BREVAgen was validated only in comparison to Gail score. Being that the Gail score is the least sensitive scoring tool available and that it is widely considered inadequate, it is hard to have confidence in the validation process. In addition, the risk calculation that depends on multiplying SNP risks by Gail raises its own questions of accuracy. Finally, there is no prospective evidence that BREVAgen produces clinical evidence.

Darabi H, Czene K, Zhao W et al. Breast cancer risk prediction and individualised screening based on common genetic variation and breast density measurement. Breast Cancer Res 2012; 14(1):R25.
Armstrong K, Handorf EA, Chen J et al. Breast cancer risk prediction and mammography biopsy decisions: a model-based study. Am J Prev Med 2013; 44(1):15-22.
Mealiffe ME, Stokowski RP, Rhees BK et al. Assessment of clinical validity of a breast cancer risk model combining genetic and clinical information. J Natl Cancer Inst 2010; 102(21):1618-27.
Zheng W, Wen W, Gao YT et al. Genetic and clinical predictors for breast cancer risk assessment and stratification among Chinese women. J Natl Cancer Inst 2010; 102(13):972-81.
Campa D, Kaaks R, Le Marchand L et al. Interactions between genetic variants and breast cancer risk factors in the Breast and Prostate Cancer Cohort Consortium. J Natl Cancer Inst 2011.
Wacholder S, Hartge P, Prentice R et al. Performance of common genetic variants in breast-cancer risk models. N Engl J Med 2010; 362(11):986-93.

For Lay version see here

Personal history of breast cancer at young age is an indication for BRCA testing. The literature variably sets the age of what is considered early at before age 50 or 40.

NCCN guidelines were revised to include the following changes from 2008 version(NCCN 2011):
•Changed age of diagnosis of personal history of breast cancer from 40 years or less to 45 years or less
•Add an indication for two breast primaries, when first breast cancer diagnosis occurred prior to age 50

•Women with triple negative disease under age 60 should have BRCA testing
Removed at least one close male blood relative with breast cancer and at least one close female blood relative breast or epithelial ovarian cancer from qualifying criteria for testing males with breast cancer
•Modified stated of family history to read “if no living family member with breast or ovarian cancer, consider testing family members affected with cancers thought to be related to BRCA1/BRCA2 such as prostate, pancreas or melanoma”.

The risk of baseline prevalence of BRCA mutations has been best established in the setting of family history. Personal history is less well attested to in guideline statements than family history but several guidelines do mention this factor. They include the ACS Guideline, NCCN, Hayes. Some guidelines, such as NICE and UPTFS, skirt this issue by deliberately noting that they do not address women with breast cancer at a young age. Nevertheless, BRCA screening is usually considered to be indicated in such cases. Other guidelines also would cover testing for this patient.

The Society of Breast Surgeons adds: “a personal or family history of ovarian cancer (particularly non-mucinous types)”. Hayes Genetic Testing Evaluation says: BRCA1 and BRCA 2: The decision to undergo genetic testing for BRCA1/2 variants may be most influenced by physician recommendation for testing and indecision about definitive surgical treatment. In addition, patients younger than 50 years of age at diagnosis and those having multiple primary tumors are more likely to undergo genetic testing for BRCA1/2 variants. However, the recommendation for testing triple negative patients is unique to NCCN at this time, according to my knowledge.

NCCN now includes patients with DCIS disease only, as it does not differentiate between invasive and non-invasive cancer.

NCCN, Screening for breast cancer, BRISK -1, BR-OV 2017

Trivers KF, Baldwin LM, Miller JW, et al. Reported referral for genetic counseling or BRCA 1/2 testing among United States physicians: a vignette-based study [published online ahead of print July 25, 2011]. Cancer. doi: 10.1002/cncr.26166

Robert A. Smith, PhD, Debbie Saslow, PhD, Kimberly Andrews Sawyer, Wylie Burke, MD, PhD (for the High-Risk Work Group), Mary E. Costanza, MD (for The Screening Older Women Work Group), W. Phil Evans, III, MD (for The Mammography Work Group), Roger S. Foster, Jr., MD (for The Physical Examination Work Group), Edward Hendrick, PhD (for the New Technologies Work Group), Harmon J. Eyre, MD and Steven Sener, MD (for The Breast Cancer Advisory Group)American Cancer Society Guidelines for Breast Cancer Screening: Update 2003 CA Cancer J Clin 2003; 53:141-169

J. Balmañaetet al, BRCA in breast cancer: ESMO Clinical Practice Guidelines
Ann Oncol (2010) 21 (suppl 5): v20-v22 K.

BART stands for BRACAnalysis Rearrangement Test, which detects large DNA rearrangements in the BRCA1 and BRCA2 genes, which the pcr for BRCA does not detect. Myriad’s postion is that BART testing is appropriate for women who have had full sequence analysis for BRCA 1/2, have tested negative and are at very high baseline risk. Myriad quotes the following statistics: when baseline risk of BRCA is 30%, BART will be _ in 2-3% or women. however, if you look at all + tests results, 10% of them are in the form of BART. Based on clinical and family history criteria, 1,035 patients were identified as severe-risk during the initial months of clinical BART analysis at Myriad Genetic Laboratories. All patients were initially tested for Comprehensive BRACAnalysis which includes BRCA1 and BRCA2 full gene sequencing plus large rearrangement panel testing for 5 recurrent BRCA1 mutations. Among severe-risk patients, 302 (29.2%) were positive for a BRCA1 or BRCA2 mutation by sequencing, 9 (0.9%) were positive by large rearrangement panel testing and an additional 27(2.6%) tested positive by BART for large genomic rearrangements. The total detection rate for deleterious mutations in severe-risk individuals was therefore 32.7%. As of August 1, 2006, Myriad conducts the BRACAnalysis Rearrangement Test on patient samples where the individual’s personal and family history is indicative of an exceptionally high level of risk, but the sample tests negative for BRACAnalysis. The Rearrangement test will be performed, when indicated, at no additional charge, and is also available for order independently for a fee of $650.

In a 2011 review, Shannon et al recommended routine testing of all BRCA testing women but many cosndiered it over-reaching since only 1.9% of the sample had this mutation.

Recently NCCN updates its recommendations based on a new paper in Cancer. NCCN now defines comprehensive genetic testing to include large genomic rearrangements. Previously, the guidelines noted that large genomic rearrangements are not detectable by primary sequencing, but did not specify that additional testing (i.e. BART) should be included as part of comprehensive testing.  This is based on new data that large genomic rearrangements account for 6-10% of BRCA1 and BRCA2 mutations. In individuals of Latin American/Caribbean and Near East/Middle East descent, these rearrangements account for approximately 20% of mutations. The following will meet the NCCN criteria for BART testing:

Patient affected with breast cancer before aged 50 AND family history of 2 or more cases of breast cancer before age 50 and/or ovarian cancer at any age.

- Ovarian cancer at any age AND family history of 2 or more cases of breast cancer before age 50 and/or ovarian cancer at any age.

- Male breast cancer at any age AND family history of 2 or more cases of breast cancer before age 50 and/or ovarian cancer at any age.

- Breast cancer at or after 50 and ovarian cancer at any age AND family history of 1 or more cases of breast cancer before age 50 and/or ovarian cancer at any age.

.

Emily Z. TouloukianUsefulness of Retrospective Analysis of BART Eligibility The Open Breast Cancer Journal,2012, 4, 2012

R. Wenstrup, T. Judkins, K. Eliason, J. Schoenberger, S. Rajamani, C. A. A. Frye, L. A. Burbidge, J. T. Trost, A. M. Deffenbaugh, B. B. Ro Molecular genetic testing for large genomic deletion and duplication mutations in the BRCA1 and BRCA2 genes for hereditary breast and ovarian cancer. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 10513

Thaddeus Judkins, et al, Clinical Significance of Large Rearrangements in BRCA1 and BRCA2, Cancer 2012;000:000–000

Shannon KM, Rodgers LH, Chan-Smutko G, Patel D, Gabree M, Ryan PD. Download BART_article_2012[1]Which individuals undergoing BRACAnalysis need BART testing?Cancer Genet. 2011 Aug;204(8):416-22.

Wendy Rubinstein Roles and responsibilities of a medical geneticist. Fam Cancer. 2007 Jul 12; : 17624600

There are some special groups in which screening may be reasonable. These include hereditary pancreatitism chronic pancreatitits and thos with a strong family history.

An individual’s risk of developing pancreatic cancer increases with the number of affected first-degree relatives, and it is estimated that hereditary factors account for at least 5% of pancreatic cancers.2 Familial pancreatic cancer (FPC) is inherited in an autosomal dominant manner, with variable penetrance. In order to diagnose FPC, it is necessary to obtain an accurate and thorough family history with particular emphasis on the oncologic history. While it is important to ascertain any family history of pancreatic cancer, it is also important to screen for a personal and family history of extrapancreatic malignancies, and to obtain a family cancer history beyond first-degree relatives, if possible. The family history allows the clinician to determine if prior cases of pancreatic cancer in relatives are more likely to be familial or sporadic.

If a diagnosis of FPC is made in conjunction with a family history of extrapancreatic malignancies, consideration should also be given to a syndromic FPC. Hereditary pancreatic cancer has been associated with colorectal cancer in the Lynch syndrome II variety of hereditary nonpolyposis colorectal cancer (HNPCC), with breast and ovarian cancer (breast–ovarian cancer syndrome), Peutz–Jeghers syndrome, and melanomas in the familial atypical multiple mole melanoma (FAMMM) syndrome. A family history of early pancreatitis suggestive of hereditary pancreatitis is also an important risk factor for subsequent pancreatic adenocarcinoma.

Although there are no consensus guidelines on what defines FPC, an assessment of the risk of developing pancreatic cancer according to the number of affected relatives is useful in clinical practice. Genetic testing might be a useful adjunct in the management of a patient with FPC, but should be performed only after appropriate genetic counseling. Many important genes that have at least a partial role in FPC, both syndrome-associated and nonsyndromic, have been identified. In a multicenter study, 40% of patients with a history of hereditary pancreatitis developed pancreatic adenocarcinoma by 70 years of age.6 Testing for the cationic trypsinogen gene (PRSS1), which is associated with hereditary pancreatitis, is available. The FAMMM syndrome, described in 1975, is associated with a germline mutation of the p16 tumor suppressor gene (CDKN2A). Testing for p16 mutations helps identify those patients at risk for pancreatic malignancy in families with a history of melanomas and pancreatic cancer. The majority of FPC cases, however, are nonsyndromic.

CT scanning, while critical in the management of pancreatic adenocarcinoma, has not proven to be of definitive benefit in screening for pancreatic malignancy in FPC, mainly because of a lack of adequate resolution to detect dysplasia. For CT scanning to exert a benefit in terms of mortality, it must detect either premalignant changes or early malignancy, so that curative surgery can be performed.

In conclusion, genetic counselling should precede radiological screening, an attempt to better define a familial syndrome should be made before screening, and there is no evidence that any screening is supror to another or to no screening at all. There is little evidence for CT scan based screening.

U.S. Preventive Services Task Force (USPSTF). Screening for pancreatic cancer: recommendation statement. Rockville (MD): Agency for Healthcare Research and Quality (AHRQ); 2004 Feb. 3 p. [4 references]

Ulrich CD; Consensus Committees of the European Registry of Hereditary Pancreatic Diseases, Midwest Multi-Center Pancreatic Study Group, International Association of Pancreatology.Pancreatic cancer in hereditary pancreatitis: consensus guidelines for prevention, screening and treatment.Pancreatology. 2001;1(5):416-22
Ellis I, Lerch MM, Whitcomb DC; Consensus Committees of the European Registry of Hereditary Pancreatic Diseases, Midwest Multi-Center Pancreatic Study Group, International Association of Pancreatology.  Genetic testing for hereditary pancreatitis: guidelines for indications, counselling, consent and privacy issues.
Pancreatology. 2001;1(5):405-15

Rajesh N Keswani, Amy Noffsinger and Irving Waxman A family history of pancreatic cancer, Nature Clinical Practice Gastroenterology & Hepatology (2006) 3, 586-591

Kanjeekal S, Biagi J, Walker-Dilks C. PET imaging in pancreatic cancer: recommendations. Toronto (ON): Cancer Care Ontario (CCO); 2009 Jan 19. 20 p. (Recommendation report – PET; no. 5).  [34 references]

On October 18, a presentation of this study and related historical data by Dr. Goetz to the Food and Drug Administration led to an advisory committee unanimously recommending a label change for tamoxifen. This change would include information about the increased risk both from genetic factors and drug interactions affecting CYP2D6. However, the relationship between endoxifen plasma concentrations and clinical outcomes has not been established.

Thus, CYPD26 inhibitors should be avoided by patients on tamoxifen but the test cannot be routinely recommended yet to select treatment. TEC assessment by BCBS concluded:” Based on the above, CYP2D6 genotyping does not meet the TEC criteria for directing endocrine therapy regimen selection for women at high risk for primary breast cancer or breast cancer recurrence.” A recent article and editorial in the Journal of Clinical Oncology confirmed that the available evidence is not sufficient to routinely recommend this testing. …”that a number of reported studies have been confounded as a result of a variety of biases and do not provide the level of evidence that is needed to recommend CYP2D6 genotyping. In fact, all published pharmacogenetic studies, by virtue of their retrospective nature (including prospective-retrospective studies), are prone to limitations; therefore, it is a minimum requirement that sample size, population stratification, quality of genotyping, and allele coverage, as well as correct genotype-phenotype assignment are vigorously addressed. Thus, studies that are based solely on the availability of samples are of little value”.

I would add that in 2009 ASCO meeting,  Aubert and colleagues presented in the clinically significant drug interaction between TAM and known CYP2D6 inhibitors. This resulted in a significant 1.9 fold higher BrCa recurrence within 2 years of initiating TAM therapy. This study has been extensively discussed but it had not resulted in any guideliens or consensus recommendations. As such, it appears premature to routinely test patients for this mutation since there is no accepted consensus on what to do with the results of the test. A 2011 Technology Review concluded: “This is a relatively new area of research that is evolving rapidly and, although international consortia are collaborating, the data are limited and conflicting. Therefore, it is not possible to recommend pharmacogenetic testing in this patient population. Future research needs to focus on which alleles (including, or in addition to, those related to CYP2D6) reflect patient response, the link between endoxifen levels and clinical outcomes, and the appropriate pathways for implementation of such pharmacogenetic testing in patient care pathways.”

Kiyotani K, Mushiroda T, Imamura CK, Hosono N, Tsunoda T, Kubo M, Tanigawara Y, Flockhart DA, Desta Z, Skaar TC, Aki F, Hirata K, Takatsuka Y, Okazaki M, Ohsumi S, Yamakawa T, Sasa M, Nakamura Y, Zembutsu H. Significant effect of polymorphisms in CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients.J Clin Oncol. 2010 Mar 10;28(8):1287-93.

Aubert, R. E., Stanek, E. J., Yao, J., Teagarden, J. R., Subar, M., Epstein, R. S., Skaar, T. C., Desta, Z., Flockhart, D. A. Risk of breast cancer recurrence in women initiating tamoxifen with CYP2D6 inhibitors  J Clin Oncol (Meeting Abstracts) 2009 27: CRA508

MP, Knox SK, Suman VJ, Rae JM, Safgren SL, Ames MM, Visscher DW, Reynolds C, Couch FJ, Lingle WL, Weinshilboum RM, Fritcher EG, Nibbe AM, Desta Z, Nguyen A, Flockhart DA, Perez EA, Ingle JN.The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen.Breast Cancer Res Treat. 2007 Jan;101(1):113-21.

http://www.bcbs.com/blueresources/tec/vols/23/cyp2d6-pharmacogenomics-of.html

van Kuilenburg, Andre B. P., Meinsma, Rutger, Zonnenberg, Bernard A., Zoetekouw, Lida, Baas, Frank, Matsuda, Koichi, Tamaki, Nanaya, van Gennip, Albert H. Dihydropyrimidinase Deficiency and Severe 5-Fluorouracil Toxicity
Clin Cancer Res 2003 9: 4363-4367

H. H. Ezzeldin and R. B. Diasio Predicting Fluorouracil Toxicity: Can We Finally Do It? J. Clin. Oncol., May 1, 2008; 26(13): 2080 – 2082.

Role of Genetic and Nongenetic Factors for Fluorouracil Treatment-Related Severe Toxicity: A Prospective Clinical Trial by the German 5-FU Toxicity Study Group Matthias Schwab, Ulrich M. Zanger, Claudia Marx, Elke Schaeffeler, Kathrin Klein, Jürgen Dippon, Reinhold Kerb, Julia Blievernicht, Joachim Fischer, Ute Hofmann, Carsten Bokemeyer, and Michel Eichelbaum JCO 2008 26: 2131-2138

http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowPDF&ProduktNr=230493&ArtikelNr=82641&filename=.pdf

Mutation in this gene results in hereditary breast and ovarian cancer syndromes. Over the last 10 years it has been noted that some families with BRCA2 mutations have a high incidence of pancreatic cancer. There may be some utility to Transesophageal Ultrasound. One retrospective report concluded that screening of high-risk individuals is warranted due to the number of significant asymptomatic pancreatic neoplastic lesions found in this cohort of individuals. To my knowledge, similar work has not been done with CT scans.

Teresa A. Brentnall MD

CANCER SURVEILLANCE OF PATIENTS FROM FAMILIAL PANCREATIC CANCER KINDREDS  Medical Clinics of North America
Volume 84, Issue 3, 1 May 2000, Pages 707-718

Nccn.org, Pancreatic Cancer

http://www.moffitt.org/CCJRoot/v15n4/pdf/280.pdf