bluuebunny/crossref_metadata_2025 huggingface dataset:
Short versus long duration of adjuvant trastuzumab (T) in HER2+ breast cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).
Authors: Sipra Qurat Ul Ain Riaz , Riaz Irbaz Bin , Husnain Muhammad , Raina Ammad , Khan Ahsan , Akhtar Maheen , Wang Zhen , Murad M. Hassan , Leon-Ferre Roberto Antonio
Published: May 2019

e12057

Background: Several RCTs have evaluated a shorter duration of T ( < 12 months) with hopes of similar efficacy, reduced cardiotoxicity, cost and burden of treatment. Of the 5 major studies, PERSPHONE showed that 6 months was non-inferior compared to 12 months. However, four additional studies of shorter duration failed to demonstrate non-inferiority. Therefore, we performed an updated systematic review and a meta-analysis to assess the optimal duration of adjuvant T. Methods: MEDLINE, EMBASE, Cochrane, Scopus and conference proceedings were searched to identify RCTs comparing one year of adjuvant T with a shorter duration in early-stage HER2+ breast cancer. The DerSimonian-Laird random-effects Meta-Analysis was performed using CMAv3 software to derive pooled Hazard Ratio (HR) estimates for overall survival (OS, Disease-Free Survival (DFS) and Odds Ratio(OR) estimates of cardiac toxicity. Q-test was used to assess between-study heterogeneity; I2 statistic was computed to express the percentage of the total observed variability due to study heterogeneity. The risk for bias was assessed using the Cochrane Collaboration’s tool. Results: We screened 1772 citations and identified 5 studies(n = 11,377) for analysis. 5691 patients were randomized to 12 months of adjuvant T while 5686 were randomized to a shorter duration (3 studies evaluated 6 vs 12 months, 2 studies evaluated 9 weeks vs 12 months). OS (HR, 1.16, 95% CI 1.03-1.31, P= 0.015,I2 0.00, p= 0.837) and DFS (HR, 1.14, 95% CI 1.02-1.26 , P = 0.016,I2 14.90, p= 0.319) were significantly worse in patients receiving shorter duration T as compared to 12 months. Cardiotoxicity was significantly higher in the 12 month group vs shorter duration (OR, 2.10, 95% CI 1.58-2.80, p = 0.000 ,I2 51.182, p= 0.085). Grade 3/4 cardiac events and cardiac events leading to discontinuation of therapy were significantly higher in patients receiving 12 months (HR 2.06, 95% CI 1.60-2.63, P = 0.000, I2 3.967, p= 0.384). There was no significant heterogeneity among studies. Risk of bias was low. Conclusions: Twelve months of adjuvant T is associated with significantly better DFS and OS compared to a shorter duration. As such, 12 months should remain the standard of care for most patients. There is an unmet need to identify lower risk groups which might do well with from shorter duration of HER2-directed therapy.
A prospective study to evaluate the accuracy of axillary staging using ultrasound and USG-guided fine needle aspiration cytology in early breast cancer patients in a high-volume center.
Authors: Singh Rashpal , Dhamija Ekta , Deo SVS , Mathur Sandeep , Thulkar Sanjay
Published: May 2019

e12060

Background: In breast cancer, axillary lymph node involvement directly impacts the patient survival and prognosis.Sentinel lymph node biopsy (SLNB) is a procedure of choice for axillary staging in early breast cancer. Currently, management options for axilla management are ALND & SLNB in node positive & in node negative respectively. In developing nation like India,where resource constraints, logistics issues and over burden health institutes create difficulty in managing patients, our study address this issue by implementing USG and USG-FNAC in early breast cancer patients in developing nation. Methods: All early breast cancer patients were screend by ultrasound axilla to categorise the nodes as suspicious or non suspicious. Suspicious nodes underwent USG & FNAC using vascualr pedicle based nodal mapping for node targeted on USG-FNAC, if node found to be positive, patient underwent ALND & negative node patients underwent SLNB.All non-suspicious nodes patient underwent SLNB. Final histopathology was taken as gold standard. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value, accuacy and false negative rate calculated for USG & USG-FNAC. Results: Total 100 patients included in which 58 were non-suspicious and 42 suspicious nodes on USG. Among suspicious group, 24 were positive on USG-FNAC & 18 were negative.In non suspicious SLNB done in all. False negative rate of USG & USG-FNAC was 38% and 17% respectively. Conclusions: Our study indicates the feasibility of USG & USG-FNAC in a high volume centre with good accuracy of around 70- 80%.Overall, 24 % of total patients can be taken up for ALND without performing SLNB.This study can guide us to utilize ultrasound and ultrasound-guided FNAC as a routine evaluation tool in the pre operative assessment of axillary lymph nodes in early breast cancer. Our study showed good and acceptable result (75%) in isolating and retrieving the targeted node by just following the Vascular pedicle based node mapping of axilla to locate the suspicious node without using any tagging or marking of node from where FNAC was performed. This finding can act as a good practicing tool in a busy high volume, logistics issue and and resource constraint hospitals.[Table: see text]
Correlation between TopIIα and ki-67 expression in tumors of luminal, primary operable breast cancer without HER2/neu overexpression in postmenopausal women as a prognostic factor.
Authors: Ulianova Elena P. , Kit Oleg I. , Tokmakov Vasilij V. , Shatova Iuliana S. , Novikova Inna A. , Sagakyants Aleksandr B. , Nepomnyashchaya Evgeniya M. , Shulgina Oksana G. , Chernikova Elena N. , Bakulina Svetlana M. , Lysenko E. P. , Bondarenko Elena S. , Vladimirova Liubov Yu
Published: May 2019

e12065

Background: Assessment of proliferative activity is important in terms of tumor prognosis. Topoisomerase IIα (TopIIα) and ki-67 are common markers of breast cancer (BC) cell proliferation. The purpose of the study was to assess the correlation between TopIIα and ki-67 expression as a prognostic factor in luminal, primary operable breast cancer without Her 2 neu overexpression in postmenopausal women. Methods: 60 postmenopausal patients with BC (invasive ductal carcinoma) were equally divided into 3 groups: I –luminal A BC, surgical treatment with subsequent radiotherapy and hormonal therapy; II – luminal B BC, surgical treatment with subsequent radiotherapy and hormonal therapy; III – luminal B BC, surgical treatment with subsequent radiotherapy, polychemotherapy and hormonal therapy. Mean age of patients: I – 76.16±3.14 years, II – 65.0±3.91, III – 74.0±2.54 years. Immunohistochemical study was performed with mouse monoclonal ki-67 (Thermo scientific) and TopIIα (Santa Cruz Biotechnology) antibodies using the Reveal Polyvalent HRP-DAB Detection System. Results were analyzed using the STATISTICA 10.0 program (StatSoftInc., USA). Results: The average expression levels of the ki-67 marker in the groups were: I - 12.3±1.4%, II - 15.1±3.1%, III - 37.0±7.1%; TopIIα expression – 3.5±1.6%, 16.0±5.9%, 21.7±6.4%, respectively. The statistically significant Spearman correlation between TopIIα and ki-67 was observed both as general in groups (r = 0.787 at p < 0.001) and in groups with luminal B subtype (groups II and III). Strong positive correlation between TopIIα and ki-67 was registered in groups II (r = 0.941 at p < 0.01) and III (r = 0.864 at p < 0.001) with luminal B subtype. Weak correlation was observed in group I with luminal A subtype (r = 0.477 at p≥0.05). Conclusions: The study revealed a correlative increase in the level of TopIIα with simultaneous overexpression of the ki-67 protein in the studied groups. This indicator can be considered predictive for breast cancer.
Impact of surgery type on survival in breast cancer patients.
Authors: Ngo Phuong Tuyet , Bhandari Shruti , Murray Drew , Mudra Sarah , Wu Xiaoyong , Lele Rachana Shirish , Srivastava Sudhir , Mandadi Mounika , Riley Elizabeth Carloss
Published: May 2019

e12072

Background: Breast cancer is the most common malignancy affecting women, and treatment is multidisciplinary. Both patient and tumor related factors impact surgical decision making. Recently, rates of mastectomy, prophylactic mastectomy and reconstruction have increased. The impact of this on modern survival, the relationship to patient and tumor related factors is not well described. Methods: The National Cancer Database identified 1,042,057 patients who underwent surgery with lumpectomy or mastectomy with or without reconstruction for stages I-III breast cancer from 2004-2014. Variables collected included gender, race, age, stage, facility type, insurance status, and overall survival. Data was analyzed using univariable and multivariable logistic and Cox proportional hazards regression models. Results: Of all surgeries, 61.2% were lumpectomy (n = 638,088), 27.9% were mastectomy without reconstruction (n = 290,463) and 10.9% were mastectomy with reconstruction (n = 113,506). African American patients were more likely to get mastectomy without reconstruction than lumpectomy (OR 1.05; 95% CI 1.03-1.06, p < 0.001) but less likely to get reconstruction than lumpectomy (OR 0.73; 95% CI 0.71-0.75). Patients 50-65 years were less likely to get mastectomy either with and without reconstruction compared to lumpectomy (OR 0.45; 95% CI 0.44-0.46; OR 0.87; 95% CI 0.86-0.88, p < 0.001, respectively). Reconstruction was more likely in patients with private insurance compared to those with Medicare (OR 1.46; 95% CI 1.43-1.50, p < 0.001) and was less likely to occur at a community center compared to an academic facility (OR 0.48; 95% CI 0.47-0.49, p < 0.001). Mastectomy without reconstruction also had a higher likelihood of death when compared to lumpectomy patients (HR 1.28; 95% CI 1.26-1.29, p < 0.00). Conclusions: The majority of women in this large dataset had breast conserving surgery. Of those patients who underwent mastectomy, only a minority had reconstruction. Age > 50 years and treatment at a non-academic facility were associated with less reconstruction along with established risk factors for worse outcome including African American race and Medicaid/Uninsured. Despite adjusting for these risk factors, mastectomy without reconstruction was still associated with a lower survival. Further analysis including tumor biology is needed to better understand the impact of these findings.
The treatment option of progressive disease in breast cancer during neoadjuvant chemotherapy: A single-center experience.
Authors: Zheng Yurong , Ding Xiaowen , Zou Dehong , Zhang Fanrong , Qin Chengdong , Yang Hongjian , Mo Wenju , Ding Yu-Qin , Yu Yang
Published: May 2019

e12082

Background: Patients’ responses to breast cancer neoadjuvant chemotherapy (NACT) differ because of heterogeneous tumor characteristics. Reports about NACT progression are sporadic. In this study, we aimed to evaluate the characteristics and treatment option of progressive disease in breast cancer after neoadjuvant chemotherapy in China. Methods: We enrolled 1187 patients who received NACT in our cancer center between January 1, 2007, and December 31, 2016. We analyzed the characteristics and treatments of patients with progressive disease (PD) or non-PD or pathological complete response (pCR). Results: In total, 45 (3.8%) patients had PD. PD patients were associated with a significantly worse disease–free survival (DFS) (hazard ratio (HR) = 3.77; 95% CI, 1.77 to 8.00; P = .001) and overall survival (OS) (HR = 3.85; 95% CI, 1.77 to 8.35; P = .001). For the PD patients, 28 (62.2%) patients received mastectomy immediately after PD, and 17 (37.8%) changed to chemotherapy. DFS and OS exhibited no significant differences between these two salvage therapies. After a change to second chemotherapy, 58.8% (10/17) patients had PD or SD. With the exception of tumor size, pretreatment T stage, and histology type, no other significant differences were noted between PD and pCR patients. Conclusions: Our results demonstrated that PD patients were associated with a significantly worse prognosis. Based on these results, we suggest to give the addition of trastuzumab to HER-2 positive patients instead of changing the chemotherapy regimen and proceeding to surgery instead of further chemotherapy once patients have PD during NACT. Given that some similar characteristics exist between PD and pCR patients, more studies to identify novel molecular markers to predict disease response to NACT should be performed.
The role of stromal tumor infiltrating lymphocytes (sTILs) as a predictive biomarker for carboplatin-based neoadjuvant chemotherapy (NACT) in triple-negative breast cancer (TNBC).
Authors: Walsh Elaine M. , O'Loughlin Mark , Shalaby Aliaa , Webber Mark , Kerin Michael J. , Glynn Sharon A. , Callagy Grace , Keane Maccon M.
Published: May 2019

e12085

Background: High numbers of sTILs are predictive of pCR in TNBCs. This study examines the role of sTILs as a predictive biomarker for carboplatin (Cb) based NACT. Methods: sTILs were scored on 88 pre NACT TNBC biopsies as per the International TILs Working Group and were scored as continuous and categorical variables: 0-10%; 11-25%; 26-49%; ≥50%. OR was calculated using non-pCR as baseline parameter. Results: Patients with sTILs > 10% had increased pCR rates compared to those with sTILs ≤10%: pCR breast (B) (61% vs 31% p = 0.004); pCR breast/axilla (BA) (52% vs 29% p = 0.021). In those treated with Cb, there were no differences in pCR B between sTILs > 10% or ≤10% (67% vs 53%; p = 0.355) or pCR BA (60% vs 53%; p = 0.500). In those who did not receive Cb, sTILs > 10% had increased pCR B (57% vs 15%; p = 0.002) and pCR BA (46% vs 12%; p = 0.005) compared to sTILs ≤10%. Similar trends were seen with sTILs > 25% and ≥50%: differences were seen in patients who did not receive Cb, but not in those treated with Cb. In LPBCs, the addition of Cb did not significantly increase pCR rates: 67% vs 83% for Cb and non-Cb regimens (p = 0.583). In non-LPBC, pCR rates were increased with Cb: pCR B 59% vs 31% (p = 0.017), and pCR BA 56% vs 23% (p = 0.005) for Cb and non-Cb regimens. The association between sTILs and pCR was significant in multivariable models adjusting for grade and Cb. In patients who did not receive Cb (n = 54), increasing sTILs were associated with increased pCR B (OR 0.15 p = 0.004; OR 0.27 p = 0.039; OR 0.10 p = 0.05 for > 10%, > 25%, ≥50%) and pCR BA (OR 0.18 p = 0.019; OR 0.08 p = 0.029 for > 10%, ≥50%). In patients treated with Cb (n = 30), increasing sTILs were not associated with pCR B (OR 1.97 p = 0.581; OR 0.27 p = 0.334; OR 0.50 p = 0.719) or pCR BA (OR 2.93 p = 0.372; OR 0.79 p = 0.831; OR 0.40 p = 0.622 for > 10%, > 25%, ≥50%). Conclusions: sTILs are predictive of pCR: as sTILs increase, pCR rates increase. Tumors with high sTILs had high pCR rates to anthracycline-taxane (AT) NACT. The effect of increasing sTILs on pCR was most notable in patients who did not receive Cb based NACT, suggesting that tumors with high sTILs are inherently sensitive to AT based chemotherapy. Intensifying NACT with Cb could be used to increase pCR rates in patients with low sTILs. sTILs should be explored as a biomarker to intensify chemotherapy in those with low sTILs, and to de-escalate chemotherapy in tumors with high sTILs.
Clinical value of CTC in predicting the efficacy of treatment in breast cancer.
Authors: Zhou Yidong
Published: May 2019

e12104

Background: Circulating tumor cells (CTCs) have proven to be underlying surrogate markers for several cancers. We aimed to investigate the diagnostic, predictive, and prognostic value of tCTCs using a four-CTC marker (CK19, surviving, Her2 and MUC1) real-time quantitative PCR (RT-PCR) assay in patients with breast cancer. Methods: In a previous study, we established a multimarker RT-PCR platform to detect and quantify CTC in colorectal cancer. By choosing four mRNA markers (CK-19/surviving/Her2/Muc1), we quantified CTC in the peripheral blood of 90 early operable breast cancer patients, 40 patients who had undergone surgery and received 6 cycles of follow-up of neoadjuvant chemotherapy, and 30 healthy volunteers. For early operable breast cancer patients, the CTC status at preoperative and postoperative time points was monitored. For the other 40 patients undergoing systemic adjuvant chemotherapy, the CTC status at six or more different time points was monitored. Results: CTCs were detected in 81% (73/90) of patients with early operable breast cancer. After surgery, 67.1% (49/73) of the patients switched to negative status. 36 out of 40 (90%) patients who received systemic adjuvant chemotherapy were CTC-positive. During follow-up, 31 out of 36 (86%,) patients became CTC-negative after 4 chemotherapy cycles. Among these 36 patients, four patients had relapsed within one year, and one had died. Three out of four relapsed patients, including the deceased one, switched into high CTC-positive status before diagnosed recurrence. Conclusions: The decrease of the levels of these CTC mRNA markers after surgery indicates that these CTC markers could be used as an indirect evaluation of tumor burden. The level of CTC mRNA markers could also help to evaluate therapeutic efficacy and disease progression.
NOTCH3 expression in metastatic TNBC cells.
Authors: D'Assoro Antonino Bonaventura
Published: May 2019

e12123

Background: Onset of metastases involves a complex multistep biological process termed the invasion-metastasis cascade, which include dissemination of cancer cells from the primary tumor to secondary organs. NOTCH signaling plays a critical role in promoting Triple Negative Breast Cancer (TNBC) metastasis. Although all four NOTCH receptors show oncogenic properties, the unique role of each of these receptors in the sequential stepwise events that typify the invasion-metastasis cascade remains elusive. Methods: We established unique TNBC cells (TNBC-M14, -M25 and –M40), isolated from patient-derived brain metastasis xenografts (PD-BMXs). NOTCH3 genetic targeting was achieved using Lenti-vector shRNAs. Immunoblot analysis was used to assess NOTCH3 expression. ALDH1 activity was measured using the ALDEFLUOR Kit. To assess self-renewal capacity and resistance to docetaxel-based chemotherapy, TNBC cells were cultured under non-adherent conditions to form mammospheres (MPS). A publicly clinical database ( http://kmplot.com ) was employed to analyze NOTCH3 expression in a selected cohort of 107 lymph- node+ TNBC patients. Results: TNBC-M14, -M25 and -M40 MPS showed NOTCH3 overexpression and higher ALDH1 activity compared to MDA-MB 231 MPS used as control. To investigate the causative role of NOTCH3 in inducing ALDH1 activity, self-renewal capacity and chemoresistance, we infected TNBC MPS with Lenti-vector shRNAs targeting NOTCH3. NOTCH3 geneting targeting induced a significant reduction of ALDH1 activity compared to TNBC MPS infected with scrambled Lenti-shRNAs. NOTCH3 geneting targeting significantly impaired MPS formation and restored sensitivity to docetaxel. The correlation between aberrant NOTCH3 expression and poor outcome in patients with advanced TNBC was validated in a publicly clinical database. Conclusions: These findings provide a compelling preclinical rationale for the design of novel clinical trials that will selectively target NOTCH3 to restore chemosensitivity and to improve the progression-free survival of TNBC patients that lack FDA-approved targeted therapies.
Estrogen receptor (ER) status and survival outcomes in HER2 positive (+) metastatic breast cancer (mBC).
Authors: DeSouza Karen , Zammit Rosa-Rita , Haire Anna , Sinha Rajesh , Simcock Richard , Moss Charlotte Hannah , Mera Anca , Mansi Janine , Karapanagiotou Eleni , Sawyer Elinor , Patel Gargi Surendra
Published: May 2019

e12503

Background: The oncological management of HER2+ mBC is complicated by the development of resistance to HER2-directed therapies (HER2-DTs). This project analyses real-world clinical data to determine disease response patterns that may guide treatment sequencing decisions. Methods: This collaborative project analysed HER2+ mBC datasets held by the Sussex Cancer Centre and Guy’s Cancer Centre, UK. The datasets were generated by reviewing clinical notes, radiology and e-prescribing records to collect clinical data on patients diagnosed with HER2+ mBC between 01/01/2013 – 30/09/2018. Results: 138 patients with a median age of 59 years (30 - 89 years) were diagnosed with HER2+ mBC during this time period: 88 were ER+ (63.7%) and 50 were ER- (36.3%); the median OS is 41.1 mos. (range 0.7 - 62 mos.). Patients with HER2+ mBC were more likely to present with visceral metastases (68.1%, n = 94). A poorer median OS was identified in patients with ER+ HER2+ mBC (35.5 mos.) vs ER- HER2+ mBC (MNR). A benefit to median OS was observed with first line treatment using Docetaxel/Trastuzumab/Pertuzumab (THP) compared to other HER2-DTs ((54.5 mos. (n = 76) vs 26.7 mos. (n = 40)) 65.2% (n = 90) were previously treated for early breast cancer (EBC), evenly distributed across the 2 groups ER+ (64.7%, n = 57) vs ER- (66%, n = 33). 53.7% (n = 50) received trastuzumab with neo-adjuvant/adjuvant therapy (NACT/ACT). Patients previously treated for EBC demonstrated a poorer median OS (34 mos.) when compared to patients with de-novo mBC (MNR). When treated for EBC, ER+ disease was less likely to have a pathological complete response (pCR) with NACT (ER+ 22.2% (n = 4/18) vs ER- 50% (n = 5/10)). PFS data in response to an array of prescribed systemic therapies will be presented. Conclusions: Though, HER2 signalling is considered the dominant signalling pathway in HER2+ breast cancer, pre-clinical research indicates that the ER pathway represents an important escape mechanism influencing the development of resistance. Lack of efficacy (pCR) to NACT in ER+HER2+ EBC may translate to poorer outcomes (OS) when these patients develop MBC. Earlier targeting of the ER pathway in conjunction with HER2-DTs may contribute to improving patient outcomes.
HD201: Analytical biocomparability and clinical trial progression of trastuzumab.
Authors: hii Jocelyn , Pivot Xavier , Park Lisa Soyeon , Kim Michael , Feyaerts Peggy , Chan Kuo Wei , Lee Jeong-Hyeon , Ang Felicia
Published: May 2019

e12505

Background: Trastuzumab, an approved prescription drug by EMA and FDA under the name Herceptin has become the key treatment in patients with HER2 positive breast cancer. HD201, developed and owned by Prestige Biopharma Pte Ltd is a biosimilar product to Herceptin (Trastuzumab). The development of HD201 from analytical biocomparability to clinical trial progression are demonstrated. Methods: Analytical biocomparability in terms of physicochemical (primary, higher order structure, glycan profiles, molecular and charge variants) and biological properties (inclusive of binding to Fcγ receptors and neonatal receptor) between HD201 and EU and US-Herceptin were compared. The first human study of HD201 (clinical phase I) was designed to assess the pharmacokinetic (PK) equivalence between HD201 and EU-Herceptin. In this randomised, blinded, single-dose comparative PK study, randomised healthy human subjects were subjected to a single 6 mg/kg IV dose of HD201 and EU-Herceptin following by PK and safety evaluations. Following this, a randomised, double-blind, parallel group, equivalence, multicentre clinical phase III trial (TROIKA) was designed to compare the efficacy, safety, and pharmacokinetics of HD201 to EU-Herceptin in 500 patients with HER2+ early breast cancer. Each group of patients (250 patients) were administered with either HD201 or EU-Herceptin once every 3 weeks up to 8 cycles in combination of a neoadjuvant chemotherapy comprising of docetazel followed by an anthracycline-containing regimen. Results: HD201 shows equivalent in physicochemical and biological properties compared to EU- and US-Herceptin. Clinical phase I study demonstrated that HD201 is safe and well tolerated with comparable PK profiles as EU-Herceptin after single dose administration to healthy male adults (Pivot et al., 2018). Analysis of sub study from clinical phase III has demonstrated comparable results with EU- Herceptin in terms of patient demographic, clinical response, safety and pharmacokinetic profile. Conclusions: HD201 is demonstrated to be equivalent in analytical biocomparability and in clinical response, safety and PK profile to Herceptin in human study. Additional data for Pharmacokinetic from Troika trial will be reported in Asco meeting. Clinical trial information: 2012-000805-56.
Tumor pathological and immunological changes in HER2+ metastatic breast cancer (MBC) following trastuzumab combined with expanded and activated autologous natural killer (NK) cell infusion.
Authors: Yadav Kritika , Shimasaki Noriko , Ow Samuel Guan Wei , Wong Andrea Li Ann , Lim Joline Si Jing , Koe Priscillia , Koh Liang Piu , Tan Lip Kun , Goh Boon C. , Campana Dario , Lee Soo-Chin
Published: May 2019

e12511

Background: A central mechanism for the anti-tumor activity of Trastuzumab, a HER2 monoclonal antibody, against HER2+ tumors is induction of antibody dependent cell cytotoxicity (ADCC) mediated by NK cells. We are conducting a first-in-human trial of Trastuzumab followed by infusion of expanded, activated autologous NK cells in refractory HER2+ MBC (ClinicalTrials.gov: NCT02030561) to test the hypothesis that NK cell infusions will augment Trastuzumab-mediated ADCC and increase immune cell infiltration in tumor. Pre- and post-infusion tumor biopsies were obtained in a subset of patients to determine degree of NK cell infiltration in tumor and histopathological and immunological effects after infusion. Methods: HER2+ MBC patients underwent apheresis to harvest NK cells for ex vivo expansion and activation. NK cells (107/kg), expressing high levels of the antibody receptor CD16, were infused 24 hours post-Trastuzumab. Histology analysis and immunohistochemistry with CD56, CD3, CD20 and cleaved caspase-3 to identify NK, T, B, and apoptotic cells respectively, was performed in pre- and post-infusion biopsies. Studies of CD4 and CD8 to further classify T cell infiltrates, and CD16 to assess NK cell functionality are underway. Results: Analysis of 7 paired tumor biopsies collected before and 7-14 days after NK cell infusion showed absolute increase in lymphocyte infiltration (mean cell count/5 HPF: 204 vs 265 in pre- vs post- biopsy, p = 0.109). Most infiltrating lymphocytes were CD3+ T cells (74.28±12.72% vs 80 ±10% in pre vs post) and CD56+ NK cell number in the immune infiltrate were increased post infusion (mean cell count/5 HPF: 4.57±3.46 vs 20.57±13.83 in pre vs post; p = 0.009). Increased tumor apoptosis was observed post NK cell infusion (mean apoptotic cell count/5 HPF: 3.14±2.48 vs 5.86±6.72 in pre vs post, p = 0.27). Conclusions: Histopathology analysis of tumors from HER2+ MBC patients demonstrated significant increase in NK and T cells in tumor following Trastuzumab and NK cell infusion, suggesting that this combination might also augment recruitment of T lymphocytes into tumor, further enhancing anti-tumor activity. Clinical trial information: NCT02030561.
Impact of mastectomy in women with stage IV HER2+ breast cancer.
Authors: Babar Arslan , Covut Fahrettin , Kewan Tariq Zuheir , Rahman Shafia , Grobmyer Stephen R. , Montero Alberto J.
Published: May 2019

e12515

Background: Women with stage IV HER2+ breast cancer typically have longer overall survival (OS) compared to other breast cancer subsets due to the effectiveness of dual anti HER-2 antibody therapy. The role of mastectomy remains controversial. Methods: We reviewed patients who were diagnosed with stage IV HER2+ breast cancer between 2/2015 and 12/2017 at Cleveland Clinic. Overall survival (OS) was estimated by the Kaplan-Meier method, and compared by the log-rank test. Univariable and multivariable analysis were performed using Cox regression to identify predictors of OS. Results: We identified 47 patients, with a median age of 58 (range: 22 – 87). Twenty-eight (60%) and 14 (30%) patients had ER+ and PR+ disease, respectively. Four patients had brain metastasis at time of stage IV diagnosis. All patients received systemic therapy. 17 (36%) patients underwent mastectomy after diagnosis of stage IV breast cancer,. Of the 30 (64%) patients who did not undergo mastectomy, 24 (80%), 2 (7%), and 4 (13%) were treated with both chemotherapy and HER2-directed therapy, chemotherapy alone, and HER2-directed therapy alone, respectively. Breast radiotherapy was performed on 9 (53%) and 8 (27%) patients in mastectomy and no mastectomy cohorts, respectively. Median follow-up time was 22 months . The two-year OS for mastectomy and no mastectomy cohorts were 94% (95% CI: 83 – 100) and 50% (95% CI: 33 – 76), respectively (p=0.009). On univariable analysis, only mastectomy vs no mastectomy (HR: 0.18, 95% CI: 0.04 – 0.80, p=0.025) predicted OS. On multivariable analysis, mastectomy vs no mastectomy has remained to be statistically significant predictor of OS (HR: 0.08, 95% CI: 0.01 – 0.66, p=0.019), whereas age, chemotherapy, HER2-directed therapy, and breast radiation were not independent predictors of improved OS (p>0.05). Conclusions: In our cohort, mastectomy was an independent predictor of longer OS in women with stage IV HER2+ breast cancer.
Real-world effectiveness of ribociclib + aromatase inhibitor, or endocrine monotherapy, or chemotherapy as first-line treatment in postmenopausal women with HR-positive, HER2-negative locally advanced or metastatic breast cancer: Baseline data from the RIBANNA study.
Authors: Wöckel Achim , Decker Thomas , Fasching Peter A. , Jackisch Christian , Luftner Diana , Marme Frederik , Reimer Toralf , Roos Christian
Published: May 2019

e12520

Background: Ribociclib, a selective CDK4/6 inhibitor, in combination with an aromatase inhibitor (AI) is approved for the treatment of HR+/HER2- advanced breast cancer (aBC) (locally advanced or metastatic). Real-world evidence for the effectiveness, safety and tolerability of ribociclib + AI in routine clinical practice is needed to support its use. Methods: RIBANNA (CLEE011ADE03) is a non-interventional study running in Germany since October 2017 involving up to 3020 postmenopausal patients receiving ribociclib + AI, endocrine monotherapy (ET), or chemotherapy (CT) as first-line treatment for HR+/HER2- aBC, prescribed in line with German guidelines. Data are collected from clinical practice in all three cohorts. Further lines of treatment are documented to examine outcomes of sequential therapy. Results: 461 patients enrolled to October 9, 2018 (Table). First-line mean daily ribociclib dose was 382 mg including and 540 mg excluding dose interruptions; mean duration of exposure to ribociclib: 128 days. Ribociclib was given in combination with anastrozole (8%), exemestane (7%), and letrozole (83%); ET comprised a selective estrogen receptor degrader (25%), nonsteroidal AI (64%), steroidal AI (5%), and a selective estrogen receptor modulator (7%); CT included taxane-based monotherapy (30%) or combination therapy (27%), anthracycline-based combination therapy (5%), other monotherapy (23%) or other combination therapy (13%). Conclusions: Population characteristics from the RIBANNA study show a diverse group of patients from a real-world setting of ribociclib treatment. Baseline demographics and characteristics. Clinical trial information: CLEE011ADE03. [Table: see text]
Real-world evidence evaluating continuation of CDK4/6 inhibitors beyond first progression in hormone receptor-positive (HR+) metastatic breast cancer.
Authors: Eziokwu Akaolisa Samuel , Varella Leticia , Kruse Megan Lynn , Jia Xuefei , Moore Halle C. F. , Budd George Thomas , Abraham Jame , Montero Alberto J.
Published: May 2019

e12538

Background: CDK inhibitors (CDKi), in combination with aromatase inhibitors (AI), are approved for the treatment of hormone receptor positive (HR+) Her2 negative metastatic breast cancer (MBC). The effectiveness of continuing CDKi beyond first disease progression is not known. This study evaluated real world evidence and assessed the impact of continuation of CDKi beyond first disease progression in combination with endocrine therapy. Methods: This is a retrospective, single institution review of HR+ MBC patients treated with CDKi from 2015-2018 who continued CDKi after initial progression. The primary outcome was progression-free survival (PFS) beyond first disease progression, as assessed by the clinician based on radiological and/or clinical criteria. Overall survival (OS) – defined as date of initial CDKi treatment to date of death or last follow up – was a secondary outcome. Results: 30 women with HR+/HER2- MBC, median age 47.5 years (range: 31 – 81), sequentially continued on CDKi beyond first progression were identified from a database of patients treated with Palbociclib. Median and average follow up times on CDKi were 27.18 and 24.53 months, respectively. Initial endocrine/CDKi regimen received included: palbociclib (PA)/letrozole (LTZ) [67%], PA/fulvestrant (FULV) [23%], and PA/other AI [10%]. Prescribed combinations beyond 1st progression were: PA/FULV [56.7%], PA/LTZ [16.7%], and PA/other AI [20%], abemaciclib plus LTZ or FULV [6%]. As of 1/31/2019, 25 patients (83.3%) were still alive, and 19 (63%) had undergone a second progression on CDKi. The estimated median PFS for the entire duration while on CDKi was 23.5 months (95% CI 12.8 – 27.8), of which 11.8 months (95% CI 5.34 – 13.13) was the median PFS beyond first progression. The estimated median OS was 45.4 months. Conclusions: Among a small cohort of HR+ MBC patients, in a non-clinical trial setting, continuation of palbociclib plus endocrine therapy beyond first progression was associated with a median PFS of approximately 11 months. Formal clinical evaluation of continuation of CDK inhibitor plus endocrine therapy beyond first progression is warranted.
New docetaxel-peptide conjugate for the treatment of sortilin-positive triple-negative breast cancer.
Authors: Demeule Michel , Annabi Borhane , Currie Jean-Christophe , Larocque Alain , Charfi Cyndia , Béliveau Richard
Published: May 2019

e12556

Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease which still lacks defined molecular biomarkers. In the last decade, targeting of specific gene/protein molecular signature of tumors emerged among the best anticancer strategies. Recently, increased expression of the Sortilin (SORT1) receptor has been reported in TNBC patients. Given SORT1 functions in protein internalization, sorting and trafficking, we developed a new peptide-anticancer drug conjugation platform to target SORT1-positive breast cancer by linking Docetaxel to a peptide (KA-peptide) that specifically targets SORT1. Methods: MDA-MB-231 cells were used as a TNBC cell model for in vitro and in vivo xenograft (CD1 nude mice) assays. Cell migration was assessed using the xCELLigence real-time system, whereas MTT assay was used for cell proliferation analysis. Apoptosis biomarkers expression was assessed by immunoblotting. Results: In MDA-MB-231, the Docetaxel-KA-peptide conjugate (DoceKA) exerted potent anti-proliferative and anti-migratory activities in vitro. DoceKA triggered faster and higher cell death mechanisms than did free Docetaxel alone. The apoptotic and anti-migratory effects were reversed by the SORT1 ligands Neurotensin and Progranulin, and upon siRNA-mediated silencing of SORT1. DoceKA altered microtubules polymerization and triggered the down-regulation of IL-6, Survivin, Bcl-xL and mutant p53 pro-survival biomarkers. In vivo, DoceKA exhibited a greater tumor regression capacity with a prolonged survival in a murine MDA-MB-231 xenograft tumor model than did Docetaxel. Conclusions: Collectively, we demonstrate that DoceKA is specifically internalized through a receptor-mediated mechanism. Such property allows for targeting SORT1-positive breast cancers, and makes DoceKA a promising novel therapy for the treatment of TNBC.
High-throughput screening (HTS) of natural products with triple-negative breast cancer (TNBC) organoids.
Authors: Sun Zhijian , Zhang Bailin
Published: May 2019

e12558

Background: Breast cancer is one of the most malignant diseases threatening the health of our society. Triple negative breast cancer (TNBC) is an aggressive histological subtype representing 15–20% of all breast cancers. Comparing with other breast cancer subtypes, TNBC is characterized with limited treatment options and a worse clinical outcome. Resistance to chemotherapies is common for TNBC. Therefore, continuously developing new anti-cancer drugs is of great importance for TNBC. Nature products a source of medicinal leads, but lacking suitable pre-clinical models, which could faithfully reflect in vivo tumor property, prevents these compounds from further characterizing. Now cancer organoids, as a new in vitro 3-D culture technique, were demonstrated to largely retain the biological characteristics of tumors from patients, and potentially served as an ideal platform for drug sensitivity test. Methods: Here we set up system to efficiently establish breast cancer organoids from clinical patients and further test the sensitivity of these organoids to various nature products. Results: A total of 29 TNBC organoid models were established with fresh biopsy or surgery tumor tissues from TNBC patients. Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) in TNBC PDOs were evaluated with qPCR, western blot, Immunohistochemistry (IHC). A high-throughput cell viability assay was established for identifying lead compounds from a unique collection of 969 natural products. Primary hits were serial diluted and further evaluated for IC50 and percentage of inhibition. Preliminary mechanism of action (MOA) studies was performed with gene reporter assays, western blot and qPCR. Interestingly, organoids derived from paclitaxel resistant TNBC patients also show less sensitivity to paclitaxel in vitro, which indicated a high clinical relevance. Conclusions: Triple negative breast cancer organoid, as a good pre-clinical model largely containing tumor in vivo property, provides an ideal platform for new drug discovery and inhibitor screening. Moreover, serving as in vitro replacements for breast cancer, organoid models make it possible to test drug sensitivity for individual patient to achieve precise and personalize medication.
Eribulin ORA: A novel oral formulation of eribulin based on combination with the P-gp inhibitor HM30181A.
Authors: Pitzonka Laura , Cutler Murray , Lau Johnson Yiu-Nam , Cutler David , Kwan Rudolf , Smolinski Michael
Published: May 2019

e12577

Background: Eribulin is a potent synthetic derivative of the marine sponge natural product Halichondrin B that uniquely targets microtubule growth to induce apoptotic cell death. Eribulin is currently administered intravenously (IV) to treat patients with breast cancer and liposarcoma refractory to taxane therapy due to its superior efficacy in taxane resistant tumor types. Methods: Utilizing a proprietary Orascovery platform, Eribulin ORA, a novel orally-administered eribulin formulation has been developed, which combines the P-glycoprotein (P-gp) inhibitor, HM30181A, with oral eribulin. Results: HM30181A significantly improves the systemic exposure of oral eribulin in rodents, which enables remarkable tumor regression in murine xenografts. HM30181A improves eribulin plasma exposure > 5-fold in mouse model (AUC0-24hr = 8224 ng*hr/mL with HM30181A vs. 1516 ng*hr/mL without HM30181A) and also improves eribulin oral bioavailability in the rat (%F = 35.0 with HM30181A vs. 16.1 without HM30181A). In vitro cell viability assays of MCF-7 and MDA-MB-231 breast cancer cell lines show eribulin is synergistic with other microtubule disrupting agents, including common first-line breast cancer therapy paclitaxel. In mice bearing orthotopic MDA-MB-231 breast tumor xenografts, oral eribulin with HM30181A was administered at eribulin doses of 0.5, 1.0, and 1.5 mg/kg Q2Dx3 (M,W,F)/week for four weeks. Only mice treated with 1.5 mg/kg (highest dose) eribulin had weight loss during treatment, with the observed weight loss was < 10%, (except for one mouse). All eribulin doses tested induced tumor regression, with 7/9 tumors in the 1.5 mg/kg eribulin group experiencing durable complete regression until study end, two-weeks post administration. Of the tumors in the Eribulin ORA-treated groups that resumed growth after treatment, the degree of tumor growth was minimal. Overall, Eribulin ORA was well tolerated and showed potent efficacy against breast cancer tumors, exhibiting nearly 100% growth inhibition at all dose levels tested. Conclusions: Eribulin ORA showed good oral absorption, efficacious systemic exposure, and importantly, excellent anti-cancer activity in a breast cancer model. In vitro studies demonstrated the synergistic potential of eribulin in combination with paclitaxel. Accordingly, the combination of Eribulin ORA with Oraxol (oral paclitaxel that has shown promising clinical data) may represent an excellent metronomic oral combination chemotherapy that warrants further investigation for patients with advanced breast cancer.
Pathological and genetic aggressiveness of left-sided breast cancer.
Authors: Abdou Yara , Asaoka Mariko , Takabe Kazuaki
Published: May 2019

e12579

Background: Breast Cancer in women consistently occurs more frequently in the left breast, with the ratio of left to right sided breast cancer cases ranging from 1.05 to 1.26. In spite of the difference in frequency, prior studies have failed to show any significant difference in clinical characteristics between left sided and right sided cancer. Methods: Genomic and clinical features were collected from The Cancer Genome Atlas breast cancer project. LVI status, mitotic rate, nuclear score and tubular score were collected from pathology reports in TIES client 5.8. Fisher's exact test was used for group comparison and survival analysis was performed with Cox regression. Cytolytic activity (CYT) indicates anti-cancer immune response and was quantified from gene expression data. Hallmark gene-sets were used for gene set enrichment analysis (GSEA). Results: Among the 1081 women with unilateral invasive breast cancer, 561 had tumor on the left side compared to 520 on the right. Our results didn’t show any significant differences between left and right side with regards to tumor location, histology, race, and tumor characteristics including stage, tumor size, nodal status and receptor status. No statistical significant differences were observed in mitotic rate, LVI status and tubular score, however, the tumor grade was significantly higher in the left side. Moreover, there were no significant differences in mutation count, CYT and overall survival between both sides. GSEA revealed cell-cycle related gene sets like G2M checkpoint, Mitotic spindle, E2F targets and MYC targets which were significantly enriched in left sided tumor. Furthermore, out of the 865 genes which were highly expressed on the left side, we identified specific genes including BRCA1, BRCA2, BRIP1, CHEK2, FANCC, PALB2, TP53 and MSH6 which are associated primarily with breast cancer genesis and mostly have established clinical management guidelines. Conclusions: Our results suggest a more aggressive nature to left sided breast cancer with a higher pathological grade perhaps requiring more aggressive treatment. Such a hypothesis needs further study to confirm or refute its validity. If confirmed, it may have a major impact with regard to biology of breast cancer and its subsequent management.
[18F] Fluorodeoxyglucose positron emission (FDG-PET) in breast cancer: Clinical utility in neoadjuvant and metastatic setting.
Authors: Morales Murillo Serafin , Gasol Cudós Ariadna , Veas Rodriguez Joel , Canosa Morales Carles , Olivé Jordi Melé , Salud Antonia
Published: May 2019

e12584

Background: FDG-PET in clinical practice is based on the detection of a relapse and the initial staging but its role as a predictive factor or its correlation with biological parameters is very controversial. Methods: We analyzed the SUV of FDG-PET in a cohort with 36 patients in neoadjuvant setting and 112 with metastatic disease. Results: The median of SUV in neoadjuvant was 8,95 (range 2,8-30) with higher SUV in triple negative (11,7 range 2,8-18,8) than HER2 positive (8,75 range 4-30) and luminal patients (7,9 range 4,4-16). We don´t find a correlation between the SUV with either histological and clinical variables but there was a slightly correlation with residual tumor (p:0,068) and initial node involvement (p:0,069). In the 112 metastatic cohort the median SUV was 7,95 (range 2-28) with higher SUV in triple negative (10,1 range 3,4-19) than HER2 positive (9,7 range 4-28) and luminal patients (7,6 range 2.21). We found only a correlation between the SUV and progesterone receptor value (OR 0,875 p:0,005) but not in estrogen receptor, Ki67 index and HER2 status. In the survival analysis we don´t find a correlation between the SUV value and the disease free and overall survival included the analysis for different phenotypes. Conclusions: The SUV of the FDG-PET is very variable in all phenotypes of breast cancer being higher in the triple negative phenotype and lower in the luminal. The SUV value is very similar in neoadjuvant and metastatic setting. We only correlated the SUV value with the progesterone receptor in the metastatic cohort. We don´t find a prognostic value of the initial value of SUV in the two cohorts.
Progression-free survival as a predictor of overall survival in patients with advanced breast cancer: A real-world study from the China National Cancer Center.
Authors: Mo Hongnan , Xu Binghe , Ma Fei , Li Qing , Zhang Pin , Yuan Peng , Wang Jiayu , Luo Yang , Cai Ruigang , Li Qiao , Li Yiqun , Guan Xiuwen , Lin Shaoyan , Chen Yimeng , Wang Zijing
Published: May 2019

e12590

Background: Use of progression-free survival (PFS) as a clinical trial endpoint in first-line treatment of patients with advanced breast cancer is attractive, but would be enhanced by establishing a correlation between PFS and overall survival (OS). Methods: From January 2003 to December 2012, 1851 patients with advanced breast cancer at start of first-line therapy were enrolled in this real-world study. An independent cohort of patients hospitalized in 2013 was used for external validation. All data were collected from the Database of China National Cancer Cancer. Results: The correlation coefficient (Pearson’s r) between PFS and OS was 0.807 in patients only receiving endocrine therapy as first-line treatment, 0.643 in those treated with chemotherapy, and 0.642 in the whole cohort. Receiver operating characteristic curve indicated that PFS = 12 months was the optimal cutoff value for predicting patient’s survival. The median OS was 30.0 months (95% CI 27.8-32.2) in the PFS < 12 months group, and 69.0 months (95% CI 60.8-77.2) in the other group (P < 0.0001). Multivariate analysis revealed that compared with patients who did not progress at 12 months, the adjusted hazard ratio (HR) for death was 2.681 (95% CI, 2.301-3.124; P < 0.0001) for patients with PFS < 12 months. Subgroup analysis based on patient’s age, molecular subtype, visceral metastasis and types of first-line treatment further confirmed that PFS < 12 months was associated with significant poor prognosis in all these subgroups. In patients with luminal type of breast cancer, the HR for death was 2.567 (95%CI 2.147-3.069; P < 0.0001) for patients with PFS < 12 months. Notably, for these patients with luminal type breast cancer who had progressed within 12 months after first-line treatment, addition of chemotherapy in the second-line therapy would surprisingly have adverse effects on patients’ survival when compared with endocrine therapy alone (HR = 1.627, 95%CI 1.016-2.604, P = 0.043). The findings were externally validated in the independent cohort. Conclusions: To our knowledge, this is the first real-world study revealed that PFS at 12 months in first-line therapy predict OS of patients with advanced breast cancer.