A randomized Phase I pre-operative window trial of transdermal endoxifen in women planning mastectomy: Evaluation of dermal safety, intra-mammary drug distribution, and biologic effects.

Breast cancer prevention only requires local exposure of the breast to active drug. However, oral preventive agents entail systemic exposure, causing adverse effects that limit acceptance by high-risk women. Drug-delivery through the breast skin is an attractive option, but requires demonstration of dermal safety and drug distribution throughout the breast. We formulated the tamoxifen metabolite (E/Z)-endoxifen for transdermal delivery and tested it in a placebo-controlled, double-blinded Phase I trial with dose escalation from 10 to 20 mg daily. The primary endpoint was dermal toxicity. Thirty-two women planning mastectomy were randomized (2:1) to endoxifen-gel or placebo-gel applied to both breasts for 3-5 weeks. Both doses of endoxifen-gel incurred no dermal or systemic toxicity compared to placebo. All endoxifen-treated breasts contained the drug at each of five sampling locations; the median per-person tissue concentration in the treated participants was 0.6 ng/g (IQR 0.4-1.6), significantly higher (p < 0.001) than the median plasma concentration (0.2 ng/mL, IQR 0.2-0.2). The median ratio of the more potent (Z)-isomer to (E)-isomer at each breast location was 1.50 (IQR 0.96-2.54, p < 0.05). No discernible effects of breast size or adiposity on tissue concentrations were observed. At the endoxifen doses and duration used, and the tissue concentration achieved, we observed a non-significant overall reduction of tumor proliferation (Ki67 LI) and significant downregulation of gene signatures known to promote cancer invasion (FN1, SERPINH1, PLOD2, PDGFA, ITGAV) (p = 0.03). Transdermal endoxifen is an important potential breast cancer prevention agent but formulations with better dermal penetration are needed.

Alternative dosing regimen of exemestane in a randomized presurgical trial: the role of obesity in biomarker modulation.

In a 3-arm presurgical trial, four-six weeks exemestane 25 mg three times/week (TIW) was non-inferior to 25 mg/day (QD) in suppressing circulating estradiol in postmenopausal women with ER-positive breast cancer. Since obesity may decrease exemestane efficacy, we analyzed changes in sex steroids, adipokines, Ki-67, and drug levels in relation to obesity. Postmenopausal women with early-stage ER-positive breast cancer were randomized to either exemestane 25 mg QD (n = 57), 25 mg TIW (n = 57), or 25 mg/week (QW, n = 62) for 4-6 weeks before breast surgery. Serum and tissue pre- and post-treatment biomarkers were stratified by body mass index (BMI)< or ≥30 kg/m2. Post-treatment median exemestane and 17-OH exemestane levels were 5-6 times higher in the QD arm compared to the TIW arm. For obese women, TIW maintained comparable reductions to QD in systemic estradiol levels, although the reduction in estrone was less with the TIW regimen. There was less suppression of SHBG with the TIW versus the QD dose schedule in obese women which should result in less systemic bioavailable estrogens. Metabolically, the effect of the TIW regimen was similar to the QD regimen for obese women in terms of leptin suppression and increase in the adiponectin-leptin ratio. Reduction in tissue Ki-67 was less for obese women on the TIW regimen than QD, although changes were similar for non-obese women. Our findings suggest that TIW exemestane should be explored further for primary cancer prevention in both normal weight and obese cohorts.

Presurgical Oral Tamoxifen vs Transdermal 4-Hydroxytamoxifen in Women With Ductal Carcinoma In Situ: A Randomized Clinical Trial.

Importance: Oral tamoxifen citrate benefits women with ductal carcinoma in situ (DCIS), but concern about toxic effects has limited acceptance. Previous pilot studies have suggested transdermal 4-hydroxytamoxifen gel has equivalent antiproliferative efficacy to oral tamoxifen, with low systemic exposure. Objective: To demonstrate that 4-hydroxytamoxifen gel applied to the breast skin is noninferior to oral tamoxifen in its antiproliferative effect in DCIS lesions. Design, Setting, and Participants: This randomized, double-blind, phase 2 preoperative window trial was performed at multicenter breast surgery referral practices from May 31, 2017, to January 27, 2021. Among 408 women with estrogen receptor-positive DCIS who were approached, 120 consented and 100 initiated study treatment. The most common reasons for nonparticipation were surgical delay, disinterest in research, and concerns about toxic effects. Data were analyzed from January 26, 2021, to October 5, 2022. Intervention: Random assignment to oral tamoxifen citrate, 20 mg/d, and gel placebo or 4-hydroxytamoxifen gel, 2 mg/d per breast, and oral placebo, for 4 to 10 weeks, followed by DCIS resection. Main Outcomes and Measures: The primary end point was absolute change in DCIS Ki-67 labeling index (Ki67-LI). Secondary end points included 12-gene DCIS Score, breast tissue tamoxifen metabolite concentrations, tamoxifen-responsive plasma protein levels, and patient-reported symptoms. Noninferiority of Ki67-LI reduction by 4-hydroxytamoxifen gel was tested using analysis of covariance; within- and between-arm comparisons were performed with paired t tests for mean values or the Wilcoxon rank sum test for medians. Results: Of 90 participants completing treatment (mean [SD] age, 55 [11] years; 8 [8.9%] Asian, 16 [17.8%] Black, 8 [8.9%] Latina, and 53 [58.9%] White), 15 lacked residual DCIS in the surgical sample, leaving 75 evaluable for the primary end point analysis (40 in the oral tamoxifen group and 35 in the 4-hydroxytamoxifen gel group). Posttreatment Ki67-LI was 3.3% higher (80% CI, 2.1%-4.6%) in the 4-hydroxytamoxifen gel group compared with the oral tamoxifen group, exceeding the noninferiority margin (2.6%). The DCIS Score decreased more with oral tamoxifen treatment (-16 [95% CI, -22 to -9.4]) than with 4-hydroxytamoxifen gel (-1.8 [95% CI, -5.8 to 2.3]). The median 4-hydroxytamoxifen concentrations deep in the breast were nonsignificantly higher in the oral tamoxifen group (5.7 [IQR, 4.0-7.9] vs 3.8 [IQR, 1.3-7.9] ng/g), whereas endoxifen was abundant in the oral tamoxifen group and minimal in the 4-hydroxytamoxifen gel group (median, 13.0 [IQR, 8.9-20.6] vs 0.3 [IQR, 0-0.3] ng/g; P < .001). Oral tamoxifen caused expected adverse changes in plasma protein levels and vasomotor symptoms, with minimal changes in the transdermal group. Conclusions and Relevance: In this randomized clinical trial, antiproliferative noninferiority of 4-hydroxytamoxifen gel to oral tamoxifen was not confirmed, potentially owing to endoxifen exposure differences. New transdermal approaches must deliver higher drug quantities and/or include the most potent metabolites. Trial Registration: ClinicalTrials.gov Identifier: NCT02993159.

Phase II Trial of Nelipepimut-S Peptide Vaccine in Women with Ductal Carcinoma In Situ.

NeuVax is a vaccine comprised of the HER2-derived MHC class I peptide E75 (nelipepimut-S, NPS) combined with GM-CSF. We completed a randomized trial of preoperative vaccination with NeuVax versus GM-CSF alone in patients with ductal carcinoma in situ (DCIS). The primary objective was to evaluate for NPS-specific cytotoxic T lymphocyte (CTL) responses. Patients with human leukocyte antigen (HLA)-A2-positive DCIS were enrolled and randomized 2:1 to NeuVax versus GM-CSF alone and received two inoculations prior to surgery. The number of NPS-specific CTL was measured pre-vaccination, at surgery, and 1 and 3 to 6 months post-operation by dextramer assay. Differences in CTL responses between groups and between pre-vaccination and 1-month post-operation were analyzed using a two-sample t test or Wilcoxon rank sum test. The incidence and severity of adverse events were compared between groups. Overall, 45 patients were registered; 20 patients were HLA-A2 negative, 7 declined participation, 1 withdrew, and 4 failed screening for other reasons. The remaining 13 were randomized to NeuVax (n = 9) or GM-CSF alone (n = 4). Vaccination was well-tolerated with similar treatment-related toxicity between groups with the majority (>89%) of adverse events being grade 1. The percentage of NPS-specific CTLs increased in both arms between baseline (pre-vaccination) and 1-month post-operation. The increase was numerically greater in the NPS+GM-CSF arm, but the difference was not statistically significant. NPS+GM-CSF is safe and well-tolerated when given preoperatively to patients with DCIS. In patients with HLA-A2-positive DCIS, two inoculations with NPS+GM-CSF can induce in vivo immunity and a continued antigen-specific T-cell response 1-month postsurgery. PREVENTION RELEVANCE: This trial showed that vaccination of patients with HLA-A2-positive DCIS with NeuVax in the preoperative setting can induce a sustained antigen-specific T-cell response. This provides proof of principle that vaccination in the preoperative or adjuvant setting may stimulate an adaptive immune response that could potentially prevent disease recurrence.

Efficacy of Alternative Dose Regimens of Exemestane in Postmenopausal Women With Stage 0 to II Estrogen Receptor-Positive Breast Cancer: A Randomized Clinical Trial.

Importance: Successful therapeutic cancer prevention requires definition of the minimal effective dose. Aromatase inhibitors decrease breast cancer incidence in high-risk women, but use in prevention and compliance in adjuvant settings are hampered by adverse events. Objective: To compare the noninferiority percentage change of estradiol in postmenopausal women with estrogen receptor-positive breast cancer given exemestane, 25 mg, 3 times weekly or once weekly vs a standard daily dose with a noninferiority margin of -6%. Design, Setting, and Participants: This multicenter, presurgical, double-blind phase 2b randomized clinical trial evaluated 2 alternative dosing schedules of exemestane. Postmenopausal women with estrogen receptor-positive breast cancer who were candidates for breast surgery were screened from February 1, 2017, to August 31, 2019. Blood samples were collected at baseline and final visit; tissue biomarker changes were assessed from diagnostic biopsy and surgical specimen. Biomarkers were measured in different laboratories between April 2020 and December 2021. Interventions: Exemestane, 25 mg, once daily, 3 times weekly, or once weekly for 4 to 6 weeks before surgery. Main Outcomes and Measures: Serum estradiol concentrations were measured by solid-phase extraction followed by liquid chromatography-tandem mass spectrometry detection. Toxic effects were evaluated using the National Cancer Institute terminology criteria, and Ki-67 was assessed by immunohistochemistry. Results: A total of 180 women were randomized into 1 of the 3 arms; median (IQR) age was 66 (60-71) years, 63 (60-69) years, and 65 (61-70) years in the once-daily, 3-times-weekly, and once-weekly arms, respectively. In the intention-to-treat population (n = 171), the least square mean percentage change of serum estradiol was -89%, -85%, and -60% for exemestane once daily (n = 55), 3 times weekly (n = 56), and once weekly (n = 60), respectively. The difference in estradiol percentage change between the once-daily and 3-times-weekly arms was -3.6% (P for noninferiority = .37), whereas in compliant participants (n = 153), it was 2.0% (97.5% lower confidence limit, -5.6%; P for noninferiority = .02). Among secondary end points, Ki-67 and progesterone receptor were reduced in all arms, with median absolute percentage changes of -7.5%, -5.0%, and -4.0% for Ki-67 in the once-daily, 3-times-weekly, and once-weekly arms, respectively (once daily vs 3 times weekly, P = .31; once daily vs once weekly, P = .06), and -17.0%, -9.0%, and -7.0% for progesterone receptor, respectively. Sex hormone-binding globulin and high-density lipoprotein cholesterol had a better profile among participants in the 3-times-weekly arm compared with once-daily arm. Adverse events were similar in all arms. Conclusions and Relevance: In this randomized clinical trial, exemestane, 25 mg, given 3 times weekly in compliant patients was noninferior to the once-daily dosage in decreasing serum estradiol. This new schedule should be further studied in prevention studies and in women who do not tolerate the daily dose in the adjuvant setting. Trial Registration: ClinicalTrials.gov Identifier: NCT02598557; EudraCT: 2015-005063-16.

Phase I Dose Escalation Study of Topical Bexarotene in Women at High Risk for Breast Cancer.

PREVENTION RELEVANCE: Bexarotene is a rexinoid that has been shown to prevent mammary tumors in mouse models but oral dosing has toxicities. This phase I study evaluates topical bexarotene, as a potential chemoprevention agent, for safety and toxicity in high-risk women for breast cancer.

Breast cancer risk for women with diabetes and the impact of metformin: A meta-analysis.

BACKGROUND: Diabetes mellitus has been associated with increased breast cancer (BC) risk; however, the magnitude of this effect is uncertain. This study focused on BC risk for women with type 2 diabetes mellitus (T2DM). METHODS: Two separate meta-analyses were conducted (1) to estimate the relative risk (RR) of BC for women with T2DM and (2) to evaluate the risk of BC for women with T2DM associated with the use of metformin, a common diabetes treatment. In addition, subgroup analyses adjusting for obesity as measured by body mass index (BMI) and menopausal status were also performed. Studies were identified via PubMed/Scopus database and manual search through April 2021. RESULTS: A total of 30 and 15 studies were included in the first and second meta-analyses, respectively. The summary RR of BC for women with T2DM was 1.15 (95% confidence interval [CI], 1.09-1.21). The subgroup analyses adjusting BMI and adjusting BMI and menopause resulted in a summary RR of 1.22 (95% CI, 1.15-1.30) and 1.20 (95% CI, 1.05-1.36), respectively. For women with T2DM, the summary RR of BC was 0.82 (95% CI, 0.60-1.12) for metformin users compared with nonmetformin users. CONCLUSIONS: Women with T2DM were more likely to be diagnosed with BC and this association was strengthened by adjusting for BMI and menopausal status. No statistically significant reduction of BC risk was observed among metformin users. IMPACT: These two meta-analyses can inform decision-making for women with type 2 diabetes regarding their use of metformin and the use of screening mammography for early detection of breast cancer.

The 2018 World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) score and diabetes risk in the Diabetes Prevention Program Outcomes Study (DPPOS).

BACKGROUND: The 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) 3rd expert report highlights up-to-date Cancer Prevention Recommendations that may reduce burdens of many chronic diseases, including diabetes. This study examined if following a lifestyle that aligns with the recommendations - assessed via the 2018 WCRF/AICR Score - was associated with lower risk of type 2 diabetes in high-risk adults participating in the Diabetes Prevention Program Outcomes Study (DPPOS). METHODS: The Diabetes Prevention Program (DPP) randomized adults at high risk for diabetes to receive a lifestyle intervention (ILS), metformin (MET) or a placebo (PLB) (mean: 3.2 years), with additional follow-up in DPPOS for 11 years (mean: 15 years total). 2018 WCRF/AICR Scores included seven components: body weight, physical activity, plant-based foods, fast foods, red and processed meat, sugar-sweetened beverages, and alcohol; the optional breastfeeding component was excluded. Scores ranged 0-7 points (with greater scores indicating greater alignment with the recommendations) and were estimated at years 0, 1, 5, 6, 9, and 15 (N=3,147). Fasting glucose and HbA1c were measured every six months and oral glucose tolerance tests were performed annually. Adjusted Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs) were used to examine the association of both Score changes from years 0-1 and time-dependent Score changes on diabetes risk through DPP and year 15. RESULTS: Scores improved within all groups over 15 years (p<0.001); ILS Scores improved more than MET or PLB Scores after 1 year (p<0.001). For every 1-unit improvement from years 0-1, there was a 31% and 15% lower diabetes risk in ILS (95% CI: 0.56-0.84) and PLB (95% CI: 0.72-0.97) through DPP, and no significant association in MET. Associations were greatest among American Indian participants, followed by non-Hispanic White and Hispanic participants. Score changes from years 0-1 and time-dependent Score changes in ILS and PLB remained associated with lower risk through year 15. CONCLUSIONS: Score improvements were associated with long-term, lower diabetes risk among high-risk adults randomized to ILS and PLB, but not MET. Future research should explore impact of the Score on cancer risk. TRIAL REGISTRATION: Diabetes Prevention Program: NCT00004992 ; Diabetes Prevention Program Outcomes Study: NCT00038727.

Lessons from the Failure to Complete a Trial of Denosumab in Women With a Pathogenic BRCA1/2 Variant Scheduling Risk-Reducing Salpingo-Oophorectomy.

Female carriers of pathogenic/likely pathogenic (P/LP) BRCA1/2 variants are at increased risk of developing breast and ovarian cancer. Currently, the only effective strategy for ovarian cancer risk reduction is risk-reducing bilateral salpingo-oophorectomy (RR-BSO), which carries adverse effects related to early menopause. There is ongoing investigation of inhibition of the RANK ligand (RANKL) with denosumab as a means of chemoprevention for breast cancer in carriers of BRCA1 P/LP variants. Through the NCI Division of Cancer Prevention (DCP) Early Phase Clinical Trials Prevention Consortia, a presurgical pilot study of denosumab was developed in premenopausal carriers of P/LP BRCA1/2 variants scheduled for RR-BSO with the goal of collecting valuable data on the biologic effects of denosumab on gynecologic tissue. The study was terminated early due to the inability to accrue participants. Challenges which impacted the conduct of this study included a study design with highly selective eligibility criteria and requirements and the COVID-19 pandemic. It is critical to reflect on these issues to enhance the successful completion of future prevention studies in individuals with hereditary cancer syndromes.

Time-Restricted Feeding Studies and Possible Human Benefit.

Metabolic syndrome consists of a constellation of clinical factors associated with an increased risk of cardiovascular disease, type 2 diabetes, and cancer. Preclinical studies demonstrate that restricting the time during a 24-hour period when an obese animal eats (time-restricted feeding) leads to metabolic benefits. These benefits, which may or may not be associated with weight loss, often lead to improvements in glucose tolerance and insulin sensitivity. Studies seeking to determine whether similar benefits result when humans restrict daily eating time (time-restricted eating) are less mature and less consistent in their findings. In this commentary, we outline some of the exciting preclinical findings, the challenges that preliminary studies in humans present, and efforts of the US National Institutes of Health and specifically the National Cancer Institute to address the role of time-restricted eating in cancer.

Report from an NCI Roundtable: Cancer Prevention in Primary Care.

The Division of Cancer Prevention in the NCI sponsored a Roundtable with primary care providers (PCP) to determine barriers for integrating cancer prevention within primary care and discuss potential opportunities to overcome these barriers. The goals were to: (i) assess the cancer risk assessment tools available to PCPs; (ii) gather information on use of cancer prevention resources; and (iii) understand the needs of PCPs to facilitate the implementation of cancer prevention interventions beyond routine screening and interventions. The Roundtable discussion focused on challenges and potential research opportunities related to: (i) cancer risk assessment and management of high-risk individuals; (ii) cancer prevention interventions for risk reduction; (iii) electronic health records/electronic medical records; and (iv) patient engagement and information dissemination. Time constraints and inconsistent/evolving clinical guidelines are major barriers to effective implementation of cancer prevention within primary care. Social determinants of health are important factors that influence patients' adoption of recommended preventive interventions. Research is needed to determine the best means for implementation of cancer prevention across various communities and clinical settings. Additional studies are needed to develop tools that can help providers collect clinical data that can enable them to assess patients' cancer risk and implement appropriate preventive interventions.

Redefining precision cancer prevention to promote health equity.

Precision cancer prevention as it is currently envisioned is a targeted, molecular-based approach to intercept carcinogenesis before cancer develops or before it becomes untreatable. Unfortunately, due to systemic biases, current precision cancer prevention interventions might not be effective in all populations, especially in minoritized communities. In addition, not all cancer risk is attributable to genetic or even biological factors, but includes social determinants of health (SDH). Here, we propose a broader framework for precision cancer prevention, anchored in optimizing the benefits to harms for all people. We propose that precision cancer prevention considers not only what is being delivered, but also for whom, where, and how, with a goal of achieving cancer prevention health equity.

Assessment of and Interventions for Women at High Risk for Breast or Ovarian Cancer: A Survey of Primary Care Physicians.

As clinical guidelines for cancer prevention refer individuals to primary care physicians (PCP) for risk assessment and clinical management, PCPs may be expected to play an increasing role in cancer prevention. It is crucial that PCPs are adequately supported to assess an individual's cancer risk and make appropriate recommendations. The objective of this study is to assess use, familiarity, attitude, and behaviors of PCPs regarding breast and ovarian cancer risk and prevention, to better understand the factors that influence their prescribing behaviors. We conducted a cross-sectional, web-based survey of PCPs in the United States, recruited from an opt-in healthcare provider panel. Invitations were sent in batches until the target sample size of 750 respondents (250 each for obstetrics/gynecology, internal medicine, and family medicine) was met. Self-reported use of breast/ovarian cancer risk assessments was low (34.7%-59.2%) compared with discussion of cancer family history (96.9%), breast exams (87.1%), and mammograms (92.8%). Although most respondents (48.0%-66.8%) were familiar with cancer prevention interventions, respondents who reported to be less familiar were more likely to report cautious attitudes. When presented with hypothetical cases depicting patients at different breast/ovarian cancer risks, up to 34.0% of respondents did not select any of the clinically recommended course(s) of action. This survey suggests that PCP use of breast/ovarian cancer risk assessment tools and ability to translate the perceived risks to clinical actions is variable. Improving implementation of cancer risk assessment and clinical management guidelines within primary care may be necessary to improve the appropriate prescribing of cancer prevention interventions.Prevention Relevance: Primary care physicians are becoming more involved in cancer prevention management, so it is important that cancer risk assessment and medical society guideline recommendations for cancer prevention are better integrated into primary care to improve appropriate prescribing of cancer prevention interventions and help reduce cancer risk.

Modeling the natural history of ductal carcinoma in situ based on population data.

BACKGROUND: The incidence of ductal carcinoma in situ (DCIS) has increased substantially since the introduction of mammography screening. Nevertheless, little is known about the natural history of preclinical DCIS in the absence of biopsy or complete excision. METHODS: Two well-established population models evaluated six possible DCIS natural history submodels. The submodels assumed 30%, 50%, or 80% of breast lesions progress from undetectable DCIS to preclinical screen-detectable DCIS; each model additionally allowed or prohibited DCIS regression. Preclinical screen-detectable DCIS could also progress to clinical DCIS or invasive breast cancer (IBC). Applying US population screening dissemination patterns, the models projected age-specific DCIS and IBC incidence that were compared to Surveillance, Epidemiology, and End Results data. Models estimated mean sojourn time (MST) in the preclinical screen-detectable DCIS state, overdiagnosis, and the risk of progression from preclinical screen-detectable DCIS. RESULTS: Without biopsy and surgical excision, the majority of DCIS (64-100%) in the preclinical screen-detectable state progressed to IBC in submodels assuming no DCIS regression (36-100% in submodels allowing for DCIS regression). DCIS overdiagnosis differed substantially between models and submodels, 3.1-65.8%. IBC overdiagnosis ranged 1.3-2.4%. Submodels assuming DCIS regression resulted in a higher DCIS overdiagnosis than submodels without DCIS regression. MST for progressive DCIS varied between 0.2 and 2.5 years. CONCLUSIONS: Our findings suggest that the majority of screen-detectable but unbiopsied preclinical DCIS lesions progress to IBC and that the MST is relatively short. Nevertheless, due to the heterogeneity of DCIS, more research is needed to understand the progression of DCIS by grades and molecular subtypes.

Breast cancer risk prediction models and subsequent tumor characteristics.

BACKGROUND: A previous study found evidence that a breast cancer risk prediction model preferentially selected for less aggressive tumors in Swedish women. In the US, the Gail model has been widely used and was used for entry criteria in two large breast cancer prevention trials. We assessed if higher risk levels from the Gail model were associated with less aggressive tumor characteristics and if risk levels were predictive of mortality and survival. METHODS: We used questionnaire data from women in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial to calculate Gail risk levels (low < 1.66%; moderate 1.66-2.99%; high ≥ 3.00%). Women aged 55-74 were enrolled between 1993 and 2001 and had detailed information on breast cancer incidence and tumors collected. We calculated breast cancer incidence and mortality rates among all women by risk levels and examined breast cancer survival and tumor characteristics among women diagnosed with breast cancer. We used Chi-squared tests and multivariable logistic regression to assess the association between risk levels and tumor characteristics. RESULTS: The study population for this analysis included 45,402 women with 1908 cases of breast cancer. Women at high risk were associated with higher risk of breast cancer mortality compared to women with low risk [rate ratio (RR) = 2.29 95% confidence interval (CI) 1.37-3.84)]. Higher risk levels were associated with lobular-type tumors [moderate: adjusted odds ratio (aOR) = 1.57 95% CI 1.13-2.17; high: aOR = 1.78 95% CI 1.25-2.54] but were not associated with any other tumor characteristics or breast cancer survival. CONCLUSIONS: We did not find evidence that higher risk levels from the Gail model are predictive of less aggressive breast cancer tumors.

Cancer Prevention in Primary Care: Perception of Importance, Recognition of Risk Factors and Prescribing Behaviors.

PURPOSE: Acceptability and uptake of cancer preventive interventions is associated with physician recommendation, which is dependent on physician familiarity with available preventive options. The goal of this study is to evaluate cancer prevention perceptions, understanding of breast and ovarian cancer risk factors, and prescribing behaviors of primary care physicians. METHODS: We conducted cross-sectional. Web-based survey of 750 primary care physicians (250 each for obstetrics/gynecology, internal medicine, and family medicine) in the United States. Survey respondents were recruited from an opt-in health care provider panel. RESULTS: Perception of importance and the practice of recommending general and cancer-specific preventive screenings and interventions significantly differed by provider type. These perceptions and behaviors reflected the demographics of the population that the primary care physicians see within their respective practices. The majority of respondents recognized genetic/hereditary risk factors for breast or ovarian cancer, while epidemiologic or clinical risk factors were less frequently recognized. Prescribing behaviors were related to familiarity with the interventions, with physicians indicating that they more frequently reinforced a specialist's recommendation rather than prescribed a preventive intervention. CONCLUSIONS: Cancer prevention perceptions, recognition of cancer risk factors, and prescribing behaviors differ among practice types and were related to familiarity with preventive options. Cancer prevention education and risk assessment resources should be more widely available to primary care physicians.

Use of Biomarker Modulation in Normal Mammary Epithelium as a Correlate for Efficacy of Chemopreventive Agents Against Chemically Induced Cancers.

In both estrogen receptor/progesterone receptor-positive (ER+/PR+) human breast cancer and in ER+/PR+ cancers in the methylnitrosourea (MNU)-induced rat model, short-term modulation of proliferation in early cancers predicts preventive/therapeutic efficacy. We determined the effects of known effective/ineffective chemopreventive agents on proliferative index (PI) in both rat mammary epithelium and small cancers. Female Sprague-Dawley rats were treated with MNU at 50 days of age. Five days later, the rats were treated with the individual compounds for a period of 14 days. At that time, normal mammary tissue from the inguinal gland area was surgically removed. After removal, the rats remained on the agents for an additional 5 months. This cancer prevention study confirmed our prior results of striking efficacy with tamoxifen, vorozole, Targretin, and gefitinib, and no efficacy with metformin, naproxen, and Lipitor. Employing a separate group of rats, the effects of short-term (7 days) drug exposure on small palpable cancers were examined. The PI in both small mammary cancers and in normal epithelium from control rats was >12%. In agreement with the cancer multiplicity data, tamoxifen, vorozole, gefitinib, and Targretin all strongly inhibited proliferation (>65%; P < 0.025) in the normal mammary epithelium. The ineffective agents metformin, naproxen, and Lipitor minimally affected PI. In the small cancers, tamoxifen, vorozole, and Targretin all reduced the PI, while metformin and Lipitor failed to do so. Thus, short-term changes in the PI in either normal mammary epithelium or small cancers correlated with long-term preventive efficacy in the MNU-induced rat model.

Breast Cancer Characteristics and Survival among Users versus Nonusers of Raloxifene.

Raloxifene reduces breast cancer incidence. However, it is unclear whether it also reduces mortality from breast cancer. For raloxifene to reduce incidence but not mortality, breast cancer survival would have to be worse for raloxifene users than nonusers. Surveillance Epidemiology and End Results-Medicare was used to identify women with invasive breast cancer diagnosed from 2007 to 2015 at ages 65-89 who had prior Medicare Part D (prescription drug) enrollment; breast cancer characteristics and survival were assessed among raloxifene regular users (≥180 days in past year) versus nonusers. Logistic regression was used to assess cancer characteristics. Two methods utilizing proportional hazards models were employed to assess breast cancer-specific survival. In method 1, survival was assessed adjusting for demographics, mammography use, and chronic conditions in the subset with Medicare fee-for-service enrollment. In method 2, predicted survival as a function of breast cancer characteristics was modeled in nonusers and the model applied to users to predict survival. A total of 116,317 raloxifene nonusers and 1,223 regular users were identified. Users were significantly more likely to have hormone receptor (HR)-negative cancers, but less likely to have T2+, N1+, and metastatic disease. There were 10,869 and 101 breast cancer-related deaths in nonusers and regular users, respectively. The HR (users vs. nonusers) for breast cancer-specific survival in method 1 was 0.94 (95% confidence interval, 0.73-1.22). In method 2, predicted survival was higher in users than nonusers (8-year survival 84.9% vs. 83.4%). Breast cancer-specific survival in raloxifene users was not worse than in nonusers, providing indirect evidence that raloxifene reduces breast cancer-related mortality.

Metabolite Profiles of Incident Diabetes and Heterogeneity of Treatment Effect in the Diabetes Prevention Program.

Novel biomarkers of type 2 diabetes (T2D) and response to preventative treatment in individuals with similar clinical risk may highlight metabolic pathways that are important in disease development. We profiled 331 metabolites in 2,015 baseline plasma samples from the Diabetes Prevention Program (DPP). Cox models were used to determine associations between metabolites and incident T2D, as well as whether associations differed by treatment group (i.e., lifestyle [ILS], metformin [MET], or placebo [PLA]), over an average of 3.2 years of follow-up. We found 69 metabolites associated with incident T2D regardless of treatment randomization. In particular, cytosine was novel and associated with the lowest risk. In an exploratory analysis, 35 baseline metabolite associations with incident T2D differed across the treatment groups. Stratification by baseline levels of several of these metabolites, including specific phospholipids and AMP, modified the effect that ILS or MET had on diabetes development. Our findings highlight novel markers of diabetes risk and preventative treatment effect in individuals who are clinically at high risk and motivate further studies to validate these interactions.

A Randomized, Placebo-Controlled, Double-Blind, Dose Escalation, Single Dose, and Steady-State Pharmacokinetic Study of 9cUAB30 in Healthy Volunteers.

9cUAB30 is a synthetic analogue of 9-cis retinoic acid with chemoprevention activity in cell lines and animal models. The purpose of this phase I placebo-controlled, double-blinded, dose escalation study of 9cUAB30 was to evaluate its safety, pharmacokinetics, and determine a dose for future phase II studies. Participants received a single dose of study drug (placebo or 9cUAB30) on day 1 followed by a 6-day drug-free period and then 28 days of continuous daily dosing starting on day 8. Fifty-three healthy volunteers were enrolled into five dose cohorts (20, 40, 80, 160, and 240 mg). Participants were randomized within each dose level to receive either 9cUAB30 (n = 8) or placebo (n = 2). 9cUAB30 was well tolerated, with no dose limiting toxicities reported and no evidence of persistent elevations in serum triglycerides or cholesterol. Treatment-emergent grade 3 hypertension occurred in 1 of 8 participants at the 20 mg dose level and in 2 of 8 at the 240 mg dose level, all considered unlikely related to study agent; no other grade 3 adverse events were observed. The AUC increased, as expected, between day 1 (single dose) and day 36 (steady state). Pharmacokinetics were linear in dose escalation through 160 mg. 9cUAB30 administered by daily oral dosing has a favorable safety and pharmacokinetic profile. On the basis of the observed safety profile and lack of linearity in pharmacokinetics at doses greater than 160 mg, the recommended phase II dose with the current formulation is 160 mg once daily.