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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.

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.

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.

Supplementary Table S5: HER2 expression in biopsy and resection specimens

Supplementary Fig. S1: Nelipepimut-S (NPS)-specific cytotoxic T lymphocyte (CTL) responses in patients receiving NeuVax with corresponding HER2 changes

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.

Supplemental Table

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

Effect of agents on cancer incidence and time to first tumor appearance

Agents that can reduce the incidence of hormone receptor negative breast cancer are currently lacking. Rexinoids such as bexarotene significantly reduced mammary tumor development in preclinical mouse models. Oral bexarotene in BRCA mutation carriers significantly decreased cyclin D1 in breast cells, suggesting biological activity on breast tissue. This study evaluated topical bexarotene 1% gel applied to one unaffected breast in women at high risk for breast cancer for 4 weeks to assess safety and toxicity. Secondary objectives included assessment of bexarotene concentrations in the plasma and breast tissue. In the dose escalation phase, women were assigned to one of three different dose levels: 10 mg (1 mL) every other day, 10 mg (1 mL) daily, 20 mg (2 mL) daily. Dose-limiting toxicity (DLT) was defined as a grade 2 skin adverse event for at least 6 days or any grade 3 or 4 adverse event related to study drug. A total of 14 women were enrolled with 10 participants at the every other day dose level and 4 participants at daily dosing. Two skin DLTs were experienced at daily dosing and therefore further enrollment was discontinued per protocol. An additional 10 participants were enrolled at the MTD as part of the dose expansion phase. These individuals tolerated the treatment with minimal adverse events. Maculopapular rash at the treatment site was the most common adverse event related to study drug and resolved within a few days of discontinuation. Bexarotene was detectable in breast tissue at the 10 mg daily every other day dose.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.

Supplementary Table 1: All Adverse Events related to topical 1% bexarotene gel.

Table showing the studies that were excluded from analysis and reasons why.

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.

Supplementary Results for Table 5 and Figure 1.

Epidemiological studies of metformin and cancer risk with BMI adjustment

The purpose of this study was to assess the feasibility of using the selective estrogen receptor modulator (SERM) acolbifene as a breast cancer prevention agent in premenopausal women. To do so, we assessed change in proliferation in benign breast tissue sampled by random periareolar fine-needle aspiration (RPFNA) as a primary endpoint, along with changes in other risk biomarkers and objective and subjective side effects as secondary endpoints. Twenty-five women with cytologic hyperplasia ± atypia and ≥2% of breast epithelial cells staining positive for Ki-67, received 20 mg acolbifene daily for 6–8 months, and then had benign breast tissue and blood risk biomarkers reassessed. Ki-67 decreased from a median of 4.6% [interquartile range (IQR), 3.1%–8.5%] at baseline to 1.4% (IQR, 0.6%–3.5%) after acolbifene (P < 0.001; Wilcoxon signed-rank test), despite increases in bioavailable estradiol. There were also significant decreases in expression (RT-qPCR) of estrogen-inducible genes that code for pS2, ERα, and progesterone receptor (P ≤ 0.026). There was no significant change in serum IGF1, IGFBP3, IGF1:IGFBP3 ratio, or mammographic breast density. Subjective side effects were minimal with no significant increase in hot flashes, muscle cramps, arthralgias, or fatigue. Objective measures showed a clinically insignificant decrease in lumbar spine bone density (DEXA) and an increase in ovarian cysts but no change in endometrial thickness (sonography). In summary, acolbifene was associated with favorable changes in benign breast epithelial cell proliferation and estrogen-inducible gene expression but minimal side effects, suggesting a phase IIB placebo-controlled trial evaluating it further for breast cancer prevention. Cancer Prev Res; 8(12); 1146–55. ©2015 AACR.

Clinicopathologic features stratified by treatment arm (RNA-seq analysis population).

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.

Previous meta-analyses have shown that the antidiabetic agent metformin is associated with reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models and recent epidemiologic studies. We performed a meta-analysis with a focus on confounders and biases, including body mass index (BMI), study type, and time-related biases. We identified 71 articles published between January 1, 1966, and May 31, 2013, through Pubmed, ISI Web of Science (Science Citation Index Expanded), Embase, and the Cochrane library that were related to metformin and cancer incidence or mortality. Study characteristics and outcomes were abstracted for each study that met inclusion criteria. We included estimates from 47 independent studies and 65,540 cancer cases in patients with diabetes. Overall cancer incidence was reduced by 31% [summary relative risk (SRR), 0.69; 95% confidence interval (CI), 0.52–0.90], although between-study heterogeneity was considerable (I2 = 88%). Cancer mortality was reduced by 34% (SRR, 0.66; 95% CI, 0.54–0.81; I2 = 21%). BMI-adjusted studies and studies without time-related biases also showed significant reduction in cancer incidence (SRR, 0.82; 95% CI, 0.70–0.96 with I2 = 76% and SRR, 0.90; 95% CI, 0.89–0.91 with I2 = 56%, respectively), albeit with lesser magnitude (18% and 10% reduction, respectively). However, studies of cancer mortality and individual organ sites did not consistently show significant reductions across all types of analyses. Although these associations may not be causal, our results show that metformin may reduce cancer incidence and mortality in patients with diabetes However, the reduction seems to be of modest magnitude and not affecting all populations equally. Clinical trials are needed to determine if these observations apply to nondiabetic populations and to specific organ sites. Cancer Prev Res; 7(9); 867–85. ©2014 AACR.

Summary of Assessment of Ki-67 Staining Problems. Supplementary Table 1: Summary of Values, Changes, and Statistical Results for Ki-67 Assessments. Supplementary Table 2: Summary of Analyses of Different Subsets of Subjects.

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.

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).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.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.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.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.

ImportanceSuccessful 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.ObjectiveTo 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 ParticipantsThis 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.InterventionsExemestane, 25 mg, once daily, 3 times weekly, or once weekly for 4 to 6 weeks before surgery.Main Outcomes and MeasuresSerum 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.ResultsA 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT02598557; EudraCT: 2015-005063-16

Background: Adjuvant oral tamoxifen (TAM) benefits women with DCIS, but toxicity concerns have limited its acceptance. Transdermal therapy with 4-hydroxy tamoxifen (4-OHT) gel applied to the breast skin is a possible solution. Previous pilot data suggest equivalent anti-proliferative efficacy of TAM and 4-OHT gel, but minimal systemic exposure with transdermal therapy. We report a prospective double blinded randomized phase 2 trial comparing TAM to 4-OHT gel in women with DCIS. Methods: 107 women with estrogen receptor positive (≥10%) DCIS were randomized to TAM (20 mg/day + placebo gel) or 4-OHT gel (2mg 4-OHT gel/breast, bilaterally + oral placebo), for 4-10 weeks prior to surgery. The primary endpoint was reduction in DCIS Ki67 labeling index (LI). Secondary endpoints included the 12-gene DCIS Score assay (Exact Sciences), breast tissue and plasma concentrations of 4-OHT and endoxifen, TAM-responsive circulating proteins, and patient reported symptoms (Breast Eight Symptom Scale). We estimated that 80 evaluable participants would provide 80.5% power to establish non-inferiority of 4-OHT, defined as relative Ki67-LI decline >35% and absolute decline >2.6%, with one-sided 𝛼=0.10. Non-inferiority of 4-OHT gel for Ki67-LI reduction was tested using an ANCOVA model. Statistical comparisons within- and between-arms were calculated with paired t-test and Welch Two Sample t-test, respectively. Results: 72 of 87 women adhered to the protocol, and were evaluable for the primary endpoint (39 TAM and 33 4-OHT gel). Mean treatment duration was 47 days for TAM and 44 days for 4-OHT gel (p=0.2). The median absolute decline in Ki67 labeling index was significant in the oral TAM (-3.7%, p< 0.001) but not in 4-OHT gel arm (-1.3%, p=0.2) (p=0.002). Ki67 results following menopausal stratification also favored the TAM arm: (-1.3%; p=0.06 in 37 premenopausal women and -3.7%; p=0.02 in 35 postmenopausal women). Similarly, DCIS score showed a significantly greater reduction in the TAM (-14, p< 0.001) but not in the 4-OHT gel arm (-4, p=0.1). Tissue 4-OHT concentrations were non-significantly higher in the TAM arm and were similar between superficial and deep sampling locations (superficial 6.1 and 4.2 ng/g for TAM and 4-OHT gel, respectively, p= 0.55; deep 5.7 and 3.8 ng/g, respectively, p= 0.06), whereas plasma 4-OHT concentration was markedly lower in the gel group (2 ng/mL and 0.24 ng/mL for TAM and 4-OHT gel, respectively, P < 0.001). Endoxifen was abundant in plasma (11 ng/mL) and deep tissue (13 ng/g) of the TAM arm, but present in trace amounts in the 4-OHT gel arm (undetectable in plasma and 0.31 ng/g in tissue; p < 0.001). Circulating TAM responsive markers (insulin like growth factor 1, sex hormone binding globulin, von Willebrand factor, and protein S total) and vasomotor symptoms were significantly and unfavorably modulated by TAM, but not by 4-OHT gel therapy. Conclusions: The non-inferiority of transdermal 4-OHT gel to Tam in terms of anti-proliferative effect in DCIS lesions was not demonstrated at the doses used for this study. DCIS Score analysis gave similar results. Tissue 4-OHT concentration in 4-OHT gel and Tam-treated subjects was roughly similar. However, endoxifen exposure was higher with oral TAM therapy and may partially explain the observed differences in major endpoints. In future studies, use of higher 4-OHT gel doses, longer duration of treatment, or different formulation may overcome these. Citation Format: Oukseub Lee, Xinlei Mi, Yanfei Xu, Luis Blanco, Azza M. Akasha, Kelly Benante, Shanshan Zhang, Carissa LaBoy, Thomas Helland, Melissa Pilewskie, Amy Degnim, Zahraa Al-Hilli, Amanda L. Amin, E Shelley Hwang, Joseph M. Guenther, Simon Steinar Hustad, Demirkan B. Gursel, Masha Kocherginsky, Gunnar Mellgren, Eileen Dimond, Marjorie Perloff, Brandy M. Heckman-Stoddard, Seema Khan. PD15-12 A pre-surgical window trial of oral tamoxifen versus transdermal 4-hydroxytamoxifen gel in women with estrogen receptor positive duct carcinoma in situ (DCIS) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD15-12.

Background: HER2, IGFBP-2, and IGF-IR are proteins that are overexpressed in breast cancer. These three proteins, when used as immunogens, provide broad antigenic coverage to all molecular breast cancer subtypes. The proteins are also up-regulated in pre-invasive and high-risk breast lesions which are associated with progression to invasive cancer. Therefore, generating protective immunity against these antigens could have the result of preventing cancer development in high risk patients. We identified epitopes derived from these proteins, termed Th1 selective epitopes, that specifically stimulated T-helper 1 immune responses in humans and mice. The tri-antigen vaccine was effective in preventing the development of breast cancer in a transgenic mouse model of neu-expressing mammary cancer. We conducted a dose finding study of a plasmid-based vaccine encoding three extended Th1 selective epitopes derived from these antigens in breast cancer patients. Methods: Patients with non-metastatic, node positive, HER2 negative breast cancer that are in remission and defined as no evidence of disease were enrolled sequentially to one of 3 dose arms: 150, 300, and 600 mcg of the tri-antigen vaccine plasmid with 10 evaluable patients per arm (NCT02780401). Vaccines were given monthly intradermally for three total doses with rhu-GM-CSF (100mcg) as an adjuvant. The primary endpoint was safety through the 6-month follow-up visit and the secondary endpoints were immunogenicity, persistence of the immune response after vaccination, and assessment of potential stimulation of T-regulatory (T-reg) cells or myeloid derived suppressor cells to the overexpressed non-mutated antigens as well as determining the recommended Phase II dose. Results: Thirty-two patients were enrolled and 97% received all three vaccinations. The mean age at enrollment was 51.9 years with 61% of patients being pre-menopausal and 39% post-menopausal. The majority of patients were Stage II/III. Eighty-eight percent of patients had hormone receptor positive tumors and twelve percent were triple negative disease. The majority of adverse events (AE) (>95%) were grade 1 or 2. The most common AE were injection site reactions, flu like symptoms, fatigue, chills, myalgia, and nausea. All doses were immunogenic with the greatest magnitude antigen specific Type I immune responses seen in the low and intermediate doses. Eighty percent of patients at the 300mcg dose retained high levels of antigen specific immunity at 1 and 6 months after immunization as compared to 57% and 50% at the 100 and 600mcg doses respectively. No antigen specific Th2 cells, MDSC or T-reg were generated with vaccination. Immunizations did not upregulate PD-1 on CD4 or CD8 T-cells. Conclusions: A plasmid-based vaccine encoding extended Th1 selective epitopes derived from HER2, IGFBP-2, and IGF-IR could be administered safely and generate high levels of antigen specific interferon gamma secreting T-cells (Th1). The 300mcg dose elicited significant immune responses in the majority of patients which persisted at least 6 months after the end of immunization. A Phase II study of the vaccine given in the neoadjuvant setting to patients with HER2 positive breast cancer is ongoing (NCT04329065). Citation Format: Sasha E. Stanton, Kari B. Wisinski, William R. Gwin, Andrew Coveler, John B. Liao, Mark Burkard, Howard Bailey, KyungMann Kim, Thomas Havinghurst, Katina DeShong, Jennifer S. Childs, Eileen Dimond, Margaret Wojtowicz, Brandy M. Heckman-Stoddard, Denise Cecil, Mary Disis. Phase I trial of the safety and immunogenicity of a tri-antigen vaccine targeting HER2, IGFBP-2, and IGF-IR in patients with non-metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-02-02.

Background: There are currently approximately 3.5 million breast cancer survivors in the U.S. This number will continue to rise due to the medical and scientific advances that have improved diagnostic tools and standards of care for women treated for breast cancer. The increasing number of breast cancer survivors also means that the population at risk for cancer recurrence will increase. Cancer recurrence is defined as a cancer that was treated, reduced to undetectable levels, and later returned either locally, regionally, or distantly. After a recurrence diagnosis, patients’ experience reduced health outcomes and quality of life as well as the financial burden of additional treatments. Post-treatment surveillance strategies are critical for the early detection of recurrences so that interventions can be more effective at ensuring long term survival and quality of life. Currently, risk factors for breast cancer recurrence are not well understood in part due to limited population level data in cancer registries world-wide. The clinical endpoints that provide recurrence estimates are disease free survival (DFS), relapse free survival (RFS), and time to recurrence (TTR). Studies that provide recurrence estimates are limited to clinical trials (which lack diversity and represent less than 5% of cancer patients) and prospective cohorts that follow patients for a defined number of years. Currently, population-based cancer registries in North America do not collect recurrence data from patients that would allow the calculation of DFS, RFS, and TTR. The absence of population level data has limited the understanding of cancer patients’ individual risks and evidence-based recommendations for recurrence prevention strategies. Moreover, recurrence data on cancers with long term latency (greater than 5-10 years) such as estrogen receptor positive breast cancer are limited.Purpose: We seek to identify which data elements and surveillance strategies are collected for recurrence data in breast cancer clinical trials. Our long-term goal is to implement these data elements into the Surveillance, Epidemiology, and End Results (SEER) program to facilitate the calculation of breast cancer recurrence estimates at the U.S. population level.Methods: We performed a systematic literature review evaluating phase II-IV clinical trials, their reported clinical outcomes, surveillance strategies, and their diagnostic tests that confirm recurrence. We used PubMed, clinicaltrials.gov, EMBASE, and the Cochrane Library for search terms “recurrence”, “relapse”, “recurrence free survival”, “surgery”, “adjuvant therapy” in breast cancer for our literature search. Inclusion criteria included clinical trials with published results, trials that compared outcomes of surgical resections, surgery with adjuvant treatments, or multiple adjuvant treatments. We included trials that provided DFS, RFS, TTR, recurrence rate, recurrence free interval, progression free survival, and time to progression. We excluded trials that did not provide recurrence estimates and those that performed recurrence modeling.Conclusion: From our review, we identified data elements and recurrence estimates for breast cancer that are collected in clinical trials but are not included in North American registries. New data elements need to be included in North American cancer registries to calculate population-based estimates for recurrence. Citation Format: Esmeralda Ramirez-Pena, Sarah Hussey, Serban Negoita, Brandy Heckman-Stoddard. Learning from breast cancer clinical trials how to capture recurrence estimates for North American cancer registries: A systematic review [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-37.

Background: Breast cancer prevention with anti-estrogens, including tamoxifen, raloxifene, and exemestane, has been shown to reduce the incidence of hormone receptor-positive breast cancer. However, agents that can reduce the incidence of hormone receptor negative breast cancer are currently lacking. Rexinoids such as bexarotene are vitamin A analogues that have been shown to be involved in cell differentiation, growth, and apoptosis. In preclinical mouse models that develop ER-negative breast cancers, bexarotene showed a significant reduction in mammary tumor development. Oral bexarotene has been evaluated in BRCA mutation carriers and significant decreases in cyclin D1 were noted in breast cells suggesting biological activity of bexarotene on breast tissue. Systemic side effects of hyperlipidemia and hypothyroidism were also found. Data from chemoprevention studies with topical 4-hydroxytamoxifen support the concept of topical agents penetrating into the breast tissue and exhibiting biological activity. We hypothesize that topical bexarotene can be applied to the breast as a prevention agent with penetration into the breast tissue and without subsequent systemic side effects as seen with oral bexarotene. Methods: Women at high risk for breast cancer were recruited and assigned to escalating doses of 1% topical bexarotene: 10mg (1ml) every other day, 10mg (1ml) daily and 20mg (2ml) daily for 4 weeks. Cohorts of 3-4 participants were enrolled and fully evaluated through 4 weeks prior to enrolling the next cohort. Each dose level enrolled a maximum of 10 participants. The primary endpoint of the study was to determine the recommended phase II dose of topical bexarotene 1% gel for evaluation in healthy at-risk women. Dose Limiting Toxicity (DLT) was defined as a grade 2 skin adverse event that persists for at least 6 days or any grade 3 or greater adverse event related to the study drug. A grade 2 skin adverse event that recurs and persists for at least 3 days is also a DLT. The Maximum Tolerated Dose (MTD) was defined as the highest dose level at which no more than 2 participants experience a DLT among 10 participants treated. Once the MTD was determined, interim biomarker analysis will be completed to assess bexarotene levels in serum and tissue samples. An expansion cohort of an additional 10 patients will be recruited at the MTD to further evaluate safety and toxicity. Secondary endpoints include serum bexarotene level, tissue bexarotene levels, and changes in thyroid function tests, lipid profile, and calcium. Results: Ten women were enrolled at the dose level of 10mg every other day and 9/10 participants experienced Grade 1 skin related events at the application site. Two participants reported Grade 2 skin related events at the application site but did not last long enough to be considered DLTs. Four women were enrolled at the second dose level of 10mg daily and 3/4 experience Grade 2 skin related events including 2 DLTs which stopped accrual to the study. Therefore, the MTD was determined to be 10mg every other day. No laboratory abnormalities were noted across either dose level and no grade 3 or 4 adverse events were reported. Conclusion: Maculopapular rash at treatment site was the most common adverse event related to study drug and resolved with discontinuation. Analysis is ongoing to assess bexarotene drug levels in serum and breast tissue samples. Citation Format: Parijatham S Thomas, Anisha B Patel, Diane Liu, J. Jack Lee, Seema Khan, Miguel Muzzio, Alejandro Contreras, Lana Vornik, Eileen P Dimond, Marjorie Perloff, Brandy Heckman-Stoddard, Powel H Brown. Interim analysis of a phase I dose escalation study of topical bexarotene in women at high risk for breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-12.

The Division of Cancer Prevention and the Division of Cancer Biology at the National Cancer Institute and the Gynecologic Health and Disease Branch in the National Institute of Child Health and Human Development organized a workshop in April 2019 to explore current insights into the progression of gynecologic cancers from benign conditions. Working groups were formed based on 3 gynecologic disease types: (1) Endometriosis or Endometrial Cancer and Endometrial-Associated Ovarian Cancer, (2) Uterine Fibroids (Leiomyoma) or Leiomyosarcoma, and (3) Adenomyosis or Adenocarcinoma. In this report, we highlight the key questions and current challenges that emerged from the working group discussions and present potential research opportunities that may advance our understanding of the progression of gynecologic benign conditions to cancer.

Agents that can reduce the incidence of hormone receptor negative breast cancer are currently lacking. Rexinoids such as bexarotene significantly reduced mammary tumor development in preclinical mouse models. Oral bexarotene in BRCA mutation carriers significantly decreased cyclin D1 in breast cells, suggesting biological activity on breast tissue. This study evaluated topical bexarotene 1% gel applied to one unaffected breast in women at high risk for breast cancer for 4 weeks to assess safety and toxicity. Secondary objectives included assessment of bexarotene concentrations in the plasma and breast tissue. In the dose escalation phase, women were assigned to one of three different dose levels: 10 mg (1 mL) every other day, 10 mg (1 mL) daily, 20 mg (2 mL) daily. Dose-limiting toxicity (DLT) was defined as a grade 2 skin adverse event for at least 6 days or any grade 3 or 4 adverse event related to study drug. A total of 14 women were enrolled with 10 participants at the every other day dose level and 4 participants at daily dosing. Two skin DLTs were experienced at daily dosing and therefore further enrollment was discontinued per protocol. An additional 10 participants were enrolled at the MTD as part of the dose expansion phase. These individuals tolerated the treatment with minimal adverse events. Maculopapular rash at the treatment site was the most common adverse event related to study drug and resolved within a few days of discontinuation. Bexarotene was detectable in breast tissue at the 10 mg daily every other day dose. 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.

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.

Oral breast cancer prevention medications entail systemic exposure, limiting acceptance by high-risk women. Delivery through the breast skin, although an attractive alternative, requires demonstration of drug distribution throughout the breast. We conducted a randomized double-blind, placebo-controlled phase II clinical trial comparing telapristone acetate, a progesterone receptor antagonist, administered orally (12 mg/day) or transdermally (12 mg/breast) for 4 ± 1 weeks to women planning mastectomy. Plasma and tissue concentrations, measured at five locations in the mastectomy specimen using liquid chromatography tandem mass spectrometry were compared. In 60 evaluable subjects, median drug concentration (ng/g tissue) was 103 (interquartile range (IQR): 46.3-336) in the oral vs. 2.82 (IQR: 1.4-5.5) in the transdermal group. Despite poor dermal permeation, within-breast drug distribution pattern was identical in both groups (R2 = 0.88, P = 0.006), demonstrating that transdermally and orally delivered drug is distributed similarly through the breast, and is strongly influenced by tissue adiposity (P

Background: Tamoxifen uptake for risk reduction has remained low due to concerns about toxicity despite the efficacy and effectiveness data available. Studies of tamoxifen in the adjuvant and preventive setting have demonstrated that a decline in mammographic density (MD) of approximately 10% is consistently associated with better outcomes. Additionally, MD is one of the strongest independent predictors of breast cancer risk, apart from older age and BRCA1/2 mutation, among women. 4-hydroxytamoxifen topical gel (4-OHT) is a transdermal agent, shown in preliminary studies to be well-tolerated with similar decreases in Ki-67 to oral tamoxifen in presurgical DCIS studies and significant drug concentration in breast parenchyma but very low levels in the systemic circulation. This study examines changes in MD, a potential surrogate biomarker of prevention activity, as the primary endpoint for this one-year early-phase prevention trial using 4-OHT gel in high risk women. Trial design: Multicenter, randomized, placebo-controlled study of 4-OHT gel (2mg per breast) versus placebo in 152 women with heterogeneously or extremely dense breast tissue for 12 months using standard of care imaging, stratified by enrollment site and baseline breast density category. The primary objective of this study is to evaluate the change in percent MD (using Cumulus software) from baseline to the week 52 in women applying 4 mg (2mg per breast) 4-OHT gel versus placebo. The secondary objectives are to compare the Cumulus vs Volpara breast density measurement methods; evaluate the percentage of women with lowering of BIRADS density; estimate percentage of women with ≥ 10% absolute decrease in quantitative MD percentage; explore patient reported experience assessed by BESS questionnaire; laboratory toxicity assessment (F VIII, vWB factor, SHBG, lipid profile); compare the 2D vs. 3D breast density measurement methods to estimate percent change in mammographic breast density; evaluate serum measurements of parent drug and related metabolite levels and factors related to 4-OHT exposures, such as IGF pathway members, CRP, estradiol, and 4-OHT; collect tissue for biomarkers (among women undergoing optional pre- and post-treatment biopsies); examine the persistence in change of mammographic density one year after 4-OHT vs. placebo gel application has stopped. Eligibility criteria: Inclusion: Women age 40-69 years, or less than 40 years if 5-year breast cancer Gail risk is greater than/equal to 1.66%; heterogeneously or extremely dense breast tissue based on mammography. Exclusion: abnormal uterine bleeding, or prior diagnosis of endometrial hyperplasia, endometrial polyps, or endometrial cancer; prior use of SERMS and AIs, except for a maximum of 3 months and at least 12 months prior. Statistical methods: Considering an attrition rate of 15%, 128 evaluable women are expected to have both baseline and 52-week measurements of percent MD. With 64 women in each group, there is 80% power to detect a decrease of 6% in the 4-OHT group versus 2% in the placebo group with a common standard deviation of 8% using a two-sided t-test with a significance level of 0.05. Study accrual: Activated January 2018, as of July 1, 2019, 92 patients have been recruited and 79 were randomized. Citation Format: Banu K. Arun, Gretchen Gierach, Marion E Scoggins, Seema Khan, Sandra S Rao, Judy Garber, Sughra Raza, Nagi B. Kumar, Heather H Han, John Heine, Bethany Niell, Pavani Chalasani, Kimberly Fitzpatrick, Lee G Wilke, Amy Fowler, Heather C Beckwith, Carrie Mays, Saba Abutaseh, Lana Vornik, Oukseub Lee, Eileen Dimond, Marjorie Perloff, Diane Liu, J. Jack Lee, Powell Brown, Brandy Heckman-Stoddard. A randomized, double-blind, placebo-controlled study of 4-hydroxytamoxifen topical gel in women with mammographically dense breasts [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-15-02.

Background: The aromatase inhibitor exemestane (EXE) has shown to lower cancer incidence in high-risk postmenopausal women. However, undesirable symptoms and side effects (i.e., bone density loss, musculoskeletal ache, climacteric syndrome) may compromise patient motivation and adherence to a long-term preventive treatment. A less frequent drug schedule, compared to the standard regimen, may be more acceptable to healthy at-risk women. We hypothesized that comparison of two alternative less frequent dose regimens with the standard daily dose regimen will show that it is possible to decrease undesirable symptoms of EXE while still effectively reducing serum estradiol. Trial Design: We are conducting a multi-center, pre-surgical, double-blind, non-inferiority phase IIb study in which 180 postmenopausal women will be randomized to receive either EXE 25 mg/day or 25 mg/three times a week or 25 mg/week for 4 to 6 weeks prior to surgery. Surgery will occur on day 29, 36 or 43 after treatment initiation. Eligible subjects are postmenopausal women with histologically-confirmed ER-positive (ER >10%) primary breast cancer candidates for surgery. Participants with T0-2, N0-1, Mx or with larger tumors who refuse neo-adjuvant therapy before surgery are eligible. Subjects are stratified according to participating site and body mass index (25 kg/m2). The primary objective is to assess if the reduction in estradiol with EXE 25 mg/three times a week and EXE 25 mg/week is comparable with the standard dose of 25 mg/day of EXE. Methods: Blood will be collected at baseline and at the end of treatment. Tissue samples will be collected from the diagnostic biopsy and at the time of surgery. The primary endpoint is the percentage change of serum estradiol concentration between baseline and surgery in the three arms in a CLIA certified laboratory. Given the expected reduction of at least 80% change with EXE at 25 mg daily considered as reference group (control arm) against 25 mg/three times a week or 25 mg weekly, for the power calculation we assume a non-inferiority difference of 6% in percentage changes of circulating estradiol after treatment from baseline, using a one-sided, two-sample t-test. Secondary outcome measures are the incidence of toxicity and menopausal symptoms according to the CTCAE (v4) and by the self-administered MENQoL; the effect of the three regimens on sex hormones (estrone, estrone sulphate, SHBG, testosterone, DHEAS and FSH) and the effect on circulating estradiol levels using an ultrasensitive method given that the serum levels in postmenopausal women under EXE may be very low. Drug and metabolites levels will be measured in blood, cancer tissue and non-cancer tissue. Evaluation of serum insulin, glucose (homeostatic model assessment index), and lipid profile (total cholesterol, high-density lipoprotein cholesterol and triglycerides), leptin and adiponectin will be performed before and after treatment. Additionally, we will measure breast estradiol concentration in cancer and non-cancer tissue and compare changes in ER, PgR, and proliferation in cancer and non-cancer tissue samples obtained at time of biopsy and definitive surgery. Finally, we will also analyze the role of the polymorphic UGT2B17 gene (involved in EXE and 17-dihydroexemestane metabolism) as well as tissue proteomics. Preliminary results: Enrollment started in February 2017 and as of July 3, 2019, a total of 170/180 participants have been randomized (94% of the expected sample size). Preliminary data will be presented at the conference. IND Sponsor: NCI/DCP NCI contract: HHSN26120120034I Citation Format: Aliana Guerrieri-Gonzaga, Parjhitham Thomas, Andrea DeCensi, Katherine D Crew, Nagi Kumar, Sara Gandini, Lana Vornik, Brandy Heckman-Stoddard, Eva Szabo, Eileen Dimond, Jack Lee, Diane Liu, Matteo Lazzeroni, Sara Cagnacci, Davide Serrano, Mauro D'Amico, Flavio Guasone, Tania Buttiron Webber, Powel Brown, Bernardo Bonanni. Alternative dosing of exemestane before surgery in postmenopausal patients with stage 0-II estrogen receptor positive breast cancer: Design and methodology [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-04-03.

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. We used questionnaire data from women in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial to calculate Gail risk levels (low

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.

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.

Lifestyle changes may reduce the burdens of diabetes and cancer. We examined how changes in the 2018 WCRF/AICR Score, reflecting key cancer prevention recommendations, are associated with diabetes risk. The Diabetes Prevention Program (DPP) randomized adults with prediabetes to a lifestyle intervention (ILS), metformin (MET), or placebo (PLB) for a mean of 3.2 years, with follow-up in DPPOS for 11 years. The Score includes 7 components: weight, physical activity, plant-based diet, red/processed meat, sugar-sweetened drinks, fast foods, and alcohol (0-7 points, with 7 as the best total score). Scores were estimated at years 0, 1, 5, 6, 9, and 15 for participants with complete baseline data (N = 3,147). Covariates included sex, age, race/ethnicity, marital status, education, family history of diabetes, hormone therapy (females), and energy intake. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) stratified by treatment group estimated the association of Score changes with diabetes risk in DPP and DPPOS within and between groups. There were significant Score improvements within all groups over 15 years (p < 0.001); the differences between groups were only significant after 1 year (p < 0.001; 15 years: p = 0.137). For every 1-unit improvement in Score during DPP, there was a 29% and 16% lower diabetes risk in ILS (95% CI: 0.58 - 0.88) and PLB (95% CI: 0.72 - 0.99), respectively, and no significant association in MET. The time-dependent Score improvements in ILS and PLB were significantly associated with lower diabetes risk through year 15 (ILS HR: 0.86, 95% CI 0.77 - 0.96; PLB HR: 0.85, 95% CI 0.76 - 0.95). Changes in weight, physical activity, and plant-based diet appeared to be drivers of the Score’s effect. Findings suggest that Score improvements are associated with a long-term, lower risk for diabetes among adults with prediabetes. Future research can explore how this risk reduction impacts cancer risk. Disclosure M. M. M. Shams-white: None. B. M. Heckman-stoddard: None. D. Research group: None. A. H. Tjaden: None. S. Edelstein: None. S. Bassiouni: None. C. Kim: None. X. Pi-sunyer: None. K. A. Temple: None. E. M. Venditti: None. J. Reedy: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK048489)

Background: Denosumab is a monoclonal antibody that inhibits RANKL and is approved for the prevention of fractures in patients with osteoporosis or bone metastases. The RANKL signaling pathway is also involved in BRCA1-associated mammary tumorigenesis via a progesterone-induced paracrine effect of RANKL on luminal progenitor cells. Pre-clinical studies have demonstrated that RANKL inhibition resulted in reduced proliferation of mammary tumors. Early findings from an ongoing pre-surgical study demonstrated that denosumab treatment resulted in decreased Ki67 proliferation index in benign breast tissue. Based on these data, denosumab is being pursued as a potential preventive agent for breast cancer in BRCA1 mutation carriers. While promising, the effect of RANKL inhibition on gynecologic tissues such as the ovaries and fallopian tubes, in which progesterone has a protective effect, is unknown. Trial design: We will conduct a multicenter, open-label randomized pilot study of presurgical administration of denosumab versus no treatment in premenopausal women with BRCA1/2 mutations undergoing risk-reducing salpingo-oophorectomy (RRSO). A total of 60 women will be randomized 1:1 to Arm 1) 3-4 doses of 120 mg denosumab subcutaneously every 4 weeks or Arm 2) No treatment. Participants will be stratified by 1) BRCA1 versus BRCA2 mutation status and 2) Use of hormonal contraceptives within the past 3 months (yes/no). Assuming a 10% unevaluable rate, we expect to have 54 evaluable participants (27 per arm). Eligibility criteria: 1) Premenopausal women (defined as < 3 months since last menstrual period OR serum follicle-stimulating hormone (FSH) < 20 mIU/mL), age > 18 years; 2) Documented germline pathogenic mutation or likely pathogenic variant in the BRCA1 or BRCA2 gene; 3) Plan for RRSO with or without hysterectomy; 4) ECOG performance status ≤ 1 (Karnofsky ≥ 70%); 5) Normal organ and marrow function; 6) Negative pregnancy test and use of adequate contraception; 7) Willingness to take supplemental oral calcium and vitamin D3; 8) Dental examination within 6 months of enrollment and no evidence of active dental issues; 9) Ability to understand and willingness to provide informed consent. Specific aims: Our primary objective is to compare the effect of denosumab to no treatment on Ki67 expression in the fimbrial end of the fallopian tube. Secondary objectives are to assess Ki67 in ovary and endometrium; cleaved caspase-3, RANK/RANKL, ER/PR, CD44, and STAT3/pSTAT3 expression in fallopian tube, ovary, and endometrium; gene expression profiling in the fallopian tube and ovary; serum markers (progesterone, estradiol, C-terminal telopeptide) and denosumab levels; and toxicity. Statistical methods: The primary endpoint is post-treatment Ki67 expression in the fimbrial end of the fallopian tube in the denosumab arm compared to the no treatment arm. Assuming a standard deviation of 5.0%, we will have 82% power to detect a 4.0% absolute difference (or effect size of 0.8) in Ki67 proliferation index between the denosumab and no treatment groups by applying a 2-sample t-test at a 0.05 significance level. Target accrual: 60 participants, to be activated in Summer 2018. Citation Format: Trivedi MS, Samimi G, Wright JD, Holcomb K, Garber JE, Horowitz NS, Arber N, Friedman E, Wenham RM, House M, Parnes H, Lee JJ, Abutaseh S, Vornik LA, Heckman-Stoddard BM, Brown PH, Crew KD. Pilot study of denosumab in BRCA1/2 mutation carriers scheduling for risk-reducing salpingo-oophorectomy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-09-01.

Background Ductal carcinoma in situ (DCIS) is diagnosed in 60,000 women annually in the US. TAM is proven to reduce risk of local recurrence and new primary breast cancer in women with estrogen receptor (ER) positive DCIS. However, acceptance of TAM has been low, primarily because of toxicity related to systemic exposure. Local delivery to the breast is an attractive alternative since low systemic levels could minimize toxicity. 4-OHT is an active metabolite of TAM. When formulated as a gel and applied to the breast skin, it is well tolerated, and results in 4-OHT breast tissue drug levels comparable oral TAM. In small pilot studies, its anti-proliferative effects on invasive breast tumors and DCIS are also similar to oral TAM [Lee O, et al. PMID 25028506]. The goal of our study is to validate these results in preparation for a Phase III trial of 4-OHT gel in comparison to oral TAM. Methods We are conducting a randomized, double-blinded, placebo-controlled, Phase IIB pre-surgical trial to demonstrate that daily application of 4-OHT gel will result in a reduction in the Ki-67 labeling index of DCIS lesions that is not inferior to that seen in women receiving daily oral TAM 20 mg daily. Ki-67 of the base-line diagnostic core needle biopsy will be compared to that of the therapeutic surgical excision sample after oral TAM or 4-OHT gel for 8 ± 2 weeks. Secondary endpoints include changes in Oncotype DCIS-Score, IHC markers (CD68, COX2, p16), hormone levels, coagulation markers, drug concentration in the plasma and breast tissue, the fraction of women with no residual DCIS in the surgical sample, and experienced symptoms. 100 women (assuming 20% non-evaluable samples or compliance issues) with DCIS (10% ER-positive) will be enrolled across six institutions into two intervention arms: oral TAM 20 mg daily, placebo gel and 4-OHT gel 4mg daily (2mg/breast), placebo capsule. All participants will be evaluable for toxicity from their first dose. All samples from all participants who receive drug will be evaluated and included in the primary analysis, which will be based on intent to treat principle. To date 15 of 100 participants have been enrolled across six institutions including: Northwestern University in Chicago, IL, St. Elizabeth Healthcare in Edgewood, KY, Duke University Medical Center in Durham, NC, Cleveland Clinic in Cleveland, OH, Memorial Sloan Kettering Cancer Center in New York, NY, and Mayo Clinic in Rochester, MN. Since study open, 69 potential participants have been contacted, 52 did not consent for screening, 17consented for screening, 2 are pending consent, and 15 have started study intervention. The most common reasons potential participants chose not to consent are wanting to schedule surgery as soon as possible, attitudes toward medical research, and current use of a prohibited concomitant medication such as a potent inhibitor of tamoxifen metabolism or exogenous sex steroid. Funding Source: NCI Contract # HHSN2612201200035I. Citation Format: Benante KA, Xu Y, Tull MB, Segura AJ, Alber KM, Kalinichenko K, Hou L, Jovanovic B, Perloff M, Heckman-Stoddard B, Dimond E, Khan SA. A phase IIB pre-surgical trial of oral tamoxifen (TAM) versus transdermal 4-hydroxytamoxifen (4-OHT) in women with DCIS of the breast [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-04-01.

Background: Breast cancer prevention with anti-estrogens, including tamoxifen, raloxifene, and exemestane, has been shown to reduce the incidence of hormone receptor-positive breast cancer. However, agents that can reduce the incidence of hormone receptor negative breast cancer are currently lacking. Rexinoids such as bexarotene are vitamin A analogues that have been shown to be involved in cell differentiation, growth, and apoptosis. In preclinical mouse models that develop ER-negative breast cancers, bexarotene showed a significant reduction in mammary tumor development. Oral bexarotene has been evaluated in BRCA mutation carriers and significant decreases in cyclin D1 were noted in breast cells suggesting biological activity of bexarotene on breast tissue. Systemic side effects of hyperlipidemia and hypothyroidism were also found. Data from chemoprevention studies with topical 4-hydroxytamoxifen support the concept of topical agents penetrating into the breast tissue and exhibiting biological activity in the tissue. We hypothesize that topical bexarotene can be applied to the breast as a chemoprevention agent with penetration to the breast tissue without subsequent systemic side effects and toxicity as seen with oral bexarotene. Trial Design: Women at high risk for breast cancer will be recruited and assigned to one of three different dose levels: 10mg (1ml) every other day, 10mg (1ml) daily, 20mg (2ml) daily to one unaffected breast for 4 weeks. The primary endpoint of the study is to determine the recommended phase II dose of topical bexarotene 1% gel for evaluation in healthy at-risk women. Dose Limiting Toxicity (DLT) is defined as a grade 2 skin adverse event that persists for at least 6 days or any grade 3 or greater adverse event related to the study drug. A grade 2 skin adverse event that recurs and persists for at least 3 days is also a DLT. The Maximum Tolerated Dose (MTD) will be defined as the highest dose level at which no more than 2 participants experience a DLT among 10 participants treated. A conservative modification of the standard “3+3” design will be applied. The first three participants will be assigned to the lowest dose level. New cohorts of 3-4 participants will not be treated until toxicity has been fully evaluated for all current participants through 4 weeks. Once the MTD has been determined, an expansion cohort of an additional 10 patients will be recruited at the MTD to further evaluate safety and toxicity at this dose level as well bexarotene concentration in the breast tissue. Secondary endpoints include serum bexarotene level, tissue bexarotene levels, and changes in thyroid function tests, lipid profile, and calcium. The planned accrual for this study if maximally accrued to all dose levels and the dose expansion cohort will be 40 participants. Citation Format: Thomas PS, Patel AB, Contreras A, Liu DD, Lee JJ, Khan S, Vornik LA, Dimond EP, Perloff M, Heckman-Stoddard BM, Brown PH. A phase I dose escalation study of topical bexarotene in women at high risk for breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-09-02.

Background: Estrogen receptor (ER)-negative tumors and human epidermal growth factor 2-Neu (HER2) positive breast cancers are known to be more clinically aggressive subtypes of breast cancer and account for 30% of all breast cancers. Women with HER2 + breast cancers, whether ER+ or ER -, require cytotoxic chemotherapy with a HER2-targeting agent, and often have adverse outcomes. Thus, preventive agents are needed to reduce the incidence of these subtypes of aggressive breast cancer. Lapatinib, a dual tyrosine kinase inhibitor, inhibits epidermal growth factor receptors (EGFR) and HER2 kinases and has shown to decrease breast cell proliferation in invasive breast cancer and adjacent premalignant lesions. Therefore, we conducted a multi-institutional randomized Phase II clinical trial to study the effects of the signal transduction inhibitor lapatinib in women with HER2-positive or EGFR-positive ductal carcinoma in situ (DCIS). Methods: Randomized participants received either lapatinib (750mg, 1000mg, or 1500mg) or placebo daily for 2-6 weeks prior to their surgery. After minimal accrual, the trial was later amended to lapatinib 1000mg or placebo. Pre-treatment breast tissue was obtained from initial diagnostic core biopsy and post-treatment breast tissue was obtained from surgical excision specimen. Blood was obtained prior to surgery to assess serum lapatinib level. Participants kept a daily symptom assessment log and had a cardiac assessment at baseline and prior to surgery. Patients were instructed to take drug up to and including the day before surgery. The dual primary endpoint for this study was change in proliferation in pre- versus post-treatment biopsies between the two treatment arms, as measured by Ki67 as well as toxicity assessment. Secondary endpoints included incidence of DCIS at surgery and modulation of tissue biomarker expression in growth factor receptors (EGFR, ErbB2); phosphorylated growth factor receptor (phospho-ErbB2); signal transduction markers (MAPK, phospho-MAPK); hormone receptors (ER, PR); and p27. Results:Twenty-two women (mean age: 51; range: 32-66) with HER2+ or EGFR+ DCIS were treated with lapatinib (1,000 or 1,500 mg) or placebo for 2–6 weeks prior to surgical excision. Ki67 expression was significantly decreased in the lapatinib treatment arms compared to placebo (p=0.0122). Diarrhea, fatigue, and skin reactions were notable adverse events that occurred predominately in the lapatinib arm compared to placebo. No grade 3 or 4 events related to the study drug were noted during the study. No changes were noted in cardiac function. DCIS was present in all surgical specimens in both arms. Invasive breast cancer was noted in 1 patient on lapatinib 1000mg and 3 patients on placebo. No statistically significant changes were noted in signal transduction biomarkers Conclusion:These results demonstrate the effectiveness of lapatinib in reducing proliferation in women with EGFR+ or HER2+ DCIS. Even low-grade toxicities can deter use of an agent in the prevention setting. This and the lack of a risk model for HER2+ and triple negative breast cancer make the development of larger scale clinical prevention trials of lapatinib for the prevention a challenge. Citation Format: Thomas PS, Contreras A, Pruthi S, Krontiras H, Rimawi M, Garber J, Wang T, Hilsenbeck SG, Vornik LA, Gilmer T, Friedman R, Heckman-Stoddard BM, Dunn B, Kuerer H, Brown PH. A phase II pre-surgical trial of lapatinib for the treatment of women with HER2 positive or EGFR positive ductal carcinoma in situ [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-07.

Background: Low uptake and poor adherence to oral drugs for breast cancer prevention and ductal carcinoma in situ has led to an interest in local routes of delivery with the intent of decreasing systemic exposure and reducing toxicity. LTT has emerged as a possible alternative; previous studies have shown selectively higher concentrations in the breast than in the serum with this delivery route. A question related to LTT is whether or not the drug will permeate and distribute throughout the breast, as is expected with oral delivery. Methods: We conducted a double-blind study of oral versus LTT delivery of the selective progesterone receptor modulator, telapristone acetate (TPA), in a presurgical window setting, enrolling 82 women planning therapeutic or prophylactic mastectomy. We randomized 67 women 1:1, to oral TPA 12 mg daily, or gel TPA applied to both breasts daily (12 mg/breast), for 4 weeks ±1 week. Mastectomy specimens were sampled at 5 non-tumor locations as well as the tumor and lymph node when available. Samples were split in two: drug concentration (conc.) assay using LC-MS/MS and histological evaluation of tissue composition (fat, fibrous stroma, epithelium). The primary endpoint was mean drug conc. across all breast locations (anticipating that the gel would deliver a mean concentration that was >50% of the mean in the oral group). A secondary endpoint was the drug distribution pattern across the breast, expecting that the distribution would be similar. The tumor sample was saved for biomarker assays related to TPA action; these are ongoing, for a pre-planned pooled analysis of data with NCT01800422 (reported in SABCS abstract 851863). Results: Of 63 evaluable women (33 oral and 30 gel group), 27 had unilateral and 36 had bilateral mastectomy. The mean drug conc. in the oral group was 166.3 ng/G (SE 11.7), and in the gel group was 10.6 ng/G (SE 10.8), (p Conclusions: The gel formulation of TPA did not permeate the skin well. However, the drug delivered to the breast was distributed throughout the breast, similar to the oral delivery route, with the highest concentration in the deep central location. These drug distribution data are novel; drug distribution at multiple locations throughout the breast has not previously been shown. Further work is needed to understand breast distribution with formulations known to have good dermal permeation. Citation Format: Lee O, Pilewskie M, Xu Y, Benante K, Blanco L, Helenowski I, Tull MB, Muzzio M, Jovanovic B, Karlan S, Hansen N, Bethke K, Kulkarni S, Perloff M, Dimond EP, Heckman-Stoddard BM, Khan SA. Local transdermal therapy (LTT): Drug permeation and distribution of telapristone acetate (TPA) in a pre-surgical window study of women undergoing mastectomy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-21-12.

519 Background: Successful therapeutic cancer prevention requires definition of the minimal effective dose of the proposed agent. Aromatase inhibitors substantially decreased breast cancer incidence in high risk postmenopausal women in phase III trials but their clinical use in prevention and adherence in adjuvant setting is limited by adverse events. We conducted a randomized presurgical phase IIb trial to evaluate two alternative doses of exemestane. Methods: We conducted a multi-center, pre-surgical, double-blind, 3-arm, non-inferiority phase IIb study in postmenopausal women with histologically confirmed estrogen receptor (ER)-positive breast cancer. Patients were randomized to receive either exemestane 25 mg/day (QD), or 25 mg/three times/week (TIW), or 25 mg once a week (QW) for 4-6 weeks before surgery. Blood and tissue biomarkers were collected at baseline and final visit. The primary aim was a non-inferiority percent change of circulating estradiol relative to the standard dose. Secondary endpoints were the change in Ki-67 and PgR expression in cancer tissue, blood sex hormones, lipid profile, toxicity and menopausal symptoms. For the power calculation we assumed a non-inferiority difference of 6% in the percentage change of estradiol among arms, using a one-sided, two-sample t-test. Assuming a 10% drop-out rate, a total sample size of 180 participants (60 per arm) had 80% power to detect a 6% margin of equivalence. The significance level for the main endpoint was 0.025 to account for multiple comparisons and 0.05 for secondary endpoints. Results: A total of 230 women were screened, 180 agreed to participate and 173 were evaluable for response. The median percent change of estradiol was -98%, -98%, and -70% for exemestane QD (n = 56), TIW (n = 57), and QW (n = 60), respectively, showing no significant difference between QD and TIW arms (p = 0.9). Similarly, no differences were observed for estrone, total estrone and estrone sulfate between QD and TIW arms. The QW arm showed some modulation in all hormones, even though less significantly so. Among the secondary endpoints, Ki-67 and PgR were reduced in all arms, with a median change of -5% vs -7.5% for Ki-67(p = 0.124), and -9 vs -17 for PgR (p = 0.246) in the TIW vs QD arms, respectively. SHBG and HDL-cholesterol had a more favorable profile with the TIW dose compared to the daily dose. Adverse events, measured according to the CTCAE (v4), and menopausal symptoms according to MENQOL were similar in all arms, but the short treatment time may not be representative. Conclusions: Exemestane 25 mg TIW retains a comparable activity than 25 mg QD. This activity was similar in both arms throughout the primary and the main secondary endpoints. This new schedule should be further assessed in prevention studies and in women on adjuvant treatment who do not tolerate the daily dose. Clinical trial information: NCT02598557.

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.

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.