This narrative review aims to clarify the role of breast and gynecological risk-reduction surgery in BRCA mutation carriers. We examine the indications, contraindications, complications, technical aspects, timing, economic impact, ethical issues, and prognostic benefits of the most common prophylactic surgical options from the perspectives of a breast surgeon and a gynecologist. A comprehensive literature review was conducted using the PubMed/Medline, Scopus, and EMBASE databases. The databases were explored from their inceptions to August 2022. Three independent reviewers screened the items and selected those most relevant to this review’s scope. BRCA1/2 mutation carriers are significantly more likely to develop breast, ovarian, and serous endometrial cancer. Because of the Angelina effect, there has been a significant increase in bilateral risk-reducing mastectomy (BRRM) since 2013. BRRM and risk-reducing salpingo-oophorectomy (RRSO) significantly reduce the risk of developing breast and ovarian cancer. RRSO has significant side effects, including an impact on fertility and early menopause . Hormonal therapy can help with these symptoms. Because of the lower risk of developing breast cancer in the residual mammary gland tissue after BRRM, estrogen-only treatments have an advantage over an estrogen/progesterone combined treatment. Risk-reducing hysterectomy allows for estrogen-only treatments and lowers the risk of endometrial cancer. Although prophylactic surgery reduces the cancer risk, it has disadvantages associated with early menopause. A multidisciplinary team must carefully inform the woman who chooses this path of the broad spectrum of implications, from cancer risk reduction to hormonal therapies. The expanding understanding and management of breast cancer risk factors denote an essential step in preventing this malignancy, just like any other neoplastic illness. There are some heritable, non-modifiable risk factors that the patient carries with her at a genetic level, in addition to the patient’s age, gender, and modifiable factors .In particular, it is estimated that about 5% of breast cancers have a hereditary basis , with a In addition to the best-known pair of genes that can predispose a patient to the development of breast cancer, namely the BRCA1 and BRCA2 genes, there are other genes with variable penetrance that can in some way increase the predisposition to this type of neoplasm. In patients with negative genetic tests for BRCA mutations, panels that include these genes are often used to rule out other types of inheritance. BRCA1 gene mutations cause familial breast-ovarian cancer-1 (BROVCA1), and BRCA2 gene mutations cause familial breast-ovarian cancer-2 (BROVCA2). Up until the age of 80, women who are BROVCA1-sensitive have a cumulative risk of 72% for breast cancer and 44% for ovarian cancer ,10. Howewww.iarc.fr, accessed on 22 November 2022). Endometrial cancer was the sixth most frequent cancer, and ovarian cancer was the eighth . Hereditary ovarian and breast cancer share various mutated predisposing genes A 7]. So. So7]. SUndoubtedly, the knowledge of predisposing gene mutations currently offers, in addition to some interesting new therapeutic options, such as the use of PARP inhibitors for patients with mutations of the BRCA genes, various prophylactic options of surgical and non-surgical types. This narrative review aims to clarify the role of breast and gynecological risk-reducing surgery in patients with BRCA mutations. In detail, we discuss the indications, contraindications, complications, technical aspects, timing, economic impact, ethical issues, and prognostic benefits of the most common prophylactic surgical options currently offered to patients carrying BRCA mutations, which we observe from the points of view of a breast surgeon and a gynecologist.A comprehensive literature assessment was performed by querying the following databases: PubMed/Medline, Scopus, and EMBASE. The databases were systematically searched from their inception to 6 August 2022. The queries’ specifics are displayed in Over the years, several techniques for bilateral risk-reducing mastectomy (BRRM) have been used, including risk-reducing skin-sparing mastectomy and risk-reducing nipple-sparing mastectomy (RRNSM). Nipple-sparing mastectomy was linked to improved psychosocial and sexual well-being and a higher quality of life ,12,13.RRNSM consists of completely removing the mammary gland through a minimal scar, saving the skin and the nipple–areola complex. Access to this procedure varies based on the preferences and personal experience of the breast surgeon. The most frequently used incisions are radial or “italic S” within the upper-outer quadrant, along the inframammary sulcus, or periareolar with a possible radial extension. For the dissection of the gland from the subcutaneous and prefascial layers, various devices can be used to promote hemostasis and reduce perioperative complications .This procedure can be bilateral in the case of healthy mutation carriers or unilateral in the case of patients submitted to contralateral breast cancer surgery. In the latter case, risk-reducing surgery can be offered at the same time as the contralateral oncological intervention, or it can be deferred if the surgical risks should be minimized to not compromise the optimal timing of any possible indicated adjuvant therapy.Reconstruction in these cases can be offered immediately during the same operative session, except in patients at high risk of complications, for which the plastic surgeon deems it more appropriate to perform a two-stage reconstruction . Postoperative complication occurrence, based on recent studies, is reported to be around 43%, and thus not very far from the postoperative complication rate of breast reconstruction after oncological surgery independent of prophylactic indications, and additional surgery for medical or aesthetic purposes was required in about 72% of cases ,15,16. HConsidering that the cumulative risk of breast cancer by age 80 is estimated to be 72% and 69% for BRCA1 and BRCA2 mutation carriers, respectively . In partTaking into account the mean age of the development of breast cancer in the case of BRCA mutation, the optimal age to undergo prophylactic breast surgery is between 25 and 30 years, as described in The prevalence of occult breast tumors in prophylactic mastectomy surgical specimens in some series exceeds 11%, despite negative preoperative radiological findings ,21, and Focusing on BRCA mutation carriers already diagnosed with breast cancer, although a meta-analysis demonstrated a contralateral breast cancer risk reduction in patients undergoing contralateral risk-reducing mastectomy (CRRM) for high familial or genetic risk  or an ascertained BRCA mutation  ,24,25, tRisk-reducing salpingo-oophorectomy (RRSO) consists of the complete removal of both ovaries and fallopian tubes up to their outlets at the level of the uterine cones. The importance of fallopian tube removal lies in their proven central role in cancer pathogenesis. In fact, there is emerging evidence that ovarian cancer among BRCA mutation carriers predominantly arises from the fallopian tube epithelium and spreads to the ovary secondarily ,36,37. TThe cumulative lifetime risk of ovarian cancer in the general female population is estimated at 1.3%, increasing up to 36–53% and 10–25% by the age 70 in BRCA1 and BRCA2 mutation carriers, respectively ,43,44,45In contrast to the general population, ovarian cancer in BRCA mutation carriers is diagnosed at an earlier median age  . The mosA prophylactic salpingo-oophorectomy reduces the risk of ovarian cancer by more than 96%, reduces the risk of breast cancer by 72% in patients with the BRCA2 mutation, reduces the risk of breast cancer by 39% in patients with the BRCA1 mutation, and also reduces the overall cancer-specific mortality ,48,49. FThe timing of RRSO is not universally established; however, there is agreement that it should not be performed before the age of 35 or before completing childbearing  Figure . DelayinThis option, however, must be regarded as experimental. It is still unclear how effectively it reduces cancer risk. The authors demonstrated in a simulation study that RRSO is the most effective option for cancer risk reduction . SimultaAmong breast cancer survivors (not screened for germline mutations), increased risks of developing uterine or ovarian cancer higher than 150% and 40%, respectively, have been observed compared to the general population . A recenThe potential link between BRCA1/BRCA2 mutations and endometrial neoplasia has recently been investigated ,69,70,71On these bases, prophylactic hysterectomy has been proposed as a possible risk-reduction surgery to be discussed in the counseling of BRCA1/2 mutation carriers undergoing RRSO ,70,72. CWomen considering a hysterectomy are concerned about the effects on their sexual functioning . Indeed,Another issue is the consequence of hysterectomy on pelvic statics. In a nationwide study, Husby and colleagues recently examined 9535 hysterectomies and 47370 controls . This stProphylactic hysterectomy may increase the number of surgical complications. In a large cohort study comprising 78,577 hysterectomies, the total complication prevalence was 10.5% . The hemp < 0.005), which was halved among premenopausal women  and was especially driven by a reduction in breast-cancer-specific mortality . The same differences were confirmed in an independent Australian cohort [Considering the perioperative mortality of this kind of abdominal surgery, which indeed overcomes that of prophylactic breast demolition, some authors investigated the effect of hysterectomy plus RRSO on breast cancer survivors using an Australian population-based data linkage study of 21,067 women diagnosed with primary breast cancer between 1997 and 2008, 1426 of which underwent risk-reducing surgery  . They asn cohort , but then cohort ,70,72. UConsidering the fact that prophylactic strategies succeed but do not completely eliminate the risk of developing hereditary neoplasms, the role of follow-up in this group of high-risk patients, even after any prophylactic interventions, is not negligible.In a survey of surveillance schemes after risk-reducing surgery from 22 centers across 16 countries and 4 continents, most participating centers agreed that BRCA mutation carriers should not be subjected to active surveillance following risk-reducing surgery . Most ceAfter prophylactic breast surgery, we strongly advise continuing imaging follow-up by undergoing regular bilateral breast ultrasounds, alternating with MRI if indicated by the breast radiologist .We recommend an annual pelvic ultrasound examination and serum Ca125 testing after RRSO. Cervical cancer screening should be continued in the case of uterus conservation. Furthermore, bone density testing and careful consideration of postmenopausal symptoms are required. Hormone therapy for menopause symptoms is covered in more detail below.Preventing the development of new primaries among patients with a recognized predisposition to breast and gynecologic malignancies is of obvious importance in containing the costs related to treating such pathologies, especially at an advanced stage. However, the variability in the type of prevention that can be chosen based on the economic possibilities of the patient and her country of origin is not equally apparent.For instance, prophylactic surgery can be more convenient than a long-term, frequent, clinical–instrumental follow-up, especially considering the average life expectancy in some low–medium-income countries. In addition, it can be more effortless by considering the low compliance in screening programs, which affects some populations for cultural or geographic reasons. As aforementioned, risk-reducing surgery does not entirely avoid cancer risk; follow-up is nonetheless suggested. However, there is still a need for explicit agreement on the best follow-up after risk-reducing surgery, and new studies are required . The ecoFurthermore, a recent value of information analysis showed high decision uncertainty associated with the uptake rates of risk-reducing interventions, suggesting that in the future this uptake rate should be given more attention in the conceptualization of health economic modeling studies .In the era of patient-centeredness, it is certainly not possible to ignore the informed and conscious choice of the patient herself. Therefore, it is very important to give her the information in a precise way, starting from the fact that risk-reducing surgery, as the term states, reduces but does not entirely nullify the risk of developing a specific type of tumor due to ectopic tissue, as can happen, for instance, in the case of breast, endometrium, and ovary tissues. Moreover, when opting for risk-reducing interventions, the patient should be led to weigh the benefit of cancer risk reduction against the potential negative consequences of these procedures, including fertility loss, premature menopause, and psychological and physical suffering, in order to eventually opt either for delaying preventive surgery or for carrying on exclusively with intensive surveillance instead ,103.Furthermore, the aspects relating to surgical complications and, in the case of breast reconstruction, short- and long-term aesthetic complications cannot be neglected. They should be extensively discussed with the patient to prevent false expectations. Then, the patient must be given the necessary time to metabolize the various options and choose the path she wishes to undertake with complete autonomy, knowing her own risks in case she decides to postpone any preventive intervention.In general, the literature shows significant variability in risk-reducing surgery uptake among BRCA mutation carriers around the world. These surgeries are widely accepted among women and physicians in Western countries, while they are less accepted in low–middle-income countries, thus reflecting remarkable cultural heterogeneity across countries . Recent A recent Malaysian study concluded that RRSO decision making involves negotiating the likelihood of developing cancer with the societal priorities of being a woman, mother, and wife . In partHistorically, risk-reducing ovarian ablation, in addition to the surgical removal of the ovaries, included radiation treatment, GnRH analogs, and chemotherapy. However, ovarian ablation using radiation is less reliable than surgery, and it is associated with increased morbidity and the risk of secondary cancer . AlthougSystemic chemopreventive schemes use drugs that inhibit sex hormones in different ways. During the fertile age, tamoxifen is used in high-risk women over the age of 35, except in cases where there is a known family history of thromboembolic events and a family or personal history of endometrial cancer. Tamoxifen, a selective estrogen receptor modulator (SERM), may be an option for these very young women, but it is associated with significant side effects , and there are no trial data on its efficacy in women under the age of 35 ,118. CheAromatase inhibitors are restricted to postmenopausal women because constitutive estrogen synthesis occurs in peripheral body fat during this period and aromatase inhibitors can block this ,121. MeaThe chemopreventive treatment duration should be based on the available evidence. Currently, chemopreventive efficacy data are based on a 5-year daily treatment ,125,126.In addition to the chemoprevention of the breast neoplasm, it should be highlighted how the use of low-dose oral contraceptives involves a significant reduction in the risk of ovarian neoplasm without increasing the risk of breast neoplasm . In BRCAFollow-up plays a crucial role in all BRCA mutation carriers who decide to conserve their breast and gynecological apparatuses. For these patients, international guidelines call for an annual breast screening MRI starting at age 25, whereas the age of onset for yearly mammograms differs between 30 and 40 or possibly 10 years earlier than the first case in the family ,128. IndIn a recent population-based study, Öfverholm and coworkers analyzed mortality in a cohort of women treated with risk-reducing surgery (BRRM and RRSO) . The meaHormone therapy (HT) can be given to counteract the symptoms of early menopause, and it is also known to reduce mortality due to cardiovascular events when given at an early age or immediately after menopause ,87,134. So far, the cost–benefit analysis for prophylactic uterine surgery has focused primarily on the potential reduction in risk associated with endometrial cancer, particularly the serous type. In our opinion, other elements must be taken into consideration. For example, suppose we remove the ovaries and the uterus in the same surgical session. In that case, it involves submitting the patient to HT only with estrogen without progestins. A recent review including observational studies found that women who received estrogen alone tended to have a lower risk of breast cancer than women who received estrogen plus progesterone . In an aThe literature shows several shreds of evidence related to the efficacy of a combined risk-reducing surgical strategy. However, one cannot ignore the risks of abdominal–pelvic surgery compared to breast surgery alone and the systemic risks dictated by the interruption of ovarian function in premenopausal women. Furthermore, excluding the case of healthy BRCA mutation carriers, in our opinion, the complications of risk-reducing gynecological surgery would not justify any delay in initiating adjuvant treatments for breast cancer when appropriate. Therefore, although reducing the number of interventions may seem advantageous at first, the timing of the various types of interventions should probably be better defined and undoubtedly discussed within a multidisciplinary setting, also taking into account the individual cardiovascular risk factors and the women’s personal desires as well as considering the possibility of salpingectomy with delayed ovariectomy, which has recently been explored.For prophylactic mastectomy, it is essential to point out that this procedure serves to contain the risk of developing breast cancer but does not entirely cancel it. Therefore, in this case, it is also good to consider that even this type of intervention is not completely free of complications, in addition to the fact that in breast cancer survivors the prognosis is certainly guided by the carcinoma that is already diagnosed and not by any carcinomas not yet in place.Finally, each patient should undergo an individualized risk assessment, possibly within a multidisciplinary setting. The most appropriate risk-reduction option should be chosen considering the patient’s goals, risk profile, and risk tolerance. In addition, we believe that even the VUS, considered negative for the moment, deserves a multidisciplinary discussion with peculiar decisions that must be taken on a case-by-case basis, such as in patients with a marked familial history or carcinomas at a very young age.Oral hormonal contraception should not be negated in BRCA1/BRCA2 mutation carriers not yet eligible for risk-reducing surgery because it significantly reduces the risk of developing ovarian cancer. Although prophylactic surgery reduces the risk of mammary neoplasm in BRCA1/BRCA2 mutation carriers, it has drawbacks related to early menopause. Prophylactic hysterectomy, in addition to lowering the risk of developing a serous endometrial neoplasm, allows for the use of estrogen-only hormonal therapy to alleviate the complications of early menopause.A multidisciplinary team comprising a breast specialist, a gynecological oncologist, and a gynecological endocrinologist must carefully inform the woman who chooses this path of the wide range of implications ranging from cancer risk reduction to hormonal therapies.We believe that a “one-size-fits-all” strategy is impossible to achieve; the timing of various types of interventions should be defined and discussed in a multidisciplinary setting, taking individual risk factors and personal desires into account, and the team should inform the women about all possible implications. We believe separating breast surgeries from ovary, fallopian tube, and uterus surgeries is advantageous. If the annexes are removed, there is an advantage to removing the uterus as well, at the expense of an increase in surgical complications. Each patient should have an individualized risk assessment, and the best risk-reduction option should be chosen based on their goals, risk profile, and tolerance.


Breast cancer (BC) is the most prevalent cancer, with a higher mortality rate in women worldwide. We aimed to investigate the association of the insulinemic potential of diet and lifestyle with the odds of BC using empirical indices, including the empirical dietary index for hyperinsulinemia (EDIH), empirical lifestyle index for hyperinsulinemia (ELIH), the empirical dietary index for insulin resistance (EDIR), and empirical lifestyle index for insulin resistance (ELIR).This hospital-based case-control study was conducted among Tehranian adult women aged≥30 years. The final analysis was performed on 134 women newly diagnosed with histologically confirmed BC as a case and 267 healthy women of the same age as control. A 168-food item food frequency questionnaire was used for assessing dietary intakes at baseline. The odds ratios (ORs) and 95% confidence intervals (CIs) of BC across tertiles of EDIH, ELIH, EDIR, and ELIR were determined using multivariable-adjusted logistic regression.trend=0.016). Furthermore, subgroup analysis showed a higher BC risk with increasing EDIH score in postmenopausal women  and those without a history of the oral contraceptive pill (OCP) use . Moreover, ELIH scores were positively associated with an increased risk of BC in postmenopausal women , those with a family history of cancer , and in individuals who did not use OCP .The mean ± SD of age and BMI of participants were 47.9±10.3 years and 29.4±5.5 kg/m2, respectively. EDIH score was related to the higher risk of BC based on fully adjusted models (OR:2.24;95%CI:1.21–4.12, POur results showed a possible link between EDIH and higher BC risk. Also, higher EDIH and ELIH scores were strongly associated with a higher risk of BC in postmenopausal women, those with a family history of BC, and those who do not use OCP. Breast cancer (BC) is the most prevalent cancer, accounting for 25% of all female-related cancers worldwide, and second cancer with the highest mortality rate in women. The disease affects about 1.4 million people annually . In 2018One of the predisposing biological agents for cancer incidence and its development is insulin-related disorders, particularly hyperinsulinemia, that play a crucial role in tumor development through insulin-like growth factor-1 (IGF-1) . Obese aRecently, Tabung et al. have proposed dietary and lifestyle indices to predict hyperinsulinemia and IR using serum connecting peptide (C-peptide) and Triglyceride (TGs) to high-density lipoprotein-cholesterol (HDL-C) ratio, respectively. The empirical dietary index for hyperinsulinemia and IR (EDIH and EDIR) includes only food groups related to insulin biomarker responses. In contrast, the empirical lifestyle index for hyperinsulinemia and IR (ELIH and ELIR) is composed of physical activity (PA) and body mass index (BMI), and also food groups correlated with insulin biomarkers.Previous studies investigated the link between these insulinemic dietary and lifestyle indices and the risk of several cancer types –14 regarAccordingly, most previous studies observed a positive relationship between the EDIH and various types of cancer. However, despite the benefits of ELIH and ELIR as lifestyle scores indicating collective effects of diet, PA, and BMI, few studies have examined their association with cancer risk. Also, to our knowledge, there is no study exploring these indices’ relationship with the BC risk. So, we aimed to perform a case-control study to investigate the possible association of dietary and lifestyle indices for hyperinsulinemia  and insulin resistance  with BC risk in a sample of Iranian adult women.n=5 controls, 2 cases). Finally, 134 cases and 267 controls remained in the final analysis.In this hospital-based, case-control study, we recruited 136 women ≥ 30 years old and newly (<6 months) diagnosed with histologically confirmed BC at Imam Hossain and Shohada hospitals, Tehran (Iran) between September 2015 and February 2016. The control group consisted of 272 women of similar age who were admitted to the same hospital for a broad spectrum of non-neoplastic diseases unrelated to smoking, alcohol consumption, and long-term diet modification. Conditions among controls included traumas and orthopedic disorders, disk disorders, acute surgical conditions, eye, nose, ear, or skin disorders. Less than 8% of subjects approached for the interview refused to participate. Seven participants were excluded from the final analysis because their reported energy intakes were outside the ±3 standard deviation (SD) of the mean energy intakes of the population  . ParticiEDIH is calculated based on two groups of food components including positive  and negative  determinants. Each of the mentioned food groups is multiplied by a particular weight previously calculated in the study conducted by Tabung and his colleague  and thenSimilarly, the ELIH is determined based on a set of direct  and inverse  components. Like the EDIH, the ELIH score was calculated .The EDIR encompasses two groups of food components, including positive and negative determinants . The posEach of the mentioned components was multiplied by a particular weight, and all weighted values were summed to form the overall scores.Trained dietitians administered all other questionnaires and measurements during the same interview. Participants’ socio-demographic, lifestyle, and clinical information collected by general questionnaires, including age (years), age at menarche (years), age at first pregnancy (years), abortion history during lifetime , number of live births (number), breastfeeding history during lifetime (month), menopausal status at this time , education , history of hormone replacement therapy during lifetime , oral contraceptive pills(OCP) consumption history during lifetime (month), benign breast diseases history , cancer family history , breast cancer family history , bra wearing , night ), marital status , smoking during lifetime , supplement intakes in last year  , and anti-inflammatory drug use . Also, data on physical activity during the last year was assessed with a valid and reliable questionnaire .Weight was measured to the nearest 0.5 kg using a digital scale , with the participant wearing lightweight clothing and no shoes. Height was measured to the nearest 0.5 cm using by tape meter fixed to a wall. Body mass index (BMI) was calculated by dividing weight (kg) by the square of height (meter). Furthermore, waist circumference (at the level midway between the lowest rib margin and the iliac) and hip circumference (at the widest point over the buttocks) were measured to the nearest 0.5 cm using a non-stretchable tape measure. Subsequently, the waist-hip ratio (WHR) was calculated.The normal distribution of variables between case and control groups was assessed using a histogram chart and the Kolmogorov-Smirnoff test. The mean values of continuous and categorical variables were compared using the independent sample t-test or Mann-Whitney U  and the chi-square test.The correlation coefficient (r) between different insulin indices was calculated using a partial correlation test. Each insulin indices were categorized as tertiles based on the three equal categories among controls. The odds ratios (ORs) and 95% confidence intervals (95% CIs) of breast cancer across tertiles of insulin indices were calculated by logistic regression analysis adjusted for various potential confounders in different models.For selecting the confounding variables, we conducted a univariate test for the list of variables discussed in previous studies and selected those with P-values lower than 0.2. So the final model was adjusted for age, age at first pregnancy, family history of cancer, menopausal status, anti-inflammatory drugs, vitamin D supplement, BMI (for EDIH and EDIR), and physical activity (for EDIH and EDIR).P-values < 0.05 were considered to be statistically significant.After testing for interaction, analyses were stratified by menopausal status, cancer family history, and OCP use (P-interaction<0.05). Statistical tests were performed using SPSS software (v.16.0). P<0.05). There were no significant differences between cases and controls in insulinemic indices, including EDIH, EDIR, ELIH, EDIH, and other variables.The baseline characteristics of participants, including demographic and lifestyle variables, medical history, and dietary intakes, are indicated in Table r=0.263), EDIH and ELIH(r=0.215), and EDIR and ELIR(r=0.851).Table P for trend=0.059). After adjusting for confounding factors in the final model, participants with the highest EDIH score had higher odds of BC than those with the lowest EDIH score . However, based on all logistic regression models, there is no significant association between ELIH, EDIR, and ELIR and the risk of BC.The association of insulin indices with the risk of BC is presented in Table Table Current research provides the first evidence about the association between EDIH, EDIR, ELIH, and ELIR and the risk of BC. Based on our findings, EDIH was related to the higher risk of BC based on fully adjusted models. Furthermore, elevated EDIH level was associated with higher BC risk based on postmenopausal and non-using OCP based on subgroup analysis. Moreover, ELIH increment in postmenopausal women, those with a family history of cancer, and not using OCP was associated with an increased risk of BC.Our findings are consistent with some previous studies investigating the possible association of the insulinemic potential of diet and lifestyle with the risk of various cancers. There is evidence that the higher score of EDIH was associated with a 26% increased colorectal cancer risk in men and women . SimilarThe subgroup analyses have revealed a positive association between EDIH and ELIH scores and the risk of BC in women who did not use OCP. Previous studies demonstrated that OCP use might increase BC’s risk ; howeverA higher EDIH and ELIH score also increased the risk of BC in postmenopausal women. Increased endogenous estrogen status  is assocIn addition, according to subgroup analysis results, a significant direct association of ELIH with the risk of BC was observed in subjects with a history of cancer. There is some evidence on the relationship between family history and the risk of BC, which expresses that first-degree family history can promote invasive BC risk . For insStrengths of the current study include the novelty of the investigation and data gathering from well-documented research centers. Furthermore, we have used valid and reliable questionnaires for dietary intake and physical activity evaluation. In addition, multiple logistic regression models, considering various confounders, were used in our study. However, we acknowledge some limitations.The main limitation of the current study was the case-control study design which cannot provide a causal relationship. Also, our trained dietitians were not masked about cases and controls; however, during training, focus was given to minimize possible information bias to collect the data without mental background about participants’ cancer status. Since the study is conducted in Tehran, Iran, we cannot generalize the results to the other women population. Also, recall bias is possible due to using FFQ for dietary assessment. Furthermore, conducting stratified analyses based on three variables may increase the possibility of showing chance findings. However, the findings about EDIH, EDIR, and ELIR were repeated. Only ELIH showed a positive association with cancer among postmenopausal women, those with the cancer family history, and those with no OCP consumption. So, these findings should be tested among mentioned subgroups in other studies for a better perception of the ELIH-cancer relationship.In conclusion, our results showed a possible link between EDIH and higher BC risk. Also, higher EDIH and ELIH scores were associated with a higher risk of BC in women in the postmenopausal period, having a family history of BC, and those who do not use OCP.


BRCA1/2 germline mutations predispose carriers to an increased risk of breast, ovarian, prostate, pancreatic, and skin cancer. Men and women are equally likely to pass on or inherit the pathogenic variant. However, there is evidence that male relatives are less involved in cascade screening than female ones. At the same time, little attention has been given to the research on psychological determinants of men’s adherence to cascade screening in BRCA1/2-positive families. Applying some principles of the Health Action Process Approach model, the present research tested a model of relationships on the adherence to BRCA1/2 cascade testing guidelines. The sample comprised 115 men’s first-degree relatives of women with verified germline mutations . A pre–post test design was applied. Significant associations emerged between the intention to uptake BRCA1/2 genetic testing and age, parental status, breast cancer risk perception, self-referred outcome expectancies, perceived benefit, coping self-efficacy, and planning. Higher perceived benefit predicted increases in intention, and higher intention and coping self-efficacy predicted increases in planning. Intention was a positive total mediator of the relationship between benefit and planning. On a theoretical level, our findings partially supported the Health Action Process Approach as a valuable model based on which interventions could be developed in the context of cascade screening for BRCA1/2 genetic testing. Those results supported the importance of integrated genetic counselling sessions with a strict collaboration between geneticists and psychologists together with interventions planned to increase men’s self-monitoring ability to support their self-efficacy. BRCA1 (BReast CAncer 1 gene) and BRCA2 (BReast CAncer 2 gene). HBOC is characterized by an increased risk for breast  and ovarian cancer. Moreover, BRCA1/2 carriers are also at a greater risk of developing other cancers, including prostate, pancreatic, and skin cancer . Perceived benefits positively affected intention  and intention, in turn, positively affected action planning . Among the covariates, age predicts intention , i.e., younger participants showed higher levels of perceived breast cancer risk.Considering that among relative risk perceptions, breast cancer is the only one that showed a significant positive correlation with the intention to undergo genetic testing, it was wondered what factors could influence the relative risk perception of breast cancer. Specifically, age showed a negative correlation with breast cancer risk perception  = 3.68, p = 0.014). Bonferroni-corrected pairwise comparisons revealed that the group with more than one relative with BRCA1/2 identified variant had a relative risk perception of breast cancer that was significantly higher  than those who had a sister with an identified variant . There was no statistically significant difference with the other groups . Furthermore, there was a significant difference between groups based on the degree of kinship, as demonstrated by the one-way ANOVA  were partially supported. Specifically, the findings from the regression analysis evidenced that only the perceived benefit associated with the genetic testing may contribute to predict the intention to undergo BRCA1/2 genetic testing. Therefore, rather than expectancies related to the self or the family, perceived benefit resulted as the key psychological determinant in influencing the intention to undergo BRCA1/2 genetic testing for men.Our hypotheses regarding the role of risk perceptions, outcome expectancies and coping self-efficacy in predicting the intention to uptake BRCA1/2 pathogenic variant. In particular, the greater the perceived benefits of undergoing a genetic test, the greater the intention and therefore the likelihood of planning this important screening behavior, adhering to cascade screening. This is another demonstration of the validity of the principles of the HAPA model applied to this research.Regarding HP1b, our results showed the role of the intention and coping self-efficacy in predicting the planning of the action, as supported by the HAPA model literature . FurtherBRCA1/2 genetic testing has more positive consequences and outcomes for one’s personal life was associated with higher intention, showing that the higher the self-referred anticipated consequences of engaging in BRCA genetic testing, the higher the intention experienced (RQ1). However, regarding RQ1 and in contrast to earlier qualitative findings [BRCA1/2 testing to protect their family  rather than to ascertain the risks to themselves, no evidence of association between family-referred outcome expectancies and intention to uptake BRCA genetic testing was detected. Related to this result and contrary to the expectations, in our study, males without children showed significantly higher intention than that shown by males with children. This latter result might be also connected to the relationship between age and intention. Indeed, in our study, younger participants, who are less likely to have offspring, showed higher levels of intention to adhere to cascade screening. Notwithstanding, future studies should investigate and verify these results by comparing males already tested and not yet tested. The participants’ recruitment of the previous studies was consequent to their BRCA1/2 genetic testing and therefore also after genetic counseling sessions, where genetic counselors had the aim, among others, to help people in understanding and adapting to familial implications of genetic information. Our hypothesis is that in a pre-intentional phase, such as the one analyzed in our study, in which the subjects have not benefited from any genetic counseling session, males may be more focused on self-referred implication without the initial awareness of the family ones.Moving on now to consider the association between intention and other factors, several interesting results should be discussed. Specifically, higher breast cancer risk perception as well as higher perceived benefit and coping self-efficacy were found to be directly associated with higher intention. Moreover, beliefs that findings ,25,46 thBRCA1/2 genetic testing, which was higher in younger males than older ones. Therefore, young age acted as a facilitating factor for the intention to undergo genetic testing. The result of this study is consistent with the literature, which identifies younger people with higher interest and more positive attitudes in genetic testing [Additionally, age was found to be negatively associated with the intention to undergo  testing ,47,48,49BRCA1/2. Some studies seem to suggest the presence of an increased perception of cancer risk in healthy men tested for BRCA1/2 , irrespective of the genetic test result [Regarding risk perception and consistent with RQ2, beliefs that personal risk perception of breast cancer is higher than other people similar for age and gender were associated with higher intention to undergo genetic screening for t result . Interest result , impactit result ,50. IndeBRCA mutation, who perceived their cancer risk as average, the others (with different degrees of kinship with the proband) perceived themself as less at risk than the average population of equal gender and age. Studies support the notion that people who are in a state of higher risk such as that determined by an identified genetic mutation perceive themselves to be less at risk of cancer than the rest of the population, that is, to reduce the distress that this awareness would cause them, applying a cognitive regulation strategies of distress reduction [Interestingly, excluding participants who have more than one relative with identified eduction . Additioeduction ,53. If reduction ,55. FutuBRCA mutations. Cancer risk perception is influenced by the experience of cancer disease within the family [Furthermore, in our sample, a negative association was found between age and perceived breast cancer risk, highlighting that younger men reported higher levels of breast cancer risk perception. In our sample, the youngest participants were generally children of probands. As supported by Liede et al. , a highee family ,57,58, ae family .BRCA1/2 genetic testing or any other exposure to information that the participants could have searched for themselves. The measures applied in the present research had the aim to collect information regarding possible psychological variables influencing intention to adhere to prescribed guidelines for BRCA1/2 genetic testing not to inform their decision-making. Participants were not exposed to any kind of genetic counseling session before entering the study. They might not be fully aware about all the implications connected to the BRCA1/2 germline mutations, and this may have influenced their intention to adhere to the guidelines for relatives of BRCA1/2 proband. Fourth, the measure of expectation of the outcome of the genetic test  was worded in a positive way only and did not consider the possible difference between short- and long-term beneficial vs. detrimental expectations. Future research should investigate these points with a more sensible measure.Despite the methodology applied in the present research and the pre–post test design, some limitations should be noted. First, this study included a small number of participants that are vulnerable to self-selection bias, particularly because the available probands were involved in contacting their male first-degree relatives. It might be that the probands who agreed to participate were the most willing to share health information with their male relatives and the most willing to involve them in the mutation identification process, as were the men who decided to participate in the study. Second, although based on HAPA model literature, there is a proven strong link between intention and planning, and between planning and subsequent implementation of the target behavior, data on the action of undergoing genetic testing itself were not collected. Future studies should test how the psychological factors identified as salient for intention affect the actual enactment of the genetic screening in a cascade screening context. Third, the present research did not test the level of the knowledge, or subjective and objective health literacy  of our pBRCA1/2 genetic testing. On a theoretical level, our findings partially supported the Health Action Process Approach as a valuable model based on which to develop interventions in the context of cascade screening for BRCA1/2 genetic testing. Specifically, the most important factor influencing the intention to adhere to the genetic testing guidelines for relatives of BRCA1/2 proband seems to be the perceived benefit of testing, while planning of the action results from the intention itself and the coping self-efficacy. Those results seem to stress the importance of integrated genetic counselling sessions with a strict collaboration between genetics and psychologists together with interventions planned to increase men’s self-monitoring ability to support their self-efficacy.The study has some peculiar strengths. Specifically, in contrast to previous studies involving first- to third-degree relatives, our study focused on a homogeneous sample of first-degree relatives only, who therefore share the same exposure to the risk (50%) of having inherited or passed on that pathogenic variant. Furthermore, our sample consists of subjects who have not previously undergone genetic counseling sessions. Therefore, their knowledge and attitudes have not yet been influenced by any formal educational intervention that provides the basis for informed decision  regardin


Diabetes and insulin levels may increase the risk of postmenopausal breast cancer. In the present investigation, we aimed at evaluating whether adherence to a diabetes risk reduction diet (DRRD) lowers the risk of breast cancer.We used data from an Italian, multicentric case-control study (1991–1994) including 2569 incident histologically-confirmed breast cancer cases and 2588 hospital controls. A food frequency questionnaire collected subjects’ usual diet. We derived a DRRD score on the basis of eight items: intake of cereal fiber, total fruit, coffee, polyunsaturated to saturated fats ratio and nuts (higher scores for higher intakes), and dietary glycemic index, red/processed meat and sugar-sweetened beverages/fruit juices (higher scores for lower intakes). The score theoretically ranged 8–37, with higher values indicating greater DRRD adherence. Odds ratios (ORs) of breast cancer according to the DRRD score were estimated using multiple logistic regression models.P for trend 0.001). Inverse associations were observed in subgroups of covariates.The DRRD score was inversely related to the risk of breast cancer. The ORs were 0.93  for a three-point score increment and 0.76  for the highest versus the lowest quartile (Higher DRRD adherence may decrease the risk of breast cancer. Diabetic subjects have a 10–30% excess risk of postmenopausal breast cancer, likely explained by residual confounding by adiposity ]  admitted to major teaching and general hospitals of the study areas. Controls were 2588 women  with no history of cancer admitted to the same hospitals for acute, non-neoplastic, nongynecological conditions, unrelated to hormonal or digestive tract diseases or to dietary-related conditions. Among controls, 22% were admitted for traumas, 33% for other orthopedic diseases, 15% for acute surgical conditions, 18% for eye diseases and 12% for other miscellaneous diseases. Less than 4% of cases and controls approached for interview refused to participate. The study was approved by the local ethics committees according to the rules at the time of data collection. All procedures were performed in accordance with the ethical standards laid down in the Declaration of Helsinki.et al., 1998; Cases and controls were interviewed in hospital by centrally trained interviewers, using a standard structured questionnaire. This included information on sociodemographic and anthropometric factors, lifestyle habits, including tobacco smoking, alcohol drinking and physical activity, as well as obstetric, gynecologic and general medical history, and family history of cancer. Subjects’ usual diet in the previous 2 years was assessed through a food frequency questionnaire (FFQ). Subjects were asked to indicate their average weekly consumption of 78 food items or food groups. Open questions were used to report foods/recipes eaten at least once a week not included in the FFQ list. The FFQ included also a few questions aiming at assessing fat intake pattern as well as information on salt and garlic use. Intakes lower than once a week, but at least once per month, were coded as 0.5/week. Nutrient and total energy intake were determined using an Italian food composition database  in the open questions of the FFQ were assigned a score of 2; a score of 1 was assigned to the remaining women. Due to the lack of trans fats information within the Italian food composition tables, trans fats intake could not be calculated and included in the score. For each woman, the DRRD score was obtained by summing up the scores in all the dietary components. The score thus theoretically ranged from 8 to 37, with higher values indicating greater adherence to the DRRD.We calculated the DRRD score according to Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) of breast cancer according to approximate quartiles (derived among controls) of the DRRD score and to a three-point increment in the score were estimated using unconditional logistic regression models. Two models were fitted: a first model included terms for study center, age and education; a second model included further terms for year of interview, BMI, physical activity, smoking, history of diabetes, parity, menopausal status and age at menopause, use of oral contraceptives and hormone replacement therapy, family history of breast cancer, alcohol intake and total energy intake. Trends in ORs across score quartiles were evaluated by including an ordinal variable for quartiles in the logistic regression models. A few missing data in the adjustment factors were replaced by the median value (continuous variables) or mode category  according to case/control status. We conducted the following sensitivity analyses: (1) we included in the models the adjustment for total vegetable intake and (2) for weight change since age 30 (the information was not available for 148 women), (3) excluded diabetic women from the analyses and (4) assessed the association between the DRRD score and breast cancer excluding each score component in turn from the DRRD score calculation. Subgroup analyses were performed according to menopausal status, education, parity, BMI and smoking status. Heterogeneity across strata was tested by a likelihood ratio test comparing models with and without interactions terms for the score quartile variables and the subgroup factors.All the analyses were conducted using the SAS software, version 9.4 .Table Table Q4vsQ1: 0.80, 95% CI, 0.67–0.94) or weight change since age 30 , as well as the exclusion of diabetic women from the analyses  did not materially affect any of the results. Fairly consistent results were found after removing each dietary factor in turn from the DRRD score calculation; the ORs for the highest versus the lowest score quartile varied between 0.70  and 0.85  .Further adjustment for total vegetable consumption , following 180 000 women for ≥26 years   .versus the lowest score quartile: 0.80, 95% CI, 0.68–0.93).Seeds oil is commonly consumed in the USA, where the score was derived, and is a major dietary contributor of polyunsaturated fats in the country. In the Mediterranean area, olive oil (in particular the extra virgin type) is the main source of dietary fat and is a major source of monounsaturated fatty acids , the similar catchment areas and interview setting for cases and controls and the lack of awareness in this population of a possible role of diet on breast cancer risk weigh against these biases. In addition, the FFQ was tested for validity and reproducibility with satisfactory results (Our study suggests that higher adherence to a dietary pattern for diabetes risk reduction lowers the risk of breast cancer. It remains unclear whether this is due to a direct effect of such diet on glycemia and related factors (e.g. IGF-1) or to other mechanisms related to the individual components and their combination. The observation that the effect is greater in premenopausal women would at least in part support the latter hypothesis.This work was supported by the AIRC  Foundation, the Italian League for the Fight against Cancer and Department funding.There are no conflicts of interest.


The term ‘pregnancy-associated breast cancer’ is no longer used as it has been consistently reported that breast cancer during pregnancy and breast cancer after delivery (postpartum breast cancer) have different characteristics and prognosis. The purpose of this study is to define postpartum breast cancer by analyzing the incidence rate, related factors, and prognosis according to the timing of breast cancer. Data from the Korean National Health Insurance Service were used to analyze 1,292,727 women aged 20-49 years who birthed their first child between 2007 and 2012. The annual incidence rate of breast cancer after delivery increased every year . The risk of breast cancer was significantly higher  in women diagnosed with gestational diabetes, but that was not associated with overall survival (OS). Patients diagnosed with breast cancer within 5 years of delivery had a poorer prognosis than those diagnosed later . In multivariate analysis of OS, the hazard ratio of patients diagnosed within 5 years after delivery was twice as high as of patients diagnosed between 5 and 10 years. Women diagnosed with gestational diabetes had an increased risk of breast cancer. Breast cancer patients diagnosed within 5 years of delivery had a poorer prognosis than those diagnosed later. In this regard, careful screening for early diagnosis of high-risk patients and intensive research on new treatment strategies are needed. Pregnancy, childbirth and lactation produce the greatest physiologic changes in the breast. Breast cancer is related to the duration of exposure to female hormones, and it is well known that childbirth and breast feeding lower long-term risk of breast cancer. However, a temporary increase in the risk of breast cancer after pregnancy and childbirth has also been reported –3.During pregnancy, the ductal system undergoes rapid proliferation and forms intra-branch alveolar structures extending from the ducts, which are used for milk production. The unique biological characteristics of the involution process, the process in which the breast returns to the mammary state before pregnancy after lactation, are related to the development of breast cancer after childbirth , 4. SimiStudies of mouse mammary glands suggest that the involution process is also related to the induction of acute-phase response genes and increases in inflammatory cytokines and modulators of apoptosis and immune cascades , 6–8, anIn the past, the term pregnancy-associated breast cancer (PABC) was used to describe breast cancer in relation to pregnancy and childbirth . PABC haHowever, more recently, the disease has been divided into breast cancer during pregnancy and breast cancer after delivery (postpartum breast cancer) , 13. BreThe definition of postpartum breast cancer is also diverse, with some definitions based on 1 year or 5 years postpartum, while recently an increase in risk has been reported up to 22 years , 20, 22.Therefore, in this study, the following questions were explored to define and understand the characteristics of postpartum breast cancer.1) Breast cancer incidence rate according to time after delivery - Is there a period when the incidence of breast cancer increases after delivery?2) Breast cancer after delivery (postpartum breast cancer) risk factors and related diseases - Are there factors associated with increased incidence of breast cancer after delivery? 3) Clinical features and pathological characteristics according to the interval between delivery and breast cancer - Are there any differences in the characteristics of breast cancer according to onset timing after childbirth?4) Prognosis according to the interval between delivery and breast cancer - Does breast cancer occurring within 5 years of delivery have a worse prognosis?In Korea, all medical providers and users  are obliged to subscribe to the National Health Insurance Service (NHIS). The NHIS categorizes insurance qualifications and payment amount by insured person, and insurance policyholders  are required to pay premiums to the NHIS. When medical services are used at a healthcare institution, the healthcare institution bills the Health Insurance Review and Assessment Service (HIRA) for the cost of medical care benefits, excluding out-of-pocket expenses. The NHIS pays insurance money, and the HIRA reviews insurance claims and evaluates the quality of medical services.https://nhiss.nhis.or.kr/bd/ay/bdaya001iv.do) had provided support of policy and academic research utilizing National Health information since 2002. Research data is largely provided as a customized DB and a sample cohort DB. “Customized DB” refers to data that are processed and provided as demand-tailored data so that the health information data that are collected, held, and managed by the NHIS can be used for policy and academic research purposes. Customized health information data are provided using statistical analysis tools in the “data analysis room,” which is a place in the industrial complex where a PC can be used for research and analysis because the size of the data is very large. The NHIS covers all citizens who reside in Korea except Medical Aid Beneficiaries and Health Care Beneficiaries for veterans; the NHIS covers 97% of the Korean population.The NHIS includes data on eligibility and insurance premiums from birth to death, hospital and hospital usage history and national health checkup results, rare incurable disease and cancer registration information, medical benefit data, and long-term care data for the elderly. The National Health Insurance Sharing Service  women were defined as having their first childbirth in 2007. The last follow-up of these subjects was December 31, 2017.Delivery was defined for inpatients using the Code of Conduct (ICD-9-CM Procedures Vol 3. version 32). First delivery was defined as a case where there was no insurance claim related to delivery between 2002 and 2006. Delivery included all kinds of delivery including vaginal delivery and Caesarean section, and the codes are listed in the The baseline characteristics of the women with/without breast cancer were compared using Student’s t-test and the chi-square test. The annual incidence rates of breast cancer were calculated by Poisson regression. Characteristics of breast cancer occurring within 5 years/5 to 10 years/>10 years after delivery were compared and analyzed using ANOVA and chi-square test. For survival analysis, the Kaplan-Meier method and log rank test and Cox proportional hazards regression were used. The Cox proportional hazards model was used to estimate the hazard ratios (HR) and 95% confidence intervals (CIs) and to identify prognostic factors for survival. P-values < 0.05 were considered statistically significant. Statistical analyses were performed using Statistical Analysis System (SAS) version 9.4 .This study was approved by the Institutional Review Board of the Korea University Anam Hospital (No. 2020an0530).The median age of the 1,292,706 women who had their first delivery between 2007 and 2012 was 30 years (range 28-33 years), among whom 44.61% were in their 20s (20-29 years), 53.23% in their 30s (30-39 years), and 2.13% in their 40s (40-49 years)  , 37.80% of patients were in their 30s (30-39 years) and 58.57% of patients were in their 40s (40-49 years). The median age at first delivery of these breast cancer patients was 32 years (29-35 years), of whom 28.58% were in their 20s (20-29 years) and 68.02% were in their 30s (30-39 years). There were 1,681 cases (56.58%) of single births, 1,194 cases (40.19%) of two births, and 96 cases (3.23%) of three or more births. Among the 1,194 breast cancer patients who delivered twice, the interval between the two deliveries was 12-24 months in 295 (24.71%) and 24-36 months in 421 (35.26%). The period from first delivery to the diagnosis of breast cancer was less than 5 years in 477 patients (16.06%), between 5 and 10 years after delivery in 1,229 (41.37%), and more than 10 years in 1,265 (42.58%).Among women who gave birth for the first time in 2007 and were observed for 12 years, the diagnosis of breast cancer showed a steady increase every year. The incidence of breast cancer 5 years after delivery was 7.7 per 10,000 person-years (95% CI 6.62-8.91), and this increased to 19.36 per 10,000 person-years after 10 years (95% CI 17.60-21.22)  when their last delivery was in their 30s, and HR 3.62 (95% CI 2.99-4.39) when their last delivery was in their 40s.The risk of breast cancer decreased as the number of deliveries increased . The HR increased to 2.48 (95% CI 1.18-5.22) when the delivery interval was less than 12 months, compared with more than 60 months.Analysis of the risk of breast cancer by age at first delivery and number of deliveries revealed that risk decreased as the number of deliveries increased in women who gave birth in their 30s. The incidence rate per 10,000 person-years was 16.09 in women who delivered once, 11.55 in women who delivered twice, and 8.66 in women who delivered three or more times   of 235,872 patients were diagnosed with preeclampsia, and 51 (1.49%) of these patients were also diagnosed with breast cancer. There was no significant difference in the risk of breast cancer with or without preeclampsia  patients were diagnosed with gestational diabetes mellitus (GDM), and 504 (1.41%) of these patients were also diagnosed with breast cancer. The annual breast cancer incidence rate in women diagnosed with GDM continued to increase, and the incidence was higher than that of women who were not diagnosed with GDM. The annual incidence rate in women with GDM was 9.58 (95% CI 6.63-13.38) after 5 years and 30.48 (95% CI 24.98-36.83) after 11 years   is associated with increased risk of breast cancer –36. HoweWhether postpartum breast cancer has a worse prognosis also remains unclear. PABC has a poorer prognosis than non-PABC. The definition of PABC varies, but it is generally defined as during pregnancy and within one year of delivery. A high frequency of higher grade, triple-negative breast cancers, and HER2+breast cancer was observed in PABC, and 5-year OS was worse –44. In aRecent studies have shown that breast cancer during pregnancy does not differ in prognosis from breast cancer in non-pregnant women. However, since postpartum breast cancer has a significantly poorer prognosis, it is more appropriate to divide breast cancer during pregnancy from postpartum breast cancer, rather than grouping them as PABC . In thisBreast cancer occurring within 5-10 years of delivery is estimated to account for 35-55% of all breast cancer cases in women under the age of 45 20]. Sev0. Sev2).The major limitation of this study is that stage and subtype could not be confirmed from this data. However, when the pattern of adjuvant treatment was analyzed, patients diagnosed within 5 years had a higher proportion of chemotherapy than those diagnosed within 5-10 years .This data is managed by the National Health Insurance Service of Korea. Only approved researchers may use the data in the designated “data analysis room”. Requests to access these datasets should be directed to . Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by SP, JSL, JY, and SYB. The first draft of the manuscript was written by SB and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.This work was supported by the research grant of the Korean Breast Cancer Society.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The aim of this study was to estimate the extra risk of second primary cancer among breast cancer patients.i.e., standardized incidence ratio (SIR)] among breast cancer patients older than 15 years. After evaluating the methodological quality of the selected studies, SIRs were pooled with consideration of heterogeneity among studies. The estimates were pooled by age and time since the diagnosis of primary breast cancer for both sexes . Age was categorized based on before 50 years and after 50 years, and time was categorized as duration of less than and more than 10 years, respectively.This is a systematic review. A comprehensive search of literature was performed in PubMed, Web of Science, Cochrane library, and Scopus. The search included all published studies up to October 2022. This systematic review included studies published in the English language that reported the risk of second primary non-breast cancer [vs. 1.21 ] as well as women after 10 years since their breast cancer diagnosis [1.33  vs. 1.24 ] were at a higher risk of developing second primary cancer. Among men, while there were no differences in risk based on age, with the increase of time, the risk of second primary cancer was reduced [SIR: 1.22  vs. 1.00 ].From 2,484 articles, 30 articles were eligible for inclusion in the systematic review and meta-analysis. The studies varied in terms of population, number of cases, study design, setting, and year of implementation of the research. The estimated SIR for men and women was 1.28  and 1.27 , respectively. Women diagnosed with breast cancer before menopause [SIR: 1.52  There is an extra risk of second primary cancer among breast cancer patients. The extra risk should be considered for further screening and preventive measures among this population.https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=336062, identifier (CRD42022336062). Breast cancer is one of the major health problems in the world and ranks number one in mortality among women of older age in many developed and even developing countries . Longer This systematic review and meta-analysis was developed based on the MOOSE Checklist for Meta-analyses of Observational Studies . A comprA systematic search was carried out up to October 7, 2022. Initially, relevant keywords were identified using the primary search in PubMed/Medline; then, the search strategy was adapted accordingly for Scopus, Cochrane Library, and Web of Science. Language restrictions were considered in the search process (only English articles). The following selected keywords were used and combined in the selected search databases: multiple primary neoplasm(s), multiple primary cancer, multiple primary malignancies, second cancer, second malignancies, breast cancer, risk, and population-based. The details of the comprehensive search strategy for this systematic review are provided in the supplementary materials. Studies were entered into EndNote X9 software , and duplicate items were detected and removed by this software.i.e., SIR) among breast cancer patients older than 15 years. The second primary cancer was defined based on IARC definition  were excluded. Articles that did not specify the coding definition were excluded if it was apparent that the definition for accepting a second primary cancer did not agree with the IARC definition. Articles reporting a second primary breast cancer usually lack information on reporting second cancer in the same or in the contralateral breast as well as histological reports of tumors. Therefore, all studies which included second primary breast cancer were excluded unless risk estimates for other sites of second primary cancer were reported. Due to the multimodal treatment of breast cancer, studies that examined the risk of second cancer based on treatment type were excluded.In the selection stage, the two reviewers separately checked the title, abstract, and full text of the articles using the inclusion and exclusion criteria, and any discrepancies between the results were resolved by discussion. The reference lists of the included studies were reviewed to identify other potentially relevant studies. If more than one article were published for one population, the newer or the one with a larger population was included. The data was extracted manually by two independent researchers. Disagreements were resolved through discussion and consensus. If there were deficiencies in the required information of the selected studies, the corresponding author of the article was contacted by email, and additional information about the results of the study was requested. The following information was extracted: first authors, publication date, country of origin, study design, study follow-up period, cases (number of first and second primary cancer), mean age at cancer diagnosis (both first and second primary cancer), gender, definition of second primary cancer, inclusion criteria for their population, and estimated SIR and its associated 95% confidence intervals (CI). The following cancer sites were included in the analysis: skin (melanoma and non-melanoma), head and neck , esophagus, stomach, colorectal, liver and gallbladder and biliary tract, pancreas, lung and mediastinum, Kaposi sarcoma, leukemia, lymphoma, multiple myeloma, soft tissue sarcoma, bone, prostate, testis, kidney, bladder and urinary tract, brain and nervous system, thyroid, eye, corpus uteri, cervix uteri, ovary, adrenal gland, and parathyroid.2)  for each estimate (SE = √observed/expected2) . Then, wI2 values, a heterogeneity test was carried out among the included studies. If the I2 value is less than 50%, it was considered as without significant heterogeneity, and we pooled the estimates using the fixed-effect model. An I2 value higher than 50% was considered as obvious heterogeneity, and we pooled estimates using the random-effect model. In addition, subgroup and sensitivity analyses were performed to identify the source of heterogeneity. The effect of a study’s quality on the estimates was measured using meta-regression and subgroup analyses. Publication bias was investigated using funnel plots , 27 studies did not provide SIR or risk estimate, and four studies did not provide SIR for specific cancer site but reported for total cancer combined. Population or period overlaps were also seen in 22 studies ], soft tissue sarcoma and bone [trim-and-fill method: 1.87 ], soft tissue sarcoma [trim-and-fill method: 2.16 ], non-Hodgkin’s lymphoma [trim-and-fill method: 1.11 ], corpus uteri [trim-and-fill method: 1.74 ], and ovary [trim-and-fill method: 1.49 ]; among female patients younger than 50 years—esophagus [trim-and-fill method: 2.27 ]; and among female patients with second cancer diagnosis less than 10 years from breast cancer diagnosis—thyroid [trim-and-fill method: 2.20 ] and kidney [trim-and-fill method: 1.32 ].P = 0.037).The meta-regression analysis revealed that study quality only influences the risk estimate in the bladder and urinary tract cancer among female patients ≥50 years , immune function, hormonal imbalances, age, race, environmental factors, and shared etiologic factors , 81. KnoThe present study is the first meta-analysis to investigate the risk of second cancers among women and men previously diagnosed with primary breast cancer by the site of second cancer, age at diagnosis of breast cancer, and time since diagnosis of breast cancer according to the IARC definition. Despite a large amount of research that has been done on the risk of developing second cancer among female breast cancer patients, few studies have been done on male breast cancer patients , 95–98. In the meta-analysis, in addition to high-quality studies, we also considered acceptable and low-quality studies. Meta-regression showed that the quality of the studies did not influence the estimated risk except in bladder and urinary tract cancer among female patients ≥50 years.As a shortcoming of our study, researchers in this field are at risk of various types of bias due to differences among studies  as well as unavoidable bias due to differences in the year the research was performed (due to advancement in breast cancer treatment and the possible change in the pattern of second cancers compared with previous decades). Therefore, we recommend that in the future, more research will be conducted that will also assess the mentioned factors.Results indicate a higher risk of developing second primary non-breast cancers among male and female breast cancer patients. Therefore, this population might benefit from prevention and screening programs. To prevent and control second primary cancers, the results of our systematic review can help researchers to design studies on screening modalities and prevention programs concerning this issue.The original contributions presented in the study are included in the article/PP, AM, MM, and AB researched, screened, and drafted the manuscript. AK and SH analyzed the data. AM and NA-Y supervised the content. All authors contributed to the article and approved the submitted version.


Although the link between sugar-sweetened beverages (SSB) and pancreatic cancer has been suggested for its insulin-stimulating connection, most epidemiological studies showed inconclusive relationship. Whether the result was limited by sample size is explored. This prospective study followed 491,929 adults, consisting of 235,427 men and 256,502 women , from a health surveillance program and there were 523 pancreatic cancer deaths between 1994 and 2017. The individual identification numbers of the cohort were matched with the National Death file for mortality, and Cox models were used to assess the risk. The amount of SSB intake was recorded based on the average consumption in the month before interview by a structured questionnaire. We classified the amount of SSB intake into 4 categories: 0–<0.5 serving/day, ≥0.5–<1 serving per day, ≥1–<2 servings per day, and ≥2 servings per day. One serving was defined as equivalent to 12 oz and contained 35 g added sugar. We used the age and the variables at cohort enrolment as the reported risks of pancreatic cancers. The cohort was divided into 3 age groups, 20–39, 40–59, and ≥60. We found young people (age <40) had higher prevalence and frequency of sugar-sweetened beverages than the elderly. Those consuming 2 servings/day had a 50% increase in pancreatic cancer mortality  for the total cohort, but a 3-fold increase  for the young. The risk started at 1 serving every other day, with a dose–response relationship. The association of SSB intake of ≥2 servings/day with pancreatic cancer mortality among the total cohort remained significant after excluding those who smoke or have diabetes , are obese , have hypertension , or excluding who died within 3 years after enrollment . Risks remained in the sensitivity analyses, implying its independent nature. We concluded that frequent drinking of SSB increased pancreatic cancer in adults, with highest risk among young people. The public health significance of pancreatic cancer and its increasing mortality have been largely ignored. Most incidence died within a few years and incidence correlated with mortality. In the United States, a 1.6 and 1.9% increase per year in incidence and mortality of pancreatic cancer, respectively, has been observed . A trendOnly a few lifestyle risk factors, such as smoking and drinking, have been identified for pancreatic cancer, but the size of increase in incidence due to these lifestyle risks is minimal –9. MoreoThe overall consumption of sugar-sweetened beverages (SSBs), the main source of added sugars in diets of people, has remained high since 1970s –14. FurtSSB consumption has been reported to be associated with increased risks of cardiovascular diseases or all-cause mortality, implying the systemic nature of this risk , 38. ThiThis prospective cohort study enrolled 491,929 individuals aged ≥20 years without known cancer history from the four MJ clinics that have been conducting a self-paid medical screening program across Taiwan with well-administered medical records since 1994 , 40. TheThe participants underwent sequential blood, urine, and pulmonary function tests and also electrocardiography. They also underwent physical examination and a review of medical history. Moreover, the participants completed a self-report structured questionnaire about lifestyle.Hypertension was defined as a self-reported history of hypertension, systolic blood pressure of ≥140 mm Hg, diastolic blood pressure of ≥90 mmHg, or use of antihypertensive agents. Diabetes was defined as a self-reported history of diabetes, fasting blood glucose level of ≥126 mg/dl, or use of hypoglycemic agents.The definition of total SSB included sugar-added drinks such as caffeinated or decaffeinated cola, carbonated SSBs, and noncarbonated SSBs . In addiWe classified the leisure time physical activity of each individual into five groups: inactive -h/week or <5 min/day), low activity (3.75–7.49 MET-h/week or approximately 15 min/day), moderate activity (7.50–16.49 MET-h/week or approximately 30 min/day), high activity (16.50–25.49 MET-h/week or approximately 60 min/day), and very high activity (≥25.50 MET-h/week or approximately 90 min/day or more) .International Classification of Diseases, Ninth and Tenth revisions, with pancreatic cancer coded as 157 and C25, respectively. We referred to age and variables at cohort enrollment in this study. Written informed consent was provided by each participant, and this study was approved by the Institutional Review Board of China Medical University in Taiwan. All data were encrypted and remained anonymous during the entire study process.The individual identification numbers of the cohort were matched with the National Death File for mortality and with the National Cancer Registry for cancer incidence. We coded mortality according to the The association of SSB with pancreatic cancer can be attributed to unhealthy behaviors accompanying SSB intake, such as smoking or alcohol, or to metabolic syndrome resulting from SSB intake , 42, 43.P <0.05 was considered significant.Univariate analysis was used to assess the possible risk factors of pancreatic cancer. Variables with statistical significance in univariate analysis were considered for multivariate analysis to assess the association between SSB intake and pancreatic cancer risk. For the total cohort, the HR was adjusted for age, sex, education level, smoking status, drinking status, physical activity, body mass index (BMI), hypertension, and diabetes. In the sensitivity analysis, adjustments for potential confounders were unnecessary. For age-classified models, the HR was adjusted for sex, education level, smoking status, drinking status, physical activity, BMI, hypertension, and diabetes. No violation of the proportional hazard assumption was noted in our study. All statistical analyses were performed using SAS 9.4 , and a two-tailed The study cohort included 491,929 participants, with 235,427 men and 256,502 women . The follow-up period was between 1994 and 2017 (median follow-up: 15 years). In total, 523 cases of pancreatic cancer deaths and 489 cases of incident pancreatic cancers were observed during a total of 89 million person-years during follow-up. Because the 5-year survival of pancreatic cancer is 10%, mortality data can be expected to be slightly less than incidence. However, mortality data were available for 2 additional years, censoring by 2017, compared with incidence data, censoring by 2015. Therefore, mortality registered in the National Death File might outnumber the incidence registered in the National Cancer Registry in our study. 2), hypertension, and diabetes  and incidence  for those consuming 2 servings/day of SSB, with a dose–response relationship observed when the intake was greater than 1 serving every other day , a cohort design rather than a case–control design, exclusion of participants who died within 3 years of enrollment, a series of sensitivity analyses conducted with risks found in both incidence and mortality, and high-quality cancer incidence data collected from the nationwide cancer registry , 56. A cThe study also has several limitations. First, the study might be subject to selection bias because only people who could afford the membership fee were likely enrolled in this self-paid screening program. Different from other self-paid medical screening programs, the MJ clinics emphasize family-centered screening, with incentives to recruit more family members, namely, members of the extended family such as uncles, cousins, or grandparents, paid for by the head of the household. Therefore, MJ participants were from almost all levels of social classes, and selection bias, as commonly perceived, was minimized. With half a million participants, constituting nearly 3% of the Taiwan population, the socioeconomic status effect was further mitigated with the internal comparison study design analyzing relative risks in this study. Furthermore, our cohort exhibited a prevalence of risk factors, incidence, and mortality of cancer that is consistent with the values for the general Taiwan population , 39. SecOur results indicate that SSB intake was independently associated with pancreatic cancer in this Asian cohort, with highest risks among young people (age <40 years). Starting from one drink a day, a dose–response relationship was observed between the amount of SSB intake and pancreatic cancer risk. The risk was compounded by the increasing popularity of bubble milk tea. Considerable effort should be devoted to encourage modification of SSB consumption behavior.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the China Medical University & Hospital Research Ethics Committee. The patients/participants provided their written informed consent to participate in this study.Study concept and design: CPW and CHC. Analysis and interpretation of data: MKT, CHL, and CW. Drafting of the manuscript: CPW and CHC. Critical revision of the manuscript for important intellectual content: CPW, CHC, RTL, CW, MKT, and CHL. Technical or material support; study supervision: CPW, CHC, CYH, XW, and TWDC. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.This study is supported in part by the Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW109-TDU-B-212-114004), the MOST Clinical Trial Consortium for Stroke (MOST 109-2321-B-039-002), the China Medical University Hospital (DMR-109-231), and the Tseng-Lien Lin Foundation, Taichung, Taiwan.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The evaluation of breast density is important, because dense breast has been shown to be associated with increased risk of breast cancer and a greater risk of a false-negative diagnostic performance due to masking a tumor. Although the relationship between parity and dense breast is under investigation, conclusive evidence is lacking. We aimed to investigate whether parity affects breast density.The study design is a cross-sectional study. The subjects are healthy Japanese women who underwent opportunistic mammographic screening at the center for preventive medicine at a single institution from January 2016 to December 2018. Clinical characteristics and lifestyle factors were obtained from questionnaires. Breast density was categorized into 4 groups, namely, almost entirely fatty dense, scattered fibroglandular dense, heterogeneously dense, and extremely dense, according to the Breast Imaging Reporting and Data System. Heterogeneously and extremely dense were considered collectively as dense breast. Multivariate logistic regression analysis was conducted to investigate the relationship between parity and dense breast among premenopausal and postmenopausal women separately.7612 premenopausal and 9252 postmenopausal women were investigated. Dense breast was shown in 62.6% of nulliparity, 57.3% of single parity, 47.3% of two parity, 37.6% of more than two parity among premenopausal women, and in 41.6% of nulliparity, 31.1% of single parity, 19.3% of two parity, 10.1% of more than two parity among postmenopausal women. For premenopausal women, two parity, single parity and nulliparity showed a higher risk for dense breast with statistically significance (Odds Ratio (OR) adjusted for potential confounding factors: 1.458 ; 1.123–1.894), 2.349 , 3.222 , respectively), compared with more than two parity. For postmenopausal women, two parity, single parity and nulliparity had a higher risk , 3.023 , 4.954 , respectively) with statistically significance, compared with more than two parity.Parity showed an inverse trend of having dense breast among both premenopausal and postmenopausal women. In particular, nulliparous women need to recognize their higher risk of dense breast. In the future, the declining fertility rate may affect the prevalence of dense breast in the world. Dense breast on mammography is one of the most important risk factors for breast cancer, although many factors are considered to be related with the risk of breast cancer. Previous studies have shown that dense breast has been shown to have a 2–5 times higher risk of breast cancer –5. To maThe etiology of the dense breast is not definitively clear. Although the relationship between parity and dense breast is under investigation, many of these related studies are retrospective nature and involve relatively small sample –19. TherThe subjects are general healthy women who underwent opportunistic mammographic screening for health check-up at the Center for Preventive Medicine at St. Luke’s International Hospital from January 2016 to December 2018. In Japan, many women undergo opportunistic mammographic screening periodically every one or two years. For women who revisited the screening several times in this period, only the data at the first visit was extracted, because the breast density does not change radically in three years during which data collection took place. Women with a history of breast cancer, women with any findings of mammography screening, and women without consent to this study were excluded.This was a cross-sectional study and the questionnaire collected demographic information concerning age, past medical history, current habit of alcohol consumption, which was chosen from three choices, none, occasional, or regular, according to frequency per week, smoking habit, which was chosen from three choices, never, past, or current, family history of breast cancer, parity, which was defined as the number of pregnancies that resulted in single or multiple childbirth except for stillbirth regardless of gestation period, menopausal status which was defined by the cessation of menstrual periods for one full year, and history of hormonal therapy use, including both premenopausal oral contraceptive use and postmenopausal hormone replacement therapy, which was selected from two choices, yes or no. Participants underwent physical measurements and mammography examination. Body mass index (BMI) was calculated as the body weight (kg) divided by square of height (m). The process of this study was to investigate and compare the characteristics of nulliparous women with that of parous women. The items of their characteristics compared in this study was selected, based on previous studies , 11, 16.Digital mammography was taken with its quality certified by the Japan Central Organization on Quality Assurance of Breast Cancer (JCOQABC). Mammograms were taken in two directions, mediolateral oblique and craniocaudal view. Breast density was categorized into 4 groups, namely, almost entirely fatty dense, scattered fibroglandular dense, heterogeneously dense, and extremely dense, according to the Breast Imaging Reporting and Data System (BI-RADS) . Heterogp-value cut-off point at 0.05 in all analyses. All statistical analyses were performed using SPSS version 24.0 .We constructed contingency tables of the clinical features and compared the characteristics between parous women and nulliparous women. The independent t-test was used for comparison of quantitative variables and the chi-square test was used for comparisons of categorical variables. The univariate logistic regression model was applied to analyze the odds ratio (OR) of dense breast with 95% confidence interval (CI). To adjust the effects of possible confounders of statistical significance in univariate analysis, the multivariate analysis was performed to calculate the adjusted OR. Statistical significance was assessed, with a The characteristics of the women recruited in this study are summarized in Table 2, parous; 21.17 ± 3.03 kg/m2). Parous women showed less likely to smoke , less likely to drink , and more likely to have hormonal therapy . In contrast, postmenopausal women comprised 3279 nulliparous and 5973 parous women and their demographic characteristics are shown in Table 2, parous; 21.70 ± 3.29 kg/m2). Parous women were less likely to smoke , less likely to drink , and less likely to have hormonal therapy .Premenopausal women comprised 3878 nulliparous and 3734 parous women and their demographic characteristics are shown in Table p for trend < 0.001). Among postmenopausal women, a similar trend was shown. The prevalence of dense breast was 41.6% for nulliparous women, 31.1% for women with single parity, 19.3% for women with two parity, and 10.1% for women with more than two parity. The higher the number of parity, the lower the prevalence of dense breast. The difference in the prevalence according to the number of parity was significant (p for trend < 0.001).The relationship between the number of parity and dense breast is shown in Fig. For premenopausal women, two parity, single parity, and nulliparity had a higher risk of dense breast , 2.229 , 2.782 , respectively), compared with women with more than two parity. In the multivariate analysis, adjusted by age, BMI, smoking status and alcohol status, parity still showed a significant relationship. Compared with women with more than two parity, two parity and single parity showed a higher risk of dense breast , OR: 2.349 , respectively), and nulliparity showed a further higher risk of dense breast ) , 4.013 , 6.322 , respectively), compared with women with more than two parity. In the multivariate analysis, adjusted by age, BMI, smoking status, alcohol status, and hormonal therapy, parity still showed a significant relationship. Compared with women with more than two parity, two parity and single parity had a higher risk of dense breast , OR: 3.023 , respectively), nulliparity showed a further higher risk of dense breast ) , which is defined as the number of children who would be born per woman, has been decreasing globally from 4.7 in 1950 to 2.4 in 2017. This means about 49.4% decline in TFR observed in this period . FurtherOur study has several potential limitations. First, this study was performed using a cross-sectional design and did not allow us to research temporal associations. Further study with a follow-up survey for these population may acquire additional information regarding the relationship of parity with breast cancer incidence and subtype. Second, recall bias may potentially existed, because most of the demographic data were extracted from the questionnaires. Third, there may be other suspicious confounders, that affect the outcome including breastfeeding, age at first birth, miscarriage. In particularly, breastfeeding has a strong relationship with parity, and affects the endogenous hormonal level. Although previous studies have investigated the impact of breastfeeding on breast density, the association between the duration of breastfeeding and mammographic breast density had discrepant results , 13. AltParity showed an inverse trend of having dense breast among both premenopausal and postmenopausal Asian women including Japanese. As the number of parity decreases, the more likely women appeared to have dense breast on mammography. In particular, nulliparous women need to be more aware of their own breast because of their higher risk of dense breast. Our findings significantly added novel information regarding the relationship between parity and breast density to the present knowledge of dense breast.