Sage Journals: Discover world-class research

Abstract

Many women at increased risk for breast cancer would benefit from referral for genetic testing, enhanced screening, preventive therapy or risk-reducing surgery. We present a visual model and a step-wise approach to assist with a personalized risk stratification and management of these women. We present current recommendations with respect to lifestyle behaviors and mammographic screening, and we review the current evidence regarding enhanced screening and risk-reducing therapies. We discuss the usefulness of three risk-assessment tools in determining whether a woman qualifies for genetic testing, enhanced screening or preventive therapy and present four cases to demonstrate the usefulness of this approach in the clinical setting.

Keywords

breast cancer genetic testing intensive screening preventive therapy risk assessment risk calculators risk-reducing surgery

Medscape: Continuing Medical Education Online

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint providership of Medscape, LLC and Future Medicine Ltd. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.

Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)^™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at www.medscape.org/journal/whe; (4) view/print certificate.

RELEASE DATE: 17th March 2015; EXPIRATION DATE: 17th March 2016

LEARNING OBJECTIVES

Upon completion of this activity, participants will be able to:

Distinguish risk factors for breast cancer

Identify different clinical screening tools for breast cancer risk

Distinguish different treatments used for the chemoprevention of breast cancer

Evaluate the efficacy and adverse effects of different chemopreventive agents for breast cancer

Financial & competing interests disclosure

Editor: Laura Dormer, Future Science Group, London, UK.

Disclosure: Laura Dormer has disclosed no relevant financial relationships.

CME author: Charles P Vega, MD, Clinical Professor of Family Medicine, University of California, Irvine, CA, USA.

Disclosure: Charles P Vega, MD, has disclosed the following financial relationships: Served as an advisor or consultant for: Lundbeck, Inc.; McNeil Pharmaceuticals; Takeda Pharmaceuticals North America, Inc.

Author & credentials: Sandhya Pruthi, MD, Division of General Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA

Disclosure: Sandhya Pruthi, MD, has disclosed no relevant financial relationships.

Ruth Heisey, MD, Department of Family and Community Medicine, University of Toronto, Women's College Hospital, Toronto, Ontario, Canada

Disclosure: Ruth Heisey, MD, has disclosed no relevant financial relationships.

Therese Bartholomew Bevers, MD, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Disclosure: Therese Bartholomew Bevers, MD, has disclosed no relevant financial relationships. No writing assistance was utilized in the production of this manuscript.

The approach to management of women at increased risk for breast cancer is complex, requiring an understanding of risks and benefits of various interventions taking into account individual level of risk. We propose a visual model (Figure 1) to assist in personalized risk stratification and management of such women. We suggest that all women should receive lifestyle counseling to encourage modification of behaviors that might increase their risk of breast cancer, thus promoting an overall healthy lifestyle [1], and all women aged 40 and older should have a discussion about benefits and harms of mammographic screening [2 –4].

Figure 1.

Management of women at risk for breast cancer.

A step-wise approach using the mnemonic REPS will assist in determining a woman's suitability for: R – referral for genetic testing, E – enhanced screening, P – preventive therapy and S – risk-reducing surgery.

We present three risk-assessment tools B-RST [5], IBIS [6] and the Gail model [7], that can be useful in identifying women suitable for referral for genetic testing, enhanced screening and preventive therapy. Women suitable for risk-reducing surgery include BRCA carriers.

Lifestyle behaviors

It makes good sense to encourage healthy eating, a healthy BMI, regular exercise and abstinence from alcohol or a moderate intake only. Smokers should be encouraged and supported to quit. Decisions regarding hormone replacement therapy should be made after careful consideration and discussion of the associated increase in breast cancer risk [8].

The World Cancer Research Fund/American Institute for Cancer Research and the International Agency for Research on Cancer conclude that there is ‘sufficient’ or ‘convincing’ evidence that the following factors increase breast cancer risk: alcohol, diethylstilbestrol, estrogen-progesterone menopausal therapy, estrogen-progesterone oral contraceptives, body fatness, X radiation and Gamma radiation, and height. They state that estrogen-alone menopausal therapy and smoking may increase risk. They have found ‘sufficient or convincing’ evidence that breastfeeding decreases risk and ‘probable’ evidence that physical activity and reduction of body fatness decreases risk [9].

Mammographic screening

The US Preventive Services Task Force (USPSTF) [2] and the Canadian Task Force on Preventive Health Care [3] suggest offering regular breast screening to all women aged 50–74. They advise against routine screening of average risk women in the 40- to 49-year-old age group but support a tailored approach to discussing the benefits and harms of screening in these women. Other organizations such as the National Comprehensive Cancer Network [4] advise offering mammography annually to all women 40 and older.

R – referral for genetic testing

BRCA mutation carriers have a substantially elevated lifetime risk (LTR) for not only breast cancer (49–57%) but also ovarian cancer (18–40%) for which there is no effective early detection tool [10]. Identification of mutation carriers can save lives [11].

Any woman with a family history of breast, ovarian or fallopian tube cancer should have a more extensive family history taken to determine whether she is eligible for referral for consideration of genetic testing. The USPSTF suggests using one of five ‘at-risk’ screening tools to determine if a woman is eligible for consideration for genetic testing (B recommendation) [12]. One of the simplest and quickest to administer is the B-RST tool (81% sensitivity/92% specificity) [13]. It can be completed by the patient or the clinician and uses a threshold of 10% likelihood of having a BRCA mutation.

E – enhanced screening

Women at significantly increased risk for breast cancer should be offered an annual MRI in addition to mammography starting at age 25–30 years [4]. An MRI is more sensitive for detecting invasive cancers and is a particularly useful surveillance tool for young BRCA carriers [14]. The American Cancer Society (ACS) has clear guidelines as to which women qualify for enhanced screening with MRI. These include women who are BRCA carriers, an untested first-degree relative of a BRCA carrier, someone with a history of therapeutic chest wall radiation between the ages of 10 and 30 years, or any woman with an LTR of ≥20–25% according to risk-assessment tools based mainly on family history [15].

The International Breast Intervention Study (IBIS) risk tool or Tyrer–Cuzick model is a validated tool based on data from the IBIS in the UK [16]. It provides a 10-year and LTR by incorporating family history, reproductive factors and certain pathological features that impact risk such as atypical hyperplasia (AH) and lobular carcinoma in situ (LCIS). The IBIS risk calculator asks for a more detailed family history and age of onset of breast cancer diagnosis of affected relatives. It is an effective tool to identify candidates suitable for enhanced screening with MRI [15].

P – preventive therapy

Selective estrogen receptor modulators (SERMs; tamoxifen, raloxifene) and more recently aromatase inhibitors (AIs; exemestane, anastrozole) have been shown to be effective at reducing breast cancer incidence in women at high risk [17 –22]. The American Society of Clinical Oncology, the National Comprehensive Cancer Network, the Canadian Task Force on Preventive Health Care and the USPSTF advise counseling women ≥35 years who are at increased risk for breast cancer regarding available medications to reduce their risk and to offer medication to women at low risk of medication-related side effects (USPSTF B recommendation) [1,23 –25]. In Canada, currently only tamoxifen is approved by Health Canada for breast cancer risk reduction while in the USA both tamoxifen and raloxifene are approved by the US FDA for this specific indication. AIs have not yet received approval for breast cancer risk reduction [25]. Raloxifene can only be used in postmenopausal women while tamoxifen can be used in pre- and postmenopausal women [25]. Raloxifene is also approved for prevention and treatment of osteoporosis.

The Gail model is a quick on-line computerized model that has been primarily used to determine eligibility for preventive therapy [26 –31]. A 5-year risk of ≥1.7% determined by using the Gail model is the threshold at which women can be considered for preventive therapy. Initially designed for estimating breast cancer risk in white women, it has been modified to provide accurate risk assessments for African American, Hispanic and Asian women [30,31].

A thorough discussion of risks versus benefits of the available risk-reducing medications should be undertaken. Freedman et al. [32] have developed risk-benefit tables for women aged 50 years or older. Based on these tables, the USPSTF concludes that, in general, women with an estimated 5-year breast cancer risk of ≥3% are likely to have more benefit than harm from using tamoxifen or raloxifene, although the balance depends on age, ethnicity, the medication used, and whether or not the patient has a uterus [25]. There are certain women that have more favorable risk-benefit ratios; women with a history of AH or women under the age of 50. This is based on the Breast Cancer Prevention Trial (BCPT) data subgroup analysis that demonstrated a significant 86% risk reduction for women with AH, far greater than the 49% risk reduction seen overall in women at increased risk as well as the finding that women under age 50 years do not incur the harms of therapy as seen in women over 50 years of age [17]. Conversely, in many older women with a 5-year breast cancer risk ≥3%, the harms of preventive therapy far outweigh the benefits as their risk of adverse effects is greater and their LTR of developing breast cancer is low when taking into consideration their age.

S – risk-reducing surgery

Women who are BRCA mutation carriers should be offered both bilateral prophylactic mastectomy (BPM) and risk-reducing salpingo-oophorectomy (RRSO). Mutation carriers can reduce their risk of breast cancer greater than 90% by a BPM [33]. Analysis of data from Hartmann et al. [33] reveals that six high-risk women would need to have the procedure to prevent one breast cancer. Women should be offered breast reconstruction and emotional support while making such a difficult decision.

In BRCA mutation carriers, RRSO reduces breast cancer risk by 50% and ovarian cancer risk by 80% [34]. Women may be offered hormone replacement therapy for symptom management [35].

Personalized risk-based assessment in practice

We will illustrate the use of this personalized risk-based assessment and management approach using the following four cases.

Case 1

42-year-old woman with a family history of breast cancer. “I want to do everything I can to reduce my risk of breast cancer.”

Her only relative with breast cancer was her mother who was diagnosed at age 85. She had her menarche at age 14. She delivered her first of two children when she was 25. She is an office administrator who drinks two glasses of wine per day. She is 5′3″ and weighs 160 lbs. She has never had a breast biopsy. She is not Jewish.

R B-RST: negative screen (does not qualify for referral to genetics).

E IBIS: LTR is 19.6% (<20–25%, does not qualify for enhanced screening).

P Gail: 5-year risk is 1.2 % (<1.7%, does not qualify for preventive therapy).

S Not a candidate for surgical risk-reduction options.

This woman is at moderate risk (LTR 19.6% vs 12.7% population) for breast cancer and a discussion of lifestyle behaviors and mammographic screening would be recommended. In view of her family history of breast cancer in a first-degree relative and her greater than average risk, she should be offered mammographic screening beginning at age 40 [1,36].

She should be advised of the link between alcohol and breast cancer [37] and that she should decrease her alcohol intake to no more than one drink per day on average as per the ACS guidelines [38]. This woman should also be advised that she lose some weight prior to menopause as a BMI >28 in a postmenopausal woman is associated with a 26% increased likelihood of breast cancer [39]. Regular exercise, such as 30-min brisk walks 5 days per week, could assist with weight loss, reduce breast cancer risk [40] and improve cardiovascular health [41]. Regular vitamin D intake (1000 IU daily) during the winter months and a healthy diet with no more than three servings of red meat per week [42,43] is less widely accepted as an effective risk-reducing strategy, but there is some evidence suggesting that it may also be beneficial.

Case 2

46-year-old woman whose sister was diagnosed with breast cancer at age 52. She has had two previous benign breast biopsies with one having shown AH. “I am worried about my breast cancer risk and want to know my options to reduce my risk.”

She had her only child at age 30. Menarche was at age 12. She is 5′2″ and weighs 120 lbs. She is not Jewish and has no other relatives with breast or ovarian cancer. She exercises regularly, abstains from alcohol and uses a nonhormonal IUD for birth control.

R B-RST: negative screen (does not qualify for referral to genetics).

E IBIS: LTR is 41.4% (≥20–25%, qualifies for enhanced screening with MRI in addition to mammography).

P Gail: 5-year risk is 7.9% (≥1.7%, discuss preventive therapy).

S Not a candidate unless she is asking for consideration.

This woman's history would indicate that she is at high risk for breast cancer and a discussion of lifestyle behaviors, preventive therapy options and enhanced screening with breast MRI would be recommended. She should be encouraged to continue her healthy lifestyle behaviors that entail regular exercise, weight management and moderation of alcohol intake.

While there are a number of preventive therapies, only tamoxifen is indicated for premenopausal women. Tamoxifen was shown in the BCPT, the largest placebo-controlled study of preventive therapy, to significantly reduce the risk of developing breast cancer by one half. Women with a history of AH obtained a significant 86% breast cancer risk reduction while women with LCIS had a 56% risk reduction. Tamoxifen has been found to improve bone health and can increase bone density in postmenopausal women. Tamoxifen given at the recommended dose of 20 mg per day for 5 years is associated with common side effects including hot flashes, night sweats, cataracts and vaginal dryness. More severe risks include endometrial cancer (four more events per 1000) and thromboembolic risk (four more events per 1000) [25]. As this woman has a personal history of AH and a Gail score risk significantly greater than 1.7% the substantial benefits she would obtain from tamoxifen therapy outweigh potential harms. Furthermore, the risk of endometrial cancer and thromboembolic events is much lower in women on tamoxifen under the age of 50 [17]. After counseling this woman using a shared decision approach and discussing the risks and benefits of tamoxifen, she elected to initiate a regimen of tamoxifen 20 mg daily for 5 years as preventive therapy.

Women receiving preventive therapy are advised to monitor for irregular vaginal bleeding or spotting, symptoms of lower extremity swelling or new onset shortness of breath. Any abnormal vaginal bleeding requires work-up with a pelvic ultrasound and an endometrial biopsy to exclude endometrial malignancy. Cervical cancer screening should be based on national guidelines.

Based on this woman's IBIS score (41.4%), it is recommended that she has an annual mammogram and breast MRI. The MRI could be staggered with the mammogram at 6-month intervals. While there is no data supporting this current practice, it is suggested that radiologic imaging every 6 months might afford a better opportunity to detect an interval cancer in high-risk women.

She should be informed that although MRI is a more sensitive tool that can detect smaller tumors than mammography, it is less specific and may result in additional investigations. If premenopausal, the MRI is best performed between days 7–14 of her cycle to reduce background enhancement [44].

If the patient is unable to have an MRI due to claustrophobia, history of an implanted metal device, or lack of availability or access to MRI, whole breast ultrasound may be considered as a screening study in addition to mammography. A large study in high-risk women comparing screening with whole breast ultrasound in addition to mammography versus mammography alone demonstrated an increase in breast cancer detection of 11.8/1000 in the combined modality group compared with 7.6/1000 cancers in the mammography only group. However, there was an increase in false positives and scan time in the combined modality group [45].

This woman is not a candidate for surgery unless a BRCA mutation is identified in her family. Certain individuals, however, ask for individual consideration after an informed discussion.

Case 3

55-year-old woman whose mother and sister had breast cancer. Mom was diagnosed at age 50 and sister at 45. Both tested negative for BRCA mutations. She has another sister who is well at 58. “What should I be doing to reduce my risk of breast cancer?”

Menarche was at age 12. She has two children, delivering her first child at age 35. She had a hysterectomy at age 44 for dysfunctional uterine bleeding. She has one alcoholic drink per day. She exercises regularly and feels that she is menopausal as she has hot flushes. She is 5′5″ and weighs 150 lbs. She has had no previous breast biopsies.

R B-RST: referral for genetic testing is not indicated as both affected first-degree relatives have tested negative for BRCA mutations.

E IBIS: LTR is 30.8% (≥20–25%, qualifies for enhanced screening with MRI in addition to mammography).

P Gail: 5-year risk is 3.5% (≥1.7%, consider for preventive therapy).

S Not a candidate for surgical risk-reduction options, unless she is asking for consideration.

This woman is also at high risk for breast cancer and will also benefit from counseling on lifestyle behaviors, enhanced screening and preventive therapy. Because she is postmenopausal there are options beyond tamoxifen for preventive therapy. The Study of Tamoxifen and Raloxifene (STAR) in high-risk women demonstrated that tamoxifen and raloxifene were equivalent in reducing breast cancer risk while women were on therapy [19]. A subsequent 81-month analysis of the STAR trial demonstrated that this benefit was more durable in tamoxifen. Raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive disease, but in terms of toxicities, raloxifene was more favorable [20]. Similar to tamoxifen, raloxifene reduces the risk of breast cancer for women with AH by 86%. Raloxifene does not increase uterine cancer risk but has been shown to be comparable to tamoxifen in the risk of thromboembolic events. Raloxifene can also exacerbate hot flashes, night sweats and vaginal dryness, and is associated with weight gain. Raloxifene is approved by the US FDA for breast cancer prevention in the USA only in postmenopausal women.

Exemestane and anastrozole are AIs that have recently been shown to reduce breast cancer risk. Exemestane reduces breast cancer risk by 65% in high-risk postmenopausal women [21], and a 53% reduction in breast cancer risk is seen with anastrozole [22]. Breast cancer risk reduction with AIs in women with AH is not as great as seen with tamoxifen or raloxifene; anastrozole reduced breast cancer risk by 69%, whereas exemestane reduced the risk by only 39%. Although both are off-label use for breast cancer prevention, recent American Society of Clinical Oncology guidelines on preventive therapy for high-risk women, published before the anastrozole findings were released, stated that exemestane should be considered as an option for prevention [23]. Common side effects of exemestane include arthralgias, fatigue, hot flashes and vaginal dryness [21]. In addition to vasomotor symptoms, musculoskeletal events (arthralgias, joint stiffness, carpal tunnel syndrome) were more common in the anastrozole arm [22]. Although AIs have been found to reduce bone density, long-term follow-up will be needed in the MAP.3 trial to assess the effect of exemestane on fracture risk [21,46]. Analyses on the bone effects of anastrozole were not a part of the initial publication of IBIS-II but are planned for a later publication [22]. Neither exemestane nor anastrozole was associated with an increased risk of thromboembolic or cardiovascular events or other cancers [21,22].

In addition to enhanced screening with breast MRI, this patient is a candidate for preventive therapy. As she is postmenopausal, all four pharmacologic therapies are an option. A determination of her bone health might be informative in deciding whether to use a SERM or an AI. If there are no bone health issues, she would obtain greater breast cancer risk-reduction benefit from an AI. Bone monitoring with bone mineral density can be considered yearly for women receiving exemestane or anastrozole. Vitamin D and calcium supplementation are encouraged [47]. If there is evidence of osteopenia or osteoporosis, a SERM is a better option as it will reduce her risk of osteoporotic bone fractures in addition to reducing her risk of breast cancer. Since she no longer has a uterus, tamoxifen would be a better choice than raloxifene as the harms of tamoxifen would be significantly lower without the risk of uterine cancer, and the benefits are more durable than with raloxifene. She should be advised to monitor for any evidence of venous thromboembolic events as previously described.

While this woman would obtain significant breast cancer risk-reduction benefits, it is important to realize that the risks of preventive therapy are greater in women over the age of 50. Individualizing preventive therapy options can be challenging and requires a shared decision-making approach with the patient [35]. She decided to have a bone mineral density test to assist in her decision making. It showed osteopenia so she opted to avoid AIs. She chose tamoxifen as it is more effective than raloxifene, and she did not have to worry about endometrial hyperplasia or cancer in view of her prior hysterectomy.

Based on this patient's IBIS score of 30.8%, she is a candidate for enhanced screening with breast MRI in addition to mammography and radiological follow-up is advised annually as per the ACS guidelines.

Case 4

38-year-old woman of Ashkenazi Jewish descent. “I know that I am going to get breast cancer because it is in my family.”

Her mother had breast cancer diagnosed at age 48 and her maternal aunt died from ovarian cancer at age 35. She had menarche at age 11 and has two children aged 6 and 4. She is 5′3″ and weighs 120 lbs.

R B-RST: positive screen (qualifies for referral to a genetic counselor).

E IBIS: LTR is 39.5% (≥20–25%, qualifies for enhanced screening with MRI).

P Gail: 5-year risk is 1% (<1.7%, does not qualify for preventive therapy based on Gail risk assessment yet clearly is an individual at increased risk of breast cancer; if she tests positive for BRCA mutation she should be counseled accordingly).

S Yes, if she tests positive for a BRCA mutation.

Based on the positive B-RST screen, this woman has a family history concerning for a genetic predisposition and should be referred for genetic counseling. Genetic counselors assist with determining the likelihood of a mutation being identified within a particular family. Genetic testing is most informative if an affected family member (her mother or maternal aunt) is first tested. If her mother (her only living affected relative) was to test positive for a BRCA mutation, other family members would be offered genetic testing. If her mother tested positive for a BRCA mutation, this woman's risk of having that specific mutation is 50% as the transmission is autosomal dominant. If this woman was to undergo testing for a BRCA mutation (without her mother or aunt having prior testing), a positive test could inform testing in other family members. However, if she was to test negative, as an unaffected individual, it would be considered an uninformative negative result. In other words, there could still be a mutation in the family but not in the patient. While genetic testing can be predictive for known genetic predispositions, it is recognized that there are genetic mutations that are currently unknown. It is important to note that women who test negative when there is a known genetic predisposition in the family do not carry the same risk as their relatives with the genetic predisposition. These women should be managed as if there is not a genetic predisposition in the family, using other risk calculators and management recommendations as previously described.

It is important to realize that the Gail model is not a good estimate of breast cancer risk in women with a family history that is concerning for a genetic predisposition. This woman's true risk is underestimated using the Gail model; in fact, her score suggests that she does not qualify for consideration of preventive therapy. Despite limited data regarding the benefits of preventive therapy in women with a BRCA mutation it should be discussed. A subset analysis from the BCPT showed a nonstatistically significant 62% reduction in breast cancer risk in BRCA2 mutation carriers using tamoxifen while women with BRCA1 mutations did not obtain any benefit [48]. Since tamoxifen reduces the risk of estrogen-receptor (ER) positive but not ER-negative breast cancers, this finding is biologically plausible as women with a BRCA2 mutation are more likely to develop ER-positive breast cancers whereas women with BRCA1 mutations are more likely to develop ER-negative breast cancers [17,48].

Women with a BRCA mutation are strongly advised to consider risk-reducing surgery, BPM with or without RRSO, as these are the only preventive strategies that have definitively been shown to reduce breast (and ovarian) cancer risk in this population. Women considering BPM should be counseled about the risks and benefits of nipple-areolar sparing surgery and should undergo consultation with a plastic surgeon to discuss reconstruction at the time of the BPM. In women undergoing RRSO, it is important that the entire fallopian tube is removed during the procedure as a high percentage of the occult cancers have been identified in the distal fimbria of the fallopian tube in women with BRCA mutations [49]. An important consideration of risk-reducing surgery is the timing of such interventions. Kurian et al. [50] developed a Monte Carlo model which provides estimates of the survival impact of breast and ovarian risk-reduction strategies (mammographic/MRI breast screening, risk-reduction surgery) according to the type of BRCA mutation present, the specific intervention(s) and the age of the woman at the time of the intervention(s). Survival estimates generated from this model can facilitate shared decision-making regarding the choice of a risk-reduction approach. Recent data suggest that the ideal timing for RRSO is by age 35 for BRCA1 carriers and by age 40 for BRCA2 carriers [51].

Based on her current IBIS LTR of 39.5%, this woman qualifies for enhanced screening annually with breast MRI and mammogram. Annual radiological follow-up and surveillance in high-risk women should continue until a life expectancy of less than 5–10 years [15].

Although her Gail risk is <1.7%, she may still be a candidate for preventive therapy if she is a BRCA mutation carrier. Should she test positive for a BRCA mutation, while continued enhanced screening and/or tamoxifen especially in the case of a BRCA2 mutation are options, she should be strongly encouraged to consider BPM and RRSO.

This woman elected to undergo genetic testing and tested positive for a BRCA1 mutation. After careful consideration and extensive discussion with a surgical oncologist, plastic surgeon and gynecologist, she opted for both a BPM with reconstruction and a RRSO.

Conclusion

Healthy lifestyle behaviors (maintaining healthy body weight, regular exercise and limiting alcohol intake) should be encouraged in all women. Women at increased risk of breast cancer have additional options for breast cancer risk reduction and early detection. The proposed visual aid with the mnemonic ‘REPS’ can provide a useful approach to the stratification and management of women at risk for breast cancer. Office-based interactive risk-assessment tools assist clinicians in making personalized decisions about risk-reducing interventions. In a shared decision-making approach, women may be appropriately offered referral for genetic testing, enhanced screening, preventive therapy and risk-reducing surgeries.

Future perspective

Clinicians caring for women at increased risk for breast cancer are faced with the challenge of how to most effectively counsel women about their options. New and more accurate breast cancer risk-assessment tools greatly enhance the personalized approach and management options. Our visual aid includes breast cancer risk-assessment tools and provides a step-wise approach to manage women at increased risk for breast cancer. It should be studied in high-risk clinics and primary care settings to determine its effectiveness.

More widespread acceptance of healthy lifestyle behaviors could reduce the incidence of not only cancers but also heart disease. More timely identification of BRCA carriers will offer more women the option of potentially life-saving surgical measures. The hope is that enhanced screening will detect tumors earlier and result in a better outcome. Increased utilization of preventive therapies may reduce breast cancer incidence or at least delay its onset. There currently exists a significant opportunity to reduce the incidence of breast cancer in women with AH in whom the risk-benefit ratio is almost always positive. Short of an absolute contraindication, all women with AH should be strongly considered for preventive therapy.

In the future, a more personalized approach to breast cancer risk reduction will utilize biological markers that identify women who would benefit from preventive therapy. These same biological markers may be followed over time to determine efficacy of the preventive therapy in an individual woman.

Executive summary

Women at increased risk of breast cancer have additional options for breast cancer risk reduction and early detection.

A step-wise approach utilizing a visual model demonstrating the mnemonic REPS to determine a woman's suitability for: R – referral for genetic testing, E – enhanced screening, P – preventive therapy and S – risk-reducing surgery can assist with risk stratification and management of women at increased risk for breast cancer.

Three risk-assessment tools can be useful in identifying women suitable for referral for genetic testing, enhanced screening and preventive therapy.

A personalized risk-based assessment and management approach involves an individualized understanding of the risks and benefits of each intervention.

Footnotes

Acknowledgements

We would like to sincerely thank G Hebl from Mayo Clinic Research and Academic Support Services for her editorial assistance with preparing the manuscript. The authors gratefully acknowledge the contribution of the Women's College Family Practice Peer Support Writing Group in the review of this manuscript.

Personalized assessment and management of women at risk for breast cancer in North America

To obtain credit, you should first read the journal article. After reading the article, you should be able to answer the following, related, multiple-choice questions. To complete the questions (with a minimum 75% passing score) and earn continuing medical education (CME) credit, please go to www.medscape.org/journal/whe. Credit cannot be obtained for tests completed on paper, although you may use the worksheet below to keep a record of your answers. You must be a registered user on Medscape.org. If you are not registered on Medscape.org, please click on the “Register” link on the right hand side of the website. Only one answer is correct for each question. Once you successfully answer all post-test questions you will be able to view and/or print your certificate. For questions regarding the content of this activity, contact the accredited provider, CME@medscape.net. For technical assistance, contact CME@webmd.net. American Medical Association's Physician's Recognition Award (AMA PRA) credits are accepted in the US as evidence of participation in CME activities. For further information on this award, please refer to http://www.ama-assn.org/ama/pub/about-ama/awards/ama-physicians-recognition-award.page. The AMA has determined that physicians not licensed in the US who participate in this CME activity are eligible for AMA PRA Category 1 Credits^™. Through agreements that the AMA has made with agencies in some countries, AMA PRA credit may be acceptable as evidence of participation in CME activities. If you are not licensed in the US, please complete the questions online, print the AMA PRA CME credit certificate and present it to your national medical association for review.

References

Papers of special note have been highlighted as:

of interest; •• of considerable interest.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) Breast Cancer Risk Reduction (Version 1.2014). www.nccn.org

The National Comprehensive Cancer Network (NCCN) website provides up-to-date guidelines on breast cancer risk reduction and algorithms and evidence-based literature support of risk-reducing strategies among high-risk women.

U.S. Preventive Services task Force. Screening for Breast Cancer. U.S. Preventive Services Task Forces recommendation statement. Ann. Intern. Med. 151(10), 716–726 (2009).

Canadian Task Force on Preventive Health Care, Tonelli M, Connor Gorber S et al. Recommendations on screening for breast cancer in average-risk women aged 40–74 years. CMAJ 183(17), 1991–2001 (2011) [Erratum in CMAJ 183(18), 2147 (2011)].

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) Breast Cancer Screening and Diagnosis (Version 1.2014). www.nccn.org

The NCCN website provides up-to-date guidelines on breast cancer screening and evidence-based literature support of screening strategies for high-risk women.

B-RST. www.breastcancergenescreen.org

10.

IBIS. www.ems-trials.org/riskevaluator

11.

Gail model. www.cancer.gov/bcrisktool

12.

Mahoney

Bevers

Linos

Willett

. Opportunities and strategies for breast cancer prevention through risk reduction. CA Cancer J. Clin. 58(6), 347–371 (2008).

13.

Cancer Research UK. Breast cancer risk factors. www.cancerresearchuk.org

14.

Chen

Parmigiani

. Meta-analysis of BRCA1 and BRCA2 penetrance. J. Clin. Oncol. 25(11), 1329–1333 (2007).

15.

Yen

. Genetic testing for BRCA mutations can save lives. Arch. Surg. 146(4), 479–480 (2011).

16.

Moyer

. US Preventive Services Task Force. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med. 160(4), 271–281 (2014).

17.

The US Preventive Services Task Force updates its guidelines for assessment of asymptomatic women with a family history of breast or ovarian cancer. It recommends using a screening tool to identify women appropriate for genetic counseling.

18.

Bellcross

Lemke

Pape

Tess

Meisner

. Evaluation of a breast/ovarian cancer genetics referral screening tool in a mammography population. Genet. Med. 11(11), 783–789 (2009).

19.

Passaperuma

Warner

Causer

. Long-term results of screening with magnetic resonance imaging in women with BRCA mutations. Br. J. Cancer 107(1), 24–30 (2012).

20.

Saslow

Boetes

Burke

. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J. Clin. 57(2), 75–89 (2007). [Erratum in CA Cancer J. Clin. 57(3), 185 (2007)].

21.

The American Cancer Society reviews evidence for annual screening MRI in addition to mammography in high-risk groups and determines that those with a lifetime risk of ≥20–25% would benefit from the addition of MRI.

22.

Quante

Whittemore

Shriver

Strauch

Terry

. Breast cancer risk assessment across the risk continuum: genetic and nongenetic risk factors contributing to differential model performance. Breast Cancer Res. 14(6), R144 (2012).

23.

Fisher

Costantino

Wickerham

. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl Cancer Inst. 90(18), 1371–1388 (1998).

24.

Fisher

Costantino

Wickerham

. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J. Natl Cancer Inst. 97(22), 1652–1662 (2005).

25.

Results from the original P1 prevention trial comparing tamoxifen to placebo in high-risk women are updated after 7 years of follow-up. The substantial reductions in ER-positive cancers persisted and the authors suggested that 2.5 million women could derive a net benefit from the drug.

26.

Vogel

Costantino

Wickerham

. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295(23), 2727–2741 (2006). [Erratum in JAMA 296(24), 2926 (2006); JAMA 298(9), 973 (2007)].

27.

Vogel

Costantino

Wickerham

. Update of the National Surgical Adjuvant Breast and Bowel Project study of tamoxifen and raloxifene (STAR) P-2 trial: preventing breast cancer. Cancer Prev. Res. (Phila) 3(6), 696–706 (2010).

28.

In long-term follow-up, raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive breast cancer with less associated toxicity in women at increased risk.

29.

Goss

Ingle

Ales-Martinez

. Exemestane for breast-cancer prevention in postmenopausal women. N Engl. J. Med. 364(25), 2381–2391 (2011).

30.

In postmenopausal women at increased risk for breast cancer, exemestane reduced the annual incidence of invasive breast cancer by 65% after a median follow-up of 3 years. Exemestane caused no serious toxic effects and only minimal changes in quality of life.

31.

Cuzick

Sestak

Forbes

. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet 383(9922), 1041–1048 (2014).

32.

Visvanathan

Hurley

Bantug

. Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline. J. Clin. Oncol. 31(23), 2942–2962 (2013).

33.

In women at increased risk of breast cancer aged ≥35 years, tamoxifen should be discussed as an option to reduce the risk of ER-positive breast cancer. In postmenopausal women, raloxifene and exemestane should also be discussed as options for breast cancer risk reduction.

34.

Levine

Moutquin

Walton

Feightner

. Canadian Task Force on Preventive Health Care and the Canadian Breast Cancer Initiative's Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. Chemoprevention of breast cancer. A joint guideline from the Canadian Task Force on Preventive Health Care and the Canadian Breast Cancer Initiative's Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. CMAJ 164(12), 1681–1690 (2001).

35.

Moyer

, U.S. Preventive Services Task Force. Medications to decrease the risk for breast cancer in women: recommendations from the U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med. 159(10), 698–708 (2013).

36.

Gail

Brinton

Byar

. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J. Natl Cancer Inst. 81(24), 1879–1886 (1989).

37.

Costantino

Gail

Pee

. Validation studies for models projecting the risk of invasive and total breast cancer incidence. J. Natl Cancer Inst. 91(18), 1541–1548 (1999).

38.

Gail

Costantino

Bryant

. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J. Natl Cancer Inst. 91(21), 1829–1846 (1999).

39.

Rockhill

Spiegelman

Byrne

Hunter

Colditz

. Validation of the Gail et al. model of breast cancer risk prediction and implications for chemoprevention. J. Natl Cancer Inst. 93(5), 358–366 (2001).

40.

Gail

Costantino

Pee

. Projecting individualized absolute invasive breast cancer risk in African American women. J. Natl Cancer Inst. 99(23), 1782–1792 (2007).

41.

Matsuno

Costantino

Ziegler

. Projecting individualized absolute invasive breast cancer risk in Asian and Pacific Islander American women. J. Natl Cancer Inst. 103(12), 951–961 (2011).

42.

Freedman

Gail

. Benefit/risk assessment for breast cancer chemoprevention with raloxifene or tamoxifen for women age 50 years or older. J. Clin. Oncol. 29(17), 2327–2333 (2011).

43.

Quick and easy-to-follow tables demonstrate risk versus benefits of tamoxifen and raloxifene among women aged 50 or older who are being considered for preventive therapy.

44.

Hartmann

Sellers

Schaid

. Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J. Natl Cancer Inst. 93(21), 1633–1637 (2001).

45.

Rebbeck

Kauff

Domchek

. Meta-analysis of risk reduction estimates associated with risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. J. Natl Cancer Inst. 101(2), 80–87 (2009).

46.

Files

Stan

Allen

Pruthi

. Chemoprevention of breast cancer. Womens Health (Lond. Engl.) 8(6), 635–646 (2012).

47.

Lee

Dershaw

Kopans

. Breast cancer screening with imaging: recommendations from the Society of Breast Imaging and the ACR on the use of mammography, breast MRI, breast ultrasound, and other technologies for the detection of clinically occult breast cancer. J. Am. Coll. Radiol. 7(1), 18–27 (2010).

48.

Zhang

Lee

Manson

Cook

Willett

Buring

. Alcohol consumption and breast cancer risk in the Women's Health Study. Am. J. Epidemiol. 165(6), 667–676 (2007).

49.

American Cancer Society. Alcohol Use and Cancer. www.cancer.org

50.

van den Brandt

Spiegelman

Yaun

. Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. Am. J. Epidemiol. 152(6), 514–527 (2000).

51.

McTiernan

Kooperberg

White

. Recreational physical activity and the risk of breast cancer in postmenopausal women: the Women's Health Initiative Cohort Study. JAMA 290(10), 1331–1336 (2003).

52.

U.S. Department of Health and Human Services. Physical activity and health: a report of the surgeon general. Atlanta, GA, USA, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion (1996). www.cdc.gov/nccdphp/sgr/pdf/sgrfull.pdf.

53.

Garland

Gorham

Mohr

. Vitamin D and prevention of breast cancer: pooled analysis. J. Steroid Biochem. Mol. Biol. 103(3–5), 708–711 (2007).

54.

Cho

Chen

Hunter

. Red meat intake and risk of breast cancer among premenopausal women. Arch. Intern. Med. 166(20), 2253–2259 (2006).

55.

Delille

Slanetz

Yeh

Kopans

Garrido

. Physiologic changes in breast magnetic resonance imaging during the menstrual cycle: perfusion imaging, signal enhancement, and influence of the T1 relaxation time of breast tissue. Breast J. 11(4), 236–241 (2005).

56.

Berg

Blume

Cormack

. Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer. JAMA 299(18), 2151–2163 (2008).

57.

Cheung

Tile

Cardew

. Bone density and structure in healthy postmenopausal women treated with exemestane for the primary prevention of breast cancer: a nested substudy of the MAP.3 randomised controlled trial. Lancet Oncol. 13(3), 275–284 (2012).

58.

Hillner

Ingle

Chlebowski

. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J. Clin. Oncol. 21(21), 4042–4057 (2003).

59.

King

Wieand

Hale

. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA 286(18), 2251–2256 (2001).

60.

Medeiros

Muto

Lee

. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am. J. Surg. Pathol. 30(2), 230–236 (2006).

61.

Kurian

Sigal

Plevritis

. Survival analysis of cancer risk reduction strategies for BRCA1/2 mutation carriers. J. Clin. Oncol. 28(2), 222–231 (2010).

62.

Excellent resource for clinicians counseling women about risk-reduction strategies which includes tables on the impact of suveillance versus risk-reducing surgery on survival with a BRCA mutation.

63.

Finch

Lubinski

Moller

. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J. Clin. Oncol. 32(15), 1547–1553 (2014).

Personalized Assessment and Management of Women at Risk for Breast Cancer in North America

Abstract

Keywords

Financial & competing interests disclosure

Lifestyle behaviors

Mammographic screening

R – referral for genetic testing

E – enhanced screening

P – preventive therapy

S – risk-reducing surgery

Personalized risk-based assessment in practice

Case 1

Case 2

Case 3

Case 4

Conclusion

Future perspective

Footnotes

Acknowledgements

Personalized assessment and management of women at risk for breast cancer in North America

References