PURPOSE:The ASPIRE trial evaluated frontline anastrozole, palbociclib, trastuzumab, and pertuzumab in patients with HR-positive, HER2-positive metastatic breast cancer (MBC). METHODS:This phase I/II trial enrolled patients with previously untreated, HR-positive, HER2-positive MBC. In Phase I, patients received escalating doses of palbociclib with trastuzumab, pertuzumab and anastrozole, using a 3 + 3 dose escalation design, and primary endpoint was maximum tolerated dose (MTD). Phase II followed an optimal Simon two-stage design where all patients received palbociclib at the MTD, plus anastrozole, trastuzumab, and pertuzumab and the primary endpoint was clinical benefit rate (CBR) in the first six months. Secondary endpoints included progression free survival (PFS), overall survival (OS) and safety. RESULTS:In Phase I, no dose limiting toxicities were observed at the 100mg (N = 3) or 125mg (N = 6) dose levels, and thus, 125mg was the MTD. An additional 23 patients were enrolled to Phase II, with a total of 29 patients in the response-evaluable population. The primary endpoint of CBR was 97% (N = 28; 95% CI: 82-99%). At a median follow-up of 45.3 months, median PFS was 24.9 months (95% CI: 17.2-44.8). Median OS was not reached at a follow-up of 39.4 months. Most common treatment-related adverse events (TRAEs) were neutropenia, leukopenia, diarrhea, and anemia. Grade 3-4 TRAEs occurred in 62% (N = 18) of patients and most were hematologic. CONCLUSIONS:The combination of anastrozole, palbociclib, trastuzumab, and pertuzumab demonstrated promising activity in this single-arm trial of patients with HR-positive, HER2-positive MBC and warrants further study in randomized trials. The regimen could provide a chemotherapy-free alternative.

Numerous studies have described the altered expression and the causal role of microRNAs (miRNAs) in human cancer. However, to date, efforts to modulate miRNA levels for therapeutic purposes have been challenging to implement. Here we find that nucleolin (NCL), a major nucleolar protein, posttranscriptionally regulates the expression of a specific subset of miRNAs, including miR-21, miR-221, miR-222, and miR-103, that are causally involved in breast cancer initiation, progression, and drug resistance. We also show that NCL is commonly overexpressed in human breast tumors and that its expression correlates with that of NCL-dependent miRNAs. Finally, inhibition of NCL using guanosine-rich aptamers reduces the levels of NCL-dependent miRNAs and their target genes, thus reducing breast cancer cell aggressiveness both in vitro and in vivo. These findings illuminate a path to novel therapeutic approaches based on NCL-targeting aptamers for the modulation of miRNA expression in the treatment of breast cancer.

Interseeding cover crops (CCs) may be a potential strategy to manage sandy soils, which are highly prone to degradation. However, how this practice affects CC biomass production and other ecosystem services in sandy soils over the traditional CC planting system (post-harvest drilling) is still unclear. We studied how broadcast interseeded (32-67 days before crop harvest) winter rye (Secale cereale L.) CC affected CC biomass production, nitrate leaching potential, soil properties, crop yields, and farm income compared with post-harvest drilled CC in an on-farm irrigated no-till corn (Zea mays L.)-soybean (Glycine max L.) experiment in a sandy loam in the western US Corn Belt for 6 years. Across the 6 years, interseeded CC produced 0.57 Mg ha-1 of biomass, while post-harvest drilled CC produced 0.37 Mg ha-1. Nitrate leaching is a concern in sandy soils, but interseeded CC had mixed effects on soil nitrate concentration. Interseeded CC did not affect soil properties (particulate organic matter and organic C concentrations, and wet aggregate stability) and crop yields. Further, interseeded CC did not reduce farm income more than post-harvest drilled CC. The limited effect of interseeded CCs is likely due to the relatively small increase in CC biomass production over the traditional CC planting system. Additional strategies including irrigation, drill interseeding, and planting green may boost interseeded CC biomass production and thus soil services in sandy soils. After 6 years, interseeded CC slightly boosted CC biomass production but minimally affected soils and crops, and both interseeded and post-harvest-drilled CCs reduced net income.

Triple-negative breast cancers (TNBCs) are associated with a high frequency of PTEN loss, which can lead to activation of the mTOR pathway and tumor proliferation but may be reversible with the mTOR inhibitor everolimus. A prior phase II single-arm trial of carboplatin and everolimus in patients with advanced TNBC demonstrated good tolerability and preliminary efficacy. A phase II randomized trial in patients with advanced TNBC, with 0–3 prior lines of therapy, was conducted. Patients were randomized 2:1 to receive carboplatin and everolimus or carboplatin alone. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and safety. Between 2015 and 2022, 59 patients were randomized to carboplatin/everolimus (n = 38) or carboplatin alone (n = 21). The median age of the population was 62 years and 68

Abstract Background: Among patients (pts) with HR-positive and HER2-positive breast cancer, crosstalk between HER2 and estrogen receptor (ER) signaling pathways may contribute to endocrine resistance but anti-HER2 agents in combination with endocrine therapy can restore endocrine sensitivity. Mechanistically, HER2/HER3 signaling promotes survival by way of PI3K-AKT activation whereas ER-CDK4/6-Rb signaling promotes cell cycle progression. The combination of anti-HER2 therapy with an aromatase inhibitor (AI) and a CDK 4/6 inhibitor would allow for blockade of both pathways and provide a novel, all biologic, and chemotherapy-free approach to the treatment of HR-positive, HER2-positive metastatic breast cancer (MBC). Methods: We conducted a phase I/II multi-institution trial in pts with previously untreated, HR-positive and HER2-positive MBC. In the Phase I portion, pts received escalating doses of palbociclib (100mg, 125mg) in conjunction with trastuzumab, pertuzumab and an AI anastrozole, using a 3+3 dose escalation trial design. In the phase II portion, pts received palbociclib at the maximum tolerated dose (MTD), anastrozole, trastuzumab, and pertuzumab. The primary endpoints of the Phase I and II portions were MTD and clinical benefit rate (CBR) defined as the sum of complete response, partial response, and stable disease for >/= 6 months, respectively. Secondary endpoints included progression free survival (PFS), objective response rate (ORR) and safety. The Phase II portion of this study was powered with 30 pts to show efficacy of palbociclib administered at the MTD in combination with anastrozole, trastuzumab and pertuzumab if the CBR achieved at 6 months exceeded 58%. The Clopper-Pearson method was used to calculate confidence intervals for ORR and CBR. The PFS distribution was estimated using the Kaplan-Meier method. Results: In the Phase I portion, a total of 9 pts were enrolled. No DLTs were observed at the 100mg dose (N=3) or the 125mg dose (N=6) level, and thus, 125mg was established as the MTD. An additional 24 pts were enrolled to the Phase II portion at the MTD, with a total of 30 pts in the modified intention-to-treat population included in the efficacy analysis. The median age of the population was 57.6 years (range 50.5-63.8) and 27% of pts were premenopausal and received ovarian function suppression as part of treatment. As shown in Table 1, the primary endpoint, CBR, was 97% (95% CI: 0.83-1.0, p<0.0001). ORR was 70% (95% CI: 0.51-0.85). Median time to objective response was 2.8 months with earliest response at 3 months. Median duration of response was not reached with range of 5.1-42.2 months. Median PFS was also not reached with range of 8-44.8 months. Safety data were consistent with known toxicity profiles of agents. Most common adverse events included diarrhea (80%), neutropenia (77%), leukopenia (70%), anemia (67%), and fatigue (60%). Grade 3-4 events occurred in 63% (19/30) of pts and included neutropenia (68%), leukopenia (32%), decrease in absolute neutrophil count (21%), and anemia (21%). Conclusions: The combination of anastrozole, palbociclib, trastuzumab, and pertuzumab was well tolerated and effective with a clinical benefit rate of 97% in pts with previously untreated HR-positive, HER2-positive MBC. The combination provides a chemotherapy-free alternative for pts with triple positive breast cancers. Further follow up will determine impact on PFS. Table 1. Results in Patients on Anastrozole, Palbociclib, Trastuzumab, and Pertuzumab Citation Format: Rima Patel, Krystal Cascetta, Paula Klein, Erin Moshier, Maryann Kwa, Julie Fasano, Anupama Goel, Melissa Accordino, Charles Shapiro, Rita Vaccaro, Gargi Atul Joshi, Joseph Sparano, Amy Tiersten. A Multicenter, Phase I/II Trial of Anastrozole, Palbociclib, Trastuzumab, and Pertuzumab in Hormone Receptor (HR)-Positive, HER2-Positive Metastatic Breast Cancer (ASPIRE) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF02-01.

Abstract Background: Both TNBC and BRCA-1 associated breast cancers are sensitive to DNA cross-linking agents such as platinum compounds due to defective DNA repair by homologous recombination. TNBCs are also associated with a high frequency of PTEN loss, which can lead to activation of the mTOR pathway resulting in tumor cell growth and proliferation. mTOR activation can confer resistance to platinum agents, and this phenomenon may be reversible by the addition of an mTOR inhibitor, such as everolimus. A prior phase II single arm trial of carboplatin and everolimus in patients (pts) with advanced TNBC demonstrated good tolerability and preliminary efficacy. Methods: We conducted a phase II, multicenter, randomized trial in pts with advanced TNBC, who had received 0-3 prior lines of therapy. Pts were randomly assigned (in a 2:1 ratio) to carboplatin and everolimus or carboplatin alone. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and safety. We planned to enroll 72 pts which would provide > 80% power for a one-sided log-rank test at the 5% level of significance, to detect a 2.5 month improvement in median PFS between treatment groups, assuming a median PFS of 2.5 months in the control group. An interim analysis for futility was planned after 36 events with a stopping boundary of P <0.375 for the comparison of PFS, using an Obrien-Fleming spending function. Of note, the trial was stopped earlier than planned based on a sensitivity/tipping point analysis which indicated that terminating the trial 3 months ahead of schedule would have no substantial impact on the primary endpoint. Results: A total of 56 pts were randomized between 2015 and 2022, of whom 36 received carboplatin/everolimus and 20 carboplatin alone. The median age of the population was 62.8 years (range: 33-87) and about 20% of pts had BRCA-1 or BRCA-2 mutations. In the overall population, pts had received a median of 1 (range 1-3) prior line of therapy in the metastatic setting, with 75% of pts receiving prior chemotherapy and 47% prior carboplatin. The median PFS was significantly improved in pts who received carboplatin and everolimus (4.7 months) versus those who received carboplatin alone (2.1 months; HR: 0.37; 95% CI: 0.19-0.72; p=0.0042). Overall survival was 22.1 months in pts on the combination versus 14.4 months on carboplatin alone (HR: 0.73; 95% CI: 0.30-1.72; p=0.3106). CBR was 61% with the combination vs 50% with carboplatin monotherapy, as shown in Table 1. Most common adverse events (AEs) on carboplatin and everolimus included thrombocytopenia (81%), anemia (69%), leukopenia (67%), fluid retention (64%), and neutropenia (61%). Overall, Grade 3/4 events occurred in 75% of pts (83% of pts on combination vs 60% on carboplatin alone) and were primarily anemia (40% vs 17%), thrombocytopenia (47% vs 0%), and neutropenia (20% vs 0%). Of note, there was an increase in thrombocytopenia with the addition of everolimus (All Grades: 81% vs 35%, Grade 3/4: 39% vs 0%). Conclusions: Treatment options for TNBC are limited due to a lack of targeted therapies. The combination of carboplatin and everolimus in this study was associated with a 63% reduction in risk of progression or death in pts with metastatic TNBC. The regimen was well tolerated and provides a promising treatment option for pts with advanced TNBC. Table 1. Results in Patients on Carboplatin and Everolimus versus Carboplatin Alone NE= Not Estimable; 1Unevaluable patients treated as non-responders in CBR and ORR calculations. Citation Format: Rima Patel, Jami Fukui, Paula Klein, Erin Moshier, Charles Shapiro, Anupama Goel, Julie Fasano, Theresa Shao, Aarti Bhardwaj, Rita Vaccaro, Gargi Atul Joshi, Joseph Sparano, Amy Tiersten. A Randomized Phase II Comparison of Single-Agent Carboplatin versus the Combination of Carboplatin and Everolimus for the Treatment of Advanced Triple Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-06-07.

While MEK inhibitors demonstrated activity in metastatic triple negative breast cancer (mTNBC) preclinical studies, preclinical, and clinical studies implicate rapid development of resistance limiting clinical benefit. The purpose of this study was to determine response rate for Trametinib alone and in combination with Uprosertib in patients with mTNBC previously treated with chemotherapy. This was an open-label, two-part, phase II, single-arm, multicenter study. Patients first received Trametinib monotherapy (2 mg daily; Part I) then at progression transitioned to Trametinib (1.5 mg) plus Uprosertib (50 mg; Part II). Between October 2013 and January 2017, 37 patients were enrolled to Part I. Subsequently, 19 patients entered Part II. Of the 37 patients receiving Trametinib monotherapy, 2 patients achieved partial response (PR) for an ORR of 5.4

Supplementary Figure Legends

Cover crop growing periods in the western U.S. Corn Belt could be extended by planting earlier. We evaluated both pre-harvest broadcast interseeding and post-harvest drilling of the following cover crops: (a) cereal rye (Secale cereale L.) [RYE]; (b) a mix of rye + legumes + brassicas [MIX1], (c) a mix of rye + oat [Avena sativa L.] + legumes + brassicas (MIX2), (d) legumes [LEGU]) and (e) a no cover crop control. These were tested in continuous corn (Zea mays L.) [corn-corn] and soybean [Glycine max (L.) Merr.]-corn systems [soybean-corn] at three sites in Nebraska for their effect on cover crop productivity, soil nutrients, and subsequent corn performance. At the sites with wet fall weather, pre-harvest broadcasting increased cover crop biomass by 90%, to 1.29 Mg ha(-1) for RYE and 0.87 Mg ha(-1) for MIX1 in soybean-corn, and to 0.56 Mg ha(-1) and 0.39 Mg ha(-1) in corn-corn, respectively. At the drier site, post-harvest drilling increased biomass of RYE and MIX1 by 95% to 0.80 Mg ha(-1) in soybean-corn. Biomass N uptake was highest in pre-harvest RYE and MIX1 at two sites in soybean-corn (35 kg ha(-1)). RYE and sometimes mixes reduced soil N, but effects on P, K, and soil organic C were inconsistent. In soybean-corn, corn yields decreased by 4% after RYE, and in corn-corn, by 4% after pre-harvest cover crops. Site-specific selection of cover crops and planting practices can increase their performance while minimizing impacts on corn.

Background: The interaction between HER2-low expression, oncotype recurrence score (RS), and their influence on the prognosis of HR+/HER2- breast cancer (BC) is not very well studied. Methods: We conducted a retrospective cohort study of patients diagnosed with resectable HER2-low and HER2-zero BC from the National Cancer Database. The primary outcome was overall survival (OS), and the association of RS with the clinical outcomes in HR+/HER2- BC was analyzed as an exploratory endpoint. Results: The distribution of RS was comparable between HER2-low and HER2-zero groups; however, the RSs of HER2-low tumors were more likely to be 16–25. Women with HER2-low tumors had longer 5-year OS than women with HER2-zero tumors in the HR-negative (84.3% vs. 83.9%; p < 0.001, HR: 0.87 (0.84–0.90), p < 0.001) but not in the HR-positive group (94.0% vs. 94.0%; p = 0.38, HR: 0.97 (0.95–0.99), p = 0.01). The survival advantage was observed in patients who received adjuvant/neoadjuvant chemotherapy (p-interaction (chemo vs. no chemo) < 0.001). Among those who received adjuvant chemotherapy in the group with higher RSs (26–100), those with HER2-low BC had higher 5-year OS than HER2-zero BC. Conclusions: Resectable HER2-low BC had a better prognosis than HER2-zero BC. Among those who received adjuvant chemotherapy in the higher oncotype RS group, those with HER2-low tumors had better survival.

Duration of cover crop (CC) management, CC biomass production, and other factors could impact how CC affects soil health. We studied the 8-year cumulative impacts of winter rye (Secale cereale L.) CC on soil physical, chemical, and biological properties in rainfed and irrigated no-till corn (Zea mays L.)-based systems in the western US Corn Belt. Average annual CC biomass production was 0.56 & PLUSMN; 0.51 Mg ha(-1) at the rainfed site and 0.98 & PLUSMN; 0.95 Mg ha(-1) at the irrigated site. After 8 years, CC improved particulate organic matter (POM) and mean weight diameter of water-stable aggregates (MWD) compared with no CC in the 0-5 cm soil depth at both sites. Cover crop increased total POM concentration by 2.8 mg g(-1) at the rainfed site and by 13.4 mg g(-1) at the irrigated site, while it increased MWD by 0.39 mm at the rainfed site and by 0.79 mm at the irrigated site. Also, CC increased soil C at a rate of 0.125 Mg ha(-1) year(-1) in the 0-5 cm depth but only at the rainfed site. Cover crop affected neither water infiltration nor available water but improved microbial biomass. Changes in other properties were site-dependent. Cover crop improved many soil properties after 8 years even though measurement taken after 4 years showed no significant effect of CC, which indicates CC slowly impacts properties in this environment. Low CC biomass production and high biomass input from corn-based systems may explain the slow soil response. In general, winter rye CC enhances near-surface soil properties in the long term.

PURPOSE Despite the growing calls for early and ubiquitous completion of advance directives (ADs), studies exploring links between AD completion and their impact on outcomes of patients with cancer have mixed conclusions. We used the ASCO Quality Oncology Practice Initiative (QOPI) registry to compare end-of-life (EOL) quality measures and the effect of QOPI certification among patients with and without early AD completion, defined as completion within the first three oncology visits after cancer diagnosis.METHODS Deidentified patient-level data were analyzed from the QOPI database from 2015 through 2017. Associations were assessed using Chi-square tests between early AD completion and patient enrollment in hospice < 7 days before death, chemotherapy receipt in the last 14 days of life, or with emergency room visits or intensive care unit admissions in the last 30 days of life.RESULTS Data from 31,558 patients eligible for the AD question were analyzed. Patients treated at QOPI-certified practices had higher rates of early AD completion than patients at non-certified practices. Early AD completion was not associated with differences in hospice enrollment for < 7 days before death, chemotherapy receipt in the last 14 days of life, or emergency room visits or intensive care unit encounters in the last 30 days of life.CONCLUSION The study found that QOPI certification is associated with higher rates of early AD completion. However, early AD completion was not associated with recognized EOL quality measures. Future research should focus on the timing, frequency, and content of AD conversations to demonstrate the impact on care at the EOL.

BACKGROUND:Lack of safe, reliable, and affordable transportation is a barrier to medical care, but little is known about its association with clinical outcomes.METHODS:We identified 28 640 adults with and 470 024 adults without a cancer history from a nationally representative cohort (2000-2018 US National Health Interview Survey) and its linked mortality files with vital status through December 31, 2019. Transportation barriers were defined as delays in care because of lack of transportation. Multivariable logistic and Cox proportional hazards models estimated the associations of transportation barriers with emergency room (ER) use and mortality risk, respectively, adjusted for age, sex, race and ethnicity, education, health insurance, comorbidities, functional limitations, and region.RESULTS:Of the adults, 2.8% (n = 988) and 1.7% (n = 9685) with and without a cancer history, respectively, reported transportation barriers; 7324 and 40 793 deaths occurred in adults with and without cancer history, respectively. Adults with a cancer history and transportation barriers, as compared with adults without a cancer history or transportation barriers, had the highest likelihood of ER use (adjusted odds ratio [aOR] = 2.77, 95% confidence interval [CI] = 2.34 to 3.27) and all-cause mortality risk (adjusted hazard ratio [aHR] = 2.28, 95% CI = 1.94 to 2.68), followed by adults without a cancer history with transportation barriers (ER use aOR = 1.98, 95% CI =1.87 to 2.10; all-cause mortality aHR = 1.57, 95% CI = 1.46 to 1.70) and adults with a cancer history but without transportation barriers (ER use aOR = 1.39, 95% CI = 1.34 to 1.44; all-cause mortality aHR = 1.59, 95% CI = 1.54 to 1.65).CONCLUSION:Delayed care because of lack of transportation was associated with increased ER use and mortality risk among adults with and without cancer history. Cancer survivors with transportation barriers had the highest risk.

Supplementary Figure 1 from Mapping Geographic Zones of Cancer Risk with Epigenetic Biomarkers in Normal Breast Tissue

RAGE/S100A7 axis inhibits breast cancer cell migration/invasion/motility.

Supplementary Figures 1-6, Tables 1-15, Methods from Epigenetic Silencing Mediated through Activated PI3K/AKT Signaling in Breast Cancer

PDF file - 596K, Table S1: Predicted GSK3b phosphorylation sites on SMO. TableS2: Predicted GSK3b phosphorylation sites on SMO. FIG S1: Generation of cell lines resistant to increasing concentration of tamoxifen. FIG S2: Mammosphere formation assay with cells resistant to increasing concentration of tamoxifen. FIG S3: Effect of Gli1 depletion on OHTR and T47D cells. FIG S4: Regulation of GLI1 by PI3k/Akt pathway.

<p>RAGE regulates macrophage recruitment.</p>

RAGE/mS100a7a15 axis enhances M2 macrophage recruitment to lungs.