difficult to combine because of hematologic toxicities in this phase I study. No maximally tolerated dose was found, and the study was terminated early.

Success of Platinum Desensitization 'Depends on the Agent' (gyn/GI focus)

medscape

" Reactions were deemed severe if they were life-threatening or the patient experienced chest pain, dyspnea, hypotension (≤90 mmHg systolic blood pressure), or severe hypertension (≥180 mmHg systolic blood pressure)."

BARCELONA, Spain ― Cancer patients receiving platinum therapy desensitization are more likely to experience hypersensitivity reactions with oxaliplatin (Eloxatin, sanofi-aventis) than with carboplatin (Paraplatin, Corden Pharma International), although the period during which patients are at risk for a hypersensitivity reaction is shorter with carboplatin, US researchers said here at the 17th World Congress on Gastrointestinal Cancer (WCGC).
Lead author Katrina Pedersen, MD, hematology/oncology fellow at the Mayo Clinic, Rochester, Minnesota, says this indicates that there may be a "low-risk" population that could be transitioned to more rapid desensitization or outpatient therapy.
Platinum agents, which are commonly used in chemotherapeutic regimens for numerous gastrointestinal and gynecologic malignancies, have been known to cause hypersensitivity reactions in up to 20% of patients. Consequently, several desensitization protocols have been developed......

Lynch Syndrome: A Primer for Urologists and Panel Recommendations - The Journal of Urology

open access

" Early descriptions of UTUC in LS were limited by small patient numbers, lack of pathological confirmation, placement in the broad categories of genitourinary malignancy (together with bladder or renal cell carcinomas) or kidney malignancy (without distinguishing renal pelvis or renal cell carcinoma) and no available molecular or genetic testing. Not until the later introduction of the Amsterdam Criteria II²⁰ and the Bethesda Criteria²¹ did patients with extracolonic malignancies receive full consideration for study inclusion."

 Article Outline

1. Materials and Methods
2. Results
   1. LS Genetics and Neoplasm Spectrum
   2. UTUC Spectrum in LS
   3. Diagnosis
      1. Clinical Criteria
      2. Tissue Testing
      3. Genetic Testing
   4. Diagnosing LS in Patients with UTUC
   5. Screening
      1. Challenges
      2. Recommendations
   6. Secondary Prevention
3. Conclusions
4. Appendix. Recommendations for Testing, Screening and Evaluating Patients with Suspected or Confirmed LS

Purpose

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is a common genetic disease. The predisposition of patients with Lynch syndrome to urological cancer, particularly upper tract urothelial carcinoma, is underappreciated. Urologists may be involved in several aspects of care involving Lynch syndrome, including identifying undiagnosed patients, surveillance of those with established Lynch syndrome or screening family members, in addition to treating patients with Lynch syndrome in whom upper tract urothelial carcinoma develops. We sought to increase awareness in the urological community about Lynch syndrome and provide some guidance where little currently exists.

Review: Paclitaxel and Its Evolving Role in the Management of Ovarian Cancer

open access

"Dose-dense therapy survival benefits were also not seen in patients with clear cell or mucinous histology type, unlike serous type."

Future Directions

A plateau has been reached regarding the benefits associated with standard 3-weekly intravenous administration of cytotoxic chemotherapy in advanced epithelial ovarian cancer. The ongoing battle for a better treatment regimen to delay relapse, promote remission, and most importantly improve the quality of life of patients with advanced epithelial ovarian cancer need not to go further than the ability to relook at the chemotherapy agents that are already available in a different approach.

Novel compounds to date have not yet shown clinical superiority, and parent compounds such as paclitaxel continue to surprise us with their feasibility, effectiveness, and manageable toxicity profiles. Intraperitoneal paclitaxel will require further evaluation. Better effort in understanding the mechanism of action of drugs including the role of dose scheduling and the effect on the immune system may provide a more cost-effective route to better clinical outcomes.

Exceptional Responders Inspire Change: Lessons for Drug Development From the Bedside to the Bench and Back

open access

 Targeted therapies have changed the landscape of cancer treatment. Unfortunately, the promise of “targeted therapy” still fails too many patients with advanced cancer. Oncologists should ask why and how can we rapidly develop novel strategies. In medicine, exciting and novel occurrences are often first publicized as a case report. This quick yet detailed description of the clinical presentation, diagnosis, treatment, and outcome of an individual patient remains an important part of medical progress. However, although case reports serve as anecdotal clinical evidence that may be shared for educational, scientific, or medical purposes, the amount of information that can be generalized to a wider group of cancer patients is typically limited. Can case reports extend knowledge beyond the single patient experience and offer mechanistic insight or lead to novel therapeutic strategies?.....

Can targeted genetic testing offer useful health information to adoptees?

Nature Publishing Group

Impact of Chemotherapy Dosing on Ovarian Cancer Survival According to BMI + Editorial

Online First

Editorial | July 02, 2015  FREE

Ovarian Cancer Survival and Chemotherapy Dosing, Body Mass Index, and Body Surface Area : Are We There Yet?

PDF

Original Investigation | July 02, 2015  FREE

 

Impact of Chemotherapy Dosing on Ovarian Cancer Survival According to Body Mass Index

PDF

Includes: Supplemental Content

Editorial: Ovarian Cancer Survival and Chemotherapy Dosing; 

Original Investigation | July 02, 2015  Open Access

 

Inflammation-regulating factors in ascites as predictive biomarkers of drug resistance/progression-free survival serous epithelial ovarian cancers

 Full text 

 Background

Platinum-based combination therapy is the standard first-line treatment for women with advanced serous epithelial ovarian carcinoma (EOC). However, about 20 % will not respond and are considered clinically resistant. The availability of biomarkers to predict responses to the initial therapy would provide a practical approach to identify women who would benefit from a more appropriate first-line treatment. Ascites is an attractive inflammatory fluid for biomarker discovery as it is easy and minimally invasive to obtain. The aim of this study was to evaluate whether six selected inflammation-regulating factors in ascites could serve as diagnostic or drug resistance biomarkers in patients with advanced serous EOC. 

 

Methods

A total of 53 women with stage III/IV serous EOC and 10 women with benign conditions were enrolled in this study. Eleven of the 53 women with serous EOC were considered clinically resistant to treatment with progression-free survival < 6 months. Ascites were collected at the time of the debulking surgery and the levels of cytokines were measured by ELISA. The six selected cytokines were evaluated for their ability to discriminate serous EOC from benign controls, and to discriminate platinum resistant from platinum sensitive patients........

Lynch syndrome: five unanswered questions - Commentary

open access

"A large proportion of deaths in LS are associated with extra-colonic and extra-endometrial cancers."

Despite the great advances that have occurred in the century following the first description of a Lynch syndrome (LS) family and more especially, in more than 20 years since the discovery of causal mutations in the mismatch repair genes (MMR), long-standing clinical questions remain unanswered. Moreover, as a result of novel technologies, new questions have arisen. With this commentary, we aim to briefly cover some of these aspects of LS. We will focus on current challenges regarding the definition of LS-related tumors, their prevention and early detection, the role of next-generation sequencing (NGS) in the molecular diagnostics of LS and advances in the treatment of LS tumors.

"Although LS was initially thought of as a colorectal cancer (CRC) syndrome, the established spectrum of LS-associated tumors includes endometrial, stomach, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain (Turcot syndrome) tumors, sebaceous gland adenomas and keratoacanthomas (Muir–Torre syndrome), and carcinoma of the small bowel [1]."

Tumor spectrum of LS: is there a risk for breast cancer?

 

Can LS-associated cancers be diagnosed early or prevented?

 

Should all colorectal and endometrial carcinomas be tested for MMR 

proteins?

Are we ready to properly implement NGS into the diagnostics of LS?

 

Should treatment of cancer be influenced by MMR status?

 

 

CA 125 : Get Facts on Testing for Tumor Marker Levels + comments (Medicinenet)

CA 125 : Get Facts (reviewed 4/2015)

 

ESMO Magnitude of Clinical Benefit Scale ESMO/theLancet Oncology

ESMO (website)

 A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS)


The ESMO-MCBS will be a dynamic tool and its criteria will be revised on a regular basis.

Read the Abstract of the Paper

• Read the accompanying Press Release: ESMO Announces a Scale to Stratify the Magnitude of Clinical Benefit of Anti-Cancer Medicines
• Read the editorial in Annals of Oncology: Proven efficacy, equitable access and adjusted pricing of anti-cancer therapies: no  ́sweetheart ́ solution by Josep Tabernero on behalf of the ESMO Executive Board

theLancet Oncology
abstract

 Several new cancer medicines are of little clinical benefit to patients, suggests a new study by investigators from the European Society for Medical Oncology (ESMO). The investigators devised a “validated and reproducible” method to assess the magnitude of cancer medicines' clinical benefits—called the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS).

Germline BRCA1/2 Mutations: Are They Good Enough to Determine Who Will Respond to Poly(ADP–Ribose) Polymerase Inhibitor Therapy in Advanced Cancer?

Correspondence

..... It remains to be shown what exactly determines the response to PARP inhibitor therapy; Is it germline BRCA1/2 mutations? Is it platinum sensitivity? Is it HRD? Or is it a combination of all? Currently, identification of germline BRCA mutations through a blood test seems to be the only US Food and Drug Administration–approved surrogate marker for HRD. However testing tumor tissue for somatic BRCA mutations as well as for genes associated with HRD may better define the subgroup of patients with cancer who would benefit from a number of PARP inhibitors yet to come into clinical practice. The recent US Food and Drug Administration approval of olaparib for ovarian cancer along with a companion diagnostic blood test of BRACAnalysis CDx (Myriad Genetics Laboratories, Salt Lake City, UT) seems to be just the beginning.

REFERENCES

1. 1.↵
   1. Kaufman B,
   2. Shapira-Frommer R,
   3. Schmutzler RK,
   4. et al.

   (2015) Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 33:244–250.

   Abstract/FREE Full Text

To BRCA or Not to PALB (Correspondence/Original research paper)

JCO - Letter

 To the Editor:
 Published online before print June 29, 2015

Kaufman et al¹ report interesting data from a nonrandomized phase II multicenter study of an oral poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib, monotherapy in a spectrum of germline BRCA1 and BRCA 2 (BRCA 1/2) –mutated cancers (ovarian, breast, pancreatic, and prostate cancer). This article by Kaufman et al adds to the growing body of evidence of the potential for PARP inhibitor inclusion in the therapeutic management of patients with BRCA 1/2 mutations.^2–5....

 

REFERENCES

1. 1.↵
   1. Kaufman B,
   2. Shapira-Frommer R,
   3. Schmutzler RK,
   4. et al.

   (2015) Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 33:244–250.
   Published online before print November 3, 2014, doi: 10.1200/JCO.2014.56.2728 JCO January 20, 2015 vol. 33 no. 3 244-250

   Abstract/FREE Full Text