Trials In Breast Cancer Patients Research Articles

Social Representativeness and Intervention Adherence-A Systematic Review of Clinical Physical Activity Trials in Breast Cancer Patients.

Representativeness in physical activity randomised controlled trials (RCT) in breast cancer patients is essential to analyses of feasibility and validity considering privileged- social groups. A step-by-step exclusion of less privileged groups through the trial process could reinforce health inequality. This study aimed at examining representativeness in breast cancer (BC) physical activity trials, investigate associations between socio-economic status (SES) and intervention adherence, and explore associations between representativeness and the relationship between SES and intervention adherence. Systematic, computerised searches were performed in PubMed, CINAHL, AMED, EMBASE and PsycINFO. Additional citation-based searches retrieved 37 articles. Distributions of education level, ethnicity, and marital status in study samples were compared to national populations data to estimate representativeness in less privileged groups. A preponderance of studies favoured educated, married and white patients. Only six studies reported SES-adherence associations, hampering conclusions on this relationship and possible associations between representativeness and an SES-adherence relationship. Less educated, unmarried and non-white individuals may be underrepresented in BC physical activity RCTs, while SES-adherence associations in such trials are inconclusive. Unintentional social misrepresentations may indicate that disguised inequity warrants revived attention.

A Phase II Study Evaluating the Effect of Intensity Modulated Postmastectomy Radiation Therapy on Implant Failure Rates in Breast Cancer Patients With Immediate, 2-Stage Implant Reconstruction With an MRI Imaging Correlative Substudy

BackgroundPostmastectomy radiation therapy (PMRT) is a mainstay in the adjuvant treatment of node-positive breast cancer, but it poses risks for women with breast reconstruction. Multi-beam intensity-modulated radiation therapy (IMRT) improves dose conformality and homogeneity, potentially reducing complications in breast cancer patients with implant-based reconstruction. To investigate this hypothesis, we conducted a single-arm phase II clinical trial of breast cancer patients who underwent mastectomy/axillary dissection and prosthesis-based reconstruction. MethodsThe primary endpoint was the rate of implant failure within 24 months of permanent implant placement, which would be considered an improvement over historical controls if below 16%. Implant failure (IF) was defined as removal leading to a flat chest wall or replacement with another reconstruction. Patients were analyzed in two cohorts. Cohort 1 (RT-PI) received RT to the permanent implant (PI). Cohort 2 (RT-TE) received RT to the TE. Implant failure rates, adverse events, and quality of life (QOL) were analyzed. Follow-up/post-RT assessments were compared to the baseline/pre-RT assessments at 3-10 weeks after exchange surgery. A subgroup underwent serial MRIs to explore the association of MRI-detected changes with capsular contracture, a known adverse effect of RT. ResultsBetween June 2014 and March 2017, 119 women were enrolled. Cohort 1 included 45 patients, and Cohort 2 had 74 patients. Among 100 evaluable participants, 25 experienced IF during the study period. IF occured in 8/42 (19%) and 17/58 (29%) in Cohorts 1 and 2, respectively. Among the IFs, the majority were due to capsular contracture (13), infection (7), exposure (3), and other reasons (2). Morphological shape features observed in longitudinal MRI images were associated with the development of Baker grade 3-4 contracture. ConclusionsThe rate of implant failure in reconstructed breast cancer patients treated with IMRT was similar to, but not improved over, conventional, 3D-conformal methods. MRI imaging features show promise for predicting capsular contracture but require validation in larger studies.

Mortality comparison between axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SND) among breast cancer pantient: A meta-analysis and systematic review study

Introduction: Axillary lymph node dissection (ALND) is a crucial surgical procedure for breast cancer. It has guaranteed locoregional control of the disease, guided adjuvant therapy, and functioned as a staging tool. However, over the past 25 years, a more conservative approach has become the standard for surgical management of the axilla. Because sentinel lymph node biopsy (SNB) is less invasive and less morbid than axillary lymph node dissection (ALND), it has become the standard surgical procedure for axillary staging of clinically node-negative breast cancer. This study aimed to compare the mortality of breast cancer patients receiving ALND and SNB procedure. Methods: Our review includes randomized controlled trials of breast cancer patients undergoing ALND or SNB surgical techniques. A systematic literature search was performed from PubMed on December 2023 to search for articles reporting on survival rates between ALND vs SNB among breast cancer patients. The data obtained then underwent statistical evaluation, and a meta-analysis was conducted using Review Manager 5.4. In order to represent primary outcomes, the risk ratio was estimated using an inverse variance technique with a random-effects model. Heterogeneity was presented with total values, 95% confidence intervals (CI), and I values. Results: As many as 208 articles were found in the PubMed database search, and only six studies were included in this study. The six included trials all used chemotherapy and radiotherapy for systematic treatment. The length of follow-up varied from 33 months to 15 years. The total number of patients in the trials was 3,585, and the study period was from 2011 to 2023. The pooled analysis of the mortality outcomes showed that the heterogeneity of the data was low (I2 21%, p = 0.4). In the pooled analysis, the mortality of patients with SNB for surgical treatment was not significantly different compared to patients with ALND (OR:0.88; 95% CI:0.65-1.19). Conclusion: The mortality of patients undergoing SNB and ALND does not differ significantly, according to this pooled study. It demonstrates that the group without axillary dissection had a primary survival outcome that was not inferior to that of the dissection group.

Different approaches to target volume definition and boost delivery in surgery de-escalation clinical trial in breast cancer patients with pathological complete response.

We evaluate various approaches to target volume definition and boost delivery in patients with complete response to neoadjuvant systemic therapy (NST) who were treated by radiotherapy without a surgery. A pathological complete response (pCR) was diagnosed in 21 of 27 patients included in "surgery de-escalation" prospective observation study. Clips were placed in the primary tumor volume (PrTV) before NST and during the vacuum aspiration biopsy. Twenty patients with pCR underwent the whole breast irradiation and a boost to the PrTV. High-dose rate brachytherapy (HDRB) was the basic technique for boost delivery. Finally, we identified the value of fused images (computed tomography [CT] before NST with simulation CT), clips and their combination for an accurate boost delivery. A complete overlap between PrTV on pre-treatment CT with the localization of the clips on simulation CT was mentioned in 10, partial mismatch in three patients. In 12 of these 13 women, HDRB was successfully used for the boost delivery. In five cases we mentioned a marked discrepancy between the PrTV on fused images and the topography of the clips. In other two women we did not find clips on simulation CT. The fused images in five of these seven patients showed anatomical landmarks (scar, fibrosis) used for identification of the gross tumor volume. In all 20 women with pCR (average follow-up of 16.6 months), there were no locoregional recurrences. Combination of the clips with fusion of pre-NST and simulation CTs is important for an accurate boost delivery.

In-Vitro and In-Silico Approach Distinguish ER-α and HER-2 Antagonistic Properties of Indian Herbal Formulation on Breast Cancer

Objectives: The anticancer effect of an Indian herbal preparation was studied under a cancer cell line, as well as the in silico computational methods that explain the probability of protein ligands binding to ER- α and HER-2 receptors.
 Method: The in vitro anticancer activity of Body Revival® suspension (BR) was determined using cytotoxicity tests, cell invasion and migration assays, and metastatic protein expression assays using MCF-7 breast cancer cells. The computational predictive biological method was applied to find out the pharmacodynamic and pharmacokinetic interactions between the active molecules present in the BR and ER- α/and HER-2 of breast cancer.
 Results: BR showed significant and dose dependent cytotoxic effects on MCF-7 cells. The 50% effective cytotoxic dose of BR was 34.27µl/ml. It restricted invasion (26%) and migration (28%) of cancer cells than BSA control. MMP-9 and IL-6 concentration were reduced significantly (p<0.001) after treatment. Cucurbitacin B had maximum in silico binding energy score (-7.8) with ER-α, while symconoside B had with HER-2 (-8.4); but, among the other interactions between the two ligands and receptors, withaferin A had the highest affinity (-15.3). Additionally, withaferin A, symconoside A, and symconoside B curcurbitacin A demonstrated bioavailability and fulfilled safety standards. 
 Conclusion: Body Revival® showed as a powerful multi-target inhibitor of ER- α and HER-2 that has prospective anticancer action without side effects, and may be useful in the therapy management following a successful trial in breast cancer patients.
 Keywords: Breast cancer, Cytotoxicity, MCF-7, ER- α, HER-2, Herbs, In Silico

HER2+ esophageal carcinoma leptomeningeal metastases treated with intrathecal trastuzumab regimen.

Materials & methods: We recently reported the largest trial of breast cancer patients with HER2 positive leptomeningeal metastases (LM) treated with trastuzumab. An additional treatment indication was explored as part of a single institution retrospective case series of HER2 positive esophageal adenocarcinoma LM (n=2). Results: One patient received intrathecal trastuzumab (80mg twice weekly) as part of their treatment regimen with durable long-term response and clearance of circulating tumor cells in the cerebral spinal fluid. The other patient demonstrated rapid progression and death as previously described in the literature. Conclusion: Intrathecal trastuzumab is a well-tolerated and reasonable therapeutic option worthy of further exploration for patients with HER2 positive esophageal carcinoma LM. An associative, but not a causal relationship, can be made regarding therapeutic intervention.

Telehealth multicomponent exercise and health education in breast cancer patients undergoing primary treatment: rationale and methodological protocol for a randomized clinical trial (ABRACE: Telehealth)

BackgroundCurrent guidelines emphasize cancer patients should increase their physical activity levels, encouraging physical exercise practice as a complementary therapy to mitigate adverse effects during treatment. Telehealth can be a feasible method to improve adherence and interventional support for breast cancer patients, of which most do not meet sufficient physical activity levels after diagnosis. The Adaptations to Breast Cancer and Exercise Using Telehealth (ABRACE: Telehealth) study aims to investigate the effects of a 12-week telehealth multicomponent training program plus a health education program (MTHE), compared to a health education program alone (HE), on physical and psychological outcomes in breast cancer patients undergoing treatment.MethodsThis study is a randomized controlled trial. Women undergoing primary treatment (during or after chemotherapy) for breast cancer (stages I–III) will be randomly assigned to MTHE (twice a week) or HE (once a week). MTHE components are mobility, aerobic, balance, resistance, and flexibility home-based exercises, supervised by video call. The primary study outcome is cancer-related fatigue. The secondary outcomes are quality of life, symptoms of depression and anxiety, physical activity level, cancer-related cognitive impairment, and functional capacity. Other outcomes are adherence to interventions and a follow-up questionnaire evaluating the individual perception in motivation, lifestyle changes, and main barriers to participation. All outcomes will be remotely assessed before and after intervention. Our analysis will follow the intention-to-treat approach and per-protocol criteria, with additional sub-group analysis.DiscussionTo our knowledge, this is the first randomized clinical trial in breast cancer patients using a face-to-face videoconference strategy to supervise physical exercise. Our hypothesis is of superiority for the effects of MTHE on primary and secondary outcomes compared to the effects of only the health education intervention.Trial registrationAdaptations to Breast Cancer and Exercise Using Telehealth (ABRACE: Telehealth), NCT04641377. Registered on 23 November 2021, https://clinicaltrials.gov/ct2/show/NCT04641377

Role of alpha-lipoic acid in counteracting paclitaxel- and doxorubicin-induced toxicities: a randomized controlled trial in breast cancer patients

Background and objectivePaclitaxel and doxorubicin are associated with neurotoxicity and cardiotoxicity respectively. This study aimed at investigating the role of alpha-lipoic acid (ALA) in counteracting paclitaxel-induced neuropathy and doxorubicin-associated cardiotoxicity in women with breast cancer.Patients and methodsThis randomized double-blind placebo-controlled prospective study included 64 patients with breast cancer who were randomized into control group (n = 32) which received 4 cycles of doxorubicin plus cyclophosphamide (every 21 days) followed by weekly doses of paclitaxel for 12 weeks plus placebo tablets once daily and ALA group (n = 32) which received the same chemotherapeutic regimen plus ALA 600 once daily for 6 months. Patients were assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 4.0) for grading of neuropathy and by 12-item neurotoxicity questionnaire (Ntx-12). The assessment included also echocardiography and evaluation of serum levels of brain natriuretic peptide (BNP), tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), and neurotensin (NT). Data were analyzed by paired and unpaired t-test, Mann–Whitney U test, and chi-square test.ResultsAs compared to placebo, ALA provoked significant improvement in NCI-CTCAE neuropathy grading and Ntx-12 score after the end of 9th and 12th weeks of paclitaxel intake (p = 0.039, p = 0.039, p = 0.03, p = 0.004, respectively). At the end of the chemotherapy cycles, ALA resulted in significant decline in serum levels of BNP, TNF-α, MDA, and neurotensin (p < 0.05) as compared to baseline data and placebo.ConclusionAlpha-lipoic acid may represent a promising adjuvant therapy to attenuate paclitaxel-associated neuropathy and doxorubicin-induced cardiotoxicity in women with breast cancer.Trial registrationClinicalTrials.gov: NCT03908528.

Abstract P3-14-11: Mammaprint and Blueprint identify genomic differences in HR+ HER2- breast cancers from young Black and White women

Abstract Introduction: Hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer, the most common immunohistochemical subtype, remains the dominant contributor to annual breast cancer deaths worldwide across all racial and ethnic groups. Black women are 41% more likely to die from breast cancer compared to White women, predominantly among women diagnosed ≤ 50 years of age. Yet, Black women remain underrepresented in clinical trials and population-based studies. Thus, it is critical to better characterize tumor molecular features from young Black women to identify factors contributing to the existing racial survival disparity. In the current study, we compared risk of distant recurrence signature, MammaPrint (MP), molecular subtyping signature, BluePrint (BP), and whole transcriptome differences between young Black women with HR+ HER2- breast cancer compared to matched White controls. Methods: This study included 156 Black women aged ≤ 50 with stage I-III, HR+ HER2- breast cancer of whom, 68 were recruited from 2009-2014 as part of the BEST study (5R01CA204819-04) with follow-up data available (median 114.5 months). The remaining 88 Black women were enrolled in the ongoing FLEX Study (NCT03053193) from 2017. White women (n=156) were randomly selected from FLEX and matched by age, tumor stage, and receptor status. Tumors were classified through MP as Low Risk (MP-LR) versus High Risk (MP-HR), with MP-HR further stratified into HR1 and HR2; HR2 tumors exhibit superior chemosensitivity as demonstrated in a prior large clinical trial of breast cancer patients (ISPY2). All women had MP and BP to classify tumors as Luminal A (MP-LR), Luminal B (MP-HR), HER2, or Basal, and full transcriptomic analyses. Differential gene expression analysis was performed with R package ‘limma’ to compare Black and White women and further compare within each molecular subtype. Differentially expressed genes (DEGs) with a false discovery rate &amp;lt;0.05 were significant. Results: Of 312 young women with localized, HR+ HER2- breast cancer, high grade tumors were more frequent among Black compared to White women (34.6% vs 25.6%; p=0.08). MP-HR tumors were significantly more frequent among Black compared to White women (67.3% vs. 50.0%; p=0.002). Among MP-HR tumors, more HR2 tumors were seen in Black (25.6%) compared to White women (14.1%). Among women with MP-HR tumors and known treatment information, most Black women (94.3%) and all White women received chemotherapy. There were more Luminal B tumors in Black compared to White women (51.9% vs. 41.7%; p=0.07). BP reclassified a larger proportion of ER+ tumors as Basal in Black compared to White women (14.1% vs. 8.3%). Of 68 Black women with available survival data, 7 had death and/or distant recurrence events, of whom 6 (85.7%) had MP-HR tumors (4 Luminal B, 1 HER2, and 1 Basal) and 1 had MP-LR Luminal A tumor. Compared to White women, Black women with: 1) Luminal B tumors had 192 DEGs with upregulation of suspected poor prognosis genes, PSPH and IGHG1; 2) Luminal A tumors had upregulation of PSPH; and 3) Basal tumors had downregulation of POTEH. Conclusion: Among young women with localized HR+ HER2- breast cancer, MP and BP molecular signatures more robustly identified racial disparities in risk and subtype distribution beyond that identified through clinical factors adjusted for age and tumor characteristics. The transcriptomic differences among Black compared to White women across all BP subtypes provide novel insights about tumor biological differences. These findings have tremendous translational potential to identify etiologic underpinnings of racial survival disparities which may guide therapeutic strategies to improve outcomes. Citation Format: Sonya Reid, Tuya Pal, Ingrid A. Mayer, Xiao-Ou Shu, Ann L. Tezak, Kent Hoskins, Dipali Sharma, Patricia Robinson, Jennifer Wei, Jake Ruby, Shiyu Wang, Josien Haan, Andrea Menicucci, William Audeh, FLEX Investigators Group. Mammaprint and Blueprint identify genomic differences in HR+ HER2- breast cancers from young Black and White women [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-11.

Abstract 9710: Prevention of Doxorubicin-Induced Cardiotoxicity Through Targeted Degradation of Topoisomerase 2b

Introduction: Doxorubicin-induced cardiotoxicity is a serious complication of cancer therapy recognized 40 years ago and remains to be a major clinical challenge today. Doxorubicin poisons topoisomerase 2a to kill cancer cells, whereas doxorubicin induces cardiotoxicity through topoisomerase 2b. When topoisomerase 2b was genetically deleted in the cardiomyocytes of adult mice, doxorubicin-induced cardiomyopathy can be prevented. Hypothesis: Pharmacological depletion of topoisomerase 2b in cardiac tissue could prevent doxorubicin-induced cardiomyopathy. Methods: Cell lines were treated with dexrazoxane (100 μM) for different time intervals with or without the proteasome inhibitor MG132 (10 μM). Cell lysates were immunoblotted with anti-topoisomerase 2a or 2b antibodies or anti-actin. Mice were injected with dexrazoxane (100 mg/kg IP) and cardiac tissues were analyzed for expression of topoisomerase 2b over time using western blot analysis. To study the effect of dexrazoxane pre-treatment on doxorubicin-induced chronic heart failure, C57BL/6 mice (n=7) were pre-treated with dexrazoxane (100 mg/kg IP) 8 hours before doxorubicin (5 mg/kg IP). Single injection of dexrazoxane (n=6), doxorubicin (n=8), or saline control (n=6) were also administered to three different cohorts of mice. This protocol was repeated weekly for 5 weeks. Pre-treatment and post-treatment cardiac MRI were obtained to evaluate the change in left ventricular ejection fraction. Results: Dexrazoxane induced a ubiquitin-dependent degradation of topoisomerase 2b, but not 2a in cell lines. In dexrazoxane-treated mice, topoisomerase 2b was not detectable 8 hours after dexrazoxane administration, but gradually returned to normal levels by 48 hours. Dexrazoxane pre-treatment 8 hours before doxorubicin prevented doxorubicin-induced reduction in ejection fraction as determined by cardiac MRI in a chronic heart failure model. Conclusions: Targeted degradation of topoisomerase 2b by dexrazoxane prevented doxorubicin-induced cardiotoxicity. Through selective degradation of topoisomerase 2b, but not 2a, doxorubicin's tumoricidal activity is preserved. This preventive strategy will be tested in a prospective clinical trial in breast cancer patients.

MC1732: Pilot/Phase II Trial of Hypofractionated Radiotherapy to the Whole Breast Alone Before Breast Conserving Surgery

To report the results of our phase II trial of breast cancer patients treated with hypofractionated whole breast radiation therapy (RT) prior to breast conserving surgery (BCS).Between 2019 and 2020, patients with cT0-T2, N0, M0 breast cancer were enrolled. Patients were treated with hypofractionated whole breast RT, 25 Gy in 5 fractions, 4-8 weeks prior to BCS. RT was delivered with proton beam therapy or photons and no RT boost or regional nodal irradiation was allowed. Pathologic assessment was performed using the Residual Cancer Burden (RCB). Toxicities were assessed according to Common Terminology Criteria for Adverse Events (CTCAE, Version 4). Quality of life (QOL) was assessed with Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE), The Breast Cancer Treatment Outcome Scale (BCTOS), Linear Analogue Self-Assessment (LASA), and patient-reported outcomes measurement information system (PROMIS). Deterioration of cosmesis was defined as going from excellent/good to fair/poor or from fair to poor according to the Harvard Cosmesis Scale.Twenty-two patients were enrolled. Median follow-up was 7.1 months (range, 0.2-16.8). Median age at RT was 64.1 years (range, 44.3-76.7). Tumor characteristics included: IDC 68%, ILC 14%, DCIS 5%, other 14%; grade 1 55%, grade 2 36%, 5%; ER+HER2- 95%, ER+HER2+ 5%; right-sided 68%, left-sided 32%. The DCIS were all ER+. Pre-treatment tumor size include Tis 5% and T1 95%. Median time from RT to BCS was 8 weeks. Seven (32%) patients and 3 (14%) patients experienced grade 2+ or 3 toxicity, respectively. Overall QOL LASA and PROMIS did not change significantly from baseline (P = 0.21 and P = 0.72, respectively). There was no clinically significant change (≥1 point) in any of the BCTOS domains. Patient satisfaction with treatment was high with over 90% of patients saying they would do RT again. Only 1 (5%) patient experienced a clinical deterioration that corresponded to a 'Fair' outcome on the Harvard Cosmesis Scale. At pathologic evaluation, 14 (64%) patients had RCB-0 or RCB-1 including 3 (14%) patients with a pathologic complete response (RCB-0). No local or distant recurrences have been observed.Hypofractionated whole breast RT prior to BCS yielded excellent pathologic responses. There were low rates of toxicities and good cosmesis. Further investigation into this approach with RT before BCS is warranted.

Interventions for Preventing Cardiotoxicity in Breast Cancer Patients Receiving Trastuzumab: A Systemic Review and Bayesian Network Meta-Analysis.

Background: Trastuzumab is associated with the risk of cardiotoxicity. Here, we aim to explore interventions for preventing trastuzumab-related cardiotoxic effects in breast cancer patients.Methods: A systematic review was performed including trials of breast cancer patients with intervention to prevent cardiotoxicity of trastuzumab. Trials were searched through databases including PubMed, Embase, and Cochrane Library.Results: Eight RCTs were included. Five trials reported the outcomes of short-duration interventions, including 6-month and 9-week durations, and only 9-week treatment has a significant difference from the 12-month group (OR 0.38; 95% CI 0.18–0.83) using cardiotoxicity as the outcome. However, 6-month treatment turned out to yield less occurrence of trastuzumab discontinuation (OR 0.32; 95% CI 0.24–0.42). Three trials reported interventions of cardioprotective drugs, and there is no significant difference shown in any cardioprotective group compared with placebo (cardiotoxicity outcome: angiotensin-converting enzyme inhibitor: OR 0.48; 95% CI 0.057–2.3; angiotensin receptor blocker: OR 1.3; 95% CI 0.12–14; β-blocker: OR 0.48; 95% CI 0.057–2.3; trastuzumab interruption outcome: angiotensin-converting enzyme inhibitor: OR 0.45; 95% CI 0.12–1.3; angiotensin receptor blocker: OR 0.87; 95% CI 0.15–4.8; β-blocker: OR 0.41; 95% CI 0.11–1.2).Conclusion: Only the 9-week group has a significant difference from the 12-month group using cardiotoxicity as the outcome. And 6-month treatment turned out to yield less occurrence of trastuzumab discontinuation. The use of cardioprotective drugs failed to prevent trastuzumab-related cardiotoxic effects in breast cancer patients.

Bone safety profile of steroidal aromatase inhibitor in comparison to non-steroidal aromatase inhibitors in postmenopausal women with breast cancer: A network meta-analysis.

527 Background: Steroidal and non-steroidal aromatase inhibitors (AIs) provide better therapeutic response in comparison to other endocrine therapies in the adjuvant treatment of breast cancer (BC). They interfere with bone turnover which may lead to increased incidence of bone related safety events. There are no head-on studies comparing the incidence of bone safety events and hence we performed this network meta-analysis (NMA) to compare the incidence of bone safety events among patients treated with steroidal and non-steroidal AIs. Methods: Literature searches were performed in PubMed and Embase with key words to identify randomized controlled trials in BC patients treated with AIs in adjuvant settings compared against tamoxifen or other AIs, reporting any bone-related safety events. The study was designed as per PRISMA guidelines; publication bias was evaluated by comparison-adjusted funnel plots. Bayesian NMA was done by R software (ver 3.2), GemtC package. Odds ratio (OR) and the surface under the cumulative ranking curve (SUCRA) values were used to interpret the results. Results: 15 studies reporting 6 different bone-related endpoints were included. Treatment with steroidal AI, exemestane led to lower incidence of bone pain (OR Vs anastrozole and letrozole: 0.59, p=0.63; 0.54, p=0.75), fracture episodes (OR Vs anastrozole and letrozole: 0.84, p=0.41; 0.85, p=0.73), joint stiffness (OR Vs anastrozole: 0.55, p=0.73) and osteoporosis (OR Vs anastrozole and letrozole: 0.86, p=0.41; 0.74, p=0.29) (Table) in comparison to letrozole and anastrozole. Reduction in bone mineral density was also lesser in exemestane than anastrozole (mean reduction in hip: 1.08; lumbar spine: 1.34). SUCRA values suggested exemestane to be the drug with maximum likelihood for reducing the incidence of bone-related adverse events. Conclusions: This NMA suggested that bone-related safety events might be lower in early BC patients treated with exemestane in comparison to non-steroidal AIs, anastrozole and letrozole. Although there was no statistical significance, further head-on studies are required to substantiate our results.[Table: see text]

Abstract PD3-12: Efficacy of the tyrosine kinase inhibitor lapatinib in the treatment of patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells - results from the randomized phase III DETECT III trial

Abstract Background: It is well-known that tumor biology may change during the course of the disease due to clonal evolution, and such changes might have important implications for response to targeted treatments. Circulating tumor cells (CTCs) could serve as a real-time liquid biopsy to detect changes in tumor biology. It has been demonstrated that patients with HER2-negative metastatic breast cancer (MBC) may have discordant, HER2-positive CTCs in the peripheral blood. However, up to now there is no randomized clinical trial investigating whether treatment decisions based on CTC phenotype provide benefits in terms of improved outcome. The aim of the DETECT III study is to investigate whether patients with initially HER2-negative MBC and HER2-positive CTCs benefit from HER2-targeted therapy with the tyrosine kinase inhibitor lapatinib. In addition, the significance of CTCs as an early predictive marker for response to therapy will be analyzed. Methods: The randomized phase III DETECT III trial (NCT01619111) compares lapatinib in combination with standard therapy versus standard therapy alone in patients with initially HER2-negative MBC and HER2-positive CTCs. Efficacy of lapatinib treatment is evaluated by CTC clearance rate, progression-free survival (PFS) and overall survival (OS). In addition, we investigate the association between CTC results and both PFS and OS to assess the utility of CTCs as an early predictive marker for treatment response. CTC enumeration and phenotyping was performed using the CellSearch® technology (Menarini Silicon Biosystems; Bologna, Italy). Survival data are analyzed using log rank tests, univariable and adjusted multivariable cox regressions. Results: First results on CTC clearance rates, PFS and OS of 105 prospectively randomized patients will be presented. Conclusion: This first randomized clinical trial in breast cancer patients with treatment decisions being based on the phenotype of CTCs will show whether patients with HER2 negative MBC and HER2 positive CTCs benefit from additional HER2-targeted therapy with lapatinib. This finding might be increasingly important as novel HER2-targeted drugs become available. Citation Format: Tanja Fehm, Volkmar Mueller, Maggie Banys-Paluchowski, Peter A Fasching, Thomas WP Friedl, Andreas Hartkopf, Jens Huober, Christian Loehberg, Brigitte Rack, Sabine Riethdorf, Andreas Schneeweiss, Diethelm Wallwiener, Franziska Meier-Stiegen, Oliver Hoffmann, Lothar Müller, Pauline Wimberger, Eugen Ruckhaeberle, Jens Blohmer, Wolfgang Janni. Efficacy of the tyrosine kinase inhibitor lapatinib in the treatment of patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells - results from the randomized phase III DETECT III trial [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 PD3-12.

Dietary Phenolics against Breast Cancer. A Critical Evidence-Based Review and Future Perspectives.

Breast cancer (BC) is the most common malignancy and the leading cause of cancer-related death in adult women worldwide. Over 85% of BC cases are non-hereditary, caused by modifiable extrinsic factors related to lifestyle, including dietary habits, which play a crucial role in cancer prevention. Although many epidemiological and observational studies have inversely correlated the fruit and vegetable consumption with the BC incidence, the involvement of their phenolic content in this correlation remains contradictory. During decades, wrong approaches that did not consider the bioavailability, metabolism, and breast tissue distribution of dietary phenolics persist behind the large currently existing gap between preclinical and clinical research. In the present review, we provide comprehensive preclinical and clinical evidence according to physiologically relevant in vitro and in vivo studies. Some dietary phenolics such as resveratrol (RSV), quercetin, isoflavones, epigallocatechin gallate (EGCG), lignans, and curcumin are gaining attention for their chemopreventive properties in preclinical research. However, the clinical evidence of dietary phenolics as BC chemopreventive compounds is still inconclusive. Therefore, the only way to validate promising preclinical results is to conduct clinical trials in BC patients. In this regard, future perspectives on dietary phenolics and BC research are also critically discussed.

A randomized controlled trial of a self-administered, online decision-aid (“Navya Patient Preference Tool”) to reduce decisional conflict in women with early breast cancer.

7033 Background: Shared decision making to confront choices with clinical equipoise, has been the privilege of those patients with access to time intensive consults with oncologists. We conducted a randomized controlled trial for breast cancer patients to use an online, self-administered, out-of-the-medical-encounter decision aid (DA) to choose between breast conserving surgery (BCS) and mastectomy. Methods: Navya Patient Preference Tool (Navya PPT) is a multilingual DA based on adaptive conjoint analysis of tradeoffs between cost, adverse effects of radiation, and breast conservation. Prior analysis established high internal reliability and external validity of the Navya PPT. Eligible cT1/2, cN0 breast cancer patients planned for surgery were block randomized, in 1:1:1 ratio, to receive the research questionnaire (RQ) to measure decisional conflict on choice of surgery (control, arm 1), Navya PPT followed by RQ (experimental, arm 2) or Navya PPT followed by RQ administered with key male family member (experimental, arm 3). Groups were stratified with respect to age, socio-economic status (SES) and educational level. The study was powered to detect a decrease in Decisional Conflict Index (DCI) by 0.25 (β-0.8, two sided α- 0.01). Results: Between June 2017 and December 2019, 247/255 patients were randomized to arm 1 (83), arm 2 (84), and arm 3 (80). Median age was 48 years (IQR 23-76), and median pT size was .5 cm (0.5-6 cm). 59% of patients were middle or lower SES and 46.2% had ≤ 12th grade education. DCI was significantly reduced in arm 2 as compared with arm 1 (1.34 vs. 1.65, Cohen’s d 0.49 (± 0.31) p&lt;0.05) as well as in arm 3 as compared with arm 1 (1.30 vs. 1.65, Cohen’s d 0.54 (± 0.31) p&lt;0.05). 80% (± 6%) of patients underwent surgery of choice as determined by Navya PPT. BCS rate was similar in all three arms (85.2, 88.9 and 86.5% respectively (p=0.779). Conclusions: Online, self-administered, adaptive DAs used out of the medical encounter can reduce decisional conflict and increase access to shared decision making for every patient; especially in practices with low doctor to patient ratios. Clinical trial information: IEC/0116/1619/001 .

Abstract P4-15-04: Strategic planning for implementing an electronic wearable device loan program for breast cancer patients in a community cancer center

Abstract Purpose: The role of physical activity (PA) for breast cancer patients and survivors, including the use of electronic wearable devices (EWD), continues to be an active area of research as PA may positively impact treatment-related side effects, quality of life, recurrence risk and survival outcomes, as well as body composition and weight status. Statistically significant outcomes cannot be achieved without establishing a standardized study methodology that increases the probability that the study participants will successfully activate and wear the EWD daily for the period of the study. This pilot study aimed to report the activation (downloading app to phone, pairing EWD to phone), synchronization of the EWD to the electronic medical record (EMR) and daily use of the EWD (EMR record of daily steps) by breast cancer patients and survivors treated in a community cancer center. Data collected will help facilitate planning of an EWD loan program for economically disadvantaged patients, patients indecisive about purchasing their own EWD and for future clinical trials. Methodology: All EWD (Fitbit™) were donated to a community cancer center for use by breast cancer patients. Twenty-nine eligible breast cancer patients and survivors were "loaned" an EWD for the 4 months study period between Oct 2017 and July 2019. All patients were provided written instructions, prepared by EMR Information Technology staff, for activation and synchronization of the EWD to the EMR. In 2019, a staff person was assigned to the study to meet participants in person to activate and synchronize the EWD with the EMR. Results: The average age of the 28 study participants was 60 years old. Of the 21 participants who have completed the 4-month study period, 7 participants (33%) used the EWD ≥95% of the study period, 2 participants (10%) used the EWD 70-75% of the study period and 6 participants (29%) used the EWD 5-40% of the study period based on EMR data. Nine participants (43%) had EWD activation problems at study onset, 5 of these participants never successfully activated and synchronized their EWD with the EMR during the 4-month study period. A total of 6 EWD were reported lost by participants during or shortly after the study period. For the last 7 participants enrolled later in the study, a staff person was assigned to provide in-person help with activation and synchronization of the EWD and all participants successfully activated and synchronized their EWD with their EMR. Conclusion: Implementation of an EWD loan program or clinical trial for breast cancer patients requires staff involvement to help participants properly activate and synchronize their EWD to the EMR. Staff time and cost of lost EWD should be considered in budgetary planning. Citation Format: Sarah Washburn, Rebecca Colvin, Fredric Kass, Sam Howland. Strategic planning for implementing an electronic wearable device loan program for breast cancer patients in a community cancer center [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 P4-15-04.

Eflapegrastim, a novel, long-acting GCSF for reducing chemotherapy-induced neutropenia: Integrated results from two phase III trials in breast cancer patients.

61 Background: Eflapegrastim (E) is a novel, long-acting GCSF comprised of recombinant human GCSF covalently linked to human IgG4 Fc fragment via a PEG linker (MW, 72 kDa). E showed increased potency vs pegfilgrastim (P) in preclinical and Phase I and II trials. Two identically designed Phase III pivotal trials (NCT02643420, NCT02953340) were conducted globally with a fixed dose of 13.2 mg E containing 3.6 mg GCSF to evaluate E vs P (6 mg) in pts receiving chemotherapy for early-stage breast cancer. Methods: Each open-label trial randomized pts 1:1 to a single subcutaneous dose of E 13.2 mg/0.6 mL or P 6 mg/0.6 mL on Day 2 of each of four 21-day cycles following Day 1 adj/neoadj docetaxel 75 mg/m2 + cyclophosphamide 600mg/m2 (TC) . The primary endpoint was to demonstrate E non-inferiority (NI) to P as measured by mean duration of severe neutropenia (DSN) in Cycle 1. Results: A total 643 intent-to-treat pts (314 E/329 P) with median age 60 yrs (24–88) were enrolled. Cycle 1 mean (SD) DSN was 0.24 (0.581) vs 0.36 (0.789) days for E and P, confirming NI (p&lt;.0001) and suggesting statistical superiority (p&lt;.029). DSN NI was also shown across cycles 2–4. Among subgroups, including elderly (≥65 yrs) and overweight (&gt;75kg) pts, DSN was reduced for E vs P. In Cycle 1, E showed an absolute risk reduction for severe neutropenia of 6.5% vs P (27.1% relative risk reduction, p&lt;.043). Neutropenic complications (hospitalization and/or anti-infective use) were 2.9% and 4.0% for E and P (p=ns) in Cycle 1. Incidence of FN was low for both E and P, 1.6% vs 1.8% in Cycle 1 and 3.2% vs 3.0% overall. ANC profiles showed sustained increased levels for E vs P in the recovery phase across all cycles. Safety profiles including events of special interest, irrespective of grade, were mostly similar for E and P. The most common ≥ Grade 3 adverse events were hematologic due to chemotherapy. Conclusions: These integrated pivotal trial results confirm a similar safety profile and non-inferiority in reducing neutropenic risk for E at a lower GCSF dose vs P. The data also suggests the potential for increased potency of E to deliver improved clinical benefit, a possibility that warrants further clinical trials. Clinical trial information: NCT02643420 and NCT02953340.

Window of Opportunity trials for biomarker discovery in breast cancer.

Window of Opportunity (WOO) studies have gain their place in current clinical and translational research in breast cancer patients. This review provides current information and future applications of this specific type of research. So far, WOO trials in breast cancer patients have demonstrated their utility in breast cancer research as: first they allow administering a treatment for a short period of time to treatment-naïve patients whose tumors have not developed mechanisms of resistance or heterogeneity because of previous therapies. Second, it brings a unique opportunity for translational research providing easy access to tumor tissue in order to evaluate antitumor effect from initial biopsy and from surgical resection specimen. They provide the perfect scenario for biomarker discovery and validation in an efficient and timely manner and valuable information about drug pharmacodynamics. Several issues need to be contemplated when designing and performing this type of trials including choice of a biological surrogate endpoint of efficacy as standard clinical activity endpoints are not feasible. Despite some limitations like the absence of information about secondary mechanisms of resistance, WOO trials represent an important support for drug development and biomarker discovery in breast cancer patients.

Abstract 4014: Clinical validation of Lantern Pharma’s Response Algorithm for Drug Positioning and Rescue (RADRTM)

Abstract Lantern Pharma has developed a technology platform termed RADRTM that can be used to predict true responders before conducting a clinical trial in order to achieve higher success rates. RADRTM is an Artificial Intelligence (Al)-based machine learning approach for complex biomarker identification and patient stratification. RADRTM is a combination of three automated modules working sequentially to generate drug- and tumor-specific gene signatures predictive of response. RADRTM integrates biological knowledge, data-driven feature selection, and robust Al algorithms to facilitate hypothesis-free drug- and cancer-specific biomarker development. We present retrospective analyses performed as part of RADRTM validation using at least 9 independent datasets of patients from selected cancer types treated with approved drugs including chemotherapy, targeted therapy and immune-oncology agents. Pre-treatment patient gene expression profiles along with corresponding treatment outcomes were used as algorithm inputs. Model training was typically performed using an initial set of genes derived from cancer cell line data when available, and further applied to a subset of patient data for model tuning and final gene signature development. Model testing and performance computation were carried out on patient records held out as blinded datasets. The response prediction accuracy, true positive rate (TPR), true negative rate (TNR) false discovery rate, positive predictive value and Matthew’s Correlation Coefficient were among the model performance metrics calculated. On average, RADRTM achieved a response prediction accuracy of 80% during clinical validation. For instance, in an analysis of 92 breast cancer patients, RADRTM generated a signature of 18 genes whose expression level was predictive of Paclitaxel treatment response at an overall accuracy of 78% and 81% TPR/ 76% TNR. The above results imply that the application of the RADRTM program to this Paclitaxel trial in breast cancer patients could have potentially reduced the number of patients in the treatment arm from 92 unselected patients to 24 biomarker-selected patients to produce the same number of responders. Moreover, we cite published evidence correlating genes from this 18-gene signature with increased Paclitaxel sensitivity in breast cancer. The value of the platform architecture is derived from its validation through the analysis of about 6 million oncology-specific clinical data points, more than 120 drug-cancer interactions, and over 600 patient records. Thus, by implementing unique biological, statistical and machine learning workflows, Lantern Pharma's RADRTM technology is capable of deriving robust biomarker panels for pre-selecting true responders for recruitment into clinical trials which may improve the success rate of oncology drug approvals. Citation Format: Yuvanesh Vedaraju, Umesh Kathad, Aditya Kulkarni, Barry Henderson, Gregory Tobin, Panna Sharma, Arun Asaithambi. Clinical validation of Lantern Pharma’s Response Algorithm for Drug Positioning and Rescue (RADRTM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4014.