Citations

Abstract Background: Ki67 values >10% 2-4 weeks (wks) after starting neoadjuvant ET (NET) indicates persistent cell proliferation, resistance to ET, and is associated with increased risk of recurrence. The ACOSOG Z1031 trial suggested that these tumors are also relatively chemotherapy (chemo) resistant with a low pathologic complete response (pCR) rate to NCT. The ALTERNATE trial (NCT01953588) is a randomized study of neoadjuvant anastrozole (ANA), fulvestrant (FUL), or ANA + FUL in postmenopausal patients (pt) with newly diagnosed clinical stage II or III ER+ (Allred score 6-8)/HER2- BC. Ki67 >10% at wk 4 or 12 after starting NET triggered triage to NCT of physician choice or weekly paclitaxel. Pts who refused protocol-directed therapy, were not candidates for NCT, or decided to undergo immediate surgery are being followed per protocol. Here we report the rates of pCR and residual cancer burden (RCB) following NCT for pts triaged to NCT due to Ki67 >10% at wk 4 or 12. Results: Of the 1,299 eligible pts randomized to receive ANA, FUL, or ANA + FUL, 286 (22%) had Ki67 >10% at wk 4 or 12. 168 of these 286 pts (58.7%) chose to switch to NCT, 32 went to surgery (11.2%), and 86 discontinued further protocol-directed therapy (30.1%). Among the 168 pts who underwent NCT, the presenting clinical T stages were cT2 (n=113; 67.26%), cT3 (n=47; 27.98%) and cT4 (n=8; 4.76%) and N stages were cN0 (n=82; 48.8%), cN1 (n=75; 44.6%), cN2/3 (n=9; 5.4%) and cNx (n=2; 1.2%). Central ER testing was performed on pre-treatment biopsies and confirmed ER Allred score 6-8 in 155 of 168 (92.2%) pts, with the rest being ER Allred score 4-5 (n=5; 3%), ER- (Allred score 0) (n=2; 1.2%), or not tested (n=6; 3.6%). Most (n=139; 82.7%) were ER+/PR+, while 17.3% (n=29) were ER+/PR-, and tumor grades were G1 (n=10; 6%), G2 (n=99; 58.9%), G3 (n=54; 32.1%), not reported (n=5; 3%). Baseline Ki67 levels prior to NET were >10% in 94% (n=158), ≤10% in 3% (n=5), and not done in 3% (n=5). NCT regimens administered included doxorubicin/cyclophosphamide (AC) followed by paclitaxel (T) (n=60; 35.71%); weekly paclitaxel (n=56; 33.33%), docetaxel/cyclophosphamide (TC) (n=33; 19.65%), other doxorubicin and/or taxane containing regimen (n=17; 10.12%), and cyclophosphamide/methotrexate/fluorouracil (CMF) (n=2; 1.19%). 35 (20.8%) pts did not complete planned course of NCT due to toxicity (n=27) or refusal (n=8). 154 NCT pts underwent surgery (mastectomy in 40.3%, and breast conserving surgery in 59.7%). The path ypT stages were Tis/0 (n=10; 6.5%), T1 (n=62; 40.3%), T2 (n=61; 39.6%), and T3/4 (n=21; 13.6%), and the ypN stages were N0 (n=66; 42.9%), N1 (n=57; 37%), N2/3 (n=30; 19.5%), and Nx (n=1; 0.6%). Among the 168 pts who started on NCT (intent to treat population), there were 8 pCRs (no invasive disease in the breast or lymph nodes) (4.8%; 95% CI: 2.1% to 9.2%). Residual Cancer Burden (RCB) categories include RCB 0 (n=8; 4.8%), RCB 1 (n=15; 8.9%), RCB 2 (n=82; 48.8%), RCB 3 (n=42; 25.0%), and not determined (n=21; 12.5%). Correlations of baseline pt and tumor characteristics with pathology response to NCT will also be presented. Conclusion: In pts with NET-resistant ER+/HER2- BC, salvage NCT is not likely to induce a complete or near complete response. More effective treatments are needed for this high-risk ER+/HER2- pt population. Support: U10CA180821, U10CA180882, U24CA196171, UG1CA189856, U10CA180868 (NRG); NCI BIQSFP, BCRF, Genentech, AstraZeneca. https://acknowledgments.alliancefound.org. Clinical Trials.gov Identifier: NCT01953588 Citation Format: Cynthia X Ma, Vera Suman, A. Marilyn Leitch, Souzan Sanati, Kiran Vij, Gary W Unzeitig, Jeremy Hoog, Mark Watson, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erika Crouch, Horacio Maluf, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J Hieken, Yang Wang, Travis Dockter, Jo Anne Zujewski, Anna Weiss, Kelly Hunt, Clifford Hudis, Eric P Winer, Matthew J Ellis, Lisa A Carey, Ann H Partridge. Neoadjuvant chemotherapy (NCT) response in postmenopausal women with clinical stage II or III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) resistant to endocrine therapy (ET) in the ALTERNATE trial (Alliance A011106) [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 GS4-05.

Abstract Background: With few targeted therapies available for triple-negative breast cancer (TNBC), there is a critical need to identify biomarkers that can predict chemotherapy-response. Copy number amplifications (CNAmps) have been implicated in tumorigenesis, progression, and treatment response. Previously, we performed a prospective neoadjuvant chemotherapy study (BEAUTY) and identified a 5 Mb CNAmp in TNBC patients associated with pathological complete response rates to taxane- and anthracycline-based chemotherapy. Here we further interrogated this amplicon and its role in chemotherapy response. Methods: Using siRNA screening of genes identified in the 5 Mb CNAmp, followed by cytotoxicity assays, we identified RDH10 significantly associated with chemo-sensitivity in TNBC cell lines. Functional studies were performed using RDH10 knockdown or overexpression followed by cytotoxicity, cell proliferation, luciferase reporter assays, HPLC or western blot. Results: RDH10 is a rate-limiting step involved in the synthesis of all-trans retinoic acid (ATRA) - the active metabolite of retinoid metabolism that is frequently aberrant in cancer. Previous studies demonstrated ATRA to be a potent inhibitor of PIN1, a key regulator of several oncogenic signaling pathways often amplified in TNBC. We discovered that genetic manipulation of RDH10 affected ATRA intracellular concentrations, contributing to PIN1 degradation and taxane-response. Furthermore, co-treatment of TNBC cells with ATRA significantly increased taxane-sensitivity. Conclusion: RDH10 amplification increases endogenous levels of ATRA and degrades PIN1 in TNBC. ATRA-mediated degradation of PIN1 sensitizes TNBC to chemotherapy, suggesting that RDH10 may be a novel biomarker of taxane response and the addition of ATRA to standard chemotherapy may improve chemo-sensitivity.

BackgroundFactors associated with receiving initial care for thyroid cancer (TC) at academic centers (ACs) versus nonacademic centers (NACs) and their impact on patient outcomes have not been reported.MethodsThe National Cancer Database with TC cases from 2004 to 2013 was evaluated for association of type of center for initial care with socioeconomic factors and disease and treatment characteristics, as well as overall survival (OS; all‐cause mortality).ResultsThe patients with TC (n = 200,824) included were predominantly women (74%), non‐Hispanic Whites (85%), and from metro areas (84%). Sixty percent received initial care at a NAC. There were no significant differences between treatment groups by age or gender. Among those treated at an AC, a higher proportion belonged to racial/ethnic minorities (16.5%) versus at a NAC (11.6%). Hormone therapy was used more in an AC versus a NAC (60% vs 47%). Patients with all TC pathologies combined had a lower likelihood of death when they received initial care at an AC (hazard ratio [HR], 0.948; P = .0006). Among individual pathologic subtypes, a lower likelihood of death was noted when initial care was received at an AC for follicular (HR, 0.828, P = .0010) and Hurthle cell cancers (HR, 792; P = .0008), as well as stage II papillary thyroid cancer (HR, 0.828; P = .0026), but not for other histopathologic subtypes.ConclusionsInitial care at an AC was associated with lower likelihood of death for patients with TC, especially for those with follicular or Hurthle cell subtypes. Optimal resource use with consideration of patients' socioeconomic and demographic factors is imperative to ensure the most appropriate management of patients with TC in various treatment settings.

AbstractBackgroundAlzheimer’s disease (AD) prevention trials aim to intervene prior to significant neuronal loss, brain damage, and symptom onset to delay or slow cognitive decline. In dominantly inherited AD (DIAD), mutation carriers develop symptomatic AD at predictable ages with near 100% penetrance. In 2012, the Dominantly Inherited Alzheimer Network Trials Unit Adaptive Prevention Trial (DIAN‐TU APT) platform launched a double‐blind, randomized, placebo‐controlled, parallel group trial of two anti‐amyloid‐beta monoclonal antibodies with two different antigenic targets, gantenerumab and solanezumab (NCT01760005). The DIAN‐TU scientific development, implementation of the first AD prevention trial, trial challenges and opportunities, including dose escalation, and top‐line results will be presented.MethodDIAN was established in 2008 in response to a call from the National Institute of Aging to establish a network to study DIAD and enable future clinical trials. Successive breakthroughs in understanding disease processes enabled the launch of the DIAN‐TU adaptive prevention trial, a global adaptive platform trial supporting testing multiple drugs in parallel. The DIAN‐TU partners include patients and families at risk for DIAD, global academic researchers, the NIH, Alzheimer’s Association, philanthropic supporters, the DIAN‐TU Pharma Consortium, and pharmaceutical companies with drugs being tested. Important milestones include developing a platform to enable a comprehensive efficient treatment trial for this rare population, adding tau PET as part of AMP AD, adapting dosing mid‐trial and extending the original biomarker trial to continue randomized dosing to test a cognitive endpoint until the last patient reaches 4 years, developing a disease progression statistical model and inclusion of DIAN observational data to increase the power to determine drug effects.ResultThe primary and key secondary outcomes of the DIAN‐TU trial will be presented for each therapy in the context of targeting amyloid‐beta at pre‐clinical and clinically symptomatic stages of disease.ConclusionThese results inform about AD hypotheses, timing of treatment and the prospect of slowing, or preventing AD in DIAD and sporadic AD.

AbstractBackgroundGantenerumab is a humanized anti‐amyloid‐beta monoclonal antibody in clinical development for the treatment of several stages of Alzheimer disease (AD). Gantenerumab was evaluated in a phase 2/3 clinical trial program designed to evaluate its efficacy in autosomal dominant AD based on a combination of clinical and biomarker evidence.MethodThe study enrolled both mutation carriers (n=69 with 3:1 randomization of treatment (n=52) vs placebo (n=17)) and non‐carriers (n=28, all on placebo) from 15 years before to 10 years after the expected age of onset inclusive. Patients were both asymptomatic (CDR 0 and MMSE >25) and symptomatic (CDR 0.5‐1 and MMSE >16). There were 41 asymptomatic and 28 symptomatic mutation carriers. The initial dose of gantenerumab was 225 mg monthly administered subcutaneously. The dose was titrated to 1200 mg/month following a protocol amendment based on the increased amyloid lowering seen at higher doses in the gantenerumab program in symptomatic AD. The treatment duration was a minimum of 4 years (range 48‐80 months). The primary outcome was change from baseline in the DIAN‐TU multivariate cognitive endpoint. Secondary clinical outcomes included the DIAN‐TU cognitive composite, Cogstate multivariate cognitive endpoint, CDR SB, and time to CDR progression of >0.5 points. Change from baseline in amyloid PET was the primary biomarker outcome. Other biomarker outcomes included MRI, tau PET, CSF amyloid, tau and phosphotau, and CSF and plasma neurofilament light (NfL). Safety outcomes including ARIA were compared between drug and placebo groups.ResultWe will report change from baseline on the DIAN‐TU multivariate cognitive endpoint, DIAN‐TU cognitive composite, CDR‐SB and other secondary efficacy endpoints. We expect significant lowering on amyloid PET with PIB and florbetapir based on the results from recent anti‐amyloid antibodies, including Gantenerumab, in sporadic AD. We will also present the results of change in other key imaging and fluid biomarkers. The frequency, duration, and severity of ARIA will be reported and compared with studies in sporadic AD.ConclusionThis clinical trial was designed to inform future for ADAD and will provide new insights on the role of amyloid reduction in both pre‐symptomatic and clinical AD.

AbstractBackgroundSolanezumab is a monoclonal antibody targeting soluble forms of β‐amyloid protein important in the pathogenesis of Alzheimer’s disease (AD). Three previous 18‐month double‐blind placebo‐controlled trials of low‐dose solanezumab in late‐onset sporadic AD found inconsistent benefits on cognitive and functional assessments. Dominantly‐inherited mutation‐associated AD subjects both before and after onset of symptoms form an ideal population to study potential benefits of solanezumab therapy.MethodMutation‐carrying asymptomatic (CDR 0, N=41) or mildly symptomatic (CDR 0.5 – 1, N=28) patients were treated for a minimum of 4 years and up to 7 years in a double‐blind 3 to 1 active versus placebo randomized clinical trial that measured disease progression by clinical, neuropsychological and biomarker evaluations. The trial was initiated with a dose of 400 mg every 4 weeks and escalated to 1600 mg when low dose trials in sporadic AD did not meet their primary endpoints. The primary cognitive outcome measure was DIAN‐MCE, composed of Delayed Recall Score of the International Shopping List Test, the Delayed Recall score of the Logical Memory IIa subtest from the Wechsler Memory Scale‐Revised, the Digit Symbol Substitution Test total score from the WAIS‐R and the MMSE total score. Secondary outcomes included a battery of other cognitive and functional measures. The study was powered to detect delay of cognitive disease progression in the DIAN‐MCE. Biomarkers include imaging modalities (volumetric MRI, FDG, amyloid and Tau PET). CSF markers included β‐amyloid, Tau and PhosphoTau species. NfL was measured in both CSF and plasma. The study used a pre‐specified Bayesian multivariate disease progression model, which included dynamic borrowing of control subjects from the DIAN Observational study.ResultThe topline efficacy, safety and biomarker results will be reported.ConclusionThis study provides the first test of targeting soluble abeta forms in DIAD. It addresses the efficacy of early initiation of higher doses of solanezumab targeting soluble forms of amyloid as a disease modifying therapy. While these results are specific to DIAD, they have the potential to inform the application of anti‐amyloid therapy in sporadic AD.

Abstract Purpose: Among a Latina population in a low resource healthcare setting, to test the effectiveness of bilingual (Spanish/English) written and interpersonal educational interventions in increasing breast density (BD) awareness, knowledge, and conversations with healthcare providers, which are goals of BD notification mandates. Procedures: This randomized trial was conducted at a Federally Qualified Health Center (FQHC) in an urban community of the Southwest U.S. Women ages 40- 74 presenting for screening mammography were recruited and randomized 1:1:1 to usual care (mailed letter with mammogram and BD results), enhanced care (letter plus BD educational brochure), or interpersonal care (letter, brochure, and telephonic promotora education). The baseline survey was administered in person at enrollment prior to the mammogram. Follow-up surveys were by phone or mail after the mammography results letter was mailed and promotora delivery was complete (median days from baseline to follow-up survey = 97 days). Differences between groups at baseline or follow-up were assessed with chi-square tests. Logistic regression using generalized estimating equations to account for repeated data was used to assess differences by time (baseline to follow-up) within group, including a time-by-group interaction. Results: Between October 2016 and October 2019, 1377 women were enrolled. Of these, 1085 (79%) self-identified Latinas completed baseline and follow-up surveys. Median age was 47 years. Most (91%) reported speaking mostly Spanish, and 69.1% had less than a high school degree. At baseline, only 20.9% reported having heard of BD, and only 30.5% of those knew their personal BD category. At follow-up, women in the interpersonal group were more likely to report seeing their BD results in the notification letter compared to the usual care and enhanced groups (70.4% vs. 52.9% and 54.3%, p < 0.001) and to report having spoken with a provider about their BD (27.3% vs. 14.2% and 15.7%, p < 0.001). They also reported higher mean understanding of BD (7.7 on a 0-10 scale vs. 6.3 and 6.6, p < 0.001). There were no significant differences on these outcomes between the usual care and enhanced groups. All groups saw significant improvement in correct responses from baseline to follow-up for questions on the ability of BD to mask tumors on a mammogram and BD as a breast cancer risk factor (p < 0.001 all groups), but the degree of improvement in masking knowledge was significantly higher for the interpersonal vs usual care group [OR for a correct response in follow-up vs baseline: 6.4 (interpersonal) vs 3.7 (usual care), p=0.01]. Conclusion: Among a Latina population in a FQHC, telephonic promotora education was more effective than written notification alone or a mailed brochure on key goals of notification mandates. Adding a brochure does not appear to be more effective than sending a letter alone on key outcomes, but the interpersonal nature of promotora education may prompt attention to mailed information and provide an opportunity for questions. Citation Format: Jennifer L. Ridgeway, Sarah M. Jenkins, Deborah J. Rhodes, Bhavika K. Patel, Edna Ramos, Bijan Borah, Karthik Ghosh, Vera J. Suman, Aaron Norman, Davinder Singh, Celine M. Vachon. Evaluating educational interventions to increase breast density awareness among Latinas: A randomized clinical trial in a Federally Qualified Health Center [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-245.

Abstract Objective: Breast density notification laws aim to increase women’s awareness and knowledge about breast density (BD). This study’s aim was to compare BD knowledge and awareness in two Hispanic populations: a safety-net clinic serving Latina population in Maricopa County, Arizona (AZ) and a national sample of Hispanic women participating in an online research panel. Materials/Methods: Women ages 40-74 were recruited at the AZ clinic from 2016-2019 at a screening mammography appointment as part of a larger clinical trial (AZ cohort). Surveys were completed in person (English or Spanish) at enrollment to assess awareness of BD, understanding of BD risk, and mammography history. The same questions were asked in a nationally representative online panel survey conducted in 2017. All data from the national survey were weighted to adjust for probability of selection into the panel and post-stratified to match known U.S. Hispanic population distributions (NS cohort). Univariate comparisons between the clinic and the national panel were performed using Rao-Scott chi-square tests. Associations with awareness and correct knowledge were examined with multivariable logistic regression. All summaries and analyses are weighted, and were performed with SAS version 9.4 SURVEY procedures (SAS Institute Inc., Cary, NC). Results: The analysis included 1332 Hispanic women from the AZ clinic and 152 Hispanic women who completed the national survey. The AZ cohort was younger (mean age: 48.5 vs 52.8), had less education (less than high school: 68.7% vs 34.8% less than high school), more likely to prefer Spanish (92.3% vs 53.1%) and less likely to have had a prior mammogram as compared NS cohort (82.8% vs 90.4%) (all p≤ 0.03). NS cohort was more likely to have awareness of BD (32.6% vs 20.7%); correct understanding of the masking effect of BD, (67.8% vs 37.0%,) and breast cancer risk (72.2% vs 32.6%,), compared to the AZ cohort (all p < 0.004). When adjusted for differences in education, age, language, and screening mammography history, BD awareness was similar between the two cohorts (adjusted odds ratio [ORadj] 0.95, p=0.83). Awareness was positively associated with more education, previous mammogram history, and English language. However, differences in BD knowledge remained (ORadj=2.8 [p=0.03] and 7.2 [P<0.001] for knowledge of masking and risk, respectively). Conclusions: There were significant differences in BD awareness and knowledge between a nationally-representative sample of Latinas and Latinas in a low-resource setting. The differences in BD awareness, but not knowledge, could be explained by education, screening history and preferred language. These findings suggest that a one-size-fits-all approach to raising BD awareness and knowledge will not work. To ensure equitable dissemination of health care to Latina women undergoing screening mammography, future work should be aimed at developing effective tools and resources for educating Spanish-speaking women about BD and risk-based screening. Citation Format: Jillian Leaver, Bhavika K. Patel, Jennifer L. Ridgeway, Sarah Jenkins, Vera Suman, Deborah J. Rhodes, Aaron Norman, Karthik Ghosh, Bijan Borah, Carrie Hruska, Edna Ramos, Davinder Singh, Matt Jewett, Carmen Radecki-Breitkof, Celine Vachon. Breast density knowledge and awareness among Latinas in a low-resource setting: A comparison nationally-representative sample of Latinas [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-238.