paywalled: Prophylactic oophorectomy rates in relation to a guideline update on referral to genetic counseling

Prophylactic oophorectomy rates in relation to a guideline update on referral to genetic counseling: Publication year: 2012


Source: Gynecologic Oncology

Objective We sought to determine whether prophylactic oophorectomy rates changed after the introduction of a 2007 health plan clinical guideline recommending systematic referral to a genetic counselor for women with a personal or family history suggestive of an inherited susceptibility to breast/ovarian cancer.

Methods We conducted a retrospective cohort study of female members of Group Health, an integrated delivery system in Washington State. Subjects were women aged ≥35years during 2004–2009 who reported a personal or family history consistent with an inherited susceptibility to breast/ovarian cancer. Personal and family history information was collected on a questionnaire completed when the women had a mammogram. We ascertained oophorectomies from automated claims data and determined whether surgeries were prophylactic by medical chart review.....

Results Prophylactic oophorectomy rates were relatively unchanged after compared to before the guideline change, 1.0 versus 0.8/1,000 person-years, (IRR=1.2; 95% CI: 0.7-2.0), whereas bilateral oophorectomy rates for other indications decreased. Genetic counseling receipt rates doubled after the guideline change (95% CI: 1.7-2.4) from 5.1 to 10.2/1,000 person-years. During the study, bilateral oophorectomy rates were appreciably greater in women who saw a genetic counselor compared to those who did not regardless of whether they received genetic testing as part of their counseling.

Conclusion A doubling in genetic counseling receipt rates lends support to the idea that the guideline issuance contributed to sustained rates of prophylactic oophorectomies in more recent years.

Family history: Still relevant in the genomics era - Cleveland Clinic

Family history: Still relevant in the genomics era

 Key points

• The family history is an underused tool for predicting the risk of disease and for personalizing preventive care.
• Barriers to the appropriate collection and use of the family history include concerns over the reliability of patient reporting, a lack of time and reimbursement, and provider knowledge gaps.
• Use of family history to inform genetic testing for hereditary cancer syndromes has been shown to improve outcomes and may reduce overall health care costs.
• Future solutions need to focus on creating time-effective ways to collect and analyze the family history, and on developing innovative methods of educating medical providers at all levels of training as to how to apply the family history in clinical practice. 

open access: Resolving the variable genome and epigenome in human disease - Knight - 2012 - Journal of Internal Medicine - Wiley Online Library

Resolving the variable genome and epigenome in human disease - Knight - 2012 - Journal of Internal Medicine

pdf file

Conclusions

There is no doubt that recent advances in genomics, currently driven by new high-throughput sequencing techniques, are taking us to remarkable new levels in our understanding of the human genome, and the genetic and epigenetic variation that exists, with important implications for our understanding of human disease. As this knowledge grows, our appreciation of the complexity with which we are faced is also underlined. For common multifactorial traits, GWAs have been very informative but leave much heritable risk unresolved. Rarer variants may prove important but in general, more integrated approaches are needed in which environmental risk factors are considered and combined with functional genomic analyses. Moreover, we need to derive functional genomic data in a disease-relevant setting as the consequences of underlying genetic and epigenetic diversity are increasingly recognized to be highly context specific.

Current technologies that can interrogate the whole genome carry with them significant caveats: these tools are new, and successful application to important biological problems requires careful experimental design and consideration of the limitations inherent in such approaches. The data sets involved are highly complex, and analysis remains extremely challenging with significant risks of false positive and negative results until the field matures. High-throughput sequencing is not a panacea but a critical tool in current genomics.  

Used wisely, it is resolving the individual genome and epigenome, at a structural and functional level, and will radically advance our understanding of disease. For Mendelian traits (Wiki) , the impact is already being felt. For common multifactorial diseases, this may take a little longer.

Prevalence of BRCA1 mutations among 403 women with triple-negative breast cancer: implications for genetic screening selection criteria: a Hellenic Cooperative Oncology Group Study.

Prevalence of BRCA1 mutations among 403 women with triple-negative breast cancer: implications for genetic screening selection criteria: a Hellenic Cooperative Oncology Group Study.:

Study
Breast Cancer Res Treat. 2012 Mar 21;

Abstract

In spite the close association of the triple-negative breast cancer immunophenotype with hereditary breast cancers and the BRCA1 pathway, there is a lack of population studies that determine the frequency of BRCA1 mutations among triple-negative breast cancer patients. To address this, we have screened a large sample of 403 women diagnosed with triple-negative invasive breast cancer, independently of their age or family history, for germline BRCA1 mutations.

Median age at diagnosis was 50 years (range 20-83). The overall prevalence of triple-negative cases among the initial patient group with invasive breast cancer was 8 %. BRCA1 was screened by direct DNA sequencing in all patients, including all exons where a mutation was previously found in the Greek population (exons 5, 11, 12, 16, 20, 21, 22, 23, 24-77 % of the BRCA1 coding region), including diagnostic PCRs to detect the three Greek founder large genomic rearrangements. Sixty-five deleterious BRCA1 mutations were identified among the 403 triple-negative breast cancer patients (16 %).

Median age of onset for mutation carriers was 39 years. (?? Blogger's Note: screening guidelines...)  Among a total of 106 women with early-onset triple-negative breast cancer (<40 years), 38 (36 %) had a BRCA1 mutation, while 27 % of women with triple-negative breast cancer diagnosed before 50 years (56/208) had a BRCA1 mutation. A mutation was found in 48 % (50/105) of the triple-negative breast cancer patients with family history of breast or ovarian cancer.

It is noteworthy, however, that of the 65 carriers, 15 (23 %) had no reported family history of related cancers. All but one of the carriers had grade III tumors (98 %). These results indicate that women with early-onset triple-negative breast cancer, and ideally all triple-negative breast cancer patients, are candidates for BRCA1 genetic testing even in the absence of a family history of breast or ovarian cancer.

ECCO: MRI screening for women with a family history of breast cancer

MRI screening for women with a family history of breast cancer

 MRI screening for women with a family history of breast cancer but no genetic predisposition is expensive but could be cost-effective for some

Lynch Syndrome: Don't Miss It (Transcript including slides))

Blogger's Opinion/Note:
guidelines indicate varying ages of screening depending on organ assuming there are screening mechanisms (eg. ovarian cancer has no screening for the general population however increased surveillance is possible for those at high risk,  albeit, ineffective; generally 25 yrs +;  'averages' are not helpful and therefore the urging of family history taking by primary/family care physicians, see NCCN guidelines for Lynch Syndrome which includes gene-specific details (eg. MLH1, MSH2/6, PMS2.....)

Lynch Syndrome: Don't Miss It (Transcript)

Clinical Implications

"Lynch syndrome is a genetic defect that has significant implications on the clinical side. A patient whose genetic testing is positive for Lynch syndrome has a likelihood of developing colon cancer that approaches 70% over his or her lifetime. The risk for uterine cancer is similar or a bit higher, and the risk for ovarian cancer is13%-15%. Almost certainly, these patients will have some type of cancer during their lifetime.

Metachronous cancers occur in 7%-10% of patients with Lynch syndrome. These patients present with one cancer, and typically in the course of a short period of time, another cancer develops. In patients with Lynch syndrome who have colon cancer, if you don't perform a subtotal colectomy because you didn't recognize that it was Lynch syndrome, the likelihood that the patient will develop a repeat colon cancer over 30 years (even in patients who are being screened) approaches 65%. This is not uncommon. A lot of these diagnoses are missed, and a secondary cancer develops."

"You need to start thinking about syndromic cancers because the relative risk is quite high. You need to be thinking about this in patients with early cancers -- not just colon cancer, but in uterine cancer and ovarian cancer as well." (Blogger's Note: and others including pancreatic, stomach, ureter, renal, bilary tract, gallbladder.....see slides)

" If you look at colon cancer in Lynch syndrome, the average age of onset is earlier (45 years) and some patients may be in their 20s. For sporadic uterine cancer, the average age is approximately 60 years, but in Lynch syndrome, it is shifted by a decade, to 50 years. When you see these cancers in a younger patient, the bell should go off and you should start thinking about Lynch syndrome and doing the appropriate testing."

"It is important to think about extracolonic cancers in these patients and to start to put the dots together because we are missing the boat on a lot of these syndromic cancers. It's not a zebra; it's 2%-3% of the patients who are presenting with cancer. We need to think outside the box. Even if you are not a gastroenterologist, include the colon when you see syndromic related cancers of the uterus, ovary, small bowel, or stomach."

open access: Adequacy of family history taking in ovarian cancer patients: a population-based study.

Blogger's Note: repost/open access

Adequacy of family history taking in ovarian cancer patients: a population-based study

Abstract:

The aim of this study was to evaluate the adequacy of family history taking in epithelial ovarian cancer (EOC) patients and to identify factors that determine adequacy. Furthermore, the validity of family history taking was assessed by comparison with self-administered questionnaires. Medical records of all 1,112 EOC patients registered by the nation-wide cancer registry and diagnosed in eleven Dutch hospitals between 1996 and 2006 were reviewed. Adequate family history taking was defined as a written notification of the presence or absence of relatives with breast or ovarian cancer. Factors that were correlated with family history taking were identified using univariable and multivariable logistic regression. 147 patients filled in a postal questionnaire. An adequate family history was taken in 41% of all cases. Younger age, an academic hospital and having undergone surgery and/or chemotherapy were associated with adequate family history taking. The comparison with self-administered questionnaires showed a disagreement in 64% mainly due to missing data in medical records. Documentation on family history is either absent or inadequate in the medical records in the majority of EOC patients. These data urge for better uptake of hereditary cancer risk assessment. Different strategies for this assessment like improved family history taking and genetic testing in EOC patients should be explored.

Limited significance of family history for presence of BRCA1 gene mutation in Polish breast and ovarian cancer cases. (300T>G mutation)

Limited significance of family history for presence of BRCA1 gene mutation in Polish breast and ovarian cancer cases.:
Limited significance of family history for presence of BRCA1 gene mutation in Polish breast and ovarian cancer cases.
Fam Cancer. 2012 Mar 1;


Abstract
It is estimated that about 5-10% of ovarian and 2-5% of all breast cancer patients are carriers of a germline BRCA1 or BRCA2 gene mutation. Most families with detected BRCA1 or BRCA2 gene mutation are qualified for molecular testing on the basis of family history of breast or ovarian cancers. The purpose of our study was to establish the frequency of positive family history of cancer in a series of Polish consecutive breast and ovarian cancer patients in two groups, with and without the BRCA1 gene mutations. We analysed the prevalence of four of the most common BRCA1 mutations: 5382insC (c.5266dupC), 300T>G (p.181T>G), 185delAG (c.68_69delAG) and 3819del5 (c.3700_3704del5). The patient group consisted of 1,845 consecutive female breast and 363 ovarian cancer cases. 19 out of 37 (51%) of BRCA1-positive ovarian cancer patients and 21 out of 55 (39%) BRCA1-positive breast cancer had negative family history of breast and/or ovarian cancer among first- and second-degree relatives.

In ovarian cancer patients, negative family history was more frequent in those with 300T>G BRCA1 gene mutation than in 5382insC carriers. This finding indicates the necessity of searching for 300T>G mutation in families with a single diagnosis of ovarian cancer in family. The high frequency of mutations detected in breast cancer patients lacking obvious family history shows that breast cancer patients should be qualified for genetic testing on the basis of wide clinical and pathological criteria.

Cancer Risks for the Relatives of Colorectal Cancer Cases with a Methylated MLH1 Promoter Region: Data from the Colorectal Cancer Family Registry

Blogger's Note: focus on MLH1

".....The cohort consisted of 3,128 first- and second-degree relatives of the 233 MLH1-methylated CRC cases with no MMR or MUTYH gene mutations.

The standardized incidence ratio (SIR) for CRC was 1.60 [95% confidence interval (CI), 1.22–2.16] for first-degree relatives and 1.08 (0.74–1.60) for second-degree relatives.

The SIR for gastric cancer was 2.58 (1.52–4.71) for first-degree relatives and 4.52 (2.23–10.61) for second-degree relatives and, for ovarian cancer, it was 2.16 (1.29–3.86) for first-degree relatives.

The risk of liver cancer was also increased significantly in first-degree relatives but the estimate was on the basis of only two cases.

These data imply that relatives of CRC cases with MLH1 methylation may be at increased risk of CRC and stomach cancer and possibly ovarian and liver cancer, suggesting that there may be a heritable factor for CRC and other cancers associated with MLH1 methylation in non–Lynch syndrome."

abstract: Family History and Women With Ovarian Cancer: Is it Asked and Does it Matter?: An Observational Study BRCA and/or Lynch Syndrome

Abstract

Objective: The objective of the study was to determine how many women in an ovarian cancer (OC) study cohort had a family history (FH) recorded in their case notes and whether appropriate action was taken on the basis of that FH.

Results: Family history was not consistently recorded. Although FH was recorded in the majority of women, 14 women had no FH recorded. In 63 women, the FH was recorded as not significant, and in 15 cases, FH information was insufficient to complete a risk assessment. Twenty-two women had significant FH meeting criteria for specialist genetics referral. In 15 of these 22 cases, the relevant history suggestive of hereditary breast cancer and OC (due to BRCA1 or BRCA2 mutations) or Lynch syndrome had been documented, but no action was recorded, and its significance was not appreciated.

Conclusions: These data indicate that training in recognizing relevant FH is needed for clinicians looking after women with OC. .....

Jan 2012: Faulty proteins may prove significant in identifying new treatments for ovarian cancer | e! Science News

Link:  PLOS One published study


 Objective
To define the BRCAness profile of sporadic ovarian carcinoma and determine whether BRCA1, PARP, FANCD2, PTEN, H2AX, ATM, and P53 protein expression correlates with response to treatment, disease recurrence, and recurrence-free survival.

"The study -- which was supported by the Sherie Hildreth Ovarian Cancer (SHOC) Foundation -- focused on proteins that are supposed to assist cells in repairing harmful breaks in DNA strands, a process called homologous recombination (HR). The malfunctioning of HR is not well understood in ovarian cancers where there is no family history of the disease. However, there is evidence that these proteins influence a patient's ability to respond to drugs and their survival rates after treatment."

abstract: Genetic Counseling: Bias in the Reporting of Family History: Implications for Clinical Care

".....This is evident by the underreporting of paternal family histories of cancer, and also, though to a lesser extent, by degree (family relationship). These discrepancies in reporting family history of cancer imply we need to take more care in collecting accurate family histories and also in the clinical management of individuals in relation to hereditary risk"

Search Results: 'family history' 2011 ASCO Abstracts

Find EXACT phrase: family history

Found 42 documents

Family Cancer Histories Are Not Highly Accurate --Doctors Lounge ASCO

Abstract
Full Text (subscription or payment may be required)
Editorial

abstract:  
Conclusions General population reports on family history for the four major adult cancers were not highly accurate. Efforts to improve accuracy are needed in primary care and other health-care settings in which family history is collected to ensure appropriate risk assessment and clinical care recommendations. 

Evaluation of predictive models for the identification in daily practice of patients with lynch syndrome - Intl Jnl of Cancer

"....Both approaches failed to identify two of the eight mutation carriers (the same two patients, aged 67 and 81 years, both with no family history). Thus, like the revised Bethesda guidelines, predictive models did not identify all Lynch syndrome patients in our series of unselected CRC. Our results support systematic screening for MMR deficiency in all new CRC cases."

Incidence and mortality in epithelial ovarian cancer by family history of any cancer - 2011

define: sororal
Of or pertaining to a sister; Related through someone's sister

Abstract
BACKGROUND:

Practically all data on familial risk in ovarian and other cancers are based on incident cancer, whereas familiality in cancer mortality is largely unknown. If fatal forms of cancer are a highly familial subtype, then familial risk for mortality may exceed that of incidence, which is relevant for clinical decision making and counseling.

METHODS:

Ovarian cancer patients in the nationwide Swedish Family Cancer Database were classified according to fatal and nonfatal (incident) family history. Familial risks for incident and fatal ovarian cancer were calculated for offspring based on their parental or sibling family history of any cancer using standardized incidence ratios (SIRs) for incidence and standardized mortality ratios (SMRs) for mortality. Offspring without family history were referents.

RESULTS:

The database included 24,757 mothers and 8138 daughters with ovarian cancer. When a mother had ovarian cancer, the SIR for incident ovarian cancer in daughters was 2.69, and when a sister had ovarian cancer it was 3.49. The SMRs for fatal cancer by fatal cancer in probands were 3.39 and 5.80, respectively. For fatal serous cancers among siblings, the SMR was 6.16, compared with 10.01 for the endometrioid type. Ovarian cancer was associated with maternal (SIR, 1.22; SMR, 1.56) and sororal breast cancer (SIR, 1.27). Another discordant association was between ovarian and paternal prostate cancer (SIR, 1.12; SMR, 1.66).

CONCLUSIONS:

Fatal familial risks were higher for concordant ovarian, ovarian-breast, and ovarian-prostate cancers than the corresponding incident risks. This may suggest that highly fatal subtypes exist for these cancers, calling for genetic dissection. Cancer 2011

full free access: Effect of preventive messages tailored to family history on health behaviors: the Family Healthware Impact Trial. Ann Fam Med. 2011 (includes ovarian cancer)

PURPOSE: We wanted to determine the impact of automated family history assessment and tailored messages for coronary heart disease, stroke, diabetes, colorectal, breast, and ovarian cancer on preventive behaviors compared with a standard preventive message. ....cont'd for full free access

Components of family history associated with women's disease perceptions for cancer: A report from the Family Healthware™ Impact Trial - abstract

PURPOSE: To determine the specific components of family history and personal characteristics related to disease perceptions about breast, colon, and ovarian cancers.

Know your pedigree: Family medical history holds key to your health - Winnipeg Free Press

"Look to both sides of the family. "I still very often hear from patients, 'My doctor told me I don't have to worry because it's from my dad's side,'" she says with evident frustration."

Comprehensive Analysis of Missense Variations in the BRCT Domain of BRCA 1 by Structural and Functional Assays

Comprehensive Analysis of Missense Variations in the BRCT Domain of BRCA1 by Structural and Functional Assays.

Lee MS, Green R, Marsillac SM, Coquelle N, Williams RS, Yeung T, Foo D, Hau DD, Hui B, Monteiro AN, Glover JN.

Authors' Affiliations: Department of Biochemistry, School of Systems Molecular Medicine, University of Alberta, Edmonton, Alberta, Canada; National Institute of Environmental Health Sciences, Durham, North Carolina; Risk Assessment, Detection, and Intervention Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; and Molecular Biology Program, Institute of Biophysics Carlos Chagas Fo., Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Abstract

Genetic screening of the breast and ovarian cancer susceptibility gene BRCA1 has uncovered a large number of variants of uncertain clinical significance. Here, we use biochemical and cell-based transcriptional assays to assess the structural and functional defects associated with a large set of 117 distinct BRCA1 missense variants within the essential BRCT domain of the BRCA1 protein that have been documented in individuals with a family history of breast or ovarian cancer....... Through a correlation of the assay results with available family history and clinical data, we define limits to predict the disease risk associated with each variant. Forty-two of the variants show little effect on function and are likely to represent variants with little or no clinical significance; 50 display a clear functional effect and are likely to represent pathogenic variants; and the remaining 25 variants display intermediate activities. The excellent agreement between the structure/function effects of these mutations and available clinical data supports the notion that functional and structure information can be useful in the development of models to assess cancer risk.