Seminars in Oncology
Volume 38, Issue 5 , Pages 605-611, October 2011

BRCA1 and BRCA2 Variants of Uncertain Significance. Part Two: Medical Management

Article Outline

 

At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each “Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers' comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at Gloria.Morris@hemonc1.com. I look forward to a lively discussion.

Gloria J. Morris, MD, PhD

Current Clinical Practice Feature Editor

In Part One we presented three cases of women with a personal and strong family history of breast cancer, all of whom were tested for BRCA mutations and found to have variants of uncertain significance (VUS), one of which was classified as a polymorphism. While polymorphic variants are typically accepted as being harmless changes that are not deleterious, these findings, along with the presence of VUS, can nonetheless be unsettling for both clinician and patient when the patient has a personal and/or family history that fits the characteristics for a hereditary cancer syndrome. We asked cancer genetics experts for their guidance on risk assessment and presented their responses in Part One. We know from landmark studies that in women who harbor a deleterious BRCA1 or BRCA2 mutation, mastectomy strongly reduces breast cancer risk.1 Bilateral salpingo-oophorectomy lowers ovarian cancer risk even in those who have prior breast cancer, in addition to lowering both breast cancer–specific, ovarian cancer–specific, and all-cause mortality rates.2, 3 Here, in Part Two, we have asked specific providers to describe their current clinical practice in managing cancer risk in individuals who have BRCA VUS that are not classified as known to be deleterious. We present specific recommendations from breast surgical oncologists, a genitourinary oncologist, and a gastroenterologist specializing in endoscopic techniques for cancer detection. For the cases presented and the genetic pedigrees, please refer to Part One.4

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Breast Surgical Oncologist's Opinion 

In 1978, Lynch et al published an article suggesting that in families which were breast cancer–prone, there was an indication for prophylactic surgery.5 Several years later, Horton and Dascombe reported that total mastectomy was the preferred surgical option for these patients because it removed a larger percentage of breast tissue when compared to subcutaneous mastectomy. They found that total mastectomy along with immediate reconstruction yielded acceptable cosmetic results.6

In 1990, Wapnir et al commenting on the evolution of prophylactic mastectomy noted that it was developed in the times when physicians often had difficulty distinguishing high-risk benign disease and malignancy and felt that “in retrospect, however, it is clear that the indications were ill defined, based often on unfounded risk and predicated on patient and physician anxiety. The scope of risk in carcinoma of the breast has been narrowed, with new information identifying only specific subsets of women with proliferative types of benign disease as more susceptible to the subsequent development of carcinoma.”7 Wapnir and colleagues noted that for familial risk, one must consider which family members were affected, their age, and bilaterality. These women should be counseled as to their hypothetical lifetime risk reduction with surgery, and the personal, individual decision should be guided by a multidisciplinary team.

By 1993, surgeons and cancer specialists were more accurately defining the indications for prophylactic mastectomy, identifying that population with high-risk factors by introducing the concept of cumulative predisposition and relative risk based on family history, proliferative breast histology, and previous cancer in one breast. Nemecek et al discussed these issues and questioned whether any mastectomy is truly prophylactic. The advice was that physicians counsel appropriate patients so they can make informed decisions.8 Vogel and colleagues recapitulated this concept of assessing risk and providing patients with quantitative estimates of the chance of developing breast cancer in their lifetime. Histopathologic assessment of premalignant disease was a critical component in the evaluation. By this time, primary chemoprevention clinical trials were available, and it was felt that this would decrease the number of indications for prophylactic mastectomy.9

Attention has focused on breast cancer prevention as there is increased understanding of risk factors for breast cancer, especially the identification of genes associated with a predisposition. The only clinically available method for breast cancer prevention is prophylactic mastectomy.10

The indications for prophylactic mastectomy, as of the year 2000, range from lobular carcinoma in situ (LCIS) to BRCA1/2-positive cosmesis and cancer phobia. Occult cancers are found in 5% of prophylactic mastectomy cases and, therefore, the role of sentinel lymph node (SLN) biopsy has been raised as a diagnostic procedure in these patients as prophylactic mastectomy excludes the subsequent option of SLN biopsy. SLN biopsy has been established as an accurate and minimally invasive method of evaluating the lymphatic basin. Since the opportunity for SLN biopsy is precluded once mastectomy is performed, premastectomy SLN biopsy should be considered for those patients felt to have a significant risk of occult disease.11

The Society of Surgical Oncology established a consensus statement about the indications for prophylactic mastectomy. Newman et al reported that clinicopathological presentations which portend an additional risk of the development of breast cancer and justify proceeding with bilateral prophylactic mastectomies include any of the following: “1. A known mutation of BRCA1 or BRCA2 or other strongly predisposing breast cancer susceptibility genes. 2. A family history of breast cancer in multiple first-degree relatives and/or multiple successive generations of family members with breast and/or ovarian cancer (family cancer syndrome). Additionally a family history of multiple family members with bilateral and/or premenopausal and/or male breast cancer may be associated with a familial breast cancer syndrome. Genetic counseling should be strongly considered, although prophylactic surgery is appropriate in women with a family history consistent with genetic predisposition and no demonstrable genetic mutation. 3. High-risk histology: atypical ductal or lobular hyperplasia, or LCIS confirmed on biopsy. These changes are especially significant if present in a patient with a strong family history of breast cancer.”12

These recommendations were updated in 2007 and stressed that there are no absolute indications for prophylactic mastectomy, but data suggest at minimum a 90% reduction in the subsequent development of breast cancer. The procedure should be total mastectomy, with the additional comments that patients considering this surgery should undergo ovarian cancer screening and consultation regarding prophylactic oophorecotomy. There should also be a discussion regarding reconstruction and the complex body image and psychosocial issues. “There is insufficient evidence at this time to recommend routine SLN biopsy for patients undergoing prophylactic mastectomy. However, this may be considered since high-risk patients may have an unsuspected cancer and axillary staging would be difficult after mastectomy.”12 “Prophylactic mastectomy may improve longevity in BRCA mutation carriers, but this must be balanced against the impact on quality of life. The benefits of prophylactic mastectomy relative to chemoprevention are unclear because there are no prospective randomized studies comparing these two strategies. Patients considering prophylactic mastectomy should be well informed of risk-reduction alternatives and the limitations in the efficacy and cosmetic results of the procedure.”12

Although in the early first decade of the 21st century prophylactic mastectomy was not performed on a large scale, it has been increasingly popular as more women are being tested and are opting for this alternative. Metcalfe and colleagues reported that 80% of the prophylactic mastectomies performed were because of a family history of breast carcinoma (89 of 99) or because of a known BRCA1 or BRCA2 mutation (10 of 99). Twenty percent of the women had no family history but had the surgery for other benign breast conditions. Metcalfe et al stated that “the introduction of genetic testing for BRCA1 and BRCA2 has the potential to change the patterns of practice for prophylactic mastectomy.”13 This new emphasis of genetic testing and mutation carriers, along with rising rates of breast cancer, resulted in increased interest in prophylactic mastectomy. Lostumbo et al14 evaluated whether it would translate to reduced breast cancer incidence and breast cancer mortality, increased disease-free survival, less physical morbidity, and better psychosocial outcomes. They searched Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Cancerlit, and the Science Citation Index. Participants from 23 studies totaled more than 4,000 women at risk for breast cancer in at least one breast. Interventions included all types of mastectomy performed for the purpose of preventing breast cancer, including subcutaneous mastectomy, total or simple mastectomy, modified radical mastectomy, and radical mastectomy. Reviewers concluded that “while published observational studies demonstrated that bilateral prophylactic mastectomy was effective in reducing both the incidence of, and death from, breast cancer, more rigorous prospective studies (ideally randomized trials) are needed. The studies need to be of sufficient duration and make better attempts to control for selection biases to arrive at better estimates of risk reduction.”14 They concluded that only high-risk women should consider this procedure. Patient satisfaction was related to the cosmetic outcome and most women reported reduced cancer worry and psychological morbidity.

Clearly, besides the reduced cancer worry, patient satisfaction with prophylactic mastectomy is related to the reconstructive outcome and cosmesis. Prophylactic mastectomy should be performed with immediate reconstruction for maximal patient satisfaction. Metcalfe et al surveyed women who underwent prophylactic mastectomy between 1991 and 2000 in the province of Ontario. The majority of women (70%) were satisfied with their decision and the remaining women who were less satisfied typically experienced postoperative complications. They concluded that “women who overestimated their breast cancer risk had lower satisfaction levels. Correcting overestimation of breast cancer risk in women who have prophylactic mastectomy may improve satisfaction with reconstruction following prophylactic mastectomy.”15 Researchers thereafter focused on better risk estimation, evidence of efficacy, and improvements in reconstruction. By 2005, BRCA mutations had been described and were being used in clinical practice as a component of risk estimation. Genetically linked breast cancers are usually estrogen receptor–negative, making them less susceptible to chemoprevention. Additionally, they tend to be higher grade and occur in younger women. Spear et al reported an estimated risk reduction of 80% to 95% with increased life expectancy from 2.9 to 5.3 years. There was a 70% reduction in cancer worry and emotional concern with excellent patient satisfaction.16

By 2008, researchers were questioning the pathologic findings in the mastectomy specimens of patients undergoing prophylactic mastectomy. In a retrospective review of 67 patients with BRCA mutations or strong family histories of breast cancer treated from 1995 to 2005, Leunen et al demonstrated a significant incidence of histological abnormalities. Fifty-eight percent had a personal history of breast cancer, of which 84% had previously undergone a unilateral mastectomy as part of their treatment. Invasive and/or non-invasive carcinoma was seen in 19% and another 3% of patients had atypical hyperplasia. Based on observations like these, as well as the global acceptance of SLN biopsy as an accurate reflection of axillary nodal status, investigators questioned the indications for SLN biopsy in women opting for prophylactic mastectomy.17 Laronga et al also performed a retrospective analysis of 449 patients treated between 1995 and 2006 with bilateral prophylactic mastectomy or contralateral prophylactic mastectomy. While none of the 28 bilateral prophylactic mastectomy patients had occult cancers, occult cancer was discovered in 4.3% of the contralateral prophylactic mastectomy patients. They concluded that “overall, SLN biopsy in patients undergoing bilateral prophylactic mastectomy or contralateral prophylactic mastectomy associated with early-stage disease is not indicated. But patients with locally advanced primary breast cancers have a significantly increased risk of occult cancer in the contralateral axilla, likely due to crossover metastasis; this select group of patients may benefit from SLN biopsy at the time of surgery.”18 Current indications for prophylactic mastectomy, either alone or in combination with therapeutic mastectomy include strong family history, prior history of breast cancer, histological risk factors, and a BRCA mutation.19 As the genetic evaluations are revealing more variants of uncertain significance and polymorphism, clinicians are faced with challenges of recommending prophylactic mastectomy versus close observation.

Recommendations for high-risk patients and close family members would include basic screening with breast examination, gynecological examinations, colonoscopy, annual mammography, and annual magnetic resonance imaging (MRI) or breast-specific gamma imaging (BSGI). The option of tamoxifen should be discussed, including potential side effects.

For the patient in case no. 1, the history of abdominal field radiation for sarcoma 12 years prior to her diagnosis also would independently increase her risk of developing breast cancer. Because this increased risk would be bilateral, bilateral mastectomy would be the treatment of choice. The typical latent period from delivery of radiation to development of a radiation-induced malignancy is 10 to 20 years. Reconstructive options would take this into consideration and a latissimus flap (with tissue expander) would be indicated since the abdominal tissue had been radiated and the use of implants only would be associated with a higher risk of complication given the radiation exposure.

Even in cases where the variant is of uncertain significance, if this was the same abnormality as was seen in the proband, relatives with the variant are likely to have significant cancer anxiety and opt for prophylactic mastectomy. It is important to thoroughly counsel individuals as to the best estimated risk and the pros and cons of prophylactic mastectomy versus observation given the individual's concerns and expectations. If prophylactic mastectomy is elected, then preoperative mammography along with MRI or BSGI is indicated to minimize the possibility of discovering an occult malignancy at the time of surgery when treatment and staging might be affected by the reconstruction. If there is any concern raised from these studies, SLN biopsy should be considered, although its role remains unclear. Patients undergoing prophylactic mastectomy typically are also candidates for prophylactic oophorectomy and this is generally recommended at age 40.

Anne Rosenberg, MD, FACS

Clinical Professor in Surgery

Kimmel Cancer Center

Thomas Jefferson University Hospital

Philadelphia, PA

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Breast Surgical Oncologist's Opinion 

The patient in case no. 1 already has had risk-reduction surgery for both breast and ovarian cancers. She should continue to be screened for gastrointestinal malignancies for which she is at higher risk. In terms of her close family members, they should undergo genetic counseling and heightened screening procedures, although the role of genetic testing is unclear in these cases. It would not be unreasonable to opt for initial genetic screening if it is covered by the patient's insurance.

It is possible that the radiation field from this patient's abdominal wall sarcoma encompassed her breast, but this is difficult to determine based on what is stated in the case report. More importantly, this malignancy would not be the typical radiation-induced cancer; these are usually much higher grade tumors than this one appears to be.

While this is not the typical BRCA1 cancer, the patient is postmenopausal, which could influence the type of cancer we see. Most BRCA-related cancers are found in premenopausal women and are higher grade. It is also possible that this is a sporadic breast cancer of the type typically found in a postmenopausal woman and the VUS of BRCA1 is not related.

Offering VUS testing to these family members, especially if not covered by insurance, should be discouraged. However, a heightened sense of awareness and an increase in screening is certainly warranted.

As stated, the patient does not meet strict clinical criteria. The p53 heterozygozity was not compelling enough for the laboratory to offer further testing. In this case, again, a heightened sense of awareness should be cautioned. I would not recommend further testing at this point, especially because the strict criteria have not been met.

Both cases no. 2 and 3 concern BRCA2 mutations of uncertain significance. In case no. 2, this appears to be a new mutation and no data exist as to whether it is associated with cancers. In case no. 3, there are additional data concerning this VUS, and it is felt that this probably does not represent a deleterious mutation. In terms of breast cancer risk, the patients and their first-degree relatives need to be counseled that these mutations have uncertain significance, and the actual lifetime risk is unknown. Based on this information, I could not advocate prophylactic mastectomy, but certainly some of these patients may decide to choose this option. If prophylactic mastectomy is not chosen, increased screening including periodic MRI is warranted. In terms of ovarian cancer, again I would not advocate prophylactic surgery for this VUS. The patients would need to be counseled that screening for ovarian cancer is somewhat more challenging than that for breast cancer. In premenopausal patients, I would certainly not advocate oophorectomy. In postmenopausal women, it would not be unreasonable to discuss this procedure.

Pancreatic cancer risk would need to be discussed, but again this risk is going to be lower and screening can be quite invasive if considering endoscopic retrograde cholangiopancreatography and/or endoscopic ultrasound (EUS). It would not be unreasonable to offer a yearly MRI of the pancreas and periodic CA 19-9 testing, and to try to convince the insurance company to pay for these procedures. There will be a higher risk of prostate cancer in first-degree relatives, which approaches 20% in true BRCA2 mutated patients. This number will probably be lower in relatives of these two families because of the uncertain significance of the mutations. I would not change the frequency of screening in terms of prostate-specific antigen (PSA) determination and examinations, but I would recommend starting at a earlier age—possibly getting a first PSA at age 35 instead of 40 or 45. Finally, for melanoma skin cancers, all first-degree relatives should be followed by a dermatologist on at least a yearly basis. Those patients with moderate to severe cases of dysplastic nevi should be seen at least every 6 months and possibly even every 3 months.

Adam Berger, MD, FACS

Associate Clinical Professor of Surgery

Kimmel Cancer Center

Thomas Jefferson University Hospital

Philadelphia, PA

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Genitourinary Oncologist's Opinion 

Current literature suggests that there is a very modest relationship between BRCA alterations and prostate cancer. However, the routine use of testing at present is not justified until further research clearly identifies the strategies that can be used in men with these findings. While the data are compelling for breast and ovarian cancer risk and BRCA1 and BRCA2 mutations, the literature on the link between prostate cancer risk and the BRCA1 and BRCA2 gene abnormalities in the general population have produced conflicting results.

One recent study from Albert Einstein College of Medicine focused on a group of Jewish men of Ashkenazi descent. Having any one of the three BRCA mutations did not increase a man's risk of developing prostate cancer. However, in men who did develop prostate cancer, two of the mutations (BRCA1 -185delAG and a mutated BRCA2 gene) increased the risk of aggressive high-grade cancer (Gleason score 7 or greater). This suggests that there may be a slight increase in prostate cancer risk among men with an Ashkenazi founder mutation. The preponderance of other published data indicate that BRCA2 carriers may be at increased risk relative to BRCA1 alterations.20 Small subpopulations of prostate cancer cells bearing BRCA1 losses are associated with tumor dissemination and might provide an early indicator of shortened disease-free survival.21

The IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer) study will likely be the best effort to define the use of these specific tests.22 This international study will evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations is the first multicenter screening study targeted at men with a known genetic predisposition to prostate cancer. It targets screening in BRCA1 and BRCA2 mutation carriers and controls. The earliest results from this study indicate a very high positive predictive value of PSA screening in BRCA mutation carriers and that screening detects clinically significant prostate cancer.

BRCA mutations are extremely rare in the general population (much less than 1%). The rationale for general genetic counseling for prostate cancer is extremely limited. At present, it appears that only Ashkenazi Jewish men with familial histories of prostate, breast, or ovarian cancers may benefit from genetic counseling. How might this information be used? With the growing interest in active surveillance, this limited group of men with BRCA alterations may not be considered good candidates for active surveillance due to the increased risk of developing an aggressive tumor. Uncertainties surrounding screening and treatment of prostate cancer in general make it difficult to encourage BRCA or other genetic testing solely for prostate cancer management at the present time.23

Leonard G. Gomella, MD, FACS

The Bernard W. Godwin Professor of Prostate Cancer

Chairman, Department of Urology

Associate Director of Clinical Affairs, Jefferson Kimmel Cancer Center

Clinical Director, Jefferson Kimmel Cancer Center Network

Thomas Jefferson University

Philadelphia, PA

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Gastroenterologist's Opinion 

There is growing experience supporting the benefit of screening protocols. Preventative screening of patients at high risk of pancreas cancer is currently under study through participation in a number of registries. Included in the high-risk cohort are kindreds with hereditary breast–ovarian syndromes as well as Li-Fraumeni syndrome, particularly in those families in whom pancreas cancer is detected.

In the patient presented in case no. 1, there are two potential genetic contributions that would place her at increased risk of developing pancreatic malignancy. The first concern is the BRCA1 VUS. Carriers of BRCA1 deleterious mutations have an estimated threefold cumulative lifetime risk of developing pancreas cancer when compared to the general population.24 The degree to which the mutation may be deleterious in our individual is a matter of debate regarding breast and ovarian cancer; the impact on the risk of pancreas cancer is similarly in question.25 The second concern is the possibility of a contributor of Li-Fraumeni syndrome, as pancreas cancer has been reported in association with affected individuals and families. The magnitude of the increase in pancreas cancer risk in Li-Fraumeni syndrome is unknown. Interestingly, in Li-Fraumeni syndrome, the high risk of adenocarcinoma of multiple types has resulted in advocating broad, whole body, screening protocols (ie, positron emission tomography). Pancreatic cancer screening by MRI (or computed tomography) and endoscopic ultrasound also provide the added benefit of dedicated assessment of the abdominal viscera for this high-risk group.

In considering our patient, the current practice at most centers is that BRCA1-affected individuals are not enrolled in screening protocols absent a family history.26 Given that her father was diagnosed with pancreatic malignancy and the possible genetic influences, it is reasonable to offer this patient participation in a screening program. In addition to annual EUS and cross-sectional imaging, careful surveillance of the individual for any clinical symptoms relating to pancreatic malignancy (ie, anorexia, early satiety, abdominal pain, weight loss, venous thrombosis, onset of diabetes, or jaundice) would be performed and, if found, prompt an aggressive evaluation.

Regarding cases no. 2 and 3, BRCA2 mutations are much more strongly associated with pancreas cancer than BRCA1, and carry a 4- to 10-fold increased risk of developing pancreatic malignancy. Moreover, BRCA mutations are associated with earlier onset of cancer.27, 28 This association is particularly strong among Ashkenazi Jews in whom 1 in 10 pancreas cancers are associated with BRCA2 mutations. In neither of the cases presented here does the proband have Ashkenazi Jewish heritage, despite one being of Eastern European descent.

When considering familial pancreas cancer, in these kindreds there have not been any cases, although the pedigrees of these individuals are somewhat limited by family size. Given the relatively uncommon incidence of pancreas cancer, the risk of developing pancreas cancer should not be overlooked. Given the fact that the older of the two patients is 76, it may be the case that identification on EUS or MRI would not alter the patient's clinical course, as she would be reaching an age where a pancreatic resection may not be feasible, and thereby limiting the utility of screening. Despite this, there is significant yield from an index screening examination and at least one MRI and EUS would be appropriate. The younger, 43-year-old woman warrants a discussion for lifelong screening should she be so motivated. Case series have reported beneficial outcomes to groups undergoing pancreas cancer screening protocols, including identification of cancers at an early, curable stage and resection for cure.29 Moreover, there have been developments in the application of molecular analysis for precursor lesions of pancreas cancer, including pancreatic cysts and intraductal papillary mucinous neoplasms, lesions that have been implicated in familial pancreas cancer.30 Recent data have demonstrated that the pancreatic carcinogenesis sequence requires in excess of a decade from the onset of the carcinogenic sequence to the development of invasive cancer.31 Using a combination of molecular, imaging, and minimally invasive strategies to screen for pancreas cancer holds promise for identification of precancerous and early-stage disease in high-risk groups.

David C. Loren, MD

Director, Endoscopy Unit

Department of Gastroenterology

Kimmel Cancer Cancer

Thomas Jefferson University Hospital

Philadelphia, PA

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Discussion 

As demonstrated, VUS in BRCA1 or BRCA2 genes offer a significant clinical conundrum in terms of concrete management recommendations. Definitive risk-reduction and early detection strategies can be implemented only after a frank in-depth discussion with the patient and after consideration of personal preferences, as well as contextualization of the paucity of data in the literature advocating aggressive screening and aggressive risk-reduction measures for findings related to VUS results. Patients obviously should be guided to participate in full discussion with clinical genetics experts and multidisciplinary specialists in order to weigh these decisions. We appreciate the opportunity to embark upon an excellent evidence-based round-table discussion of this clinical quandary, and invite readers to further comment on these and other cases, and to participate in this endeavor.

Susan Miller-Samuel, RN, MSN, APNG

Advanced Practice Nurse in Genetics

Thomas Jefferson University Hospital

Jefferson Breast Care Center

Philadelphia, PA

Gloria J. Morris, MD, PhD

Attending Physician, Hematology and Oncology Associates of Northeastern PA, PC

Director, Family Risk Assessment Program

Assistant Professor of Medicine, The Commonwealth Medical College

Scranton, PA

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References 

  1. Meijers-Heibor H, van Geel B, van Putter W, et al. Breast cancer after prophylactic bilateral mastectomy in women with BRCA 1/2 mutation. N Engl J Med. 2001;345:159–164
  2. Domcheck SM, Friebel TM, Neuhausen SL, et al. Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: a prospective cohort study. JAMA. 2000;283:2260–2265
  3. Domchek S, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1- and BRCA2-mutation carriers with cancer risk and mortality. JAMA. 2010;304:967–975
  4. Miller-Samuel S, McDonald D, Weitzel JN, et al. Variants of uncertain significance in breast cancer–related genes: real-world implications for a clinical conundrum (Part one: clinical genetics recommendations). Semin Oncol. 2011;38:469–480
  5. Lynch HT, Harris RE, Organ CH, Lynch JF. Familial indications for prophylactic surgery in breast-cancer-prone families. Lancet. 1978;1:265
  6. Horton CE, Dascombe WH. Total mastectomy: indications and techniques. Clin Plast Surg. 1988;15:677–687
  7. Wapnir IL, Rabinowitz B, Greco RS. A reappraisal of prophylactic mastectomy. Surg Gynecol Obstet. 1990;171:171–184
  8. Nemecek JR, Young VL, Lopez MJ. Indications for prophylactic mastectomy. Mo Med. 1993;90:136–140
  9. Vogel VG, Yeomans A, Higginbotham E. Clinical management of women at increased risk for breast cancer. Breast Cancer Res Treat. 1993;28:195–210
  10. Bilimoria MM, Morrow M. The woman at increased risk for breast cancer: evaluation and management strategies. CA Cancer J Clin. 1995;45:263–278
  11. Dupont EL, Kuhn MA, McCann C, Salud C, Spanton JL, Cox CE. The role of sentinel lymph node biopsy in women undergoing prophylactic mastectomy. Am J Surg. 2000;180:274–277
  12. Newman LA, Kuerer HM, Hung KK, et al. Prophylactic mastectomy. J Am Coll Surg. 2000;191:322–330
  13. Metcalfe KA, Goel V, Lickley L, Semple J, Narod SA. Prophylactic bilateral mastectomy: patterns of practice. Cancer. 2002;95:236–242
  14. Lostumbo L, Carbine N, Wallace J, Ezzo J. Prophylactic mastectomy for the prevention of breast cancer. Cochrane Database Syst Rev. 2004;CD002748
  15. Metcalfe KA, Semple JL, Narod SA. Satisfaction with breast reconstruction in women with bilateral prophylactic mastectomy: a descriptive study. Plast Reconstr Surg. 2004;114:360–366
  16. Spear SL, Carter ME, Schwarz K. Prophylactic mastectomy: indications, options, and reconstructive alternatives. Plast Reconstr Surg. 2005;115:891–909
  17. Leunen K, Drijkoningen M, Neven P, et al. Prophylactic mastectomy in familial breast carcinoma (What do the pathologic findings learn us?). Breast Cancer Res Treat. 2008;107:79–86
  18. Laronga C, Lee MC, McGuire KP, et al. Indications for sentinel lymph node biopsy in the setting of prophylactic mastectomy. J Am Coll Surg. 2009;209:746–752
  19. Hoover DJ, Paragi PR, Santoro E, Schafer S, Chamberlain RS. Prophylactic mastectomy in high risk patients: a practice-based review of the indications (Do we follow guidelines?). Breast Dis. 2010;31:19–27
  20. Mitra AV, Bancroft EK, Barbachano Y, et al. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study. BJU Int. 2011;107:28–39
  21. Agalliu I, Gern R, Leanza S, Burk RD. Associations of high-grade prostate cancer with BRCA1 and BRCA2 founder mutations. Clin Cancer Res. 2009;15:1112–1120
  22. Gallagher DJ, Gaudet MM, Pal P, et al. Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res. 2010;16:2115–2121
  23. Bednarz N, Eltze E, Semjonow A, et al. BRCA1 loss preexisting in small subpopulations of prostate cancer is associated with advanced disease and metastatic spread to lymph nodes and peripheral blood. Clin Cancer Res. 2010;16:3340–3348
  24. Brose MS, Rebbeck TR, Calzone KA, et al. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst. 2002;94:1365–1372
  25. Axilbund JE, Argani P, Kamiyama M, et al. Absence of germline BRCA1 mutations in familial pancreatic cancer patients. Cancer Biol Ther. 2009;8:131–135
  26. Klapman J, Malafa MP. Early detection of pancreatic cancer: why, who, and how to screen. Cancer Control. 2008;15:280–287
  27. The Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. 1999;91:1310–1316
  28. Kim DH, Crawford B, Ziegler J, Beattie MS. Prevalence and characteristics of pancreatic cancer in families with BRCA1 and BRCA2 mutations. Fam Cancer. 2009;8:153–158
  29. Verna EC, Hwang C, Stevens PD, et al. Pancreatic cancer screening in a prospective cohort of high-risk patients: a comprehensive strategy of imaging and genetics. Clin Cancer Res. 2010;16:5028–5037
  30. Toll AD, Kowalski T, Loren D, Bibbo M. The added value of molecular testing in small pancreatic cysts. J Pancreas. 2010;211:582–586
  31. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467:1114–1117

PII: S0093-7754(11)00124-2

doi:10.1053/j.seminoncol.2011.04.009

Seminars in Oncology
Volume 38, Issue 5 , Pages 605-611, October 2011

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