Estimates of contralateral breast cancer (CBC) risk in the modern treatment era by year of diagnosis and characteristics of the first breast cancer are needed to assess the impact of recent advances in breast cancer treatment and inform clinical decision making.We examined CBC risk among 419,818 women (age 30–84 years) who were diagnosed with a first unilateral invasive breast cancer and survived ≥ 1 year in the US Surveillance, Epidemiology, and End Results program cancer registries from 1992 to 2015 (follow-up through 2016). CBC was defined as a second invasive breast cancer in the contralateral breast ≥ 12 months after the first breast cancer. We estimated standardized incidence ratios (SIRs) of CBC by year of diagnosis, age at diagnosis, and tumor characteristics for the first breast cancer. Cumulative incidence of CBC was calculated for women diagnosed with a first breast cancer in the recent treatment era .p-trends < 0.001), but the strongest decline was after an ER-positive tumor. The 5-year cumulative incidence of CBC ranged from 1.01% (95% CI = 0.90–1.14%) in younger women (age < 50 years) with a first ER-positive tumor to 1.89% (95% CI = 1.61–2.21%) in younger women with a first ER-negative tumor.Over a median follow-up of 8 years (range 1–25 years), 12,986 breast cancer patients developed CBC. Overall, breast cancer patients had approximately twice the risk of developing cancer in the contralateral breast when compared to that expected in the general population . SIRs for CBC declined by year of first diagnosis, irrespective of age at diagnosis and estrogen receptor (ER) status (Declines in CBC risk are consistent with continued advances in breast cancer treatment. The updated estimates of cumulative incidence inform breast cancer patients and clinicians on the risk of CBC and may help guide treatment decisions.The online version contains supplementary material available at 10.1186/s13058-021-01400-3. In the USA, overall 5-year survival rates for breast cancer now exceed 90%  and a grThus, the aim of our study was to describe CBC risk in the USA across these periods of significant advances in treatment and to include assessment by HER2 status for the first time as well as immunohistochemistry (IHC)-defined breast cancer subtypes. For this study, we used nationally representative data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program, a large-scale and population-based group of cancer registries with detailed records and long-term follow up, to examine CBC risk compared to the general population from 1992 to 2016 according to calendar year of diagnosis, age at diagnosis, and tumor characteristics for the first breast cancer. To help inform clinical decision making, we also calculated the 5-year cumulative incidence of CBC in the recent treatment era from 2004 to 2016 according to characteristics of the first breast cancer.We obtained female breast cancer case and population data using the SEER 13 Registries Database excluding the Alaska Native Tumor Registry  . Those dWe defined CBC as an invasive second breast cancer diagnosed in the contralateral unaffected breast ≥ 12 months after the first invasive breast cancer diagnosis. We excluded the first 12 months of follow-up to reduce potential misclassification of metastases or undetected synchronous bilateral breast cancer as CBC . Follow-Patient and tumor characteristics for the first breast cancer included calendar year of diagnosis, age at diagnosis, American Joint Committee on Cancer (AJCC) stage , histology , estrogen receptor (ER) status , HER2 status , and IHC-defined breast cancer subtype . HR status was defined as a joint combination of ER and progesterone receptor (PR) status . For breast cancer subtype, borderline tumors were categorized as unknown for HER2 status and positive for ER/PR status using the standard SEER algorithm. ER/PR status has been routinely collected in the SEER database since 1990 while collection of HER2 status began in 2010. Histologic categories were based on the International Classification of Diseases for Oncology, third edition (ICD-O-3) codes, and categorized as ductal , lobular , mixed ductal/lobular (8522), and other . First course of treatment  has been recorded in the SEER registries and categorized as known receipt (yes) and no or unknown receipt (no/unknown). Women without treatment and unknown treatment are combined in SEER data due to the limited sensitivity of treatment variables in the SEER registries . Type ofWe estimated standardized incidence ratios  and 95% confidence intervals (CIs) for CBC overall and according to characteristics of the first breast cancer. SIRs for CBC by HER2 status and subtype of the first breast cancer were also evaluated in a subgroup of women diagnosed with a first breast cancer between 2010 and 2015 and followed through 2016. SIRs were calculated as the observed number of incident breast cancers  compared to the expected number in the general population .To describe temporal trends in CBC risk, SIRs for CBC were stratified by calendar period of first breast cancer diagnosis . We first conducted this analysis including all women to describe long-term trends in CBC risk among the general population of breast cancer survivors. We then estimated SIRs excluding patients with contralateral prophylactic mastectomies or unknown surgery type among those diagnosed with a first breast cancer from 1998+ when type of breast cancer surgery was available in SEER. We did not exclude these patients in our main approach since we aimed to describe CBC risk on a population level and found that exclusion of women with contralateral prophylactic mastectomies did not substantially change our findings. Trends were examined overall and according to age at diagnosis  and ER To provide an absolute measure of CBC risk in the recent treatment era, we estimated cumulative incidence of CBC among 1-year survivors diagnosed with a first breast cancer between 2004 and 2015 and followed through 2016. We estimated cumulative incidence of CBC overall and according to characteristics of the first breast cancer. We calculated the 5-year cumulative incidence of CBC from the index date using a competing risk approach to account for death and other second cancers as competing events , 20. We p values < 0.05 were considered statistically significant. P for trends were calculated using the smrby package in Stata. Analyses were performed using SEER*Stat software (version 8.3.5), Stata version 11 and 15 .All statistical tests were two-sided and Table We identified 12,986 cases of CBC among women diagnosed with a first breast cancer between 1992 and 2015 and followed through 2016 . This decreasing temporal trend in CBC risk was observed regardless of age at diagnosis and ER status of the first breast cancer (p-trends < 0.001). Trends in CBC risk differed with joint stratification by age at diagnosis and ER status of the first breast cancer. Specifically, we observed a significant decreasing trend in CBC risk regardless of age at diagnosis after an ER-positive tumor (p-trends < 0.001) but not after an ER-negative tumor . The observed overall decline in CBC risk after an ER-negative tumor appeared driven by younger women diagnosed with a first breast cancer between 2010 and 2015. SIRs were overall slightly higher in magnitude with exclusion of women with contralateral prophylactic mastectomies, but similar temporal trends were observed even with the exclusion of these patients. Trends by detailed categories of age at diagnosis and ER status for the first breast cancer showed significant declines in SIRs among all age groups except for age < 40 years and some variability by ER status with significant trends only observed among ER-positive patients  when compared to that expected in the general population. However, our analysis showed a decline in CBC risk over calendar time, consistent with advances in breast cancer treatment, particularly after a first ER-positive breast cancer. Notably, the 5-year cumulative incidence of CBC was low, ranging from 1 to 2%, among women diagnosed with a first breast cancer during the most recent treatment era.Previous studies examining trends in CBC incidence among US women have reported a decline since the early 1980s through 2006 , 4. Our In our study, we observed that CBC risk after an ER-positive tumor has continued to decline past 2006, the end of our previous follow-up period . The widInterestingly, we observed an overall decline in CBC risk after an ER-negative tumor which differs from previously reported trends through 2006, where there were no clear decreases in CBC incidence after an ER-negative breast cancer . In our In our study, we observed a 5-year cumulative incidence of CBC of 1.31% for women diagnosed with a first breast cancer in the recent treatment era. These results are substantially lower than earlier studies –26. HoweThis is the first study to our knowledge to provide population-based estimates of 5-year cumulative incidence of CBC in US breast cancer patients according to HER2 status and breast cancer subtype, which only became available in the SEER registries starting in 2010. Although we found no difference in the 5-year cumulative incidence by HER2 status of the first tumor, we observed the highest 5-year cumulative incidence of CBC after a triple-negative tumor. These results differ slightly from the previous Dutch study  which reThe strengths of this study include the large-scale and population-based design with almost 13,000 CBCs, long-term follow-up from 1992 to 2016, and detailed tumor characteristics, which provided the opportunity to assess CBC risk and temporal trends in risk by characteristics of the first breast cancer. In addition, we had surgical data on the removal of the uninvolved contralateral breast and were therefore able to describe the overall limited impact of contralateral prophylactic mastectomies on the declining trends in CBC risk. There were also several limitations to our analysis including lack of detailed treatment data and individual-level risk factors. Due to under ascertainment of cancer treatment in the SEER registries, we were unable to directly compare CBC risk among women who did and did not receive treatment. Importantly, specificity of treatment data in SEER registries is high and therefore it is unlikely that known receipt of treatment is misclassified . In addiIn summary, the decline in CBC risk in breast cancer patients is likely related to continued advances in systemic breast cancer treatment. Although breast cancer patients had an overall increased risk of developing an incident breast cancer  when compared to that expected in the general population, the current probability of developing CBC at 5 years was low (1–2%). These estimates can further inform breast cancer patients and clinicians on the risk of CBC and help guide treatment decisions.Additional file 1. Contains supplementary tables and figures.


Breast cancer is the leading cause of cancer-related death in the female population. Health education interventions based on the use of mobile technologies enable the development of health self-care skills and have emerged as alternative strategies for the control of breast cancer. In previous studies, WhatsApp has stood out as a useful tool in health education strategies; however, it has not yet been applied for breast cancer education.This study aimed to analyze the potential of WhatsApp as a health education tool used to improve women's knowledge on the risk reduction of breast cancer. It also aimed to understand how women feel sensitized within the WhatsApp group throughout the intervention and how they incorporate information posted to improve knowledge about early detection and risk reduction methods.The study involved a pre-post health educational intervention with 35 women (aged 45-69 years) included in a WhatsApp group to share information  over 3 weeks on the early detection and risk reduction of breast cancer. Data were collected through questionnaires on topics related to risk reduction, as well as qualitative content analysis of group interactions. Effectiveness and feasibility were analyzed through conversations and the comparison of the scores obtained in the questionnaires before and after the intervention.P<.001). The intervention enabled women to improve their knowledge on all topics addressed, especially “myths and truths,” “incidence,” “clinical manifestations,” and “protective factors.” Some themes emerged from the interactions in the group, including group dynamics, general doubts, personal narratives, religious messages, daily news, and events.A total of 293 messages were exchanged (moderator 120 and users 173). The average scores of the participants were 11.21 and 13.68 points before and after the educational intervention, respectively, with sufficient sample evidence that the difference was significant (The use of groups for women in WhatsApp for health education purposes seems to be a viable alternative in strategies on breast cancer control, especially as it provides a space for the exchange of experiences and disinhibition. However, the need for a moderator to answer the questions and the constant distractions by members of the group represent important limitations that should be considered when improving this strategy. Breast cancer represents the main cause of death by cancer among women around the world . The morConsidering financial constraints, it is suggested that the most prudent action to be applied in cancer control is the guarantee of early diagnosis and access to treatment without delay ,10. NeveThe wide availability and functionality of mobile devices have made them great tools for planning, executing, and evaluating health interventions ,18. IndeAmong the apps with the potential for use in health education interventions, WhatsApp (WhatsApp Inc) stands out ,28. It iDespite the popularity of WhatsApp and its promising potential in health education and health care strategies ,32-34, oA 3-week pre-post intervention study was conducted among women enrolled in the Brazilian Unified Health System, and a breast cancer screening control study design was adopted to evaluate the feasibility of WhatsApp as an educational tool to increase women's knowledge about the risk reduction and early detection of breast cancer. The study was performed at a basic health unit in the city of Maringá-PR, south Brazil, from July to September 2017. The basic health unit offers free primary care services, including clinical breast examination and mammography, and the annual census reports care for approximately 8000 patients per month. The patient data can be accessed on an electronic information system. The study protocol was approved by the local research ethics committee (protocol number 2.015.313). Written informed consent was obtained from each participant.Participants were adult women aged 45 to 69 years, who were chosen because this is the age group in which the breast cancer incidence is the highest . A samplgn) in each regional strata, corresponding to areas of coverage, was calculated according to the following equation:In the first step, stratified randomization was performed by age group. The number of women necessary to compose the sample , and gp is the prevalence of the characteristics to be researched, which was established as 0.5 for all groups, since there is no previous information.The level of significance considered was α=5%, and the maximum error allowed between the estimate and the real parameter value was e=0.05 . The number of women registered in the After calculation, the finite population correction factor was used as follows:Thus, the sample size obtained with the help of the R Statistical Environment  was 326 women.In the second step, a list was generated from the electronic records of the 326 women in order to identify those who had a cell phone number. After applying this criterion, 110 women were excluded. In the third step, a telephone call was made to the remaining 216 women with the aim to invite them to a face-to-face meeting to explain the study objectives. Among these women, 58 did not answer the calls after three attempts on different days, 45 had incorrect telephone numbers registered, 43 did not show interest in participating in the study, and 14 did not have or use WhatsApp . In the fourth step, only 35 of the remaining 56 women attended the meeting, and sociodemographic data were collected and a questionnaire was applied to identify the knowledge level on breast cancer–related topics.A WhatsApp group, named “AllAboutBreastCancer” (in Portuguese), was created to allocate the 35 women participants, two observers, and one content mediator, who was responsible for sending messages and clarifications. Throughout the intervention, nine women left the WhatsApp group (dropped out of the study) and eight did not answer the questionnaire to identify the knowledge level on breast cancer after 4 weeks of the intervention. Thus, the data of a total of 18 women were analyzed., and they corresponded to risk factors, protective factors, definitions, incidence, clinical signs and symptoms, diagnostic examinations, mammography, myths and truths, and places to seek support. It is a publicly accessible website. However, both the direct sources of content and the information on the existence of the questionnaire to be used were not disclosed at any time during the intervention.Topics related to breast cancer were identified on the Brazilian National Cancer Institute (NCI) websiteFor each identified topic, we selected specific media  and freely available media databases on NCI and Brazilian Ministry of Health websites. In total, two videos, 23 images, and four audios were utilized in the media database.The data were collected at two time points (pre and post intervention) through the application of a two-block structured questionnaire based on information available in the Breast Cancer Early Detection Guidelines, Ministry of Health, and materials from the NCI . In the The score attributed to each question ranged from 0 to 1, with a maximum score of 18 points. The scores of questions 1, 2, 3, 5, 7, 14, 15, and 16, for which all listed alternatives were correct, were calculated as the number of marked alternatives divided by the total number of alternatives. The score of question 4, for which one alternative was incorrect and the other three alternatives were correct, was calculated as the number of correctly marked alternatives divided by the total number of correct alternatives minus one-third if the incorrect alternative was marked, or was considered to equal 0 if the incorrect alternative was the only one marked. The scores of questions 6, 8, 9, 10, 11, 12, 13, 17, and 18, for which only one listed alternative was correct, was calculated as 1 if the correct alternative was marked or 0 if the incorrect alternative was marked.The intervention consisted of daily sessions of text, figure, video, and voice messages during 3 weeks. The mediator followed a content submission protocol to send messages between 9 AM and 9 PM. The content was distributed over the period according to the topics. Additional media were created or adapted by the team, according to the demands and dynamics of the group.Data were analyzed using the R statistical software . For the classification of the level of education, we considered the years of education in Brazil, with middle school (minimum 9 years of education), high school (minimum 12 years of education), and higher education (minimum 14 years of education) levels.t test when its assumptions are not accepted. In this case, the score distribution was not normal (one of the assumptions), so the Wilcoxon test was chosen.To assess the intervention effectiveness, the nonparametric paired Wilcoxon test was applied, with the significance level set at 5%, and the scores obtained before and after the intervention were compared for each individual. The test used is a nonparametric alternative to the paired Inductive content analysis  was applThe preanalysis initially focused on assessment of the 30 most frequent words present only in the user messages, with the goal of identifying the themes that emerged from the group conversations in the original language (Brazilian Portuguese). The parameters used for the preanalysis through the most frequent words in the WhatsApp conversations were as follows: (1) words with four or more characters, (2) words grouped by synonyms, according to the NVIVO 11 Portuguese language dictionary, and (3) exclusion of words that did not have any direct relation to the project content . Two of the authors (TFRL and LFG) applied the analysis, and this step focused on building thematic categories that emerged during the process. The following five categories were created: (1) group dynamics; (2) general questions; (3) personal narratives; (4) religious messages; and (5) daily news and events. The data inference, treatment, and interpretation steps focused on the analysis of the text excerpts of each participant within each category, so that they were characterized in the theme. After the categorization process, a translator assisted with the translation of all sentences in each category from Brazilian Portuguese to English.Regarding the sociodemographic characterization of the women who participated in the study, all were over 30 years old, and 9 out of 18 (50%) participants were aged 50 years. For the ethnic-racial profile, 16 out of 18 (89%) participants declared themselves to be white people. Additionally, 10 out of 18 (56%) participants reported a lower degree of education than a completed higher education, 11 out of 18 (61%) declared being married and having children, and 12 out of 18 (67%) declared living with more than two adults. Regarding family income, 6 out of 18 (33%) participants declared monthly income below Brazilian Real 3,520 (approximately US $850). Regarding religious belief, 17 women declared themselves Christian and 1 Buddhist (data not shown).Concerning life habits, 11 out of 18 (61%) participants reported consuming high-fat foods at least three times a week and consuming fruits and vegetables daily, 15 out of 18 (83%) reported not consuming alcohol or smoking, and 12 out of 18 (67%) reported not practicing physical activity. In addition, 9 out of 18 (50%) participants reported being postmenopausal, 12 out of 18 (67%) reported not using oral contraceptives , and 16 out of 18 (89%) reported not taking hormone replacement therapy . Finally, 12 out of 18 (67%) participants did not report any cases of breast cancer in the family and 13 out of 18 (72%) underwent mammography (data not shown).A total of 293 messages were exchanged (moderator 120 and users 173). From the preanalysis step, it was possible to identify five main thematic categories and three subcategories .The category “group dynamics” addressed group participants’ interventions regarding group functioning. In this sense, the following three subcategories stand out in relation to group dynamics: (1) feedback, in which participants express their feelings about the shared content; (2) self-regulation, in which participants express their discomfort regarding content not related to the theme of the group, thus agreeing on some parameters about the group discussions; and (3) coexistence (mostly short messages), in which participants introduce themselves to the group, wish “good morning,” “good afternoon,” or “good night,” and express some expectations about what the group can offer.The category “general doubts” deals with questions and doubts from the participants mostly about the topic “myths and truths” related to breast cancer. Among the main doubts, there were doubts regarding breastfeeding, contraceptive use, deodorant use, and signs and symptoms that may or may not be related to cancer, as well as lifestyle issues, such as the practice of physical exercise.The category “personal narratives” deals with participants’ personal reports on their knowledge of cancer cases in their social circle, especially in the family.The category “religious messages” is about biblical excerpts shared by users without apparent relation to the group work content.The category “daily news and events” is about the sharing of a public safety event in the city.Regarding factors that increase the chances of developing breast cancer, before the intervention, 9 out of 18 participants mentioned only family history of breast cancer, smoking, and alcohol consumption. After the intervention, all listed factors had a higher frequency of response, and factors, such as consumption of high-fat foods, first pregnancy after 30 years of age, first period before 12 years of age, and end of menstruation after 55 years of age, were mentioned by less than half of the women.Regarding family history, before the intervention, 15 out of 18 participants indicated that having at least one first-degree relative diagnosed with cancer in one breast increases the risk of developing this type of cancer in women under the age of 50 years, which did not change after the intervention. Similarly, most of the participants responded that the risk also includes a family history of at least one first-degree relative diagnosed with cancer in both breasts or ovarian cancer in any age group, which also did not change after the intervention. The increased risk for family history of male breast cancer was only mentioned after the educational intervention by one-third of the participants.Concerning protective factors, before the intervention, 15 out of 18 participants mentioned only diet with many fruits and vegetables, which did not change after the intervention. However, all the other listed protective factors had a higher mentioning frequency after the educational intervention, with breastfeeding as the most frequently mentioned protective factor (16 out of 18 participants).Regarding knowledge about the concept of the disease, before the intervention, 8 out of 18 participants incorrectly pointed out that breast cancer can be a benign tumor. After the intervention, this answer was chosen by only three participants. The most mentioned signs and symptoms before the intervention were small nodules in the underarm (armpit) or neck region and the appearance of a fixed usually painless lump, which did not change after the educational intervention.Regarding the early detection of breast cancer, before the intervention, the three recommendations listed as ways of contributing to early detection were mentioned by 9 out of 18 (50%) participants, with mammography as the main examination for lesion tracking. After the intervention, all of these items were mentioned more frequently. In addition, after the intervention, all of the participants stated that doing the breast self-examination or being asymptomatic does not exclude the necessity for a clinical breast examination or mammography.Nevertheless, after the intervention, most women indicated the correct concept of clinical breast examination and pointed out the recommendation of age range and periodicity for the examination. Lastly, it was observed that all the participants continued to point out that the basic health unit was an ideal place to look for assistance and information regarding doubts or any initial manifestations. After the intervention, all women mentioned “breast cancer is curable.”Regarding mammography, most participants had already scored correctly in the examination concept, maintaining the score after the intervention. However, the same was not observed with the recommendations regarding periodicity, age group, and details about the examination, as most women did not score correctly.After the intervention, all the listed statements were considered as myths with more frequency, and the most mentioned was “large breasts represent a higher risk of developing the disease.”P<.001)  .To our knowledge, this is the first study to use WhatsApp as a health education tool for Brazilian women from the public health system, with a focus on the risk reduction and early detection of breast cancer. The 3-week intervention, which used the app as an online space to mediate content selected from the NCI and the Brazilian Ministry of Health websites, enabled women to improve their knowledge in all topics addressed, especially in “myths and truths,” “incidence,” “clinical manifestations,” and “protective factors.” The app, which is known by women as a daily tool to interact with friends and relatives, allowed a receptive space to solve doubts not commonly discussed during presential care. In general, the results obtained herein suggest that WhatsApp could be incorporated as an additional tool in traditional health communication actions and campaigns.No woman reported having difficulties when interacting with the device or app, or asked for training on how to use it. Many aspects may have contributed to the gains in pre- and postintervention scores. The combination of text, image, video, and audio may partly explain the gain in knowledge. This multimedia aspect differentiates WhatsApp interventions from other mobile interventions that exclusively use SMS text messaging. Mayer  has talkThe data confirm the viability of the app as a health learning tool. However, the majority of articles that describe this type of gain involve health students or health professionals . For exaRegarding the advantages and disadvantages of the use of WhatsApp in health care settings, two positions seem to coexist in the scientific debate. First, one that exposes and underlines all of the positive aspects of the phenomenon as follows: improvement of communication, no requirement for a computer, time saving, possibility of an immediate response, improvement of health worker performance, reduction of consultation time, and smoothening of hierarchy between health groups. Second, one that highlights the negative aspects linked in particular to the clinical risks for patients, data security, and privacy protection .In another promising direction, the app was used in social marketing campaigns to increase the uptake of free mammography for underprivileged women in Malaysia .When compared with other types of media, the advantage of using this timeless tool is always mentioned. Web-based forums on websites are alternatives to debate about breast cancer ,56, and In our case, the group dynamics and feedback shared by the users confirmed that the app is an informal environment of learning. During the intervention process, three women mentioned that they added value to the content and shared the knowledge and media to friends and relatives. This easy possibility to share content with the tool can also extend the impact of our intervention beyond the intended primary target . The parI’m reading it, liking it and learning, and I’m already talking to my friends to share what I’ve learned.…I’m passing it on…Participating in this project was really good, besides from adding knowledge I also pass it on a lot to my relatives, Antonio.In addition to the informal environment, the diversity of women and the quality of grouping them (since they were not a group before the intervention) may have contributed to some conflicts during the intervention (see coexistence and self-regulation messages). There were 35 messages dedicated to self-regulation, where the participants negotiated what kind of content can be shared. Some of the messages were as follows:Hi, what’s up? I don’t think it’s cool to start forwarding chain messages in here. The group has a purpose, let’s just talk about it. It’s better this way Girls, I think everything is relevant, but if this group doesn’t stay limited to scientific information about the subject matter, I will leave the group, sorry.The chain messages are good, but let’s focus on our health.Deviation of the main theme is a natural phenomenon from a diverse group, and the dos and don’ts inside the community were expected to avoid information overload. However, WhatsApp allows copying and forwarding messages of other groups, which has been described by Church and De Oliveira  and was During the intervention process, the creation of a friendly and harmonious interaction environment (a persistence online space) enabled the users to continually handle situations and slowly establish social norms and community parameters. They decided what could and could not be shared between them. In this case, the qualitative data showed two topics that emerged during the intervention, which were not directly related to the initial planned themes, as follows: (1) religious messages and (2) daily news. These deviation topics triggered a heated regulation discussion, causing the drop-out of three women from the group . Although they belonged to the same neighborhood, the fact that the intervention was preventive was not enough to create a sense of identity as in studies involving patients already with the disease. It is relevant to remember that researchers who deal with online social networking emphasize that groups are assembled by common interests and not by geographic location ,63. LikeIn the first case of one of the themes shared among the participants (religious messages), the literature shows that cancer is usually and symbolically associated with death and religious topics . Indeed,The other topic “daily news” occurred after the news “prisoners that escaped the Maringá prison.” The concern about security was shared in the group, advising others to stay safe at home. For an alert (in the sense of “breaking news”), WhatsApp was perceived as a better tool to share information, overpassing the primary goal of the group.We believe that the topics “definitions,” “examinations,” and “mammography” corresponded to the content with the lowest score gain because they are of technical or instrumental nature and require more cognitive resources to memorize concepts, such as age range, conceptual differences, and high-risk criteria. A study performed with 914 women also identified limited knowledge about mammography . The divIn our intervention, information was delivered with emphasis on the recommended age range for the examination and its technical characteristics. Exposure to breast cancer content traditionally puts women in a passive position . Thus, tIn addition, a study analyzing the online search behavior of women on mammography identified that there is a greater interest during the month in which the national campaign called “Pink October” occurs every year . In our Myths and truths about cancer received more interaction and more questions, and similarly, it was the topic that showed gain in the posttest period. We understand that health professionals preferably provide medical information to avoid misinformation. In our case, the tutor was responsible for managing the content by provoking discussions about it.We did not find any studies that discussed women’s knowledge gain related to the deconstruction of popular untruths common in daily life. Given the frequency at which these issues are debated among laypeople and the impact on the behaviors of individuals, such as wearing a bra, using deodorant, and using breast prosthesis, it is assumed that the level of interest and attention to this topic was a variable that contributed to the gain.The doubts formulated by the participants can be compared as “fake news” contents, a key topic of discussion nowadays, which is alarming public health authorities because of its potential to spread quickly  and the Can you say that the intake of pesticides/industrialized products can also influence?Additionally, there were concerns about protective factors as follows:About the breastfeeding… is there a time for this protection? I breastfed my first child for 5 months and now I’m breastfeeding my second child, but I think I won’t be able to do it for much more than 6 months...The cancer theme is indeed very complex. Doubts indicate the need to increase the health literacy of women, and even with the investments in health communication strategies during the month of the campaign “Pink October,” frequent doubts remain.“Pink October” is a set of communication strategies integrated by the NCI since 2010 as part of the National Breast Cancer Control Program, with adherence to several television programs. However, despite the national effort, it was noted in a study from 2013 that the campaign was able to legitimate an audience (people were able to interpret and judge the message conveyed as positive and important), but was not effective for behavior change . It is wA positive moment of interaction was when participants shared family history of cancer. The narratives and descriptions were an opportunity for the mediator to later make some comments about risk factors. The stories were about close relatives as follows: but she travels to Sao Paulo every 6 months to have a follow-up care!I also have cases in my family, my sister decided not to have children and had breast cancer, she found out in the beginning and treated it…Even stories concerning people with no direct genetically bonds were shared as follows:.My mother-in-law had breast cancer 3 years ago, and has now been diagnosed with liver and lung metastasis Another woman recognized the risk factor by considering the genetical factor as follows:.I don’t have any genetic factors or cases in the family, but I am already 55 years old and very sedentary. Take some action, walk! Additionally, previous stories of survival were shared as follows:My maternal grandmother had it. Today she is 94 years old, this was 20 years ago.My mother had it with 45 years old. It’s been 17 years.No death stories were shared. This aspect may have been influenced by the usage context of WhatsApp, which is seen by many users as more informal when compared with SMS text messaging. In a study by Church and De Oliveira , users rRegarding the protective factors, before the intervention, 15 out 18 (83%) women only mentioned eating many fruits and vegetables, which did not change after the intervention. However, all other listed protective factors had a higher frequency of occurrence after the educational intervention, with breastfeeding being the most frequently mentioned protective factor . Not coincidentally, the participants formulated many interactions and questions about breastfeeding as a protective factor during the intervention.Even with formulated doubts, the participants waited for expert clarification. None of the women in the group tried to solve the doubts or answer them. A more dialogical approach, in which women participate more and do not wait for an “expert voice,” can add another perspective. Our intervention may have reinforced a receptive profile to messages rather than the creation of an active approach, recognizing the role in the search of information. These challenges had already been identified in previous group research, which pointed out that women preferred to expose themselves to content already created by health authorities (particularly in the figure of a doctor). This can be the result of the following two aspects: (1) women did not feel as part of a group or had the willingness to collaborate and try to find answers for themselves and (2) there is a passive posture for receiving information about cancer.Despite the “Pink October” campaign in the country, breast cancer still represents a challenge for the public health sector, which needs more efficient screening techniques for early diagnosis. Thus, communication challenges and health education actions encourage alternative communication tools that add up to traditional campaigns. The use of WhatsApp is promising because it is a low investment tool and can act on a massive scale, especially in developing countries, such as Brazil, where there are higher rates, mainly due to the lack of early detection and adequate treatment .The authors acknowledge that the mediation that directed the content may have contributed to the maintenance of a passive posture by the participants on receiving messages. However, during the intervention, owing to the high necessity of the mediator to suggest and deliver content, we perceived a challenge to provide a top-down model of health information release and to place individuals as participants in the teaching process and health learning approach.In addition, we recognize that a more expressive sample is important to perform a more meaningful analysis. Our initial analysis was based on a representative sample size of the target population of the study. However, participant loss was greater than expected. The reasons were diverse but consistent with the peculiarities of the investigated population. Nevertheless, we believe it is relevant to present the results of the statistical analysis, as they enable a better understanding of the phenomena that occurred throughout the intervention when integrated with the qualitative analysis.Lastly, we highlight that even though knowledge gain can create a change in behavior, this is a multifactorial aspect of complex measurement. In our initial proposal, there was a desire to follow the participants in order to observe if the group would continue with new behaviors to reduce the risk of breast cancer after the end of the study. However, owing to the high dropout rate at the beginning of the study and recruitment difficulties, we chose to implement the analysis of knowledge gain.This study explored the use of WhatsApp as a tool to facilitate knowledge exchange for the risk reduction and early detection of breast cancer between women and a content moderator. The results confirm our hypothesis that the app is a useful tool that can be incorporated into health education strategies that focus on breast cancer. Although the intervention improved the knowledge of the participants with regard to breast cancer, they expected that the moderator would send content and solve their doubts, suggesting a need for new strategies directed at the encouragement of dialogic communication. Nevertheless, the results obtained demonstrate that WhatsApp is a feasible online space for women to seek answers for general doubts that are not covered in communication campaigns on breast cancer.


Because of the mixed reports from smaller studies, we examined associations of race with mammographic breast density and evaluated racial differences in the determinants of breast density.Participants included 37 839 women (23 166 non-Hispanic white and 14 673 African American) receiving screening mammograms at the Joanne Knight Breast Health Center at Washington University School of Medicine from June 2010 to December 2015. Mammographic breast density was assessed using the Breast Imaging Reporting and Data System (5th edition). To determine the association of race and participant characteristics with mammographic breast density, we used multivariable polytomous logistic regression models .African American women had increased odds of extremely dense  and reduced odds of heterogeneously dense breasts  compared with non-Hispanic white women. Altogether, race, parity and age at first birth, current age, current body mass index (BMI), BMI at age 18 years, menarche, family history of breast cancer, oral contraceptive use, alcohol use, and menopausal status explained 33% of the variation in mammographic breast density. Among African American and non-Hispanic white women, these factors explained nearly 28.6% and 33.6% of the variation in mammographic density, respectively. Current BMI provided the greatest explanation of breast density .The determinants of mammographic breast density were generally similar between African American women and non-Hispanic white women. After adjustments for confounders, African Americans had higher likelihood of extremely dense breasts but lower likelihood of heterogeneously dense breasts. The greatest explanation of breast density was provided by BMI, regardless of race. In the United States, among those diagnosed with breast cancer, the overall survival from breast cancer has increased by more than 21% because of improvements in breast cancer screening practices and treatment modalities . MammogrHigher mammographic breast density is associated with a four- to sixfold increased risk of breast cancer . It is eTo clarify the association of race with mammographic breast density and to determine whether the determinants of mammographic breast density differ by race, we analyzed data from a large population of women undergoing screening mammograms.Study participants were women undergoing screening  mammograms at the Joanne Knight Breast Health Center at Siteman Cancer Center at Washington University School of Medicine, St. Louis, Missouri, from June 2010 to December 2015. We obtained additional information as part of routine data collection for risk stratification estimation, and investigators returned risk information to women and their providers as part of their care. The Breast Health Center provides mammography services for women from varying socioeconomic and racial backgrounds in the St. Louis region, including those with coverage through breast and cervical cancer screening programs (Centers for Disease Control and Prevention and state funded), the Komen Fund and Barnard Fund coverage for the uninsured, and regularly insured women with private insurance or Medicare coverage. In addition, the Breast Health Center has a breast mammography van that travels throughout the metropolitan St. Louis area to provide mammography services for women within the community setting. For the current study, we excluded women with preexisting cancer (n = 3462); missing information regarding self-reported race and ethnicity (n = 2156); and missing information on mammographic breast density (n = 6226); and those who visit the health center for diagnostics (n = 6740), leaving 37 839 participants included in analyses. The Institutional Review Board at Washington University School of Medicine in St. Louis approved this study (IRB No. 201107282). We obtained informed consent from all participants during visits.Women received digital or tomosynthesis mammogram screenings. Qualitative assessment of mammographic density using the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS 5th edition) included almost entirely fatty, scattered areas of fibroglandular density, heterogeneously dense, and extremely dense. We used the most recent mammographic density information and data collected during participants’ latest visit.As part of routine breast health services, we collected data on breast cancer risk factors including: age; weight; weight at age 18 years; height; family history of breast cancer; alcohol use; contraceptive use; menopausal hormone use; reproductive characteristics such as age at menarche, parity, and age at first birth; menopausal status; and age at menopause . We identified women as postmenopausal based on self-report of cessation of menstrual periods at the time of mammography. Women were considered postmenopausal if they had undergone bilateral oophorectomy and hysterectomy by the time of mammography. Anthropometric measurements  were taken at the time of mammography. We identified whether participants had a first-degree relative  with a history of breast cancer. Average alcohol use over the past year was assessed as nondrinkers, less than 1 drink per month, no more than 1 drink per week, 2–6 drinks per week, and 1 drink per day. Current alcohol use was very low in our study population; hence, we recategorized alcohol consumption into three groups: nondrinkers, current drinkers, and missing. We collected data on oral contraceptive and hormone replacement therapy use. We categorized women as either current, past, or never users based on their self-reported use of oral contraceptives.2 tests for categorical variables, t tests for parametric continuous variables, and Wilcoxon rank-sum tests for nonparametric continuous variables. We calculated age-adjusted proportions for participant characteristics using indirect standardization . To determine the association of race and participant characteristics with mammographic breast density, we used multivariable polytomous logistic regression models  and reported odds ratios (ORs) and 95% confidence intervals (CIs). The interpretations of odds ratios derived from polytomous logistic regression are analogous to odds ratios derived from traditional logistic regression and can be interpreted as the log odds of having either extremely dense, heterogeneously dense, or scattered fibroglandular tissue relative to the log odds of having almost entirely fatty (the referent mammographic breast density category) per unit increase or level comparison in a specific covariate  were missing, we performed regression modeling with multiple imputations using the fully conditional specification method. When estimating imputed values, we included the following variables in the imputation model: race; age; BMI; BMI at age 18 years; parity and age at first birth; family history of breast cancer; alcohol use; oral contraceptive use; hormone replacement therapy; menopausal status; age at menarche; and age at menopause. We used the fully conditional specification method because we assumed that our underlying data were missing at random, and this approach allows for regression estimation among continuous variables and use of the discriminant function among categorical variables ,18. = 26 914); and age at menopause . We assessed collinearity between current BMI and BMI at age 18 years by calculating the correlation and variance inflation factor. There was no evidence of collinearity between current BMI and BMI at age 18 years, because the variance inflation factor was 1.0 and the correlation was 0.49. We repeated these analyses stratified by race; however, we did not include race as a predictor in the race-stratified models. In addition, we examined BMI categories  as an effect modifier and repeated main analysis associating race with mammographic breast density stratified by BMI categories. We examined the multiplicative interaction of race and BMI by introducing an interaction variable within our model and present the corresponding P value for this association.We decided a priori to adjust models for variables that are associated with breast cancer. Therefore, our models were controlled for race; age; BMI; BMI at age 18 years; age at menarche; parity and age at first birth; family history of breast cancer; alcohol use; ever oral contraceptive use; menopausal status; menopausal hormone use  vs nondense breasts . We additionally performed analysis with missing categorized as a level of each covariate and presented these within 2) compared with the non-Hispanic white women .A total of 37 839 women were included in this analysis: 14 673 (38.8%) African American and 23 166 (61.2%) non-Hispanic white women. A flowchart depicting inclusion criteria is presented in P <.001; . The Afr2. Similar, but attenuated, associations were observed for BMI at age 18 years. Postmenopausal status was associated with reduced odds of extremely dense breasts  compared with premenopausal women.The odds of having extremely dense breasts  were higher among African American women, but the odds of heterogeneously dense breasts  were lower when compared with non-Hispanic white women . Age, cuAge at menarche, family history of breast cancer, current alcohol use, and menopausal hormone use were positively associated with mammographic breast density . A 1-yeaWithin each race, we examined associated factors for having dense breast using stratified analysis . Factors2) there was more than 50% increased odds  of having extremely dense breasts comparing African-American with non-Hispanic white women . Women with higher BMI tend to have larger breasts with more nondense tissue . Dr Han was supported by foundations from Barnes-Jewish Hospital and Breast Cancer Research Foundation (award ID: BCRF-17–028). Dr Colditz is supported by the Breast Cancer Research Foundation (award ID: BCRF-17–028). Dr Toriola is supported by grants from the Susan G. Komen Foundation (CCR15332379); NIH/NCI (R21CA216515 and R37CA235602) and Siteman Cancer Center Siteman Investment Program  and NCI Cancer Center Support (grant no. P30 CA091842).The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication.Disclaimer: The authors have no conflict of interests to report.Justin Xavier Moore, Graham Colditz, and Adetunji Toriola conceived and designed the study. Graham Colditz, Catherine Appleton, and Adetunji Toriola oversaw data collection. Justin Xavier Moore and Yunan Han conducted the analysis. Justin Xavier Moore, Yunan Han, Graham Colditz, and Adetunji Toriola contributed to the interpretation of the. Justin Xavier Moore drafted the manuscript and all authors contributed to its critical review.pkaa010_Supplementary_DataClick here for additional data file.


Breast, Ovarian, and Prostate cancer). Upon sequencing and bioinformatic processing, rare coding variants in 14 cancer susceptibility genes were categorized according to the American College of Medical Genetics guidelines and compared between ethnicities. Overall, 107 different variants were identified, the majority of which were benign/likely benign. A pathogenic/likely pathogenic variant was detected in 8.6% and 6.5% of African American and European American cases, respectively, which was not statistically significant. However, African Americans were more likely to have at least one variant of uncertain significance ; they also had significantly more VUSs in BRCA1/2 compared to European Americans . Additionally, 51.4% of African Americans and 32.3% of European Americans harbored multiple rare variants, and African Americans were more likely to have at least one VUS and one benign/likely benign variant , as well as multiple benign/likely benign variants . Moreover, of the 15 variants detected in multiple breast cancer cases, ATM c.2289T>C (p.F763L), a VUS, along with two likely benign variants, BRCA2 c.2926_2927delinsAT (p.S976I) and RAD51D c.251T>A (p.L84H), were determined to be associated with African American breast cancer risk when compared to ethnic-specific controls. Ultimately, B.O.P. screening provides essential insight towards the variant contributions in clinically relevant cancer susceptibility genes and differences between ethnicities, stressing the need for future research to elucidate inherited breast cancer risk.African American breast cancer genetics is less understood compared to European American breast cancer susceptibility. Despite the many advantages of gene panel screening, studies investigating African American inherited breast cancer risk and comparing variant contributions between ethnicities are infrequent. Thus, 97 breast cancer-affected individuals of African and European descent from the Alabama Hereditary Cancer Cohort were screened using the research-based gene-panel, B.O.P. ( The introduction of next-generation sequencing (NGS) and implementation of gene-panel screening have significantly reduced sequencing costs and has enabled the analysis of multiple genes-of-interest simultaneously , 2. As sThere are many breast cancer disparities between African and European Americans . DespiteBreast, Ovarian, and Prostate cancer) [The Alabama Hereditary Cancer Cohort (AHCC) provides an opportunity to study breast cancer genetics in underrepresented individuals . Alabama cancer) , 17. Rar™ 2500 at the Genomic Services Laboratory at HudsonAlpha Institute for Biotechnology. Following capture and sequencing, variants were called using an in-house bioinformatics pipeline [Auburn University Institutional Review Board approved this study. Study participants were recruited and enrolled into a cancer genetic study through IRB-approved protocols, 14–232, 14–335, and 15–111. Informed consent was obtained in writing from all study participants. In total, 97 (35 African American and 62 European American) seemingly unrelated breast cancer cases were selected from the AHCC for genetic analysis based on sequential enrollment. The specific recruitment and enrollment efforts involved for the AHCC were previously described . With avATM (NM_000051), BARD1 (NM_000465), BRCA1 (NM_007300), BRCA2 (NM_000059), CDH1 (NM_004360), BRIP1 (NM_032043), CHEK2 (NM_001005735), NBN (NM_002485), PALB2 (NM_024675), PTEN (NM_000314), RAD51C (NM_058216), RAD51D (NM_001142571), STK11 (NM_000455), TP53 (NM_000546). The depth of coverage of each assessed gene was calculated using DepthOfCoverage tool within the GATK (v.3.4–46) and ranged from 408X-970X  clinical management guidelines regarding the genetic risk of breast cancer and/or ovarian cancer  were sel08X-970X . Only vaD1 NM_00065, BRCA1After filtering, true positives were identified according to criteria established through B.O.P.’s initial analytical assessment . As a reOverall, 107 different (unique), rare coding variants were classified as true positives; since 15 of the unique variants were found in multiple individuals, a total of 129 true positives were identified . Most vap-value 0.016; p-value 0.006; BRCA1/2 compared to European Americans ; African Americans also had more breast cancer cases with multiple benign/likely benign variants, resulting in a p-value trending toward significance , which is a VUS. Interestingly, ATM c.2289T>C (p.F763L), along with two other variants currently classified as likely benign, BRCA2 c.2926_2927delinsAT (p.S976I) and RAD51D c.251T>A (p.L84H), were determined to be associated with African American breast cancer risk when compared to ethnic-specific controls (BRCA2 c.2926_2927delinsAT (p.S976I), which was solely detected in African American cases, was the only variant statistically more likely to be observed in either ethnic group  are sometimes reported through breast cancer risk assessment [A pathogenic/likely pathogenic variant was detected in seven breast cancer cases, representing 7.2% of the total cohort and corresponding to 8.6% and 6.5% of African American and European American cases, respectively. This slightly higher frequency in African Americans was not statistically significant but was similarly observed in a recent report by Jones et al. . Though et al. , the peret al. . For ins history  and are  history , 24, butsessment , but wersessment , 8; thusBRCA1/2 are recognized as the most commonly mutated genes in hereditary breast cancer cases [BRCA1/2 pathogenic/likely pathogenic variants detected in European American cases in this study. This finding is contrary to the results of African Americans for which BRCA1/2 variants represented 67% of the detected pathogenic/likely pathogenic variants. Even though it was unexpected to not observe any BRCA1/2 variants in European Americans, our results corroborate a recent study by Kurian et al. that reported more BRCA1 pathogenic variants in African American compared to European American breast cancer cases [et al. also reported that CHEK2 pathogenic variants were more common in European Americans compared to other minorities. We observed similar results, detecting pathogenic/likely pathogenic CHEK2 variants solely in European Americans. Overall, with African Americans reported to have high genetic diversity and a unique spectrum of variants [er cases . Kurian variants , it is np-value 2.71 X 10−3) [p-value 0.016). This occurrence was primarily a result of the difference in VUSs, being in 40% and 14.5% of African Americans and European Americans, respectively . Even though VUSs were identified in 11 of the 14 assessed genes, there were significantly more BRCA1/2 VUSs in African Americans compared to European Americans. Such differences have been reported since some of the earliest multi-ethnic BRCA1/2 screening studies [Previously, in our initial publication describing the B.O.P. panel, we assessed coding variants  with MAFs ≤2% in cancer-affected cases from the AHCC and identified a significant difference in the number of African Americans with at least one variant compared to European Americans  X 10−3) . Similar studies , 16 and −3 . Simi studies , 13. Thu studies , 27. Thi studies , and AfrATM c.2289T>C (p.F763L), which is a VUS, and two other variants currently classified as likely benign, BRCA2 c.2926_2927delinsAT (p.S976I) and RAD51D c.251T>A (p.L84H). Considering that reclassification rates vary by ancestry and are highest in ethnic minorities [BRCA2 c.9976A>T; p.K3326X, they may be low-risk variants, which are currently not clinically relevant [BRCA2 c.9976A>T; p.K3326X, which we identified in three European American breast cancer cases, is classified as likely benign according to the ACMG guidelines. Ultimately, to truly understand risk, all risk variants will need to be considered, no matter where they fall on the spectrum.Even though ACMG guidelines have been developed for the clinical interpretation of genetic variants in clinically valid susceptibility genes , in realrelevant , 30, 31.BRCA1 and BRCA2 mutation carriers have been identified [p-value 0.084). This overall difference seemed to be specifically related to more African Americans having multiple benign/likely benign variants , as well as at least one VUS and one benign/likely benign variant , the latter being statistically significant. Despite that some of the VUSs could eventually be re-classified as pathogenic/likely pathogenic and associated with high risk, overall these variants may individually only slightly elevate risk and specific combinations of these variants may multiplicatively influence risk of developing breast cancer. Therefore, comparing such rare variant combinations between cases and ethnic-specific controls using NGS approaches will provide essential insight towards polygenic breast cancer risk, particularly in African Americans [NGS, including gene panel screening, detects the full spectrum of variants in the targeted region(s) for each individual screened, which provides an opportunity to explore how combinations of variants contribute towards polygenic risk . Althougentified , 34. ConATM c.2289T>C (p.F763L), BRCA2 c.2926_2927delinsAT (p.S976I) and RAD51D c.251T>A (p.L84H). Additionally, while this study focused on variants with ethnic-specific MAF≤1%, a previous B.O.P. analysis identified a slightly more common, synonymous variant  associated with African American breast cancer  when compared to ethnic-specific controls (MAF of 1.5%) [Lastly, with the launch of NGS, several whole-exome sequencing investigations have been carried out to identify novel breast cancer risk variants; however, the majority of those studies were relatively unsuccessful due to the heterogeneity of breast cancer genetics . Notewor1T>A p.L8H. Additiof 1.5%) , and scrS1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(AA) African American; (Alt.) Alternate; (BC) Breast cancer; (Chr) Chromosome; (EA) European American; (#) esp6500siv2; (Het) Heterozygous; (MAF) minor allele frequency; (Ref.) Reference; (VUS) Variant of Uncertain Significance.(XLSX)Click here for additional data file.


Estrogen is a well‐established risk factor for various cancers. It causes endometrial proliferation, which is assessed routinely as endometrial thickness (ET) using transvaginal ultrasound (TVS). Only one previous study, restricted to endometrial and breast cancer, has considered ET and the risk of non‐endometrial cancer. The aim of this study was to explore the association between baseline and serial ET measurements and nine non‐endometrial hormone‐sensitive cancers, in postmenopausal women, using contemporary statistical methodology that attempts to minimize the biases typical of endogenous serial data.This was a cohort study nested within the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). In the ultrasound arm of UKCTOCS, 50639 postmenopausal women, aged 50–74, underwent annual TVS examination, of whom 38 105 had a valid ET measurement, no prior hysterectomy and complete covariate data, and were included in this study. All women were followed up through linkage to national cancer registries. The effect of ET on the risk of six estrogen‐dependent cancers  was assessed using joint models for longitudinal biomarker and time‐to‐event data, and Cox models were used to assess the association between baseline ET measurement and these six cancers in addition to liver cancer, gastric cancer and non‐Hodgkin's lymphoma (NHL). All models were adjusted for current hormone‐replacement therapy (HRT) use, body mass index, age at last menstrual period, parity and oral contraceptive pill use.P = 0.001), ovarian  and lung  cancers. There were no statistically significant associations between ET and the remaining six cancers.The 38 105 included women had a combined total of 267 567  valid ET measurements. During a combined total of 407 838  years of follow‐up, 1398 breast, 351 endometrial, 381 lung, 495 colorectal, 222 ovarian, 94 pancreatic, 79 bladder, 62 gastric, 38 liver cancers and 52 NHLs were registered. Using joint models, a doubling of ET increased significantly the risk of breast (hazard ratio (HR), 1.21; 95% CI, 1.09–1.36; Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.Postmenopausal women with high/increasing ET on TVS are at increased risk of breast, ovarian and lung cancer. It is important that clinicians are aware of these risks, as TVS is a common investigation. © 2019 The Authors.  What are the novel findings of this work?vis‐à‐vis the only prior study that considered breast cancer. A doubling of ET was found to increase significantly the risk of ovarian and lung cancer in addition to breast cancer.This is the first study to investigate the association between endometrial thickness (ET) and the risk of eight non‐endometrial hormone‐dependent cancers in postmenopausal women, and has much greater power What are the clinical implications of this work?Clinicians performing transvaginal ultrasonography should be aware that postmenopausal women with high/increasing ET are at an increased risk of breast, ovarian and lung cancer.Cumulative estrogen exposure is linked to many types of cancers, particularly female cancersEstrogen receptors are expressed in many tissues, including the endometrium. Cumulative estrogen exposure, especially in postmenopausal women, leads to endometrial proliferation which could be easily assessed as endometrial thickness (ET) using transvaginal ultrasound (TVS). In postmenopausal women, the adipose tissue provides an additional source of estrogen, which in turn causes proliferation of the endometriumUsing a prospective cohort design in the ultrasound arm of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)ClinicalTrials.gov NTC00058032) is a multicenter randomized controlled trial of 202 638 postmenopausal women aged 50–74 years, from England, Wales and Northern Ireland, randomized to annual screening either using TVS  or serum CA125  or to no screening rd June 2000. Participants provided written consent for use of their data in secondary studies. This analysis used data from the ultrasound arm, in which women were offered annual TVS screening between 17th April 2001 and 31st December 2011. We limited the analysis to those who had not undergone hysterectomy prior to recruitment, had complete covariate data and had at least one valid ET measurement.UKCTOCS , breast (C50), lung (C34), colorectal and anal (C18–C21), pancreatic (C25), bladder (C67), liver (C22), gastric (C16) and NHL (C85).All women were flagged with the NHS Digital, for England and Wales and Northern Ireland, Cancer Registry and cancer notifications  included in this analysis were diagnosed by 31Data on hysterectomy, height, weight, current or past use of the oral contraceptive pill (OCP), parity, current use of hormone‐replacement therapy (HRT) and age at last menstrual period (LMP) were captured at recruitmentOf nearly 270 000 ET measurements, 10 values > 50 mm (maximum of 503 mm) were excluded arbitrarily from the analysis. The remaining ET measurements were transformed to the binary logarithmic scale; the calculated hazard ratios (HR) therefore reflect a doubling of ET.The association between ET and each cancer type was explored using joint models, that modeled simultaneously the two related processes of serial measurements over time  and time to clinical outcome . Modeling either process in isolation may introduce biasFor the longitudinal submodel, current use of HRT at baseline and at each ET measurement, age at LMP, body mass index (BMI), parity and OCP use were included as fixed effects, in addition to a subject‐specific random intercept. The survival submodel included the same adjustment covariates, as well as the association parameter that links the two submodels. We specified the current value link, which is the fitted value including random effects from the longitudinal submodel. The baseline hazard was modeled using a Weibull distribution for all cancers except breast cancer, which used a cubic spline model with one interior knot. Further details of the joint model are given in st December 2014Both longitudinal and survival submodels used age as the time metric, implying delayed entry for the survival analysis. Analysis time was defined as from age at first ET measurement to age at cancer diagnosis of interest. Censorship was age at 31stjm’2 ET measurements) and presented graphically for the age range, 50–80 years. One‐, 5‐ and 10‐year absolute risk estimates were calculated for selected cancers, ET measurements and ages.In addition, a standalone longitudinal mixed model, restricted to ET measurements in women with none of the nine investigated cancers or endometrial cancer, was used to construct age‐dependent reference curves at various centiles for normal ET measurements. All statistical analyses were performed using Stata 15.1  and the joint models were fitted using the user‐written command ‘Of 50 639 women randomized to the ultrasound arm in UKCTOCS, 9651 had undergone hysterectomy prior to recruitment and 237 underwent hysterectomy between recruitment and the first scan. A further 1893 women had no ET measurements and 753 (1.9%) women had missing data on at least one of the included covariates. The analysis therefore included 38 105 women who had at least one ET measurement and complete data on covariates  years and 17.4% of women were currently using HRT. Of the women, 88.0% were parous and 60.4% had used OCP.At recruitment, the median age of the women was 60.6  years, median BMI was 25.6  kg/mP < 0.0001) with ET, except for smoking (P = 0.254) and OCP use (P = 0.021). Age and alcohol use were associated negatively with ET, whereas age at LMP, BMI, parity, HRT use and OCP use were associated positively with ET. Figure n = 34 922), based on a stand‐alone mixed model. Median ET was estimated to be 2.91 mm in women at age 50 years, with the endometrium thinning slightly over time to 2.46 mm at age 80.Table ng P = 0.54 and OCDuring a combined total of 407 838  years of follow‐up, 1398 breast, 381 lung, 495 colorectal, 222 ovarian, 94 pancreatic, 79 bladder, 62 gastric and 38 liver cancers and 52 NHLs were registered. For the joint models, there was a slight difference in sample size between the analyses for each cancer type, which was due to the cancer of interest occurring between recruitment and first ET measurement in some cases. The sample size in the six successfully fitted joint models varied from 38 078 (breast cancer) to 38 105  women (Table P = 0.001). This model was the only instance in which a Weibull baseline hazard was not suitable (P = 0.0002). The one‐year absolute risk of breast cancer for a woman aged 50 with an ET of 5 mm was 165 in 100 000 vs 136 in 100 000 for an ET of 2.5 mm. For ovarian cancer, the HR was 1.39  and for lung cancer the HR was 1.25 . A sensitivity analysis specifically for lung cancer, that additionally included alcohol intake and smoking as covariates, yielded a higher HR , although it was not statistically significant (P = 0.066) due to fewer events (157/25469). The association between ET and cancer risk was not significant for colorectal , pancreatic  or bladder  cancer. One‐, 5‐ and 10‐year absolute risks for breast, ovarian and lung cancer at selected ages and ETs are shown in Table In the joint models, there was statistical evidence at the 5% level of a positive association between ET and the risk of three of the six cancer types Table . The strP = 0.015). HR was < 1 for each of the three cancers not fitted by a joint model , but with P‐values > 0.1.Table Figure In this prospective cohort study of 38 105 postmenopausal women with a combined total of 267 567 ET measurements, and over 400 000 years of follow‐up, we report on the association between ET measured using TVS, as a functional surrogate for cumulative circulating estrogen, and the risk of nine non‐endometrial cancers that may be affected by estrogen exposure. A doubling of ET was associated with an increased risk of breast (21%), ovarian (39%) and lung (25%) cancer. There was no association with pancreatic cancer, a non‐significant increased risk of colorectal cancer and a non‐significant decreased risk of bladder, liver and gastric cancers and NHL.Key strengths of this study include its prospective multicenter design, the large cohort size, measurement of ET using a standard protocol and similar ultrasound machines across the centers and over time, completeness of cancer notification through linkage to national cancer registries and long‐term follow up of the cohort. We report for the first time on the association between ET and eight  cancers. The only prior study investigating the association between ET and breast cancerThere is inherent intrasubject variability in ET over time, which may have obscured the association with cancer risk, particularly in a baseline‐only model. Other limitations include the lack of data on histological subtype, which may have indicated stronger associations for those deemed to be estrogen‐dependent. Similarly, we did not have data on HRT type, nor potential confounders such as exercise and diet.et al.The validity of ET measurement as a surrogate for estrogen exposure has been a topic of debate, with Sit et al.vs < 3 mm. However, the latter report was based on 91 breast cancers compared with 1398 in this analysis, which therefore provides more precise estimates and much greater statistical association. Breast cancer was the only analysis for which the estimated hazard function did not rise monotonically with age, and use of a cubic spline demonstrated a notable decline in the risk associated with increasing ET in women over 65 years of age. This may reflect the age range (50–70 years) of the NHS breast‐screening program and associated overdiagnosis in women of these ages. In postmenopausal women, an increase in breast cancer risk has been reported previously in women with high levels of endogenous sex hormones, including E2 and estrone, with odds ratios of 2.00 and 2.19, respectively, when the highest quintiles are compared to the lowestA doubling of ET resulted in a HR of 1.21 for breast cancer, compared with the HR of 2.00 reported by Felix P = 0.018). Trabert et al.We found a strong association between a doubling of ET and ovarian cancer . This increased risk persisted even after inclusion of the additional covariates of alcohol and smoking, which were available for only a subset of women. This is in keeping with the latest belief that estrogen is responsible for augmenting the risk of lung cancer in smokersThe other statistically significant finding was for lung cancer, for which doubling of ET was associated with a 25% increased risk, which would not have been found using the baseline ET value alone , and despite an increase in risk , the association with a doubling of ET was not significant at the 5% level (P = 0.15). Although increasing circulating estrone has been reported to be associated with an elevated risk of colorectal cancerColorectal cancer was the only other common cancer in our study , gastric and liver cancer and NHL, the HRs were around 0.85 or lower and it is conceivable that a significant association might be found with greater numbers. These indications of protective effects are broadly consistent with findings from the limited extant studiesOne of the benefits of using ET as a proxy/surrogate marker for circulating estrogen is its relative ease of measurement. Serum E2 levels are usually measured using a radioimmunoassay. Mass spectrometry is used increasingly because it provides greater specificity and sensitivity, especially for the low E2 concentrations observed in postmenopausal womenIn conclusion, in this study exploring the association between ET measured using TVS and the risk of nine non‐endometrial, potentially hormone‐sensitive, cancers in postmenopausal women, we found that high/increasing ET was associated significantly with an increased risk of breast, ovarian and lung cancer. This suggests that ET may merit inclusion in future risk prediction models for these cancers. While our findings need further validation, clinicians might wish to assess appropriately women with high or increasing ET measurements on TVS who do not have endometrial cancer.U.M. has stocks in Abcodia Ltd., awarded to her by University College London. I.J. is a coinventor of the Risk of Ovarian Cancer Algorithm (ROCA), which has been licensed to Abcodia Ltd. by Massachusetts General Hospital (MGH) and Queen Mary University of London (QMUL). I.J. has a financial interest in Abcodia Ltd., as a shareholder and director, and is entitled to royalty payments via MGH and QMUL from any commercial use of the ROCA.AppendixS1 Supplementary methodsClick here for additional data file.


Background: The field of hereditary cancer syndromes and genetic testing for patients and families is a rapidly evolving discipline, with an emphasis on cancer prevention.Methods: We review the literature regarding the most common genetic syndromes associated with gynecologic malignancies and discuss the management of these conditions. We also examine the logistic process surrounding cancer genetic testing and identify some perceived barriers.Results: Five genetic syndromes are known to be associated with gynecologic malignancies: hereditary breast and ovarian cancer, Lynch, Cowden, Peutz-Jeghers, and Li-Fraumeni. Each is associated with varying risks of breast, ovarian, and uterine malignancies. The National Comprehensive Cancer Network guidelines regarding the management of these syndromes are focused primarily on reducing the risk of developing gynecologic malignancies. However, great complexity is involved with genetic testing for patients and their families, and barriers exist for the widespread use and implementation of such testing.Conclusion: Genetic testing is fundamental to primary cancer prevention and to oncologic care. Physicians, payers, and institutions must work collaboratively to maximize genetic testing with the goals of primary cancer prevention and treatment. Historically, changes to cancer management based on genetic testing results were lacking. However, beginning in 2014, the US Food and Drug Administration has approved some treatments, including poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors for the treatment of women with BRCA-mutated ovarian cancer and immunotherapy for endometrial cancers with microsatellite instability consistent with Lynch syndrome.8In 2015, President Barack Obama executed an initiative that encouraged the development of precision medicine in all disease sites. Precision medicine is medical care designed to optimize therapeutic benefit for particular groups of patients, especially by using genetic or molecular profiling. One of the models for precision medicine in the field of gynecologic oncology is the genetic predisposition to gynecologic cancers, the most common of which are hereditary breast and ovarian cancer syndrome and Lynch syndrome.In this article, we review the 5 genetic syndromes associated with gynecologic malignancies and their management. We also highlight some of the logistics surrounding the evolving subject of cancer genetic testing.9 These mutations increase a woman's lifetime risk of ovarian cancer up to 40% for BRCA1 carriers and up to 20% for BRCA2 carriers.10 Estimates of the lifetime risk of breast cancer for BRCA1/2 mutation carriers range from 41% to 90%. In a sample of 488 women with nonmetastatic breast cancer, 6.1% had a BRCA1/2 mutation, but mutation prevalence decreased with age (12% in women diagnosed at 45 years of age or younger and 3% in women diagnosed at 46 years of age or older).11 Other genes in the homologous recombination pathway, such as RAD51C, RAD51D, BRIP1, PALB2, and BARD1, may also influence breast and ovarian cancer risk and biology.14 Patients with an increased likelihood of having inherited a predisposition to breast and ovarian cancer should receive genetic counseling and be offered genetic testing  screenings. The age to begin screening can be individualized if the family history includes a breast cancer diagnosis prior to 30 years of age. Breast MRI screening is preferred to mammogram in the 25- to 29-year age group because of increased breast tissue density. For patients between 30 and 75 years of age, both annual mammogram and breast MRI should be done, alternating every 6 months. For patients older than 75 years, management should be considered on an individual basis.Recommendations for the medical management of hereditary breast and ovarian cancer are based on an appreciation of the increased risk for cancer and the early onset of disease. For a woman who is a carrier of a BRCA1/2 mutation, the National Comprehensive Cancer Network (NCCN) guidelines suggest that training in breast awareness with monthly self-examinations should begin at 18 years of age, and semiannual clinical breast examinations should begin at 25 years of age.17Counseling for women with a confirmed BRCA1/2 mutation includes discussion of risk-reducing mastectomy and/or risk-reducing salpingo-oophorectomy. Risk-reducing salpingo-oophorectomy is the standard of care for ovarian cancer risk management in BRCA1/2 carriers. For women who do not elect risk-reducing salpingo-oophorectomy, screening with transvaginal ultrasound (TVUS) and the cancer antigen 125 (CA-125) test can be considered every 6 months. However, providers should acknowledge the lack of high-quality data to inform these recommendations, and some patients may reasonably prefer not to undergo screening. In a cohort of 888 women carriers of BRCA1 or BRCA2 mutations who underwent screening with annual TVUS and CA-125, 5 of 10 cancers were diagnosed in women who had had normal screening results 3 to 10 months previously. Eight of the 10 cancers were stage III at diagnosis.18 Women with Lynch syndrome also have a 25% to 50% lifetime risk of colorectal cancer, a somewhat lower risk than their male counterparts.19 Other cancer risks include pancreatic, central nervous system, and urothelial malignancies. Patients with an increased likelihood of having Lynch syndrome should receive genetic counseling and be offered genetic testing . Women with Lynch syndrome have increased risk for endometrial and ovarian cancers. The lifetime risks are 20% to 71% and 0% to 13.5% for endometrial and ovarian cancer, respectively. testing .1516 No clear evidence supports routine screening for gynecologic cancers in these carriers. Annual endometrial sampling can be considered beginning at 30 to 35 years of age.20 Routine TVUS and CA-125 screening is not typically recommended because these screening tests have not been shown to be sufficiently sensitive or specific.21 Colonoscopy should be performed every 1 to 2 years starting at age 20 to 25 years or 2 to 5 years prior to the earliest familial cancer diagnosis. Additional cancer screening can be considered based on the specific gene mutation.The NCCN guidelines suggest that carriers of MLH1, MSH2, MSH6, or PMS2 mutations consider total abdominal hysterectomy and/or bilateral salpingo-oophorectomy when childbearing is complete.23 The lifetime risk for breast cancer for women diagnosed with Cowden syndrome has been estimated at 25% to 50%, with an average age of 38 to 50 years at diagnosis.23 Thyroid disease, including benign multinodular goiter, adenomatous nodules, and follicular adenomas, has been reported to occur in approximately 30% to 68% of adults with PTEN mutations,24 and the lifetime risk for thyroid cancer has been estimated at 3% to 10%.22 Macrocephaly and autism spectrum disorders are strongly associated with Cowden syndrome.25 Patients with an increased likelihood of having Cowden syndrome should receive genetic counseling and be offered genetic testing  2 or more Peutz-Jeghers-type hamartomatous polyps of the small intestine; (2) mucocutaneous hyperpigmentation of the mouth, lips, nose, eyes, genitalia, or fingers; and (3) a family history of Peutz-Jeghers syndrome.Peutz-Jeghers syndrome is characterized by gastrointestinal polyps; mucocutaneous pigmentation; and elevated risk for gastrointestinal, breast, and nonepithelial ovarian cancers. The syndrome is associated with mutations in the STK11/LKB1 gene. The breast cancer risk in women with Peutz-Jeghers syndrome is 8% at 40 years of age, 13% at 50 years, 31% at 60 years, and 45% at 70 years.30 As with other hereditary syndromes, screening for ovarian cancer in women with Peutz-Jeghers syndrome is controversial, given the lack of proven benefit in reducing mortality from ovarian cancer.17 However, TVUS can be considered beginning at age 18 to 20 years. Monthly breast self-examinations for women with Peutz-Jeghers syndrome starting at age 18 years and annual breast MRI and/or mammography starting at age 25 years are suggested.30Women with Peutz-Jeghers syndrome are advised to undergo annual screening for cervical cancer (including Pap smear) starting at age 21 years.31 Li-Fraumeni syndrome is associated with a high lifetime risk for cancer; an analysis from the NCI Li-Fraumeni Syndrome Study (n=286) showed a cumulative lifetime cancer incidence of nearly 100%.32 Li-Fraumeni syndrome is characterized by a wide spectrum of neoplasms occurring at a young age, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.33Li-Fraumeni syndrome is a rare hereditary cancer syndrome associated with TP53 mutations. Only approximately 300 families with Li-Fraumeni syndrome are listed in a registry maintained by the National Cancer Institute (NCI).34: (1) a member of a kindred with a known TP53 mutation; (2) a combination of an individual diagnosed at 45 years of age or younger with a sarcoma and a first-degree relative diagnosed with cancer at 45 years of age or younger, and (3) an additional first- or second-degree relative in the same lineage with cancer diagnosed at younger than 45 years of age or a sarcoma diagnosed at any age.Classic Li-Fraumeni syndrome diagnostic criteria, based on a study by Li, Fraumeni, and colleagues involving 24 Li-Fraumeni syndrome kindreds, are the following16 Annual breast MRI and mammography beginning at age 20 years (or at the age of earliest known breast cancer in the family if younger than 20 years) are recommended because of the very early age of onset of breast cancer in families with Li-Fraumeni syndrome.The NCCN recommendations for breast cancer screening in patients with Li-Fraumeni syndrome are similar to those for BRCA-related breast and ovarian cancer syndrome management, although screening is recommended to begin at an earlier age.15Genetic risk assessment starts with a detailed family history, even for patients who already meet testing criteria, because some women might be best served by testing for multiple genes or syndromes. Genetic testing requires informed consent that should include pretest education and counseling concerning the risks, benefits, and limitations of testing, including the implications of both positive and negative results. False negative results are a risk, and uncertainties are associated with genetic variants of unknown significance. Posttest counseling should include education on risk-reduction strategies.The family member affected with cancer has the highest likelihood of carrying the mutation and thus should be tested first whenever possible. If more than one family member is affected, members with the following factors should be considered for testing first: youngest age at diagnosis, bilateral disease or multiple primaries, and most closely related to the proband. Testing of unaffected individuals should only be considered when an appropriate family member is not available for testing . Another important consideration is that family histories change over time and should be reassessed regularly. For example, patients and family members may have had a hysterectomy and/or ovarian removal which may mask the number of cancers identified in a family.35Genetic assessment for Lynch syndrome, in contrast to BRCA1/2 mutation, may be performed first through tumor testing. Immunohistochemistry for the 4 most common mismatch repair proteins is inexpensive and available through most pathology laboratories. Loss of mismatch repair proteins can direct targeted germline genetic testing. The distinction between germline testing and tumor, or somatic, testing is noteworthy. Germline mutations are present in germ cells at conception and can be inherited by future generations, in contrast to somatic mutations that occur after fertilization and are only perpetuated through mitosis within a specific cell lineage or neoplasm.12 Hereditary cancer panel testing is designed to detect mutations in a menu of genes that might contribute to cancer risk and can identify a more robust population of women at increased risk of cancer. The disadvantages of panel testing include a higher rate of variances of unknown significance and findings of deleterious mutations in unexpected genes on a panel test. With the increasing number of cancer susceptibility genes identified, multiplex testing of many cancer susceptibility genes has become increasingly attractive as a cost- and time-efficient testing strategy.The indications for and implications of gene-specific testing vs multiplex/panel testing are another testing issue. Following the discovery of BRCA1/2, it was apparent that these 2 genes were not responsible for all familial cases of breast and ovarian cancer.36 However, an obstacle to communicating results is a patient's potential lack of desire to inform relatives, secondary to the emotional burden of cancer or a guilty sentiment about possibly passing a mutation to her children. Therefore, a nonjudgmental environment and practical resources to help patients understand the meaning of a positive test are essential.If a hereditary syndrome is identified, the affected patient is faced with communicating the results and recommendations for cascade testing to her relatives. Cascade testing is genetic counseling and testing of blood relatives of individuals who have been identified with specific genetic mutations. Testing protocols and interventions may save lives and improve the health and quality of life for these family members.37 the following provisions afford some level of protection:38The Health Insurance Portability and Accountability Act (1996) specifically states that genetic information in the absence of a current diagnosis of illness does not constitute a preexisting condition.39Executive Order 13145—To Prohibit Discrimination in Federal Employment Based on Genetic Information (February 2000) prohibits federal executive branch agencies from discriminating against applicants and employees on the basis of genetic information.40The Genetic Information Nondiscrimination Act (May 2008) prohibits group health plans from denying coverage to a healthy individual or charging higher premiums based solely on a genetic predisposition to developing a disease in the future.Most women and their families are empowered by informative results of genetic testing. However, availability of health insurance coverage and other types of health care discrimination for those identified as mutation carriers are concerns. While legal protection against genetic discrimination is not complete,42 Multiple factors may contribute to low testing rates, including lack of physician awareness or time to fully assess family history, lack of patient acceptance, delays and/or denials by third-party payers, variable availability of genetic counseling professionals, lack of reimbursement for genetics professionals, racially and culturally disparate populations, and/or uninsured populations.43Despite strong support from the United States Preventive Services Task Force and the NCCN, genetic testing rates remain low. Genetic testing is universally recommended for women with ovarian cancer, but the testing rates in this population are estimated to be 20% to 30%.46 Reducing financial barriers to genetic testing may improve access to services, especially among medically underserved, uninsured, or impoverished patients.Improvements in awareness of hereditary cancer, availability of genetics services, and communication of the importance of genetics evaluation can increase the rates of genetic testing. Strategies for increasing patient access to genetics services include telegenetics ; group counseling sessions; integration or embedment of services within specialty oncology clinics; initial genetic testing performed by nongenetic clinicians; quality improvement initiatives; and other clinic support tools such as video education, computer-assisted family history collection, and patient navigation.Many barriers to widespread genetic testing for patients and their families exist, but genetic testing of individuals who meet testing criteria is fundamental to oncologic care. Physicians, payers, and institutions must work collaboratively to maximize genetic testing with the goals of primary cancer prevention and treatment.