Female breast cancer is the most commonly diagnosed malignancy worldwide. Risk assessment helps to identify women at increased risk of breast cancer and allows the adoption of a comprehensive approach to reducing breast cancer incidence through personalized interventions, including lifestyle modification, chemoprevention, intensified surveillance with breast imaging, genetic counseling, and testing. Primary prevention means acting on modifiable risk factors to reduce breast cancer occurrence. Chemoprevention with tamoxifen, raloxifene, anastrozole, and exemestane has already shown benefits in decreasing breast cancer incidence in women at an increased risk for breast cancer. For healthy women carrying BRCA 1 or BRCA 2 pathogenic/likely pathogenic (P/LP) germline variants, the efficacy of chemoprevention is still controversial. Adopting chemoprevention strategies and the choice among agents should depend on the safety profile and risk–benefit ratio. Unfortunately, the uptake of these agents has been low. Lifestyle modifications can reduce breast cancer incidence, and the recommendations for BRCA 1 or BRCA 2 P/LP germline variant carriers are comparable to the general population. This review summarizes the most recent evidence regarding the efficacy of chemoprevention and lifestyle interventions in women with sporadic and hereditary breast cancer. Female breast cancer is the most commonly diagnosed malignancy worldwide . GLOBOCAFamilial breast cancer accounts for 15% to 20% of all breast cancer cases, and about 5% to 10% of breast cancers are due to genetic predisposition ,7. HormoIn 2010, the fraction of breast cancer attributable to lifestyle and environmental factors in the United Kingdom was around 27%, of which 18.5% was related to alcohol, diet, overweight, and obesity . PrimaryIndividualized breast cancer risk assessment helps to identify women at increased risk of breast cancer, allowing them to benefit from personalized risk management strategies . A comprEvidence-based risk reduction strategies according to different risk categories should be implemented to decrease breast cancer burden. This review summarizes the most recent evidence regarding primary prevention, focusing on the efficacy of lifestyle interventions and chemoprevention according to breast cancer risk.Chemoprevention with tamoxifen or raloxifene  and anastrozole or exemestane  has shown to reduce breast cancer occurrence in women at increased risk of developing breast cancer ,16,17,18Women who could benefit most from chemoprevention with endocrine therapy are those who “have been diagnosed with atypical  hyperplasia or lobular carcinoma in situ (LCIS) or have an estimated 5-year risk  of at least 3%, a 10-year risk  or have at least 5%, or a relative risk of at least four times the population risk for their age group if they are age 40 to 44 years or at least two times the population risk for their age groups if they are age 45 to 69 years” . p < 0.00001) and noninvasive breast cancer by 50% (two-sided p < 0.002). The incidence of estrogen receptor-positive (ER+) tumors was reduced by 69%, but no difference was observed in the occurrence of estrogen receptor-negative (ER-) tumors [In 1992, the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1 Study) following the observation that using tamoxifen for adjuvant therapy reduced the incidence of contralateral breast cancer . The stu) tumors . Tamoxif) tumors . After s) tumors .p = 0.013) [p = 0.004) [Along this line, the first International Breast Cancer Intervention Study (IBIS-I) reported the risk reduction of invasive breast cancer with tamoxifen use as well . This st= 0.013) . In addi= 0.004) .p = 0.10). Of note, the incidence of ER+ tumors was significantly lower in the tamoxifen arm  [The Royal Marsden Hospital study was a pilot randomized placebo-controlled trial that included healthy women with an increased risk of developing breast cancer based on strong family history (between October 1986 and June 1993). The study aimed to evaluate the efficacy of tamoxifen 20 mg/day for up to 8 years in reducing breast cancer incidence ,26. This= 0.005) .The Italian Tamoxifen Prevention Study randomized 5408 healthy women—between 35 and 70 years old—who had undergone a previous hysterectomy to receive tamoxifen or placebo for five years. No difference in breast cancer incidence was observed in the overall study population at a median follow-up of 46, 81.2, and 109.2 months, respectively ,29,30. IRaloxifene is a second-generation SERM with similar anti-estrogenic effects and less endometrial stimulation than tamoxifen . The plaThe Continuing Outcomes Relevant to Evista (CORE) trial evaluated the impact of 4 additional years of raloxifene on the incidence of invasive breast cancer in 4011 women enrolled in the MORE trial . RaloxifThe Raloxifene Use for The Heart (RUTH) trial randomized postmenopausal women with a high risk for coronary heart disease to receive raloxifene or placebo ,34. AccoThe NSABP STAR trial (P-2 Study) compared the efficacy of tamoxifen versus raloxifene to reduce breast cancer incidence. A total of 19,747 postmenopausal women aged > 35 years with high risk for invasive breast cancer, based on the modified Gail model or with a personal history of LCIS, were randomized to receive tamoxifen 20 mg/day or raloxifene 60 mg/day for five years. The efficacy was similar ; however, thromboembolic events and cataracts occurred less frequently in the raloxifene group  [p< 0.001) and lasofoxifene [Other SERMs have shown a reduction in the incidence of invasive breast cancer in postmenopausal women with osteoporosis. Arzoxifene  reduced foxifene  by 79% (p<0.0001), and vertebral fractures reduced by 34%  [A meta-analysis with individual participant data from nine prevention trials assessed the efficacy of chemoprevention with four SERMs  in reducing all breast cancers’ incidence during ten years of follow-up. The analysis evaluated data from 83,399 women during a median follow-up of 65 months. Breast cancer incidence decreased by 38% , while the frequency of thromboembolic events increased with all SERMS  .p = 0.002). The frequency of skeletal fractures, cardiovascular events, or deaths related to treatment were similar [Aromatase inhibitors have also been evaluated for primary prevention in women with an increased risk for breast cancer. The MAP.3 randomized, placebo-controlled, double-blind trial randomized 4560 postmenopausal women ≥ 35 years old with moderately increased risk for breast cancer to receive a placebo or exemestane. Women eligible for the study were ≥60 years old, had a Gail 5-year score > 1.66%, had prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ, or had a history of ductal carcinoma in situ with mastectomy. During a median follow-up period of 3 years, the annual incidence of invasive breast cancer decreased in patients receiving exemestane compared with placebo ; the reduction occurred mainly in high-grade tumors compared with intermediate- or low-grade tumors [p < 0.0001) and a 59% decrease in ductal carcinoma in situ , mainly in participants with ER+ tumors . No significant difference was observed in overall deaths  or deaths for breast cancer. In addition, breast cancer incidence showed a significant continuing reduction in long-term follow-up [The international, double-blind, randomized, placebo-controlled IBIS-II trial assessed the efficacy and safety of anastrozole for preventing breast cancer in 3864 postmenopausal women at increased risk [ollow-up .A meta-analysis of six studies evaluated the efficacy and acceptability of breast cancer prevention agents in 50,927 women at above-average risk of developing breast cancer. Tamoxifen use reduced breast cancer risk compared to placebo  but increased the risk of severe toxicity , particularly endometrial cancer and thromboembolism. Aromatase inhibitor use reduced the risk of breast cancer by 53%  but increased the risk of severe toxicity by 18% , especially hot flashes, diarrhea, and arthralgia .The US Preventive Services Task Force conducted a systematic review (46 studies) to evaluate medication use for the risk reduction of primary breast cancer in women . In placTamoxifen, raloxifene, and aromatase inhibitors were associated with acute, long, and late adverse effects that differed between medications. Raloxifene was associated with a reduced incidence of vertebral fractures compared with tamoxifen . Thromboembolic events occurred more frequently in patients receiving tamoxifen (RR 1.93: CI 95% 1.33–2.68) and raloxifene (RR 1.56: CI 95% 1.11–2.60) compared with placebo. In addition, tamoxifen increased the risk of endometrial cancer  and cataracts (RR1.22: CI 95% 1.08–1.48) compared to the placebo. Vasomotor and musculoskeletal events varied by medication . Concerns about the burden of adverse effects of chemoprevention raised doubts regarding the use of chemoprevention, considering the benefit overestimated, especially for healthy women . In addip < 0.001) [A systematic review including 24 articles with 21,423 women reported a pooled uptake of 16.3% (95% CI 13.6–19.0) of breast cancer prevention agents. In addition, the uptake of preventive agents was significantly higher in patients treated in trials  than in routine care . Moreover, the presence of risk factors for breast cancer increased chemoprevention uptake only in women aged ≥ 50 [A study evaluated whether chemoprevention uptake differs among women according to the presence of risk factors for breast cancer. The results showed that women aged ≥ 50 were more likely to use chemoprevention than women younger than 50 . In addition, the incidence of contralateral breast cancer was decreased by 64% for patients with tamoxifen . The number needed to be treated with tamoxifen to prevent one case of a breast event was 22 in five years and 14 in ten years. Low-dose tamoxifen reduced recurrence by 50%  in the DCIS cohort, the subgroup representing 70% of the overall population. Low-dose tamoxifen did not increase the risk of serious adverse effects, including deep venous thrombosis and endometrial cancer. Therefore, low-dose tamoxifen represents an alternative for women diagnosed with intraepithelial neoplasia [At a median follow-up of 9.7 years, patients assigned to low-dose tamoxifen had a significant 42% reduction in neoplastic breast events (in situ or invasive); the annual rate per 1000 person-years was 11.3 for patients with tamoxifen versus 19.5 with placebo . The authors concluded that antiplatelet drugs are not good pharmacologic candidates for breast cancer prevention [The E3N cohort assessed the association between breast cancer risk and low-dose aspirin or clopidogrel use in postmenopausal women . Among 6evention .Metformin is an oral glucose-lowering agent used in first-line therapy for type 2 diabetes mellitus . A systeVeronesi et al. evaluated the efficacy of the retinoic acid derivative fenretinide in reducing second primary breast cancers . The stup = 0.71) [A meta-analysis assessed the effect of vitamin D supplementation in reducing breast cancer risk in 19,137 females. The analysis described no effect on breast cancer risk reduction  .Two randomized clinical trials assessed the efficacy of alendronate and zoledronic acid in breast cancer risk reduction . The FraPreclinical studies assessed the role of various natural compounds in preventing breast cancer, including curcumin , genisteFor women carrying BRCA1 and BRCA2 P/LP germline variants, the cumulative breast cancer risks to age 80 are estimated at 72% and 69%, respectively . The golThe first evidence of breast cancer risk reduction with tamoxifen in healthy BRCA1 and BRCA2 germline variant carriers came from a subgroup analysis of the P-1 trial. The P-1 study evaluated the efficacy of tamoxifen (versus placebo) for reducing breast cancer incidence in 13,388 women at increased risk for breast cancer. Of 288 patients who developed breast cancer after being enrolled in the study, 19 (6.6%) carried BRCA1 P/LP (n = 8) or BRCA2 P/LP (n = 11) germline variants . TamoxifAlthough the evidence for chemoprevention with tamoxifen for primary breast cancer in BRCA germline variant carriers is controversial, studies have shown that tamoxifen reduces the occurrence of contralateral breast cancer . Accordip = 0.73) in the overall population. Similar results were described in women with or without breast cancer and BRCA1 or BRCA2 carriers. Limitations included the small number of patients (170 of 270 expected) and the high dropout rate. The randomized, double-blinded, placebo-controlled phase III French Liber Trial evaluated chemoprevention with aromatase inhibitors in postmenopausal women carrying BRCA1 or BRCA2 P/LP germline variants. The study compared the treatment with letrozole 2.5 mg/day for five years (n = 84) versus a placebo (n = 86) in decreasing breast cancer incidence . The stuThe uptake of chemoprevention agents is low among women carrying BRCA1 and BRCA2 P/LP germline variants. Metcalfe et al. examined differences in the uptake of preventive practices  by 2677 women with BRCA1 and BRCA2 P/LP germline variants from nine countries. Approximately half of the women at risk for breast cancer did not opt for preventive measures and relied solely on regular screening. On the other hand, 1531 (57.2%) women opted to undergo a bilateral prophylactic oophorectomy. Among the 1383 women who did not have breast cancer, 248 (18%) underwent a prophylactic bilateral mastectomy. For those who did not choose to have a prophylactic mastectomy as a preventive option, only 76 women (5.5%) decided to take tamoxifen and 40 (2.9%) raloxifene for breast cancer risk reduction. The uptake of the different preventive options varied among different countries. Women from the US were the most likely to take tamoxifen or raloxifene (12.4%), while no women from Norway, Italy, Netherlands, or France reported using these drugs. Furthermore, among women without breast cancer, those who had undergone an oophorectomy had a higher tamoxifen usage rate (15.6%) compared with those who had not undergone a prophylactic oophorectomy (1.7%) . Table 1The association between breast cancer and overweight/obesity, fat diet, low physical activity, alcohol intake, and hormone replacement therapy is well known . A healtThe Vitamins and Lifestyle (VITAL) cohort study examined the association between the incidence of invasive breast cancer and six recommendations of the WCRF/AICR cancer prevention program, focusing on body fatness, physical activity, foods that promote weight gain, plant-based foods, red and processed meats, and alcohol consumption over a follow-up of 6.7 years . The stuA systematic review and meta-analysis conducted in January 2020 evaluated the effect of 15 preventable factors on breast cancer risk . The RRsp trend < 0.01) and vigorous  recreational activities was observed. Women who reported five or more weekly hours of vigorous recreational activity had a lower risk of breast cancer  than women who reported neither moderate nor vigorous recreational activity. In addition, physical activity remained protective for women at high risk of breast cancer based on BMI, family history of breast cancer, nulliparity, and HRT use [The French E3N populational-based cohort study analyzed the relationship between physical activity and breast cancer incidence between 1990 and 2002 among 90,509 women between 40 and 65 years of age. A linear decrease in the risk of breast cancer with increasing amounts of moderate  compared with inactive subjects .A prospective assessment examined the association between physical activity and breast cancer risk in 45,631 women from the US Radiologic Technologists cohort. The authors observed that women practicing walking/hiking ≥ 10 h per week had the most substantial risk reduction than those reporting no walking/hiking  .On the other hand, the relationship between body mass index (BMI) and breast cancer is more complex. Age and menopausal status modify the effect of BMI on the development of breast cancer . Women wp < 0.01). In addition, women who gained 10 kg or more since menopause compared with weight maintenance had an increased risk for breast cancer  [The prospective cohort Nurses’ Health study assessed the impact of weight change on the occurrence of invasive breast cancer in 87,143 postmenopausal women aged 30 to 55 years. The researchers followed women for 26 years, from age 18 (from 1976 to 2022). The study also evaluated weight change since menopause among 49,514 women over 24 years. The results revealed that women who experienced a weight gain of 25 kg or more since age 18 had a higher risk of developing breast cancer compared with those who had maintained their weight  .The PREDIMED study randomized 4282 women between 60 and 80 years old, from 2003 to 2009, at high cardiovascular risk to three different diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). After a median follow-up of 4.8 years, the Mediterranean diet nuts group showed a nonsignificant risk reduction compared with the control group . When both Mediterranean diet groups were merged, the risk relative reduced by 51%  [Population-based studies have suggested that the impact of dietary composition on breast cancer risk might be particularly significant during adolescence and early adulthood . A prospA systematic review of 14 cohorts and 18 case-control studies assessed the associations between different dietary patterns and the risk of breast cancer . The resp = 0.01) and a decrease in breast cancer-related deaths . There was also a significant reduction in worse-prognosis ER+ PR-negative (PR-) breast cancer (p = 0.01) occurrence in the low-fat dietary intervention group [The WHI DM trial randomized 48,835 postmenopausal women with no prior breast cancer, aged between 50 and 79, and consuming ≥ 32% of their energy from dietary fat to receive the usual diet comparison group (60%) or the dietary intervention group (40%). The goals were to decrease fat consumption by 20% and increase fruit, vegetable, and grain intake. After a median 19.6-year follow-up, the researchers described a noteworthy reduction in overall mortality after breast cancer  for light , RR of 1.23 (95% CI 1.19–1.28) for moderate (≤50 and >50 g/day), and 1.61 (95% CI 1.33–1.94) for heavy drinking (>50 g/day) [Another meta-analysis conducted a dose-response assessment between various alcohols and the risk of breast cancer. The analysis included 22 cohort studies involving 45,350 cases of breast cancer. The results showed a higher risk of developing ER+ tumors for current drinkers than for never-drinkers. The dose-response analysis indicated a significant linear correlation between breast cancer risk and total alcohol intake and wine consumption. For every additional 10 g of alcohol consumed per day, the risk of breast cancer increased by 10.5%  for total alcohol and 8.9%  for wine. In postmenopausal women, the risk of breast cancer increased by 11.1% (95% CI 1.09–1.13) with every 10 g increase in total alcohol consumption. Moreover, the study found that the percentage of breast cancer cases attributed to alcohol consumption was higher in Europe compared to North America and Asia .Two nested case-control studies assessed the risks of breast cancer associated with different types and durations of HRT in the UK. The analyses included 98,611 women (59–79 years old) with a primary diagnosis of breast cancer between 1998 and 2018, matched by age, general practice, and index date to 457,498 female controls . OverallA recent meta-analysis of individual participant data from prospective studies (from 1 January 1992 to 1 January 2018) included 108,647 postmenopausal women who developed breast cancer, of whom 55,575 (51%) had used HRT. Of interest, every HRT type, except vaginal estrogens, was associated with breast cancer risk, which steadily increased with the duration of use. In addition, the risk was higher for estrogen and progesterone than for estrogen-only preparations. The analysis included current users up to 5 years after last-reported HRT use. The participants had a clear excess risk even during the first four years ; the risk increased to twice during years 5–14  .p < 0.0001). Ever breastfeeding decreased breast cancer risk for both luminal and triple-negative subtypes  [Another meta-analysis assessed the association between breast cancer risk and parity, age at first birth, and breastfeeding. The analysis included 21,941 patients with breast cancer and 864,177 controls. The findings revealed that parity reduced the risk of the luminal subtype by 25%  .Finally, the Nurses’ Health Study (1976–2012) and NHSII (1989–2013) investigated the association between breastfeeding, parity, and breast cancer risk, considering hormone receptor and molecular subtypes. A total of 12,452  breast cancer cases were diagnosed among 199,514 women. They observed that parous women compared with nulliparous women had a lower risk of ER+ breast cancer . In addition, among parous women, breastfeeding was associated with a lower risk of ER- versus never breastfeeding  [Besides intensified surveillance, chemoprevention, and risk reduction surgeries, strategies for decreasing breast cancer risk for P/LP germline variant carriers also comprise lifestyle factors .p-trend = 0.01). Moreover, another study revealed a connection between adolescent and young adult physical activity and older age at breast cancer diagnosis (p = 0.03). Based on the limited evidence available, there are indications that physical activity during the formative years of adolescence and young adulthood may decrease or postpone the occurrence of breast cancer in individuals carrying BRCA1 and BRCA2 P/LP germline variants [A systematic literature review investigated whether physical activity levels during adolescence and young adulthood could decrease the lifetime risk of breast cancer among individuals carrying BRCA1 or BRCA2 germline variants. The review identified five relevant articles that met inclusion criteria and utilized self-reported physical activity data during these development stages. Among these studies, one assessed sports involvement, while the others focused on recreational activities. Four studies reported decreased breast cancer incidence over a lifetime with physical activity levels during adolescence and young adulthood. However, one study reported limited protection for premenopausal breast cancer  and BRCA2 (n = 276) P/LP germline variant carriers . The resAnother meta-analysis included three cohort studies for 1100 healthy women with BRCA1 and BRCA2 P/LP germline variants who underwent risk-reducing bilateral salpingo-oophorectomy before the onset of natural menopause to assess the association between breast cancer incidence and HRT. The results did not find an increased risk associated with using HRT beyond the baseline increase in the risk of breast cancer for women carrying BRCA germline variants .p = 0.008) in breast cancer for breastfeeding for at least one year among BRCA1 germline variant carriers and a more significant decrease in risk for two or more years of breastfeeding . However, results showed no significant association between breastfeeding for at least one year and breast cancer risk among BRCA2 germline variant carriers  [A matched case-control study included 1665 pairs of women with BRCA1 (n = 1243 pairs) and BRCA2 (n = 422 pairs) P/LP germline variants to assess the association between breastfeeding and breast cancer risk. They observed a 32% risk reduction  .p = 0.02). Women who had their first live birth after the age of 30 years had a slightly increased breast cancer risk . Parity , age at menarche , and use of oral contraceptives  did not independently change breast cancer risk [Khincha et al. conducted the first study to assess the association between female reproductive factors and breast cancer risk in women carrying a germline TP53 P/LP variant . The rescer risk .Breast cancer is the most commonly diagnosed cancer in women. For this reason, lifestyle recommendations to decrease breast cancer risk, such as increased physical activity, healthy diet, and reduced alcohol consumption, should be counseled to everyone. Breastfeeding should also be encouraged. Implementing specific preventive strategies should always be discussed during counseling and personalized risk assessment. The choice among different chemoprevention agents should consider patient comorbidities and each agent’s adverse effect profile. In addition, effective programs to increase chemoprevention agent uptake should be implemented.Our group is now evaluating multimodal and combination strategies. We are starting a randomized phase II trial for breast cancer prevention, including healthy high-risk women and patients with intraepithelial neoplasia. The intervention groups will be low-dose tamoxifen (10 mg every other day); low-dose tamoxifen combined with intermittent caloric restriction (ICR two days/week); lifestyle intervention (LSI diet according to WCRF recommendations and step counter); and LSI combined with ICR. We hypothesize that the combination of low-dose tamoxifen and intermittent caloric restriction will improve risk biomarkers with a better quality of life. Furthermore, we aim to peruse the low dose regiments, and we are designing a study for post-menopausal women with intraepithelial neoplasia comparing tamoxifen 10 mg every other day versus exemestane 25 mg every other day, balancing efficacy, side effects, and quality of life.


BRCA1 and BRCA2 mutations; high-risk vs. population screening; and the definition and implementation of guidelines for surveillance of asymptomatic mutation carriers. Since 1995, oncogenetics has been transformed from a rare oddity to a pivotal player, and it represents a successful example of implementing personalized preventive medicine by identifying and providing care and by offering means for early detection and risk reduction for adults who are genetically predisposed to develop a potentially life-threatening disease—cancer in this case. Lastly, I outline my personal vision for the possible way forward for oncogenetics.In early 1995, I established the oncogenetics service at the Genetics Institute of the Sheba Medical Center in Israel. The purpose of this article is to describe the key points and issues that were raised throughout my personal journey since then: physician and public awareness; ethical and legal issues; guidelines for oncogenetic counseling; the development of oncogenetic testing within the unique Israeli reality of the limited spectrum of  What kind of a specialty is this?”“Why do I need to know my cancer risk? This is TMI. You are going to cause women to be depressed and even commit suicide.”“I am an oncologist. I can provide all the information on genetics and cancer risk to all my patients. No need for oncogenetic counseling.”This is just a short and non-representative list of some of the comments and responses that I was receiving in early 1995.Rb, APC, VHL, and RET). The rapidly evolving sequencing technologies and the concomitant reduction in sequencing costs, combined with the explosion of discoveries of cancer susceptibility genes underlying more commonly encountered cancer types—breast, colon, and ovary—have led to the notion of creating a clinical platform that would address the needs of high-risk individuals—an oncogenetic service. Indeed, in the early-to-mid-1990s, the cloning of the two BRCA genes , and findings on the rate of these mutations in consecutive unselected ovarian cancer cases and the general AJ population  enumerated an eligibility list of individuals whose oncogenetic counseling was to be covered by the Israeli “health services basket” . Soon af therapy . The pive missed , led to n screen . Current“What data do you need to collect in the course of oncogenetic counseling?”“Do we have to provide face-to-face (F2F) pretest counseling for all counselees?”“Who should we offer F2F disclosure of test results?”“Why can’t I test my daughter at 12 years of age without her knowledge? I want to know what her genetic status is”BRCA carrier and an individual’s personal risk of developing BC/OvC  were in their infancy and not as accurate as they are now. In order to maximize our ability to collect data that seemed relevant to oncogenetic counseling, we constructed our own questionnaire based on a literature search for factors known to affect cancer risk; these included primarily family history, but also reproductive factors, personal habits, and anthropomorphic measures, to name a few. In hindsight, some of the data collected made no sense in the Israeli reality. Over the years, we have consistently asked about alcohol consumption, and of the 35,000+ women who have undergone oncogenetic counseling at the Oncogenetics unit of the Sheba Medical Center, none have reported consuming more than one or two drinks per week. Moreover, data that were not corroborated by medical documents or based on objective definitions  seemed to be skewed and inaccurate: height (for men), weight (for women), smoking status (“I marked ‘non-smoker’ because I stopped smoking last month after 40 years of smoking one pack a day”), engagement in sports (more noticeable in men), and reproductive factors (for women in the older age group). The paucity of existing, easy-to-use algorithms for visualization of the pedigree (or the prohibitively high cost of existing ones) also led to the use of hand-drawn pedigrees, with all the inherent difficulties of deciphering the shorthand and the handwriting (even by myself for my own pedigree drawings).In 1995, there were no readily available questionnaires in Hebrew that focused on collecting data relevant to the evaluation of the possibility of an inherited predisposition to cancer. Moreover, the algorithms that enable more structured assessment of the risks of being a Six upgrades were made to the questionnaires over the years, with the current format having been stable since 2015: the questionnaires were made more streamlined by foregoing questions that were consistently answered in the negative or were non-contributory, and items collecting more relevant information were added, such as email addresses rather than landline telephone numbers. During the COVID-19 pandemic, these questionnaires have been administered online, and the possibility of online genetic counseling has been advanced, but the concept remains imperfectly developed. One of the issues that needs to be resolved is pedigree drawing: this is urgently needed, preferably at an affordable price and in a user-friendly, app-adoptable form.“So, what do I do when I leave your office, Dr Friedman?”“Who is going to take care of me now?”“How will I keep up with new developments relevant to my health?”“Is it safe to take oral contraceptives and hormone replacement therapy?”BRCA mutation carrier in the late 1990s was “what do I do now?”. Indeed, the only available option in Israel at that time was to refer these women to individual specialists  and to refer the relevant family members for oncogenetic counseling. There was no straightforward way to keep these BRCA mutation carriers or other affected family members updated on developments relevant to their health and surveillance guidelines, nor was there any solution in terms of a comprehensive assessment of the short- and long-term psychosocial effects of being a “high-cancer-risk individual.” It became painfully clear that there was in fact a clinical need to provide a “one-stop shop” for all high-risk BRCA mutation carriers. To this end, through the devoted efforts of Joel Feldshaw  daughter, Meirav, to breast cancer at a young age), the Meirav high-risk clinic was established in 2007. The clinic offers a one-stop shop for carriers, providing ready access to all clinical, radiological, and (when necessary) biopsy services via the same team of healthcare professionals and secretarial support staff. Family members eligible for oncogenetic counseling are encouraged to consult with the geneticist, and informal dialog and counseling are provided by mail and/or telephone calls. The clinic also serves to keep women informed in real time of possible studies that they can join, evolving technologies , and updates to guidelines . In my view, this is the single most important clinical innovation in oncogenetics to date.A recurring theme after a woman was informed that she was a • Point-of-care (POC) oncogenetic testing using POC technologies ;• Tele-oncogenetics for genetic counseling and disclosure of genetic test results;• Ongoing educational efforts to enable primary care physicians to provide basic oncogenetic counseling;• Population screening for all actionable cancer-susceptibility genes;• One-stop shop clinics for high-risk individuals applying internationally harmonized early detection protocols and catering to the needs of all carrier family members: genetic, psychosocial, radiological, surgical, and medical;• International collaborations and bio-genetic banks to promote research—Penetrance modifier factors; novel early detection schemes for ovarian and pancreatic cancers; definition of the missing heritability in breast cancer;BRCA mutation carrier status by the MoH/insurers.• Coverage of all procedures arising from


This study aimed to investigate clustering patterns of lifestyle risk factors for stomach cancer and examine the association of risk factor clusters with stomach cancer screening adherence. Data from the 2019 Korean National Cancer Screening Survey, an annual cross-sectional nationwide survey, were used. The study population included 3539 adults aged 40–74 years with no history of cancer. Six stomach cancer risk factors, including smoking, drinking, physical inactivity, obesity, meat intake, and salted food intake, as well as stomach cancer screening behaviors, were assessed. The most frequent risk factor for stomach cancer was physical inactivity, followed by smoking in males and high salted food intake in females. Compared with participants subjects with no risk factors, those with three or more risk factors were less likely to adhere to screening guidelines . Our findings indicate a disparity in stomach cancer screening, such that those with more risk factors are less likely to get screened. Increasing public awareness, providing behavioral counseling, and targeting high-risk populations for screening interventions are critical for promoting cancer screening adherence and reducing the disparity in cancer screening. Each year, approximately 1,000,000 people are diagnosed with stomach cancer worldwide, and about 760,000 patients die from this disease2. Moreover, in 2019, 29,493 new cases of stomach cancer, accounting for 11.6% of total cancers, were observed in Korea3.Stomach cancer is a common malignant disease5 and modifying unhealthy lifestyle risk factors7, are the main methods of prevention. Several lifestyle risk factors, including smoking tobacco, drinking alcohol, obesity, unhealthy diets, and physical inactivity have been found to be associated with the initiation and progression of stomach cancer12. Modifying these lifestyle risk factors can significantly reduce the risk of stomach cancer6. For example, smoking cessation has been reported to prevent 11% of stomach cancer cases worldwide13 and 19.4% of cases in Korea14. However, lifestyle risk factors are not randomly distributed but tend to cluster and interact to exponentially elevate the risk of cancer17. Therefore, the synergy between lifestyle risk factors plays a role in controlling stomach cancer.Both primary and secondary prevention measures contribute to preventing stomach cancer. Primary prevention strategies, such as eradicating Helicobacter pylori18. Specifically, all Koreans aged 40 years and older are recommended to be screened for stomach cancer every other year via upper endoscopy or upper gastrointestinal series (UGIS). According to recent estimates from the Korean National Cancer Screening Program, participating in stomach cancer screening can significantly reduce the stomach cancer death rate by 19–23%19. Efforts to motivate stomach cancer screening and modify lifestyle risk factors may hold the most significant promise for reducing stomach cancer incidence and mortality.In Korea, stomach cancer has been considered a suitable disease for mass screening since 199920 and cigarette smoking21, and stomach cancer screening participation. However, to date, no study has assessed the association between multiple lifestyle risk factors and adherence to stomach cancer screening recommendations. Therefore, in the current study, we aimed to identify clustering patterns of six well-established lifestyle risk factors for stomach cancer  among Korean adults aged 40–74 years and to examine the association of the clusters with adherence to stomach cancer screening.Previous studies have highlighted the relationship between several lifestyle risk factors for stomach cancer, such as alcohol consumption22. The survey participants were randomly selected through a multi-stage random sampling method that was stratified by geographic area, sex, and age. The sampling frame was based on resident registration population data. Details about the sampling procedure are available elsewhere23.Data for this study were obtained from the 2019 Korean National Cancer Screening Survey (KNCSS), an annual, nationwide, population-based cross-sectional survey conducted since 2004 to determine cancer screening rates among the Korean populationA professional research agency conducted face-to-face interviews using a structured questionnaire. They recruited study subjects through door-to-door visits at least three times to ensure that all eligible participants  had an opportunity to participate. All study participants were provided with a sufficient explanation, and they provided informed consent to participate in the survey.In the 2019 KNCSS, participants were asked about their screening history for five types of cancers , health behaviors, health status, family history of cancer, and demographic characteristics. Of the 4500 respondents, 3539 adults aged 40–74 years were eligible for stomach cancer screening and included in this study . We defined ever smokers as those who have smoked at least 100 cigarettes throughout their lifetime26. The total daily alcohol consumption amount (g/day) was calculated by multiplying the daily consumption frequency with the amount of alcohol per time. Based on the association between alcohol consumption and the risk of stomach cancer in a previous study among the Korean population27, heavy drinking was defined as consuming ≥ 20 g/day for females or ≥ 40 g/day for males.Participants answered a series of questions regarding their frequency of alcohol consumption in the past year  and the number of standard drinks (cups) consumed per each drinking session. A standard drink was defined as a specialized cup for each type of alcoholic beverage . Each cup has a different volume but a similar amount of alcohol 28.Subjects were asked about the number of days they had at least 10 min of moderate-to-vigorous-intensity physical activity during the last week and the number of minutes per day. Moderate-to-vigorous-intensity physical activities include hiking, swimming, shoveling, bicycling fast, basketball game, tennis singles, etc. Information on the total number of minutes per day and the number of days per week was used to calculate the total minutes per week. Participants who did not perform at least 75 min of moderate-to-vigorous-intensity physical activity per week were defined as having “physical inactivity” based on the recommendation of the World Health Organization (WHO)2]), individuals with a BMI of ≥ 25 kg/m2 were defined as overweight or obese, based on the standard for the general population suggested by the WHO29.Based on self-reported height and weight data and using a standard formula for calculating body mass index  to one serving and asked participants about the frequency of red and processed meat consumption per week. The frequency was classified into three categories: “one serving per week,” “two to three servings per week,” and “four or more servings per week.” Individuals who reported consuming four or more servings per week were denoted as reporting high red or processed meat intake.We asked participants about how much they prefer salty flavor using a 5-point Likert scale: (1) “like very much ,” (2) “like ,” (3) “neither like nor dislike ,” (4) “dislike (moderate),” and (5) “dislike very much (light).” Individuals who reported “like ” or “like very much ” were denoted as consuming a high level of preference for salty flavor.30.Participants were asked a series of questions regarding their stomach cancer screening history. The questions were as follows: “Have you ever undergone a UGIS or endoscopy for stomach cancer screening?” “Which screening method did you undergo?” and “When did you last undergo stomach cancer screening with this method?”. Based on the responses, we defined patients as adherent to stomach cancer screening if they had undergone either a UGIS or endoscopy within the last two years, in accordance with the guidelines of the Korean National Cancer Screening ProgramAll participants provided detailed demographic information, including sex, age, education level, monthly household income, and residential area, as well as their health-related status, including their self-perceived health status , comorbidities , and family history of cancer.31, which visualize complex intersections of a lifestyle risk factor matrix in which the rows represent different sets of combinations, and the columns represent the percentage of participants having these combinations.The frequency and percentage were used to present the demographic characteristics of the study population, stomach cancer screening status, and six lifestyle risk factors. Chi-squared tests were conducted to determine a difference between two categorical variables. We assigned a binary score (1: yes and 0: no) for each risk factor and estimated the number of risk factors by summing all risk factors reported by each participant . To describe the combinations of each cluster, we used upset diagramsp value < 0.05. All analyses were performed using STATA software version 17 .Multiple logistic regression analysis was conducted to examine the association between adherence to stomach cancer screening and lifestyle risk factors adjusted for demographic and health-related factors. The outcome was adherence to stomach cancer screening (yes/no), and the independent variables were the six risk factors or multiple lifestyle risk factors, classified into four groups: 0, 1, 2, and 3 + risk factors. The adjusted odds ratio [aOR] and 95% confidence interval [CI] were presented, and the dose–response relationship was examined using a linear trend. Additionally, we performed multinomial logistic regressions to determine the association between adherence to stomach cancer screening according to screening modality and lifestyle risk factors. The odds of having undergone a UGIS or endoscopy was estimated compared with that of not having undergone either procedure. Statistical significance was set at a All individuals who enrolled in the 2019 KNCSS provided written informed consent. The study was approved by the Institutional Review Board of the National Cancer Center, Korea . This study was conducted in accordance with the principles of the Declaration of Helsinki and the Ethical Guidelines for Medical and Biological Research Involving Human Subjects.The sociodemographic characteristics of the study participants from 2019 are presented in Table Table In the multiple Poisson regression analyses, the number of lifestyle stomach cancer risk factors was significantly decreased in males with education levels above undergraduate and significantly increased in males with comorbidities  and the relationship between the clusters and adherence to stomach cancer screening in Korea using nationally representative survey data. Among all six lifestyle risk factors, physical inactivity was the most frequent risk factor in both sexes, followed by smoking in males and high salted food intake in females. More males tended to exhibit clustering of multiple lifestyle risk factors than females. Specifically, 58.5% of males and 36.8% of females had a cluster of at least two risk factors. Regardless of sex, more lifestyle risk factors were associated with a lower likelihood of adherence to stomach cancer screening. Our study provides significant empirical evidence to guide prevention strategies and cancer screening programs to reduce the burden of stomach cancer.32. This consistent evidence is particularly alarming as insufficient physical activity is a strong risk factor for other types of cancer and non-communicable diseases34.Previous studies have demonstrated the prevalence of lifestyle risk factors among Korean adults; however, comparisons should be made with caution due to differences in target populations and variations in the investigation and measurement of risk factors. In the present study, physical inactivity was the most frequent risk factor. This finding is consistent with a study that examined five lifestyle risk factors  in 9945 Koreans aged 45 years and older36. The higher prevalence of clustering of risk factors could partially explain why stomach cancer is more common in males38.In our study, most female participants had one risk factor, whereas clusters of two to three risk factors were more common among males. This finding is consistent with studies performed in other countries39. These findings indicate that screening services are provided inequitably, as people with a higher number of lifestyle risk factors are less likely to get screened. There are several possible explanations for this trend. First, people with lifestyle risk factors often take less care of themselves and participate less in screening programs40. Second, inadequate knowledge about cancer risk factors and early detection may provide a barrier to adherence to screening guidelines41. Finally, the lack of recommendations from health professionals could result in a decrease in participation in screening. Therefore, efforts to improve the cancer screening rate and prevent delays in diagnostic evaluation should address these specific barriers.We observed a close relationship between the presence of multiple lifestyle risk factors and stomach cancer screening. Compared with those with no risk factors, those with three or more combined risk factors were less likely to adhere to stomach cancer screening guidelines, with an aOR of 0.35 (95% CI 0.23–0.53) in males and 0.32 (95% CI 0.21–0.48) in females. Because this is the first study to assess the association between combined risk factors and stomach cancer screening, we cannot directly compare our results with others. However, a recent study has highlighted the link between composite behavioral risk factors and a lower rate of non-uptake preventive health services, including blood pressure and cholesterol testing, cytology, and mammography43. Therefore, more targeted prevention strategies, such as H. pylori eradication, smoking control, and healthy diet, should be formulated for people adapting to different genders, age groups, and regions42. Moreover, effective cancer-prevention campaigns, such as warning about risk factors and promoting favorable behaviors in the general population, should be formulated. For instance, in Norway, mass media campaigns aimed at colorectal cancer prevention led to an increase in the number of individuals correctly identifying risk factors and expressing willingness to participate in colorectal cancer screening44. Further research and surveillance system should be developed to monitor and modify the prevalence of risk factors.Recent research emphasized that stomach cancer is expected to contribute to a substantial number of cases in many countries and is an important cause of mortality if no further action is taken45 Lastly, several lifestyle risk factors could not be assessed due to the availability of the data. For example, low fruit consumption9, one of the most critical risk factors for stomach cancer development, could not be evaluated.For a correct interpretation of our results, some methodological comments are needed. First, the study utilized cross-sectional data, which limits the ability to establish causation. The relationship could thus be bidirectional, i.e., the uptake of stomach cancer screening might influence lifestyle changes or vice versa. Second, behavioral risk factors and the screening data were self-reported and may reflect either over- or under-reporting and recall biases. Third, in the current study, we could not collect information on the quantity and frequency of salt intake. We could also not use objective measurements such as 24-h urinary Sodium measurement alongside the self-reported salt flavor preference. Relying on self-report may inevitably introduce misclassification and reporting bias. However, a previous study demonstrated a good correlation between self-reported dietary salt intake and a 24-h urine assay of salt.In conclusion, our results indicate a disparity in stomach cancer screening, in which those who have a more significant number of risk factors are less likely to get screened. Increasing public awareness of lifestyle risk factors and regular cancer screening, providing counseling at the time of screening, and targeting high-risk populations (those with multiple risk factors) for screening interventions are critical to promote cancer screening adherence and motivate health behavior changes. Supplementary Tables.


The human intestinal microbiota is regarded as the second set of the human genome and plays an important role in human metabolism, immunity, and the occurrence and development of tumors. The diversity of the human intestinal microbiota and its metabolites may affect the immune response in the tumor microenvironment . ObesityZhou et al. reviewed a series of studies on preclinical antitumor bacterial vaccines and new cancer combination therapies, focusing on the bacterial vaccines with the greatest chance of clinical application. Combining them with traditional therapies might successfully enhance the antitumor effect and allow us to understand clinical translation problems such as the treatment mode, biosafety, and production methods of bacterial vaccines. This is a strategy using external methods to translate microorganisms to exert antitumor benefits.In the first article, Wang et al. have examined this possibility with evidence-based results. The characteristics of the intestinal microbiota and metabolic disorders caused by obesity may damage immune cells in the tumor microenvironment. Therefore, the favorable changes in intestinal microbial metabolites caused by bariatric surgery, such as short-chain fatty acids (SCFAs), inosine bile acid and spermidine, play an important role in anticancer immunity, providing a strategy to realize tumor immunotherapy by using supplementary microbial metabolites to simulate bariatric surgery.Our human body has a strong self-balancing and self-regulating ability and so it is possible that a change in intestinal microbiota caused by weight loss could also have anti-tumor benefits. Sun et al. focused on the changes in breast density caused by bariatric surgery, which is an independent risk factor for breast cancer and serves as an intermediate marker affecting the risk of breast cancer  colonized the intestines and breast ducts and secreted B. fragilis toxin, which accelerated the early spread of breast cancer cells from the primary tumor, caused systemic inflammation, and promoted the development of metastatic lesions by changing the tumor immune microenvironment. B. fragilis is a common intestinal colonization bacterium that is associated with obesity in children and adolescents  and fed Lactobacillus brevis, which is recognized as a probiotic that can improve blood glucose and body weight , lipopolysaccharides (LPS) and trimethylamine oxide (TMAO). This shows the potential antitumor effect of probiotic intervention on T2DM+HCC.y weight . Their sIn conclusion, the articles included in this Research Topic significantly enhance our understanding of the important role of intestinal microorganisms and their metabolites associated with weight loss and metabolic improvement in tumorigenesis and metastasis to improve the effect and prognosis of cancer immunotherapy. They contribute to a better understanding of: (i) bacterial-mediated tumor immunotherapy, which may be an effective treatment for cancer patients, (ii) the effects of microbial metabolites associated with obesity and bariatric surgery on the characteristics and prognosis of certain tumor types (such as breast cancer), (iii) the relationship between microbiota characteristics and host metabolic heterogeneity in solid tumors such as breast cancer, and (iv) the palliative effect of probiotics in the codisease of metabolic diseases and malignant tumors that reveals the possibility of exerting antitumor effects by regulating metabolism.YG: Writing – original draft. LQ: Writing – review & editing. OC: Writing – review & editing. SC: Writing – review & editing. DZ: Writing – review & editing.


BRCA1/2 germline pathogenic variant (GPV) are advised to undergo surgery to remove their ovaries and fallopian tubes at a young age to prevent tubal/ovarian cancer. This surgery is called a risk-reducing salpingo-oophorectomy (RRSO). Previous studies have suggested that RRSO may also decrease breast cancer (BC) risk by decreasing female hormone levels. The aim of this prospective study was to investigate the effect of RRSO on the risk and histopathological features of BCs in these women. We linked data from our hospital-based data/biobank to data from the Dutch Nationwide Pathology databank (PALGA). We included 1312 women in our study with 164 diagnosed BCs. RRSO did not influence BC incidence and there were no differences in histopathological features between BCs before and after RRSO. Therefore, the purpose of RRSO remains to decrease tubal/ovarian cancer risk only.Women with a BRCA1/2 germline pathogenic variant (GPV) carriers to reduce tubal/ovarian cancer risk. RRSO may also affect breast cancer (BC) incidence. The aim was to investigate the effect of RRSO on BC incidence and histopathological features in female BRCA1/2 GPV carriers. Methods: Prospectively collected clinical data from BRCA1/2 GPV carriers in our hospital-based data/biobank were linked to the Dutch Nationwide Pathology Databank (PALGA) in January 2022. Multivariable Cox-proportional hazard models were used to calculate hazard ratios (HRs) with 95% confidence intervals (95% CIs), where the pre-RRSO group was considered the reference group and the primary endpoint was the first primary BC. Histopathological features of BCs pre- and post-RRSO were compared using descriptive statistics. Results: In 1312 women, 164 incident primary BCs were observed. RRSO did not decrease BC risk for BRCA1 GPV  or BRCA2 GPV  carriers. BCs tended to be smaller post-RRSO (median: 12 mm) than pre-RRSO . There were no statistically significant differences in histopathological features. Conclusions: RRSO did not decrease BC risk or affect BC features in BRCA1/2 GPV in this study, although BCs diagnosed post-RRSO tended to be smaller.Background: Risk-reducing salpingo-oophorectomy (RRSO) is advised for female  BRCA1/2 germline pathogenic variant (GPV) have an increased risk to develop breast and ovarian cancer. The cumulative lifetime risk up to age 80 to develop breast cancer is 72% for BRCA1 GPV (95% CI: 65–79%) and 69% for BRCA2 GPV (95% CI: 61–77%). For tubal/ovarian cancer, the cumulative lifetime risk up to age 80 is 44% for BRCA1 GPV (95% CI: 36–53%) and 17% for BRCA2 GPV (95% CI: 11–25%) [BRCA1 and 40–45 years for BRCA2) [Women with a  95% CI: 6–53% andBRCA1/2 GPV carriers by up to 50% [BRCA1/2 GPV carriers who underwent RRSO with a median follow-up of 28 months, Fakkert et al. could not confirm this [BRCA1/2 GPV carriers [It has been suggested that RRSO at premenopausal age also reduces the risk of breast cancer in p to 50% . The hypirm this ,7,8,9. Acarriers .BRCA1 GPV  followed-up for a mean of 5.4 years [BRCA2 GPV carriers, RRSO carried out before or after age 45 did not decrease breast cancer risk , followed-up for a mean of 4.9 years. Nonetheless, HRs for BRCA2 GPV carriers decreased with increasing time since RRSO  [BRCA1/2 GPV has not yet been reached. In a multi-center prospective cohort, Mavaddat et al. did not find a breast cancer risk-reducing effect of RRSO in 2272 women with a .4 years . For 16026–0.99) . Stjepan26–0.99) . Results26–0.99) . To summBRCA1/2 GPV carriers. In a case-control study, in which 20 primary breast cancers diagnosed post-RRSO were matched to 36 breast cancers of BRCA1/2 GPV carriers pre-RRSO, Van Verschuer et al. showed that breast cancers post-RRSO were smaller , with lower mitotic activity index  [BRCA1/2 GPV carriers on breast cancer incidence and its histopathological features. We hypothesized that RRSO does not affect breast cancer incidence, but that tumors found post-RRSO are smaller and less aggressive compared to tumors diagnosed pre-RRSO. Besides incidence, the histopathological features of the breast cancers that develop before and after RRSO may provide us with more insight into the effects of RRSO on breast cancer in  < 0.05) . They diIn January 2022 data from OncoLifeS, the hospital-based data- and biobank of the University Medical Center of Groningen (UMCG)  were linIn the UMCG, women with a hereditary risk to develop breast and/or tubal/ovarian cancer are referred to the family cancer clinic for counseling on the choice and timing of genetic testing and possible risk-reducing strategies to prevent  breast and tubal/ovarian cancer . BRCA1/2 GPV in our hospital [BRCA1 GPV and 40–45 years for a BRCA2 GPV. If DNA testing is performed before reaching the recommended age range, uptake of RRSO during the recommended age range is high (95%) in our cohort [Since 2009, ovarian cancer screening is no longer advised for women with a hospital ,18. Instr cohort . From 1994, after written informed consent, all newly referred women to the family cancer clinic are prospectively included in our data/biobank, OncoLifeS . In OncoPathology excerpts were requested by the research board of PALGA. Data available from PALGA are, amongst others, tumor type, tumor size, grade, metastatic regions, lymph node involvement, hormone and HER2 receptor status and surgical margins, if applicable. Pathology reports from all diagnosed breast cancers, tubal/ovarian cancers, RRMs and RRSOs were requested for this study. PALGA has had nationwide coverage since 1 January 1989 .Clinical data retrieved from OncoLifeS were the date of birth, mutation type, status and date of DNA test, status and date of RRM, status and date of RRSO and date and type of breast cancer surgery. A link with the Dutch Personal Records Database was performed for all participants to retrieve the date of death. The following breast cancer features were collected from PALGA: date of diagnosis, tumor type, size, T-stage, N-stage and hormone- and HER2-receptor status. From PALGA excerpts, date and histopathological features of tissue from RRMs and RRSOs could also be retrieved. All PALGA excerpts were thoroughly reviewed (AS) and in case of uncertainties the report was checked by our pathologist (BV). All secondary cancers were compared to the primary cancers and reviewed together with our pathologist (BvdV) to determine if it was a local recurrence or a second primary tumor. BRCA1 or BRCA2 GPV and were 25 years or older at the time of data linkage (January 2022), since the Dutch guidelines recommend yearly screening for women with a BRCA1/2 GPV from age 25 onwards [Women were selected from OncoLifeS if they had a proven  January 22, sinceDescriptive statistics were performed to describe the patients in the pre-RRSO group versus the post-RRSO group. Prevalent and incident breast cancers diagnosed pre- and post-RRSO were described. Prevalent cancers were considered all primary breast cancers that were diagnosed in this cohort before the DNA-test date or before age 25 (before the start of breast cancer screening). Breast cancers were considered incident cancers if they were diagnosed after the DNA-test date of the individual and after age 25. Tumor size, T-stage, N-stage and hormone- and HER2-receptor status were only shown for invasive cancers. BRCA1 and BRCA2 GPV, stratified per pre-RRSO and post-RRSO groups. Person-years pre-RRSO were attributed to the pre-RRSO group, including a 6-month latency period post-RRSO, i.e., breast cancers diagnosed within 6 months post-RRSO were attributed to the pre-RRSO group. After this latency period, which was based on BRCA-specific tumor-volume doubling time [The breast cancer incidence rate per 1000 person-years was calculated for both ing time , person BRCA1 and BRCA2 GPV. All models were corrected for age at baseline and birth year. RRSO was coded as a time-dependent variable, including a latency period of 6 months post-RRSO. A sensitivity analysis was performed in which the effect of undergoing RRSO before age 45 was assessed (within the recommended age range for BRCA2), where RRSO was coded as a time-dependent variable and women who underwent RRSO after age 45 were attributed to the pre-RRSO group. Multivariable Cox-proportional hazard models were used to assess the effect of RRSO on breast cancer risk, the primary endpoint being the first diagnosis of breast cancer. Hazard ratios with 95% confidence intervals (95% CIs) were calculated, where the pre-RRSO group was considered the reference group. Separate analyses were performed for p-values were considered significant if p < 0.05. To compare breast cancer characteristics pre- and post-RRSO, Chi-square tests were performed for categorical data. For non-parametric data, Mann–Whitney U tests were performed. IBM SPSS statistics package version 28 was used for all analyses. BRCA1/2 GPV included in this study are shown, of which 725 had a BRCA1 GPV and 587 had a BRCA2 GPV. The median observation time after the date of the DNA-test was 5.3 years (IQR: 1.5–9.8). A number of 798 women had undergone RRSO at a median age of 43.9 years. Of the 502 breast cancers diagnosed, 338 breast cancers were diagnosed before DNA-testing  and 164 were diagnosed after DNA-testing (incident cancers). A number of 373 women had undergone a censoring event before DNA-testing (28.4%), of which 23 (6.2%) had ovarian cancer and 15 (4.0%) had undergone bilateral mastectomy. In total 572 women (43.6%) underwent RRM and 82 (6.3%) were diagnosed with ovarian cancer. A number of 106 women (8.1%) developed a second primary breast cancer at a median age of 47.2 years, 8.5 years  after the first diagnosis. Of those breast second primary breast cancers, 31 were diagnosed (6.0%) pre-RRSO and 7 (9.4%) post-RRSO. Of these breast cancers, 59 were in the contralateral breast. In BRCA1 and BRCA2 GPV carriers, pre- and post-RRSO, per 1000 person-years of observation. In BRCA1 GPV carriers, the incidence rate pre-RRSO was 34.4/1000 person-years, and post-RRSO 28.9/1000 person-years. In BRCA2 GPV carriers, the incidence rate pre-RRSO was 25.7/1000 person-years and 20.5/1000 person-years post-RRSO. In In p 0.08). In p < 0.001), more often staged T1  and characterized as in situ .BRCA1/2 GPV, after RRSO the breast cancer risk did not decrease for both BRCA1  and BRCA2 GPV carriers  compared to pre-RRSO. There was no statistically significant difference in histopathological features between breast cancers diagnosed pre-RRSO and post-RRSO, although breast cancers diagnosed post-RRSO tended to be smaller (12 mm) compared to breast cancers diagnosed pre-RRSO .The aim of this study was to investigate the effect of RRSO on breast cancer incidence and its histopathological features. In this cohort of 1312 women with a BRCA1 GPV carriers). Choi et al. [BRCA1 GPV  and in 1925 women with a BRCA2 GPV , especially during the first 5 years post-RRSO. The crude-incidence rate of breast cancer post-RRSO was indeed lower in the current study, 25.0/1000 person-years post-RRSO vs. 30.5/1000 person-years pre-RRSO. As a direct result of the high uptake of RRSO after diagnosis of a BRCA1/2 GPV in our cohort (95%) [BRCA1 and 17% for BRCA2 GPV carriers in our population by Van der Kolk et al., whereas between 40 and 55 years, a breast cancer incidence of 30% was observed in BRCA1 and 42% for BRCA2 GPV carriers [We did not find a risk-reducing effect of RRSO or RRSO <45 years on breast cancer incidence in our Cox-regression analysis, which corresponds with Heemskerk-Gerritsen et al.  and withi et al.  did findcarriers . If RRSOBrca1-knockout mice, breast tumor onset could statistically significantly be delayed after oophorectomy: median tumor onset was 300 days post-oophorectomy vs. 206 days without oophorectomy  [Brca1-mutant mice showed somewhat different results, namely that breast tumor incidence of oophorectomized and intact mice remains similar until 135 days post-oophorectomy. However, at 180 days, mammary tumor formation in oophorectomized mice was reduced by approximately 50%, with an average number of 1.1 tumors, compared to an average number of 1.7 tumors in non-oophorectomized mice [In p 0.049) . Anotherzed mice . AlthougBRCA1/2 GPV carriers are more often triple-negative and have a higher histologic grade when diagnosed at a younger age [BRCA1-associated tumorigenesis is influenced by progesterone-mediated activation of the RANKL/RANK/NF-κB pathway [BRCA1-associated tumors that develop are often ER- and PR-negative, but the possible ‘cell of origin’ in mice is RANK-positive, which is hyper-responsive to progesterone. Therefore, one might expect that premenopausal RRSO would decrease breast cancer risk because progesterone levels drop. In the Netherlands, however, the majority of women who have not been diagnosed with breast cancer are offered hormone replacement therapy (HRT) after premenopausal RRSO and women with a uterus in situ are offered progesterone-containing HRT [Our study results regarding the histopathological features of breast cancers after RRSO correspond with Verschuer et al. , who repnger age ,26,27, w pathway . The BRCning HRT . This maTo the best of our knowledge, this is the largest cohort in which histopathological features of breast cancers diagnosed pre- and post-RRSO are compared. A strength of this study is the use of PALGA data, which has excellent nationwide coverage and provided accurate histopathological information on RRMs, RRSOs, ovarian cancer and breast cancers in our cohort. Other strengths are the prospective inclusion of study participants and a relatively long median period of observation, 5.3 years. Furthermore, we avoided cancer-induced testing bias by starting observation after DNA-test of the individual and only including incident cancers, in addition to the avoidance of immortal person-time bias by treating RRSO as a time-dependent variable in our Cox-regression analysis. In the Netherlands, screening for breast cancer in this high-risk group begins at age 25. Therefore, breast cancers that occurred before the age of 25 years were not included in our analyses, because by definition, these are unscreened cancers, known to be larger ,27. Thisp 0.01), in addition to a lower mitotic count/mm2. Unfortunately, we did not have information on the mitotic activity index in the current study. Another limitation is our relatively small study population and a lack of information on important confounders, such as the use of hormone replacement therapy, smoking, parity, breastfeeding, and family history of breast cancer. An important limitation of this study is that we could not correct for age in the comparison of histopathological features of breast cancers pre- and post-RRSO. Verschuer et al.  matched BRCA1 GPV carriers and between 40 and 45 years for BRCA2 GPV. This may be too late to prevent hormone-related breast cancer in BRCA1/2 GPV. In our cohort, the median age for primary breast cancer was 41.7 years in the pre-RRSO group, meaning that 50% of the women that developed breast cancer pre-RRSO, were diagnosed before the age of 42 years. However, considering the severity and burden of menopausal symptoms even 10 or more years post-RRSO [Another possible explanation for not finding a risk-reducing effect of RRSO on breast cancer risk is that the optimal timing of RRSO to prevent tubal/ovarian cancer is between 35 and 40 years for ost-RRSO , cliniciBRCA1/2 GPV. Nonetheless, if RRSO would not affect breast cancer incidence at all, one would have expected a somewhat higher risk in the post-RRSO group. Breast cancers diagnosed post-RRSO seemed to be of smaller size compared to breast cancers diagnosed before RRSO. No statistically significant differences in the frequency of in situ carcinoma, breast cancer subtype, hormone and HER2 receptor expression or tumor grade were found. Larger studies with a longer observation time and more information on important confounders are necessary to draw final conclusions. The primary purpose of RRSO is still to prevent tubal/ovarian cancer. Information on the possible protective effect of RRSO on breast cancer risk should be conveyed cautiously to women opting for RRSO. In the current study, we did not find breast cancer risk reduction after RRSO in


Chronic cancer-related fatigue is a critical problem for breast cancer survivors and effective and sustained management is a key for improvement. A six-week tango Argentino program showed to be effective in reducing fatigue and improving quality of life, here we examined the sustainability of this effect over a twelve month period. It was observed that in the tango cohort, breast cancer survivors experienced a sustained improvement in physical functioning and a reduction in fatigue symptoms for at least six months, but not in a control cohort. Tango may be an appropriate activity to promote quality of life and also eventually to improve long-term clinical outcomes of cancer survivors.n = 108) who did not participate in the tango program. Using the European Organization for Research and Treatment of Cancer Questionnaire C30 (EORTC-QLQ-C30) and the German version of the cancer fatigue scale (CFS-D) self-reported quality of life parameters were assessed and longitudinal changes, correlations, and association factors were calculated. Results: Significant improvements in fatigue (p = 0.006), physical functioning (p = 0.01), and diarrhea (p = 0.04) persisted in the 50 Tango participants at 6 months, but not in the control cohort. Twelve months after joining the tango program, increased fatigue was associated with reduced sporting activities (p = 0.0005), but this was not the case for tango dancing. Conclusions: The present results suggest that tango may be appropriate as a component of early supportive and follow-up care programs, to promote health-related quality of life and physical activity and also eventually to improve long-term clinical outcomes of breast cancer survivors. Trial registration: Trial registration numbers DRKS00013335 on 27 November 2017 and DRKS00021601 on 21 August 2020 retrospectively registered.Background: Chronic cancer-related fatigue is difficult to manage in breast cancer survivors. The tango trial showed that a six-week tango Argentino program was effective in reducing fatigue and improving quality of life, and here we investigated the sustainability of this tango program for breast cancer survivors. Methods: Stage I–III breast cancer survivors with increased fatigue symptoms were analyzed. The fifty participants in the tango trial were compared with a control cohort ( Breast cancer continues to be the most common form of cancer among women worldwide . ApproxiHere, we conducted a real-world data (RWD) study by longitudinal evaluation of the tango trial  and the The NO is a multi-centre oncological register study to evaluate therapy concepts in health services research . In addiSelf-reported symptoms of fatigue and quality of life were assessed using German versions of the questionnaires: the cancer fatigue scale (CFS-D)  and the t-tests were performed to detect differences; p-values < 0.05 were considered significant. Adjusted multivariable linear regression analyses were performed to analyze associations between QoL scales and sport , dance , or online sport  activities, respectively. Adjustments were made for the variables of age and the menopausal status.For statistical analyses Excel 2010  and the R software , a language and environment for statistical computing, were used. For longitudinal analyses mean differences were estimated and Student’s Breast cancer survivors with elevated fatigue symptoms were enrolled in the tango trial an average of 1.7 years after their primary cancer diagnosis, and fifty completed the six-week Tango program  and wereA total of 50 (100%) participants from the tango group answered the six-month follow-up survey, and 49 (98%) answered the twelve-month follow-up survey. The longitudinal changes of the patient-reported QoL outcomes from the tango participants and the 108 breast cancer survivors in the control cohort were evaluated.p = 0.01) and 12 months (p = 0.02) in the tango cohort. Fatigue (p = 0.006) and diarrhea (p = 0.04) were also reduced by 7% after 6 months, while insomnia was not. Improvements on some of the EORTC QLQ-C30 scales were reported at 6 and 12 months in the tango cohort and at 12 months in the control cohort . SpecifiThere were no known cases of any of the fifty participants in the tango trial who did not survive the 12-month follow-up period. Between the 6th and 12th month of follow-up, an additional cancer diagnosis was reported in 3 (6%) participants , and 4 (8%) participants self-reported secondary diseases . Participants in the tango trial were surveyed about their activities and preferences in sports and dance at six months and again at twelve months .2 = 3.52; Cohen’s D d [95%CI] = 0.38 ) can be inferred. In the 6-month survey, a free-text question was asked, “Did you like dancing in a group? Or did you prefer dancing alone with the instructor?” 92% of the Tango cohort experienced tango as a good group program, 4% would have preferred individual instructions  and likewise regarding online sports . Furthermore, increases in global health status  and role functioning , as well as decreased pain  were associated with increases in sports engagements, whereas no associations were found between any QoL scale and dance exercises (Specifically, an association between high affective fatigue and lower sports engagement was found 12 months after Tango (estimate β = −0.034; xercises .The randomized, controlled tango trial in breast cancer survivors found superiority of the tango over wait-list controlled-for fatigue symptoms , and theThe key elements of dance movement therapy as a group intervention are behavioral engagement, the increase in bodily awareness, and the stimulation of creativity and imagination . The effAs a common side effect of cancer therapy, approximately one-third of breast cancer survivors experience symptoms of diarrhea , but thiMeanwhile, recent results from randomized controlled trials with breast cancer survivors show that dancing as an adjunctive therapy may improve QoL and decrease depression and pain perception ,16. It hAlthough adherence to the six-week tango program was good, dropouts had worse baseline fatigue and QoL scores . Thus, tSome limitations of this study are that we had a non-blinded study design, no objective outcome measures, we did not have a direct parallel comparison group that did not receive tango, and detailed information on sleep quality and exercise was not available for this control cohort. In addition, our results presented here are limited to early stage breast cancer patients, as the study participants were predominantly stage I and II breast cancer patients. Furthermore, the fact that tango and most of the follow-up occurred during the COVID-19 pandemic limits generalizability. The strengths of our study are the high adherence despite the COVID-19 pandemic situation, and that adjusted multivariate regression analyses reduced confounding bias and allowed the identificatino of association factors between QoL scales and physical activity.The present follow-up evaluation of the tango trial indicates a sustained efficacy of the Argentine tango program on quality of life, including fatigue, in breast cancer survivors. A number of interventions have been proposed that have been shown to be effective in treating cancer-associated fatigue. However, they are not suitable for all cancer survivors. A program that is not too physically demanding and can be tailored to individual needs can reach those who need the most support. As dancing activities were found not to interfere with any of the QoL scales, dancing may be a way to motivate physical activity despite fatigue. Dancing the tango is a way to develop body awareness and creativity in a group setting that simultaneously addresses cognitive, social, and emotional skills as well as individual passions. Therefore, as part of early supportive and follow-up care, it is necessary to develop outpatient rehabilitation programs that consist of multiple components to prevent fatigue, promote quality of life, and also eventually improve the long-term clinical outcomes of breast cancer survivors.


A priori healthful or unhealthful pro-vegetarian food patterns distinguished between healthy plant foods  and less-healthy plant foods . Cancer incidence was defined as the earliest diagnosis of cancer from hospital discharge records over a median follow-up of 12.9 years. In multivariable-adjusted analyses, a general pro-vegetarian food pattern was associated with a lower rate of cancer incidence ; no association was observed between the healthful or unhealthful pro-vegetarian food patterns and overall cancer incidence. A healthful pro-vegetarian pattern, however, was inversely associated with digestive cancer , while the unhealthful pro-vegetarian pattern was directly linked to respiratory cancer . Our findings in a Mediterranean population support the hypothesis that some, but not all pro-vegetarian diets, might prevent some cancers.Besides the Mediterranean diet, there is a paucity of studies examining plant-based diets in relation to cancer outcomes in Mediterranean populations. We analyzed 22,081 apparently cancer-free participants (mean age 55 ± 12 year) from the Moli-sani study . A general pro-vegetarian food pattern was computed by assigning positive or negative scores to plant- or animal-derived foods, respectively from a 188-item FFQ.  Cancer represents a leading cause of premature death in Europe and is progressively surpassing cardiovascular diseases (CVD) as the principal cause of death . HoweverSeveral healthful dietary patterns are favorably associated with cancer outcomes. These are mostly plant-based diets characterized by a large amount of food , that are natural sources of bioactive compounds with potential anti-cancer activities .To date, a number of studies have examined the potential advantages of a traditional Mediterranean diet against certain cancers, but evidence varies greatly according to different cancer sites, with moderate evidence being reached only for cancer mortality and colorectal cancer risk, while being rated as “low” or “very low” for other cancer subtypes  . AlthougOn the contrary, strictly vegetarian diets completely exclude meat, meat-derived foods, and other products obtained from animals . They arAlthough the proportion of true vegetarians is relatively scarce in most populations , the cona priori between healthful and unhealthful pro-vegetarian food patterns, based on existing literature data [To estimate adherence to a pro-vegetarian food pattern distinct from full vegetarianism, a general pro-vegetarian food pattern index was first developed, weighing both plant-derived and animal-derived foods . Subsequure data . In facture data .a priori-defined plant-based indices with risk of cancer  [In the last 10 years, several large cohort studies supported the health advantages of a plant-based/pro-vegetarian diet, mostly in relation to mortality ,14,15,16pecific) ,20,21,22pecific)  is less To fill this knowledge gap and contribute to clarifying the uncertain relationship between plant-based diets and cancer risk, we sought to examine the association of three previously defined pro-vegetarian food patterns, defined as general, healthful, and unhealthful, in relation to cancer incidence in a general population residing in a Southern Italian region.We analyzed data from the Moli-sani study, which is a prospective population-based cohort consisting of 24,325 men and women aged ≥35 years, who were randomly recruited from the general population of the Molise region in Southern Italy. The cohort was established in 2005–2010 with the main aim of investigating the contribution of environmental and genetic risk factors in the onset of major non-communicable diseases and mortality. Pregnancy at the time of recruitment, disturbances in mental or decision-making impairments, current poly-traumas or coma, or refusal to sign the informed consent were exclusion criteria. The study design was described previously . From thAt baseline visit, data on participants’ dietary intake in the preceding year were assessed by an interviewer-administered, semi-quantitative EPIC (European Prospective Investigation into Cancer and Nutrition) food frequency questionnaire (FFQ), which was validated and adapted to the Italian population . The FFQWe computed a general pro-vegetarian food pattern which assigned positive scores to plant-derived foods and reverse scores to animal-derived foods, as proposed by Martinez-Gonzalez et al. . For theThe five animal-derived food groups  were scored negatively both in healthful and unhealthful pro-vegetarian food patterns, whose final scores potentially ranged from 17 to 85 points .a priori 9-item Mediterranean diet score (MDS) proposed by Trichopoulou et al. [Adherence to a traditional MD was measured through the u et al. , which r2), overweight (>25 and <30 kg/m2), or obese (≥30 kg/m2). Participants’ smoking habit was categorized as never, current, or former smoker (reporting to have not smoked in the previous 12 months or more at the time of interview). Housing tenure was classified as rented, ownership of one dwelling, and ownership of more than one dwelling. Marital status was coded as married/live-in couple, separated/divorced, single, and widower. Additional covariates were considered for females only and included the menopausal status, use of oral contraceptives, and use of hormone replacement therapy.At study entry, participants completed an interview that included sociodemographic information, lifestyle, and clinical variables. Based on the highest qualification attained, education was categorized as (1) up to lower secondary school (approximately ≤8 years), (2) upper secondary school (>8–13 years), and (3) post-secondary education (>13 years). Personal history of cardiovascular disease  was self-reported and confirmed by clinical records and therapy. Comorbidities, such as hypertension, hyperlipidemia, or diabetes, were defined if the participant reported having a treatment with disease-specific drugs. Regular use of low-dose aspirin for primary or secondary CVD prevention (no/yes) was recorded. Leisure-time physical activity for sport, walking, and gardening was assessed by a structured interviewer-administered questionnaire  and exprThe outcome examined in this study was cancer incidence, which was defined as the earliest diagnosis of cancer from hospital discharge records. A hospitalization was defined as any length of stay of at least 24 h in a hospital or clinic. If a patient was transferred to another hospital or facility, it was considered a single hospitalization. Hospitalizations for rehabilitation and chemotherapy and/or radiotherapy  were excluded. Primary and secondary diagnoses for hospitalization were coded using the 9th version of the International Classification of Diseases. A cancer hospitalization was assessed if the primary or the first secondary diagnoses of admission to the hospital were coded as ICD-9: 140–172, 174–208. The Moli-sani study cohort was followed-up for cancer hospitalization from study entry (2005–2010) through 31 December 2020.We quantified differences in the distribution of baseline covariates across fifths of a general pro-vegetarian food pattern using generalized linear models for both continuous and categorical variables adjusted for age, sex, and energy intake , . Associations of three pro-vegetarian food patterns  with the rate of cancer hospitalization were calculated as hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazard models. No violations of the proportional hazard assumption (log(−log) survival plots curves) were visually identified.a priori and identified based on existing literature, rather than deferring to statistical criteria [Potential confounders (measured at baseline) were defined criteria , on the criteria ,32,33. TMissing data on covariates were handled using multiple imputation , over different simulations (n = 10 imputed datasets) to avoid bias introduced by not-at-random missing data patterns. The data analysis was generated using SAS/STAT software, version 9.4 .p-value <0.0001) and showed a weak inverse relationship with an unhealthful pro-vegetarian food pattern ; the healthful and unhealthful pro-vegetarian food pattern were moderately correlated . The Spearman correlation coefficients of a general, healthful, and unhealthful pro-vegetarian food pattern with the Mediterranean diet score were 0.52, 0.49, and −0.30, respectively , suggesting weak to moderate strengths of these associations [Sociodemographic characteristics of the analyzed sample across fifths of adherence to a general pro-vegetarian food pattern are shown in ciations .Subjects with higher adherence to the general pro-vegetarian food pattern tended to have higher adherence to the traditional Mediterranean diet, to be older, to have higher household income, and were more physically active. However, participants following a general pro-vegetarian food pattern were more likely to report a history of cardiovascular disease, hypertension, hyperlipidemia, and daily aspirin use than those with lower adherence to this food pattern .p-value for trend across fifths = 0.045). Similarly, an increment of 1 SD in the general pro-vegetarian food pattern was linked to a reduction of 5% in cancer rate   . Further91–0.99) . Neither91–0.99) .None of the baseline risk factors act as an effect modifier of the association between the pro-vegetarian food patterns  with cancer risk . SensitiIn this large prospective cohort of Italian men and women, who were apparently without cancer at baseline, a higher adherence to the general pro-vegetarian food pattern was associated with a lower rate of cancer incidence overall, specifically for digestive or respiratory cancers. Adherence to healthful or unhealthful pro-vegetarian food patterns was not associated with overall cancer risk. However, when specific cancer sites were considered, a healthful pro-vegetarian food pattern was linked to a reduced rate of digestive cancer, whereas an unhealthful pro-vegetarian food pattern was associated with a higher likelihood of respiratory cancers.The relationships between plant-derived foods and diets with cancer risk have currently different levels of evidence, based on the food group and the cancer site. Probably, some key food groups that are positively scored in the general and healthful pro-vegetarian food patterns  could reduce the risk of colorectal cancer, while coffee consumption  has been associated with lower incidence of liver cancer . LimitedAlso, we acknowledge that although the total number of cancer hospitalizations was considerably large, the number of specific cancers was restricted; therefore, possibly limiting the statistical power of analyses for different cancer sites .Of interest, in our study, the inverse association of a general pro-vegetarian food pattern with overall cancer risk was independent of adherence to the Mediterranean diet. This is possibly due to the fact that there are some important differences between the pro-vegetarian food pattern and its healthful version and the traditional Mediterranean diet, mostly in relation to the scoring criteria for three foods: potatoes, fish, and alcohol. This is further supported by the moderate correlation observed between pro-vegetarian and Mediterranean diet scores, indicating that these novel dietary indices might be able to capture novel unique relations of a pro-vegetarian diet with respect to cancer outcomes .This is possibly the first study that has been conducted on Italians to examine three different pro-vegetarian food patterns in relation to cancer risk and acknowledge the quality of plant-derived foods.Our findings on the general pro-vegetarian food pattern and cancer risk are in line with prior analyses in the large NutriNet-Santè cohort in France, showing a reduced risk of overall cancer for participants with strict adherence to a pro-vegetarian diet . As showProspective analyses from the Health Professionals Follow-Up Study in US supported evidence that greater consumption of healthful plant-based foods was associated with a lower risk of prostate cancer, specifically aggressive forms among men aged <65 years . HoweverA relatively low number of cohort studies have analyzed plant-based diets in relation to cancer death, but the evidence is not conclusive. A prospective cohort study conducted in the US found an inverse association of an overall plant-based diet with cancer mortality, but the quality of plant foods was unrelated to the outcome . SimilarThere are several potential mechanisms through which greater adherence to a plant-based diet may influence cancer risk. High amounts of vegetables, fruits, and legumes increase the dietary intake of phytochemicals and vitamins with antioxidant and antiproliferative activity ,38,39,40The health advantages of a pro-vegetarian diet could also be due to a low dietary share of animal-based foods; indeed, elevated intakes of some animal-derived foods, such as red and processed meat, have been reportedly associated with overall cancer risk ,52 and cOther detrimental effects, aside from the poor quality of some unhealthful plant-based foods, could be due to non-nutritional factors, such as increased exposure to additives, toxic contaminants migrated from food packaging, and exposure to acrylamide, which is produced during cooking procedures at high-temperature and may increase cancer risk ,56,57. IThe strengths of this study include the large sample size, a prospective population-based cohort design, a follow-up of more than 10 years, and the large number of covariates used to minimize, at least in part, confounding. Moreover, we computed three indices of pro-vegetarian food patterns that are easily reproducible for further comparisons. Also, we used sensitivity analyses to support the robustness of the results, by excluding participants who might have modified habitual dietary intakes due to illness.Several limitations should be considered when interpreting our findings. The possibility of residual confounding remains, given the observational design, so that any causality relationship is only proposed. However, the main potential confounders were considered; therefore, it is unlikely that residual confounding entirely explains the observed results. Limitations in the outcome definition should be also acknowledged, since in this study, we only analyzed cancer hospitalizations, and consequently, cases of cancer that were managed in outpatient settings were missed.Additionally, interpretation of risk estimations for specific cancer sites should consider the restricted number of events in subgroups, which may affect the statistical power and precision of CIs. Another weakness is the lack of repeated dietary assessments during follow-up, although dietary habits in adulthood tend to remain stable over time . MoreoveOur findings in a Mediterranean population suggest that, as already known for a traditional Mediterranean diet, a pro-vegetarian diet, based on healthful plant-derived foods and limited animal-derived products intakes, could be effective in reducing cancer incidence. Moreover, our data support prior evidence showing that a large dietary share of unhealthful, though plant-based foods, mostly highly processed, is associated with an increased risk of certain cancers ,22 or caIn conclusion, a diet that contains high amounts of healthful plant products and minimal amounts of animal products should be encouraged, when a traditional Mediterranean diet cannot be followed. Future targeted analyses could be helpful to understand whether the observed health advantages associated with this pro-vegetarian dietary pattern are mostly due to the large amount of plant foods or to the lower consumption of animal foods or both. In addition, studies could attempt to establish the ideal ratios of high plant food consumption and low animal food consumption to maximize health benefits. In all instances, it is important in public health recommendations and dietary guidelines worldwide to discourage the consumption of unhealthful, especially ultra-processed, plant-derived products.