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BREAST CANCER PREVENTION ACROSS THE CANCER CARE CONTINUUM JENNIFER R. KLEMP OBJECTIVES: To review the current state of breast cancer prevention from primary prevention through survivorship, highlight cross-cutting issues, and discuss strategies for clinical integration and future research.

DATA SOURCES: Published articles between 1985 and 2015 and original research.

CONCLUSION: Cancer risk persists across the lifespan. Interprofessional strategies to reduce morbidity and mortality from cancer include primary, secondary, and tertiary prevention (survivorship). Prevention strategies across the cancer care continuum are cross-cutting and focus on measures to: prevent the onset of disease, identify and treat asymptomatic persons who have already developed risk factors or preclinical disease, and restore function, minimize the negative effects of disease, and prevent disease-related complications.

IMPLICATIONS

FOR NURSING PRACTICE: Oncology nurses and advanced practice nurses are vital in the delivery of breast cancer prevention strategies.

KEY WORDS: Breast cancer prevention, breast cancer risk

Jennifer R. Klemp, PhD, MPH, MA: Associate Professor of Medicine, Division of Clinical Oncology, Director, Cancer Survivorship, Cancer Risk and Genetic Counseling; Founder/CEO, Cancer Survivorship Training, Inc. Address correspondence to Jennifer R. Klemp, PhD, MPH, MA, Associate Professor of Medicine, Division of Clinical Oncology, Director, Cancer Survivorship, Cancer Risk and Genetic Counseling; Founder/CEO, Cancer Survivorship Training, Inc. KU Cancer Center, 2330 Shawnee Mission Parkway, Westwood, KS 662025. e-mail: [email protected] Published by Elsevier Inc. 0749-2081/3102-$36.00/0. http://dx.doi.org/10.1016/j.soncn.2015.03.002

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reast cancer remains the most common cancer in women, affecting more than 200,000 women annually and killing more than 40,000 women each year.1 In the United States, more than $20 billion is spent annually to screen and treat this disease.2 Personalized breast cancer prevention strategies are necessary to accurately predict the risk of developing breast cancer and to find better ways to prevent the disease altogether. Breast cancer prevention is the ‘‘action taken to decrease the chance of developing cancer.’’3 This definition is challenging to put into action because it requires an individual to play an active role in avoiding risk factors such as smoking,

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obesity, lack of exercise, alcohol consumption, and radiation exposure, and increasing protective factors such as engaging in regular physical activity and maintaining a healthy weight and a healthy diet.3 In addition to lifestyle modification, cancer prevention can be achieved through chemoprevention and risk-reducing surgery. However, few interventions to date have demonstrated a survival advantage. The challenge is to determine which women are at highest risk for developing a primary or secondary breast cancer. The ability to risk stratify has been enhanced by years of epidemiologic and clinical research and the understanding of how certain risk factors impact the short- and longterm risk of developing breast cancer. General recommendations should include lifestyle modification focused on increasing exercise and weight control. A more personalized approach focused on individualized risk is necessary to recommend appropriate breast cancer screening, chemoprevention, and preventive surgery. This review will cover the current state of breast cancer prevention, from primary prevention through survivorship, highlight cross-cutting issues, and will discuss strategies for clinical integration and future research.

Hereditary Cancer Risk Having a germline mutation can increase the risk of breast cancer from 1.5RR to >5RR. BRCA1 and BRCA2 mutations are the most common genes associated with hereditary breast (and related) cancers. However, with nextgeneration sequencing of multiple genes there is the ability to test for many genes, regardless of penetrance. Table 1 includes a list of high- and moderate-penetrance mutations and the types and lifetime risks of cancer. Genetic testing and the review of personal and family history is recommended across the cancer control continuum: prior to, at the time of, and ongoing into breast cancer survivorship.13

UNDERSTANDING BREAST CANCER RISK

Mammographic Breast Density Having dense breast tissue (heterogeneously or extremely dense by mammogram) is linked to an increased risk of developing breast cancer compared with women with less dense breast tissue. However, there is not a standard for measuring breast density. In addition, many states have passed laws requiring breast density to be included in patient result letters, but there are limited follow-up options outside of additional imaging for certain individuals with increased breast density.16

Assessing breast cancer risk has been enhanced over the past two decades, with more comprehensive risk assessment models and the ability to calculate and integrate risk factors and estimates into electronic health records. Models include many factors for assessing breast cancer risk a age, reproductive factors and sex hormone exposure, biopsy history and results, and family history of breast and ovarian cancer. Models for a highrisk population, especially those with precancerous changes, include the Breast Cancer Risk Assessment Tool (BCRAT or GAIL Model)4,5 or the International Breast Cancer Intervention Study (IBIS) or Tyrer-Cuzick model,6 and those more specific to the probability of carrying a BRCA1 or BRCA2 mutation include the BOAD ICEA, CLAUS, and BRCAPRO (an upcoming enhancement to the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) will include PALB2 and RAD51).7-12

Single-Nucleotide Polymorphisms In addition to germline testing for high- and moderate-penetrance gene mutations, there are also panels of low-penetrance genetic risk factors or single-nucleotide polymorphisms (SNPs). Although SNPs are not used as part of standard clinical practice, current estimates suggest that there are over 65 SNPs that might, either by themselves or in combination, be helpful in refining breast cancer risk assessment. The challenge will be to incorporate SNP testing into a clinical workflow and to interpret the impact on risk beyond of those factors already established.14,15

Intra-Epithelial Neoplasia Because of widespread use of breast cancer imaging, early proliferative lesions or intraepithelial neoplasia (IEN) has become more prevalent.17 IEN includes proliferative breast disease without atypia, atypical ductal and lobular hyperplasia, and in situ breast cancer (Fig. 1). IEN is an established risk biomarker with the closest direct biologic association with invasive breast cancer.17 Normal or non-proliferative tissue

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TABLE 1. Breast Cancer Susceptibility Genes

Syndrome

Gene or Locus (Chromosomal Location)

High-Penetrance Mutations for Breast and Other Cancers Hereditary breast/ovarian BRCA1 (17q12-21) cancer syndrome (HBOC) BRCA2 (13q12-13) Li-Fraumeni syndrome

TP53 (17p13.1)

Cowden syndrome

PTEN (10q.23.3)

Peutz-Jeghers syndrome

STK11 (19p13.3)

Hereditary gastric cancer

CDH1 (16q.22.1)

Moderate Penetrance Mutations for Breast and Other Cancers ATM ATM (11q22.3) CHEK2 CHEK2 (22q12.1) PALB2 PALB2 (16p12.1)

Neoplasm

Lifetime Risk

Female breast, ovarian cancer Female and male breast, ovarian, prostate and pancreatic cancers Breast cancer, sarcoma, leukemia, brain tumors, adrenocortical carcinoma, lung cancer Breast, thyroid, endometrial cancer Other: benign hamartomas, macrocephaly Breast, ovarian, cervical, uterine, testicular, small bowel, and colon cancer Other: hamartomatous polyps of the small intestine, mucocutaneous pigmentation Hereditary diffuse gastric, lobular breast, and colorectal cancer

40% to 80% 20% to 85%

Breast and ovarian cancer Breast, colorectal ovarian, bladder cancers Female and male breast, pancreatic, and ovarian cancers

56% to 90%

25% to 50% 32% to 54%

60%

15% to 20% 25% to 37% 20% to 40%

NOTE. This table is not inclusive, but provides a general list of high- and moderate-penetrance gene mutations for breast and other cancers.

is assigned a relative risk of 1. Hyperplasia is associated with a relative risk of 1.4 to 2.0, and atypical hyperplasia a relative risk of 4 to 5.18,19 Women presenting with atypical hyperplasia should be informed of this increased risk and that they have options for breast cancer risk reduction. A longitudinal study from Mayo Clinic reported long-term absolute risk associated with atypical hyperplasia resulted in a cumulative incidence of breast cancer approaching 30% at 25 years of follow-up.19 Because atypical hyperplasia is such a strong predictor of the development of breast cancer and is theoretically reversible, IEN has been used as a surrogate end point biomarker in primary and secondary breast cancer prevention studies. Breast tissue and cells have been collected by core biopsy, random-periareolar fine needle aspiration (RPFNA), ductal lavage, and nipple aspirate for risk assessment and prevention trials.20 Our group at the University of Kansas Cancer Center (Kansas City, KS) reported that women with hyperplasia with atypia in their RPFNA and a projected 10-year GAIL risk above our cohort’s

median of 4% have an observed incidence of breast cancer development of 15% at 3 years. From this seminal work, we have incorporated breast cancer prevention therapies, natural products, and lifestyle modification into a clinical trial design using the RPFNA pre and post targeted intervention.21 With many modalities available to assess breast cancer risk, unfortunately, only a small percentage of women at high risk for developing breast cancer are identified. Nursing Implications There is need to develop and/or update a systemic approach to collect personal and family history of cancer and other breast cancer risk factors to assess and manage breast cancer risk. Advanced practice nurses are key stakeholders in the management of women (and men) at high risk. In many cases, advanced practice nurses are the ideal providers within a high-risk clinic, to provide cancer risk counseling and access to genetic testing, to manage breast imaging and follow-up, and to deliver ongoing survivorship care.

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FIGURE 1. Intra-epithelial neoplasia. (Adapted and reprinted with permission from Fabian et al.20)

INTERVENTIONS FOR BREAST CANCER RISK REDUCTION Chemoprevention Selective Estrogen Receptor Modulators. Selective estrogen receptor modulators (SERMS), specifically tamoxifen, have been long been used in the treatment (early and late stage) and prevention of breast cancer. Tamoxifen is a wellestablished and effective treatment for estrogen receptor (ER)-positive breast cancer.22-29 Because of the positive impact of tamoxifen, the role of another SERM, raloxifene, was explored in post-menopausal women with osteoporosis. The Multiple Outcomes of Raloxifene Evaluation (MORE) reported that raloxifene compared with placebo significantly reduced the risk of breast cancer.30 This resulted in the National Surgical Adjuvant Breast and Bowel Project (NSABP) P2, a head-to-head comparison of tamoxifen versus raloxifene in women at high risk. Both were similar in the reported reduction of developing a new invasive breast cancer by almost 50%. Compared with raloxifene, tamoxifen had a significant reduction in the incidence of DCIS (ductal carcinoma in situ) but had a higher rate of side effects, including uterine cancer and thromboembolic events.31,32 Even with the compelling evidence to support the use of SERMS as a breast cancer chemopreventive agent, uptake remains low because of concerns of toxicity. In addition, many women are not aware that they are at increased risk of breast cancer and chemoprevention may not have been discussed as a risk-reducing strategy.33,34 Carry-Forward Effect of Tamoxifen. The International Breast Cancer Intervention Study I (IBIS-I) was initiated in 1992 and recruited women at high risk of developing breast cancer to receive

oral tamoxifen (20 mg daily) or matching placebo. After a median follow-up of 4.2 years, tamoxifen showed a significant reduction of 32% for all types of breast cancer, including DCIS. Recent reports describe that after a median follow-up of almost 20 years, the preventative carry-forward effect of tamoxifen reduced the rate of breast cancer by about 30% for ER-positive breast cancer, but had no effect for ER-negative breast cancer. To date, tamoxifen for the primary prevention of breast cancer has yet to demonstrate a survival advantage.35 Aromatase Inhibitors. Initially used for early stage, post-menopausal ER-positive breast cancer, aromatase inhibitors have become a mainstay for the treatment of breast cancer from early to latestage disease, and can be used alone or in combination with other therapies. There have been two large breast cancer prevention trials in post-menopausal women at high-risk of developing breast cancer. The Mammary Prevention 3 (MAP.3) trial compared the aromatase inhibitor exemestane with placebo, resulting in a 65% reduction of ER-positive invasive breast cancers with exemestane.36 The International Breast Cancer Intervention Study II (IBIS-II) trial investigating anastrozole versus placebo reported a 53% reduction of invasive breast cancer and DCIS and a 58% reduction in ER-positive invasive breast cancer.37 In post-menopausal women, both exemestane and anastrozole reported greater reductions in ER-positive breast cancer than that previously reported with tamoxifen and provide additional options as breast cancer chemoprevention. However, tamoxifen remains the only breast cancer chemopreventive for pre-menopausal women at high risk of developing breast cancer. Aromatase Inhibitors, SERMS, and Ovarian Suppression. Traditionally aromatase inhibitors were used in the treatment of post-menopausal women only. A recent combined report of the TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) found that exemestane plus ovarian function suppression was superior to tamoxifen alone or tamoxifen plus ovarian function suppression in pre-menopausal women with hormone receptorpositive early breast cancer. Treatment with exemestane plus ovarian function suppression reduced the risk of any second primary invasive

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cancer by 28%, and reduced the risk of invasive breast cancer recurrence by 34%, compared with treatment with tamoxifen plus ovarian function suppression. At 5 years from study entry, 92.8% of women remained free from breast cancer after treatment with exemestane plus ovarian function suppression; 88.8% were breast cancer-free after receiving tamoxifen plus ovarian function suppression.38,39 Current Clinical Recommendations. In summary, a recommendation recently provided by the American Society of Clinical Oncology Practice Guidelines suggest that in women at increased risk of breast cancer age $ 35 years, tamoxifen (20 mg per day for 5 years) should be discussed as an option to reduce the risk of ER-positive breast cancer. In post-menopausal women, tamoxifen (20 mg per day for 5 years), raloxifene (60 mg per day for 5 years), and exemestane (25 mg per day for 5 years) should also be discussed as options for breast cancer risk reduction.40 Bisphosphonates. The use of bisphosphonates, especially in reducing the risk of breast cancer, has been limited to secondary prevention. Adjuvant bisphosphonate treatment significantly improves breast cancer survival (17% reduction in deaths) and reduces bone recurrence (34% reduction) in post-menopausal women with early breast cancer. The same benefits were not seen in premenopausal women. Especially for women taking an aromatase inhibitor and who are at greater risk of bone loss, bisphosphonates have become a standard part of clinic care.41,42 Agents Under Investigation Metformin. Metformin was first introduced as a treatment for non-insulin–dependent (type 2) diabetes in the late 1950s and is currently a target for both primary and secondary breast cancer prevention, as well as other cancers (including colorectal, prostate, and endometrial). Much of the human data on metformin and cancer has come from epidemiologic studies of people with diabetes and retrospective studies; however, there are numerous studies under way exploring this relationship.43-47 For non-diabetic women with early stage breast cancer there are several studies evaluating the relationship between metformin and breast cancer recurrence. These trials will compare metformin versus placebo
letrozole;
lifestyle

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modification, and
bisphosphonates in phase II and III trials.48 There are also several trials in primary prevention focused on both pre- and post-menopausal overweight women at high risk for breast cancer using metformin versus placebo. Targets for these studies include a change in breast density and breast cytology.49 Vitamin D. Vitamin D supplementation might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcomes, but to date it has not been shown to do so. There are many studies, both pre-clinical and clinical, that are evaluating whether Vitamin D3 supplementation can alter breast density and other markers of breast cancer risk.50 Vitamin D supplementation is also of interest in tertiary prevention, especially targeting muscloskeletal symptoms from aromatase inhibitors and a common presentation of Vitamin D deficiency. At the University of Kansas Cancer Center, we found in a randomized study that increasing circulating levels 25(OH)D was safe and improved aromatase inhibitor-associated symptoms.51 Statins. There has been an interest in exploring the relationship between statins and breast cancer. However, clinical data reported to date do not provide a strong association between statin use and breast cancer risk in average-risk women. Could there be a role in a high-risk population? Several observational cohort studies have demonstrated reduced risk of breast cancer recurrence in women using statins, which may suggest a role for statins for secondary prevention, but further research is needed to support this intervention.52 Omega-3-fatty Acid. Increased intake of omega-3 fatty acids (n-3) associated with decreased omega-6 (n-6), resulting in a higher n3/n-6 ratio compared with the Western diet are inversely associated with breast cancer risk.53 Primary prevention studies have focused on both pre- and post-menopausal women at high risk of developing breast cancer. Studies including dietary modification or supplementation targeting the n-3/n-6 ratio are focused on demonstrating adherence and safety, changes in breast adiposity and density, and modulation of precancerous breast disease.54

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Tertiary prevention in post-menopausal breast cancer survivors on aromatase inhibitors have focused on the use of supplementation to improve joint pain and to modulated breast adipose and mammary epithelial cells.55 Challenges remain in identifying effective doses and determining intermediate biomarkers to use for an indicator of response. In addition, the identification of well-defined subpopulations that are most likely to benefit from this prevention approach are needed.56 Preventive Surgery The use of prophylactic mastectomy (PM) is generally reserved for those at hereditary cancer risk.57 Women who carry a germline mutation in either the BRCA1 or BRCA2 gene have a lifetime risk of breast cancer of 60% to 87%,58 and once diagnosed with breast cancer, are at increased risk of a second primary breast cancer. The risk of a contralateral breast cancer within the first 5 years of diagnosis is increased up 27.1% in women with BRCA1 mutations,5 23.5% in women with BRCA2 mutation, or a combined estimate of 34% within 15 years of diagnosis.59,60 PM has been shown to reduce the risk of breast cancer in high-risk women by more than 90%,61 and studies have demonstrated that PM specifically reduces the risk of breast cancer in women with mutations in BRCA1 or BRCA2 by 89.5% to 100%.62-66 In a non-randomized observational study, women with BRCA-associated breast cancer who were treated with bilateral mastectomy were 48% less likely to die of breast cancer within 20 years of diagnosis than women treated with unilateral mastectomy. The clinical implications of this study suggest that bilateral mastectomy should be discussed as an option for young women with a BRCA mutation and early onset breast cancer. However, this question requires further investigation in a larger study with more events in this very high-risk population.67 Women with a diagnosis of breast cancer are faced with making surgical decisions at times of great stress. Current trends in breast cancer surgery often result in women without a BRCArelated breast cancer opting for bilateral mastectomies over breast conservation and unilateral mastectomy. The question has been asked if this is overtreatment of the breast cancer? Many women cite survival benefits as a reason for undertaking double mastectomy on receiving a diag-

nosis of unilateral breast cancer, but is there data to support this notion? A traditional randomized study has not been conducted to answer this question, but it has been reported by using a Markov model to predict survival outcomes that the absolute 20-year survival benefit (in women with breast cancer and not at hereditary cancer risk) from a contralateral PM was less than 1% among all age, ER status, and cancer stage groups.68,69 In addition, prophylactic bilateral salpingoophorectomy has also been shown to reduce the risk of breast cancer by up to 68% in women who have not been diagnosed with breast cancer with BRCA1 and BRCA2 mutations. This risk reduction was more profound in women before age 40,70 and may have little to no benefit in women over the age of 50.71 The protective effect of prophylactic oophorectomy with regard to breast cancer was also seen in women taking hormone replacement therapy post oophorectomy and should not be withheld in women undergoing early menopause unless otherwise contraindicated.72 To date, reports on the risk reduction of a second primary breast cancer with prophylactic oophorectomy are conflicting. Following a bilateral salpingoophorectomy, there are reports of no evidence for risk reduction of a second primary breast cancer diagnosis72 and the opposite, reporting a significant decrease in the risk of ipsilateral and contralateral breast cancer, in BRCA carriers with a prior stage I or II breast cancer, by up to 75% and 60%, respectively.73-75 Nursing Implications. Risk stratification by gene status is important for understanding primary and secondary cancer risk and making appropriate surgical management decisions. Nurse navigators and advanced practice nurses can play an active role in increasing access to and delivery of cancer risk and genetic counseling, genetic testing when indicated, and the use of a shared decision model when counseling women about prophylactic surgery to reduce the risk of breast cancer and for treatment and medical management. Lifestyle Modification Lifestyle modification focused on increasing physical activity, striving for a healthy weight, decreasing alcohol consumption, and smoking cessation are essential to reducing the risk of cancer.

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FIGURE 2. 2012 American Cancer Society nutrition and physical activity guidelines for cancer survivors. (Data from Kushi et al84 and Rock et al.85) Current estimates by the World Cancer Research Fund/American Institute for Cancer Research suggest that over 40% of post-

menopausal breast cancer could be prevented by reductions in alcohol, excess body weight, and inactivity.75 However, dietary and physical

FIGURE 3. Cross-cutting issues in cancer control. (Data from the National Cancer Institute.86)

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activity interventions have not consistently been shown to modify breast cancer risk. It is reasonable to provide clinical recommendations to encourage patients to work toward an ideal body weight and participate in regular physical activity. High body mass index (BMI) is a known risk factor for the development of postmenopausal breast cancer.76,77 In addition, more than half of women diagnosed with breast cancer will experience weight gain, which is multifactorial in nature. This weight gain has been associated with an increased risk of recurrence and death compared with women who maintained or lost weight.77-81 To put this into context, women with a high BMI have double the risk of 5-year breast cancer recurrence and a 60% increased risk of death over 10 years in comparison with women with a BMI in the normal range.82 The American Institute for Cancer Research suggests that the same recommendations apply for primary and secondary breast cancer prevention.83 A summary of guidelines is provided in Figure 2. There are a multitude of studies in primary, secondary, and tertiary breast cancer prevention that have been undertaken and focus on single or bundled changes in lifestyle and will continue to be a priority for future research and clinical integration.

Nursing implications. Education and interventions that encourage a healthy lifestyle are recommended across the cancer control continuum. Oncology nurses and advanced practice nurses are in ideal positions to provide education, recommendations, and referrals that increase access to interventions focused on lifestyle modification.

CONCLUSION Breast cancer prevention across the cancer continuum is a process that has cross-cutting issues. Figure 3 highlights the importance of an interprofessional approach to address cross-cutting issues including: lifestyle modification, surveillance, communication and navigation, health disparities, genetic and genomic testing, process improvement, epidemiology, and clinical trials. Breast cancer prevention impacts every patient and requires an understanding of risk, strategies to stratify and manage risk, and hopefully, enlist strategies for risk reduction. This approach provides a framework for oncology nurses and navigators and advanced practice nurses to include aspects of these cross-cutting issues into their clinical practice through education, management, mitigation, and care coordination.

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