BRCA1/2 germline testing, risk management advice given by health professionals to women with pathogenic BRCA1/2 variants and uptake of such advice by patients.This nationwide study assessed the impact of nationally agreed cancer genetics guidelines on use of BRCA1/2 pathogenic variants at 12 familial cancer clinics between July 2008–July 2009 (i.e. before guideline release), July 2010–July 2011 and July 2012–July 2013 (both after guideline release) were audited to determine reason given for genetic testing. Separately, the clinic files of 599 female carriers without a personal history of breast/ovarian cancer who underwent BRCA1/2 predictive genetic testing and received their results pre- and post-guideline were audited to ascertain the risk management advice given by health professionals. Carriers included in this audit were invited to participate in a telephone interview to assess uptake of advice, and 329 agreed to participate.Clinic files of 883 women who had initial proband screens for p = 0.88). Rates of documentation of post-test risk management advice as per guidelines increased significantly from pre- to post-guideline for 6/9 risk management strategies. The strategies with the highest compliance amongst carriers or awareness post-release of guidelines were annual magnetic resonance imaging plus mammography in women 30–50 years (97%) and annual mammography in women > 50 years (92%). Of women aged over 40 years, 41% had a risk-reducing bilateral mastectomy. Amongst women aged > 40 years, 75% had a risk-reducing salpingo-oophorectomy. Amongst women who had not had a risk-reducing bilateral mastectomy, only 6% took risk-reducing medication. Fear of side-effects was cited as the main reasons for not taking these medicines by 73% of women.There were no significant changes in the percentages of tested patients meeting at least one published indication for genetic testing - 79, 77 and 78% of files met criteria before guideline, and two-, and four-years post-guideline, respectively (χ = 0.25, Guidelines did not change the percentages of tested patients meeting genetic testing criteria but improved documentation of risk management advice by health professionals. Effective approaches to enhance compliance with guidelines are needed to improve risk management and quality of care.The online version contains supplementary material available at 10.1186/s13053-021-00180-3. BRCA1/2 has evolved since the mid-1990s. Although testing has improved and costs have reduced, it is still important to offer genetic testing as a priority to families where it is most likely to be useful. The identification of a causative pathogenic variant allows for tailored management of the cancer-affected individual and for predictive genetic testing for others in the family. Initially, genetic testing was funded by state health departments, and individual family cancer clinics (FCCs) determined the criteria used locally to guide the offer of a BRCA1/2 genetic test to women affected by breast and/or ovarian cancer. Research generally guided the development of criteria to be used by FCCs for an offer of testing, whereby individuals with at least a 10% chance of having a BRCA1/2 pathogenic variant were offered testing. However, the Cancer Institute New South Wales convened a national expert group to develop consensus guidelines on criteria for consideration of BRCA1/2 genetic testing, so that access to such testing would be equitable across Australia. Guidelines were to be based on evidence and/or expert opinion in the absence of evidence. The resulting agreed guidelines were then published and made available on web-based national clinical point-of-care guidelines [Genetic testing in Australia for pathogenic variants in BRCA1/2 pathogenic variants [While rigorous controlled trials of cancer risk management strategies are few in the hereditary breast/ovarian cancer field, there is increasing evidence for the use of specific cancer risk management interventions, such as preventing ovarian cancer and reducing the risk of breast cancer associated with variants . IndividBRCA1/2 have a high lifetime risk of breast and ovarian cancer. For carriers of pathogenic variants in BRCA1, the average cumulative risks by age 80 years is 72%  for breast cancer and 44% (36–53%) for ovarian cancer, and the corresponding estimates for BRCA2 are 69% (61–77%) and 17% (11–25%) respectively [BRCA1/2 may consider risk-reducing bilateral mastectomy to reduce cancer incidence by up to 95% and breast cancer-specific mortality by 80% [(BRCA2) [BRCA1/2 pathogenic variant, may also consider use of selective oestrogen receptor modulators (e.g. tamoxifen) as a risk-reducing strategy. Studies have shown that the use of such agents can reduce the risk of developing oestrogen-receptor-positive breast cancer by up to 50% [BRCA1/2 variants recommend annual magnetic resonance imaging (MRI) in combination with mammography and/or ultrasound as a screening tool to maximise the sensitivity of breast cancer screening in this group [Female carriers of pathogenic variants in [BRCA2)  and redu and 17% –25% respp to 50% . Finally  and redis group –16.BRCA1/2 pathogenic variants.However, simply having guidelines agreed by national experts and published is not sufficient; in order to improve clinical outcomes the appropriate advice  must be provided to each woman and to her primary health professional. Clinical practice guidelines aim to facilitate decision-making processes in patient care and have been shown to be capable of supporting improvements in quality and consistency in healthcare . HoweverBRCA1/2 germline testing for women with breast and/or ovarian cancer. The study also assessed documented compliance by clinicians with respect to national risk management guidelines for unaffected female BRCA1/2 pathogenic variant carriers. Furthermore, the study surveyed patients to investigate their uptake of strategies from the national risk management guidelines. Specifically, the study aimed to assess the extent to which carriers adhered to recommended risk management guidelines. Finally, the patient surveys permitted exploratory questions about perceived barriers or reasons underlying any failure to undertake recommended risk management strategies.This current study addresses this gap in the literature by investigating two key areas. The first part of the study investigated the impact of the publication of Australian clinical practice guidelines on use of The design of the study was an uncontrolled before and after design. Such a design is considered appropriate for guideline evaluation, because randomised controlled trials are not feasible for practical and ethical reasons .BRCA1/2 variants. FCCs without a risk management service refer patients back to their non-genetics medical specialist or primary care physician for ongoing care, while those with an associated risk management service manage at least some of the patients themselves. Risk management advice at FCCs is provided by clinicians with medical qualifications  as well as genetic counsellors, who are not medically trained. For this study, participation occurred at 12 out 18 of public FCCs  following approval from the head of each of the FCCs, who was invited to participate via an invitation email that described the study.Australia has 18 public familial cancer clinics (FCCs); their functions vary in relation to coordinating and delivering care to carriers of pathogenic BRCA1/2 germline testing against eviQ cancer genetics guidelines amongst women who were tested and (ii) document risk management advice given to unaffected female BRCA1/2 pathogenic variant carriers. The criteria for eligibility for genetic testing and the risk management recommendations for carriers are presented in Tables Two file audits were undertaken at each FCC to (i) assess eligibility for BRCA1/2, the Queensland FCC did not participate, because they used a higher minimum positive predictive value to identify a BRCA1/2 pathogenic variant (20%) compared to other FCCs (10%) to determine eligibility for BRCA1/2 testing at the time of the study. For the audit on reasons for genetic testing, participating FCCs prepared a list of all women who had genetic testing during three time periods: July 2008–July 2009 (i.e. before guideline release), July-2010-July 2011 and July 2012–July 2013 (both after guideline release). Women who self-funded BRCA1/2 genetic testing were excluded, because genetic testing eligibility guidelines do not apply to this group. From these lists, up to 32 women per FCC and per assessment time period were randomly selected. Due to the roll out of the guidelines at slightly different times at different clinics, the three assessment time periods were separated by 12-months periods.For the file audit to ascertain women’s eligibility for genetic testing for A checklist was completed by the local ICCon co-ordinator to indicate the reason the woman relating to the file was offered genetic testing. An example checklist is provided in Supplementary File BRCA1/2 genes without breast/ovarian cancer who had undergone predictive testing and were identified as carriers during the three assessment time periods. We were unable to include enough carriers for the third time period for the guidelines on risk management, and hence the files from this period were not included in the analyses on risk management.As an initiative of the Inherited Cancer Connect (ICCon) Partnership, a national database has been established to house de-identified data on individuals found to carry a pathogenic variant in a known hereditary cancer susceptibility gene through all public Australian FCCs. Using ICCon data, study co-ordinators working in the participating FCCs prepared lists of all female carriers of pathogenic variants in BRCA1 were published: Version 1 (July 2011–June 2012) and Version 2 (July 2012–December 2013). The two versions did not differ on age-specific advice about the main risk management strategies of breast and ovarian cancer screening, surgical prevention and risk-reducing medication; however they were updated for lifestyle advice. Appropriate checklists corresponding to each version were used.Similar to the genetic testing eligibility audit, a checklist for each guideline was completed by the local ICCon co-ordinator to indicate whether the file related to each of the included carriers documented that the woman was informed about each risk management strategy listed in the guideline. An example checklist for the risk management file audit is provided in Supplementary File BRCA1/2 pathogenic variants included in the risk management advice file audit to participate in a telephone interview. Participants were given the option of opting out via mail, phone or fax if they preferred not to be contacted. Two weeks after the letters were sent out, the local ICCon co-ordinator called women who had not opted out to investigate their uptake of risk management strategies, using a checklist to record whether or not the carrier had implemented each of the risk management strategies. An example of an interview checklist is shown in Supplementary File An invitation letter was sent by heads of FCCs to those carriers of BRCA1 and BRCA2 pathogenic variant carriers were quite similar, the data on carriers of BRCA1 and BRCA2 pathogenic variants were combined for analyses. Chi square and Kruskal-Wallis tests were performed to compare the rates of compliance before and after the introduction of guidelines. Significance level was set at p < 0.05. Reasons for non-compliance, which were provided using open-ended response options, were extracted, categorised and then tallied.The checklists were completed electronically using the University of New South Wales survey provider and analysed by the central study co-ordinator using the statistical software SPSS  Version 25. For the files on guidelines for genetic testing use, a Manchester score  was calcBRCA1/2 genetic testing, and the overall k statistic was 0.84. A total of 883 files were audited for the genetic testing reason audit over the three time periods. For the 11 participating FCCs, the number of files ranged between 7 and 35 for the pre-guideline period, and between 12 and 35 and between 13 and 35 for the two-years and four-years post-guideline periods respectively.Interrater reliability coefficients (k statistics) for assessing individual guidelines were between 0.79–0.87 for reasons for BRCA1/2 testing against set criteria for testing. Before the release of the guidelines, 79% of the files met at least one of the criteria, while 21% of files did not meet any of the criteria. Two- and four-years post-guideline release, 77 and 78% of files met at least one genetic testing criterion respectively. The compliance to genetic testing guidelines was not significantly different between the three time periods .Table Table BRCA1/2 pathogenic variants and the overall k statistic was 0.92. A total of 599 files were audited, and of these, 316 (53%) and 283 (47%) related to carriers of pathogenic variants in BRCA1 and BRCA2 respectively. Of these 373 (62%) files were from the time period before the guidelines were published and 226 (38%) from the post-guideline time period. For the 12 participating FCCs, the number of files ranged between 12 and 58 for the pre-guideline period, and between 6 and 33 and between 4 and 53 for the two- and four-years post-guideline periods respectively.Interrater reliability coefficients (k statistics) for assessing documentation of individual guidelines in patient records were between 0.85–0.94 for risk management of carriers of Results of comparisons of clinicians’ recommendations documented in women’s files on risk management strategies pre- and post-release of guidelines are shown in Table Overall documentation of advice around items of risk management strategies following guideline release ranged from 29 to 98%. The highest rates of documentation post-release were for the following recommended strategies: risk-reducing salpingo-oophorectomy for ovarian cancer prevention (98%), risk-reducing bilateral mastectomy (92%), and breast cancer screening in 30- to 50-year-old women (88%). Low rates of documentation post-release were annual screening in women above 50 years of age (49%); however, 50 and 67% of pre- and post-guidelines files respectively stated that the patient was still young and that it would be discussed at an appropriate age. Additional analyses showed that amongst women aged > 50 years, only 30% were documented as being provided with advice on annual mammography . Also, the lowest rate of documentation was found for: “If pregnant - no MRI or mammography and consider ultrasound if pregnant” (29%). However, 62 and 67% of pre- and post-guidelines files respectively stated that management of screening during pregnancy was left to the specialist.2 = 13.96, p < 0.001), maintaining a reasonable weight  and breastfeeding . No significant changes were observed in documentation of advice on avoiding post-menopausal HRT after 50 years of age . Despite the increase of the documentation of lifestyle-related advice, it was below 50% for all lifestyle factors . The mean age of the women at the time of interview was 40 years old . Table Amongst women aged < 40 years, 26% had a risk-reducing bilateral mastectomy, amongst those aged 40–59 years 49%, and amongst those aged 60+ years 29%. The most common reasons cited for not having had a risk-reducing bilateral mastectomy were : young age (53%); family not completed yet (44%); pregnancy or breastfeeding (9%); or being happy to have regular screening (60%). (Note: more than one reason could be given).Twenty-three percent of women aged < 40 years, 71% of those aged 40–59 years, and 73% of women aged 60+ years, had a risk-reducing salpingo-oophorectomy. The most common reasons cited for not having risk-reducing salpingo-oophorectomy were young age (53%) and still completing family (44%).As we expected few of the women interviewed use risk-reducing medication, we pre-planned to ask all women participating in interviews who had not had risk-reducing bilateral mastectomy: “To what extent do you agree that each of the following influences your decision whether or not to use a medicine to reduce your risk of developing breast cancer?” Attitudes were assessed with Likert-type response options. Responses are shown in Table Seventy-seven percent women agreed ‘somewhat’ or ‘very much’ that the most common reasons affecting their decision to not take risk-reducing medication was fear of side-effects, and 57% ‘somewhat’ or ‘very much’ agreed that it was other women’s experiences with it.Eighty-one percent of patients responded that they exercised, 73% that they maintained a reasonable weight, 94% that they ate a healthy diet, 91% that they avoided smoking, and 97% that they limited their alcohol intake. Of the 56 women who reported having had children since receiving their genetic testing result, 96% reported breastfeeding.BRCA1/2 testing. The lack of significant changes may reflect the fact that guidelines were developed by consensus and reflected current accepted practice that was already in place when the clinical practice guidelines were codified. Furthermore, post-guideline reasons for testing were provided for all tests not meeting guideline-based testing criteria. These findings suggest that current guideline-based testing criteria are too narrow, and that in practice FCCs apply broader criteria when offering testing, taking into account family-specific and individual factors. If these are considered reasonable factors to guide testing, then consideration should be given to amending guidelines to ensure equity of access to testing across the country.We found no significant changes in relation to use of germline Regarding rates of documentation of risk management recommendations in files of carriers, rates increased significantly from pre- to post-guideline for 6/9 risk management strategies, and these six included the most clinically effective strategies, risk-reducing mastectomy and salpingo-oophorectomy. No statistically significant increases in documentation were observed for recommendation of: risk-reducing salpingo-oophorectomy for breast cancer prevention; screening from 5 years prior to earliest age affected if breast cancer has been diagnosed in this family < 35 years; and annual breast cancer screening in carriers from > 50 years. However, regarding the guidelines on screening from > 50 years, 50 and 67% of pre-and post-guideline files respectively stated the patient was young, and that it would be discussed at an appropriate age. Regarding screening during pregnancy, 62 and 67% of pre-and post-guideline files respectively stated that management of screening during pregnancy was left to the specialist.This study shows that the three risk management strategies with the highest rates of documentation of advice in files post-release of guidelines  are risk management strategies with a strong evidence base. These results show that FCC staff prioritise advice on strategies with proven efficacy. This study also found low rates of post-guideline documentation of annual breast cancer screening recommended for women aged > 50 years (49%); amongst women interviewed aged > 50 years, only 30% women had received advice on annual mammography. These low rates of documentation of advice may be because 92% of women aged > 50 years were already having regular breast screening based on their family history prior to testing. Further, it is possible that more carriers were provided with advice on annual breast screening for women > 50 years than was documented in their clinic files; however, without documentation, carriers and their doctors have no opportunity to refer to it for advice. Ensuring that women aged > 50 years receive a recommendation for annual breast screening consistently, along with improved documentation, may result in even higher percentages of carriers taking up annual breast screening. It is important to highlight that we have not stratified documentation rates with the age of carriers at the time of delivery of the advice. Clearly advice, and therefore documentation, may have been tailored to the specific individual learning their mutation status and certain risk management strategies omitted from the discussion if they were not age- or life-stage-appropriate.BRCA1/2 pathogenic variants, and/or that FCC staff are reluctant to leave direction for their risk management to non-genetics specialists leading them to provide specific risk management advice more readily compared to that for Lynch syndrome. The FCC clinicians may feel more confident in providing risk management advice to BRCA1/2 pathogenic variant carriers compared to those with variants in MMR genes; if so, this may be the result of a greater volume of research being available regarding the efficacy of risk management in BRCA1/2 pathogenic variant carriers and/or FCC staff being more experienced in providing advice to such carriers, given that most patients attending FCCs are from hereditary breast ovarian cancer families rather than families with Lynch syndrome [The significant increases in concordances pre- to post-guideline release for the majority of risk management strategies is in contrast to our findings on concordance with regard to guidelines on advice related to Lynch syndrome, where we found statistically significant increases in concordance for only two out of eight risk management strategies . It mighsyndrome .When comparing the rates of documented advice and uptake amongst carriers of risk management strategies, fortunately, it was found that the rate of uptake of annual mammography amongst women aged > 50 years (92%) and uptake of no MRI or mammography in pregnant women (78%) was much higher than the advice documented in the clinic file. This suggests that once again either the advice was not documented in the clinic file, or that women received additional recommendations from other health professionals. We also found that only 58% of women reported having been told that serum CA125 and/or transvaginal ultrasound is not recommended, and this could have resulted in some women having ovarian cancer screening in the false belief it was beneficial. Fortunately 75% of women > 40 years had risk-reducing salpingo-oophorectomy at the time of the survey; nonetheless there is still room to improve the delivery and documentation of this important piece of advice. We did not ask detailed questions why 25% of women > 40 years had not had the surgery. While some are likely to be in their 40s and not at the right life stage to contemplate menopause or have other co-morbidities that render surgery inappropriate, there is still an important number who are eligible for surgery; strategies need to be developed to engage this group in order for them to gain the most clinical benefit from their genetic diagnosis .We also found that only 6% of women who had not had a risk-reducing bilateral mastectomy were taking risk-reducing medication. This low rate of uptake of risk-reducing medications is consistent with literature showing that the actual reported uptake of tamoxifen by women at increased risk for breast cancer is low e.g. –26 HowevBRCA1/2. Inter-rater reliabilities of assessments were excellent. Limitations of the study are a relatively low participation rate of carriers in the interview study (52%); due to ethical stipulations we were not able to follow up non-responders more than once. However, similar participation rates have been reported by other studies using medical records [BRCA1/2, morbidity of risk-reducing surgery, and the effectiveness of cancer surveillance. The way carriers are counselled is likely to impact on whether they have made an informed decision. Future studies should assess information-giving and counselling behaviours during counselling sessions, for example by digitally recording consultations and subjecting recordings to a rigorous communication analysis [The study’s strengths and limitations should be noted. Strengths included the fact that almost all Australian FCCs participated, leading to low institutional bias and high representativeness and generalisability of the data, providing nationwide data on the impact of guidelines relating to carriers of pathogenic variants in  records , 29. Anoanalysis .Additional file 1.Additional file 2.Additional file 3.


The BRCA 1 and BRCA 2 genes are associated with an inherited susceptibility to breast cancer with a cumulative risk of 60% in BRCA 1 mutation carriers and of 30% in BRCA 2 mutation carriers. Several lifestyle factors could play a role in determining an individual’s risk of breast cancer. Obesity, changes in body size or unhealthy lifestyle habits such as smoking, alcohol consumption and physical inactivity have been evaluated as possible determinants of breast cancer risk. The aim of this study was to explore the current understanding of the role of harmful lifestyle and obesity or weight change in the development of breast cancer in female carriers of BRCA 1/2 mutations.Articles were identified from MEDLINE in October 2020 utilizing related keywords; they were then read and notes, study participants, measures, data analysis and results were used to write this review.Studies with very large case series have been carried out but only few of them have shown consistent results. Additional research would be beneficial to better determine the actual role and impact of such factors. Breast cancer (BC) is the most common female malignancy worldwide. Approximately 5–10% of breast cancer cases are hereditary and arise from autosomal dominant mutations in specific cancer genes, including the two breast cancer susceptibility genes BRCA 1 and BRCA 2. Women who carry these mutations have up to an 80% risk of developing breast cancer . IdentifGiven the high penetrance of BRCA 1 and BRCA 2 mutations, prevention and lifestyle changes have an extremely important risk-reducing role in women who have a higher risk of developing breast cancer.A broad review of the literature was carried out using MEDLINE (via PubMed) and sixteen articles published from 2002 to 2020, were selected from a total of one hundred. Search terms included keywords, combining the conditions , obesity, change in body weight and lifestyle . We included only original peer-reviewed articles on large prospective, retrospective and cohort studies that investigated obesity and unhealthy lifestyle habits as probable risk factors for the development of breast cancer. The selected articles concerned BRCA1 / 2 mutant women and investigated whether this status could increase the risk of breast cancer in relation to exposure to certain lifestyles. Studies that considered women without BRCA 1/2 mutations (in the case or control group), those with analyses that incorporated untested individuals or tested negative women, series with fewer than 100 patients enrolled, meta-analyses and reviews were excluded from this review  while BMI was inversely associated with breast cancer risk  [In a recent article of 2019, Qian F et al. investigated whether height or body mass index (BMI) could change the risk of developing breast cancer in 11,451 cases of breast cancer in BRCA 1/2 mutation carriers. These authors found that height was positively associated with breast cancer risk  thereafter . Weight gain later in life was not associated with increased risk . In a mu1Smoking, drinking alcoholic beverages , 25 and In a recent retrospective and prospective cohort study of 2020, Li H et al. investigated the association between smoking and alcohol consumption and the risk of developing breast cancer in 13,118 BRCA 1/2 mutation carriers and found that the only variable associated with the risk of BC for both carrier groups it was for mutated women who had smoked for at least 5 years before their first pregnancy compared to first-time mothers who had never smoked before. The results, found no correlation between BC cancer risk and alcohol intake in in both groups .In 2020, Kehm RD et al. carried out a prospective cohort study on 15,550 women who had a familial breast cancer risk and investigated the association between recreational physical activity and decreased risk in adult women. The authors tested interactions of physical activity with predicted absolute familial BC risk based on BRCA 1 and BRCA 2 mutation status and concluded that physical activity can reduce the risk of getting BC by about 20% even women with high penetrance due to their genetic family history or medical history .van Erkelens A et al. in a cohort study in 2017, investigated the correlation of unhealthy lifestyles  in 268,0 women with BRCa 1 and 2 mutation reporting that 38% of the participants had at least 2 high risk factors for BC, plus age the diagnosis of the mutation correlated with a decrease in physical activity  and a prevalence of overweight  .Dennis J et al. in 2010 conducted a case-control study of 1925 premenopausal women who carried a BRCA 1 or BRCA 2 mutation to investigate alcohol consumption and the risk of breast cancer, reporting an inversely proportional association between alcohol intake and increased risk of developing BC only in BRCA1-mutated women, while no association was found in BRCA2-mutated women  vs OR = 1.00; CI 0.71–1.41) .In 2004, Ghadirian P et al. studied the correlation between smoking and the risk of breast cancer in a large cohort of BRCA 1 and BRCA 2 mutation carriers . The autTwo other eligible studies by Ko KP et al. in 2018 and Ginsburg O et al. in 2009 investigated the association between smoking and increased breast cancer risk. The first was a cohort study of 7195 women that demonstrated an increased risk of breast and ovarian cancer in women smokers with a BRCA 1 or BRCA 2 mutation ,  and the 2In the general population, multiparity and breastfeeding are among the protective factors of the risk of developing breast cancer, while the use of oral contraceptives could represent a predisposing factor; the data in the literature on the use of contraceptives in mutated women are still discordant but a possible role of estrogens on carcinogenesis has its foundation , 36. TheIn 2018, Schrijver LH et al. investigated the association between the use of oral contraceptives and breast cancer risk in BRCA 1 and BRCA 2 mutation carriers in a retrospective and prospective cohort study of 9839 cases. They found no association between the use of oral contraceptives and BC risk in women with a BRCA 1 mutation  while for BRCA 2 mutation carriers, the authors highlighted an increased risk of developing breast cancer in mutated women taking oral contraceptives  and this risk was also related to the duration of treatment particularly in the period prior to the first full-term pregnancy .In a 2008 population-based study on 1469 women and 444 control subjects Lee E et al. investigated reproductive factors and oral contraceptive use in BRCA 1/2 mutations carriers and non-carriers and reported no association between oral contraceptive use and BC risk in women carrying the mutations .In 2002, in a matched case-control study on 1311 pairs of women with a known BRCA 1/2 mutation Narod SA et al. found an increased risk of breast cancer in women with a BRCA 1 mutation who first used oral contraceptives before age 30, or who used them for more than 5 years, while a similar risk did not appear in BRCA 2 mutation carriers . The sum3The presence of BRCA1 and 2 mutations may predispose to a higher risk of breast cancer in the percentage of 60 and 30% respectively. It is important to underline that not all mutated women will certainly develop cancer during their lifetime, but knowing the genetic or environmental risk factors that can increase the subjective predisposition to cancer is of fundamental importance. It has been proposed that several lifestyle factors such as smoking, alcohol consumption, poor nutrition or sedentariness may be potential modulators of BRCA penetrance, but the data reported in the literature are still conflicting and incomplete. The BRCA 1 gene and the BRCA 2 gene located on chromosome 17 and on chromosome 13, respectively (Fig. Numerous factors have been reported to modify breast cancer risk. Our review of the specific literature has highlighted that there are few consistent results across different studies and that additional research would be beneficial to better determine the actual role and impact of such factors.


Breast cancer prevention is a major challenge worldwide. During the last few years, efforts have been made to identify molecular breast tissue factors that could be linked to an increased risk of developing the disease in healthy women. In this concern, steroid hormones and their receptors are key players since they are deeply involved in the growth, development and lifetime changes of the mammary gland and play a crucial role in breast cancer development and progression. In particular, androgens, by binding their own receptor, seem to exert a dichotomous effect, as they reduce cell proliferation in estrogen receptor α positive (ERα+) breast cancers while promoting tumour growth in the ERα negative ones. Despite this intricate role in cancer, very little is known about the impact of androgen receptor (AR)-mediated signalling on normal breast tissue and its correlation to breast cancer risk factors. Through an accurate collection of experimental and epidemiological studies, this review aims to elucidate whether androgens might influence the susceptibility for breast cancer. Moreover, the possibility to exploit the AR as a useful marker to predict the disease will be also evaluated. Breast cancer is the most prevalent female malignancy and the leading cause of cancer death in women, surpassing lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases 11.7%) worldwide 1.7% worl.Among the molecular markers potentially linked to the risk of developing breast cancer in healthy women ,6, steroMost studies have highlighted the contribution of estrogens and progesterone in breast cancer risk and tumour development. The role of androgens in breast tumour growth, prognosis and treatment has only recently emerged, even though androgen treatment was historically used as an effective therapeutic option for breast cancer. Indeed, for the first half of the 20th century, therapies utilizing androgen receptor (AR) agonists, such as testosterone propionate and fluoxymesterone, were reserved for postmenopausal breast cancer patients, showing a disease regression rate of ~20–25%, which was only slightly less effective than the rate observed following estrogen-based therapy ,11,12,13AR expression and action differ among the various breast cancer subtypes. The AR shows a higher positivity in estrogen receptor alpha-positive (ERα+) luminal A tumours than in triple negative breast cancer (TNBC) ,15,16. MOn the other hand, the role of the AR in ERα negative (ERα-) breast cancer is controversial and its prognostic value remains uncertain ,28,29. ATherefore, the heterogeneity of androgen action within the different breast cancer subtypes has driven the chance to exploit specific AR signalling pathway(s) for successful therapeutic interventions in ongoing clinical trials, employing both AR agonists and antagonists for the treatment of different cohorts of breast cancer patients  41]..41].Despite this well-documented importance of AR signalling in breast cancer growth and progression, very little is known about the association of androgens, AR expression and breast cancer risk in healthy individuals. This review aims to elucidate whether AR activity might impact on breast cancer susceptibility by collecting evidences of AR-dependent signalling in normal breast epithelium and on its relationship with well-known breast cancer risk factors.Normal mammary epithelium arises from three specific subsets of cells, hierarchically classified in one population of basal and two populations of luminal mammary epithelial cells. The latter are identified as secretory or hormone-sensing cells and also named as L1 and L2, respectively. L1 secretory luminal mammary epithelial cells are mainly involved in milk production and are characterized by the lack of both ER and progesterone receptors (PR); L2 hormone-sensing mammary epithelial cells, instead, express ER and PR and have a crucial role in the endocrine stimulation of the gland ,43. IndeInterestingly, within the normal human breast tissue, AR has been found to be expressed in both basal and, to a greater extent, in hormone-sensing mammary epithelial cells ,43. ThisThus, the AR-dependent signalling operates in both basal and luminal mammary epithelial cells. Findings regarding its participation in the mammary gland developmental process are controversial.ex3ΔKO) female mice at the pubertal time, compared to wild-type females. The latter, instead, responded to DHT administration with a ~50% reduction in ductal extension [−/− mice after puberty, a reduced ductal branching was observed. This condition was partially restored during pregnancy, but the number of milk-producing alveoli remained smaller [Gao et al., observed a significant increase in ductal growth and extension and a higher number of terminal end buds,   in AR-knxtension . Oddly,  smaller .2)–testosterone (T) ratio is altered due to estrogen excess and/or androgen deficiency, gynecomastia can occur [In the human breast, androgens mainly exert anti-proliferative effects under physiological conditions. In males, when the estradiol , the higher the AR activation [The potential correlation between AR structure and breast cancer susceptibility has been investigated in a number of studies. Exon 1 of the tivation ,63,64. Ttivation ,66 and ctivation .These evidences suggested investigating if the CAG length could also impact on breast cancer risk. A potential increased risk was evidenced by Haiman et al., among Caucasian women with long CAG repeats only with a concomitant first-degree breast cancer family history . HoweverAs stated above, characterization of the hierarchical organization and function of mammary epithelial cells is crucial for a better comprehension of how breast cancer arises as well as for the identification of novel breast cancer risk biomarkers ,45. In tMore recently, the possibility of using the AR as a predictor marker of breast cancer risk was investigated in a nested case-control study on women with benign breast disease (BBD). In the analysed population (78 patients vs 276 controls), no associations were found between AR expression in normal human mammary tissue, evaluated by immunohistochemistry on BBD biopsies, and breast cancer risk. However, when AR expression was assessed in relation to ERα (47 patients vs 127 controls), high levels of AR were moderately associated with a lower risk of disease . UnfortuTherefore, even if the available findings  seem to Androgens have often been used for therapeutic purposes in women, mainly to treat hypoactive sexual desire disorder or menopausal symptoms ,79. Ther2 implant therapy [The effects of T exposure on breast cancer development have been recently investigated in a prospective 10 year cohort study enrolling 1267 pre- and postmenopausal women receiving implants of T to treat the symptoms of androgen deficiency or T implants in combination with the aromatase inhibitor anastrozole . Invasive breast cancer (IBC) was diagnosed in 11 women, while 3 patients developed ductal carcinoma in situ (DCIS). Interestingly, comparing the results with the age-matched Surveillance, Epidemiology, and End Results (SEER) Program, used for the assessment of breast cancer incidence rates, showed that the incidence of both IBC and DCIS was lower in the examined population  . Accordi therapy . However therapy .This protective effect of exogenous androgens is consistent with previous studies, which detected a lower proliferative index in mammary tissues from women undergoing estrogen–progestin hormone replacement therapy (HRT) in combination with T, compared to HRT alone , as wellNevertheless, these observations are in contrast with the findings that contraceptive progestins with androgenic activity, such as the T-related and widely used levonorgestrel, promote hyperproliferation of the breast epithelium with cytological changes, in a xenograft model obtained through intraductal injection of human mammary cells expressing hormone receptors . Though A good tool to investigate the potential correlation between exogenous sex steroid hormones and breast cancer susceptibility is provided by transgender patients since androgen therapy is crucial to achieve the gender switch through physical feature changes in trans men with female sex assigned at birth. According to androgens’ anti-proliferative properties on breast epithelial cells, T therapy reduces mammary gland volume, increases fibrous connective tissues and inhibits the incidence of breast cancer in transgender men ,89. HoweAnother recent retrospective cohort study investigated the consequence of hormone therapy in 3489 Netherland transgender (2260 trans women and 1229 trans men). Only four cases of IBC were diagnosed in trans men, who were associated with a high risk, compared to cisgender men, and with a lower risk, compared to cisgender women .Thus, the role of exogenous androgens in preventing or promoting breast cancer is still controversial. However, available data suggest that androgen administration might be likely to be associated with a reduced or, at least, unchanged risk of developing breast cancer.Androgen over-production may occur in para-physiological and pathological conditions  . In suchAccordingly, increased prepubertal androgen levels have been associated with earlier breast development .2, earlier breast development might be likely to be linked to estrogen production. Thus, these patients may also be considered at high risk of developing breast cancer [Houghton et al., recently reported that androstenedione, T and free-T (fT) levels were higher in girls with a first-degree breast cancer family history (BCFH) than in those without a BCFH, while dehydroepiandrosterone sulfate (DHEA-S) was increased only in girls with breast cancer-specific distress, presumably following adrenal gland hypersecretion due to the hypothalamic–pituitary–adrenal axis activation. Importantly, since DHEA-S is not only a natural precursor of androstenedione and T but also of Et cancer .2 proliferative stimulus on breast cells [Increased levels of androgens can also result from ovarian stromal hyperplasia. Therefore, a proposed therapeutic approach in postmenopausal women with excessive ovarian androgen production and at high risk of developing breast cancer consists of reducing high T blood levels by administrating gonadotropin-releasing hormone analogues, leading to a medically-induced oophorectomy: lowering T serum concentrations means losing substrate for estrogen synthesis and, in turn, depriving Est cells .The positive association between high endogenous androgens’ serum levels and breast cancer risk has been confirmed by several other studies, both in pre- ,99,100 aConclusively, being a source of estrogens, androgens’ hyperproduction seems to correlate to an increased risk of breast cancer. However, since most of the studies evaluated circulating T levels that are metabolized in estrogens  and the Several factors contribute to a woman being considered at high risk of developing breast cancer, including family history, high-risk predisposition genes, high mammographic density (MD) and Single Nucleotide Polymorphisms . MD has AR gene and resulting in a deficient AR activity, has been associated with an increase in breast cancer risk at an early age in patients carrying the BRCA-1 mutation [An important correlation also exists between germ-line mutations in breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2), which are associated with a 40–85% lifetime breast cancer risk , and AR mutation . Of notemutation .In the struggle to defeat breast cancer, prevention programs play an essential role, even long before disease onset: valuable breast cancer risk markers and prediction models, by improving individualized risk assessment, could be helpful, not only for the patients but also for their health providers, in making decisions about the right screening program and/or chemoprevention procedure to adopt.Endogenous sex hormones’ levels have been associated with increased breast cancer risk. Due to the pivotal role of estrogens in normal breast proliferation and the identification of increased ERα expression as a risk factor for breast cancer development, preventive therapy is aimed at reducing estrogen levels and/or antagonizing receptor activity.On the other hand, very few reports focus on the potential role of androgens and AR status as markers of breast cancer risk in healthy individuals, and this review was meant to cope with this aim.Nevertheless, given the complexity of AR action within the breast, no univocal conclusion could be drawn. Indeed, the available data on the role of androgens/AR in preventing or promoting breast cancer are still controversial. In fact, AR-dependent signalling has been reported to exert either beneficial or deleterious effects on breast tissue, even if, under physiological conditions, its activation seems to protect against breast cancer development, at least in part for its ability to counteract ERα action.These discrepancies are mostly due to the lack of normal breast sample availability and non-uniform cohorts of patients recruited for clinical studies , as well as due to the complexity of androgen intracrinology within the mammary gland.Therefore, future studies are needed to accurately discern the role of androgens/ARs in normal breast tissue, so as to unambiguously understand whether the receptor might become a useful and reliable biomarker in breast cancer preventive screening programs. As happened for ERα, this understanding will shed light on the possible exploitation of SARMS or antagonists as novel potential chemoprevention agents in women with a high risk of breast cancer.


Assessing the long-term risk of breast cancer after diagnosis of benign breast disease by mammography is of utmost importance to design personalised screening strategies. We analysed individual-level data from 778,306 women aged 50–69 years with at least one mammographic screening participation in any of ten breast cancer screening centers in Spain from 1996 to 2015, and followed-up until 2017. We used Poisson regression to compare the rates of incident breast cancer among women with and without benign breast disease. During a median follow-up of 7.6 years, 11,708 (1.5%) women had an incident of breast cancer and 17,827 (2.3%) had a benign breast disease. The risk of breast cancer was 1.77 times higher among women with benign breast disease than among those without (95% CI: 1.61 to 1.95). The relative risk increased to 1.99 among women followed for less than four years, and remained elevated for two decades, with relative risk 1.96 (95% CI: 1.32 to 2.92) for those followed from 12 to 20 years. Benign breast disease is a long-term risk factor for breast cancer. Women with benign breast disease could benefit from closer surveillance and personalized screening strategies. Benign breast disease is a major risk factor that doubles the risk of subsequent breast cancer ,2. Most The recent debate on personalized screening strategies and how to improve the effectiveness of breast cancer screening require reliable identification of women at risk of developing breast cancer. The debate has created a need for information on how the incidence of breast cancer after a benign breast disease varies with the characteristics of the patient, and over time. Different individualized risk prediction models for breast cancer use previous benign breast disease as a risk factor ,7. The lSeveral cohort studies analyzing the risk of breast cancer in women with benign breast disease have been conducted in recent years ,10,11. HTherefore, to provide further information on the long-term consequences of benign breast disease, we undertook a population-based study characterizing the risk of breast cancer after a benign breast disease among women participating at biennial screening mammography in Spain.Mammographic screening in Spain started in 1990 and achieved national coverage in 2006. It is population-based, follows the recommendations of the European Guidelines ,13,14, a® assessment categories are used to rate the probability of cancer [Screening mammograms are read by certified breast radiologists who interpret at least 1500 screening mammograms per year. The BI-RADSf cancer ,17. PrioData for the study were obtained from ten centers of the Breast Cancer Screening Program in Spain , Vallès Oriental (Granollers), Vallès Occidental Est (Parc Taulí), Hospital Clinic i Provincial de Barcelona, Hospital de la Santa Creu i Sant Pau de Barcelona, Barcelona- Àrea Metropolitana Sud). The centers prospectively register information on patient-related factors, screening mammography examinations, recall, further assessments and diagnoses performed in their defined catchment areas. The resulting dataset included information about 782,352 women aged 50–69 years screened at least once between January 1996 and December 2015, with follow-up until December 2017. To be included in the study, women needed at least one negative mammographic screening prior to the mammogram that diagnosed their cancer. Thus, we excluded 4046 women with a breast cancer diagnosed at first screen. This left 778,306 women for analyses.n = 654), we included the first benign breast disease occurrence. If women had more than one histological diagnosis at biopsy or they had bilateral benign disease, we selected the benign breast disease with the highest risk of breast cancer (proliferative disease > non-proliferative disease).All breast biopsies were examined and classified by hospital pathologists in each screening Centre. All biopsies with a non-malignant diagnosis were considered as benign breast disease. In order to perform subgroup analyses, benign breast diseases were classified into non-proliferative and proliferative disease, following the criteria stablished by Dupont and Page . NonprolAll invasive cancers and ductal carcinoma in situ were included as breast cancer cases. We included screen-detected cancers and interval cancers for analyses. Interval cancers were defined as breast cancers diagnosed in the interval between a non-malignant screening result and the next screening examination. Breast cancer cases are systematically identified using the screening center databases, hospital-based cancer registries, regional Minimum Data Set, and population-based cancer registries.For each woman in the study population we defined an index screening mammogram for start of follow-up. Follow-up for women without a benign breast disease started at the date of first mammographic screening participation. Follow-up for women with a benign breast disease started at date of diagnosis of their first benign breast disease. Since we identified all interval cancers, follow-up for all study participants ended at the date of breast cancer diagnosis, or at last screening participation plus two years of follow-up, whichever came first.Observed rates of breast cancer were calculated for women with and without benign breast disease as the number of breast cancer cases divided by the number of women in each group. We calculated observed rates for year at index mammogram , age at index mammogram , and time since index mammogram . In addition, we calculated crude rate ratios of observed breast cancer rates. We used Poisson regression to estimate the rate ratios of breast cancer in women with and without benign breast disease adjusted by year at index mammogram, age at index mammogram, and time since index mammogram. We tested for interactions between the presence of benign breast disease and the adjusting factors .We plotted cumulative incidence rates of breast cancer by the presence or absence of a previous benign breast disease as the number of incident breast cancer cases divided by the number of women at risk over the observed 20-year time horizon. Survival curves over the 20 years study period were stratified by age at index mammogram and year at index mammogram, to test the effect of these two potential confounding variables. Confidence intervals were calculated using exact Poisson distribution . We perfn = 442) had a breast cancer diagnosis whereas for those without benign breast disease the proportion was 1.5% .By December 2015, a total of 778,306 women had been screened at least once in any of the ten participating screening centers and were included in the study. The median follow-up was 7.6 years. Fifty-nine per cent were aged below 55 years at index mammogram, 19.3% aged 55–59, 15.6% aged 60–64, and 5.4% aged 65–69 years . By DeceThe overall rates of breast cancer by year, age, and time since index mammogram stratified by the presence or absence of benign breast disease are shown in Within age strata, the cumulative incidence rate of breast cancer for women with benign breast disease also diverged with increasing time . By 10 yp-trend < 0.05) (p-trend < 0.05), with the highest risk observed in women aged 65–69 years . Interestingly, the adjusted risk comparing women with and without benign breast disease remained steady stable across time since index mammogram, with RR of 1.99 (95% CI: 1.73 to 2.29) in those with four years or less, and RR of 1.96 (95% CI: 1.32 to 2.92) in those with time 12 to 20 years, with no trend across time periods (p-trend = 0.97).Overall, women with benign breast disease had an increased risk of breast cancer , compared with women without benign breast disease. The more recent the year at index mammogram, the higher the adjusted rate ratio of breast cancer for women with benign breast disease compared with women without benign breast disease, with the highest risk observed among those with index mammogram in 2011 to 2015  with a significant trend across calendar periods ( < 0.05) . Similarp-trend < 0.05)  . RegardiSensitivity analyses including invasive breast cancer only were consistent with the estimates in the full model, with modest variations in the risk estimates .Consistent with previous studies ,20,21,22Of particular importance is the evidence that the increased risk of breast cancer persists for over 20 years after the diagnosis of benign breast disease. Since benign breast disease and its associated biopsies are frequent at breast cancer screening ,23, beniDifferent from most studies ,20,21,22The finding that women with a previous benign breast disease had an increased risk of breast cancer that remained steady stable over 20 years suggests that benign breast lesions might be risk markers rather than precursors of subsequent breast cancer. The sustained long-term increased risk strengthens the idea of an increased proliferative nature of glandular breast tissue in some women that are more likely to develop abnormalities, which may later present as benign breast disease or malignant tumors. In a previous study we found that between 40% and 45% of breast cancer cases were contralateral to the prior benign breast lesion, which has also been shown in other studies ,2. PreviIt should be mentioned that pathologic and diagnostic techniques have evolved during the study period. Fine needle aspiration cytology was more common at the start-up of screening programs, while today, core-needle biopsy is the preferred procedure to identify abnormalities for pathologic analyses due to improvements in techniques and accuracy. This has influenced the number of benign breast diseases diagnosed over time, but also the proportion of proliferative lesions among them, which helps to explain the increased risk associated with benign breast disease in later years (RR = 3.11 in 2011–2015 vs. RR = 1.95 in 2006–2010).The relationship between benign breast disease and the increased risk of breast cancer is well documented in the clinical context ,10,18,21Most individualized risk prediction models for breast cancer include previous benign breast disease as a risk factor, such as the Breast Cancer Surveillance Consortium, and Tyrer-Cuzick models ,25,26,27Data for the study were collected from a consolidated population-based screening program that has been operating for more than 20 years, with an average participation of 67% of invited women, and a re-attendance rate of 91.2%, which is a major strength of this study . This stThis study has several limitations. In our analyses, we have made efforts to control for confounding factors. However, additional information on variables such as body mass index, hormone therapy use, and menopausal status was lacking because the screening centers did not collect this information. Also, we lacked information on socioeconomic and demographic factors that are known to also be associated with the risk of breast cancer. Adjusting for these and other risk factors would have been desirable and could have refined our estimates. Nevertheless, we expect that these variables have a modest effect on the association between a benign breast disease and the risk of breast cancer, and the bias introduced by this lack of adjustment would be small. Another limitation is that information on the benign breast disease subtype was missing on 32.9% of benign breast disease diagnoses, limiting our ability to draw conclusions regarding benign breast disease subtypes. The lack of an exact histology of benign breast disease diagnosed at screening is common due to fine needle aspiration biopsies. Also, the number of incident breast cancer cases after diagnosis of a non-proliferative and proliferative benign breast disease was relatively small, again limiting our ability to identify robust associations for sub-group analyses. Despite these weaknesses, the overall quality of the data in our study is high and we were able to perform robust analyses on the impact of benign breast disease. Lastly, during the study period, there was a transition from screen-film mammography to full-field digital mammography. Full-field digital mammography was introduced in 2004 and gradually became widespread. The transition from film to digital mammography might have had an effect on recall rates, and consequently on benign breast disease and cancer detection rates. However, previous studies have shown that these outcomes were not affected by the introduction of digital mammography ,29.We have provided evidence of the long-term nature of the risk of breast cancer after diagnosis of benign breast disease by screening mammography. The increase in risk was sustained for at least 20 years after diagnosis, and affected women of all ages as well as to all years at index mammogram. Our results also show that women who had a proliferative benign disease had a higher long-term risk than those with non-proliferative disease. Women with a diagnosis of benign breast disease could benefit from closer surveillance and more personalized screening strategies.


Breast cancer has become a real public health problem in Cameroon, particularly in rural areas due to late diagnosis, resulting partly from the absence of national screening programs. This work is aimed at assessing breast cancer awareness in the North Region of Cameroon. Participants were selected in six health centers surrounding the rural area of Garoua, North Region, Cameroon, and administered a questionnaire aimed at assessing their awareness about breast cancer risk factors and screening. Out of the 475 women  interviewed, 45.5% attended at least secondary school; 91.3% were aware of the disease with the main sources of information from those around them (64.8%), media (46.5%), and health professionals in health facilities (42.7%). 23.3% had misconceptions and myth-based ideas on the origin of the disease. Ignorance was the main reason preventing the performance of breast self-examination, and the high cost prevents individuals from going for mammography. The highest awareness rate was observed in employed women with higher level of education. Our study highlights the need to raise awareness among the populations in North Region, Cameroon, about the risk factors and clinical signs of breast cancer and the importance of screening practice for early diagnosis of breast cancer. Breast cancer is a major public health challenge worldwide, as it is the leading cause of cancer-related deaths among women, particularly in developing countries , 2. AbouBreast cancer generally has a favorable prognosis in developed countries, partly due to detection at early and asymptomatic stages, thanks to the establishment of screening practices and therapeutic advances , 15. TooIn Cameroonian cities, few women attend national screening programs when available, partly due to the lack of awareness about breast cancer and screening methods , 20. In The present study was aimed at assessing breast cancer awareness in the North Region of Cameroon, to contribute to the identification of the factors underlying the increased incidence and late diagnosis of breast cancer observed recently in Cameroon.Our study participants were 475 women randomly selected among the residents of the rural areas around the city of Garoua, North Region, Cameroon. Signed informed consent was obtained from each participant at recruitment. Before analysis, data collected were anonymized to protect the privacy of participants. All the procedures of the study were approved by the North Regional Delegation of the Ministry of Health.From August to December 2019, a cross-sectional and descriptive study was conducted in six health facilities of the North Region of Cameroon. Participants were recruited in the health facilities using simple random sampling. Women previously diagnosed with breast cancer and women undergoing unilateral or bilateral mastectomy were not included.After being presented individually with the study rationale and detailed information on procedures, each participant willing to join the study had to sign an informed consent form. Afterwards, she was administered a questionnaire which was aimed at assessing awareness about breast cancer and screening practice and its risk factors and collecting some sociodemographic data. Then, physical breast examination was performed.Demographic characteristics like age, education, and occupationPhysiological factors with established risk potential in breast cancer context such as age (to assess whether age was advanced), age at first menarche (to determine early onset), and the presence and onset of menopause (late vs. early)Personal history and family-related factors such as parity (to distinguish nulliparous from multiparous), age at first pregnancy (to determine whether it occurred late), history of breastfeeding, history of exposure to ionizing radiation, history of hormonal treatment, history of OCP use, family history of breast cancer, and history of alcohol and tobacco consumptionAwareness about breast cancer, associated risk factors, and recommended screening methods was assessed using a questionnaire collecting the following information:the awareness about the recommended screening methods for breast cancer early detection (breast self-examination and mammography)knowledge about commonly reported breast cancer symptoms like nipple discharge, change in skin appearance, change in breast size, the presence of breast masses, and inflamed axillary lymph nodesIn addition, the questionnaire also included questions aimed at assessingWhen a nodule was identified as well as its characteristics  during physical breast examination performed in the gynecology service of the health facility, fine-needle aspiration (FNA) was performed with the consent of the participant, using recommended standard clinical procedures. Each sample collected was mounted on a slide, processed for May Grünwald-Giemsa staining and analyzed using bright-field microscopy (magnifications 4x to 40x) at the Laboratory of Anatomo-Cytopathology of the University Hospital Center of Yaoundé. In case of cancer, Fisher's simplification of Black's nuclear grading scheme was used to determine the grade.Alternatively, when nipple discharge occurred during the examination, characteristics were determined and recorded as well . Moreover, palpation of the armpits was also performed to assess eventual axillary lymph node inflammation. The following characteristics of inflamed axillary lymph nodes were determined and recorded: number, size, and mobility relative to surrounding tissue.χ2 test was used to compare proportions, and correlations were determined between education, occupation, and breast cancer awareness and also between education, occupation, and breast cancer screening awareness and its practice. Statistical significance was set at p < 0.05.Data analysis was performed using XLStat Version 2019. The 475 women were involved in this study, of which 37 (7.7%) were health professionals. p < 0.0001) for most of the risk factors and symptoms (p < 0.0001 vs. other groups) (Participants had to choose among 10 choices on risk factors of breast cancer (including two erroneous concepts) and 5 choices on clinical signs/symptoms and the screening tools. symptoms . Health symptoms . Partici groups) .p < 0.0001 vs. other groups)  practice among the study participants are presented in  groups) .i) a lack of awareness about breast cancer screening methods and fear of discovering that they are sick, (ii) lack of time for screening, (iii) that should it be breast cancer it could only result from witchcraft and thus they would not need hospitals to deal with it, and (iv) that they do not have any complaint and no history of breast cancer in their family, so there is no need for any exam. Other astonishing reasons proposed to reject screening included the following: (i) “Breast cancer results from keeping coins in bra and I never do so”; (ii) “This lump in my breast has always been there and never had a problem or any complaint with it, so there is no need for a test”; (iii) “I do not want to know whether my lump is or is not cancer, because it could result in stress, and I will be rejected by my husband if my breast is removed”; (iv) “No one in my family ever had breast cancer and I never had any complaint, that is why I will not perform any screening”; and (v) “I do not know how to perform BSE, nobody ever taught me.”Participants mainly claimed , breast pain (34.0%), and skin ulceration on the breast (23.5%), as reported in previous studies %, breast. Indeed,p < 0.0001). However, misconceptions on the origin of the disease were also found here. Of the 48 women with university degrees, 15 (31.2%) had no idea about disease risk factors, and 14 (29.1%) and 13 (27.0%), respectively, mentioned traditional breast massage and extended wearing of tight bra as risk factors. These women revealed that their erroneous information came from their entourage, and they did not see the importance of verifying it before participating in the study. This further suggests a lack of public awareness about breast cancer and underlines the need for education about early diagnosis and better prognosis of the disease. Media could help in disseminating the right information, as they are a source of information for 46.5% of the participants. Health facilities could help as well, as 28.7% of the participants reported that the health education sessions in local languages held during prenatal consultations and immunization days in Cameroonian healthcare centers are their major source of medical information. Studies in comparable contexts showed that presentations in local languages by qualified health professionals attract a large audience [In the present study, highly educated and employed women identified breast cancer risk factors more accurately than uneducated and unemployed women , breast self-examination 22.60%), and mammography as screening tools. However, a low level of practice of mammography screening 4.11%) and BSE (6.16%) was also observed here, also due to high cost of mammography, together with a lack of mastery of the breast self-examination (BSE) technique and the fear of actually discovering a disease sign, considered a harbinger of mastectomy and death , 19, 29.1% and BS.60%, andSurprisingly, 79 (16.63%) participants refused clinical examination in this study, as they feared discovering breast cancer or to show their breasts to the medical professionals performing the examinations due to religious reasons (to preserve their intimacy). This also justified the refusal of several participants to be sampled for cytopathological examination of the nodules, as they argued that they needed the consent of their husbands. Breast palpation coupled with fine-needle aspiration, a cost-effective cytopathological analytic technique efficient in this context , revealeOur study highlights the need to raise awareness among the public about the risk factors and clinical signs of breast cancer and the importance of screening practice by both mammography and regular practice of BSE and CBE in the diagnosis of breast cancer at early stage and management of the disease. The Cameroonian health authorities should organize mammography screening campaigns for an early detection of asymptomatic cases of breast cancer, considering the positive implications for treatment outcome.


To explore the experiences of women with breast cancer taking part in an early physiotherapy-led exercise intervention compared with the experiences of those receiving usual care. To understand physiotherapists’ experience of delivering the trial intervention. To explore acceptability of the intervention and issues related to the implementation of the Prevention Of Shoulder Problems (PROSPER) programme from participant and physiotherapist perspective.Qualitative semistructured interviews with thematic analysis.UK National Health Service.Twenty participants at high risk of shoulder problems after breast cancer surgery recruited to the UK PROSPER trial (10 each from the intervention arm and control arm), and 11 physiotherapists who delivered the intervention. Trial participants were sampled using convenience sampling. Physiotherapists were purposively sampled from high and low recruiting sites.Participants described that the PROSPER exercise intervention helped them feel confident in what their body could do and helped them regain a sense of control in the context of cancer treatment, which was largely disempowering. Control arm participants expressed less of a sense of control over their well-being. Physiotherapists found the exercise intervention enjoyable to deliver and felt it was valuable to their patients. The extra time allocated for appointments during intervention delivery made physiotherapists feel they were providing optimal care, being the ‘perfect physio’. Lessons were learnt about the implementation of a complex exercise intervention for women with breast cancer, and the issues raised will inform the development of a future implementation strategy.A physiotherapist-delivered early supported exercise intervention with integrated behavioural strategies helped women at risk of shoulder problems following breast cancer treatment to feel more confident in their ability to mobilise their arm post-surgery. A physiotherapist-delivered early supported exercise intervention with integrated behavioural strategies may address the sense of powerlessness that many women experience during breast cancer treatment.Trial registration number ISRCTN35358984. Interviewing multiple groups  in this study enabled us to triangulate the data and explore experiences from multiple perspectives.We note that the participants we interviewed were a particularly motivated group, and it is possible we did not capture some of the challenges which other, less motivated, women may have experienced.We obtained consent to be approached for interview prior to randomisation, independent of treatment allocation, in an attempt to minimise bias. We tried to minimise the risk of social desirability bias by asking neutral questions and explaining there were no right or wrong answers.We used a convenience sampling approach, which is a potential weakness of this study as it may have resulted in a lack of diversity among participants.Our sample was overwhelmingly white, with only one of the participants identifying as another ethnic identity. Findings may not reflect the experiences of black, Asian and other minority ethnic groups.Treatment to the chest and axilla for breast cancer can result in upper body problems, such as reduced range of movement in the shoulder, muscle weakness, pain, lymphoedema and functional limitations.Loss of a sense of control, loss of self-identity, and alienation from their bodies during and after treatment are often reported by individuals with cancer.The UK Prevention Of Shoulder Problems (PROSPER) trial evaluated the clinical and cost-effectiveness of an early supported home-based physiotherapist-led exercise intervention in women with newly diagnosed breast cancer at higher risk of developing shoulder problems after treatment.The aims of the qualitative study were:To understand the acceptability of the exercise intervention to participants.To explore how the exercise intervention or control affected their experiences of recovery after cancer treatment.To investigate the experiences of physiotherapists delivering the exercise intervention.To explore participants’ and physiotherapists’ perspectives on issues related to the implementation of the PROSPER programme to inform future plans for implementation.The study was underpinned by critical realism, assuming that an underlying reality is experienced and given meaning by individuals.On recruitment to the trial, we offered all trial participants the option to take part in an interview at a later date see . We recoAfter conducting and analysing seven interviews with intervention participants, we decided to interview control arm participants, to compare their experiences. We used our database of those who had consented prerandomisation to select a sample comparable with the intervention sample in terms of time since randomisation, so that women were at similar stages of postoperative treatment and could reflect back over their experiences of recovery.We informed all physiotherapists delivering the intervention about the interview study. We then sampled physiotherapists from low and high recruiting trial sites to allow exploration of different perspectives on intervention delivery. SR approached therapists via email or telephone.We developed flexible topic guides with women with breast cancer, based on the aims of the study and relevant literature. One-off interviews were conducted by SR either at the participant’s home, by telephone  or in a private room at their place of work (physiotherapists). Physiotherapists who worked together were interviewed in pairs. The physiotherapists who volunteered for the interviews and were interviewed in pairs worked closely together. Interviewing them in pairs allowed physiotherapists to share and reflect on their experiences and aided recall where they had only treated a small number of participants, for example. It is possible that interviewing them in pairs could have affected their responses, but participants were remarkably candid about the challenges they experienced, thus we were not concerned that this was happening. Only the researcher and interviewees were present. All interviews were audio-recorded. We took study materials  into the interview to aid recall and discussion. Informed consent was gained before the interview began.Interviews were transcribed verbatim, checked for accuracy and anonymity by SR, and then uploaded to QSR NVivo Pro V.11.Interviews were conducted sensitively by a female researcher experienced in interviewing people with cancer (SR).We recruited 392 women (196 per arm) to the PROSPER clinical trial from 17 breast cancer centres in England. Overall, 67% (n=264/392) of trial participants provided signed consent to be contacted for an interview. In total, we attempted to contact 53 women regarding an interview. Of these, 11 were not contactable, 17 agreed initially for an interview but could not be reached again and 5 declined. Ten participants from the intervention arm and 10 from the control arm were interviewed from 11 of the 17 study sites see . There wInterviews were carried out with 11/44 (25%) physiotherapists  from six study sites. Ten were interviewed in pairs and one individually. The physiotherapists had treated between 1 and 16 trial participants (median 5) and were based at hospitals that did not routinely provide postoperative physiotherapy after breast cancer surgery. They were experienced in the management of musculoskeletal conditions but did not currently work in breast cancer or oncology units. Some physiotherapists had experience of treating people with breast cancer presenting with problems such as restricted shoulder movement preventing the start of radiotherapy. One physiotherapist had past experience working on a cancer inpatient ward.We identified three themes from the data: ‘healing’; ‘being the perfect therapist’ and ‘delivering physiotherapy to women with breast cancer’. The themes and subthemes are illustrated by participant group in This theme refers to trial participants’ and physiotherapists’ comments about how the exercise intervention shaped the experience of healing for the women with breast cancer.In the acute period after surgery, participants from both the intervention and control groups reported feeling afraid to move their upper body. This is known as kinesiophobia.It’s quite tender…you don’t feel like you ought to be doing it…you feel like it’s too soon…I was aching so much that I just thought ‘I just can’t do this’. —Qualitative Respondent (QR24) Because you don’t know whether it’s good or not, do you know what I mean, you don’t know if you’re doing well or not or if this is where you would be, you know, or you should be and it was quite nice because you got ‘oh no you’re doing really well’ or ‘oh yeah that will be tight’ and it was that… it was quite nice to have the feedback. —QR12 Participants allocated to the intervention arm subsequently felt reassured by physiotherapists that they were capable and able to move. They felt reassured that bodily sensations, such as stiffness, were normal and not something to worry about. Physiotherapists felt that they were able to increase participants’ confidence in moving their bodies, and that this lifted participants’ confidence more broadly.The, er, physiotherapist…was able to tell you whether you were doing things right or wrong or how things were going within your body. —QR09 Interviewer: What do you think they get out of coming to see you?PT02 (Physiotherapist): I think confidence. Confidence to actually move…confidence to look after themselves, that they can do things.Some described this as giving participants ‘permission’ to move, which was necessary to prevent movement restrictions in the upper body.This theme refers to physical improvements felt by participants in the intervention arm. This included how far they could stretch and how strong they were. Improvements were measurable and tangible, and participants highlighted the central role of the physiotherapist in creating this sense of progress.You saw results and sometimes with your cancer…you don’t see results until the end ’til they say ‘You’re all clear’ you are just going through awful, awful, awful praying and hoping…But it is a really positive thing to think ‘Oh something is getting better’. —QR12 You could kind of measure it yourself and assess it yourself because you knew how far you could get your arm up…You could feel when, when things started to get a bit better. —QR08 Where intervention participants spoke about the improvement they felt in the months following their surgery, control arm participants also spoke about improvement, but for them this remained an ongoing process even more than 12 months on.When I’m washing myself and, and if I touch myself I’m tender but I suppose that will go. —QR17 I have still got a seroma on my chest which is a bit of a nuisance which is, um, sort of swelling of fluid isn’t it. Um, it’s less than it was and I think it’s gradually going ’cause it was enormous at the very beginning but it’s getting less. —QR16 Over time, intervention participants progressed from gentle stretching to more advanced stretching and strengthening exercises as they improved. Graduating to harder exercises gave them a sense of achievement.When we would do the exercises and when we would move the kind of categories in the folder that was given, that made me feel good and made me want to kind of continue. —QR13 Progression was fulfilling and rewarding, particularly in the context of cancer treatment where a sense that they were improving or getting better was lacking. To be able to measurably perceive progress in strength and movement helped to restore a sense of bodily autonomy for the women who felt disempowered by cancer treatment. During this profoundly difficult time of undergoing cancer treatment, feeling improvement and graduating to harder exercises helped them to feel that they were getting better, at least in some way.During breast cancer treatment, women passively receive treatment.In collaboration with their physiotherapist, participants receiving the exercise intervention could choose which exercises they performed from a menu, selecting exercises they felt most confident and comfortable doing. The physiotherapists felt that joint decision-making was a patient-centred approach which added to trial participants’ sense of ownership and control of their exercises. Physiotherapists and participants both noted that this gave participants an opportunity to be proactive, taking control of one aspect of their recovery. This sense of responsibility and ownership motivated them to exercise.I think it was more than the exercise. I think it was because you were doing something, because so much of um cancer care is being done to you…It was just quite nice to have something proactive for you to do rather than just turn up and have the drugs. —QR12 I think when we were sort of promoting why we think the exercises were useful I talked about self-determination this is something that you can do for yourself and your care…particularly the way it was designed that enabled the patients to say well we could do this exercise or we could do that one. —PT10This was a key difference to the control arm interviewees. Most control arm participants spoke about accepting postoperative problems or just waiting for them to improve over time, apart from a few highly motivated individuals who described inventing their own exercises.Lifting up now and I can feel the stretching down that left-hand side, but, um, you know I don’t know, I suppose it’s had trauma. —QR15 The tightness on my chest does limit movement sometimes and it’s sort of more of a discomfort than a pain and just a blessed nuisance really but everyone I’ve seen says it’s normal that they take a while and it’s nothing they can do so it will just go when it’s ready I suppose and I kind of live with it. —QR17 Wanting to be a ‘good patient’ and doing as one was told motivated control group participants to follow the exercises on the Breast Cancer Care leaflet.Well I’d like to think I was a good patient, I started my exercises the day after I came out of hospital. —QR26 Just the fact that the hospital gave them you and, you know, they know what they're talking about. You do it because you've been told to. —QR23 This is in contrast to the sense of self-determination, control and progress described by participants receiving the intervention.Some participants continued to draw on knowledge gained from the intervention to alleviate ongoing problems with tightness and stiffness, and appeared to feel quite confident in managing this in the future.Now I’m just doing the massage for lymphoedema and exercises only if I feel the problem…For example if, if I feel the problem to reach the shelf I’m taking [the] band and I might warm it up just do the exercises with the elastic band exactly for this movement. —QR10 In a couple of months or so, I would like to kind of start using weights so that I can strengthen my arms…It’s kind of like building up the strength that I was building towards whilst I was doing the [PROSPER] exercises before. —QR13 They felt assured that continuing with such activities would help them, and that they would know what to do or where to seek help if required.This theme describes the physiotherapists’ perspectives on the trial intervention compared with their usual practice and how it enabled them to deliver an optimal service.It almost like it made you be the perfect physio and the perfect way you should treat patients but you don’t always have time to do that. —PT03Agreed goals [and] agreed exercises actually that should be what we’re doing anyway that shouldn’t be anything radically different but sometimes because of time pressures you don’t…If you work more collaboratively with patients there are massive benefits to it and I think it just reinforced that for me. —PT10This was supported by participant responses, where they described the relationship they built with their physiotherapist.For me, you know, having the same… the same desired outcome as the physiotherapist and [wife] you know, kind of, being all, all, all wanting the same thing. And it kind of felt if I did those things then I would eventually achieve it. —QR08 She’s brilliant, she’s so lovely and fantastic hugger that’s what I found if somebody you meet is happy to give you a hug when you are in this kind of situation it… it just makes everything so much easier… you [physiotherapists] not only do you do your jobs but when you’re dealing with people like me you are counsellors as well. —QR12 Physiotherapists felt that having longer appointment times and an emphasis on shared goals and shared decisions, both of which encouraged exercise adherence, represented an ideal way of working. Many of the therapists remarked that they were pleased to be able to offer this service to people with breast cancer because of their previous experience of treating women struggling with chronic immobility, pain and psychological issues in the longer term as a result of shoulder problems following breast cancer surgery.When you pick up those patients [later] they come with a lot of emotional baggage and sort of their belief systems and it may have been years since they used their shoulder normally and then you know again if you’ve got body dysmorphic issues and they’ve been carrying that around for two years that’s a lot more challenging to support. —PT06We get people coming in about two years later and they’ve never touched their scar, they never saw a physio, they’re stiff, their scar’s horrible, they’ve got awful myofascial trigger points and tightness…They still think two years down the line they’re going to hurt themselves if they over stretch so if you get them in at the early stage then it’s just better…I had a lady who had a mastectomy it was three years later she never went back to work, she never went back to any exercise, she never touched her scar, her mental wellbeing was like absolutely awful when I first started seeing her because she just didn’t even know that she could have her life back. —PT01Physiotherapists connected this to the broader organisation of the NHS, and the need allocate resources to preventive care.I think we work too much reactive in the NHS don’t we and I think a direction to move in is work in prevention rather than cure. —PT02This theme reports views on delivering a new physiotherapist-led intervention for individuals with breast cancer.Participants and physiotherapists suggested that adjuvant treatment, such as chemotherapy, interfered with the participants’ ability to maintain the exercise programme. After stopping the exercises when they felt unwell, it was physically more difficult to start doing the exercises again. Physiotherapists reflected that intervening at this point may have helped encourage and motivate participants to continue.On day 17 after chemotherapy it has been a struggle…the last three weeks with the first lot of chemo this…[doing the exercises has] been a lot harder than I ever anticipated. —QR11 A patient would come in for their first appointment and probably just post-surgery and most of them were quite positive had quite a lot of goals… they’d start their chemotherapy and then it was a whole different ball game because it was just kind of managing their fatigue and we struggled to get people back in for appointments. —PT02The physiotherapists noted that participants needed emotional support, and that it was difficult to provide this in a curtained cubicle in an open-plan space, where they potentially felt more vulnerable.We’re working in curtained cubicles a lot of the time and I felt that didn’t set the tone, I think if you’re asking someone to take their bra off. —PT10Two therapists felt that physiotherapists should be women as they would better understand the meaning of losing a breast and more able to engage in the emotional and physical work of treating women with breast cancer.They would probably connect better with a female and I was surprised how much women wanted to talk to me about their connection with their breasts so for a lot of them they felt like that was their femininity or that was um a connection to their womanhood and so I think most guys couldn’t relate to how that feels so I could get where they were coming from. —PT08This issue was not mentioned by the trial participants we interviewed.Physiotherapists typically provide emotional support to their patients, however, some therapists highlighted particular challenges in relation to this group due to the context of cancer treatment, for example, people with cancer were fearful of dying from breast cancer. This was in contrast to their usual caseload which often involved caring for people with chronic musculoskeletal conditions.I am a person who cries quite easily so I was like ‘Ok I need to keep things under control myself because I am the professional’… If I was to do it longer term I would need some better kind of guidance and help to deal with that…sometimes I felt a little bit lost. —PT08We were lucky because we had each other but there were times where it was upsetting to hear…If we were permanent members of staff in oncology you would be given some…de-briefing or kind of decompression but we were never offered that… both of us have had very close relatives die because of cancer…nobody considered that at all. —PT06The physiotherapists felt they would need emotional support if they worked routinely with people with breast cancer.Delivering the intervention was time-consuming for physiotherapists.I would say giving them the choice of exercise is time consuming which you wouldn’t have in real life, you wouldn’t have the time. —PT09Trial appointments were longer than usual and there were doubts about how this could be practically implemented as part of routine NHS clinical care given current time restrictions on appointments. The physiotherapists felt confident in identifying and treating physical shoulder problems, but often expressed a need for training about breast cancer, its treatments and cancer-specific complications. Cording, lymphoedema and seroma were unfamiliar postoperative complications to some physiotherapists until they took part in the trial.We are MSK [musculoskeletal] physios and we know what a tight shoulder is and we know how to get it moving, so actually the assessment and the exercises wasn’t so much of a worry, but patients occasionally asked me a question that maybe I couldn’t answer…the background behind the cancer, a bit more about the actual surgical techniques they did and why and a little bit more about the reasoning of why lymphedema and cording does actually develop and what it means, I might have benefitted from more training from that aspect. —PT03Being able to advise people a bit more around like scar massage or kind of…any of the manual treatments that we could’ve done and when is right and wrong to use them [was difficult]. —PT02Physiotherapists felt disconnected from the surgical or oncology team treating the person with breast cancer which was challenging.There’s not necessarily the integration with like the nurses or the lymphedema team, we are quite a separate team from them so I think it does need to be a multi-disciplinary approach and because we’re not involved with them it makes it a little bit difficult [to know] whether we should or shouldn’t be doing those interventions. —PT03I sometimes found it difficult to ask about things like chemo, radiotherapy and repeat surgeries because I almost felt like it was something that I should know… that’s what I’d want as a healthcare professional I want them to know what’s going on I shouldn’t have to tell you when I am having my chemo or this is happening. —PT05Better integration with the oncology team would have given them greater understanding of the specific individual’s treatment schedule as they sometimes felt uncertain about whether the interventions were appropriate at a particular stage of cancer treatment.This qualitative study embedded within a large multicentre clinical trial makes a unique contribution to the literature. Our study illustrates that an individual supported exercise intervention is perceived as acceptable and beneficial by both women with breast cancer and physiotherapists. Comparing the intervention and control arm enabled us to demonstrate that the intervention helped participants feel empowered and regain a sense of control, whereas participants in the control arm spoke of passively accepting the upper limb limitations they experienced. Previous studies have explored perceptions of exercise in the context of an exercise intervention,Uncertainty has been identified as a feature of the experience of cancer.Being diagnosed with a serious illness such as cancer can cause an individual to lose trust and confidence in their bodily knowledge and of what their bodies are capable of doing.The physiotherapists enjoyed seeing positive improvements in the participants and felt passionate about delivering what they viewed as high-quality care to individuals with breast cancer (subtheme of ‘being the perfect therapist’). Physiotherapists felt satisfaction in being able to take preventive action against problems arising in the future for these women. Intervention arm participants also appreciated the supportive nature of the intervention, sharing decisions and working together towards the same goal. Other authors have called for a more proactive model of healthcare provision for this patient group and identified the need to improve physiotherapists’ confidence in supporting those with breast cancer.The theme ‘Delivering physiotherapy to women with breast cancer’ highlighted considerations for the implementation of an exercise intervention for patients with breast cancer. The intervention should be delivered in a private walled room, ideally with a specifically trained  physiotherapist who is part of the multidisciplinary oncology team caring for the person. The most important ingredient of the intervention was contact with the physiotherapists, suggesting resources should be focused on training and supporting physiotherapists to provide this care. Some physiotherapists reported feeling upset when treating patients because of the woman’s distress or their own experiences of cancer. This suggests that healthcare professionals caring for oncology patients should be given the opportunity of debriefing and emotional support. This is an important consideration when designing future interventions for this group.In the PROSPER trial, participants underwent a 1-hour assessment and then subsequent 30-minute follow-up appointments. Routine UK physiotherapy outpatient appointments are often 40 min (assessment) and 20 min (follow-up). Physiotherapists worked with participants to select the exercises. This may be challenging to deliver in a resource-stretched NHS context. However, longer appointments with physiotherapists, creating shared goals and making shared decisions about exercises were viewed as the most important ingredients in the successful delivery of the intervention. This was brought out in all our themes. Other studies have highlighted how autonomy of choice over exercises may increase motivation and adherence.Acting more proactively by providing good access to physiotherapy treatment early after, or alongside, breast cancer treatment could help to reduce the number of people with cancer (or a history of cancer) presenting with musculoskeletal complications.This study has highlighted how a physiotherapist-led home exercise programme, with built-in progression and shared decision-making, helped women undergoing breast cancer treatment gain a restored sense of control over their well-being and empowered them during a highly disempowering experience.