The incidence and prevalence of endometrial cancer is increasing globally. The main factors involved in this increase have been the way women live today and what they eat and drink. In fact, the obesity pandemic that is sweeping across the planet is considered to be the main contributory feature. This review aims to introduce to a new audience, those that are not experts in the field, what is known about the different types of endometrial cancer and the mechanisms for their induction and protection. We also seek to summarise the existing knowledge on dietary and lifestyle factors that prevent endometrial development in susceptible populations and identify the main problem in this arena; the paucity of research studies and clinical trials that investigate the interaction(s) between diet, lifestyle and endometrial cancer risk whilst highlighting those areas of promise that should be further investigated.Endometrial cancer is the most common cancer affecting the reproductive organs of women living in higher-income countries. Apart from hormonal influences and genetic predisposition, obesity and metabolic syndrome are increasingly recognised as major factors in endometrial cancer risk, due to changes in lifestyle and diet, whereby high glycaemic index and lipid deposition are prevalent. This is especially true in countries where micronutrients, such as vitamins and minerals are exchanged for high calorific diets and a sedentary lifestyle. In this review, we will survey the currently known lifestyle factors, dietary requirements and hormonal changes that increase an individual’s risk for endometrial cancer and discuss their relevance for clinical management. We also examine the evidence that everyday factors and clinical interventions have on reducing that risk, such that informed healthy choices can be made. In this narrative review, we thus summarise the dietary and lifestyle factors that promote and prevent the incidence of endometrial cancer. What people eat (dietary patterns) and how they live (lifestyle habits) are the main modifiable risk factors associated with the development of cancer . KeepingFor cancers in women, this is of particular importance because oestrogen generated from the fats and lipids stored in adipose tissue or produced by the adrenal cortex are known to be associated with breast, ovarian and endometrial cancer (EC) ,12,13,14This review will focus on the underlying mechanism(s) for the development of EC in relation to these factors, dietary patterns and lifestyle habits ,37,38,39A literature search of the Embase, Medline, ClinicalKey, CINAHL and PubMed databases was conducted (from 1974 to May 2020) with the following search terms .ti,ab) AND (*“Diet”/OR (“lifestyle*”).ti,ab)) [Publication types Article OR Conference Paper OR Journal OR Review] [English language] [Female] [Human age groups Adult 18 to 64 years OR Aged 65+ years] [Humans]’ and yielded 523 PubMed/Embase results and 579 Medline results. Duplicate or irrelevant references were omitted revealing 154 directly applicable citations. The Cochrane systematic reviews database was also searched using the search terms “heathy lifestyle index” and “endometrial cancers” and generated three articles (one from 2015 and two from 2018). The reference lists of these were also scanned, aided by citations provided by the article reviewers and additional references obtained. Only literature supportive of the statements used are provided.EC is the 4th most common cancer affecting women in the United Kingdom, accounting for 5% of all new cases annually. It is the 8th most common cause of death in women in the UK, with 34% of the EC cases considered to be preventable . It is mAlthough EC incidence has historically been much lower in Asia, Africa and South America  40,41,4,441,42, 2), but this association was no longer evident among users who had previously used HRT  than with type 1 EC (5–14%) (PTEN mutations are associated more with type 1 EC (64–80%), than with type 2 EC (serous carcinoma (2–3%), carcinosarcoma (11–33%) and clear cell carcinoma (0–21%)). Details on other TCGA gene mutations  groups B. Copy ner group . Linkinger group , but in  (5–14%) B 71]. B. BPOLE g therein ,73. ObviFirstly, it is known that long-lasting and widespread use of unopposed exogenous oestrogen therapy by postmenopausal women for the treatment of perimenopausal and postmenopausal symptoms  increases the risk of developing endometrial pathologies, such as epithelial cell hyperplasia, cystic gland formation, polyp formation, adenomyosis, leiomyomata and in some cases these pathologies converge into type 1 EC in susceptible women ,85. ManySecondly, extended longevity, resulting in a higher median age for women, results in a promulgation of these effects such that DNA or oxidative damage and other DNA/RNA/ miRNA mutational events accumulate in affected cells and so create the focus for endometrial hyperplasia that is a precursor for the early stage development of EC ,88. ThisA third factor is a sedentary lifestyle . As womeAdditionally, a sedentary lifestyle and a daily routine that does not include any physical activity are thought to play a role because increased risk of insulin resistance leading to the development of type 2 diabetes mellitus ,96. TypeA fourth and final contributory factor, is changes in diet that involve altered absorption and reabsorptions of sterols, since they can alter the regulation and metabolism of oestrogens . This efTP53 [PTEN [HER2-neu, which responds to the actions of epidermal growth factor (Although most women (80–90%) present with endometrioid (oestrogen-dependent) EC, there are a minority that present with the most difficult form of EC to treat; Type 2 EC (oestrogen-independent), which tend to be an adenocarcinoma-like tumour but not driven by oestrogen  38,74,1,118,119.TP53 ,128,129,53 [PTEN  or over-h factor  [130,131TP53 mutations in EC too. Furthermore, an increased risk of TP53 gene mutations in breast cancer patients due to extended alcohol consumption has been reported [TP53 mutagenesis, then excess alcohol consumption puts women at risk of developing p53 mutations, and that leads directly to the development of breast and other cancers. Another factor that needs consideration is a Western diet, which consists of a high glycaemic index (amount of sugar absorbed into blood over 2 h), red meat and processed food that is known to contribute to colon cancer development, also through a TP53 missense mutation [Because dietary factors, lifestyle and environmental factors are known to affect p53 function in hepatoma cancer reported ,139,140 reported ,143,144,reported . Some inreported . The autreported . Since fmutation ,147. TheDiabetes mellitus and hyperinsulinaemia are associated with EC ,150,151.POLD1 mutation is now known to be associated with increased risk of EC but the POLE mutation seems to be protective [There are also hereditary syndromes that affect the gastrointestinal tract that predispose some women to simultaneous or later development of EC . Many ofotective ,70.Prominent mechanisms by which metformin combats EC appear to be through promotion of progesterone receptor expression and the reversal of progestin resistance ,167. SinNatural progesterone also exerts several anti-cancer effects in endometrial tissue, primarily related to cell differentiation. In one experimental study, administration of progesterone to EC cells reduced cancer cell proliferation by activating the metabolic regulators p21 and p27 . In addiProgesterone also augmented the anti-tumour effects of vitamin D by upregulating the expression of the vitamin D receptor in EC cells , whilst EC appears to be especially influenced by dietary and lifestyle factors  with a vDietary omega fatty acid composition increases the risk of developing several diseases, including cardiovascular disease and cancer. There are two primary omega fatty acids: omega-3 lipids and omega-6 lipids, differentiated by their chemical structure. Omega-3 lipids are generally viewed as exerting anti-inflammatory action, whereas their omega-6 counterparts are easily metabolised into pro-inflammatory end products . Given tOne of the healthiest eating styles in the world is the so-called “Mediterranean diet”, a traditional dietary pattern of populations of the Mediterranean region that includes the Southern European states, the North African states and those of the western fringes of the Middle East . This diVitamin A is an essential vitamin that is found in plants and stored in the liver. It is part of a family of pigments found in plants called the carotenoids, which are normally yellow. The most well know of the carotenoids is called beta-carotene, which under the actions of bile acids is converted in retinal, then into the active form of vitamin A. Vitamin A and some vitamin A derivatives, are active at retinoic acid receptors where they act as transcriptional regulators . On actiAs stated above, vitamin C may aid in the prevention of EC. This vitamin (ascorbic acid) has been reported in many studies to significantly reduce the risk of developing EC ,221,222.It is now clear that in vitamin E consumption results in a significantly reduced risk of developing EC ,215. ManVitamin E naturally occurs in more than one form, with each form having a different level of biological activity) . Of the Selenium is an essential micronutrient required for numerous metabolic processes throughout the body . GynaecoEverybody knows that calcium is good for healthy teeth and bone. It is found in many dairy products and in its ionic form is intimately involved in the release of hormones from endocrine glands, neurotransmitters from nerves, initiating muscle contraction, and for maintaining bone . It is a2+ ion which acts a weak oestrogen [2+ ions [Cadmium is a chemical element that is ubiquitous in Nature and is found in air, water, soil and plants. It is also extracted from rocks and processed in order to make the expanding nickel-cadmium (Ni-Cd) battery industry. These batteries are increasingly used in many modern electronic devices. Exposure to cadmium is greater in industries where it is processed and ingested from contaminated hands, from plants that absorb it from the environment, or from cigarette smoking . In the estrogen ,262, binestrogen . Studiesestrogen ,265 in bestrogen . By cont[2+ ions  despite [2+ ions . DespiteIn conclusion, the role of vitamins and minerals in providing protection against EC is only partially supported by scientific consensus ,37 and aPhytoestrogens have long been known to ameliorate perimenopausal symptoms and have significant health benefits in postmenopausal women. The key natural phytoestrogens found in plants such as flaxseed and sesame are the lignans . The actSoya beans and other legumes contain significant amounts of isoflavones, as do green tea, red clover, lentils and flaxseeds. Increased ingestion of such food results in lower EC risk . PostmenCoffee consumption has been linked with a reduction in the development of all types of oestrogen-driven cancers, including EC ,300,301,Drinking green tea has historically been associated with reduced incidence of many cancers ,312. TheAgaricus blazei Murill Kyowa, ABMK) looks a little like a chestnut mushroom and the family includes the common button mushroom used in kitchens throughout the world. This particular mushroom and its extracts has been studied in cancer patients in two clinical trials. In one study of 100 women with gynecological cancers, including those with EC, found that chemotherapy could be improved by 6 months supplementation with ABMK extract whereby there was increased anti-cancer immune natural killer cell activity [The agaricus mushroom  but is now more commonly extracted from the skins of grapes. In vitro studies using several uterine models indicate that resveratrol not only inhibits cancer growth, but also initiates apoptosis [Resveratrol is a polyphenol molecule first identified n Japanese knotweed  that significantly inhibits cancer cell proliferation through numerous cellular targets . It alsoCruciferous vegetables such as cabbage, cauliflower, radishes, broccoli and Brussel sprouts all contain high concentrations of indole-3-carbinol (I3C), which in vivo is rapidly converted into diindoylmethane (DIM) . DIM posRats genetically prone to developing EC, and given a diet for 660 days that was supplemented with I3C, had a lower EC rate when compared to similar rats fed a standard diet . The autMelatonin, is a natural hormone produced by the pineal gland that regulates energy metabolism and sleep patterns . It is pIn conclusion, the role of plant derived materials and hormones in the incidence of EC is stronger than that for vitamins and minerals. Some organisations, such as the IARC , the WorIt is been known for many years that a diet rich in mono-saturated and trans-fats are detrimental to the development of cancers and that diets rich in plant foods are beneficial , yet theThe biggest study designed to investigate the relationship between nutrition and cancer is the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which is an ongoing multi-centre prospective cohort study . It is wAarestrup and colleagues in 2012 conducted a study investigating the association of whole grains and dietary fibre with the incidence of EC in Danish women and showed there to be no clear associations between intake of whole grains or dietary fibre and the incidence of EC . In addiThese studies performed in China, the United States of America, Canada, Mexico and Denmark provide limited and inconclusive evidence regarding the association of these modifiable factors with the risk of developing EC. To our knowledge, no study has yet been performed to determine the association of dietary pattern and lifestyle habit with the risk of developing EC among women in the UK, although there is an on-going study (ISRCTN1538157) that is examining the effect of general weight loss through a 12 month weight loss programme on the incidence of endometrial cancer (and breast cancer); the results are awaiting trial completion in 2023. In women previously diagnosed with endometrial cancer, a pilot trial (NCT02433080) on the general effect of diet and exercise on quality of life by questionnaire demonstrated a significantly improved quality of life (difference of 8.9) at 24 weeks, but suffered from small sample numbers (29 in the intervention group and 31 in the control group), with incomplete follow-up . In the In an on-going phase II clinical study (NCT03192059), curcumin is under evaluation as an adjuvant (food supplement) in patients with advanced and/or refractory cervical cancer, endometrial carcinoma or uterine sarcoma who are simultaneously being treated with an immunomodulatory cocktail , followed by pembrolizumab, combined with radiation . No prelIn preparing this manuscript it has become increasingly obvious that research into the effects of nutrition, diet and lifestyle on the prevention of cancer and general health is difficult . AlthougTo move forward, a new generation of studies need to be created to improve estimates of long-term exposure with, for example, repeated dietary records, which are now feasible using web-based questionnaires ,397 evenIn all of these cases, the best model for study is the patient at highest risk of developing EC and that is the adult woman. Although other models, such as human and animal cell lines, rodent, primate and other animal models (including xenobiotic implants) are useful in defining the molecular mechanisms and physiology of interactions between food, nutrients and EC risk, they are not as useful for studying interactions between lifestyle interventions , even if the recovering EC patient does not adhere to advice . There iAlthough there is substantial evidence that moderate levels of physical activity, bearing children, delayed menopause and eating foods that are rich in lutein (fruits and vegetables) can protect against obesity and the associated conditions of hyperinsulinaemia and metabolic syndrome and the risk of developing type 2 diabetes mellitus  and thatRecommendations for women wishing to prevent EC and for those wishing to prevent recurrence, are difficult and although the global incidence of EC is increasing, prevention can be achieved if the patient modifies her diet and lifestyle. Women at risk should; (1) lose weight (if overweight or obese (as many EC patients are)) since doing so can reverse their risk of developing hyperinsulinaemia; (2) eat a diet rich in protein but with a low GI that contains wholegrains, vegetables, fruits and legumes, whilst reducing their consumption of foods that are high in fat, sugar or starch, red or processed meats. They should also (3) restrict their alcohol consumption, but drink 2–3 cups of filter coffee per day instead, because this aids the ‘slimming’ process and may reduce the risk of recurrent disease, or drink 1–2 cups of green tea, and although the evidence is limited, (4) make sure that she spends at least 20 min every day doing some form of moderate to intense exercise, since this aids the ‘slimming process’ and reduces the risk of entering a chronic inflammatory state , but especially gynaecological cancers such as EC.


Purpose: We qualitatively evaluated breast cancer survivors’ perception of the relation between breast cancer development and both childhood trauma and stressful life events in adulthood.Methods: Women (N = 50) who have or had a positive breast cancer diagnosis completed a close-ended survey, a timeline of significant life events, and an in-depth interview. All interviews were transcribed and inductively coded using thematic analysis with an emphasis on patient perspectives of illness.Results: Participants reported a perceived connection between breast cancer development and stressful life events, and four themes were identified: 1) experiencing major interpersonal stress in both childhood and adulthood, 2) ideas about the relationship between emotional stress and physical disease, 3) ideas about how different types of stress contribute to developing breast cancer, 4) post-treatment post-traumatic growth and meaning-making.Conclusions: Our findings suggest that of the participants who felt something could be causally attributed to their developing breast cancer, most of them made causal attributions between social, personal, and physical stress and trauma across the lifetime to the aetiology of their breast cancer. We suggest that breast cancer patients and survivors may benefit from additional psycho-social, stress-reducing, and/or somatic-based trauma-informed therapies to address stress and trauma. Breast Cancer is the most common cancer diagnosis in women worldwide , as connected to their breast cancer development?” We hypothesized that individuals might perceive the triggering of childhood trauma in adulthood as precipitating their breast cancer diagnosis. To investigate this hypothesis, we conducted an exploratory qualitative research study to evaluate survivors’ perceptions of the relationship between lifetime trauma and breast cancer development.We recruited participants through the Institute of Noetic Sciences (IONS) listserv, blogs, general eNewsletter , Community Groups-specific eNewsletter, targeted email outreach, through IONS associated social networks , as well as our affiliate organizations’ social networks, women’s cancer centres, and social media pages. Fifty American women who had or currently have breast cancer were recruited to participate in the study. Study activities were approved by the Institute of Noetic Sciences Institutional Review Board (IRB) WAHH_2018_04. All participants met the following inclusion criteria: women, ages of 35–90, breast cancer diagnosis , and currently accessing (or had regular access to) mental health resources at the time of the study.Women who completed the screening and were eligible for the study were contacted by a research coordinator and provided with an online written Informed Consent. Consenting women completed an online questionnaire, a health and lifetime events timeline, and participated in a 1-hour phone interview. Participants who completed all three study activities received $150 for their participation in the form of a Visa Gift Card.surveymonkey.com), which allows for HIPAA compliant data collection and provides detailed tracking of invitations and survey completion. Surveys were collected between 3 May 2019, to 17 July 2019. The survey included demographic information, general health, lifestyle questions, and breast cancer history .Each participant completed a 45–60 minute structured interview conducted by one of three researchers trained in interview and qualitative research methods. Probing questions were designed to elicit conversation about the overall research question and the timeline. To this end, the interview included questions on the following topics: 1) the event they believe impacted their life the most 2) events they believe reduced their vitality  3) any perceived connections between their childhood and adult experiences 4) events that they believe are associated with their developing breast cancer 5) experiences that increased or diminished a sense of “feminine nature” 6) their relationship with their mother or mother figure, 7) feelings of helplessness, hopelessness, anger or rage, and 8) any experiences with post-traumatic growth . The interview questions also referred to the participants’ timeline.The interviews were conducted and recorded via Free Teleconference and subsequently transcribed and uploaded to Dedoose, a qualitative analysis program . The recordings and transcriptions were de-identified before they were stored.One researcher (EN) analysed the data using qualitative thematic analysis consisting of six steps , no breast cancer diagnosis (16), other cancer diagnoses (24), no mental health care (116), did not complete the survey (19), resulting in a final sample size of 50 women, all of whom did each of the three parts of the study. Percentages, means, and standard deviations of demographic variables, lifestyle factors, and breast cancer parameters are reported in Four major themes were identified: 1) Experiencing major interpersonal stress in childhood and adulthood , 2) ideas about the relationship between emotional stress and physical disease , 3) ideas about how different types of stress contribute to developing breast cancer  and 4) post-treatment post-traumatic growth and meaning-making . The themes are reflected in Most of the participants spoke of experiencing recurring interpersonal conflict across their lifetimes. Stressful or traumatic events in childhood and relational conflict in adulthood were experienced in varying degrees by nearly all the participants. Nearly every participant described adverse events that occurred in childhood as significantly impactful to them. Various types of relational stress in childhood were discussed, from more mild stressful events such as a general feeling of low self-esteem or feeling “left out” to more extreme stressful events such as bullying, emotional, verbal, sexual, or physical abuse. In adulthood, nearly all the participants described the recurring stressful interpersonal conflict with others, primarily concerning romantic, familial, and professional relationships, significantly impacting their lives.… I think it was just like … a series of events, or … the way my parents were raised was the way that they raised us, which wasn’t perfect … a lot of sort of verbally abusive comments, and some bullying …The majority of participants recalled a variety of events in their childhood that they considered to be stressful. These events involved parents, family acquaintances, and peers. They included relational issues such as bullying or abuse and uncomfortable feelings of confusion, and low self-esteem. For example, one participant described how they felt their parents mistreated them as a child:… Although I don’t remember experiences about a trauma as a kid, with the reflection and therapy and counseling that I’ve had throughout my lifetime I really think that sort of like … neglect … had the biggest impact of all those things … for most of my life I felt like it wasn’t in a real conscious way … like I had a low perception of my worth … And that has been challenging … I know it just thinking that I’m not that valuable. Sort of (on) a core, subconscious level.Another person described a feeling of low self-worth as a child:… I would say the biggest impact were the assaults that happened to me at age, I think I was 13. I might have been 12, but in any event, it was in junior high. That I think was huge, more than I ever realized …Another participant described the experience of sexual assault, which significantly impacted their life:… I remember, especially in junior high … I just felt very hopeless about going to school every day. I knew I was just going to get teased and tormented and feel really uncomfortable. I know I’ve had a lot of moments where I’ve just felt hopeless about making friends.Another person remembered feeling hopeless as a child due to being bullied at school:… My children totally cut me off because they blamed me for being responsible for the divorce, and that was fueled very much by (my ex-husband’s) new wife who played on that as much as she could. So, I lost my communication with the two most important … people in my life, my children. And, you know, you think of your breast as being the source of their nourishment when they’re babies. And that’s why I think it affected me there.In addition to childhood stress, participants frequently mentioned experiencing stress in adulthood. The majority of this conflict was interpersonal and stressful, and included family, romantic partners, friends, children, and co-workers. One participant felt that issues with her ex-husband and children were particularly stressful:Well, I guess just from a trauma standpoint, I do EMDR now, a type of therapy, and she says we work with ‘little t’ trauma. It’s funny, I feel like I’m one of very few women that hasn’t been sexually abused, or raped or something, and obviously those are ‘huge t’ traumas … the divorce for me, I remember having this feeling of my daughter is getting pulled away from me …. And I felt like my heart was just getting ripped out of my body. I’ve never felt anything … like I couldn’t breathe, I couldn’t cry, I just felt like I was getting ripped inside out. And that happened for a long time … it was like … a couple of years … and we just fought about custody in court for a year and … I felt like I had died during that time.Another participant explained how feeling disconnected from her daughter was traumatic for her:I mean when my son was first born, I felt like I didn’t know how to do anything. I don’t know if that was really a feeling of helplessness as much as just floundering … just being a new parent. What really sticks out though is I had this one relationship right after my first child was born …, and it was not a very good relationship. He wasn’t a good partner. And I felt like I had nowhere to turn. Like none of my support systems were there … I really was pretty isolated. And for a while, I felt very kind of trapped, and helpless in that relationship.Another person described how she felt helpless in her romantic relationships:Most participants experienced significant interpersonal stress at some point in their lives, and they referred to such stress as significant life events. These conflict areas were often located within the family, in romantic relationships, or with co-workers or employers. Notably, many participants felt that these events contributed to their stress, leading to their breast cancer development.The majority of participants identified a relationship between emotional stress and physical disease in the body. Specifically, the idea that emotional stress can cause physical illness alluded to the idea that there was a connection between personal life experiences and physical effects on the body. Stress was considered to relate specifically to participants’ own experience with breast cancer. However, there was also a broader concept that stress was related to developing the disease through various mechanisms, mainly through cumulative stress causing the disease to emerge and stress making the body weaker or more vulnerable to disease.… it made me really think about the stress in your life and how it can impact some of your physical things. When I looked for example, at my ovarian cyst … that was right around the time I was going through the divorce. And then when I looked at my migraines, I thought … I got those … at the end of moving out of my house and it ended after my divorce … my thyroid condition at age 56 … that was right around the time I lost some people in my life. And I thought, wow, could some things have triggered … the stress in my life. Because I’m a very healthy person, I take really good care of myself so I always wondered why would I get breast cancer? And then I was like well you’ve been under stress almost your whole life … that timeline was very eye opening for me.Many participants felt that stress and emotions could physically impact the body and potentially cause diseases to develop. Stress was conceptualized as something that could accumulate, both in the frequency of stressful situations and in its general presence in the body. Many participants thought that accumulating stressful events over time could cause disease to emerge from within them. One person made connections between cumulative stressful life events as triggering various health conditions :… I think it’s a whole picture … your life experiences are your life experiences, and they add up, and what happens is what happens, and I think your health issues have something to do with that. And the other thing that I felt is that, what’s wrong, because I have a really good life now, I really do. And, you know, my bad childhood is just like, I felt it was more living in my body that I couldn’t get rid of it, rather than in my thinking mind. I understand, you know, it’s obviously both places, but I just felt like, oh, I need to do something to get rid of this, and it lived in me.Another participant stated that cancer had “lived” in her body since she experienced the stress of her childhood, which is where it emerged from in adulthood as a result of accumulated life experiences:My cancer was probably in process for many years but the mental stress and everything that I was going through the last few years is what made it so on fire. It wasn’t about the physicality, it was about what was going on inside me mentally, emotionally, it really made it happen that way.Another person described how emotional and mental stress that had built up made her cancer worse over time:… what I have felt over the last three years I’d say is that I have been under such insane emotional stress, and verbal abuse from two boyfriends …. and because of the gut feeling that I had while I was being verbally abused, and what that made me feel like afterwards, and how things have triggered me since that I feel like there’s a connection … Even though I know that it’s probably likely that the cancer in my body was set up, you know, a little earlier than these particular events … one leads to another, these events were the qualifying events that pushed me over the edge, and into the zone of allowing … my body (to be) so … depleted, and so emotionally damaged, and psychically damaged … I don’t know that I’ll ever get over those things that I heard, but I definitely feel that those had an impact on push coming to shove … I’ve been religious, and having my mammograms for 30 years, and nothing has ever been seen outside of, you know, dense breast tissue. And then, this last year was the year that something was seen, and then … that’s where push became shove.Finally, another participant felt that stressful events which accumulated over time “pushed” cancer in her body into developing further:I haven’t had anyone die who’s close to me. But I’ve definitely experienced a huge death of being separated from my child because I was a stay at home mom, breast fed her for tons of years and very, very connected to my kid and still am. … It was absolutely horrible. I’m surprised, like I do attribute a large part of (that to) getting cancer, but I want to say the vulnerability of my own body I think I became very vulnerable just due to that stress event, that anything could have occupied me and taken over, so I’m kind of not surprised. I think cancer is a combination of things, but I think that’s a huge contributing piece.Participants felt that stress could cause cancer to grow faster and make the body weaker, so it cannot “fight it off” as well. The concept of the body being vulnerable to cancer due to stress is related to the idea that stress breaks down the body’s defences, which is the point when cancer has a chance to emerge or “take hold.” One participant felt that the stress of a situation itself (being separated from her child) made her body more vulnerable, and this vulnerability made her body open to the breast cancer “taking over”:I would say that traumatic events in your life lead to stress, and anxiety, and both stress and anxiety are very, very hard on your body, and so you’re almost allowing something like breast cancer to happen. I’m not saying you chose it … I didn’t choose that, but I think that anytime we go through a high level of trauma, or something very significant, it’s going to have an effect on you physically as well as mentally, and emotionally. And absolutely anytime that you do something that alters your body, you’re allowing … I don’t think I’m explaining this right … I’m making myself more susceptible to getting cancer … if I don’t eat right, if I don’t exercise, if I have trauma …Another participant explained that emotional experiences such as trauma, stress, and anxiety are “hard on the body,” which makes one more susceptible to developing cance:r… I think everything was building up. I mean I think on a physical level, I had just exhausted my body to such a great degree just from the stress that I think that maybe it could have fought off if there were … the little scout cells … if the cancer was just brewing. If I had been in a better physical condition, and not so stressed, I wonder if my body could have fought it off. But … I don’t know that my father dying … I wouldn’t attribute it that much to that, but I would say mostly - I would put it more towards the health.Another participant explained how stress caused her body to be less able to “fight off” cancer already present in her body:I would say the events of my life in that last couple of years, stressful marriage, moving to Europe, moving back home, then surgery, jaw surgery, the failed hysterectomy, all the stress and all the things from that, my feeling about it is that something that might have been low grade maybe would have never even turned into anything huge, went crazy. Like (it) grew from the stress and effects on my immune system. And all the exposure, the radioactive dyes. Put the whole package together (and) it created a terrain for something that might have been mild and almost fairly undetectable to … go crazy and produce five tumors in my breast in one year. Because I had a clean mammogram one year before my diagnosis. And then I have five tumors.Finally, one participant felt that the reason she got cancer is that stress caused her immune system to weaken and created a “terrain” for cancer to develop:The specificity of the concept of stress “building up” in and “breaking down” the body was a recurring theme among participants. Participants conceptually viewed diseases such as cancer as something that “takes root” in the body or emerges and “takes over” as a result of stress accumulating. The view of the patient’s own body as a site of accumulated stress points to the highly personal aspects of the disease, as participants related their cancer to their own stressful emotional and social experiences throughout their lives. While participants perceived the experience of stress to have a substantial impact on their well-being, the participants also attributed a relationship between their emotional life experiences and outcomes of their physical health, specifically in feeling there was a pathway between stressful events and cancer.Approximately half of the participants personally attributed a specific cause to their breast cancer development related to stressful emotional or social experiences. Participants who did attribute a specific cause to their developing breast cancer cited events such as relationship issues, general stress, negative emotions, mental health issues, a physical event, such as another illness or injury, or a culmination of stressful events over time. Of the other half of participants, some were uncertain of a specific event that may have contributed to their developing breast cancer but suggested possible relevant events, while some others said they thought no specific events contributed to their developing breast cancer.Well, I wrote a book, and I did it in six months. I had a co-author. But, it’s kind of unheard of to write a book that fast. That was a pretty stressful experience. And that happened – let’s see, we published in 2004, and I was diagnosed in 2006. So, you know, I had a stressful marriage. I had, you know, this book thing – I mean I do wonder about that. I just wonder whether that was – you know, I mean I was a newspaper reporter. I was used to being in a high-stress kind of situation, but I kind of wonder if at that particular time, that may have, you know, pushed my health over the edge in some way.Cumulative stress was often cited as a reason breast cancer may have developed. Instances of cumulative stress included interpersonal, career, and physical stress and featured over the lifetime from childhood to adulthood. One participant described how a series of stressful events happened for a few years before her diagnosis, which made her identify the connections between the two:… I was constantly having to … fight for myself (at work). A common … subtext throughout … most of my life is not being believed and having to … advocate on my behalf in a way that has been so hard on me that it caused me to get sick over time. Whereas, had I had the supportive environment at home, or supportive environment on the job, or the support of physicians who … understood what was going on with me, things would have been different, but they weren’t.Another participant explained how stressful relational problems throughout her lifespan caused her to get “sick over time”:I’ve often questioned if it was brought on because of my couple of years prior to finding the lump were quite stressful, the one dealing with my fiancé’s ex and having to deal with step-kids and then also my job was just increasingly demanding. I had a specific person at work that was going out of her way to make my life difficult. Ultimately, I quit the job because of how stressful it was. I could tell that it was not good for my health … I literally found the lump the day after I quit. So, for me I feel like it was like the universe going like this is not good for you. You’re gonna have a bigger hurdle to jump over. And the timing just felt eerie. It was like I quit at 11pm the night before and at 7am my fiancé found the lump. So, it wasn’t even a 24 hour turnaround when that happened. It was crazy, yeah.Another participant felt that an accumulation of stressful events coincided with her discovering a lump that turned out to be breast cance:rI don’t know if there are any specific events. But, I do think for me, it’s related a lot to the toxicity of my relationship within my marriage. And there’s various events … throughout my marriage. I mean … arguments, or the way we related to each other, the way I was treated, things like that. It was like … the whole picture of my entire marriage that contributed to my breast cancer. So, it’s not one specific event. But … I do remember … when I was going through my cancer treatment … it was one of the chemo treatments … I was feeling nauseous, and I am on the bathroom floor, and I am shaking, and I am … hugging the toilet. And my husband comes and starts yelling at me … because my daughter was crying. And I remember thinking at that moment that … there’s something wrong here … the way he is yelling at me … this shouldn’t be. And I remember thinking that that was cancer. So … that moment was the first time I saw how … the situation I’m letting myself be in is causing me to get cancer. And it was that day I took off my ring.Relationship stress, mainly related to romantic relationships and issues within the family, was often cited as to why someone felt they developed breast cancer. Relational abuse, illnesses within the family, and “falling out” with people were examples of specific relationship problems that participants experienced. One participant described how the “toxicity” of her marriage caused her to get cancer:I had a lot of stress in the couple of years before my cancer, with school, and my dad, and that kind of stuff. I’m not sure what else I would link with it …. especially when my dad was sick, I was with him five days a week, and then I would drive – he was about 100 miles away from here where he lived, and I would drive home on the weekends, and my sister would go take care of him. And I just felt like I wasn’t seeing my family enough, and I was always on the road, and it was very – physically, and emotionally exhausting.Another participant explained how the stress of dealing with illness in her family contributed to her exhaustion, leading to her developing cancer:… A few years before being diagnosed with breast cancer I did kind of have a big falling out with some family members, especially my husband’s family. There was a lot of stress with that relationship. And it got to the point where I didn’t see them for a year. So sometimes yes that was a very upsetting time for me. And I myself sort of maybe, it was very, very stressful, that might have brought things (breast cancer) on … there’s always been issues with the family … I would say at that point a couple years before my breast cancer I did feel quite traumatized by it.Another person reported that arguments within her extended family contributed significantly to her stress, which may have “brought on” her breast cancer:I don’t know. Let me clarify. I do think my breast cancer is genetic and environmental, with a strong psychological component. And I don’t know what that component is … I don’t know if it’s hopelessness. I don’t feel like it’s the depression. I think it’s a component of the depression. I think it’s that hopelessness. And not seeing a way out of something …. I never actively wanted to kill myself, but it was like, what am I living for? I think if anything that’s the theme that I associate the breast cancer with. But I can’t connect it to one event or say, oh, I got this because my marriage or I got this because my father …Many participants also felt that psychological or emotional events, such as depression, hopelessness, being overwhelmed, or experiencing mental illness, may have somehow been related to their developing breast cancer. One participant did not feel certain that any one event caused her breast cancer but made the connection that her diagnosis was associated with the negative experience of her depression:I was feeling kind of – I mean sort of like the main stage things were pretty, my work was good, my daughter doing great, my relationship was difficult, but I had a nice – my home environment otherwise was nice. I had a lot of friends and support. But I was feeling like I just wanted to slow everything down. I felt like life was just too fast and there’s too much happening. And I remember telling my friend, I just want to stop working. I just want to not work for a while. And I really thought about that in retrospect. That was about five, six months before I was diagnosed.Another participant explained how feeling overwhelmed with her life led up to her diagnosis:… Well, the year leading up to it, I was feeling so depressed that I would think about never killing myself, but, you know, if a car were to hit me, that might be – welcome [laughter]. This was really a dark time …. And … my mom had had breast cancer … stage one when they found it … it was a whole different kind of thing than I had. But, I always expected to have it, but I also always expected to survive it too. So, I wasn’t real surprised when I was diagnosed. And I’ve always blamed it in a way on that period of time when I was so miserable. Actually, having the breast cancer changed my life, and I’m never sad anymore.Another participant felt her period of depression before her diagnosis was to blame for her developing breast cancer:The majority of the participants believed that their breast cancer was caused, in part, by stress or traumatic or interpersonal issues across the lifespan. Participants perceived a relationship between stress, particularly of a social or emotional nature, and breast cancer development, which suggests that patients may situate their experience with breast cancer within the larger narrative framework of their lives as a way to understand their diagnosis. Since breast cancer emerges in adulthood and is usually an emotionally challenging experience, connections between personal events and a diagnosis potentially allow patients to draw on their personal, embodied experiences of the disease to ask existential questions such as “why me?” when thinking about their breast cancer experience and the reasons why they may have developed breast cancer.Most of the participants felt that having breast cancer led them to experience post-traumatic growth. People identified connections between their experience with breast cancer and self-improvement, improving their relationships with others and giving them a larger sense of belonging to a community of other survivors, their medical team, and their local communities. Many participants also felt that breast cancer allowed them to re-evaluate what was important to them in their lives and allowed them to start a “new life.” Additionally, many participants felt that participating in the research brought them a sense of contributing to something larger than themselves by potentially helping others.… I think there was definitely a silver lining to the cancer …, like most people that helped me appreciate life more knowing that … life could be taken away at any moment. I was kind of an overachiever before I got the cancer. So, I was working a full-time job … So, having the cancer … the universe is saying, “You need to slow down.” So, I got out of politics. And then, I had the time to start dating again. And that’s when I met my husband … I feel like that was a really good positive thing to happen. I think that most major stressors … once it’s over, I feel better about having … survived it, and maybe learned some lessons.Many participants felt that having breast cancer was a learning experience for them and allowed them to change their lives. One participant described how she felt that cancer gave her a new appreciation for life:Well, because of all this, I moved out here … where my life has been extremely happy because of my involvement with volunteer activities … And those have all been happy, confirming experiences that I look back with such joy, and such pleasure, so much delight that I am doing those things. And I wouldn’t be if I was still back (there) in a sense, mourning because of, you know, being in familiar places with negative memories. So, I was spurred to come out here, because that was my chance to get away, and start a new life.Another participant felt that she was able to move forward with her life quickly after her experience with breast cancer:Yeah, I did something actually through … the hospital. They had something where they would connect you … and you would help support other people going through a similar diagnosis of what you had. So, you could share your experience, and be there to support them while they went through it. And I did that for a while too. So, all of those things helped me process what I was going through, but then also allowed me to help others.Many participants felt that having breast cancer gave them a sense of connecting to and helping others, leading to feeling the benefits of prosocial behaviour. One participant discussed how supporting others with a similar diagnosis helped her process her own:In some senses it’s helped me to just see a sense of beauty within darkness. And with cancer it’s interesting because it seems like in some ways it brings people together. There’s a lot of people I’ve connected with and made friends with who I probably would never have connected with if I didn’t have cancer. And just the outpouring of support and love that people have given me throughout my process has been amazing.Another participant explained how her experience with cancer connected her to people she did not expect:The breast cancer, what it did for me, it opened – it sounds terrible, I don’t mean it that way, but it opened so many doors of, I would say like compassionate, a community – just the whole community surrounding breast cancer, other women who have experienced it, the support teams, and people that help you get through it, the doors that opened, and the opportunities that opened to do volunteer work, and to work as an advocate were huge …Another participant felt that her diagnosis “opened doors” to a new community of people:Post-traumatic growth has been reported among breast cancer survivors, suggesting positive attitude changes towards oneself and life after treatment (Barthakur et al., Although cancer aetiology is examined from various approaches and perspectives, this study’s purpose was to examine patient perspectives of the determinants of their cancer development and progression through qualitative, in-depth interviews. Investigating the perceived causes of breast cancer from a patient’s subjective standpoint is useful because it situates the phenomenon of breast cancer within the patient’s experience. Patient narratives, particularly regarding why participants thought they developed breast cancer, can be useful to understanding the experience of the disease itself. According to Nordenfelt’s philosophy on “The Reverse Theory of Disease and Illness,” a patient’s subjective experience of having a cluster of symptoms not only contributes to further understanding and treatment of a specific illness but is also the necessary precursor to the identification of oneself as having a disease (Nordenfelt, While the majority of participants reported experiencing some level of childhood trauma or interpersonal stress across the lifetime, our hypothesis that individuals might perceive the triggering of childhood trauma in adulthood as precipitating their breast cancer diagnosis was generally not held by participants. However, of the participants who did attribute a cause to their developing breast cancer, the majority causally attributed trauma and stress to their breast cancer diagnoses, specifically through the effect of emotional stress on the physical body itself. Many participants believed that the accumulative effect of stress, as well as the “weakening” of the body due to stress, may lead to the emergence of breast cancer. While diagnosis and treatment of breast cancer may itself be traumatic or stressful, our research shows that patients’ trauma and stress during their experience with breast cancer can also be related to more personal and existential experiences, particularly due to early childhood trauma or interpersonal stress. Our results find that many women who have or have had breast cancer often attribute their developing breast cancer to trauma and stress which occurred across the lifetime due to the impact of these specific types of stress on the body. While not scientifically proven, these causal attributions by the participants point to the presence of stress while receiving treatment for breast cancer, which may inform the usage of further emotion-based therapies for patients undergoing treatment for breast cancer.Additionally, studies show that participating in stress-reducing treatments and therapy while undergoing breast cancer treatment, while not improving survival rates, can improve both quality of life and adjustment. One RCT showed that supportive-expressive group therapy reduced trauma symptoms, prevented depression, reduced “hopelessness-helplessness”, and improved social functioning (Kissane et al., These findings are useful in that they can provide information regarding how women with breast cancer experience their diagnosis and treatment in order to support the benefits of additional psycho-social, stress-reducing, or trauma-informed therapies during and post-treatment. Because women felt that breast cancer may be a result of trauma or stress, and they also felt that having breast cancer was a transformative experience for them which stimulated post-traumatic growth, it might be beneficial for therapy providers to frame the breast cancer experience as both a means of physical healing as well as an emotionally therapeutic process through which early childhood trauma or current interpersonal stressors can be addressed through psychological support, potentially improving health-related quality of life and adjustment. Knowing about these ideas held by women undergoing breast cancer treatment allows us a deeper and more holistic insight into the potential benefits of supplemental emotional care. Therefore, we recommend providing psycho-social, trauma informed, and/or stress-reducing support for breast cancer patients to alleviate stress associated with childhood trauma and interpersonal stress during treatment. Additionally, because many women felt that stress has a substantive effect on the physical body itself, it may be of benefit for such women to utilize somatic based emotional therapies.Finally, womens’ experiences, particularly regarding influences of stressful, emotional, and interpersonal experiences relating to breast cancer, warrants more research and investigation. It is essential to seek a deeper understanding of the potential relationships between traumatic life experiences, interpersonal conflict, stress, and breast cancer and incorporate traumatic histories and patient narratives into psychosocial treatment areas for breast cancer patients. Further research should look deeper into the influence of ACES and early childhood stressful experiences on breast cancer, but should also look into stress occurring across the lifetime. Particular attention should be paid to adult relationships and long-term emotional and interpersonal issues and their potential impact on the breast cancer experience.The main limitation of the study is that the specific questions being asked necessarily inform the answers given. Regardless, the results can inform future studies and therapeutic interventions.Participants frequently discussed how childhood trauma and adult interpersonal stress significantly impacts their lives and breast cancer experiences. There was an overall idea from the participants that these events may have contributed to their developing breast cancer, specifically regarding lifetime stress’ cumulative effect on the body or stress making the body more vulnerable in some way. Additionally, although childhood and adult interpersonal conflict were perceived as contributing to breast cancer development, entering remission appeared to promote feelings of increased social connection and post-traumatic growth. We recommend that providers working with breast cancer patients consider providing emotionally therapeutic resources, particularly with a somatic, psycho-social, trauma-informed or stress-reducing focus which address trauma, stress, and interpersonal issues, in order to help patients conceptualize their breast cancer treatment as an overall psychologically healing process, which may positively influence adjustment and quality of life.Click here for additional data file.


There is evidence linking air pollutants associated with vehicular traffic such as polycyclic aromatic hydrocarbons with breast carcinogenesis. Epidemiological studies have shown conflicting results regarding air pollution and breast cancer risk, which could be explained by the multitude of other risk factors that could affect the association. In Chile, air pollution has reached alarming levels, either due to motorised vehicle traffic or the combustion of wood for heating; therefore, our objective was to evaluate the association between the incidence of breast cancer and the concentration of the main air pollutants monitored in the country.R = 0.82; p = 0.044), whose significance tends to be lost when age and the communal HDI are included in a regression model.We carried out a cross-sectional ecological study that evaluated the association between the average incidence of breast cancer in years (2016 to 2018) and the average annual concentration of six atmospheric pollutants in the 5 years prior to the estimation of the rate in communes of Chile, using the population of beneficiaries of Instituto Oncológico Fundación Arturo López Pérez. The annual incidence of breast cancer was 72.21 cases per 100,000 women and it varied significantly in the communes studied compared to the human development index (HDI) and to the proportion of women in the age group at highest risk. Assessing the relationship between the incidence of breast cancer and the average concentration of atmospheric pollutants, we only found a direct correlation between the level of nitrogen dioxide and the rate ( Breast cancer is the leading cause of mortality attributed to malignant neoplasms in female population of Chile  and it is also the most common cancer diagnosed in women in developed countries . The WorBreast cancer is a heterogeneous disease and therefore the associated risk factors vary according to the expression of oestrogen and progesterone receptors in the tumour, the hormonal status of the patient and the invasive nature or in situ of the disease , 5. AmonIn oncology, environmental pollution and in particular atmospheric pollution, which is a known risk factor for some types of cancer such as lung cancer, has gained increasing interest. Polluted air contains polycyclic aromatic hydrocarbons (PAHs) and metals that can act as endocrine disruptors or carcinogens. PAHs have an oestrogenic effect and induce mammary tumours in animal models , 8. In hChile has a network of air quality monitoring stations located in the main cities or in places where productive activities such as mining, heavy industry and thermoelectric power generation generate pollution. There are cities in which air pollution has reached alarming levels, either due to motorised vehicle traffic or the burning of wood for heating .Our objective was to evaluate whether there is an association between the incidence of breast cancer and the concentration of the main air pollutants monitored in Chile through an ecological study.An ecological cross-sectional study that evaluated the association between average incidence of breast cancer in 3 years  and the average annual concentration of the 5 years prior to estimated incidence of six air pollutants in communes of Chile.In order to obtain the study population, a health centre in Chile focused on cancer management and that has a captive population was selected. The Instituto Oncológico Fundación Arturo López Pérez (FALP) meets these characteristics. The population cared for in this institution has the possibility of contracting an agreement for coverage of diagnostic benefits and treatment against neoplastic events, called an oncological agreement.With the approval of the Scientific Ethics Committee of the FALP, the distribution by age, sex and commune of the beneficiaries of the oncology agreement was obtained, as well as the new cases of breast cancer treated at the Institute in 2016, 2017 and 2018. The Incidence estimation was performed for female sex and only breast cancer cases in beneficiaries of the oncology agreement were considered.To correct the potential inherent bias projecting the incidence of breast cancer from the population in the FALP oncology agreement to the Chilean population, this rate was adjusted by age distribution from 2012 census using the direct method.2), nitrogen monoxide (NO), nitrogen dioxide (NO2) and ozone (03). The techniques to determine the concentration of atmospheric pollutants are available on the website of the National Air Quality Information System (SINCA) [The average annual concentration of atmospheric pollutants was based on data records obtained from the air quality monitoring stations distributed in Chile. The pollutants studied were respirable PM 2.5, PM 10, sulphur dioxide (SO (SINCA) . The aveConsidering that the literature recognises an association between the risk of breast cancer and pollutants linked to motor vehicle traffic , 14, we To evaluate the association between the incidence of breast cancer and the average concentration of air pollutants, we selected those communes with a female population of beneficiaries in an oncology agreement greater than 5,000 people and that will have active monitoring stations and validated records.p-value <0.05 was considered statistically significant. Finally, using multiple linear regression, we evaluated the effect of air pollution on the incidence of breast cancer as a dependent variable, considering age and HDI by commune.Statistical analysis was performed with the R program version 3.6.0 . The correlation between the incidence of cancer with the average concentration of contaminants, the HDI and the proportion of beneficiaries of the oncology agreement in the age group at risk for breast cancer was analysed using Pearson’s correlation coefficient. A During the 2016–2018 period, 661 new cases of breast cancer were treated in women with an oncology agreement. The female population in the agreement was 275,768, 310,162 and 339,096 in 2016, 2017 and 2018, respectively. The incidence of breast cancer per 100,000 women in oncology agreement per year was 80.9, 70.3 and 64.9 in 2016, 2017 and 2018, respectively .p = 0.007)  .2 level and the rate .The association with NO2 tends to be lost when analysing the effect of the level of the six air pollutants on the incidence of breast cancer by borough as a dependent variable in a linear regression model that includes the variables age and HDI .According to Global Observatory of Cancer (GLOBOCAN) estimates, breast cancer accounts for 24.2% of new cancer cases in women worldwide. The average incidence of this disease is 54.4 cases per 100,000 women per year in countries with high HDI and 31.3 cases per 100,000 women per year in countries with medium and low HDI. For South America, the GLOBOCAN estimate is 56.8 cases per 100,000 women per year . Our stuThe 14 communes selected for analysis, considering a population of beneficiaries of the FALP oncology agreement greater than 5,000 people, are distributed throughout the country and have important geographic and socio-economic differences . In them2 that however loses statistical significance when using a multiple linear regression model that considers other risk factors. According to SINCA [2 is produced by the burning of fuels at high temperatures that combined with volatile organic compounds in the presence of sunlight forms O3 and by doing with water contributes to the production of acid rain and increasing the levels of PM 10 and PM 2.5. The commune of Las Condes exhibits the highest average annual concentrations of NO2 and has the highest adjusted average annual incidence of breast cancer. In the case of O3, we observed an R coefficient of 0.61 but it did not reach statistical significance. The Sister cohort study in the United States reported an increased risk of ductal carcinoma in situ for high levels of NO2 and for invasive carcinoma only in the southern states [2 contamination and invasive breast cancer [2 was used as a marker of motor vehicle traffic, being the pollutants associated with breast carcinogenesis PAHs and metals [By evaluating the correlation between the incidence of breast cancer and the average annual concentration of six air pollutants in the previous 5 years, we found an association with the concentration of NOto SINCA  NO2 is pn states . Previout cancer . In thesd metals . The com2 have low incidences of breast cancer. There is also the possibility of selection bias in the beneficiaries of the oncology agreement, since they could have hired it because they have risk factors for cancer, increasing the incidence of the disease in relation to the general population. However, the rate found is similar to that proposed by GLOBOCAN [One of the limitations of our study is the lack of validated records of all pollutants in the air quality monitoring stations. In those communes that are part of the largest conurbations in Chile , the registry is complete, while in communes of smaller conurbations it is limited to contaminants previously recognised as critical. The direction of this bias would possibly not affect the results since the communes that did not register NOIn conclusion, the incidence of breast cancer in the studied population is similar to that of countries with high HDI and there is a direct correlation between the frequency of breast cancer and an air pollutant mainly related to motor vehicle traffic; however, this association is lost by considering the effect of variables such as age and HDI. New studies are required whose design makes it possible to evaluate the effect of other risk factors and establish the temporality of the association between exposure to air pollutants and incidence of breast cancer.None.None.


To evaluate whether mammographic texture features were associated with second primary contralateral breast cancer (CBC) risk, we created a “texture risk score” using pre-treatment mammograms in a case–control study of 212 women with CBC and 223 controls with unilateral breast cancer. The texture risk score was associated with CBC  after adjustment for mammographic percent density and confounders. These results support the potential of texture features for CBC risk assessment of breast cancer survivors. CBC risk factors include younger age and an estrogen receptor (ER)-negative first breast cancer, family history of breast cancer, and stray radiation dose received by the contralateral breast during treatment for the first breast cancer6. Mammographic percent density (MPD), among the stronger known predictors for first primary breast cancer, also predicts CBC risk, but the associations are generally weaker than for first primary breast cancer8. Other quantitative features from mammograms  are possibly associated with first primary breast cancer risk10, but it is not known whether these features may also identify breast cancer survivors at increased risk of subsequent CBC. In this study, we developed and tested a “texture risk score” for CBC using the Women’s Environment, Cancer, and Radiation Epidemiology (WECARE) Study.Breast cancer survivors have a high risk of developing a second primary contralateral breast cancer (CBC), between 2 and 6 times greater than the risk of first primary breast cancer in the general populationλ = 0.033), which identified three features with non-zero coefficients: gray level run length matrix (GLRLM) short run low gray level emphasis (weight = −0.032); gray level size zone matrix (GLSZM) small area emphasis (weight = −0.093); and GLSZM small area low gray level emphasis (weight = −0.066). The Pearson correlation between the texture risk score and MPD was 0.37 (standard error = 0.04). The score was approximately normally distributed with mean = 0, standard deviation = 0.14, and skewness = −0.98 . The association of CBC with the texture risk score was greater for women with body mass index (BMI) ≥ 25 kg/m2  compared with women with BMI < 25 kg/m2  , but not for postmenopausal women ; the OPERA estimates did not differ statistically from one another  for first primary breast cancer, the association with CBC is generally weaker, as reported in the WECARE Study and elsewhere13.This study evaluated the association of quantitative mammographic features with CBC risk for breast cancer survivors, whose absolute risk of CBC is high14. Additionally, we identified possible effect modification of the association between CBC and the texture risk score by BMI, which is consistent with BMI-modified associations between mammographic density and first primary breast cancer15.The association of CBC with our texture risk score was essentially unchanged after adjusting for MPD, suggesting that this score, though weakly correlated with MPD, is capturing independent sources of variation in CBC risk that are potentially causal for breast cancer risk17. Third, while the WECARE Study is the largest imaging study of CBC risk with extensive clinical and epidemiological data, we were unable to conduct well-powered subgroup analyses.Strengths of this study include control for epidemiological and clinical risk factors of CBC, as well as the use of mammograms taken prior to receiving systemic therapy for the first primary breast cancer, which ensured our findings were not influenced by treatment-related changes to the breast. There were several limitations, however. First, this study lacks external validation of the texture risk score for CBC risk. We attempted to reduce the probability of overfitting by selecting the feature reduction method based on a random subset of the data, as well as by developing only one risk score, and we hope to evaluate this risk score in other large imaging studies of CBC risk when feasible. Second, the WECARE Study recruited participants during the era of film mammograms, which are rarely used today. However, previous studies comparing mammogram-based measures on film and digital images have found little difference in measuring breast size, mammographic density, and risk associations using texture featuresIn conclusion, mammographic texture features—which are objective and can be generated automatically—are a promising approach to improve risk stratification and tailor surveillance for CBC beginning at the time of the first primary cancer diagnosis.18. Case women were diagnosed with a first primary invasive breast cancer followed ≥1 year later by a second primary invasive cancer in the contralateral breast. Control women were diagnosed with a first primary unilateral invasive breast cancer (UBC) but did not have a second primary invasive CBC and were selected such that each matched control had similar time at risk for CBC (“at-risk time”) as her matched case, with additional matching on age, year of diagnosis, race/ethnicity, and recruitment center. After providing informed consent, participants completed a structured questionnaire and study staff completed medical record abstraction. In the second recruitment phase, the WECARE II Study (2010–2012), participants identified from four population-based cancer registries  also provided consent to access their mammogram of the unaffected breast taken prior to systemic treatment for the first breast cancer. The WECARE Study did not collect the characteristics of facilities where the mammograms were obtained. Nearly all images were film mammograms, which were digitized at two study sites (Seattle and Toronto) using two Kodak Lumisys Digital Scanners set to 12-bit gray-scale resolution with regular calibration , Fred Hutchinson Cancer Research Center, Cancer Prevention Institute of California, Mount Sinai Hospital, and Memorial Sloan Kettering Cancer Center and by the Committee for the Protection of Human Subjects of the State of California.The WECARE Study is a multicenter, population-based, individually matched, case-control study of CBC9. From the discretized masks, we calculated five texture matrices: the gray level co-occurrence matrix (GLCM), the gray level run-length matrix (GLRLM), the gray level size zone matrix (GLSZM), the neighborhood gray tone difference matrix (NGTDM), and the neighborhood gray level dependence matrix (NGLDM), with detailed extraction parameters provided in Supplementary Table 20, were calculated for the entire breast area from these matrices. Features were centered prior to analysis. Calculation of matrices and features was conducted using the open-source MATLAB package, CERR21.A fully automated analysis pipeline was used to calculate texture features from digitized cranio-caudal view film mammograms taken prior to systemic therapy for the first breast cancer. Automated in-house software was used to identify the breast area mask . The range of gray levels within the mask were binned (discretized) into eight gray levels based on intensity quantiles, rather than absolute intensity, to account for possible between-image brightness differences attributable to image acquisition and digitizationλ between 10−3 and 103 . After identifying the best tuning parameters for the ridge, elastic net, and LASSO models, we selected one model from the three that produced the lowest unadjusted root mean square error for CBC prediction in the 30% holdout data. The chosen model was used to develop a “texture risk score” calculated for each WECARE Study participant as a linear combination of the scaled feature values multiplied by the coefficients from the selected penalized regression model.To identify combinations of features associated with CBC, we considered three different penalized regression models: ridge (L2 regularization), elastic net (L1 and/or L2 regularization), and lLASSO (L1 regularization). To identify the tuning parameters for each model without overfitting, we selected 70% of CBC cases and UBC controls at random, and for each model type used 10-fold cross-validation repeated 20 times to select a value of 22. We evaluated the association between each OPERA measure and CBC risk, and then further adjusted the models for menopausal status at time of mammogram; stage  and ER status at the time of the first diagnosis; receipt of chemotherapy, hormonal therapy, and radiation therapy for the first breast cancer; first-degree family history of breast cancer; age at menarche; and matching factors. Exploratory stratified models were estimated within subgroups defined by menopausal status at time of mammogram and BMI (<25 kg/m2 vs ≥25 kg/m2) prior to the first diagnosis.The association between CBC and the texture risk score was examined by fitting a logistic regression model. To enable direct comparison of the texture risk score and MPD, both measures were parameterized as odds ratio per adjusted standard deviation (OPERA) by dividing the age- and body mass index (BMI)-adjusted residuals of each measure for the controls by the standard deviation of the residualsFurther information on research design is available in the Supplementary InformationReporting Summary