Reduce Breast Cancer Incidence Research Articles

Bariatric Surgery Reduces Breast Cancer Incidence in a Prospective Trial.

Bariatric Surgery Reduces Breast Cancer Incidence in a Prospective Trial.

Abstract PS07-03: Randomized trials of oestrogen-alone and breast cancer incidence: a meta-analysis

Abstract Background Findings from cohort studies compared with those from the Women's Health initiative (WHI) randomized, placebo-controlled clinical trial regarding estrogen-alone and breast cancer risk are discordant. The WHI randomized trial enrolled 10,729 postmenopausal women with prior hysterectomy, mean age 64 years (33.2% 50-59), no prior breast cancer and a non-suspicious baseline mammogram. After 7.2 years intervention and 16.2 years cumulative follow-up, conjugated equine estrogen (CEE)-alone (vs placebo) significantly reduced breast cancer incidence by 22% (P = 0.005) and significantly reduced breast cancer mortality by 40% (P = 0.04) (Chlebowski JAMA 2020). In contrast, cohort studies had opposite findings, estrogen-alone use was associated with significantly higher breast cancer incidence and significantly higher breast cancer mortality. Therefore, we identified all available estrogen-alone randomized clinical trials where breast cancer findings were reported to conduct a meta-analysis examining the totality of the randomized clinical trial evidence regarding estrogen-alone influence on breast cancer incidence. Methods We conducted PubMed and Google Scholar searches on randomized trials and: estrogen, hormone therapy, and breast cancer, and searches from a prior meta-analyses and reviews. In the current meta-analysis, for trials with published relative risks (RR) and 95% confidence intervals (CI), each log-RR was multiplied by weight = 1/V, where V = variance of the log-RR, and V was derived from the corresponding 95% CI. For smaller trials with only breast cancer numbers, a different method was used, the corresponding log-RR = (O – E)/weight, where O is the observed case number in the oestrogen-alone group and E the corresponding expected case number, E = nP. Findings Ten randomized trials, incorporating WHI findings, and findings from nine smaller trials included 14,272 randomized participants and 591 incident breast cancers. Of 9 smaller trials, 6 required negative baseline screening mammograms; mean entry age: 50 to 56 years in 5 trials and 62 to 71 years in 4 trials. In the nine smaller trials, 1.2% (24 of 2029) vs 2.2% (33 of 1514) randomized to estrogen-alone vs placebo (open label, one trial) were diagnosed with breast cancer, respectively (RR 0.65 95% CI 0.38-1.11, P = 0.12). For 5 trials evaluating estradiol formulations, RR = 0.63 95% CI 0.34-1.16, P = 0.15. In the WHI trial, 4.5% (238 of 5310) vs 5.5% (296 of 5429) randomized to estrogen-alone were diagnosed with breast cancer, respectively (RR 0.78 95% CI 0.65-0.93, P = 0.005)). Combining smaller trials and WHI results, 3.6% (262 of 7339) vs 4.7% (329 of 6943) randomized to estrogen-alone vs placebo were diagnosed with breast cancer, respectively (overall RR 0.77 95% CI 0.65-0.91, P = 0.002). Results from a sensitivity analysis for the smaller trials using exact conditional logistic regression were essentially unchanged (RR 0.64 95% CI 0.35-1.13). Interpretation The totality of randomized clinical trial evidence supports a conclusion that estrogen-alone use, among postmenopausal women with prior hysterectomy, significantly reduces breast cancer incidence. This consistent pattern seen in these randomized trials suggests the WHI CEE-alone findings are not “stand alone” outcomes or due to chance. Citation Format: Rowan Chlebowski, Aaron Aragaki, Kathay Pan, Joanne Mortimer, Karen Johnson, Jean Wactawski-Wende, Meryl LeBoff, Sayeh Lavasani, Dorothy Lane, Rebecca Nelson, JoAnn Manson. Randomized trials of oestrogen-alone and breast cancer incidence: a meta-analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS07-03.

Randomized trials of estrogen-alone and breast cancer incidence: a meta-analysis.

In the Women's Health initiative (WHI) randomized clinical trial, conjugated equine estrogen (CEE)-alone significantly reduced breast cancer incidence (P = 0.005). As cohort studies had opposite findings, other randomized clinical trials were identified to conduct a meta-analysis of estrogen-alone influence on breast cancer incidence. We conducted literature searches on randomized trials and: estrogen, hormone therapy, and breast cancer, and searches from a prior meta-analysis and reviews. In the meta-analysis, for trials with published relative risks (RR) and 95% confidence intervals (CI), each log-RR was multiplied by weight = 1/V, where V = variance of the log-RR, and V was derived from the corresponding 95% CI. For smaller trials with only breast cancer numbers, the corresponding log-RR = (O - E)/weight, where O is the observed case number in the oestrogen-alone group and E the corresponding expected case number, E = nP. Findings from 10 randomized trials included 14,282 participants and 591 incident breast cancers. In 9 smaller trials, with 1.2% (24 of 2029) vs 2.2% (33 of 1514) randomized to estrogen-alone vs placebo (open label, one trial) (RR 0.65 95% CI 0.38-1.11, P = 0.12). For 5 trials evaluating estradiol formulations, RR = 0.63 95% CI 0.34-1.16, P = 0.15. Combining the 10 trials, 3.6% (262 of 7339) vs 4.7% (329 of 6943) randomized to estrogen-alone vs placebo (overall RR 0.77 95% CI 0.65-0.91, P = 0.002). The totality of randomized clinical trial evidence supports a conclusion that estrogen-alone use significantly reduces breast cancer incidence.

Identification of TBK1 inhibitors against breast cancer using a computational approach supported by machine learning.

Introduction: The cytosolic Ser/Thr kinase TBK1 is of utmost importance in facilitating signals that facilitate tumor migration and growth. TBK1-related signaling plays important role in tumor progression, and there is need to work on new methods and workflows to identify new molecules for potential treatments for TBK1-affecting oncologies such as breast cancer. Methods: Here, we propose the machine learning assisted computational drug discovery approach to identify TBK1 inhibitors. Through our computational ML-integrated approach, we identified four novel inhibitors that could be used as new hit molecules for TBK1 inhibition. Results and Discussion: All these four molecules displayed solvent based free energy values of -48.78, -47.56, -46.78 and -45.47Kcal/mol and glide docking score of -10.4, -9.84, -10.03, -10.06Kcal/mol respectively. The molecules displayed highly stable RMSD plots, hydrogen bond patterns and MMPBSA score close to or higher than BX795 molecule. In future, all these compounds can be further refined or validated by in vitro as well as in vivo activity. Also, we have found two novel groups that have the potential to be utilized in a fragment-based design strategy for the discovery and development of novel inhibitors targeting TBK1. Our method for identifying small molecule inhibitors can be used to make fundamental advances in drug design methods for the TBK1 protein which will further help to reduce breast cancer incidence.

Sociodemographic Factors Associated with Breast Cancer Screening Among Women in Serbia, National Health Survey

Background: Approximately 2.3 million female breast cancer cases were identified globally in 2020, resulting in 685,000 fatalities among women. Serbia too experiences a high breast cancer burden. Effective reduction of breast cancer incidence and mortality necessitates strategic measures encompassing the implementation of cost-effective screening technology. However, various impediments to screening implementation persist. We aimed to estimate the impact of socioeconomic factors on breast cancer screening in Serbia.
 Methods: Data from the 2019 National Health Survey of the population of Serbia was. The research was a descriptive, cross-sectional analytical study by design, on a representative sample of the population of Serbia. Data from women aged 15+ yr were used to examine the demographic and socioeconomic factors associated with breast cancer screening inequalities.
 Results: In Serbia the age group of women who predominantly participated in organized breast cancer screening (39.5%) were the ones aged 65+ yr. Women with a secondary education were 2.1x more likely to undergo a screening exam voluntarily (57.5%), compared to women with a higher education background (26.6%). When considering marital and financial circumstances, married/unmarried women from an affluent financial category exhibited a notably higher frequency of self-initiating a mammography (73% and 48.5%) in comparison to those financially struggling (27.6%).
 Conclusion:  Strong support is imperative for countries to establish prevention and early detection programs for cancer.

The role of breastfeeding in breast cancer prevention: a literature review.

Breast cancer stands as the most prevalent malignancy globally. Despite the array of treatment options, its mortality rate continues to rise annually. Thus, reevaluation of factors directly linked to breast cancer emergence is imperative, alongside the development of more effective preventive measures. Estrogen levels, profoundly tied to reproduction, play a pivotal role in breast cancer development. Speculation centers on the potential of breastfeeding to mitigate cancer risk in women. However, the precise mechanism remains elusive. Breastfeeding is a modifiable reproductive factor extensively studied. Studies highlight a direct connection between lack of breastfeeding and breast cancer emergence, potentially linked to DNA methyltransferase expression alteration, aberrant methylation levels, pregnancy-associated plasma protein-A, cellular microenvironment, and oncogenes. This study reviews recent mechanisms underlying breastfeeding's role in reducing breast cancer incidence.

Chemoprevention and Lifestyle Modifications for Risk Reduction in Sporadic and Hereditary Breast Cancer.

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.

Impact of early mammography screening on time to diagnosis.

e18870 Background: Initial mammography screening age recommendations vary by organization, with the United States Preventive Services Taskforce recommendations beginning at 50 years and the American College of Obstetricians and Gynecologists and the National Comprehensive Cancer Network recommendations beginning at age 40 years. This study aimed to examine the impact of early age recommendation for initiating screening mammography (i.e., 40 years) on time to breast cancer diagnosis. Methods: This is a retrospective cohort study of adult women who received a screening mammogram between 1/1/2012 and 12/31/2022. The outcome of interest was a breast cancer diagnosis (ICD-9 code: 174.X; ICD-10 code: C50.X) any time after the initial screening. Members were stratified by age at the initial mammogram, with on-time mammograms defined as those occurring during the 50th year of life and early mammograms defined as those occurring in the 40th year. Survival analysis was conducted between the two groups. Incidence rate differences (IRD) and ratios were calculated between groups for 1-, 3-, 5-, and 10-year follow-up analysis; logistic regression modeling was also performed. All analyses were conducted in Python and R; p < 0.05 was considered significant. Results: In total, 22,843 members were included in the study, with 11,730 (51.4%) having on-time mammograms. On-time screening members were more likely to have unknown socioeconomic status (SES) compared to early screening members (26.4% vs. 24.6%, p = 0.022) and to reside in rural zip codes (42.2% vs. 39.1%, p < 0.001). After 10 years of follow-up, 285 of 2,647 remaining members developed breast cancer (incidence rate 10.77 cases per 1,000 person-years [PY] observed [95% confidence interval (CI) 9.55-12.1 cases per 1,000 PY]). Early mammograms were associated with significantly lower IRD at 3- (IRD: -1.85 cases per 1,000 PY [95% CI -2.76 to -0.93]; p = 0.0001), 5- (IRD: -1.92 cases per 1,000 PY [95% CI -2.86 to -0.97]; p = 0.0001), and 10- (IRD: -7.15 cases per 1,000 PY [95% CI -9.66 to -4.64], p < 0.0001) year follow up periods. Early mammograms were associated with significantly longer time to diagnosis during survival analysis (97.5% diagnosis-free vs. 95.4%, p < 0.0001). Controlling for SES, early mammograms were associated with significantly lower hazard for breast cancer diagnosis at any time (hazard ratio [HR]: 0.62 [95% CI 0.48-0.78], p < 0.0001). Unknown SES was also associated with significantly lower hazard compared to those with medium SES (HR: 0.47 [95% CI 0.33-0.67], p < 0.0001); however, no other SES categories demonstrated significant differences. Conclusions: The primary goal of breast cancer screening is to reduce breast cancer incidence and mortality. In this study, early mammography at age 40 years was associated with significantly lower incidence rates after 3-, 5, and 10-year follow-ups. Additional studies on the impact of early mammography and breast cancer mortality in this population are warranted.

(114) Vaginal/Vulvar Symptoms with Lasofoxifene versus Fulvestrant in ESR1-mutated, ER+/HER2- Metastatic Breast Cancer Patients

Abstract Introduction Endocrine therapy (ET), specifically aromatase inhibitors (AIs) that lower estrogen to subphysiologic levels and estrogen receptor (ER) degraders that non-selectively and negatively impact ER function, may induce genitourinary syndrome of menopause (GSM) in breast cancer patients. Novel therapies with positive impacts are desirable. Lasofoxifene reduced breast cancer incidence in a large clinical study, while demonstrating ER agonist activity on the urogenital system and bone in clinical trials, including two phase 3 studies in postmenopausal women with moderate to severe vulvovaginal atrophy. Lasofoxifene is currently under investigation as a targeted ET in patients with disease progression on prior ET for metastatic breast cancer (mBC) harboring ER mutations (mESR1). Prevalence of vaginal/vulvar symptoms and potential impact of endocrine treatments on GSM in this patient population are unclear, thus data were gathered from one of the largest studies of lasofoxifene in this patient population to assess its potential positive impact in this area. Objective To investigate changes in vaginal/vulvar symptoms with lasofoxifene versus fulvestrant in women with mESR1, ER+/HER2- mBC in ELAINE 1. Methods Women in the multinational (US, Canada, Israel), phase 2, ELAINE 1 study were randomized to oral lasofoxifene 5 mg (daily) or IM fulvestrant 500 mg (days 1, 15, and 29, then every 28 days), until disease progression/severe toxicity. Vaginal/vulvar symptoms were evaluated as an exploratory endpoint using the vaginal (VAS) and vulvar (VuAS) assessment scales, instruments validated in breast cancer patients to assess dryness, soreness, irritation, and pain using a 4-point scale (0=none, 1=mild, 2=moderate, 3=severe). English-speaking patients completed the VAS/VuAS at baseline and every 8 weeks until disease progression. Changes in the mean composite VAS/VuAS score (average of all reported scores for a patient) and the mean score for the most bothersome symptom (the symptom with the greatest baseline score for a patient) over 16 weeks of treatment were analyzed. Results Of 103 enrolled patients, 39/52 (75%) lasofoxifene patients and 33/51 (65%) fulvestrant patients completed the VAS/VuAS; 9/39 (23%) and 10/33 (30%) had ≥1 moderate/severe symptom, respectively (Table). Among those who completed the VAS/VuAS (median age 61.5 years), the mean composite score changed from baseline to week 16 by −74% in lasofoxifene patients versus +36% in fulvestrant patients; the mean score for most bothersome symptom changed by −65% with lasofoxifene and by −5% with fulvestrant. In women with ≥1 moderate/severe symptom at baseline, percent changes from baseline to week 16 in the mean composite VAS/VuAS score were −72% with lasofoxifene versus +32% with fulvestrant. Conclusions In this exploratory analysis in mBC patients unselected for GSM symptoms, lasofoxifene 5 mg/day numerically improved vaginal/vulvar symptoms relative to fulvestrant, albeit with a small sample size. Baseline prevalence of moderate/severe GSM symptoms (20–30%) appears to have been under-reported in this population, which may be due to patients minimizing symptoms less important than mBC disease control or being embarrassed to communicate sexual concerns to their oncologists. Further studies are warranted to evaluate potential clinical benefits of lasofoxifene on GSM symptoms and sexual health in patients with breast cancer. Disclosure Yes, this is sponsored by industry/sponsor: Sermonix Pharmaceuticals. Clarification: Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Sermonix Pharmaceuticals.

The Women's Health Initiative randomized trials of menopausal hormone therapy and breast cancer: findings in context.

The menopausal hormone therapy (MHT) association with breast cancer has been controversial for more than 40 years. Most recently, findings from cohort studies have been discordant compared with those from the Women's Health Initiative (WHI) randomized trials. In cohort studies, both estrogen therapy and estrogen plus progestin were associated with higher breast cancer incidence. In contrast, in the WHI randomized trials, findings for estrogen plus progestin are concordant with cohort study reports, whereas estrogen therapy significantly reduced breast cancer incidence. In addition, concerns have been raised regarding the WHI findings from both trials. In this report, we briefly summarize findings for MHT on breast cancer from cohort studies and the WHI randomized trials. The report focus is addressing, point-by-point, concerns raised regarding the WHI findings. For cohort studies, we relied on the latest findings from (1) the meta-analysis of the Collaborative Group on Hormonal Factors in Breast Cancer and (2) the Million Women's Study. To identify commentaries and editorials, "Menopause" and "Climacteric" were searched from 2002 to present; PubMed and Google Scholar were searched for commentaries, editorials, and breast cancer, MHT, estrogen, conjugated equine estrogen, estradiol, "hormone replacement therapy," and "HRT." Thirty commentaries challenging WHI findings were identified. All were reviewed, and issues needing response were identified. Findings from the meta-analysis from the Collaborative Group on Hormonal Factors in Breast Cancer and the Million Women Study were summarized and compared with finding in the two WHI randomized trials evaluating estrogen therapy and estrogen plus progestin. Based on the randomized clinical trials, estrogen therapy, for women with prior hysterectomy, decreases breast cancer incidence and mortality. In contrast, estrogen plus progestin increases breast cancer incidence, which persists through two decades. Women considering estrogen plus progestin use for vasomotor symptoms should understand the breast cancer risk.

Metabolomic profiles of metformin in breast cancer survivors: a pooled analysis of plasmas from two randomized placebo-controlled trials

BackgroundObesity is a major health concern for breast cancer survivors, being associated with high recurrence and reduced efficacy during cancer treatment. Metformin treatment is associated with reduced breast cancer incidence, recurrence and mortality. To better understand the underlying mechanisms through which metformin may reduce recurrence, we aimed to conduct metabolic profiling of overweight/obese breast cancer survivors before and after metformin treatment.MethodsFasting plasma samples from 373 overweight or obese breast cancer survivors randomly assigned to metformin (n = 194) or placebo (n = 179) administration were collected at baseline, after 6 months (Reach For Health trial), and after 12 months (MetBreCS trial). Archival samples were concurrently analyzed using three complementary methods: untargeted LC–QTOF-MS metabolomics, targeted LC–MS metabolomics (AbsoluteIDQ p180, Biocrates), and gas chromatography phospholipid fatty acid assay. Multivariable linear regression models and family-wise error correction were used to identify metabolites that significantly changed after metformin treatment.ResultsParticipants (n = 352) with both baseline and study end point samples available were included in the analysis. After adjusting for confounders such as study center, age, body mass index and false discovery rate, we found that metformin treatment was significantly associated with decreased levels of citrulline, arginine, tyrosine, caffeine, paraxanthine, and theophylline, and increased levels of leucine, isoleucine, proline, 3-methyl-2-oxovalerate, 4-methyl-2-oxovalerate, alanine and indoxyl-sulphate. Long-chain unsaturated phosphatidylcholines (PC ae C36:4, PC ae C38:5, PC ae C36:5 and PC ae C38:6) were significantly decreased with the metformin treatment, as were phospholipid-derived long-chain n-6 fatty acids. The metabolomic profiles of metformin treatment suggest change in specific biochemical pathways known to impair cancer cell growth including activation of CYP1A2, alterations in fatty acid desaturase activity, and altered metabolism of specific amino acids, including impaired branched chain amino acid catabolism.ConclusionsOur results in overweight breast cancer survivors identify new metabolic effects of metformin treatment that may mechanistically contribute to reduced risk of recurrence in this population and reduced obesity-related cancer risk reported in observational studies.Trial registrationClinicalTrials.gov identifier: NCT01302379 and EudraCT Protocol #: 2015-001001-14.

Abstract A015: The β-blocker carvedilol prevents DMBA-induced mammary gland tumors

Abstract Breast cancer is the most diagnosed cancer globally and is the fifth leading cause of cancer related mortality worldwide. Chemoprevention is a promising method of reducing cancer mortality. However, there are no drugs that are used routinely as breast cancer preventative agents. Carvedilol (CAR), a beta-adrenergic receptor blocker, use in humans reduces breast cancer incidence; therefore, we hypothesized that carvedilol acts as a breast cancer preventative agent. Two protocols were used to evaluate the ability of carvedilol to prevent 15 mg 7,12-Dimethylbenz(a)anthracene (DMBA)-induced mammary tumors. In protocol 1, two doses of carvedilol (2 and 10 mg/kg) were provided as a 7-day pretreatment and throughout the study. In protocol 2, 10 mg/kg tamoxifen and 10 mg/kg carvedilol were provided as a 7-day pretreatment and treatment was halted after six weeks. In all studies carvedilol and tamoxifen were administered in the drinking water, animals were palpated weekly beginning at week 5 to detect the presence and location of mammary tumors, tumors were measured via calipers, and the experiments terminated at week 13. In protocol 1, 10 mg/kg, but not 2 mg/kg carvedilol was effective in delaying the tumor occurrence (P = 0.0002); the first appearance of tumors and median tumor appearance were separated by 6 and 4 weeks, respectively, compared to rats receiving DMBA alone. However, the tumors that appeared, grew at similar rate as those in the DMBA group. In protocol 2, tamoxifen prevented all but 1 rat developing a tumor and was similar to the negative control; however, 10 mg/kg carvedilol was indistinguishable from the DMBA group. Although tamoxifen prevented DMBA-induced breast cancer, the rats drank significantly less water resulting in statistically lower body weight than all other groups. The rats also drank significantly less of the carvedilol-laced water, but not to a degree that affected their body weight. Therefore, continuous carvedilol treatment is essential to achieve the observed chemopreventive effects. Our data demonstrates the chemopreventive activity of carvedilol in a rat model of mammary gland carcinogenesis. The results provide significant implications in breast cancer chemoprevention using carvedilol, which is a safe FDA-approved medicine. Citation Format: Pabitra K. Sardar, Ayaz Shahid, Steven Yeung, Bradley T. Andresen, Ying Huang. The β-blocker carvedilol prevents DMBA-induced mammary gland tumors [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A015.

Sustained weight loss may reduce cancer risk.

Although it is widely accepted that obesity is a cancer risk factor, there has been little research showing that losing weight and maintaining that loss reduce the risk of developing and possibly dying of certain cancers. A new study by Cleveland Clinic Health System (CCHS) researchers, published in the Journal of the American Medical Association (doi:10.1001/jama.2022.9009), does just that by focusing on patients who underwent bariatric surgery. Although the biological mechanisms are still incompletely understood, it is believed by many that obesity can affect cancer development and growth by causing increased inflammation, by altering microbiota, by causing insulin resistance, and by increasing the levels of circulating insulin-like growth factor, estrogens, and adipokines. Lead study author Ali Aminian, MD, professor of surgery at the Lerner College of Medicine and director of Cleveland Clinic’s Bariatric & Metabolic Institute, says that the researchers focused on bariatric surgery because it is an effective and long-lasting way for patients with obesity to lose weight. The risk of developing 13 different types of cancers that account for 40% of all annual cancer diagnoses in the United States increases with obesity. Bariatric surgery patients had a 32% lower incidence of obesity-associated cancer and a 48% lower risk of death from cancer than patients in a nonsurgical control group. The primary composite end point of this retrospective, observational, matched cohort study was the time to first incidence of one of 13 obesity-associated cancers: esophageal adenocarcinoma; renal cell carcinoma; postmenopausal breast cancer; cancer of the gastric cardia, colon, rectum, liver, gallbladder, pancreas, ovary, corpus uteri, or thyroid; and multiple myeloma. The secondary end point was cancer-related mortality. The SPLENDID study included 5053 adult patients with obesity who underwent either Roux-en-Y gastric bypass or sleeve gastrectomy at Cleveland Clinic hospitals between 2004 and 2017. Each surgical patient was matched with five patients who did not undergo bariatric surgery. These 25,265 nonsurgical control patients were selected via a logistic regression model based on 10 potential self-reported potential confounders, including the following: race (Black, White, or other), body mass index (35–39.9, 40–44.9, 45–49.9, 50–54.9, 55–59.9, or 60–80 kg/m2), smoking history (never, former, or current), presence of type 2 diabetes, Elixhauser Comorbidity Index, Charlson Comorbidity Index, and state of residence (classified as Florida or as Ohio [because many patients were treated at CCHS facilities in those states] or as other US states combined). The median age of the patients was 46 years. Most were female (77%), and 73% were White. The median follow-up interval was 5.8 years for the bariatric surgery group and 6.1 years for patients in the nonsurgical control group. The CCHS researchers found rather dramatic results: The bariatric surgery patients had a 32% lower incidence of obesity-associated cancer and a 48% lower risk of death from cancer than the patients in the nonsurgical control group. At the 10-year mark, the bariatric surgery group lost 19.2% more body weight than the control group did; this corresponded to a 54.7pound difference in weight loss. The researchers also found that 96 patients in the bariatric surgery group and 780 patients in the nonsurgical control group developed an obesity-related cancer by 2021 during the 17-year follow-up period; this yielded a 10-year cumulative incidence of this primary end point of 2.9% in the bariatric surgery group and 4.9% in the nonsurgical control group. Also, 21 patients in the bariatric surgery group (0.41%) and 205 patients in the control group (0.81%) died of cancer-related causes; these rates corresponded to 0.6 and 1.2 cancer-related deaths, respectively, per 1000 person-years of follow-up. “What we found is striking,” said Dr Aminian in an official release from the Cleveland Clinic. “The greater the weight loss, the lower the risk of cancer.” Dr Nissen adds, “Our findings also showed that losing weight with bariatric surgery could decrease the risk of developing precancerous lesions, such as endometrial hyperplasia, ductal carcinoma in situ of breast, colorectal polyps, and Barret’s esophagus.” Marji McCullough, ScD, RD, senior scientific director of epidemiology research at the American Cancer Society (ACS) in Kennesaw, Georgia, who was not involved in this study, points out that it supports a growing body of literature showing that weight loss among those with morbid obesity may reduce the risk of developing cancer, especially obesity-related cancers. “Many questions remain, however,” she says. “Is this association causal? What are the mechanisms? Should certain patients be prioritized for bariatric surgery? How much weight loss is required to see an effect?” Dr McCullough also notes that although long-term weight loss without surgery typically does not result in as dramatic of a weight loss, other observational studies suggest that more modest weight loss may also lower the risk of certain obesity-related cancers. Lauren R. Teras, PhD, Dr McCullough’s colleague at the ACS and a senior scientific director of epidemiology in the ACS’s Department of Population Science, notes that the study did not find a lower risk of breast cancer with bariatric surgery. “This may be due to the young age of the participants, who were age 46 on average at study entry, with a median follow-up of about six years. The increased risk of breast cancer for obesity is restricted to postmenopausal breast cancer only.” Thus, a study that enrolled older patients or one with much longer follow-up might have shown even more favorable results, including a reduction in breast cancer incidence and mortality rates. “When considering the broader implications of the study, it’s important to note that results from bariatric surgery studies may not be applicable to the general population,” Dr Teras adds. “Bariatric surgery patients undergo preoperative health screening, have an extremely high body weight before surgery, lose extremely large amounts of weight in a short period of time, and undergo hormonal and metabolic changes from the surgery that induce more pronounced biological responses.” Dr McCullough notes that criteria for evaluating who is a good candidate for bariatric surgery exist from many sources, including the American Society for Metabolic and Bariatric Surgery and the National Institute of Diabetes and Digestive and Kidney Diseases: “For general guidance on cancer prevention, clinicians can refer to the American Cancer Society Guideline for Diet and Physical Activity for Cancer Prevention [https://www.cancer.org/healthy/eat-healthy-get-active/acs-guidelines-nutrition-physical-activity-cancer-prevention/guidelines.html].”

Estrogen therapy and breast cancer in randomized clinical trials: a narrative review.

In the Women's Health Initiative (WHI) randomized trial with 10,739 postmenopausal women with prior hysterectomy, conjugated equine estrogen (CEE) alone significantly reduced breast cancer incidence and breast cancer mortality. In contrast, epidemiological studies in a meta-analysis from the Collaborative Group on Hormonal Factors in Breast Cancer (Collaborative Group) with 108,647 breast cancers and the Million Women's Study cohort significantly associated estrogen-alone therapy with higher breast cancer incidence and breast cancer mortality. The Collaborative Group included a meta-analysis of five smaller randomized trials and the WHI randomized trial; however, findings were restricted to the Collaborative Group appendix. Our objective is to facilitate understanding of these discordant results. Data sources supporting our review findings include the randomized WHI CEE-alone trial and the meta-analysis of five smaller randomized trials evaluating estrogen alone. We summarize the smaller randomized trials' details of breast cancer relevance and place the findings in clinical context. We review findings of the WHI randomized trial evaluating CEE alone in the context of issues raised by Collaborative Group and the Million Women Study authors. We trace the evolution of the time-from-menopause, "window of opportunity" concept and augment the Collaborative Group meta-analysis by including the most recent WHI findings. Consideration of the smaller randomized trials evaluating estrogen alone with breast cancer signals that the WHI findings of lower breast cancer incidence and lower breast cancer mortality with CEE-alone use are not a "stand-alone" outcome or due to the play of chance. The serial reports of consistent favorable breast cancer findings through 20 years of cumulative follow-up suggest CEE-alone use initiates changes that persist. After full consideration of risks and benefits, randomized trial evidence provides reassurance for postmenopausal women with prior hysterectomy who are close to menopause considering estrogen alone for climacteric symptom management.

Selected Articles from This Issue

Colorectal cancer (CRC) screening has proven to be very effective in preventing this deadly disease. However, effectiveness can be improved, and costs can be reduced by using additional biomarkers for candidate selection. Arnau-Collell and colleagues developed a polygenic risk score and evaluated its effectiveness in determining which individuals should undergo a colonoscopy after a positive FIT result considering their CRC-associated genetic risk. The study highlights the potential application of these variants when applied to stratify people at a higher risk of CRC in the context of screening programs, while underlining the need to incorporate additional biomarkers.Breast cancer incidence is greater among non-Hispanic White and Black women compared to other women. In a large population-based study, Barnard and colleagues observed that the distributions of two breast cancer risk factors, body mass index (BMI) and mammographic density (MD) varied dramatically by race and ethnicity, with the highest MD among Asian women and the highest BMI among Native Hawaiian and Pacific Islander women. Magnitudes of association between BMI and MD did not vary by race or ethnicity. Future efforts to reduce breast cancer incidence should consider the distributions of breast cancer risk factors to ensure equitable prevention strategies.Gastric cancer (GC) has a particularly high mortality rate in the US, as it lacks specific symptoms resulting in diagnosis at later stages. In and colleagues conducted a nested case-control study within the PLCO Screening Trial to examine the utility of pepsinogen as a predictor of incident GC. The authors found that pre-diagnostic pepsinogen sero-positivity was associated with 8.5-fold increased risk for GC. This suggests that despite the overall low incidence of GC in the US, serum pepsinogen holds potential to be used as biomarker to identify individuals at higher risk of GC for US-based targeted screening or interventions. 5-alpha reductase inhibitors (5-ARIs) are common medications among older men with benign prostatic hyperplasia. Conflicting results on 5-ARIs and prostate cancer mortality have led to debate about its effectiveness in primary chemoprevention. Vaselkiv and colleagues studied 38,000 men followed for 20 years and detailed information on screening and healthcare use. In the setting of regular screening, 5-ARI use was not associated with increased prostate cancer mortality, while it lowered risk of low-grade cancers. These findings together with those from other cohorts highlight the importance of framing risks and benefits of 5-ARIs in the context of real-world data and in light of the importance of clinical follow-up of men on 5-ARIs.

Physical Activity in Young BRCA Carriers and Reduced Risk of Breast Cancer

A systematic literature review was conducted to determine whether physical activity levels during adolescent and young adult years were associated with a reduced lifetime risk of breast cancer among carriers of deleterious mutations in BRCA1 and BRCA2 genes. Ovid/MEDLINE, Embase, CENTRAL, WOS, and CINAHL were searched for articles including information about adolescent and young adult physical activity and breast cancer incidence among women carrying deleterious BRCA1 and BRCA2 gene mutations (search was initiated in October 2019; last update and full analyses were in March 2021). Independent reviewers screened articles at the title/abstract and full-text levels, resolving differences by consensus with lead authors. The NIH Quality Assessment Tools were used to assess sources of bias. A total of 1,957 unique articles were identified; 5 met inclusion criteria. Samples size ranged from 68 to 1,185. All studies relied on self-reported adolescent and young adult physical activity. One study measured sports involvement; the others measured recreational activity. One large study was null, whereas 4 others showed a reduction in breast cancer incidence later in life with higher adolescent and young adult physical activity (p≤0.05). However, the protection was limited to premenopausal breast cancer in 1 of the studies (OR=0.62; 95% CI=0.40, 0.96; p-trend=0.01). In addition, adolescent and young adult physical activity was associated with older age at breast cancer diagnosis in 1 study (p=0.03). A limited number of studies suggest that adolescent and young adult physical activity may reduce or delay the risk of breast cancer incidence among carriers of deleterious mutations in BRCA1 and BRCA2 genes.

Simulation modeling as a tool to support clinical guidelines and care for breast cancer prevention and early detection in high-risk women.

10525 Background: To evaluate the incremental short- and long-term benefits and harms of primary prevention with risk reducing medication in high-risk women receiving screening mammography. Methods: We adapted an established, validated Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer discrete event microsimulation model developed to synthesize data the impact of using risk-reducing medication and annual mammography among women with a 3% or higher five-year risk of developing breast cancer. We also examined the effects of supplemental MRI. The model follows a simulated cohort of millions of US women from birth to death. We used large observational and clinical trial data to derive input parameters for cohort-specific birth rates, breast cancer risk, incidence and stage, screening performance, survival by age, stage, and subtype, treatment efficacy, and other cause mortality. Breast cancer risk was modeled based on family history, breast density, age and history of past breast biopsy. We compared two strategies, annual 3D mammography alone vs. annual 3D mammography and a 5-year course of risk reducing medication at various starting ages, and adding MRI to each approach. Outcomes included the benefits of risk-reducing drugs (avoiding breast cancer) and screening (stage, breast cancer death). Harms included drug side effects and screening false positives and overdiagnosis. Sensitivity analysis tested the impact of uncertainty in model inputs and assumptions on results. Results: Compared to mammography alone, adding risk reducing medication could decrease invasive breast cancer incidence by 30%, and breast cancer deaths by 30% (Table). However, due to reduction in breast cancer incidence, risk reducing medication could result in a 3% increase in false positive results; adding MRI increases benefits but also increases false-positive results. Benefits and harms of risk reducing medication and breast cancer screening strategies for women at high-risk of developing breast cancer. Conclusions: Risk-reducing mediation reduces the risk of hormone-receptor positive breast cancer, and combining this with mammography (and/or MRI) improves earlier detection. Additional work is ongoing to incorporate adverse effects of therapy. Simulation modeling can be used to provide individualized data to facilitate discussions about breast cancer prevention and early detection among high-risk women seen in clinical practice.[Table: see text]

Topical Endoxifen for Mammographic Density Reduction-A Randomized Controlled Trial.

Although breast cancer incidence is increasing, there are few primary preventive initiatives. Tamoxifen can reduce breast cancer incidence but is rarely used for primary prevention due to adverse events and tolerance issues. We tested if endoxifen, a tamoxifen metabolite, applied directly to the skin of the breast, could reduce mammographic density, a proxy for therapy response. Ninety women were randomized to placebo, 10 and 20 mg of topical Z-endoxifen for 6 months. Mammographic density and symptoms were measured at baseline and study exit. Despite a high discontinuation rate, driven by skin rashes, we found a significant mammographic density decrease, a dose-dependent increase in the concentration of plasma Z-endoxifen but no systemic side effects. Topical application of tamoxifen metabolites has the potential to decrease breast cancer incidence without major systemic side effects. However, endoxifen may not be suitable for topical administration and is unlikely to be used for breast cancer prevention.

Revisiting the MMTV Zoonotic Hypothesis to Account for Geographic Variation in Breast Cancer Incidence.

Human breast cancer incidence varies by geographic location. More than 20 years ago, we proposed that zoonotic transmission of the mouse mammary tumor virus (MMTV) from the western European house mouse, Mus musculus domesticus, might account for the regional differences in breast cancer incidence. In the intervening years, several developments provide additional support for this hypothesis, including the limited impact of genetic factors for breast cancer susceptibility revealed by genome-wide association studies and the strong effect of antiretroviral therapy to reduce breast cancer incidence. At the same time, economic globalization has further expanded the distribution of M. m. domesticus to Asia, leading to a significant increase in breast cancer incidence in this region. Here, we revisit this evidence and provide an update to the MMTV zoonotic hypothesis for human breast cancer at a time when the world is recovering from the global COVID-19 zoonotic pandemic. We present evidence that mouse population outbreaks are correlated with spikes in breast cancer incidence in Australia and New Zealand and that globalization has increased the range of M. m. domesticus and MMTV. Given the success of global vaccination campaigns for HPV to eradicate cervical cancer, a similar strategy for MMTV may be warranted. Until breast cancer incidence is reduced by such an approach, zoonotic transmission of MMTV from mice to humans as an etiologic factor for breast cancer will remain controversial.

Abstract P1-10-03: Estrogen and breast cancer benefits: Emerging hormone replacement therapy breast cancer paradigms

Abstract BACKGROUND. Large scale clinical hormone replacement therapy [HRT] studies have yielded conflicting breast cancer [BrCa] outcomes. The studies reviewed include:. Two Non-Randomized Studies [Non-RS], based on either estrogen+progestin Provera [E+P HRT]; or estrogen-alone [E-HRT]:. 1. Collaborative Group Meta-analysis of 58 HRT studies [CG-M] [1]. 2. Million Women Study [MWS] [2]. Two Randomized Studies [RS] - the Women’s Health Initiative [WHI] Trials 1 and 2:. 1. WHI HRT Trial 1 - based on E+P HRT [3] 2. WHI HRT Trial 2 - based on E-HRT [3]. Of all the above HRT studies, only the WHI HRT Trial 2 showed long-term reductions in Breast Cancer Incidence [BrCa-I] and Mortality [BrCa-M], while all others showed varying degrees of BrCa harms. OBJECTIVES. To evaluate differences between the representative HRT studies, their results and conclusions. METHODOLOGY. Compared were BrCa outcomes:. i. Between the two the RS - WHI HRT Trial 2 vs. 1 (Analysis 1) ii. E-HRT impact from a RS [i.e., the WHI HRT Trial 2] vs. Non-RS [the CG-M/MWS] (Analysis 2). For both analyses, risk ratios (RR) for BrCa-I & BrCa-M, and the corresponding 95% confidence intervals (CI), were obtained from the studies [RR1 and RR2, respectively]. Subsequently, the ratio of “risk ratios” (R-RRs), were estimated, in each analysis, separately for BrCa-I and BrCa-M. The 95% confidence intervals and p-values for the R-RRs were derived through logarithmic transformation of the risk ratios and 95% CI originally reported. RESULTS. CONCLUSIONS.. Based on these outcomes, the following emerging HRT paradigms can be considered:. PARADIGM 1: The addition of Progestin Provera abrogates the benefits of E-alone HRT [4]. PARADIGM 2: Considering the presence of many confounding factors in non-randomized HRT studies [e.g., selection bias, with more high-risk women receiving HRT (5)], the reduction of BrCa-I and BrCa-M rates observed in the WHI Trial 2 has to be accepted as the least biased conclusion of the E-HRT impact on breast cancer. PARADIGM 3: The mechanism of the E-alone based HRT breast cancer benefit could be explained by the Estrogen Duality [endogenous estrogen remaining breast carcinogenic, while the exogenous estrogen emerging breast cancer suppressive] - a concept articulated already in 2010 [6], now confirmed in the WHI HRT Trial 2 final outcomes, and in these analyses. REFERENCES. 1. Collaborative Group on Hormonal Factors in Breast Cancer. The Lancet, 2019; vol. 394(1024). 2. Beral V et al. The Lancet, 2019; vol. 394. 3. Chlebowski R et al. JAMA, 2020; vol. 324(4). 4. Ragaz J et al. AACR, 2019; vol. 79(4) Supplement. 5. Shapiro S et al. J Fam Plann Reprod Health Care, 2013; vol. 39(2). 6. Ragaz J et al. Ca Res, 2010; vol. 70(24) Supplement. Analysis 1: RS WHI Trial 2 vs. 1 [ 3]RS - RRs: E-HRT vs. Placebo. RR1 [95% C.I.]RS - RRs: E+P HRT vs. Placebo. RR2 [95% C.I.]Ratio of “Risk Ratios” [R-RRs]PBrCa Incidence0.78 [0.65-0.93]1.28 [1.13-1.45]0.61 [0.49-0.76]<0.001BrCa Mortality0.60 [0.37-0.97]1.35 [0.94-1.95]0.44 [0.25-0.81]0.008Analysis 2: [E-HRT] of RS vs. Non-RS - [WHI Trial 2 vs. CG-M/MWS 1,2]RS: E-HRT vs. Placebo- RRs. RR1 [95% C.I.]Non-RS E-HRT “users” vs. “Non-users” - RRs. RR2 [95% C.I.]R-RRs. RR1/RR2 [95% C.I.]PBrCa Incidence0.78 [0.65-0.93]1.33 [1.28-1.38]0.59 [0.49-0.70]<0.001BrCa Mortality0.60 [0.37-0.97]1.35 [1.24-1.47]0.44 [0.27-0.72]0.001 Citation Format: Joseph Ragaz, John J Spinelli, Hong Qian, Hubert Wong, Shayan Shakeraneh, Joel Fox, Kenneth S Wilson. Estrogen and breast cancer benefits: Emerging hormone replacement therapy breast cancer paradigms [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-10-03.