Breast Cancer Chemoprevention: Use and Views of Australian Women and Their Clinicians

Although breast cancer mortality has improved, incidence continues to rise, presenting a major burden for health services worldwide (1). Better implementation of evidence-based breast cancer prevention interventions, such as chemoprevention (also known as risk-reducing medication) in women at increased risk, could reduce this burden (2).

Selective estrogen receptor modulators (tamoxifen and raloxifene) and aromatase inhibitors (anastrozole and exemestane), taken daily for 5 years, reduce breast cancer risk by one-third to one-half in women at increased risk (3–8). For tamoxifen and anastrozole, the preventive benefit continues for at least 15 and 5 years, respectively, after completion (9, 10). Low-dose tamoxifen for only 3 years may also be an efficacious, low side-effect option for women who do not tolerate the standard 20-mg daily dose, although long-term efficacy for this shorter duration, lower dose regimen is unknown (11, 12).

Guidelines recommend consideration of risk-reducing medication for women at elevated breast cancer risk (12–15). Despite this, risk-reducing medication is underutilized. A meta-analysis, including data from 21,423 women, reported a pooled risk-reducing medication uptake estimate of 16% (16), although in individual studies, uptake ranged from 0% to 55%. Uptake was higher in trial (25%) compared with non-trial (8.7%) settings, suggesting it may be more difficult for clinicians to implement risk-reducing medication within routine practice.

Reasons for low use of risk-reducing medication are multifactorial, including patient- and physician-related factors. Concern about side effects is a well-described barrier to use (17–23). Physician recommendation, family history of breast cancer, abnormal breast biopsy, higher perceived breast cancer risk, and higher cancer-specific anxiety are associated with risk-reducing medication use (21, 24).

Tamoxifen became government subsidized for primary breast cancer prevention in Australia in 2016, but national guidelines have recommended doctors consider it for women with a lifetime risk of breast cancer at least 1.5 times population risk (i.e., ≥ 16%) since 2010 (https://www.canceraustralia.gov.au/publications-and-resources/cancer-australia-publications/advice-about-familial-aspects-breast-cancer-and-epithelial-ovarian-cancer). This study aimed to determine the past or current use of risk-reducing medication by Australian women at increased risk of breast cancer and to examine barriers and facilitators to the use of risk-reducing medication.

Participants were women (and their clinicians) from multiple-case breast cancer families recruited to the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer cohort (kConFab) between 1997 and 2008 (https://www.kconfab.org/). Multiple-case breast cancer families were defined as families where a BRCA1 or BRCA2 mutation, or a mutation in another breast cancer susceptibility gene, had been identified, or families where no predisposing mutation had been identified but two or more family members on the same side of the family were affected by breast cancer. The proband was recruited after a clinic consultation in any of 15 Australian genetics clinics. Other family members were not required to attend a genetics clinic to enroll. kConFab women were mailed follow-up questionnaires every 3 years (25) asking questions regarding doctors involved in their care, use of risk-reducing medication, educational level, parity, pregnancy, breastfeeding, marital status, family history, participation in clinical trials of risk-reducing medication, and details of any bilateral mastectomy or cancer diagnoses. In addition to follow-up questionnaires, all kConFab women eligible for the study reported here were sent a survey on risk-reducing medication in late 2018 (see surveys of kConFab women section below). This study was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent and the kConFab cohort study has Human Research Ethics Committee approval at all participating sites, and this survey study has Human Research Ethics Committee approval at the Peter MacCallum Cancer Centre.

Understanding the behavioral determinants of use of risk-reducing medication for both clinicians and patients is the first step in implementing practice change to increase use of risk-reducing medication. We used the Theoretical Domains Framework (26) to guide the development of survey questions. The Theoretical Domains Framework was developed to identify the cognitive, affective, social, and environmental influences on health professional and patient behavior related to implementation of evidence-based recommendations. It consists of 84 theoretical constructs grouped into 14 domains and maps directly to the COM-B (capability, opportunity, motivation, behavior) behavioral change model (27), to suggest intervention functions and relevant policy categories to guide pathways to behavioral change.

A 68-item survey (Supplementary data 1) was developed based on a literature review and semi-structured interviews with 62 kConFab women from different geographical locations, socioeconomic status, and ethnicities to identify barriers and facilitators to using risk-reducing medication. Survey questions, based on the Theoretical Domains Framework (Tables 1 and 2), were developed by the research team, including experts in health sociology, qualitative research, breast surgery, and primary care. The survey was piloted for usability with nine kConFab women in face-to-face cognitive interviews and refined. kConFab women were eligible if, at the time of survey, they were aged between 25 and 70 years, resided in Australia, and had a BOADICEA (28) lifetime breast cancer risk of ≥16% but had not had bilateral mastectomy, previous breast cancer ever, or other invasive cancer in the previous 6 years. Women who had participated in the IBIS prevention trials (3, 6) or the survey pilot study were also excluded. The survey was mailed or emailed, and non-responders were followed up three times.

In Australia, family physicians and breast surgeons primarily undertake breast cancer prevention. Medical oncologists do not have a primary role in discussion of risk-reducing medication. A literature review and focus group interviews were undertaken with family physicians and breast surgeons to inform survey development (29, 30). The 49-item clinician survey (Supplementary Data 2) was developed using the Theoretical Domains Framework (Tables 1 and 2). Eligible clinicians were family physicians or breast surgeons involved in the care of kConFab women and practicing in Australia with a valid address. Non-responders to the mailed questionnaire were followed up.

The survey responses for both clinicians and kConFab women were analyzed using descriptive statistics (numbers and percentages) in R-version 3.6.1 (R Core Team (2015; ref. 31).

Of the 5,231 women unaffected with breast cancer when enrolled in kConFab between 1997 and 2008, 1,097 declined follow-up, 332 died during follow-up, and 2,689 were excluded based on their characteristics at the time of survey (previous breast cancer (1,045), not aged between 25 to 70 years (499), not residing in Australia or invalid address (294), participation in pilot study (9), invasive cancer in last 6 years (61), bilateral mastectomy (191), <16% lifetime breast cancer risk (537), or participation in IBIS trials (53)). Of 1,113 eligible women, 725 (65%) responded to the survey. Table 3 describes responder characteristics. A minority (7%) were BRCA1 or BRCA2 mutation carriers. Only 16% had a high lifetime breast cancer risk (≥ 30%) but 30% of respondents had high perceived breast cancer risk.

Approximately half (48%) of respondents were aware of medications to reduce breast cancer risk. Few (1.4%) had ever taken risk-reducing medication (Table 3).

kConFab women were asked to rank side effects of risk-reducing medication from most to least important to them. The side effects most frequently ranked as most important were endometrial cancer (45%) and blood clots (36%; Fig. 1). Of the 322 women who ranked endometrial cancer as most important, 201 (62%) were under age 50 years. Only 21 (3%) women ranked vasomotor symptoms as most important.

kConFab women (n = 715) who had not taken risk-reducing medication were asked to identify the strongest of 29 possible barriers to taking it (Supplementary Data 3) and to rate the strength of each barrier (Fig. 2). The barriers most frequently identified as the strongest were side effects (31%) and side-effect experiences of family or friends when taking similar medications (4%; both map to the “beliefs about consequences” in the Theoretical Domains Framework), as well as inadequate information to make a decision (23%, Theoretical Domains Framework “knowledge” domain) and preferring healthy lifestyle choices to medication (6%, Theoretical Domains Framework “intentions” domain).

The information ranked most important by women before deciding whether to take risk-reducing medication pertained to side effects (33%) and extent of breast cancer risk reduction (31%).

Respondents also identified the strongest of 16 facilitators for taking risk-reducing medication (Supplementary Data 3) and rated the strength of each facilitator (Fig. 2). The strongest facilitator was that taking risk-reducing medication can reduce breast cancer risk for up to 20 years (35%, Theoretical Domains Framework “knowledge”, “beliefs about consequences”, and “goals” domains). Additional strong facilitators were knowledge of being at high risk of breast cancer (11%, Theoretical Domains Framework “knowledge” domain), if risk-reducing medications would improve the chance of staying healthy for family (13%, Theoretical Domains Framework “social role/identity” and “goals” domains), and having an abnormal biopsy that increases breast cancer risk (13%, Theoretical Domains Framework “environmental context and resources” domain). Doctor's recommendation was the strongest facilitator for 10% of women, but family or friend recommendation only for 1%. Cholesterol reduction (with tamoxifen) and reduced osteoporosis (with tamoxifen or raloxifene in postmenopausal women) were infrequently identified as the strongest facilitators (1% and 4%, respectively) but most women did identify them as facilitators (55% and 79%, respectively).

Of 554 breast surgeons and family physicians identified by women as involved in their care, 30 were excluded (13 not currently practicing and 17 invalid address). Of 524 eligible clinicians (394 family physicians and 130 breast surgeons) mailed the survey, 221 (42%) responded (57% of breast surgeons and 37% of family physicians). Clinician characteristics are shown in Table 3.

Most (76%) clinicians had heard of risk-reducing medication (97% of breast surgeons and 65% of family physicians). Few (3%) family physicians were “very confident” in providing information about risk-reducing medication, compared with 56% of breast surgeons. Many family physicians (32%) were “not at all confident” compared with 1% of breast surgeons. Approximately one third (29%) of family physicians had never discussed or prescribed cancer risk-reducing medication, although most (75%) responded it was their role to initiate such discussions and 98% that it was their role to write ongoing prescriptions. Only three (4%) surgeons had never discussed or prescribed risk-reducing medications. Most surgeons perceived their role as initiating discussion and writing first prescriptions (89% and 81%, respectively). Almost half of breast surgeons (47%) but only 10% of family physicians had heard of the iPrevent tool, an Australian tool for women and clinicians to assess and manage breast cancer risk (https://www.canceraustralia.gov.au/affected-cancer/check-your-cancer-risk-online; refs. 32, 33).

Clinicians who had heard of risk-reducing medication (168) were asked to identify the strongest of 22 barriers to discussing or prescribing risk-reducing medication (Supplementary Data 4) and to rate the strength of individual barriers (Fig. 3). The strongest barriers for family physicians were insufficient knowledge (45%, Theoretical Domains Framework “knowledge” domain), lack of confidence in providing advice about risk-reducing medications, and inadequate training and confidence in breast cancer risk assessment (9% and 6%, respectively, Theoretical Domains Framework “beliefs about capabilities” and “skills” domains), medication side effects (7%, Theoretical Domains Framework “beliefs about consequences” domain), difficulty identifying suitable patients (7%, Theoretical Domains Framework “skills” domain), and wanting to achieve other things during a consultation (6%, Theoretical Domains Framework “goals” domain). For breast surgeons, the strongest barriers were medication side effects (40%, Theoretical Domains Framework “beliefs about consequences” domain) and lack of time during a consultation (14%), lack of surrogate markers of medication efficacy (7%), difficulty accessing good patient information (7%), and difficulty finding resources to estimate a patients risk (5%), all operating within the “environmental context and resources” domain of the Theoretical Domains Framework.

Of 14 facilitators, the strongest for family physicians was clear guidelines and recommendations (50%), better tools to identify suitable patients (12%), strong family history of breast cancer (10%), and specialist support (9%), all of which operate within the “environmental context and resources” domain of the Theoretical Domains Framework. For surgeons the strongest facilitators were strong family history (28%), clear guidelines and recommendations (22%), and patients with lobular carcinoma in situ (20%), all of which operate in the “environmental context and resources” domain of the Theoretical Domains Framework, as well as expecting positive outcomes for women who take risk-reducing medications (11%, “optimism” and “beliefs about consequences” domains).

This Australia-wide study of women at increased risk of breast cancer, and their clinicians, demonstrates very low use of risk-reducing medication (1.4%) by international standards (16). Women in our study may have had greater exposure to information about risk-reducing medication due to their involvement in kConFab, so use of this efficacious prevention intervention could be lower still in other Australian women at increased risk of breast cancer. This study is unique in assessing the views of both women and their clinicians regarding risk-reducing medication. The response rate was high compared with some other survey studies (20); however, the views of nonresponders may differ from those reported here. Regardless, this study has identified several important factors that influence the use of risk-reducing medication, and the behavioral domains in which they operate.

Deficiencies in the “knowledge” domain for both clinicians and women were a prominent barrier to risk-reducing medication use. Unexpectedly, 25% of women in this study perceived their breast cancer risk as low (1%) or average (24%), and this important subset of our study sample is unlikely to have considered use of risk-reducing medication. The reasons for their inappropriately low risk perception are unclear and require further research. Consistent with other studies (34), half of kConFab women and a third of their family physicians had never heard of risk-reducing medication, thus expecting those clinicians to prescribe risk-reducing medication, and women to ask for them, is unrealistic. The potential reasons why a large number of women were unaware of risk-reducing medication was not addressed by this study but would be important to address in future research. Only half of breast surgeons felt very confident in providing information on risk-reducing medications. A clear framework is required in order to improve knowledge, and consequently uptake, of risk-reducing medication. Application of the COM-B behavior change wheel (27) suggests that interventions focused on education, training, and enablement (Table 1) may be effective. Risk-reducing medications are all off patent; thus, no commercial incentive exists for pharmaceutical companies to educate clinicians or women about these older generic prevention medicines. In Australia, peak bodies, policymakers, and consumer organizations such as The Royal Australian College of General Practitioners, Cancer Australia, Breast Cancer Network Australia, and BreastSurgANZ could take on this role.

Breast cancer risk assessment is encouraged in Australian primary care guidelines (35). Family physicians identified barriers and facilitators within the domains of “environmental context and resources” (difficulty selecting suitable patients and need for better tools to identify suitable patients) and “skills” (inadequate confidence in breast cancer risk assessment). This is consistent with previous research demonstrating that family physicians lack confidence in personalized medicine, knowledge of risk, and risk perception (36). These findings point to environmental restructuring interventions, such as development of national guidelines mandating routine breast cancer risk assessment, and incorporating prompts into family physician software to assess breast cancer risk and to discuss risk-reducing medication if criteria are met (which has been shown to be effective in other health promotion settings (37)). They also point to the importance of training to impart skills to clinicians in breast cancer risk assessment. Active education strategies such as workshops focusing on assessment and discussion of breast cancer risk and appropriate risk-reducing strategies may improve family physician confidence in discussing risk-reducing medication. Tools to enhance informed decision-making about risk-reducing medication, which present the benefits and potential harms of these medications, could support discussions in primary care (38). Use of iPrevent (an Australian online breast cancer risk assessment and risk management decision support tool for women and clinicians that is endorsed by Cancer Australia; https://www.canceraustralia.gov.au/affected-cancer/check-your-cancer-risk-online) may improve breast cancer risk assessment in primary care and provide easy-to-access, personalized information on the benefits of risk-reducing medication (32, 33, 39). For women, a public campaign around knowing your breast cancer risk and available interventions may increase awareness of risk-reducing medication. Breast cancer screening programs may provide a convenient platform to roll out education about risk-reducing medication. It has been demonstrated in a large study embedded in a screening program in the Manchester area of the UK, that the majority of women want to know their breast cancer risk, and that providing personalized risk information in this setting does not cause psychological harms (40), and results in engagement in prevention programs (41). One Australian state, Western Australia, has mandated that women receive information on their mammographic density from the free breast cancer screening program (similar to several jurisdictions in the United States), but a personalized risk estimate is not provided, nor is this linked to specific prevention information or programs.

Abnormal breast biopsy was identified as a strong faciliatator to clinicians to discuss or prescribe risk-reducing medication. Atypical hyperplasia and lobular carcinoma in situ are associated with a significant increase in breast cancer risk, and risk-reducing medication reduces risk of invasive breast cancer in these conditions (6, 11, 42). Women with atypical hyperplasia have low uptake of risk-reducing medication and often underestimate their breast cancer risk (43). Environmental restructuring with mandated routine discussion of women with atypical hyperplasia or lobular carcinoma in situ at multidisciplinary meetings, after their surgery or biopsy, could help prompt consideration of risk-reducing medication. Automatic prompts in clinician software may also be helpful.

Consistent with previous research, the strongest barrier to risk-reducing medication identified by women and breast surgeons was side effects (18, 22). Seeing family and friends experience side effects from similar medications was also a strong barrier. In our familial breast cancer cohort setting, these experiences are likely to have been in relatives receiving these medications for cancer treatment. Experience of side effects differs when used for breast cancer treatment compared with prevention, because side effects of endocrine therapies are often confused with chemotherapy toxicities (22). This needs to be carefully outlined when discussing options to prevent overestimation of side effects. Fear of side effects in our study was mainly focused on endometrial cancer and venous thromboembolism. Aromatase inhibitors and raloxifene do not increase endometrial cancer risk, and tamoxifen only increases it in postmenopausal women where the risk is approximately 1 in 250 over 5 years (resolving on completion; ref. 44). Most (62%) women in our study who ranked endometrial cancer risk as most important to them were under the age 50 years, despite tamoxifen conferring no increased risk of endometrial cancer in premenopausal women; this emphasizes the importance of personalized discussions and education to address these misconceptions. Aromatase inhibitors do not increase incidence of venous thromboembolism, and in women on tamoxifen or raloxifene, the absolute risk is generally small (1 in 250 over 5 years of use; ref. 44).

The nocebo effect has the potential to influence patient acceptability of treatments and compliance (45). This is supported by the IBIS prevention trials, which demonstrated similar rates of adverse reactions in both intervention and placebo groups (3, 6). For example in the IBIS II trial, 57% of those in the intervention arm and 49% in the placebo arm experienced vasomotor symptoms, suggesting that only about 1 woman in 12 will experience these symptoms due to risk-reducing medication. Online tools, such as iPrevent (32), can help clinicians provide personalized estimates of the absolute risk reduction, as well as the absolute risk of serious side effects with risk-reducing medication. Considering a short trial of therapy to assess side-effect profile, before a 5-year course, may be a useful approach (2). Low-dose tamoxifen (5 mg daily for 3 years) may be a useful alternative for women who do experience side effects on the standard dose (11). Behavioral change theory (27) also points to incentivization as a possible strategy to address barriers that operate in the Theoretical Domains Framework “beliefs about consequences” domain, as does concern about side effects of risk-reducing medication. Highlighting the potential beneficial effects of risk-reducing medication may be important. Over half of women in our study identified that reduction in cholesterol and the potential prevention of osteoporosis would make it easier to take risk-reducing medication.

It is important to note that for a small number of women we were unable to identify the barriers and facilitators to risk-reducing medication, indicating that there may be other barriers and facilitators that we did not elucidate.

Despite many lacking awareness and confidence, the majority of family physicians (75%) viewed initial discussion of risk-reducing medication as part of their role. Fewer (31%) felt that writing the first prescription was appropriate but 98% were happy to provide ongoing prescriptions. This is consistent with other studies (46) but is potentially a major hurdle, as optimal implementation of risk-reducing medication may require family physicians to prescribe the first dose.

Reducing breast cancer incidence requires a clear strategy that incorporates routine breast cancer risk assessment with implementation of evidence-based risk reduction strategies, including risk-reducing medication. We have identified a significant knowledge and resource gap for both women and clinicians. Application of a behavioral change model suggests that both an individual and a system-based approach, including interventions in education, training, incentivization, and environmental restructuring, could be instrumental in increasing uptake of risk-reducing medication.

L.A. Keogh reports grants from NHMRC during the conduct of the study. S.C. Jones reports grants from Cancer Australia and grants from National Breast Cancer Foundation during the conduct of the study. M.L. Friedlander reports grants, personal fees, and other from AstraZeneca, personal fees from MSD, Lilly, Takeda, and GSK, and grants and personal fees from Novartis outside the submitted work. R.L. Milne reports grants from NHMRC during the conduct of the study. K.-A. Phillips reports grants from Cancer Australia, the National Breast Cancer Foundation, National Health and Medical Research Council, National Institutes of Health, Cancer Councils, Queensland Cancer Fund, and Cancer Foundation Western Australia during the conduct of the study; in addition, Dr Phillips has a patent for System Process for Cancer Risk Estimation, Australian Innovation Patent No. 2012101273 issued. No disclosures were reported by the other authors.

C. Macdonald: Conceptualization, data curation, formal analysis, validation, investigation, methodology, writing–original draft, writing–review, and editing. C.M. Saunders: Conceptualization, supervision, investigation, visualization, writing–review, and editing. L.A. Keogh: Conceptualization, data curation, formal analysis, supervision, investigation, visualization, writing–review, and editing. M. Hunter: Data curation, software, formal analysis, investigation, and methodology. D. Mazza: Conceptualization, supervision, visualization, methodology, writing–review, and editing. S.-A. McLachlan: Conceptualization, supervision, writing–review, and editing. S.C. Jones: Conceptualization, supervision, writing–review, and editing. S. Nesci: Resources, data curation, software, funding acquisition, project administration, writing–review, and editing. M.L. Friedlander: Conceptualization, visualization, writing–review, and editing. J.L. Hopper: Conceptualization, validation, methodology, writing–review, and editing. J.D. Emery: Conceptualization, supervision, methodology, writing–review, and editing. M. Hickey: Conceptualization, visualization, writing–review, and editing. R.L. Milne: Conceptualization, resources, software, formal analysis, investigation, methodology, writing–review, and editing. K.-A. Phillips: Conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, validation, investigation, visualization, project administration, writing–review, and editing.

We thank Sandra Picken, Lucy Stanhope, Sarah O'Connor, Gerda Evans, Leslie Gilham, Heather Thorne, Eveline Niedermayr, Sharon Guo, the kConFab research nurses and the heads and staff of the Family Cancer Clinics. We thank the women, their families, and the clinicians that participated in this research. This research was supported by Cancer Australia and the National Breast Cancer Foundation (PdCCRS #1100868). kConFab and the kConFab Follow-Up Study have received additional funding support from Cancer Australia (809195), the Australian National Breast Cancer Foundation (IF 17), the Australian National Health and Medical Research Council (454508, 288704, and 145684), the National Institute of Health USA (1RO1CA159868), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. K.-A. Phillips is an Australian National Breast Cancer Foundation Fellow (PRAC17–004). The contents of this manuscript are solely the responsibility of the authors and do not necessarily reflect the views of Cancer Australia.

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