Trials In Breast Cancer Patients Research Articles

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.

Abstract 1000: Targeting androgen receptors and cyclin-dependent kinases 4 and 6 in breast cancer

Abstract Androgen receptor (AR) is a transcription factor that plays dual roles in breast cancer: promoting or inhibiting proliferation depending on expression and activity of estrogen receptor-alpha. Expression of AR is detected in up to 90% of all breast cancers. The duration of treatment with aromatase inhibitor and expression of AR are correlated in circulating-tumor cells (CTCs) from breast cancer patients with bone metastases. Constitutively active splice variants of AR (AR-Vs) are expressed in primary breast cancer specimens, cell lines, and CTCs from breast cancer patients. Detection of AR-Vs in CTCs from breast cancer patients is associated with bone metastases. Hence, targeting AR is a potential therapeutic strategy for AR-positive breast cancers. Anti-androgens such as enzalutamide and bicalutamide are in clinical trials for breast cancer patients. However, these approaches target the AR C-terminal ligand-binding domain, which is not present on AR-Vs. Expression of AR-Vs can drive cancer cell growth and resistance to antiandrogens. Ralaniten is an effective AR antagonist that targets AR N-terminal domain (NTD) to inhibit the transcriptional activities of both AR and AR-Vs. Cyclin-dependent kinases 4 and 6 (CDK4/6) are activated by cyclin D1 to phosphorylate Rb and are critical in the transition from G1 to S phase in cell cycle. Luminal AR subtype of triple negative breast cancer is particularly sensitive to CDK4/6 inhibitors and this sensitivity is associated with AR expression. Our objective is to evaluate efficacy of ralaniten in combination with palbociclib on the growth of AR-expressing breast cancers. AR-expressing breast cancer cell line, SUM159PT, and AR-negative cell line, MDA-MB-468 (negative control) were used. To assess the effects of ralaniten on cell growth, we examined cell proliferation by BrdU incorporation, cell viability by alamarBlue staining, and cell cycle by BrdU and 7-aminoactinomycin D staining. Cells were treated with ralaniten with or without palbociclib, or control vehicle. Each analysis was performed after 1 doubling time. Ralaniten significantly inhibited proliferation of SUM159PT, but not AR-negative MDA-MB-468 cells. Enzalutamide was less effective than ralaniten to block proliferation. Cell viability assays showed an additive effect on SUM159PT cells in combination treatment of ralaniten and palbociclib. Ralaniten disrupted cell cycle in SUM159PT cells and caused cell accumulation in late S phase. Interestingly, combination treatment caused cell accumulation in G1 phase and cell reduction in late S phase. In summary, ralaniten effectively inhibited the growth of AR-expressing breast cancer cells. Additional cell lines are being tested. In vivo efficacy of ralaniten and combinations to inhibit the growth of AR-expressing breast cancer xenografts are under investigation. Targeting AR by ralaniten or an analogue may benefit breast cancer patients whose cancers express AR. Citation Format: Amy H. Tien, Nasrin R. Mawji, Jun Wang, Marianne D. Sadar. Targeting androgen receptors and cyclin-dependent kinases 4 and 6 in breast cancer [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 1000.

Development and clinical validation of Lantern Pharma’s AI engine: Response algorithm for drug positioning and rescue (RADR).

3114 Background: The Response Algorithm for Drug positioning and Rescue (RADR) technology is Lantern Pharma's proprietary Artificial Intelligence (Al)-based machine learning approach for biomarker identification and patient stratification. RADR is a combination of three automated modules working sequentially to generate drug- and tumor type-specific gene signatures predictive of response. Methods: RADR integrates genomics, drug sensitivity and systems biology inputs with supervised machine learning strategies and generates gene expression-based responder/ non-responder profiles for specific tumor indications with high accuracy, in addition to identification of new correlations of genetic biomarkers with drug activity. 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 patient data for model tuning, cross-validation and final gene signature development. Model testing and performance computation were carried out on patient records held out as blinded datasets. Response prediction accuracy and sensitivity were among the model performance metrics calculated. Results: On average, RADR achieved a response prediction accuracy of 80% during clinical validation. We present retrospective analyses performed as part of RADR validation using more than 10 independent datasets of patients from selected cancer types treated with approved drugs including chemotherapy, targeted therapy and immunotherapy agents. For an instance, the application of the RADR program to a 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. Also, we cite published evidence correlating genes from RADR derived biomarkers with increased Paclitaxel sensitivity in breast cancer. Conclusions: The value of RADR platform architecture is derived from its validation through the analysis of about ~17 million oncology-specific clinical data points, and ~1000 patient records. By implementing unique biological, statistical and machine learning workflows, Lantern Pharma's RADR 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.

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

539 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 < .0001) and suggesting statistical superiority (p < .029). DSN NI was also shown across cycles 2–4. Among subgroups, including elderly (≥65 yrs) and overweight ( > 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 < .043). Neutropenic complications (hospitalization and/or anti-infective use) were 2.9% and 4.0% for E and P (p = ns). 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 were similar for E and P, including primarily for expected hematologic AEs and for bone pain and other musculoskeletal pain. 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, NCT02953340.

Abstract P3-15-01: Metastatic breast cancer: A retrospective study of clinical trials versus standard therapy

Abstract Background: Breast cancer is a leading cause of death in women. Metastatic breast cancer (MBC) was the leading cause of death among the 41,000 patients with breast cancer who died this year. The number of available clinical trials for breast cancer patients has dramatically increased over the last two decades, yet recruitment to trials remains low. To better understand the characteristics of women with MBC who agree to participate in clinical trials (CT) as compared to those who do not, control (C), we: 1. Compared the characteristics (age, race, tumor characteristics, and disease course) of women with MBC in the groups CT and C. 2. Compared the outcomes of women with MBC (metastatic survival), who enrolled in a clinical trial vs those who did not. 3. Noted the predictors for poor MBC survival overall Methods: Patients with MBC, from the year 2000 to 2017, were analysed retrospectively from an established metastatic database at our institution. Characteristics and outcomes were compared for patients enrolled in clinical trials (CT) with patients who were not enrolled in any trials (C). Characteristics included race, receptor status (ER/Her2), site of initial metastasis, presence of visceral and/ or CNS metastasis, number of chemotherapy and metastatic hormonal therapy cycles. Comparison of groups utilized the Chi-square test for proportions and Student's T test for means. Univariable and multivariable associations with survival were analysed using Cox regression. Results: Of the 660 patients, 249 enrolled in clinical trial (CT) and 411 served as controls (C). Demographic analysis showed that the age at first metastasis was identical in both the groups (52.8 ± 11.4 in CT and 53.8 ± 11.2 in C). Racial distribution was predominantly Caucasian, n= 92% (CT) vs n= 89% (C), with African Americans forming 4.5% (n=11) and 8.3% (n=34) in the respective non-Caucasians in the CT and C groups (p= 0.13). No significant differences were noted between CT and C groups in the proportion of CNS metastasis, receptor status (ER/ Her2), initial site of metastasis (visceral/ non-visceral), number of cycles of chemotherapy or a diagnosis of de novo metastatic disease. The proportion of patients with visceral metastases was higher in the CT patients (82.3%) vs. (71.3%) (p < 0.012). Mortality was noted to be higher in the CT group (85.9%), when compared to C (73.2%), measured over the study duration. Survival from the diagnosis of metastatic disease was not significantly different between CT and C patients. Worse survival outcome overall was noted in patients with triple negative disease (HR 1.7, p < 0.0001), presence of visceral metastases (HR 1.6, 2.0 and 1.9 for 1, 2 and 3+ visceral metastases respectively (p < 0.0001) and CNS metastases (HR 1.5, p < 0.0001) in the CT group. Conclusion: No significant demographic differences were identified between the patients enrolled in CT vs C. Higher mortality was noted in the CT group over the study duration of 17 years. The CT group had a higher number of patients with visceral metastases, but lower CNS metastases as expected for clinical trial enrolment. Although no survival difference was identified based on trial enrolment, worse outcomes were seen in patients with triple negative disease, presence of visceral or CNS metastases. Citation Format: Sritharan N, Tuft M, Rosenzweig MQ, Jankowitz RC. Metastatic breast cancer: A retrospective study of clinical trials versus standard therapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-15-01.

Immunotherapy in breast cancer: Current status and future directions.

Breast cancer, one of the leading causes of death in women in the United States, challenges therapeutic success in patients due to tumor heterogeneity, treatment resistance, metastasis and disease recurrence. Knowledge of immune system involvement in normal breast development and breast cancer has led to extensive research into the immune landscape of breast cancer and multiple immunotherapy clinical trials in breast cancer patients. However, poor immunogenicity and T-cell infiltration along with heightened immunosuppression in the tumor microenvironment have been identified as potential challenges to the success of immunotherapy in breast cancer. Oncodrivers, owing to their enhanced expression and stimulation of tumor cell proliferation and survival, present an excellent choice for targeted immunotherapy development in breast cancer. Loss of anti-tumor immune response specific to oncodrivers has been reported in breast cancer patients as well. Dendritic cell vaccines have been tested for their efficacy in generating anti-tumor T-cell response against specific tumor-associated antigens and oncodrivers and have shown improved survival outcome in patients. Here, we review the current status of immunotherapy in breast cancer, focusing on dendritic cell vaccines and their therapeutic application in breast cancer. We further discuss future directions of breast cancer immunotherapy and potential combination strategies involving dendritic cell vaccines and existing chemotherapeutics for improved efficacy and better survival outcome in breast cancer.

Association between fatigue and laboratory parameters in a longitudinal randomized controlled mistletoe trial in breast cancer patients

Association between fatigue and laboratory parameters in a longitudinal randomized controlled mistletoe trial in breast cancer patients

PO-022 Benzamide class of HDACi differentially enhance sodium iodide symporter expression in breast cancer

IntroductionSodium iodide symporter (hNIS) expression is reported across all subtypes of breast cancer (BC) and is a potential endogenous gene target for radioiodine therapy [PlosOne8(1:e54055, 2012]. Successful clinical application however relies on very high expression of functional NIS in BC cells. We have been exploiting various transcriptional regulation approaches for NIS, of which use of HDAC inhibitors (HDACi) have shown promising amplification of endogenous NIS expression in BC [Scientific Reports6:19341, 2016]. Here, we show that differential induction of NIS expression in BC is possible using Benzamide class of HDACi (bHDACi) with minimal off-target effects on other cell types.Material and methodsThe effect of bHDACi, i.e. CI-994, Chidamide, MS-275 and AR-42, on NIS gene transcription was verified on a panel of human cancer cells by RTPCR. Functional in vitro assessment was done by non-radioactive iodine uptake. I131therapeutic efficacy was measured by clonogenic assay. Promoter binding transcription factor (TF) profiler array was done to identify novel TFs responsible for differential activation in BC cells. Further, in vivo therapeutic efficacy was monitored by bioluminescence imaging (BLI) of ZR-75–1-fl2.tdt orthotopic model.Results and discussionsUsing a non-toxic, low dose of bHDACi(s) treatment on a cancer cell panel, including breast, thyroid, lung, glioma, fibrosarcoma and ovarian, a significant induction of NIS expression (p<0.05) was observed only in BC cells. Observed differences of NIS expression was confirmed by protein expression and functional assessment on BC cells. Further, novel TFs (FOXA1, FOXOF2 etc.) were identified which show differential activation in BC after CI-994 treatment. Only in case of BC cells pre-treated with bHDACi(s), cell survival assay results showed enhanced cell death on exposure to I131. Further, AR-42 drug was tested in vivo which showed similar results. AR-42 pre-treated ZR-75–1 fl2tdt orthotopic tumour showed increased NIS expression. In comparison to untreated and only I131 treated group, a combination treatment of AR-42 with 1mCi I131, BLI imaging showed 20% and 30% signal drop on day1 and day 2 respectively indicating specific radio-ablation effect.ConclusionbHDACi(s) show differentially higher regulation of endogenous NIS with minimal effect on non-breast tissues and thus may potentially benefit NIS-based radioablation therapy trials in BC patients with low/moderate expression of NIS.

Perioperative inhibition of β-adrenergic and COX2 signaling in a clinical trial in breast cancer patients improves tumor Ki-67 expression, serum cytokine levels, and PBMCs transcriptome

Catecholamines and prostaglandins are secreted abundantly during the perioperative period in response to stress and surgery, and were shown by translational studies to promote tumor metastasis. Here, in a phase-II biomarker clinical trial in breast cancer patients (n = 38), we tested the combined perioperative use of the β-blocker, propranolol, and the COX2-inhibitor, etodolac, scheduled for 11 consecutive perioperative days, starting 5 days before surgery. Blood samples were taken before treatment (T1), on the mornings before and after surgery (T2&T3), and after treatment cessation (T4). Drugs were well tolerated. Results based on a-priori hypotheses indicated that already before surgery (T2), serum levels of pro-inflammatory IL-6, CRP, and IFNγ, and anti-inflammatory, cortisol and IL-10, increased. At T2 and/or T3, drug treatment reduced serum levels of the above pro-inflammatory cytokines and of TRAIL, as well as activity of multiple inflammation-related transcription factors (including NFκB, STAT3, ISRE), but not serum levels of cortisol, IL-10, IL-18, IL-8, VEGF and TNFα. In the excised tumor, treatment reduced the expression of the proliferation marker Ki-67, and positively affected its transcription factors SP1 and AhR. Exploratory analyses of transcriptome modulation in PBMCs revealed treatment-induced improvement at T2/T3 in several transcription factors that in primary tumors indicate poor prognosis (CUX1, THRa, EVI1, RORa, PBX1, and T3R), angiogenesis (YY1), EMT (GATA1 and deltaEF1/ZEB1), proliferation (GATA2), and glucocorticoids response (GRE), while increasing the activity of the oncogenes c-MYB and N-MYC. Overall, the drug treatment may benefit breast cancer patients through reducing systemic inflammation and pro-metastatic/pro-growth biomarkers in the excised tumor and PBMCs.

Abstract P3-14-05: Safety of granulocyte colony-stimulating factors and their biosimilars: A meta-analysis of randomized clinical trials in breast cancer patients receiving cytotoxic chemotherapy

Abstract Background: Neutropenia is a common adverse event reported in cancer patients undergoing cytotoxic chemotherapy. Granulocyte colony-stimulating factors (G-CSFs) such as filgrastim and pegfilgrastim are widely used to prevent neutropenia. Several biosimilars of G-CSF are now available. Biosimilar development involves a series of comparisons between the proposed biosimilar and reference performed in a step-wise fashion to eliminate any concerns regarding the similarity of the medicines. Randomized clinical trials (RCTs) are then performed to confirm that the reference product and its biosimilar provide the same clinical efficacy and safety. Patients with breast cancer (BC) are the most sensitive population in which to confirm similarity of G-CSF biosimilars, however there are some differences between clinical studies. The aim of this meta-analysis was to compare the safety profiles of approved or proposed G-CSF biosimilars (filgrastim or pegfilgrastim) with reference G-CSF in patients with BC. Methods: A Medline literature search up to March 2017 identified randomized clinical trials (RCTs) comparing biosimilar G-CSF to reference in BC patients. Safety analyses included calculation of risk ratios for bone pain events, myalgia events and serious adverse events. Random effect models were fitted to obtain the pooled estimates of the risk ratio for the outcomes and their corresponding 95% confidence intervals (CIs). Results: Eight eligible RCTs were included in this meta-analysis. Risk ratios for bone pain events (risk ratio 1.01 [95% CI -0.76, 1.34]; Table), myalgia events (risk ratio 0.94 [95% CI 0.63, 1.40]) and serious adverse events (risk ratio 1.01 [95% CI 0.76, 1.34]) showed no significant differences between reference and biosimilar G-CSF. Risk ratios for bone pain events BiosimilarsReference productsRisk RatioStudy and year of publicationReference G-CSF / Biosimilar G-CSFEventsTotalEventsTotalWeightIV, Random, 95% CIBlackwell 2015Filgrastim / Filgrastim331073810729.9%0.87 [0.59, 1.27]Blackwell 2016Pegfilgrastim / Pegfilgrastim101551715311.8%0.58 [0.27, 1.23]Harbeck 2016Pegfilgrastim / Pegfilgrastim715981577.3%0.86 [0.32, 2.33]Waller 2010Filgrastim / Filgrastim48183169521.1%1.56 [0.94, 2.59]Waller 2016Pegfilgrastim / Pegfilgrastim51127246729.7%1.12 [0.76, 1.65]Total (95% CI)731579100%1.01 [0.76, 1.34]Heterogeneity: Chi2 = 5.86, df = 4 (P = 0.21); I2 = 32% Test for overall effect: Z=0.07 (P=0.94) Conclusions: This meta-analysis showed no differences in the safety profile of biosimilar and reference G-CSF in breast cancer patients. Citation Format: Krendyukov A, Botteri E, Curigliano G. Safety of granulocyte colony-stimulating factors and their biosimilars: A meta-analysis of randomized clinical trials in breast cancer patients receiving cytotoxic chemotherapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-05.

Abstract ES10-3: Breast cancer patient-derived xenografts as models for metastatic progression and therapeutic response

Abstract Metastasis is the main cause of death from breast cancer, and yet little is understood with regard to how to prevent tumors from appearing in distant organs as metastases, or how to treat them once they appear. Using new models and approaches, we have discovered a new pathway regulating metastasis to lungs and bones. We found that RON kinase regulates breast cancer metastasis through cell-autonomous and non-cell-autonomous mechanisms. This presentation will cover use of various models of breast cancer to study metastasis and therapy response, including patient-derived xenograft (PDX) models. PDX models represent the diversity of human breast tumors, and can be feasibly utilized to test new drugs and drug combinations to find therapeutic approaches that match with molecular features of various tumor types. The goal of our work is to utilize PDX and other relevant in vivo models to obtain preclinical data that will facilitate prioritization of drugs to be tested in breast cancer clinical trials, including RON kinase inhibitors. Taken together, these elements converge to reveal high-priority treatment strategies for future clinical trials in breast cancer patients. Citation Format: Welm AL. Breast cancer patient-derived xenografts as models for metastatic progression and therapeutic response [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES10-3.

Prevention of acute radiodermatitis by photobiomodulation: A randomized, placebo-controlled trial in breast cancer patients (TRANSDERMIS trial).

Acute radiodermatitis (RD) is a distressing and painful skin reaction that occurs in 95% of the patients undergoing radiotherapy (RT). The aim of this study was to evaluate the effectiveness of photobiomodulation therapy (PBMT) in the prevention of acute RD in breast cancer (BC) patients undergoing RT. This study was a randomized, placebo-controlled trial including 120 BC patients that underwent an identical RT regimen post-lumpectomy. Patients were randomly assigned to the laser therapy (LT) or placebo group, with 60 patients in each group. Laser or placebo treatments were applied 2 days a week, immediately after the RT session, starting at the first day of RT. PBMT was delivered using a class IV MLS® M6 laser that combines two synchronized laser diodes in the infrared range (808-905 nm) with a fixed energy density (4 J/cm2 ). Skin reactions were scored based on the criteria of the Radiation Therapy Oncology Group (RTOG) and the Radiation-Induced Skin Reaction Assessment Scale (RISRAS). The patients completed the Skindex-16 questionnaire to evaluate their quality of life. All the measurements were collected at the first day, at a RT dose of 40 Gray (Gy), and at the end of RT (total dose 66 Gy). At a RT dose of 40 Gy, there was no significant difference between the groups in the distribution of RTOG grades. However, at the end of RT the severity of the skin reactions significantly differed between the two groups (P = 0.004), with a larger percentage of patients experiencing RTOG grade 2 or higher (e.g., moist desquamation) in the placebo group (30% vs. 6.7%, for the placebo and laser group, resp.). The objective RISRAS score confirmed these results. In addition, the Skindex-16 and RISRAS subjective score demonstrated that the patients' quality of life was significantly better in the LT than in the control group. The results of this trial show that PBMT is an effective tool to prevent the development of grade 2 acute RD or higher in BC patients. In addition, it also reduces the patients' symptoms related to RD. Lasers Surg. Med. © 2018 Wiley Periodicals, Inc.

Success Rate and Possible Causes of Failures of Phase 3 Clinical Trials in Patients with Breast Cancer: A Systematic Review

Background: Besides the high unmet medical needs of cancer patients, the success rate of phase 3 clinical trials in this disease area is relatively low compared with other disease areas. Breast cancer is the most frequently diagnosed cancer among women. The incidence of breast cancer has increased, representing a major health problem worldwide. Objectives: This systematic review aimed to investigate the success rate of phase 3 clinical trials in patients with breast cancer according to primary endpoints and to identify possible causes of failures to meet these endpoints. Methods: We performed an online database search of phase 3 clinical trials in patients with breast cancer in articles published from January 2011 to June 2017, and identified “positive” (met the primary endpoint) and “negative” (failed to meet the primary endpoint) trials. The success rates were sorted by primary endpoints. Possible causes of failures to meet the primary endpoints were investigated by assessing the accuracy of pre-trial estimates. Results: We identified 113 trials, consisting of 39 positive and 74 negative trials (overall success rate: 35%). Most of the primary endpoints (77%) were progression-related or recurrence-related. The success rates of trials assessing progression-related and recurrence-related endpoints were 39% and 17%, respectively. Progression-related and recurrence-related endpoints in the control arm showed significant improvement, compared with pre-trial estimates, which were associated with negative results. Conclusions: The accuracy of pre-trial estimates critically influenced the success rate of phase 3 clinical trials in breast cancer patients. Although these trials need to be designed to retain the reproducibility of pre-trial estimates, the changes in diagnostic measurement and/or standard therapy from the time of study planning could provide a potential risk of underestimation of pre-trial estimates in the control arm.

Comparing granulocyte colony–stimulating factor filgrastim and pegfilgrastim to its biosimilars in terms of efficacy and safety: A meta-analysis of randomised clinical trials in breast cancer patients

BackgroundGranulocyte colony–stimulating factors (G-CSFs) are widely used to prevent neutropenia in cancer patients undergoing myelosuppressive chemotherapy. Several biosimilar medicines of G-CSF are now available, with their development involving a step-wise series of comparisons to demonstrate similarity to reference biologics. Randomised clinical trials (RCTs) are considered confirmatory, and for G-CSF biosimilars, patients with breast cancer (BC) undergoing myelosuppressive chemotherapy are the most sensitive population in which to confirm similarity. This meta-analysis aimed to compare the clinical efficacy and safety of approved or proposed G-CSF biosimilars (filgrastim or pegfilgrastim) with reference G-CSF in patients with BC. MethodsA Medline literature search up to March 2017 identified RCTs comparing biosimilar G-CSF to reference in BC patients. The primary efficacy end-point was mean difference in duration of severe neutropenia (DSN). Secondary efficacy end-points were differences in depth of absolute neutrophil count (ANC) nadir, time to ANC recovery and incidence of febrile neutropenia. Safety analyses included calculation of risk ratios for bone pain events, myalgia events and serious adverse events. Random effect models were fitted to obtain the pooled estimates of the mean difference for continuous outcomes and the risk ratio for dichotomous outcomes and their corresponding 95% confidence intervals (CIs). FindingsEight eligible RCTs were included in this meta-analysis. Overall difference in DSN between reference and biosimilar medicines was not statistically significant (0·06 d [95% CI −0·05, 0·17]). The analysis of secondary efficacy end-points showed no significant differences between reference biologics and biosimilar medicines, as well as the analysis of bone pain events, myalgia events and serious adverse events. InterpretationThis meta-analysis showed no significant differences in clinical efficacy and safety between biosimilar and reference G-CSF in BC patients.

Effect of statins on breast cancer recurrence and mortality: a review

Statins, or 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are medications that have been used for decades to lower cholesterol and to prevent or treat cardiovascular diseases. Since their approval by the US Food and Drug Administration in the 1980s, other potential uses for statins have been speculated on and explored. Basic science and clinical research suggest that statins are also effective in the management of breast cancer. Specifically, in various breast cancer cell lines, statins increase apoptosis and radiosensitivity, inhibit proliferation and invasion, and decrease the metastatic dissemination of tumors. Clinical trials in breast cancer patients support these laboratory findings by demonstrating improved local control and a mortality benefit for statin users. A role for statins in the management of aggressive breast cancers with poor outcomes – namely, inflammatory breast cancer and triple-negative breast cancer – is particularly implicated. However, data exist showing that statins may actually promote invasive breast disease after long-term use and thus should be prescribed cautiously. Furthermore, a general consensus on the type of statin that should be administered, for how long, and when in relation to time of diagnosis is lacking. Given their low toxicity profile, affordability, and ease of use, consideration of statins as a therapy for breast cancer patients is imminent. In this review, we summarize current evidence regarding statins and clinical breast cancer outcomes, as well as discuss potential future studies that could shed light on this increasingly relevant topic.

A critical evaluation of quality of life in clinical trials of breast cancer patients treated with radiation therapy.

The aim of this study was to investigate the extent to which health-related quality of life (HRQOL) parameters have been reported in phase III trials with breast cancer patients (BCPs) who received radiation therapy (RT). We also examine the frequency and correlates of significant HRQOL gains. A systematic review was conducted. When HRQOL was a study endpoint, we extracted data on the instruments used for HRQOL analysis, assessing if there was formal statistical comparison between study groups and the results of such comparisons as reported by the authors of the studies. In result, 182 trials were included. HRQOL was considered as endpoint in 38 (20.8%) of the studies and it was used as primary endpoint in 10.9% of them. Of 22 trials that had a positive primary endpoint, 18 had a significant benefit in HRQOL, in favor of the experimental arm. Of 13 trials that had a negative primary endpoint, there were no differences in HRQOL among the study groups. With respect to HRQOL assessment, statistical methods and definition of timing of evaluation were described in 32 (84.2%) and 36 (94.7%) trials, respectively. In conclusion, HRQOL has been infrequently investigated in trials in BCP who received RT. Statistical methods and timing of evaluation were infrequently described with sufficient detail to be informative.

PO128 - G-CSF and G-CSF Biosimilars: A Meta-Analysis of Randomized Clinical Trials in Breast Cancer Patients Undergoing Myelosuppressive Chemotherapy

PO128 - G-CSF and G-CSF Biosimilars: A Meta-Analysis of Randomized Clinical Trials in Breast Cancer Patients Undergoing Myelosuppressive Chemotherapy

PO113 - Gisel Study Group Proposal: A Phase II Randomized Clinical Trial in Breast Cancer Patients with Skin Metastases Treated with or without Electrochemotherapy (ECT) during the First Line of Treatment

PO113 - Gisel Study Group Proposal: A Phase II Randomized Clinical Trial in Breast Cancer Patients with Skin Metastases Treated with or without Electrochemotherapy (ECT) during the First Line of Treatment

Psychological and/or pharmacological short perioperative interventions to reduce cancer recurrence: A planned randomized clinical trial in breast cancer patients

Several surgery-related processes, including sympathetic-activation and inflammation, may promote metastatic progression. In two recent biomarkers clinical trials in breast (n = 38) and colorectal (n = 34) cancer patients, a 5-day pre-operative beta-adrenergic blockade and COX2-inhibition (employing propranolol and etodolac for 11-perioperative days) significantly reduced pro-metastatic markers in the excised tumor, presumably through mitigating stress. However, due to medical contraindications, less than 50% of patients were eligible for this treatment. Thus, in a phase-II clinical trial, we plan to compare a perioperative psychological intervention to the above perioperative pharmacological treatment. Psychological intervention layout: Starting 3 weeks before surgery, a six-week treatment will include five individual sessions around routine clinic visits. Between sessions, bi-weekly phone support will be provided by a psychologist. A stress-management intervention tailored for each woman will address the following domains: (i) physiological (ii) cognitive, and (iii) emotional aspects of stress. Additionally, (iv) medical psycho-education, and (v) perceived social support will be addressed. A 2X2 design will be used: Placebo, Pharmacological, Psychological + Placebo, or both treatments. Additionally, patients with contra-indications to pharmacological treatment will be randomized to Placebo vs Psychological treatment + Placebo (n = 30 in each of the 6 groups). Short-term outcomes: tumor mRNA profiling, self-report questionnaires (e.g., BSI 18), Heart-Rate-Variability, circadian saliva cortisol. The combined approach is hypothesized to be optimal. Future studies may assess long-term clinical outcomes such as disease progression or survival.