Cancer susceptibility genes and their potential implication regarding systemic therapy for early-stage breast cancer

Editorial (full access requires paid $$)

 The development of leukemia after chemotherapy and/or radiotherapy for breast cancer has been recognized for 4 decades. In this issue, Churpek et al have conducted a retrospective study that expands on a growing body of knowledge for understanding an individual's genetic risk, not only for breast cancer, but also for second cancers such as leukemia.

Inherited mutations in cancer susceptibility genes are common among survivors of breast cancer who develop therapy-related leukemia

abstract

BACKGROUND

Risk factors for the development of therapy-related leukemia (TRL), an often lethal late complication of cytotoxic therapy, remain poorly understood and may differ for survivors of different malignancies. Survivors of breast cancer (BC) now account for the majority of TRL cases, making the study of TRL risk factors in this population a priority.

METHODS

Subjects with TRL after cytotoxic therapy for a primary BC were identified from the TRL registry at The University of Chicago. Those with an available germline DNA sample were screened with a comprehensive gene panel covering known inherited BC susceptibility genes. Clinical and TRL characteristics of all subjects and those with identified germline mutations were described.

RESULTS

Nineteen of 88 survivors of BC with TRL (22%) had an additional primary cancer and 40 of the 70 survivors with an available family history (57%) had a close relative with breast, ovarian, or pancreatic cancer. Of the 47 subjects with available DNA, 10 (21%) were found to carry a deleterious inherited mutation in BRCA1 (3 subjects; 6%), BRCA2 (2 subjects; 4%), TP53 (tumor protein p53) (3 subjects; 6%), CHEK2 (checkpoint kinase 2) (1 subject; 2%), and PALB2 (partner and localizer of BRCA2) (1 subject; 2%).

CONCLUSIONS

Survivors of BC with TRL have personal and family histories suggestive of inherited cancer susceptibility and frequently carry germline mutations in BC susceptibility genes. The data from the current study support the role of these genes in TRL risk and suggest that long-term follow-up studies of women with germline mutations who are treated for BC and functional studies of the effects of heterozygous mutations in these genes on bone marrow function after cytotoxic exposures are warranted. 

Microsatellite instability in pulmonary adenocarcinomas: a comprehensive study of 480 cases (MSH-H)

abstract

 A major molecular pathway of genetic instability in cancer is DNA mismatch repair deficiency, leading to accumulation of numerous mutations at repetitive DNA sequence stretches (microsatellites), known as high-level microsatellite instability (MSI-H). In colorectal cancer, MSI-H tumors show a clinical behavior different from microsatellite-stable (MSS) tumors. Data about the prevalence of MSI among non-small cell lung cancer (NSCLC) are conflicting, and clinical relevance of MSI is largely unknown. We analyzed a series of 480 pulmonary (lung)  adenocarcinomas (ADC) for MSI using a sensitive mononucleotide marker panel (BAT25, BAT26, and CAT25). Positive cases were further analyzed by immunohistochemical staining for DNA mismatch repair proteins. Results were correlated with clinicopathological variables. MSI-H was detected in 4/480 (0.8 %) cases. In none of these, a background of Lynch syndrome was found. Three of the patients developed a metachronous carcinoma (esophagus, pancreas, and kidney). All MSI-H cases were stage I and occurred in smokers/ex-smokers. Mutations were found in EGFR (n = 2), KRAS (n = 1), or BRAF (n = 1). MSI-H neoplasms had a higher proliferative activity (38.7 %) than MSS neoplasms (28.3 %). Mean overall survival for MSS and MSI-H cases was 64.8 (CI 60.4-69.1) and 47.1 (CI 21-73.2) months, respectively. When specific mononucleotide marker panels are applied, the MSI-H phenotype is rare and predominantly found in early stage ADC of smokers. However, the frequency of MSI-H is in the range of other relevant molecular alterations. In the era of precision therapy, associations with distinct clinicopathological variables merit further investigation.

Seromucinous Tumors of the Ovary. What’s in a Name?

abstract

 The recent 2014 World Health Organization (WHO) Classification of Tumours of the Female Reproductive Organs introduced a new category of ovarian neoplasm designated “seromucinous tumours”. The recognition of this distinctive group of tumors is an important addition to the classification but the term “seromucinous” has serious flaws that obscures the nature of these neoplasms. Morphologically, seromucinous tumors in addition to serous and endocervical-type mucinous epithelium, contain endometrioid, indifferent and squamous type epithelium. Their immunoprofile is characterized by frequent expression of ER, PR, infrequent expression of WT1 and lack of expression of CK20 and CDX2, an immunostaining pattern consistent with a “müllerian” immunophenotype. Unlike serous and intestinal type mucinous tumors, seromucinous tumors are frequently associated with endometriosis making them more analogous to endometrioid and clear cell neoplasms. Indeed, recent studies have shown that a high proportion of seromucinous tumors lost expression of ARID1A, a tumor suppressor gene, that is mutated in approximately 50% of endometrioid and clear cell tumors, in sharp contrast to serous and intestinal-type mucinous tumors which do not contain ARID1A mutations or lose its expression. Therefore, based on their clinicopathologic, immunohistochemical and molecular genetic features we believe a more appropriate designation for this group of tumors is “mixed müllerian tumors” which can be subcategorized as “mixed müllerian cystadenomas”, “mixed müllerian atypical proliferative (borderline) tumors” and “mixed müllerian carcinomas”.

International Survey: Many Physicians Ill-Prepared to Manage the Sickest Patients

Commonwealth Fund 

About the Study

Researchers analyzed survey responses from more than 11,000 primary care doctors in Australia, Canada, Germany, the Netherlands, New Zealand, Norway, Sweden, Switzerland, the United Kingdom, and the United States. Response rates ranged from 19 percent in Germany to 47 percent in Sweden.

 

Is There a Role for Tertiary (TCR) and Quaternary (QCR) Cytoreduction in Recurrent Ovarian Cancer?

abstract

Background: The aim of the present study was to evaluate the efficacy of tertiary and quaternary cytoreduction in recurrent ovarian cancer patients.
Patients and Methods: Between January 1997 and December 2014, 53 patients were submitted to cytoreductive surgery for second and third ovarian cancer recurrence at our Unit.
Results: Median age at first diagnosis was 48 years (range=20-69). Forty-six patients (86.8%) underwent tertiary cytoreduction. At the time of surgery, isolated and diffuse disease was observed in 48 (90.6%) and 5 (9.4%) patients, respectively. Complete and optimal cytoreduction was obtained in 41 (77.5%) and in 1 (1.9%) patients, respectively. We did not observe any statistically significant survival differences according to residual tumor. Patients with TFI >12 months showed longer PFS (38 vs. 7 months, p<0.002) than those with TFI <12 months. In 18 of these patients a third recurrence was observed. In 12 patients (66.7%) a complete quaternary cytoreduction was performed. Longer PFS (16 vs. 21 months; p=0.032) and OS (152 vs. 116 months; p=0.015) in patients submitted to cytoreduction with respect to those treated with chemotherapy were observed.
Conclusion: Our data suggest that selected ovarian cancer patients who develop a secondary and tertiary recurrence may benefit from additional cytoreductive attempts. The benefit seems to be greater in patients with TFI >12 months showing a single-site recurrence disease, in which complete cytoreduction is achievable. Further studies are required to better-define the role of tertiary and quaternary cytoreduction (search) in recurrent ovarian cancer patients.

Pressurized Intraperitoneal Aerosol Chemotherapy with Cisplatin and Doxorubicin in Women with Peritoneal Carcinomatosis: A Cohort Study

abstract

Aim: We aimed to assess the objective tumor response (OTR) to laparoscopic pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with peritoneal carcinomatosis (PC).

Patients and Methods: We carried-out a retrospective cohort study of women with PC undergoing repeated courses of PIPAC with 7.5 mg/m² of cisplatin and 1.5 mg/m² of doxorubicin. OTR was defined as histological regression. Peritoneal carcinomatosis index (PCI) improvement on video-laparoscopy and ascites volume reduction were secondary outcomes. Quality of life was assessed by the European Organization for Research & Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-30+3. 

Results: A total of 252 PIPACs were performed in 99 women with PC and ovarian (n=84), primary peritoneal (n=6), cervical (n=3), endometrial (n=3), fallopian tube (n=1), and breast (n=1) cancer and pseudomyxoma peritonei (n=1). Laparoscopic non-access rate was 17% (17/99). Fifty women had more than one PIPAC procedures, with an OTR of 76% (38/50) and PCI improvement in 64% (32/50). Ascites volume significantly decreased from 762±1170 ml to 167±456 ml (p=0.02). A high initial Karnofsky Index was correlated with receiving more than one PIPAC (p<0.0001) and a high number of previous surgeries with laparoscopic non-access (p=0.01). Twenty adverse events of Common Terminology Criteria for Adverse Events grade 3 or more were noted. Absence of ascites (odds ratio=8.45, 95% confidence interval=1.9-3.6; p<0.0001), but not patient age, serum cancer antigen-125, and Karnofsky Index independently predicted OTR. EORTC QLQ-30+3 scores for global physical health, nausea/vomiting, appetite loss, and constipation improved during therapy. 

Conclusion: PIPAC with cisplatin and doxorubicin is an active treatment in women with PC and preserves quality of life. Appropriate patient selection regarding performance status and the number of prior surgeries is important.

Malignant Ovarian Germ Cell Tumors in Postmenopausal Patients: The Royal Marsden Experience and Literature Review

abstract

Background: Ovarian germ cell tumors (OGCT) account for 2-5% of ovarian malignancies, with an annual incidence of 1:100,000, and typically occur in young women and adolescents. The yolk sac tumor (YST) is the second most common subtype of OGCTs and has an aggressive phenotype. Their rarity in postmenopausal women has the potential to cause initial diagnostic uncertainty and lead to delayed or sub-optimal treatment. In this article, we report two cases. The first case is a 67-year-old woman with a pure YST and the second refers to a 59-year-old patient with YST with neuroendocrine differentiation. We also review and summarise the current literature.  
Discussion: YSTs in older women, either in association with ovarian epithelial tumors or without an identifiable epithelial precursor, are a challenging clinical situation. The disease is aggressive and the outcome remains poor. Thirty-seven cases, including the two reported in this article, have been described in the literature to date. 12/ 37 described patients with malignant OGCTs died within 8 months of diagnosis.
Conclusion: Ovarian cancer with a YST component in postmenopausal women has an aggressive behaviour and adjuvant platinum-based chemotherapy should be considered.

A new conceptual framework for investigating complex genetic disease | Genetic Disorders

 Blogger's Note: some interesting observations eg. BRCA/Lynch Syndrome amongst others

Frontiers (open access)

 Concluding Remarks

The primary, perhaps only reason we should harbor hopes that such a framework is correct, is that it would make it considerably easier to define and develop routes to therapy, as this could be specifically targeted against the single causative monogenic factor within families. Such hopes of course have little or nothing to do with scientific reality and it is very possible that the framework presented here is incorrect. The jury is still very much out for the polygenic rare-variant hypothesis, and the previous overwhelming consensus regarding the polygenic common-variant hypothesis was, for most intents and purposes, wrong. I thus feel rather apprehensive to conclude with a comment regarding how likely it is for this proposed framework to hold true to fact. However, the framework appears broadly consistent with recorded observations past and present, and if correct, the potential benefits are huge; testing of the model is clearly incumbent.

Assessing cancer-related distress in cancer patients and caregivers receiving outpatient psycho-oncological counseling

Abstract
 

Purpose

The diagnosis of cancer, the symptoms of the illness and its treatment have an influence on how patients and their caregivers experience distress. However, data focusing on caregivers and their cancer-related distress in the outpatient setting is sparse. This study aimed to compare cancer-related distress of caregivers and patients and to derive implications for the system of outpatient psycho-oncological care.

Methods

One hundred thirty-eight patients and 102 caregivers receiving psycho-oncological counseling completed a standardized interview based on a self-assessment questionnaire (Questionnaire on Stress in Cancer Patients, FBK).

Using a personalized measure (Patient Generated Index (PGI)) to identify what matters to people with cancer

abstract
 

Purposes

Patient Generated Index (PGI) is designed to both ask and document quality of life (QOL) concerns. Its validity with respect to standard QOL measures has not been fully established for advanced cancer when QOL concerns predominate. The specific objective of this study is to identify, for people with advanced cancer, similarities and differences in ratings of global QOL between personalized and standard measures.

Methods

A total of 192 patients completed five QOL measures at study entry: PGI, generic measures (SF-6D, EQ-5D), and cancer-specific measures of QOL (McGill Quality of Life Questionnaire and Edmonton Symptoms Assessment Scale). Comparisons among total scores were compared using Generalized Estimating Equations (GEE).

Results

Patients voiced 114 areas of QOL concerns by the PGI with the top three being fatigue, sleep, and pain (39.2, 22.6, and 21.6 %, respectively). PGI total QOL score was 25 to 30 percentage points lower than those documented by the other measures, particularly when QOL was poor. Correlations between PGI and other measures were low.

Conclusion

PGI allowed patients to express a wide range of QOL concerns, many that were not assessed by other QOL measures. If only one QOL measure is to be included, either in a clinical setting or for research, the PGI would satisfy many of the criteria for “best choice.” PGI could be considered a cancer-specific QOL measure.

Implications for cancer

This study provides evidence that the PGI would be a good measure for patients and clinicians to use together to identify areas of concern that require attention and monitor changing needs.

Defining cancer-related fatigue for biomarker discovery

Commentary (open access)

 ...Hence, specific terms such as “radiation-related fatigue,” “chemotherapy-related fatigue,” or “tumor-related fatigue” might be more useful when reporting biologic correlates or proposing etiologic mechanisms of CRF (Cancer-related fatigue).

Oral Contraceptive Use and Reproductive Characteristics Affect Survival in Patients With Epithelial Ovarian Cancer: A Cohort Study

Open access

Cytokeratin 5–Positive Cells Represent a Therapy Resistant subpopulation in Epithelial Ovarian Cancer

open access (technical)
 

Conclusions: Cytokeratin 5 is expressed in a significant proportion of epithelial ovarian cancers and represents a slower proliferating chemoresistant subpopulation that may warrant cotargeting in combination therapy.

Potential risks associated with traditional herbal medicine use in cancer care: A study of Middle Eastern oncology health care professionals

abstract
 

BACKGROUND

The authors assessed the use of herbal medicine by Middle Eastern patients with cancer, as reported by their oncology health care professionals (HCPs). Herbal products identified by the study HCPs were evaluated for potential negative effects.

METHODS

Oncology HCPs from 16 Middle Eastern countries received a 17-item questionnaire asking them to list 5 herbal products in use by their patients with cancer. A literature search (PubMed, Micromedex, AltMedDex, and the Natural Medicine Comprehensive Database) was conducted to identify safety-related concerns associated with the products listed.

RESULTS

A total of 339 HCPs completed the study questionnaire (response rate of 80.3%), identifying 44 herbal and 3 nonherbal nutritional supplements. Safety-related concerns were associated with 29 products, including herb-drug interactions with altered pharmacodynamics (15 herbs), direct toxic effects (18 herbs), and increased in vitro response of cancer cells to chemotherapy (7 herbs).

CONCLUSIONS

Herbal medicine use, which is prevalent in Middle Eastern countries, has several potentially negative effects that include direct toxic effects, negative interactions with anticancer drugs, and increased chemosensitivity of cancer cells, requiring a reduction in dosedensity. Oncology HCPs working in countries in which herbal medicine use is prevalent need to better understand the implications of this practice. The presence of integrative physicians with training in complementary and traditional medicine can help patients and their HCPs reach an informed decision regarding the safety and effective use of these products

Podcast: John Ioannidis - "scourge of sloppy science"

Podcast

 The BMJ called him “the scourge of sloppy science.”
Asked to summarize his personality in 3 words, he used: “Uncompromising…gentle…maniac.”
He’s Dr. John Ioannidis.  He’s made a career out of doing science about science. Doing good science about bad science, about flawed science, about irreproducible science, about science that lacks transparency – to other scientists and certainly to the general public.
He now co-directs METRICS – or Meta-Research Innovation Center at Stanford – which held its first conference two weeks ago. I was honored to be invited to speak at the conference.  The Stanford project – and HealthNewsReview.org – both receive funding from the Laura and John Arnold Foundation.
Here is our podcast interview with Ioannidis, recorded during a short break at the conference. Ioannidis’ work carries important messages for journalists and for the general public about what they need to know about so many of the studies they hear about.

Gene summit organizers urge caution on human gene editing (CRISPR-Cas9)

media

Official Trailer: "PINK & BLUE: Colors of Hereditary Cancer "

Official Trailer

Examination of the Fractalkine and Fractalkine Receptor Expression in Fallopian Adenocarcinoma Reveals Differences When Compared to Ovarian Carcinoma

abstract

Fallopian adenocarcinoma is a rare malignancy arising in the epithelium of the fallopian tube. Fallopian tube epithelium has been proposed as a tissue origin for high-grade serous ovarian carcinoma, the deadliest gynecologic malignancy. Given the commonalities in dissemination and treatment of these malignancies, we contemplated the possibility of similar patterns of gene expression underlying their progression. To reveal potential similarities or differences in the gene expression of fallopian adenocarcinoma and high-grade serous ovarian carcinoma, we tested expression of the fractalkine receptor (CX₃CR1) and its ligand, fractalkine (CX₃CL1), in the specimens of normal and pathologic fallopian tube using immunohistochemistry. Our data show that CX₃CR1 is expressed in the normal, cancer adjacent normal, inflammatory, and malignant fallopian epithelium. CX₃CL1 was expressed only by the normal and cancer adjacent normal fallopian tube epithelium; its expression was largely lost in the inflammatory and malignant fallopian epithelium. In opposite, both CX₃CR1 and CX₃CL1 are expressed in high-grade serous ovarian carcinoma. These findings are consistent with an idea that fallopian adenocarcinoma and high-grade serous ovarian carcinoma, although currently thought to arise from the same organ, may not share similar molecular characteristics.

Paclitaxel Through the Ages of Anticancer Therapy: Exploring Its Role in Chemoresistance and Radiation Therapy

Free Full-Text   (technical)

Ovarian mucinous adenocarcinoma with functioning stroma in postmenopausal women: aromatase and SF-1 expressions

Open access - 2 Case Reports

Background

It is known that elevated serum levels of steroid hormones including estradiol (E₂) are present in postmenopausal women with common epithelial ovarian tumors [1–4]. Such ovarian tumor stroma exhibiting lutein-like or theca-like cells, or both, is frequently detected with morphological studies and has been termed “ovarian tumors with functioning stroma” [1]. Recently, from a pathogenic perspective, it has been reported that P450 aromatase, which converts androgens to estrogens, was exclusively expressed in stromal cells, although not all serum estrogens are produced in functioning stroma [5]. However, the mechanism of the initiation and development of ovarian tumors with functioning stroma and the significance of the expression of P450 aromatase in functioning stroma are still unclear.....

.... A meta-analysis showed that ovarian cancer risk was significantly greater in ever-users than in never-users of hormone therapy. However, regarding histopathological type, risk was definitely increased only for the two most common types, serous and endometrioid, but not mucinous and clear adenocarcinoma [21]....

Conclusions

The present case showed that some elderly women with common epithelial tumors have an extremely high E₂ level. Immunohistochemical and RT-qPCR evaluations showed that SF-1 may promote estrogen biosynthesis through regulation of P450 aromatase expression in ovarian tumors with functioning stroma, and that this in turn induces a high serum E₂ level.

Further large-scale studies should provide additional insights into the mechanism whereby ovarian tumors, which contain functioning stroma with a high serum estrogen level and high expressions of P450 aromatase and SF-1, affect the prognosis and clinical outcomes of ovarian tumor patients. These studies have the potential to identify new biomarkers for anti-angiogenetic therapy and new treatments for some ovarian tumors.

Perspectives: Crucial interventions: between survival and wholeness

The Lancet (worth reading - not specific to OC)

 ....For many of those who undergo it, the story of surgery is not awe or gratitude at the operative brilliance of a surgeon. It is learning to deal with the memory of pain and its persistence, and to live in an altered, perhaps diminished body, one that has become newly visible, vulnerable, and mortal. These experiences may last days, decades, or a lifetime. In this sense surgery, for all its triumphs, remains what it always was: a necessary compromise—emotional as well as physical—between survival and wholeness.

Editorial: HRT for menopause: a NICE treatment?

 The Lancet

Does Everything Cause Cancer? No.

Does Everything Cause Cancer? No

 ...When it comes to breaking news, a healthy skepticism will help distinguish responsible science reporting from the “shocking-breakthrough”/”everything-you-thought-you-knew-was-wrong” clickbait. These stories can engender a deep distrust of many scientific findings, even those that are recognized by the scientific community as strong and convincing. And that is unfortunate, because this distrust can turn into the frustration and apathy that’s causing many Americans to mistakenly conclude that everything causes cancer.

BRIP1, BARD1, PALB2, and NBN Mutations in Ovarian Cancer

medscape

Expanded Access to Investigational Drugs: What Physicians and the Public Need to Know about FDA and Corporate Processe

Article American Medical Association Journal of Ethics December 2015

Author: Paige E. Finkelstein is a second-year medical student in
the University of Miami Miller School of Medicine’s combined MD/MPH program. She is the co-founder of the health care startup ERinfo.me, a patent
-pending mobile application. She received a bachelor of science in chemical engineering and biology from the Massachusetts Institute of Technology in 2014 and hopes to pursue a residency in general surgery followed by a fellowship in surgical oncology.

Related in the
AMA Journal of Ethics
The Terminally Ill, Access to Investigational Drugs, and FDA Rules, August 2013

SUO 2015 Lynch Syndrome in UTUC: Significance, Screening, and Surveillance

In today’s second symposium on upper tract urothelial carcinoma, Dr. Morgan Roupret discussed his group’s work on Lynch syndrome, including recommendations for screening and surveillance. Lynch syndrome, also known as Hereditary Non-Polyposis Colon Cancer (HNPCC) is the most common hereditary cause of colorectal cancer, accounting for 7% of such tumors.
Disease features include young age at diagnosis (median age is 44 vs 65 yo in non-hereditary cases) and autosomal dominant transmission. Upper tract urothelial carcinoma (UTUC) is often a presenting finding, and patients have a 6% lifetime risk of developing disease (22x higher than that of the general population).
Screening is a key issue in identifying patients with UTUC who may have Lynch Syndrome. Amsterdam II criteria includes 3 relatives with HNPCC, of whom one is a first degree relative, 2 successive generations are affected, and one is diagnosed before the age of 50. Review of these criteria has shown a diagnosis rate of only 5% with this screening protocol. Dr. Roupret’s group reviewed a French national database and found that hereditary cases of UTUC were more likely to be female, less associated with smoking history, and were more likely to be low grade cancers in the renal pelvis; OS and CSS were similar between hereditary and sporadic cases. Based on these findings, the group proposed a checklist to identify patients at risk for hereditary disease, which had a 21% success rate in the study (see figure below) (Audenet et al, BJUI 2012).
Despite adequate early diagnosis through effective screening, continued surveillance of these patients is vital as recurrence is common. Archer and colleagues recommended a surveillance schema based on family history. Their work concluded that high risk patients (those with prior personal history of urothelial Ca) should get annual urine cytology, NMP22, and dipstick, along with annual contrast CT and cystoscopy. Depending on the histological variant, more frequent surveillance may be necessary. Further treatment of these patients hinges on adequate family history and attention to other potential disease sites, as well as addressing the need for Surgical Oncology, Gynecology, Dermatology, and Genetics referrals.
Finally, it is important to identify microsatellite instability, as this can impact chemotherapeutic response.

Presented by:
Dr. Morgan Roupret, MD, PhD
Pitie-Salpetriere Hospital
Reported by:
Dr. Nikhil Waingankar,MD from the 2015 Winter Meeting of the Society of Urologic Oncology (SUO) "Defining Excellence in Urologic Oncology" December 2 - 4 Washington, DC USA
Fox Chase Cancer Center, Philadelphia, PA USA

 

Hormone replacement therapy after treatment for a gynaecological malignancy

abstract
 

Purpose of review: Provision of hormone replacement therapy (HRT) to women following a diagnosis of a gynaecological malignancy is a complex and controversial area associated with a lack of published guidance. As the average age of women affected by gynaecological cancer decreases and survival following provision of effective therapies increases, clinicians face new considerations for longer-term health concerns of patients. Additionally, there is a growing understanding of the influence of tumour biology upon response to cytotoxic therapies and it is essential that we use this knowledge to guide provision of HRT.

Recent findings: Available evidence for ovarian, vulval, cervical, and endometrial cancers demonstrates no excess risk of recurrence in patients taking HRT with the exception of some subtypes of cancer (uterine sarcomas, granulosa cell, and low-grade serous ovarian cancer). Evidence for the incidence of hormone receptor status is suggestive that HRT may be ill-advised in an additional proportion of patients and we recommend characterization of all tumours in patients who may require HRT.

Summary: The risk and benefits of HRT should be evaluated for all women who undergo a premature menopause as a result of gynaecological malignancy to reduce menopausal symptoms and protect against cardiovascular and skeletal morbidity. There is no evidence to suggest a higher rate of disease recurrence in women using HRT in comparison to nonusers in the majority of gynaecological malignancies. Routine histological testing of tumours for hormone receptor status is an achievable goal and may help to stratify patients further into low and high-risk groups for hormone therapy.

Incidental Serous Tubal Intraepithelial Carcinoma and Non-Neoplastic Conditions of the Fallopian Tubes in Grossly Normal Adnexa

abstract
 Incidental Serous Tubal Intraepithelial Carcinoma and Non-Neoplastic Conditions of the Fallopian Tubes in Grossly Normal Adnexa: A Clinicopathologic Study of 388 Completely Embedded Cases

 Serous tubal intraepithelial carcinoma (STIC), the putative precursor of the majority of extrauterine high-grade serous carcinomas, has been reported in both high-risk women (those with a germline BRCA mutation, a personal history of breast carcinoma, and/or family history of breast or ovarian carcinoma) and average risk women from the general population. We reviewed grossly normal adnexal specimens from 388 consecutive, unselected women undergoing surgery, including those with germline BRCA mutation (37 patients), personal history of breast cancer or family history of breast/ovarian cancer (74 patients), endometrial cancer (175 patients), and a variety of other conditions (102 patients). Among 111 high-risk cases and 277 non-high-risk cases, 3 STICs were identified (0.8%), all in non-high-risk women (high risk vs. non-high risk: P=not significant). STIC was found in 2 women with nonserous endometrial carcinoma and 1 with complex atypical endometrial hyperplasia. Salpingoliths (mucosal calcifications), found in 9% of high-risk cases, and fimbrial adenofibromas in 9.9% of high-risk cases, were significantly more common in high-risk as compared with non-high-risk women (1.8% and 2.5%, respectively; P<0.007). Mucinous metaplasia was found in 3.1%, salpingitis isthmica nodosa in 3.4%, hemosiderin or pseudoxanthoma cells in 4.9%, and fibrous luminal nodules in 4.1%. None of these latter features differed significantly in the high-risk versus non-high-risk groups. These findings suggest a possible association between STIC and endometrial hyperplasia and carcinoma, and clarify the frequency of non-neoplastic tubal findings in grossly normal fallopian tubes.

Low-Stage High-Grade Serous Ovarian Carcinomas: Support for an Extraovarian Origin

abstract

 Many adnexal high-grade serous carcinomas (HGSCs) may derive from microscopic precursors in the fallopian tube. By studying a series of low-stage ovarian carcinomas, we anticipated that HGSCs would be distributed in a pattern suggesting secondary involvement, helping to indirectly validate the fallopian tube origin theory, and that most ovarian carcinomas other than serous carcinomas would demonstrate features consistent with derivation from precursors located in or transplanted to the ovary. Seventy-six patients with low-stage (FIGO I/II) sporadic ovarian carcinoma who underwent primary surgical management at Memorial Sloan Kettering Cancer Center from 1980 to 2000 were included in the study. Histologic type was assigned using Gilks' criteria. Similar to the approach taken when distinguishing primary and metastatic mucinous or endometrioid carcinoma involving ovary, cases interpreted as showing a "primary" pattern of ovarian involvement had ≥3 of the following features: unilateral tumor, size >12 cm, no surface involvement, no multinodularity, and no destructive stromal invasion. All other cases were considered to show a "metastatic" pattern of ovarian involvement. Cases were evaluated for p53 and WT-1 expression, using standard techniques on a tissue microarray. TP53 gene sequencing was also performed. Cases comprised HGSC (n=22), endometrioid carcinoma (n=30), clear cell carcinoma (n=13), and mucinous carcinoma (n=11). HGSCs displayed substantially more "metastatic features" than the non-HGSC group and a mean overall size that was smaller (8.85 vs. 14.1 cm). Statistically significant differences were found for bilaterality (63% vs. 7.3%), P=0.0001; multinodularity (55% vs. 7.3%), P=0.0001; tumor size, P=0.003; and surface involvement (50% vs. 13%), P=0.002. Five of 22 (23%) of HGSCs showed a "primary pattern" of ovarian involvement. There were no significant differences between these cases and "metastatic pattern" HGSCs when comparing morphology, immunophenotype, TP53 mutational status, and clinical outcomes. Most low-stage HGSCs demonstrate patterns of ovarian involvement that suggest metastasis from another source, such as the fallopian tube. Both metastatic pattern HGSCs and unilateral, low-stage HGSCs can behave aggressively.

Phase 1b Safety Study of Farletuzumab, Carboplatin and Pegylated Liposomal Doxorubicin in Patients with Platinum-Sensitive Epithelial Ovarian Cancer

abstract
 

Highlights

• •Farletuzumab (FAR), a monoclonal antibody to folate receptor alpha, which is expressed in epithelial ovarian cancer (EOC).
• •FAR has shown activity against EOC in platinum-sensitive relapse when combined with carboplatin and a taxane.
• •Carboplatin in combination with pegylated liposomal doxorubicin (PLD) is a frequently used alterative regimen.
• •This safety study assessed the addition of FAR to carboplatin/PLD, with a view toward future larger studies.
• •This combination was generally well tolerated; adverse event profile was similar to that of carboplatin/PLD alone.

Gynecologic Oncology December 2015 Index

Index (subscriber-based journal $$)

Social Media Use Among Physicians and Trainees: Results of a National Medical Oncology Physician Survey

abstract

Purpose: Cancer management requires coordinated care from many health care providers, and its complexity requires physicians be up to date on current research. Web-based social media support physician collaboration and information sharing, but the extent to which physicians use social media for these purposes remains unknown. The complex field of oncology will benefit from increased use of online social media to enhance physician communication, education, and mentorship. To facilitate this, patterns of social media use among oncologists must be better understood.

Methods: A nine-item survey investigating physician social media use, designed using online survey software, was distributed via e-mail to 680 oncology physicians and physicians in training in Canada. Responses were analyzed using descriptive statistics.

Results: A total of 207 responses (30%) were received; 72% of respondents reported using social media. Social media use was highest, at 93%, in respondents age 25 to 34 years and lowest, at 39%, in those age 45 to 54 years. This demonstrates a significant gap in social media use between younger users and mid- to late-career users. The main barrier to use was lack of free time.

Conclusion: The identified gap in social media use between age cohorts may have negative implications for communication in oncology. Despite advancements in social media and efforts to integrate social media into medical education, most oncologists and trainees use social media rarely, which, along with the age-related gap in use, may have consequences for collaboration and education in oncology. Investigations to further understand barriers to social media use should be undertaken to enhance physician collaboration and knowledge sharing through social media.

Chemotherapy-induced peripheral neurotoxicity and complementary and alternative medicines: progress and perspective | Ethnopharmacology

Frontiers |  Ethnopharmacology (open access)

 In summary, when considering CAMs use in the treatment of CIPN, the therapeutic potential of alternative therapies still needs to be rigorously investigated with large scale randomized controlled trials. Additionally, the interactions of CAMs with chemotherapy, potential toxicities associated herb medicines, as well as molecular mechanisms and bioactive compounds responsible for the neuroprotective effects should also be further investigated.

A new government, a new chance for Cochrane Canada

Cochrane Canada

Standard 1st-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): phase 3

abstract
 Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial

Background

Angiogenesis is a target in the treatment of ovarian cancer. Nintedanib, an oral triple angiokinase inhibitor of VEGF receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has shown activity in phase 2 trials in this setting. We investigated the combination of nintedanib with standard carboplatin and paclitaxel chemotherapy in patients with newly diagnosed advanced ovarian cancer.

Methods

In this double-blind phase 3 trial, chemotherapy-naive patients (aged 18 years or older) with International Federation of Gynecology and Obstetrics (FIGO) IIB–IV ovarian cancer and upfront debulking surgery were stratified by postoperative resection status, FIGO stage, and planned carboplatin dose. Patients were randomly assigned (2:1) via an interactive voice or web-based response system to receive six cycles of carboplatin (AUC 5 mg/mL per min or 6 mg/mL per min) and paclitaxel (175 mg/m²) in addition to either 200 mg of nintedanib (nintedanib group) or placebo (placebo group) twice daily on days 2–21 of every 3-week cycle for up to 120 weeks. Patients, investigators, and independent radiological reviewers were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01015118.

Findings

Between Dec 9, 2009, and July 27, 2011, 1503 patients were screened and 1366 randomly assigned by nine study groups in 22 countries: 911 to the nintedanib group and 455 to the placebo group. 486 (53%) of 911 patients in the nintedanib group experienced disease progression or death compared with 266 (58%) of 455 in the placebo group. Median progression-free survival was significantly longer in the nintedanib group than in the placebo group (17·2 months [95% CI 16·6–19·9] vs 16·6 months [13·9–19·1]; hazard ratio 0·84 [95% CI 0·72–0·98]; p=0·024). The most common adverse events were gastrointestinal (diarrhoea: nintedanib group 191 [21%] of 902 grade 3 and three [<1%] grade 4 vs placebo group nine [2%] of 450 grade 3 only) and haematological (neutropenia: nintedanib group 180 [20%] grade 3 and 200 (22%) grade 4 vs placebo group 90 [20%] grade 3 and 72 [16%] grade 4; thrombocytopenia: 105 [12%] and 55 [6%] vs 21 [5%] and eight [2%]; anaemia: 108 [12%] and 13 [1%] vs 26 [6%] and five [1%]). Serious adverse events were reported in 376 (42%) of 902 patients in the nintedanib group and 155 (34%) of 450 in the placebo group. 29 (3%) of 902 patients in the nintedanib group experienced serious adverse events associated with death compared with 16 (4%) of 450 in the placebo group, including 12 (1%) in the nintedanib group and six (1%) in the placebo group with a malignant neoplasm progression classified as an adverse event by the investigator. Drug-related adverse events leading to death occurred in three patients in the nintedanib group (one without diagnosis of cause; one due to non-drug-related sepsis associated with drug-related diarrhoea and renal failure; and one due to peritonitis) and in one patient in the placebo group (cause unknown).

Interpretation

Nintedanib in combination with carboplatin and paclitaxel is an active first-line treatment that significantly increases progression-free survival for women with advanced ovarian cancer, but is associated with more gastrointestinal adverse events. Future studies should focus on improving patient selection and optimisation of tolerability.

Taking a Chance or Playing It Safe: Reframing Risk Assessment Within the Surgeon's Comfort Zone (U of T)

open access (print version)

open access (html)

Introduction

The practice of surgery is associated with inherent risk and potential harm to patients, sometimes caused by poor decisions and errors.^[1] As a result, regulatory bodies are increasingly being held accountable for ensuring adequate self-regulation among surgeons and placing increasing emphasis on system-wide analyses of quality-assurance and quality-improvement strategies.^[2–5] Although system-based understanding of error has evoked positive change in surgery,^[6–9] factors affecting self-regulation by individual surgeons and their effects on surgeon behavior and decision making have received less attention as a focus of research.^{[10–12]....}

Methods

The subjects for this study were surgeons working at tertiary referral academic centers affiliated with the University of Toronto. After obtaining appropriate research ethics board approval, surgeons were contacted by e-mail and their voluntary participation in this study was requested....
 

Results

Eighteen semistructured interviews lasting approximately 60 minutes were conducted. Thirteen subjects were males. Our sample included 7 general surgeons (representing subspecialties including hepatobiliary surgery, transplantation, breast oncology, colorectal surgery, pediatric surgery, and bariatric surgery) 2 thoracic surgeons, 2 cardiac surgeons, 2 urologists, 2 orthopedic surgeons, 2 gynecologists, and 1 vascular surgeon. Three had been in practice less than 10 years, 13 had been in practice more than 10 years, and 2 were retired. Our sample included surgeons who demonstrated characteristics that might place them along various points of the risk taking spectrum as outlined in Table 2.....

Variation Reduction to Reduce Readmission: A Figment of Imagination or Reality of the Future?

Commentary (requires paid $$ to view in full)

 One of the principles of the Six Sigma methodology is variation reduction. Since the publication of the Institute of Medicine’s monograph, “To Err is Human: Building a Safer Health System,”¹ health care systems and the Centers for Medicare and Medicaid Services have been interested in reducing variation through the application of standard process measures in an attempt to achieve the following 6 pillars of high-quality health care: safety, timeliness, effectiveness, efficiency, equity, and patient centeredness. The standardization of process measures and management pathways has clearly led to improved results in many clinical situations. However, we face a significant problem in medicine, referred to as common cause variation in the principles of the Six Sigma. This is the variation introduced by uncontrollable patient factors. The study by Gani et al² addresses a gap in knowledge regarding the problem of readmission. This article tackles the issue of variability in readmission rates and reveals that variability is primarily due to the common cause of patient-related factors (including race/ethnicity, insurance status, comorbidity, complications, and length of stay) rather than surgeon- or surgical subspecialty–specific factors. There are limitations in this administrative claims–derived data set, including the lack of more robust complication data, which likely is reflected in the fact that only 30% of readmitted patients were reported to have a complication when the overwhelming data show that surgical readmissions are driven by complications, specifically those that occur after discharge^3- 5; the lack of knowledge regarding readmissions to other hospitals, which has been found to occur in about 15% of cases⁶; and a paucity of information on sociodemographic factors, which, at a minimum, likely influence the decision to readmit.⁷

Related:

Understanding Variation in 30-Day Surgical Readmission in the Era of Accountable Care: Effect of the Patient, Surgeon, and Surgical Subspecialties

JAMA Surg. 2015;150(11):1042-1049. doi:10.1001/jamasurg.2015.2215.

Defining Rates and Risk Factors for Readmissions Following Emergency General Surgery

JAMA Surg. Published online November 11, 2015.;():1-7. doi:10.1001/jamasurg.2015.4056.

Does Decreasing Variability Affect Quality?

JAMA Surg. Published online October 28, 2015.;():1. doi:10.1001/jamasurg.2015.3654.

The Uninsured and Underserved and the Hospitals That Care for Them: Who’s to Blame?

JAMA Surg. Published online October 14, 2015.;():1. doi:10.1001/jamasurg.2015.3216.

Analysis of Morbidity and Mortality Outcomes in Postoperative Clostridium difficile Infection in the Veterans Health Administration

JAMA Surg. Published online November 25, 2015.;():1-9. doi:10.1001/jamasurg.2015.4263.

Breast Cancer Following Ovarian Cancer in BRCA Mutation Carriers + Comment/Response

Original Investigation
Breast Cancer Following Ovarian Cancer in BRCA Mutation Carriers
JAMA Surg. 2014;149(12):1306-1313. doi:10.1001/jamasurg.2014.1081. 

 

Comment & Response
Effect of Breast Cancer After Ovarian Cancer on Mortality for BRCA Mutation Carriers
JAMA Surg. 2015;150(5):490-491. doi:10.1001/jamasurg.2015.0193.

Palliative Care Interventions for Surgical Patients: A Systematic Review

Abstract JAMA Surgery

.... However, many studies were small, performed in academic settings, and methodologically flawed and did not measure clinically meaningful outcomes.....

Individualized Treatment of Patients With Early-Stage Epithelial Ovarian Cancer After Incomplete Initial Surgery

abstract

 Results: Of 246 patients, 130 underwent restaging surgery and 116 received chemotherapy only. Follow-up duration ranged from 4 to 148 months (median, 72 months). The 5-year overall survival (OS) rates were 87.5% and 74.7% in the restaging and chemotherapy groups, respectively.

Correspondence: Preventing Ovarian Cancer

JCO Correspondence (open access)

Ovarian Cancer Early Detection Needs Better Imaging, Not Better Algorithms or Biomarkers

Open access

New gene map reveals cancer's Achilles heel

science news

Complete Surgical Excision Is Essential for the Management of Patients With Breast Implant–Associated Anaplastic Large-Cell Lymphoma

abstract

 Conclusion Surgical management with complete surgical excision is essential to achieve optimal EFS (event free survival) in patients with BI-ALCL.

Essay: Palliative Care Versus Assisted Death

Longwoods.com

About the Author
Duncan G. Sinclair is Professor Emeritus, Department of Physiology, Fellow, School of Policy Studies, Queen’s University, Kingston, ON
 
Palliative care versus assisted death? I don’t get it!
Many advocates of palliative care are opposed to assisted suicide and I don’t know why. They seem complementary to me......

Endpoints in clinical trials: What do patients consider important? A survey of the OCNA

abstract

Highlights

•

Clinicians have debated the selection of ovarian clinical trial endpoints.

•

Optimal endpoint selection should reflect true patient benefit.

•

We surveyed patients to ascertain what constitutes meaningful gains in clinical trials.

---

Objective

In order to understand the patient's perspective in regards to meaningful surrogate clinical trial endpoints and the impact of treatment-related toxicity, and quality of life, we surveyed women with gynecological cancers to ascertain their preferences.

Methods

A 28-question anonymous online survey was posted on the OCNA website (www.ovariancancer.org). Survey questions included demographic factors, tumor data, and patients' preference regarding side effects and therapy endpoints. Data was analyzed for frequency and percentage of each response. Student t-test, Fisher's exact test and Wilcoxon rank sums were preformed.

Results

There were 1413 survey responses. Participants reported that for a new agent to be meaningful, the minimum extension of progression-free survival (PFS) and overall survival (OS) should be five or more months, 77% and 85% of the time, respectively. Most subjects (55%, n = 612) were interested in an agent that would keep tumor growth relatively static without change in OS. Addressing the impact of adverse aspects from a hypothetical new agent as a function of response, there was significant migration (P < 0^.0001) to acceptance of greater toxicity and cost under the scenario of a 5–6 months OS gain, despite three-fold higher neurotoxicity, as compared to a PFS gain of 3–4 months/no OS without toxicity. Response patterns weren't altered by recurrence status.

Conclusions

Herein, we show that magnitude of outcome is a desired effect, even given the prospect of significant toxicity and cost. However, these preferences appear to differ between those with primary and recurrent disease.

(Commentary) Ovarian cancer: beyond resistance

Nature Publishing Group

....In the United States, for example, 5-year survival (OC) has inched up from about 40% in 1985 to a still parlous 45% today. By comparison, 5-year survival for breast cancer stands at 90%.....

Inverse birth cohort effects in ovarian cancer: Increasing risk in BRCA1/2 mutation carriers ....

Inverse birth cohort effects in ovarian cancer: Increasing risk in BRCA1/2 mutation carriers and decreasing risk in the general population
  

Highlights

•

Breast cancer risk increases with more recent birth cohorts, while results for ovarian cancer are inconsistent.

•

Birth cohort effects in ovarian cancer in BRCA mutation carriers and the general population were studied.

•

Ovarian cancer risks increase with birth cohort in BRCA carriers and decrease in the general population. The reason is unknown.

Objective

BRCA1/2 carriers are at increased risk of ovarian cancer, and some reports suggest an increasing risk in more recent birth cohorts. In contrast, decreasing incidences have been observed in the general population. The aim was to assess the birth cohort effect on ovarian cancer risk in BRCA1/2 carriers relative to their background general population.

Nutrient-wide association study of 57 foods/nutrients and epithelial ovarian cancer

abstract
 Nutrient-wide association study of 57 foods/nutrients and epithelial ovarian cancer in the European Prospective Investigation into Cancer and Nutrition study and the Netherlands Cohort Study

Background: Studies of the role of dietary factors in epithelial ovarian cancer (EOC) development have been limited, and no specific dietary factors have been consistently associated with EOC risk. 

Objective: We used a nutrient-wide association study approach to systematically test the association between dietary factors and invasive EOC risk while accounting for multiple hypothesis testing by using the false discovery rate and evaluated the findings in an independent cohort. 

Design: We assessed dietary intake amounts of 28 foods/food groups and 29 nutrients estimated by using dietary questionnaires in the EPIC (European Prospective Investigation into Cancer and Nutrition) study (n = 1095 cases). We selected 4 foods/nutrients that were statistically significantly associated with EOC risk when comparing the extreme quartiles of intake in the EPIC study (false discovery rate = 0.43) and evaluated these factors in the NLCS (Netherlands Cohort Study; n = 383 cases). Cox regression models were used to estimate HRs and 95% CIs. 

Results: None of the 4 dietary factors that were associated with EOC risk in the EPIC study (cholesterol, polyunsaturated and saturated fat, and bananas) were statistically significantly associated with EOC risk in the NLCS; however, in meta-analysis of the EPIC study and the NLCS, we observed a higher risk of EOC with a high than with a low intake of saturated fat (quartile 4 compared with quartile 1; overall HR: 1.21; 95% CI: 1.04, 1.41). 

Conclusion: In the meta-analysis of both studies, there was a higher risk of EOC with a high than with a low intake of saturated fat.