In addition to the affected person, diagnosis and treatment of breast cancer also severely affects her husband. Therefore, it is worth paying attention to the needs of husbands of women with breast cancer. Therefore, the aim of the present study was to explain the experiences of spouses of women with breast cancer. The present study was a qualitative study with conventional content analysis approach. Purposive sampling was carried out by selecting 6 spouses of women with breast cancer. Data were collected through semi-structured interview. The recorded interviews were transcribed verbatim. Content analysis was used to reduce and name the data, obtain analytical codes, and finally recognize the theme. Data analysis resulted in the extraction of 4 categories of couples’ mental challenges, multifaceted romantic meditation, multifaceted traumas caused by the disease, dual energies (inductions) of relatives, and 12 subcategories. Scarifying your life to save your wife’s life”” as an extract from the experience of spouses of women with breast cancer. Knowing and understanding this point by clinical staffs and policy makers can provide pave the way for planning to provide comprehensive support to these men.In spite of suffering from all the challenges and traumas, husbands of women with breast cancer have not left their wives alone and have done their best to improve their lives; so, we can raise ““ Husbands make up 30-40% of informal caregivers in chronic diseases . Breast cancer also has direct effects on the husbands of these patients . Because breast cancer is not only a female breast disease, but also a disease involving both couples . Making a good decision is an basic and important aspect in different situations . As women experience cancer, their husbands often become fragile, they consider cancer a factor threatening their sexual partner’s life and fear that they will not be able to support and provide proper care for their wives . Basically, evidence indicate high levels of psychological distress experienced by family caregivers, especially spouses of cancer patients ; in other words, complication of cancer and its treatment, in addition to the patient, negatively affect the quality of life of their spouses who act as informal caregivers and provide the highest level of support for married women . Basically, breast cancer-related needs of husbands of women with this disease are worthy of attention because if they are not helped, the disease and its subsequent pressure imposed on husbands can have detrimental consequences on the quality of couples’ relationship  in particular when these patients, in addition to psychological problems and disorders, also have problems with marital satisfaction and experience fragile relationship with their spouses . Because the disease targets one of the most important sexual organs of women and is directly related to the sexual identity of women, and this can lead to impaired sexual and marital relationships ; while these women expect mental support from their husbands . Considering that the spouses of these patients can play a special role as a source of support for them , on the one hand, and that successful management of patients and their family caregivers requires a thorough understanding of the experiences of those involved ; on the other hand, the aim of the present study was to explain the experiences of spouses of women with breast cancer using content analysis method. It is hoped that this study can provide the treatment team with a guide for implementing healthcare strategies by providing a clear picture of human experiences.The experiences of 6 spouses of women with breast cancer were evaluated in this qualitative content analysis study using a conventional approach. Participants were selected through purposive sampling. Data collection was carried out by the researcher by referring to the chemistry clinic of the hospital and the participants’ home after coordinating with them and obtaining their permission. First, the aim of the research was explained to them, and then the sampling was continued until data saturation. The criterion for achieving data saturation included the lack of achieving new concepts and codes in subsequent interviews.Tell us about your experiences after knowing about your spouse having breast cancer? How has your life changed since your spouse developed breast cancer?” During the interview, the researcher helped participants state their experiences without directing their conversations. Probing questions were also used if necessary. Face to face Interviews were conducted using audio recorder(Samsung) in a quiet environment and each interview lasted between 45-60 minutes in one or two sessions depending on the condition and patience of the participants. All interviews were analyzed by the recorded researcher, typed verbatim, reviewed, coded, and analyzed immediately. Two of interviews repeated by researchers. There was no dropout of participants and all of them participated. In fact, data analysis was performed simultaneously and continuously with data collection. Maxqda version 12 used for managing the data. Data were analyzed using conventional content analysis approach in a way that each interview was first read carefully for obtaining an initial grasp, important statements were underlined, and recorded as codes . The participants’ own words and implicating codes (researcher’s perceptions of the statements) were used for initial coding. Then, codes that were conceptually similar to each other were modified and subdivided into categories and subcategories to clarify meaning. The data analysis process was performed according to the steps of Graneheim and Lundman . In order to meet credibility, the coded interviews were given to the participants to confirm that they match with their experiences, and corrections were made in some cases. In order to meet the trustworthiness criterion, the codes and concepts obtained were consulted with and investigated by the experts and colleagues of the research project. Moreover, several colleagues were asked to decode some parts of the transcript of the interviews and then review the degree of agreement for coding. To confirm the transferability of the findings, attempts were made to select participants with different demographic characteristics and different experiences and the researcher assessed all aspects of behavior, events, and living experiences. The confirmability of findings was met by the detail-rich descriptions of all stages of the research, while the details of the research were carefully documented to allow the evaluation of external observers. The following ethical consideration were also taken into account: obtaining an introduction letter, obtaining informed consent from the participants for recording interviews, confidentiality of information, and allowing them to withdraw from the study.The data collection method included semi-structured in-depth interviews using open-ended questions, including, “The individual characteristics of the participants are presented in Couples’ mental challengesThe experiences of spouses of women with breast cancer show that women and their spouses have experienced numerous mental challenges following the disease.Wife’s mental challengesAccording to the experiences of the spouses of women with breast cancer, these women were shocked after being informed about the diagnosis, were mentally disturbed, fearful of chemotherapy, feeling depressed, indifferent towards themselves, crying, and brooding in a way that preferred solitude, isolation, and staying at home. They also felt alienation with their spouse and showed some sort of emotional withdrawal with him so that they avoided verbal communication with him and felt that they could no longer be a women of married life. As one of the participants said about his wife’s isolation:“My wife has been senseless since she become ill and stays in a corner, she is lethargic due to the medications she is taking, she does not even talk to me and children.” (P. 4)Husband’s mental challengesAccording to the experiences of the spouses of women with breast cancer, after being informed about their wife disease, these men were shocked and denied it, were psychologically disturbed, were upset with the changes in their spouse’s appearance, felt depressed, and got bored of messy situation in their life, had permanent mental conflicts due to problems caused by their spouse’s disease, feared the spread of the disease and the possible death of their spouse, had lower tolerance threshold, and became aggressive. In this regard, one participant reported his shock after being informed about his wife’s disease:“It was shocked when the doctor said that my wife had breast cancer. It was hard to believe and I said oh, my God what was this? (P. 2)Multifaceted romantic meditationThe experiences of the spouses of women with breast cancer showed that these men were meditating on their wives in mental, therapeutic, sexual, and spiritual aspects because they loved their wives very much.Romantic mental meditationAccording to the experiences of the spouses of women with breast cancer, these men had made every effort to maintain the morale of their spouse, didn’t leave her alone, didn’t show sensitivity to the facial changes caused by the disease, gave no sign of disease problems, and behaved normally so that their spouses would not be embarrassed by these changes, consoled their wife, and said that they still loved her and were not thinking of remarriage. To avoid pity, they have restricted relationship with relatives or hid the disease. They were trying to help the patient get rid of mental obsession and remove them from isolation by telling jokes. In this regard, one of the participants stated about his attempt to maintain his wife’s morale:“I stopped mixing with my coworkers and neighbors because of my wife’s disease because I don’t want them to ruin my wife’s morale with their words.” (P. 1)Therapeutic-romantic meditationAccording to the experiences of the spouses of women with breast cancer, these men did their best for the treatment of their spouses to the extent they accompanied her during treatment, paid for medical care costs, and took care of her after chemotherapy. In this regard, one of the participants stated about his effort to cover the cost of his spouse’s treatment:“Even though I’m a worker, but I swear to God that I did not fail to treat my wife, I even borrowed(money), but paid for her medications. If I spend money much higher for my wife, it is still low.” (P. 5)Sexual-romantic meditationAccording to the experiences of the spouses of women with breast cancer, to observe their wives’ conditions, these men had reduced their sexual intercourse with their spouse considering their spouse’s reduced sexual desire and pain during the intercourse. In this regard, one of the participants described their sexual intercourse as follows:“Because of the chemotherapy drugs, my wife doesn’t want to have sex, so I showed my consideration to her conditions and I don’t ask for sex so much.” (P. 3)Spiritual-romantic meditationAccording to the experiences of the spouses of women with breast cancer, these men sought to mediating their spouse by turning to spirituality through relying on God, vowing, appealing to the Ahlul-Bayt, and increasing their spiritual tendencies. As one of the participants said in this regard:“When I found out that my wife was having cancer, I told her it must have been the God’ will and we started treating her with trust in God.” (P. 2)Multifaceted traumas of the diseaseThe experiences of spouses of women with breast cancer showed that these men were traumatized in different respects by their spouse’s disease.Trauma to role playingAccording to the experiences of spouses of women with breast cancer, these men have had problems with playing their role in the workplace due to their caregiving role, such as absenteeism or use of unpaid leave due to lack of paid leave and fatigue. In addition to taking care of the patient and assuming their job duties, they also had to endure the double burden of household chores to help their spouse with their household chores since they face with their spouse’s disability. As one of the participants stated about unwanted absences from work due to his spouse’s disease:“While I was involved with my wife’s disease, I was frequently absent from work. My job task could remain unfinished.” (P. 4)Financial damageAccording to the experiences of the spouses of women with breast cancer, these men had financial difficulties in paying for medical care costs so that they experienced imbalances in income and costs and sometimes had to discontinue chemotherapy due to their inability to afford the costs. As one of the participants described her inability to pay for his spouse’s treatment costs as follows:“The doctor told recommended chemotherapy for my wife, where do I get money to pay one million seven hundred thousand tomans for chemotherapy? They told me to have six chemotherapy sessions for my wife but I don’t have the money for one session, let alone pay for 6sessions”. (P. 6)Traumas to married lifeAccording to the experiences of the spouses of women with breast cancer, these men had experienced numerous traumas to their married lives, including convulsions, cold and shortness of breath, disruption of the normal routine, and disintegration of the married life. As one of the participants said about the feeling of disintegration of their married life after their spouse got cancer:“After this disease, it seems as if our lives were disintegrated, we were no longer living as before, and we were only thinking about the treatment of my wife.” (P. 3)Traumas to childrenAccording to the experiences of the spouses of women with breast cancer, these men had experienced damage to their children’s body following the disease, including crying, grief, fear, shock, worry, and educational failure. As one of the participants described children cried due to their mother’s disease:“My spouse’s hair and eyebrows fell out during chemotherapy. My kids started crying when they saw their mother in this condition and told her what we would do without you if you died? If you die we would have no mom.” (P. 5)The dual energies (inductions) of relatives The experiences of spouses of women with breast cancer showed that these men are positively and negatively influenced by two types of energy (inductions) of the relatives.Positive energy (inductions) of relativesAccording to the experiences of the spouses of women with breast cancer, these men felt positive energy through empathy, financial support, and psychological support from relatives. If one of the participants explained family financial support as follows:“Our family has been very supportive of us, even though they live in the village and have no income, they still sell their sheep, which were all they have and gave us the money to spend on treatment.” (P. 3)Negative energy (inductions) of relatives According to the experiences of the spouses of women with breast cancer, some of relatives bothered these men by inducing the futility of treatment, incorrect (disabilities) restrictions, and feeling guilty, showing pity, and sympathy for the patient, and encouraging the men to remarry.“Since my wife has had breast cancer, my family has put mw under pressure several times to leave my wife and marry another woman.” (P. 4)Couples’ mental challengesIn the present study, husbands of women with breast cancer pointed to the mental challenges of their wives. Joulaeeet al., (2012) study, women with breast cancer reported experiences of living with cancer as losing important things, lack of self-confidence, living with fear, psychological dysregulation, and feeling the need to supported in the face of the negative aspects of living with cancer. However, Khansari et al., (2016) concluded in their study that although most breast cancer patients had feelings such as anger and sadness at the time of diagnosis, but they get along with the disease and its complications over time. They have got along with this issue and none of them regarded this change as a negative experience. This result is somewhat different from the result obtained in the present study and such difference may be due to the fact that Khansari et al., (2016)’s study focused on the psychological experiences of women with breast cancer and the present study identifies the psychological experiences of these patients indirectly from their husbands’ comments.In the present study, husbands of women with breast cancer pointed to a number of mental challenges. Duggleby et al., (2012) and Lopez et al., (2018) also referred in their studies to the exposure to psychological distress as experiences of husbands with breast cancer. Alacacioglu et al., (2014) concluded that sexual partners of cancer patients are affected by psycho-social and psycho-sexual effects of cancer more greatly than cancer patients. Also Bigatti et al., (2011) showed in a study that spouses of cancer patients had a high depression score.Multifaceted romantic meditationExperiences of women with breast cancer in relation to their spouses,” Sanchooli et al., (2017) showed that all of them had no similar experiences. Some women had unpleasant experiences, such as rejection and helplessness, and felt that they were oppressed by their husbands, were unwilling to continue their married life, and had somehow felt being imposed. However, some of them had pleasant experiences and were satisfied with their spouse’s spiritual companionship, spiritual meditation, sexual meditation, and cooperation during their treatment. Such discrepancy may be somewhat attributed to the study population.The experiences of the spouses of women with breast cancer showed that these men were meditating on their wives through their spiritual, therapeutic, sexual, and spiritual aspects considering their great love for their spouses. The results of a qualitative study by Lin et al., (2013) also showed that husbands of women with breast cancer, despite facing great suffering, strived to live a better life with their wives, to fulfill their responsibilities, and to maintain the love between themselves and their spouse. The results of the Youssef et al., (2012) and Mentford et al., (2016) studies also showed that husbands of women with breast cancer had a supportive role for their wives. With regard to the romantic spiritual meditation, husbands of women with breast cancer supported them by focusing on their women’s feelings and providing appropriate relevant care . Duggleby et al., (2012) also found that husbands of women with breast cancer mentally supported their wives. With regard to therapeutic romantic meditation, husbands of breast cancer women participated throughout their women’s healing process . With regard to the romantic-sexual meditation and spiritual-romantic meditation, mental challenges were also one of the themes obtained in a qualitative study carried out by Youssef et al., (2012) who examined experiences of husbands with breast cancer, because these women induction they were no longer attractive to their husbands and had negative inductions in this regard. Another theme was psychological defense, pointing out that these prevent mental problems by using spiritual affairs. However, in a study titled “Multifaceted traumas of the diseaseThe experiences of the spouses of women with breast cancer showed that these men were affected by their spouse’s disease in various aspects, including role playing, financial, married life, and children. To confirm the trauma to role playing, Montford et al., (2016) showed in a study that some experiences of spouses of women with breast cancer included their altered roles and participation in household chores. Husbands of women with breast cancer also managed all household chores throughout the treatment period . Alacacioglu et al., (2014) also writes that spouses of cancer patients face numerous problems, including work-related and lifestyle distress, and poor quality of life. They are required to support their spouses in daily activities and to assume greater responsibility for household chores and children. To confirm the financial trauma, Lopez et al., (2018) showed in their review study that they posed economic problems as experiences of husbands of women with breast cancer. To confirm trauma to married life, the results of Khademi and Sajadi, (2009) ’s study also showed that patients with breast cancer and those involved in the disease experienced a disturbance in their daily activities. To confirm the trauma to children, Mazzotti et al., (2012) also concluded that cancer is a real threat to the stability of the maternal role since it reduces their ability to care for their children. Möller et al., (2014) also concluded that, their children experience more emotional and behavioral problems in response to this diagnosis due to their mother’s disease. Kim et al., (2012) also concluded that one of the concerns of mothers with breast cancer is the permanent challenges their caregiving role because they have to pay attention to themselves due to the disease, but such attentions act as an interfering factor in relation to their children. To confirm this finding, Vaziri et al., (2014) writes that breast cancer diagnosis and treatment necessitates new family roles, as maternal focus is on treatment, and the disease interferes with maternal role and performance, relationship with children, and children performance.The dual energies (inductions) of relatives The experiences of spouses of women with breast cancer showed that these men are positively and negatively influenced by two types of energy (inductions) of the relatives. To confirm the positive energy (induction) of the relatives, Esmaeili et al., (2012) referred to support from family and relatives as one of the categories of data extracted. LeSeure and Chongkham-ang, (2015) also writes that family caregivers play an important role in supporting the patients and such care is a full-time job for them. To conform the negative energy (inductions) of relatives, the results of Sanchooli et al., (2017)’s study also showed that some of these women received negative feedback from their spouse’s family in the form of stimulating their spouses for separation and despair and consequently they had experienced a sense of helplessness. Probably one of the reasons for negative energy inductions from relatives is their lack of awareness or inability to adapt to existing conditions and solve existing problems. Consistent with this finding, Sajjadian et al., concluded in their study that sufficient attention must be paid to the patient care to provide better quality care to patients. The greatest need of caregivers seems to the lack of specialized information on breast cancer and provision of care to themselves and the patient . Micharoen et al., (2013) also write that family caregivers are vulnerable and at-risk population ignored by healthcare providers and have not received the necessary attention because caregivers primarily focus on patients.Scarifying your life to save your wife’s life” as the extract from the experience of spouses of women with breast cancer. Knowing and understanding this point by clinical staffs and policy makers can provide the basis for planning to provide comprehensive support to these men.In conclusion, husbands of women with breast cancer despite all the challenges and traumas, they did not leave their wives alone with their disease and had done their best to help their wife recover. Therefore, we can pose “


The purpose of this study is to evaluate the predictive value of the amount of fibroglandular tissue (FGT) and background parenchymal enhancement (BPE), measured at baseline on breast MRI, for breast cancer development and risk of false-positive findings in women at increased risk for breast cancer.Negative baseline MRI scans of 1533 women participating in a screening program for women at increased risk for breast cancer between January 1, 2003, and January 1, 2014, were selected. Automated tools based on deep learning were used to obtain quantitative measures of FGT and BPE. Logistic regression using forward selection was used to assess relationships between FGT, BPE, cancer detection, false-positive recall, and false-positive biopsy.p = 0.050, and OR 1.475, p = 0.003) and to more frequent false-positive biopsies at baseline , but were not predictive for false-positive findings in subsequent screening rounds.Sixty cancers were detected in follow-up. FGT was only associated to short-term cancer risk; BPE was not associated with cancer risk. High FGT and BPE did lead to more false-positive recalls at baseline  contains supplementary material, which is available to authorized users. BRCA mutation carriers) [Women at increased risk of breast cancer (≥ 20–25% lifetime risk) are eligible for intensified screening programs, including a yearly breast magnetic resonance imaging (MRI) study. Depending on the underlying risk factors, MRIs may be performed on an annual basis from the age of 25 (in arriers) , 2. Womearriers) , 4. HoweBRCA mutation carriers [Mammographic breast density (BD), for example, correlates to breast cancer risk in the general female population and in carriers , 6. Conscarriers –10.The increased use of breast MRI allows for evaluation of additional risk factors to improve current risk prediction tools. Recent publications indicate that the amount of fibroglandular tissue (FGT) and/or background parenchymal enhancement (BPE) measured on breast MRI may be useful to predict breast cancer risk in women undergoing breast MRI –13, althWhile in breast MRI all normal FGT enhances after contrast injection, the strength and speed of enhancement is dependent on variations in hormone levels, as determined by menstrual cycle phase, menopausal status, tamoxifen therapy, and hormone replacement therapy –17. StudA further problem is that visual rating of BPE on a four-point scale , as used in studies so far, suffers from high interrater variability . This liThe purpose of this study is to study whether FGT and BPE, as computed on a cancer-free baseline MRI scan using an automated tool, are predictors of future breast cancer in a breast MRI screening program. Furthermore, we evaluate whether FGT and BPE predict false-positive findings.This retrospective cohort study was approved by our local institutional review board, and the requirement for informed consent was waived.BRCA mutation carriers, the screening regimen starts with breast MRI only at age 25. Mammography is added from age 30. Others start screening with both modalities at age 35 or 40, depending on the age at which relatives developed breast cancer. The first MRI scan performed for screening is hereafter referred to as “baseline” MRI.The breast cancer screening program for women with a lifetime risk of ≥ 20–25% at our institution consists of annual breast MRI and mammography , 19. In BRCA mutation was present and whether and when a risk-reducing salpingo-oophorectomy (RRSO) was performed. Women in whom a cancer was detected at baseline MRI or within 6 months thereafter, women with a prior history of breast cancer, and women in whom automated assessment of BPE failed were excluded. We did not exclude women who had a false-positive finding in the first round of screening.The local database was searched to identify all patients who underwent breast MRI screening between January 1, 2003, and January 1, 2014. The case selection process is presented in Fig. Normal or benign screening examinations were confirmed by at least one year of clinical follow-up and regarded as true negative when no cancer was detected before the subsequent screening examination. When no biopsy was indicated at short-term follow-up, at least one year of clinical follow-up was required to confirm benignity. Biopsied lesions were identified by a cross-computer search with our pathology records. We subsequently analyzed if the biopsy was performed based on screening findings or for other reasons .MRI protocols varied over time . DynamicAutomatic tools were used to objectively calculate percentages of FGT and BPE on breast MRI volumes. Breast and FGT were segmented on native T1-weighted pre-contrast acquisitions using a deep-learning-based method as described and validated in . The fraWomen who developed cancer were identified by linkage of our data to the Netherlands Comprehensive Cancer Organisation. False-positive MRI examinations were defined as examinations that led to recall in women in whom no breast cancer was detected. False-positive recalls (FPR) include all women who were recalled (with or without performance of biopsy). False-positive biopsies (FPB) only include women for whom the recall led to biopsy. We separated FPR and FPB in first rounds from those that occurred in subsequent screening rounds.To investigate the influence of time between the baseline scan and cancer development, we performed a subgroup analysis in patients who developed breast cancer within 2 years after the baseline MRI scan.Z test for single proportions. Continuous data were compared with the Student’s t test or Pearson correlation coefficient (r) when normally distributed; otherwise, Mann-Whitney U tests were used. Bootstrapping (N = 1000) was used to calculate 95% CI. To increase statistical power, FGT and BPE were dichotomized into two categories based on the optimal categories in ROC analysis (0–50th percentile and 50–100th percentile). A binary logistic regression model was constructed to find independent predictors for breast cancer or false positives. Separate and combined models were performed for FGT and BPE. Inclusion of variables in the model was based on existing knowledge of risk factors for breast cancer and/or false positives (covariates: age and BRCA status). Non-linear effects were evaluated using Box-Tidwell tests and when needed transformations were performed. The value of predictors was assessed by using forward feature selection . Interactions between predictors were evaluated in the final models by including interaction terms along with the main-effect terms. The final model was bootstrapped (N = 1000). Shrinkage using the heuristic method was applied to account for over-optimism [p ≤ 0.05 was considered significant. All statistics were performed in SPSS .Incomplete data was assumed to be missing at random and was excluded. Descriptive statistics were prepared with the use of contingency-table analyses for categorical data and Fisher’s exact tests. The 95% confidence intervals (95% CI) for proportions were estimated using the optimism . Odds raBRCA mutation carriers (Supplementary Table BRCA mutation carriers and 44 years for others). In 60 (3.9%) women, cancer was identified after a negative baseline scan. Forty-five (75%) cancers were screen-detected cancers, six (10%) were interval cancers, and nine (15%) were detected in prophylactic mastectomies. Forty-three (71.7%) cancers were invasive and 17 (28.3%) were ductal carcinoma in situ (DCIS) only. The median time between the negative baseline scan and cancer detection was 3 years . Of the 573 BRCA mutation carriers, 103 (18%) women had a RRSO prior to the first screening round, while 227 underwent RRSO after the first screening round.The final analysis evaluated baseline breast MRI scans of 1533 women, including 573 (37.4%) Three hundred thirty-seven 22.0%) women had a false-positive recall. Seventy-three 21.7%) of these women were recalled based upon mammography findings. Two hundred sixty-four 78.3%) women had at least one false-positive recall based on the MRI exam , and 203 (13.2%) women had at least one false-positive biopsy due to MRI findings . Median FGT measured on MRI was 12.7% (interquartile range (IQR), 18.9%), and median BPE was 67.7% . Tables .7% of th2.0% wome% women hBRCA status was found in both percentages (p = 0.001) and the dichotomous scores (p < 0.001). BRCA mutation carriers had lower FGT scores than others. The BRCA mutation carriers had a lower age at the baseline scan . A similar association was found between the percentage of BPE and BRCA status (p = 0.005), as BRCA mutation carriers had significantly lower BPE scores. When dichotomizing BPE, this remained significant (p = 0.020). FGT and BPE were negatively correlated to age , also when using dichotomous values (p ≤ 0.007). In BRCA mutation carriers, coefficients were r = − 0.418 (p < 0.001) and r = − 0.132 (p = 0.002), respectively, and in women without a BRCA mutation, r = − 0.307 (p < 0.001) and r = − 0.152 (p < 0.001). FGT and BPE were not correlated (p = 0.879). Plots of the univariate analysis are presented in Figs. BRCA mutation carriers, BPE was not associated with a history of RRSO  and dichotomous values (p = 0.511). In regression analysis, FGT was not considered an independent risk factor for breast cancer; only BRCA status was . Likewise, percentages and dichotomized BPE scores of the baseline MRI scan were not associated with breast cancer (p = 0.625 and p = 0.236). In regression analysis, adjusting for the only significant risk factor (BRCA status), BPE was also no significant predictor of cancer (p = 0.112). When evaluating both FGT and BPE, both were not significantly associated with breast cancer risk (p = 0.824 and p = 0.112). Also in the subgroup of the BRCA and non-BRCA mutation carriers only, BPE and FGT were not associated to breast cancer.In univariate analysis, FGT was not associated with breast cancer for both discrete (p = 0.302), but FGT was (p = 0.030). Dichotomizing BPE (p = 0.234) and FGT (p = 0.012) did not change results. In regression analysis, FGT was associated to breast cancer (p = 0.036), but BPE was not (p = 0.137). Details of predictors can be found in Table The subgroup analysis on cancers developed in the first two years after baseline MRI scan included 17 cancers and a total of 1499 baseline MRI scans. In univariate and multivariate analyses, continuous BPE was still not associated to breast cancer . For subsequent rounds (prognostic model), higher FGT at baseline was still significantly related to higher FPR in both continuous and dichotomized values (p ≤ 0.029). BPE, however, was not related to FPR (p ≥ 0.818) in univariate analysis. In regression analysis, only age remained as related factor to FPR in follow-up , both FGT and BPE were correlated to higher FPR  and OR, 1.807 (p = 0.002), respectively).When excluding the FPB in the first round (prognostic model), FGT and BPE were both not related to FPB (p ≥ 0.066) in univariate analysis. Regression analysis showed that age was negatively related to FPB in follow-up , both FGT and BPE were correlated to higher FPB  and background parenchymal enhancement (BPE) in predicting breast cancer risk in a population at increased risk of developing breast cancer. Additionally, the effect of FGT and BPE on false-positive recalls and biopsies was investigated. Our results show that neither FGT nor BPE at baseline was associated with the overall risk of developing breast cancer. However, in subgroup analysis only evaluating the cancers detected in the first 2 years after the baseline MRI scan, we found an association with FGT. Both higher FGT and BPE did lead to higher odds ratios for false-positive findings in the baseline examination. We did not observe any predictive value of FGT or BPE for FPR or FPB in subsequent screening rounds.BRCA mutation carriers increased the risk of breast cancer, with a relative risk similar to that observed in the general population. In our subgroup analysis, we found that FGT might be associated with early cancer development, and as FGT and BPE may change due to normal hormonal changes, it might be logical that the predictive potential in the longer run is relatively limited in this generally young population. However, as this analysis included small cancer numbers and results showed extremely large confidence intervals, these results need to be evaluated with caution. It should be noted that the differences between those studies and our findings may at least partly be explained by the automated volumetric FGT estimation in our study, which provides a different representation of the FGT than visually inspected BD in mammography, albeit previous studies showed a clear correlation between these measurements [It has already been well established that mammographic breast density (BD) impairs mammographic sensitivity . In an aurements , and theurements . It may Current clinical practice is shifting towards personalized screening, making risk prediction tools increasingly important. Recent case-control studies have shown that BPE might be predictive of breast cancer risk , 12, altBRCA mutation carriers had significantly lower FGT and BPE values compared to women without a BRCA mutation, while the age of BRCA mutation carriers was significantly lower than that of women without BRCA mutation. This counterintuitive result may be due to differences in the effect of hormones on FGT in women with and without BRCA mutation [BRCA mutation carriers who did and did not undergo a RRSO before the baseline MRI also points in this direction. Nevertheless, prior research showed that RRSO may still reduce both BPE and FGT values [BRCA mutation carriers after the baseline examination may have had impact on the predictive value of FGT and BPE in these women.Evidence suggests that BPE correlates negatively with age and increases with hormonal activity –32. Intemutation . The facT values , and theWomen with high BPE scores had a 1.5 times higher chance to get a FPR, and 1.8 times higher chance to get a FPB in the first screening round. This is in line with previous studies, describing that more focal, regional, or asymmetric BPE was associated with a higher likelihood of BI-RADS 3 assessment in the screening setting . Giess eThe automated algorithm for BPE estimation eliminates intra- and interrater variability. This is relevant as previous studies reported only a fair interrater variability for BPE when using observer scores according to the BI-RADS lexicon . The autOur study has some limitations. Due to the retrospective nature of our data, it was not always possible to retrieve data on the menstrual cycle or menopausal status. Therefore, we could not correct for these factors. Obviously, menopausal state is partly covered by including age in the risk model. However, future research is needed to better investigate the influence of menopausal status on the predictive value of FGT and BPE for future breast cancer occurrence. In addition, this was a single-institutional study, which potentially limits its generalizability. We chose to include all cancers that were detected in the period after the baseline scan to find a relation between the baseline scan and any future breast cancer occurrence (in on average 3 years follow-up). However, relative risks for a shorter period of time might also be very interesting to study. In addition, changes of FGT and BPE from the baseline might also be predictive of risk. As our cohort is too small to answer these questions, this needs further evaluation in a future study. During the study period, we changed from a 1.5- to a 3-T scanner, and also adapted scanning protocols several times which could potentially influence the results of the BPE calculation algorithm. However, we ensured that BPE was measured between 90 and 120 s after contrast administration, and since BPE is evaluated only semi-quantitatively , we aimed to minimize this effect. Still, further standardization of imaging parameters may improve homogeneity of FGT and BPE estimations and potentially improve the predictive potential. Another possible limitation of the study was that only in the case of false-positive findings did we not exclude women who had a false-positive finding directly after the first screening round. In theory, this could alter FGT and BPE scores, although we minimized this effect by averaging scores over two breasts.In conclusion, automatically computed FGT and BPE measures at baseline were not associated with subsequent breast cancer occurrence in a cohort of women at high risk for breast cancer. This has implications for personalized screening, as FGT and BPE cannot be implemented in risk prediction models. Higher FGT and BPE were, however, associated with higher rates of false-positive findings at baseline; patient counseling should therefore include these outcomes before starting MRI screening.ESM 1(DOCX 23 kb)


Germline CDH1 mutations, classically associated with hereditary diffuse gastric cancer (HDGC), also imply an increased lifetime risk of developing lobular breast cancer (LBC) in a highly penetrant autosomal dominant manner.We report a 44-year-old woman CDH1 mutation carrier with a strong family history of cancer, who previously had prophylactic total gastrectomy. We registered normal findings at the breast and axilla assessment. Mammography, ultrasonography and breast MRI scans were negative for cancer. In our Institute a bilateral prophylactic mastectomy followed by breast reconstruction was performed. Foci of atypical lobular hyperplasia(ALH) and lobular carcinoma in situ (LCIS) were histologically shown.The current consensus guidelines for women with pathogenic CDH1 mutations recommend annual mammography, ultrasound, breast MRI scans and clinical breast examination starting at the age of 35. Due to the well-documented aggressive behavior of this particular type of cancer, bilateral mastectomy and reconstruction would be more beneficial for this kind of high-risk patients.Conflicting evidences and lacking data about the benefits in terms of overall survival, disease-free survival and the long-term outcomes related to prophylactic bilateral mastectomy for CDH1 mutation carriers restrict the instruction for this type of procedure to selected cases, which should always be managed by a multidisciplinary team. An important role is played by genetic factors, up to 25% of hereditary cases is due to mutations of highly penetrant genes, such as BRCA1, BRCA2, CDH1, PTEN, TP53 and STK11, each one regulating a specific clinical syndrome [In particular, the lifetime risk of developing hereditary diffuse gastric cancer (HDGC) and lobular breast cancer (LBC) in CDH1 mutation carriers has been estimated to be 80% and 60% respectively .CDH1 gene is located on chromosome 16q22.1 and encodes for E-cadherin, a transmembrane glycoprotein that mediates cellular adhesion. CDH1 mutation is involved in the loss of E-Cadherin expression, which leads to disruption of cell-binding complexes. It results in the loss of cellular cohesion typical of lobular neoplasia ,4.In this report we describe our experience in CDH1 mutation carriers management, not well-established in literature yet. Our study outlines how pathogenic CDH1 mutation correlates closely with LBC and that enables an invasive procedure such as bilateral prophylactic mastectomy.This work has been conducted in line with the SCARE criteria .2A 44-year-old woman with an inherited pathogenic CDH1 mutation visited our department asking for a bilateral prophylactic mastectomy. The patient had no palpable mass, pain or other breast cancer symptoms and she had already undergone prophylactic total gastrectomy. She suffered from epilepsy treated with Tegretol (carbamazepine) due to a cerebral surgery scar after a venous haemorrhage in the parietal lobe .Fig. 1AlOur Institute is specifically committed to breast cancer prevention in patients with hereditary risk. Since January 2016 an Oncogenetic Counseling Service is available to identify people with high risk of developing breast and ovarian cancer and to detect pathogenic genetic mutations.The patient exhibited medical records which attested genetic test results confirming the patient as a CDH1 mutation carrier. She had also been tested for BRCA mutations with negative results.The patient’s three-generation family pedigree examination allowed to identify four cases of HDGC and two cases of LBC.We recorded normal clinical findings at the breast and axilla assessment.The bilateral prophylactic mastectomy was performed one year after her initial medical exam, during that year we reviewed the updated literature and she was subjected to a preoperative multidisciplinary evaluation including radiological, psychological and plastic surgery examinations.Mammography, ultrasonography and breast MRI scans were negative for cancer. Neither fine-needle aspiration (FNA) nor biopsy were carried out.We performed a bilateral nipple-sparing mastectomy with one-stage immediate reconstruction. This technique involves the use of a porcine-derived acellular dermal matrix (ADM) that completely wraps the prosthesis, maintains the pectoral muscle intact and allows implant placement in the subcutaneous tissue. This novel approach can improve aesthetic results and avoid morbidity through the support provided by the biological mesh packed into.The patient had an uneventful postoperative recovery. Histological evaluation revealed rare foci of atypical lobular hyperplasia and lobular carcinoma in situ.The resident oncologist’s indication was annual US and breast MRI scans as radiological follow-up.3Atypical lobular hyperplasia (ALH) and LCIS are defined as pre-invasive lesions and non-obligate precursors of breast cancer. Nevertheless, several studies demonstrate that these tumors have a fourfold to fivefold increased risk of developing malignant breast cancer, especially invasive lobular carcinoma .Ma et al. studied molecular aspects and gene-expression of breast atypical hyperplasia, carcinoma in situ and invasive carcinoma. They demonstrated the precursor role of atypical hyperplasia in the development of breast cancer .Even though there are no evidences about an overall survival benefit with bilateral mastectomy in patients with LCIS , a SurveLobular neoplasia is often diagnosed in premenopausal women, with a mean age at diagnosis of 45 years, it is generally multicentric and bilateral [The aggressive behavior of invasive lobular carcinoma combined with the high penetrance of CDH1 mutations justifies breast Risk-Reducing options.3.13,20,The current consensus guidelines for CDH1 mutation carriers recommend annual mammography, ultrasound and breast MRI scans, combined with clinical breast exam starting at the age of 35.3.2Benign lesion (ALH and LCIS) are usually estrogen-receptor-positive and/or progesterone-receptor-positive and human epidermal growth factor receptor 2-negative.As a result of the National Surgical Adjuvant Breast and Bowel (NSABP) P-1 trial, which demonstrated the effectiveness of Tamoxifen in reducing the onset rate of breast cancer up to 80%, since 1999 FDA approved its use for patients with an elevated risk of future breast cancer .Indeed also Raloxifen, another selective estrogen receptor modulator (SERM), Exemestane and Anastrozole, two aromatase inhibitors, have been approved by FDA for the same reason in postmenopausal women .Preventive therapy for breast cancer with anti-estrogens is effective in high-risk women but their compliance is low, due to the side effects .3.3Mastectomy is not recommended as a routine procedure in high-risk patients. The lack of data about the risk of developing breast cancer in CDH1 mutation carriers brings risk-reducing surgery currently under discussion.Invasive lobular cancer is characterized by a tumor density similar or equal to a normal breast tissue density: for this reason conventional imaging, as mammography, is burdened by consistent limitations in detecting this kind of cancer .Moreover, the young onset of malignant breast neoplasia associated with a genetic susceptibility led the American Society of Breast Surgeons (ASCO), the Society of Surgical Oncology (SSO) and the NCCN breast cancer risk-reduction Guidelines to regard bilateral risk-reducing mastectomy as a reasonable option for women with deleterious mutations in BRCA1, BRCA2, CDH1, TP53, PALB2, STK11 or PTEN ,15.The prophylactic surgery procedure has been demostrated to confer survival benefits in CDH1 mutation carriers even if it doesn’t completely eliminate breast cancer risk .Preoperative evaluation includes mammography, US and MRI techniques in order to exclude suspicious lesions: in this case conservative mastectomy can be performed.There are two most commonly followed tecniques: skin sparing mastectomy (SSM), all the breast glandular tissue is removed leaving the skin envelope, and nipple sparing mastectomy (NSM), the nipple-areola complex (NAC) is preserved. The oncological risk of these conservative procedures is due to remaning glandular tissue with the skin flap and/or in NAC: for this reason surgeons should remove all glandular visible tissues and dissect thin skin flap and NAC .Surgery related risks include bleeding, infection, seroma, skin flap necrosis, nipple necrosis, pain. Pathogenic mutation carriers prefer these complications rather than the fear of developing breast cancer .Women that opt for prophylactic surgery can receive immediate reconstruction. This possibility encourages surgical risk-reducing strategies. The implant-based breast reconstruction with acellular dermal matrix (ADM) is the preferred one, because it improves the aesthetic outcomes. Other advantages of pre-pectoral reconstruction consist of avoiding the pectoralis detachment pain, arm weakness and minimizing capsule formation .Postoperative rates of complications such as seroma, red breast syndrome, wound dehiscence, flap necrosis, infection, implant rotation or loss are low: that’s why we can consider this surgical approach useful and safe .The preoperative psychological counseling is a crucial point to investigate the impact of bilateral prophylactic mastectomy and to establish risk factors for postoperative distress. The patient was greatly motivated to approach this prophylactic surgery due to her genetic condition and the fear of leaving her little son orphan. Her psychological status was fundamental in the decision process leading to the bilateral prophylactic mastectomy.4The recognition of hereditary cancer syndromes is essential in the clinical practice to guide further genetic counseling/testing. Genetic counseling can be provided to discuss detection of one or more alterations and the implications of an identified mutation on a patient’s quality of life.Early onset of cancer, an increased overall cancer risk, a high probability of second primary tumors conduct to increased medical expenses: therefore it’s necessary to guarantee tailored care for this high-risk population.Even if many individuals would benefit from the awareness of their hereditary cancer status, this induces also several problems such as coping with their own and their children cancer risk, anxiety, the physical and psychological impact related with prophylactic surgery.To reduce the psychological impact due to bilateral mastectomy, we used one-step breast reconstruction, named muscle-sparing ADM wrap technique.This least-invasive technique could improve aesthetic and functional results: reduced hospitalization, rapid return to normal activities and good cosmetic outcomes.In addition, there are clear economic benefits related to the decreased operating time and days of hospitalization.To this day there is no uniformly accepted indication to perform prophylactic mastectomy in CDH1 mutation carriers: current consensus guidelines often recommended breast surveillance. In our experience we combined accurate radiological breast monitoring with a dedicated multidisciplinary team to offer the best management of the risk of developing LBC. In some selected cases we consider, instead, that surgical procedure should be performed. We would need more informations about the long term outcomes of women who had elective prophylactic mastectomy and gastrectomy performed.A full multidisciplinary team is fundamental to focus on all aspects for the management of these patients.The authors declare that they have no conflict of interest.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.No research ethics approval was necessary for this case report.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.Sara Mirandola: conceptualization, investigation, data curation, writing , visualization and supervision.Francesca Pellini: conceptualization, investigation, data curation, writing , visualization and supervision.Eleonora Granuzzo: investigation, data curation, writing (review and editing) and visualization.Maya Lorenzi: investigation, data curation, writing (review and editing) and visualization.Beatrice Accordini: investigation, data curation, writing (review and editing) and visualization.Maurizio Ulgelmo: investigation, data curation, writing (review and editing) and visualization.Alessandra Invento: investigation, data curation, writing (review and editing) and visualization.Davide Lombardi: investigation, data curation, writing (review and editing) and visualization.Marina Caldana: investigation, data curation, writing (review and editing) and visualization.Giovanni Paolo Pollini: investigation, data curation, writing (review and editing) and visualization.All authors read and approved the final manuscript.researchregistry4584.Dr’s Sara Mirandola and Francesca Pellini are to be considered the co-guarantor’s for this manuscript.Not commissioned externally peer reviewed.


Ninety percent of patients had heard of breast cancer, but few could describe the causes. Almost one fifth of patients believed that breast cancer was a kind of spiritual attack. Clinical genetics services, by and large, are unavailable in Nigeria, and it is not surprising that 91% of patients did not know anything about cancer genetics or genetic testing.The field of cancer genetics is entering the mainstream of clinical oncology. At least that is the case for many high-income—and some upper-middle income—countries. We hope that these developments will lessen the burden of cancer in countries with limited resources and will not divert funds that could be better invested elsewhere. In the article that accompanies this editorial, Adejumo et al2 The genetic counselor provides a detailed assessment of the patient’s family history of cancer and provides tailored, guidelines-based advice on cancer risk reduction for unaffected women with positive genetic test results. This information can also inform risk reduction for future cancers as well as precision treatment for patients with a current cancer diagnosis. Genetic testing has become increasingly complex with the adoption of multigene panels and the attendant flurry of variants of uncertain significance, often in genes of questionable importance. One wonders how many patients will benefit from these technical advances, whether in North America or Nigeria. We applaud efforts to modernize cancer prevention and treatment by increasing genetic knowledge around the world, but we ask the authors if it is wise to pursue such a study in any country in which the health system is fragile and fragmented. Nigeria, among the largest economies in sub-Saharan Africa, is classified as a lower-middle income country.3 Nigeria’s maternal mortality ratio is ranked as the fourth highest globally.5 According to the World Bank, in 2014 the country ranked among the lowest in terms of health expenditures in the public sector at 0.9% of gross domestic product.6 Out of pocket expenditures are estimated at 49.5%.A comprehensive state-of-the-art program in clinical cancer genetics includes cancer risk assessment and genetic counseling and testing.7 has led to several important discoveries that are not only relevant for women in Nigeria but also for women of West African ancestry. A study of Nigerian women with breast cancer unselected for age or family history demonstrated that 7.1% tested positive for a pathogenic mutation in BRCA1, and 3.9% had BRCA2 mutation; the 11% total for unselected women is among the highest rates of any population studied.7 To translate this knowledge into a reduced cancer burden will require systematic testing and appropriate follow-up of carriers and their at-risk relatives for clinical interventions, including breast screening and risk-reduction surgery . We should not deny the potential impact of such research when counseling and testing an individual and family can lead to life-saving cancer prevention and risk-reduction opportunities, and we should strive to make these options acceptable, available, and affordable. Of interest, the traditional paradigm of nondirective counseling may run into problems when there is little background knowledge of genes and disease and superstition persists. Adejumo and colleagues note these challenges to the traditional—Western—genetic counseling model. That study participants had limited knowledge of their family histories challenges the paradigm for how we identify individuals who may harbor a germline mutation in a high-risk cancer susceptibility gene. This issue, along with other social and cultural factors that make case ascertainment and cancer genetic counseling challenging, have been described in other populations, notably in Asia8 and the Carribbean.9Editorialists should not make naïve assumptions about health financing priorities in any country, nor should we dictate how policymakers use their resources. We acknowledge that cancer genetics research has the potential to advance our understanding of genetics and may reduce global disparities in cancer incidence and mortality. In Nigeria, the pioneering work of Olopade et al10 A recent study from Brazil, published in Journal of Global Oncology,11 explores these factors and provides recommendations for priorities in planning for comprehensive cancer genetics services. In 2015, ASCO highlighted the critical issues of quality assurance, informed consent, and patient privacy and rights, including protection from genetic discrimination, cancer genetics education among cancer care providers, and disparities in access to clinical genetics services.12 Adejumo and colleagues make a reasonable case for investing in clinical cancer genetics services in Nigeria. They call for pretest counseling with informed consent, post-test counseling with disclosure of high-quality results, and the promotion of evidence-based interventions, ideally within the public health system or at reasonable cost in the private sector.Factors that influences the acceptability, availability, and uptake of clinical cancer genetics services can be considered to fall under a few broad categories: knowledge of hereditary cancer among providers and the public; sociocultural factors; infrastructure; and ethical, financial, legal, and regulatory considerations.


Epidemiologic data suggest that parity increases risk of hormone receptor-negative breast cancer and that breastfeeding attenuates this association. Prospective data, particularly on the joint effects of higher parity and breastfeeding, are limited.n = 8235; ER− n = 1978) breast cancers were diagnosed among 199,514 women. We used Cox proportional hazards models, adjusted for breast cancer risk factors, to calculate hazard ratios (HR) and 95% confidence intervals (CI).We investigated parity, breastfeeding, and breast cancer risk by hormone-receptor (estrogen (ER) and progesterone receptor (PR)) and molecular subtypes  in the Nurses’ Health Study  and NHSII (1989–2013). A total of 12,452 (ER+ Phet = 0.03). Among parous women, breastfeeding was associated with lower risk of ER− (vs. never 0.82 [0.74–0.91]), but not ER+, disease . Compared to nulliparous women, higher parity was inversely associated with luminal B breast cancer regardless of breastfeeding  and luminal A disease only among women who had breastfed . Basal-like breast cancer risk was suggestively higher among women with higher parity who never breastfed; associations were null among those who ever breastfed.Parous women had lower risk of ER+ breast cancer ; no association was observed for ER− disease  contains supplementary material, which is available to authorized users. Within the consortium, parity was associated with increased risk of ER− breast cancer; this risk was attenuated among women who reported ever breastfeeding. Further, breastfeeding was only inversely associated with ER− disease; no association was observed for ER+ breast cancers.Data from recent prospective , 2, caseTo our knowledge, there are no prospective data on the combined effects of parity and breastfeeding by molecular phenotype . Case-control , 7, 18 aIf breastfeeding is confirmed to reduce risk of hormone receptor-negative breast cancer, it represents an accessible and cost-effective risk-reduction strategy for this aggressive subtype. We hypothesized heterogeneous associations between parity and breastfeeding and ER+ and ER− breast cancer risk, with inverse associations hypothesized between parity and ER+ disease risk and between breastfeeding and ER− disease risk, and a positive association between parity and ER− breast cancer subtypes among women who did not breastfeed. Given intriguing, but inconsistent, prior results on the association between parity, breastfeeding, and breast cancer by subtype, and sparse prospective data on the combined effect of higher parity and breastfeeding, we examined these associations in the NHS and NHSII among almost 200,000 women.The NHS was initiated in 1976 when 121,701 registered nurses, ages 30–55, completed and returned a mailed questionnaire ) . The association between parity and ER+ tumors did not differ by breastfeeding history , and parity was not associated with ER− breast cancer risk in either breastfeeding history subgroup .The associations between parity, breastfeeding, and breast cancer risk differed by tumor ER status (Ptrend among ever breastfed = 0.02), but no significant associations were observed in categories of duration . The associations between breastfeeding and ER− breast cancer risk were similar regardless of breastfeeding duration . Patterns were similar for ER+/PR+ and ER−/PR− breast cancer  in analyses considering the cross-classification of parity and breastfeeding. For ER+ disease, parity ≥ 3 among women who never breastfed was more strongly associated with breast cancer risk in the NHS (HR = 0.75 [0.67–0.84]) than in the NHSII (HR = 0.85 [0.67–1.08]); associations were similar in other categories .Overall, results were similar in the individual cohorts (NHS and NHSII). We observed significant heterogeneity between cohorts for ER+ disease . Inverse associations between parity and ER+ disease and breastfeeding and ER− disease were observed only in women diagnosed 10+ years after last pregnancy  occurs in the final trimester; this is hypothesized to be an important mechanism linking full-term pregnancy to long-term reduced risk of breast cancer, shielding the breast tissue from carcinogenic transformation . Recent Direct data describing underlying physiologic mechanisms between breastfeeding and breast cancer subtypes are limited . Post-prn = 1252; parous vs. nulliparous, RR = 1.33 [1.11–1.59]). Higher risk was observed with higher parity among women who did not breastfeed  but not among women reporting ever breastfeeding (RR = 1.33 [0.91–1.95]). Ever parous, or number of children, were not significantly associated with ER− breast cancer in the current study, regardless of breastfeeding. Importantly, the AMBER consortium includes women of African-American descent, whereas the NHS/NHSII study population is predominantly non-Hispanic white. ER−/PR− (and triple negative) breast cancer is more common among African American women, as are higher parity [While some prior research is suggestive of a positive association between parity and ER− breast cancer, data to date are not consistent (reviewed in ). The AMr parity  and lower parity . Consistr parity . In analr parity –16. AddiFew prior studies have examined the joint effects of parity and breastfeeding and breast cancer risk by molecular phenotype , 9, 18. We provide the largest prospective study to date on parity, breastfeeding, and breast cancer by subtype, and add to the limited literature on these associations by molecular phenotype. While we expect that parity was accurately reported, there may be misclassification of breastfeeding duration. We would expect any misclassification to be nondifferential. Tumor tissue to define molecular phenotype was available for 33% of the cases, resulting in small case numbers in some subgroups.Our results support a role for breastfeeding in reducing risk of hormone receptor-negative breast cancer, adding to the established benefits of breastfeeding. While further research is needed to describe the mechanistic pathway resulting in this decreased risk, our investigation provides additional compelling evidence that breastfeeding is a modifiable risk factor for the breast cancer subtypes with the fewest targeted therapies and the least favorable outcomes.Additional file 1:Table S1. Multivariate-adjusteda hazard ratios (HRs) and 95% confidence intervals for breast cancer by ER/PR status in relation to parity and lactation: Nurses’ Health Study (1976–2012) and Nurses’ Health Study II (1989–2013). Table S2. Multivariate-adjusteda hazard ratios (HRs) and 95% confidence intervals for breast cancer by ER status in relation to parity and lactation, stratified by time since last birth: Nurses’ Health Study (1976–2012) and Nurses’ Health Study II (1989–2013) (DOCX 30 kb)


Lung cancer is the commonest cancer worldwide. Mortality and incidence rates are traditionally used to assess cancer burden and as public health indicators. However, these metrics are difficult to interpret at an individual level. Providing the lifetime and 10-year risks of cancer could improve risk communication. Our aim was to estimate current lifetime and 10-year risks of lung cancer by smoking status and changes in these risks between 1995 and 2013 in a Swiss population. We used all lung cancer cases recorded between 1995 and 2013 by two population-based cancer registries in the contiguous cantons of Vaud and Valais, in Western Switzerland. We estimated sex-specific lifetime risk and 10-year risk of lung cancer using the current probability method, accounting for competing risk of death. Estimates were also provided by smoking status. Between 1995 and 2013, 9623 cases of lung cancer were recorded. During this period, the lifetime risk decreased in men from 7.1% to 6.7% and increased in women from 2.5% to 4.1%. In both sexes, the 10-year risk of lung cancer increased with age until the age of 60–70 and decreased thereafter. Difference in the cumulative risk between current, former, and never smokers were very large and reported in user-friendly charts to ease risk communication. These lifetime and 10-year risk estimates could be used systematically as public health indicators. Regularly updating risk estimations are necessary for conditions like lung cancer whose incidence has changed substantially. •Providing the lifetime and cumulative 10-year risks of cancer by smoking status could improve risk communication and serve as public health indicators.•These indicators can be estimated with cancer registry data and smoking data from surveys using the current probability method.•In these regions of Switzerland, between 1995 and 2013, the lifetime risk of lung cancer decreased in men from 7.1% to 6.7% and increased in women from 2.5% to 4.1%.•Difference in the cumulative risk between current, former, and never smokers were very large. In SwitBecause cancers are feared diseases, an adequate risk communication about the individual chance of developing cancer is important . To asseThe lifetime risk of cancer has been estimated and is publicly available in several countries, such as Canada or the United States. To our knowledge, the 10-years cumulative risk is not systematically computed by any country worldwide. Our goal was therefore to estimate the sex-specific lifetime risk and 10-year risk of lung cancer in a Swiss population, by smoking status, and assess changes in these risks between 1995 and 2013. Further, we provided sex-specific user-friendly tables and graphical tools for risk communication about lung cancer.22.1We conducted a population-based temporal trend study of the risk of lung cancer in two regions of Western Switzerland  between 1995 and 2013. The total number of inhabitants in the cantons of Vaud and Valais is 1,123,998 corresponding to 13% of the total population of Switzerland.2.2www.nicer.org). Quality control procedures are based on the guidelines from the European Network of Cancer Registries  compiles and aggregates this data (gistries . Variablwww.iumsp.ch) and the Valais Cancer Registry  at the Observatoire Valaisan de la Santé . These registries collect data on all new (incident) cases of cancer diagnosed in the cantons of Vaud and Valais, since 1974 and 1989 respectively. Data on all cases of lung cancer recorded between 1995 and 2013 were used for this study. A recent evaluation of the completeness of cancer case ascertainment in Switzerland, including the Vaud and Valais Cancer Registries, indicated a high completeness for most cancer types, including lung cancer (www.suchtmonitoring.ch).We used data from the Vaud Cancer Registry  at the Institut Universitaire de Médecine Sociale et Préventive , no ethical approval was needed for such analyses.3Between 1995 and 2013, 9623 lung cancer cases were diagnosed in Vaud (69% of cases) and Valais (31% of cases), of which 6317 occurred in men (66% of cases) and 3306 in women (34%) . There wThe lifetime risk decreased in men from 7.1% to 6.7% (with a maximum of 7.3% in 1999–2003) while it increased regularly among women from 2.5% to 4.1%, between 1995 and 1998 and 2009–2013, respectively . The difference in lifetime risk between men and women decreased with time.The cumulative risk and lifetime risk of lung cancer, by sex, ages, and smoking status are reported in The 10-year risk (in absolute %) of lung cancer, by age group and time-period in men and women, between 1995 and 2013 are shown in Supplemental Table S3. Using estimates for the time period 2009–2013, a 10-year risk chart was designed to facilitate the representation of the individual risk of developing lung cancer over the next 10 years in men and women between 40 and 90 years of age, according to smoking status . In both4Between 1995 and 2013, the lifetime risk of lung cancer in Switzerland has slightly decreased in men from 7.1% to 6.7% while it increased in women from 2.5% to 4.1%. The difference in lifetime risk has consequently decreased between men and women with time. The 10-year cumulative risk of lung cancer has decreased in men at all ages, excepted in men over 80 years of age in whom the risk increased. Among women, the 10-year cumulative risk increased from age 50 years onwards. Difference in the cumulative risk between current, former, and never smokers were very large and reported in user-friendly charts to ease risk communication. Updating risk estimations are necessary for adequate communication on conditions like lung cancer whose incidence has changed substantially. Further, these lifetime and 10 years cumulative risk estimates could be used systematically as public health indicators.To our knowledge, no previous study has estimated the lifetime risk and 10-year cumulative risk of lung cancer in Switzerland. While several studies have estimated the lifetime or period-specific risk of being diagnosed with any cancer, lifetime risk of lung cancer has been rarely estimated in other countries. In Scotland, between 2001 and 2005, a study estimated the lung cancer lifetime risk to be 8.8% in men and 6.5% in women . In CanaSeveral strengths of our study deserve to be noted. First, it is based on high quality population data from two cancer registries recording all cases of cancers in patients living in a region of Western Switzerland. It allows us estimating reliably the incidence and mortality rates, as well as the cumulative risk of lung cancer. Second, we used the current probability method described as the gold standard for estimating cumulative and lifetime risk with data containing only the first primary cancer . This meOur study has also some limitations. It is restricted to two cantons of Switzerland. Lung cancer standardized incidence rate decreased in Switzerland between 1995 and 2013 from 66.9 to 50.1/100,000 and increased in women during the same time period from 18.2 to 27.7/100,000 . These nInformation is central in health decision making for patients and health professionals, as well as for policy makers . To takeImportantly, risk of diseases need to be frequently updated in order to convey correct and reliable information to patients and doctors. For most diseases, risk charts have indeed a local or regional value, depending on the risk level in a given population and can be outdated, if the risk of disease changes promptly across time . When es5Because mortality and incidence rates - both traditionally used to assess cancer burden at a population level - might be difficult to interpret at an individual level, we propose life-time and 10-year risks to be estimated systematically for all major cancers and used as public health indicators. Charts showing the huge difference in cumulative risk in current, former and never smokers could be used to help current smokers realize the benefit to quit smoking.None.


Obesity and elevated breast density are common risk factors for breast cancer, and their effects may vary by estrogen receptor (ER) subtype. However, their joint effects on ER subtype-specific risk are unknown. Understanding this relationship could enhance risk stratification for screening and prevention. Thus, we assessed the association between breast density and ER subtype according to body mass index (BMI) and menopausal status.2 versus overweight/obese, ≥ 25 kg/m2). We used Wald chi-squared tests to assess for interactions between percent density and BMI. Our analysis was stratified by menopausal status and hormone therapy usage at the time of index mammogram.We conducted a case-control study nested within two mammography screening cohorts, the Mayo Mammography Health Study and the San Francisco Bay Area Breast Cancer SPORE/San Francisco Mammography Registry. Our pooled analysis contained 1538 ER-positive and 285 ER-negative invasive breast cancer cases and 4720 controls matched on age, menopausal status at time of mammogram, and year of mammogram. Percent density was measured on digitized film mammograms using computer-assisted techniques. We used polytomous logistic regression to evaluate the association between percent density and ER subtype by BMI subgroup  interaction between percent density and BMI in premenopausal women only. Specifically, elevated percent density was associated with a higher risk of ER-negative than ER-positive cancer in overweight/obese premenopausal women . In postmenopausal women, elevated percent density was associated with similar risk of ER-positive and ER-negative cancers, and no substantive differences were seen after accounting for BMI or hormone therapy usage.Percent density was associated with increased risk of overall breast cancer regardless of menopausal status or BMI. However, when analyzing breast cancer across ER subtype, we found a statistically significant  contains supplementary material, which is available to authorized users. Breast cancer risk is multifactorial, with > 40% of women having multiple risk factors . MoreoveElevated breast density and overweight/obesity are the two most prevalent risk factors for breast cancer . Breast An important clinical question is whether elevated breast density and overweight/obesity act to synergistically increase risk. Whereas recent work has estimated the population-wide effects of breast density and BMI , few stuWe hypothesized that the combined effects of elevated breast density and overweight/obesity exceed their individual effects. We further hypothesized that these differences would vary by menopausal status and ER subtype. Therefore, we examined the individual and combined effects of percent breast density and overweight/obesity on ER subtype-specific risk within two screening cohorts.We conducted a nested case-control study within two pooled cohorts, the Mayo Mammography Health Study (MMHS) , 17 and Cases were women diagnosed with invasive breast cancer, as ascertained by linkage to the California Cancer Registry (SFMR), clinic- or state-based cancer registries (MMHS), or from pathology reports (MMHS). ER status was ascertained by immunohistochemical staining. To limit prevalent cases, we included breast cancers diagnosed > 6 months after the index mammogram used for density measurement. We excluded 590 cases due to missing data; of these, 50 were missing ER status  and screening facility (SFMR). The study was approved by the institutional review boards of the University of California, San Francisco, and the Mayo Clinic. Participants provided passive permission (SFMR) or informed consent (MMHS) for use of data.Breast density measurements were performed on digitized images of pre-diagnostic film screening mammograms. We measured percent density using Cumulus, a computer-assisted threshold technique , and USC2) at the time of index mammogram using questionnaire response or medical record review.Menopausal status and postmenopausal HT use were ascertained through questionnaire responses collected at the time of index mammogram. Postmenopausal women were those who had both ovaries removed, whose periods had stopped naturally, were currently using HT, or were age 55 or older. Premenopausal women reported a period < 180 days ago, were under age 40, or were currently using birth control. Due to differing associations between combined hormonal and unopposed estrogen on breast cancer risk , HT userWe constructed multivariable logistic regression models to evaluate the individual and combined effects of BMI and percent density on invasive breast cancer . To evaluate ER subtypes, polytomous  logistic regression models were fit with three outcomes: no cancer (reference), ER-positive cancer, and ER-negative cancer. Our main predictor was percent density. We present the odds ratio (OR) and corresponding 95% confidence interval (CI) per standard deviation (SD) increment of standardized percent density, after square root transformation.In overall analyses of ER-positive and ER-negative cancer, we tested for evidence of interactions among BMI categories, menopausal status , and percent density by fitting appropriate multiplicative interaction terms. Based on the interaction test results, we performed stratified analyses according to menopausal status and BMI. For our main analysis, we dichotomized BMI into normal/underweight (< 25) and overweight/obese (≥ 25) subgroups due to sample size constraints. In supplemental analyses, we divided BMI into normal/underweight (< 25), overweight (25–29.9), and obese (≥ 30) subgroups to assess trends with increasing BMI.All models were adjusted for age and study. Individual associations between BMI and breast cancer  were performed with and without adjustment for percent density. To account for residual confounding from differences in BMI within BMI subgroups, we performed supplemental analysis adjusting for continuous BMI within each BMI subgroup. Associations between percent density and breast cancer  were stratified by BMI subgroup, with additional adjustment for continuous BMI within BMI subgroups.Phet). Similar contrasts were used to test for heterogeneity of association of BMI subgroups by ER subtypes. We used Wald chi-squared tests to examine multiplicative interaction effects between BMI subgroups and continuous percent density (Pint) on subtype-specific risk within each menopausal stratum. Differences in associations between breast density and breast cancer for the BMI subgroups were evaluated by estimating an ordinal density trend within each subgroup and then testing for differences in these trends between BMI subgroups as a multiplicative interaction. To examine for confounding by race and time since prior mammogram, additional analyses were performed in Caucasians only and with additional adjustment for year of index mammogram. All tests were two-sided with α = 0.05. We performed the analyses using SAS software .Contrasts were constructed within the polytomous logistic model framework to test for heterogeneity of associations between density measures and ER subtypes within BMI subgroups  Risk Factors Dataset . This daWe included 1538 ER-positive and 285 ER-negative breast cancer cases and 4720 controls (Table p = 0.02) and percent density by BMI categories (p = 0.04). Based on these interactions, we evaluated the associations between overweight/obese BMI and breast cancer by ER subtype, across menopausal status (Table Phet = 0.04). Postmenopausal HT non-users who were overweight/obese also had increased risk of ER-negative cancer [OR 1.62 (95% CI 1.06–2.94)] and ER-positive cancer [OR 2.28 (95% CI 1.86–2.81)] relative to their normal/underweight counterparts, though the heterogeneity of ER subtype-specific risk did not reach statistical significance (Phet = 0.13). Postmenopausal HT users who were overweight or obese had increased risk of ER-positive cancers only [OR 1.58 (95% CI 1.23–2.04)].Interaction tests revealed evidence of differential ER subtype associations for BMI by menopausal categories p = 0.0 and percNext, we evaluated the associations between percent density and breast cancer by ER subtype . In postmenopausal HT non-users and users, the associations between percent density and overall breast cancer were similar across BMI subgroups. Adjusting for residual confounding by BMI within BMI subgroups did not substantively change the results (data not shown).We then evaluated the associations between percent density and overall invasive breast cancer across BMI and menopausal status subgroups Table . ElevatePint = 0.008), Table Phet = 0.01]. In contrast, among normal/underweight women, elevated percent density tended to be associated with lower risk of ER-negative compared to ER-positive cancer . The interaction between percent density and BMI remained after adjusting for residual confounding within strata (data not shown), and when analyzing BMI across normal/underweight, overweight, and obese subgroups  for overall breast cancer. There was no evidence of interaction in premenopausal women (Pint = 0.32), although this group comprised < 25% of the study [The main implication of our findings is that BMI acts an effect modifier for percent density in premenopausal women, with the effect varying by ER subtype. Our findings expand the literature, which had previously evaluated the BMI-percent density interaction in the context of overall breast cancer risk only. A prior analysis of 1699 cases and 2422 controls reported a BMI-density interaction of borderline statistical significance (he study . Our stuPint = 0.92) [In contrast, we found no interactions between percent density and BMI in postmenopausal women. This result is consistent with an analysis of postmenopausal women from the Nurses’ Health Study, where BMI did not modify the association between percent density and overall breast cancer ( = 0.92) . Though  = 0.92) .Our findings contribute to the evolving understanding of BMI’s effect on ER-negative cancer risk. We replicate findings from case-control  and caseOne unexpected finding was that premenopausal normal/underweight women, compared with their overweight/obese counterparts, had substantially elevated ER-positive risk commensurate with increased breast density. Whereas overweight/obesity is thought to increase ER-positive cancer through peripheral aromatization of estrogens by adipose tissue and through insulin signaling , our finOur study has several notable strengths. Since we assessed BMI at the time of pre-diagnostic mammogram, rather than at the time of diagnosis, we could assess the downstream risk associated with being overweight/obese. Our results describe the distal effects of premenopausal overweight/obesity, which is of greater relevance for risk stratification than overweight/obesity immediately prior to diagnosis. Other strengths include the ability to leverage two established mammography cohorts containing quantitative, area-based density measurements and detailed tumor characteristics assessed from cancer registries or institutional records. Although participant characteristics differed somewhat between cohorts, we have previously shown that breast density, our main predictor, displays similar associations with breast cancer across MMHS and SFMR .Our study has several limitations. First, although our BMI measurements preceded diagnosis by a median of 5 years, we had limited ability to measure longitudinal changes in BMI before and after the index mammogram. The duration of exposure to increased BMI, and trajectory of BMI, may both affect risk. For instance, adult weight gain has been found to modify the associations between BMI and ER subtype-specific risk in some studies , 32, butIf our findings are replicated across other volumetric density measures, and in diverse populations, they may have important implications for risk stratification in premenopausal women, 18% of whom have BI-RADS category heterogeneously dense or extremely dense breast density and BMI ≥ 25, according to our analysis of a large database of US women undergoing mammography screening. These women may benefit from counseling on their risk for ER-negative cancers and the importance of achieving and maintaining a normal BMI. Most studies on the relationship between weight trajectory and breast cancer risk have focused on postmenopausal women, with several showing that weight loss decreases risk –37 and oOur findings could potentially be leveraged to enhance decision-making around chemoprevention, given the observed association between percent density and ER-positive cancers in normal/underweight women. The BCSC , 42 and Elevated breast density and premenopausal overweight/obesity are risk factors for ER-negative breast cancer and interact synergistically to augment ER-negative risk. Both risk factors coexist in a substantial proportion of premenopausal women. Our findings demonstrate how prevalent, commonly captured risk factors can enhance understanding of overall and phenotypic breast cancer risk. Premenopausal women at elevated risk of ER-negative cancer represent a population where further studies on weight loss and physical activity interventions are especially needed.Additional file 1:Figure S1. Flow diagram of subjects included in pooled analysis. Table S1. Baseline characteristics of 6543 women, by study. Table S2. Associations of percent density with ER-positive and ER-negative invasive breast cancer, by menopausal status for 1823 cases and 4720 controls. Table S3. Associations of percent density with ER-positive and ER-negative breast cancer, by BMI  and menopausal status for 1823 cases and 4720 controls. Table S4. Associations of percent density with ER-positive and ER-negative breast cancer, by BMI and menopausal status for 1330 Caucasian cases and 3365 Caucasian controls. Table S5. Associations of percent density with ER-positive and ER-negative breast cancer, by BMI and menopausal status, and adjusted for year of index mammogram, for 1823 cases and 4720 controls. (DOCX 2426 kb)


British Journal of Cancer reveals suboptimal rates of utilisation of surveillance/preventative measures globally.While the elevated lifetime risk of breast and ovarian cancer is well recognised for patients with a BRCA mutation, the implementation of effective risk reduction strategies has been fraught with challenges. This report from an international database and published in the  Despite the availability of national and international guidelines to guide prevention efforts,3 physicians' attitudes towards preventative therapeutic interventions, such as prophylactic bilateral mastectomy, have been variable.6 Furthermore, high-risk screening and prevention efforts are challenging to implement in a younger target population, and are often overseen by primary care providers who may not be privy to the most recent and rapidly changing recommendations. Few reports of the uptake of these preventative measures longitudinally and across countries are available.While the majority of breast cancers are sporadic, it is estimated that ~5-10% of breast cancers are due to pathogenic mutations in BRCA1 and BRCA2.British Journal of Cancer, Metcalfe et al.7 report the international trends in the uptake of cancer risk-reduction strategies in women with a BRCA1 or BRCA2 mutation. Women were recruited from an international database of BRCA mutation carriers in 59 centres, across 10 countries, with data for a mean follow-up time of 7.5 years and a minimum of 1.5 years. A questionnaire was administered at the time of genetic testing and then twice yearly thereafter. Data sets from an earlier report published in 20085 were included and compared with this expanded and contemporary cohort from 2009 onwards. Furthermore, analyses of geographic location and comparisons between time cohorts were carried out. A total of 6226 women met the pre-specified inclusion criteria. The median age of the study population was 52.1 years (27–96 years), including 42.3% with a prior diagnosis of a unilateral breast cancer. Women with a history of cancer other than unilateral breast cancer were excluded. Furthermore, women diagnosed with breast cancer during the follow-up period were also excluded. Outcomes of interest were prophylactic risk-reducing surgeries, including bilateral mastectomy and bilateral salpingo-oophorectomy (BSO), chemoprevention with tamoxifen or raloxifene, and breast cancer screening with mammography and/or MRI.In this issue of the 7 run by the Hereditary Breast Cancer Clinical Study Group, offers insight into the uptake of preventative strategies globally for women with a BRCA mutation who carry a high lifetime risk of breast and ovarian cancer. One of the particular strengths of the study is the ability to compare the utilisation of preventative strategies longitudinally to further understand the impact of an evolving prevention/surveillance landscape for women with a BRCA mutation. With regard to risk-reducing surgeries, 27.9% underwent bilateral prophylactic mastectomy, with the highest rates in the USA (at 49.9%) and the lowest in Poland (at 4.5%). Furthermore, 62.8% went on to have prophylactic BSO, which was consistent over time, with a mean age of 45.6 years at the time of BSO. Chemoprevention remained a minimally utilised preventative strategy, with reported rates of 6.3%, although its use was notably higher in the USA (at 14.7%). Finally, with regard to breast screening, the uptake of mammography was 82.1% and decreased over time, whereas rates of MRI screening increased over time, up to 81.3% in the contemporary cohort.The study,7 is one of the few to compare and contrast global trends of preventative strategies within a high-risk group of women with deleterious BRCA mutations. While the Hereditary Breast Cancer Clinical Study Group should be acknowledged for their co-ordinated efforts in reporting the data relative to breast cancer, it is interesting that only patients with a prior history of breast cancer were enrolled in the study, since many BRCA mutations are detected at the time of diagnosis of epithelial ovarian cancer (EOC).9 Furthermore, although rates of breast cancer after a diagnosis of EOC are lower than the opposite sequence, the reported rates of uptake of breast cancer screening strategies in patients with EOC remain suboptimal, with a 2014 report suggesting rates of annual mammography of 59.3%, annual MRI of 44.4% and rates of prophylactic bilateral mastectomy of 9.6%.10This report7 rates of BSO were 70.7% after a diagnosis of breast cancer, despite data showing that EOC can be reduced by more than 90% when performed before menopause.12 It remains unknown if greater knowledge of the updated guidelines would have translated into higher rates of uptake in this patient population. While the suboptimal uptake is undoubtedly reflective of patient preference, physicians should emphasise to patients that there are no effective screening strategies for EOC, which is associated with a higher stage at presentation and high morbidity and mortality.13 Moreover, 73.4% of patients included in this study had a BRCA1 mutation,7 which is associated with earlier onset of EOC compared with BRCA2,9 although the mean age of BSO for patients with a BRCA1 mutation was 44.7 years in this study.It is also interesting to note that women who were diagnosed with breast cancer at the time of enrolment into the study were excluded from future analyses, as the uptake of BSO for that population would have been an interesting metric to capture. In fact, in patients with a prior history of unilateral breast cancer included in this study,7 highlighted a number of trends, which should be recognised. MRI screening for high-risk individuals is supported by most guidelines for patients with a BRCA mutation.3 However, while MRI has been effective in conjunction with mammography as a screening tool to reduce breast cancer mortality,15 evidence supporting a survival advantage with MRI screening alone is lacking. The authors7 demonstrated that the uptake of MRI has increased overtime, with a parallel reduction in mammography. However, guidelines suggest that a screening approach that includes annual MRI starting at 25 years of age, in combination with mammography starting at 30 years of age, is probably most effective at balancing the risks and benefits of screening.16 It is not clear from the details provided whether the lower rates of mammography are related to a younger age at the time of genetic testing or if there was an overall decrease in mammography across all cohorts. Even in the country with the lowest reported rates of mammography, mean age at the time of baseline interview was 46.6 years. Ultimately, the risk of breast cancer in those at 70 years of age with a BRCA mutation is in the order of 45–65% and the risk of contralateral breast cancer as high as 80%,18 which highlights the need for effective and standardised high-risk screening protocols that can be adopted outside a tertiary cancer care centre.Finally, this studyResearch in the field of cancer genetics is evolving and preventative measures, including prophylactic surgery and high-risk screening protocols, are constantly being refined to integrate novel findings that can be applied to clinical practice. It is therefore important that studies like these are conducted to evaluate the real-world effectiveness of preventative efforts and also to avoid missed opportunities.