bluuebunny/crossref_metadata_2025 huggingface dataset:
Practice-changing use of 21-gene oncotype DX breast recurrence score assay in a public hospital in Brazil: Results of 155 cases.
Authors: Mattar Andre , Fonseca Guilherme Ribeiro , Romão Murilo Barato Agudo , Shida Jorge Yoshinori , Stiepcich Monica Maria Agata , Jakubowski Debbie M , Chao Calvin Y. , Oliveira Sergio C , Gebrim Luiz Henrique
Published: May 2020

e12518

Background: The 21-gene assay estimates risk of recurrence expressed as a Recurrence Score result between 0 and 100. The assay is clinically validated to predict chemotherapy (CT) benefit in node-negative (N0) and node-positive (up to three axillary nodes, N1) hormone receptor-positive (HR+) early-stage breast cancer (ESBC). The TAILORx study, which randomized 6711 women with N0 ESBC and Recurrence Score result 11-25 to hormonal therapy (HT) ± CT, demonstrated that patients older than 50 years derived no benefit from CT+HT, although younger patients with Recurrence Score result 16-25 may derive some benefit. The 21-gene assay has been incorporated in practice guidelines worldwide, based on evidence of clinical utility in N0 and N1 ESBC. We evaluated the impact of the 21-gene test on treatment decisions for patients with N0 and N1 ESBC at Sistema Único de Saúde in Brazil. Methods: Eligible patients were post-surgery with T1/T2 tumors, had HR+, HER2−, N0 or N1 ESBC, and were candidates for adjuvant systemic therapy. Treatment recommendations, CT+HT or HT alone, were captured before and after 21-gene test results. All patients were seen at Pérola Byington Hospital, a public hospital in São Paulo, Brazil. TAILORx results were used to guide decisions for or against CT for each patient. Results: From 08/2018 to 04/2019, 155 women were enrolled. Patient mean age was 57.6 years (29-78), 116 (75%) were postmenopausal, and 53 (34%) had N1 breast cancer. Based on clinical data alone, 151 patients had pre-assay recommendations of CT. Post-assay, 106 of 151 patients (70%) had changes in CT recommendation: 104 (69%) initially recommended CT received HT alone, and 2 (1%) initially recommended HT alone received CT+HT (Table). Using the modified Adjuvant!Online criteria for clinical risk classification, 109 of 155 patients (70%) had high risk, 48 (44%) of whom received CT. Of 46 patients with low clinical risk, 10 (22%) received CT. CT use trended with histologic grade: 11% with grade 1, 69% with grade 2, and 61% with grade 3. Most of our patients had tumor bigger than 2 cm (61%) with 8% bigger than 4 cm. Conclusions: The change in clinical practice at this public hospital was greater than expected: 69% of initial treatment recommendations were changed with the Recurrence Score result to omit CT. Clinicopathologic criteria did not correlate well with Recurrence Score results and did not identify those most likely to benefit from CT. A cost-effectiveness study is underway at our institution. [Table: see text]
Nine weeks versus six months of adjuvant trastuzumab in HER2-positive breast cancer: 3-year disease-free survival results.
Authors: Saifo Maher
Published: May 2020

e12530

Background: A total of 12 months adjuvant trastuzumab is still the optimal choice for patients with HER2-positive early breast cancer. However, the shorter course of 9 weeks may be considered as a cost-effective and safe option in developing countries such as Syria. Purpose: We aimed at investigating whether short-course 9-week adjuvant Trastuzumab is non-inferior to 6-month treatment at Albairouni University Cancer Center. The primary endpoint was disease-free survival (DFS). The secondary objective was assessing toxicities, especially cardiotoxicity. Methods: Patients with HER2-positive stage I-IIIC breast cancer were assigned to receive either 9 weeks or 6 months of trastuzumab in combination with adjuvant chemotherapies (sequentially). The 9-week group; 90 patients received trastuzumab intravenously (loading dose 4 mg/kg; then 2mg/kg weekly), whereas in the 6-month group; 157 patients, trastuzumab was delivered every 3 weeks intravenously (loading dose 8 mg/kg then 6 mg/kg). The LVEF was measured pretreatment and every 3 months afterwards. Results: 3-year DFS was 71.87% in the 9-week group versus 76.43% in the 6-month group, (Non-significant). No obvious side effects have been noticed during the follow-up period in the 9-week group. Congestive heart failure was reported in 2.55% of patients in the 6-month group. Conclusions: Short-course 9-week adjuvant trastuzumab is less effective than 6 months of treatment, with less cardiotoxicity. The short course could be considered in patients with heart disease and low risk of recurrence.
Effect of farrerol on the proliferation of estrogen receptor-positive breast cancer by downregulating oncogenic genes with estrogen receptor response elements.
Authors: Lu Xiao-Qing , Yang Rui , Zhang Jia-Qian , Zhang Shengxiao , Zhang Huan-Hu
Published: May 2020

e12541

Background: Breast cancer (BC) is the most common malignant tumor among women worldwide, the most common of which is estrogen receptor (ER) -positive BC. Farrerol, a noval estrogen-like chemicals, is closely associated with ER positive BC. In this study, we will explore the anticancer effect of farrerol on ER-positive BC and the detailed mechanism. Methods: Cloning formation assay and MTT assay were used to evaluate the effect of farrerol on proliferation ofcells. The affinity of farrerol, estrogen and tamoxifen with ER was tested by molecular docking technique. Point mutation was performed on the possible binding sites of ER according to the results of virtual docking, and Surface Plasmon Resonance (SPR). ER response elements in BC cells with farrerol were evaluated by qPCR. Results: With the increased farrerol concentration, the number of cell clones formed gradually decreased and the volume of clones became smaller in the ER positive McF-7 cell group, while a completely opposite clones was observed in non- ER positive MDA-MB-231 cells. The proliferation inhibition rate of McF-7 cells in the 160 mol/L and 320 mol/L groups was 45.86% and 65.3% respectively, significantly higher than that of MDA-MB-231 and normal mammary epithelial cells (P < 0.05). Both molecular docking technique and SPR experiment showed that farrerol could bind to ER at different sites than estrogen binding. Fiarrerol effectively down-regulated the transcription of the oncogenes MYC and TFF1, and suppressed ER-positive BC. Conclusions: Farrerol has the opposite effect with estrogen, which inhibited the proliferation of ER-positive BC cells, and downregulated the expression of oncogenic genes with ER response elements in BC cells. Therefore, farrerol, as a natural ingredient, could be further developed and applied with its obvious inhibitory effect on ER-positive BC in the future.
Hormones as indicator of relapse-free period in breast cancer (BC).
Authors: Samaneva Natalia Yu. , Frantsiyants Elena M. , Vladimirova Liubov Yu , Storozhakova Anna E. , Sheiko Elena A. , Bandovkina Valeria A. , Cheryarina Natalia D. , Tikhanovskaya Natalia M. , Kit Oleg I. , Lisutin Aleksandr E. , Shatova Iuliana S. , Vashchenko Larisa N.
Published: May 2020

e12550

Background: BC is still one of the main causes of death in women due to the tumor recurrence and/or resistance to anticancer therapy. The criteria to assess the effectiveness of BC treatment are important. The purpose of the study was to analyze blood levels of steroid and pituitary hormones in BC patients after two chemotherapy cycles. Methods: The study included 42 patients with various biological BC subtypes: luminal A, luminal B and triple-negative BC (TNBC). Levels of estradiol, testosterone, progesterone, prolactin, LH, FSH and cortisol were measured by RIA in the blood of all patients before and after two neoadjuvant chemotherapy cycles. Significance of differences was evaluated by the Student’s t-test. Results: Levels of many hormones were high before the treatment in patients with all BC subtypes. After two chemotherapy cycles, unidirectional changes in the values were found in patients with subsequent remission for more than three years. Levels of estradiol decreased in luminal A BC by 1.7 times (p˂0.05), in luminal B BC – by 11.6 times (p˂0.05), cortisol decreased by 2.4 and 1.7 times (p˂0.05) respectively, and prolactin – on average by three times (p˂0.05). LH levels increased in luminal A and luminal B BC by 1.65 times (p˂0.05). In patients with TNBC, levels of estradiol decreased by 1.8 times, and cortisol – by two times (p˂0.05). Patients with subsequent remission regardless of BC subtypes had unchanged levels of testosterone, progesterone and FSH. Patients with luminal B and TNBC subtypes with progression in 6-12 months did not show significant changes in prolactin and cortisol levels after two chemotherapy cycles, compared with the values before treatment. Conclusions: A decrease in blood levels of prolactin and cortisol after two chemotherapy cycles is an indicator of a long-term remission in patients with breast cancer.
WNT/β–catenin pathway activation correlates with the increase of tumor-associated macrophages in triple negative breast cancer (TNBC).
Authors: Timperi Eleonora , Ye Mengliang , Dubois Thierry , Meseure Didier , Salomon Anne Vincent- , Romano Emanuela
Published: May 2020

e12564

Background: Triple negative breast cancer (TNBC) occurs in about 20% of all breast carcinomas. Because only a fraction of TNBCs responding to immune checkpoint blockade show a pre-existing T cell-inflamed tumor microenvironment (TME), it is critical to understand the mechanisms of T-cell exclusion. Tumor-cell intrinsic activation of the WNT/β–catenin pathway, overexpressed in 30% of human breast cancers, is linked to a T-cell excluded TME. In β–cateninhigh TNBC, however, the quality of the myeloid compartment has not been evaluated. Methods: A total of seventy-five, early-stage, untreated, TNBC patients was assessed (patient cohorts approved by IRB). β–catenin expression was detected by IHC and scored as high, intermediate, and low. The presence of T cells, tumor-associated macrophages (TAMs) and LAMP-expressing dendritic cells (LAMP+ DCs) was assessed by IHC using aCD3, aCD68, aCD163, and aLAMP, respectively. Public TNBC datasets TCGA (N = 157) and METABRIC (N = 319) were interrogated for correlations between β–catenin- and immune-associated genes. Results: Three patient groups (N = 25/group) were identified according to the negative, medium and high intracellular expression of β–catenin. As opposed to β–cateninlow TNBC, the β–cateninhigh group displayed significantly lower CD3+ T cells (median 5% ±7.37 SD vs median 30% ± 18.28 SD, p < 0.0001) and LAMP+ DCs (median 1% ± 2.515 SD vs median 10% ± 7.038 SD, p < 0.0001). The β–cateninlow group was enriched in lymphocyte-predominant TNBC. For the first time, we show that the immune-suppressive, CD68+CD163+ TAMs were strongly accumulated in the β–cateninhigh group (median 20% ± 12.20 SD vs median 5% ± 6.831 SD, p < 0.0001). The interrogation of the public TNBC datasets TCGA and METABRIC confirmed that – after patient statification according to the expression level of a WNT/β–catenin gene-signature (i.e. MMP7, SFRP1, WNT10A, WNT16, WNT9B) – multiple TAM-associated genes – identified by our group in a single-cell RNAseq dataset – were strongly upregulated in WNT/β–cateninhigh signature, highlighting the role of the WNT/β–catenin signaling pathway not only in T-cell exclusion but also in selective TAM accumulation. Conclusions: Immune-suppressive TAMs are accumulated in β–cateninhigh, T-cell excluded TNBCs emphasizing the importance of tumor-intrinsic factors in shaping the quality of the immune infiltrate.
Breast cancer: The Indian scenario.
Authors: Gogia Ajay , Deo Svs , Sharma Dayanand , Mathur Sandeep
Published: May 2020

e12567

Background: This study was undertaken to evaluate the clinic-pathological characteristics and outcome of patients with female breast cancer at I.R.C.H, AIIMS, New Delhi, one of the largest tertiary-care cancer center in India. Methods: This ambispective study included patients with breast cancer in females, registered at our institute from January 1st, 2014 to December 31st, 2018.We retrieved data from prospectively maintained clinical case records. Results: We included 997 patients with median age of 47.5 years (21–90) The TNM (AJCC-7th edition) stage distribution was stage I, 40 (4.01%); stage II, 326 (32.70%); stage III, 419 (42.02%); and stage IV, 212 (21.26%). The median tumour diameter was 5 cm. Infiltrating ductal carcinoma (96%) was the most common histologic subtype. Fifty eight percent of cases were positive for ER or/ and PR whereas 30.89% patients were HER2/neu positive. Triple negativity was found in 29.88 % of cases. Patients underwent breast conserving surgery in 28.2% of cases, 41.7% were received neo-adjuvant chemotherapy and 9.5 % of patients offered palliative chemotherapy. The pathological complete response was seen in 20.5% of cases. Loco-regional recurrence occurred in 2.8%, and 23.2% of patients developed distant metastases. The discordance of receptor was present in 20.5% for ER, 25.1% for PR, and 15 % for HER2/neu on re-biopsy at the time of relapse . Only 37.83% of the eligible patients received trastuzumab upfront. For non- metastatic group, the median time of relapse was 36 months, 3 year relapse free survival (RFS) was 73.5% and overall survival (OS) was 82.1% . Clinical stage(stage III), triple negativity and HER2 neu positivity were associated inferior RFS however pathological node involvement (HR 1.4, 95% CI 1.01–2.18, p = 0.01) and triple negativity (HR 1.9, 95% CI 1.36–2.90, p = 0.001) were associated with poor OS . For metastatic group, the median time of progression was 18 months and 3 year progression free survival (PFS) was 35% and OS was 20%. More than 2 sites of metastasis, upfront brain metastasis, triple negativity, and poor performance status (ECOG III/IV) were associated with inferior survival. Conclusions: This is one of the largest comprehensive data from a single center. Majority of our patients are younger in age, advance in stage, aggressive in biology and unaffordability of targeted therapy on eligible patients might lead to poor overall outcome. Triple negativity is found in around 30% of cases and associated with poor survival.
Alter between gut bacteria and blood metabolites and the anti-tumor effects of Faecalibacterium prausnitzii in breast cancer.
Authors: Ma Ji , Sun Lingqi , Liu Ying , Ren Hui , Shen Yali , Bi Feng , Zhang Tao , Wang Xin
Published: May 2020

e12575

Background: The aim was to evaluate the changes of 16S rDNA sequencing and LC-MS metabolomics in breast cancer and explore the growth inhibition of breast cancer cells by Faecalibacterium prausnitzii. Methods: We performed the 16S rDNA sequencing of gut bacteria and the LC-MS metabolomics analysis of blood samples in 25 breast cancer patients and 25 benign breast disease controls. Correlation analysis of significant flora and metabolites were processed, including correlation coefficient calculation, matrix heat map analysis, cluster analysis, correlation network analysis, and scatter plot analysis. We screened for intestinal flora that may participate in breast cancer development and try to test and verify. CCK-8, apoptosis and transwell assays were explored to detect the growth inhibition of breast cancer cells by Faecalibacterium prausnitzii. Western blot was used to analyze the changes of IL-6/STAT3 pathway by Faecalibacterium prausnitzii. Results: Total 49 significantly different flora and 26 different metabolites were screened between two groups, and the correlation was calculated. Relative abudance of Firmicutes and Bacteroidetes were decreased, while relative abundance of verrucomicrobla, proteobacteria and actinobacteria was increased in breast cancer group. Differentially expressed metabolites were mainly enriched in pathways such as linoleic acid metabolism, retrograde endocannabinoid signaling, biosynthesis of unsaturated fatty acids, choline metabolism in cancer and arachidonic acid metabolism. Lipid upregulation was found in breast cancer patients, especially phosphorocholine. The abundance of Faecalibacterium was reduced in breast cancer patients, which was negatively correlated with various phosphorylcholines. Moreover, Faecalibacterium prausnitzii, the most well-known species in Faecalibacterium genus, could inhibit the secretion of IL-6 and the phosphorylation of JAK2/STAT3 in breast cancer cells. Faecalibacterium prausnitzii also suppressed the proliferation and invasion and promoted the apoptosis of breast cancer cells, while these effects disappeared after adding recombinant human IL-6. Conclusions: Flora-metabolites combined with the flora-bacteria (such as Faecalibacterium combined with phosphorocholine) might a new detection method for breast cancer. Faecalibacterium may be helpful for prevention of breast cancer. Faecalibacterium prausnitzii suppresses the growth of breast cancer cells through inhibition of IL-6/STAT3 pathway.
E2F cell cycle pathway score as a predictive biomarker of ER+/HER2- breast cancer response to neoadjuvant chemotherapy.
Authors: Oshi Masanori , Tokumaru Yoshihisa , Katsuta Eriko , Yan Li , Endo Itaru , Takabe Kazuaki
Published: May 2020

e12593

Background: Although the survival rate of patients diagnosed with breast cancer has greatly improved over the last decades, the metastatic stage of the disease remains incurable. Estrogen receptor positive (ER+)/human receptor 2 negative (HER2-) breast cancers accounts for approximately 70% of metastatic breast cancers and, it is responsible for most of the deaths from the disease. Another issue of ER+/HER2- breast cancer is its poor response to neoadjuvant chemotherapy (NAC). Recently, several clinical trials have shown that endocrine therapy plus FDA-approved cyclin-dependent kinases (CDK) 4/6 inhibitors have improved the treatment response to patients with advanced ER+/HER2 breast. The CDK 4/6 is an important E2F-related factor. Therefore, we hypothesized that E2F pathway is predictive biomarker for treatment response of ER+/HER2- breast cancer. Methods: METABRIC dataset was used for training cohort. And TCGA breast cancer as well as four neoadjuvant therapeutic cohorts were used as validation cohort. The E2F pathway score was calculated by Gene Set Variant Analysis (GSVA). Results: Tumors with high E2F pathway score enriched cell proliferation and cell cycle pathway related gene sets (G2M, MYC v1, and v2, MITOTIC, MTORC1, PI3K AKT MTOR, and DNA repair; FDR < 0.001). The high E2F pathway score was significantly associated with TNBC and HER2+ (p < 0.001), which are known to be clinically aggressive, and advanced stage (p < 0.001) and high grade (p < 0.001). The score also correlated with copy mutation (r = 0.605, p < 0.01). The patients, who had early recurrence before 5 years, had significantly high score rather than non-recurrence patients (p < 0.001). Moreover, these results were validated in TCGA cohort. The high E2F pathway score group had a higher pCR rate than the low score group with ER+/HER2- breast cancer (p < 0.001). Interestingly, the tumors in high score group expressed higher CDK pathway related molecules compared to low score group. Conclusions: The E2F pathway score was found to be a predictive biomarker for neoadjuvant chemotherapy in ER+/HER2- breast cancer patients.
Neoadjuvant endocrine therapy versus neoadjuvant chemotherapy in young women with breast cancer: Prognosis and axillary node surgery.
Authors: Gwark Sung-chan , Ahn Sei Hyun , Ahn Jin-Hee , Jung Kyung Hae , Kim Sung-Bae , Gong Gyungyub , Lee Sae Byul , Kim Jisun , Chung Il Yong , Ko Beom Seok , Lee jong Won , Son Byung Ho , Kim Seon-Ok , Kim Hee Jeong
Published: May 2020

e12626

Background: We aimed to evaluate patient-reported outcomes (PROs) in the NEST phase III trial, in which neoadjuvant endocrine therapy (NET) compared to conventional neoadjuvant chemotherapy (NCT) for hormone-responsive lymph node-positive premenopausal breast cancer. Methods: Premenopausal women with estrogen receptor (ER)-positive, HER2-negative, and lymph node-positive premenopausal breast cancer patients were enrolled. Patients were randomized to either 24 weeks of neoadjuvant chemotherapy with adriamycin plus cyclophosphamide (AC) followed by taxane (T) or neoadjuvant endocrine therapy with zoladex and tamoxifen. PROs were assessed at day 1 (baseline) and at the end of treatment, using the breast cancer module of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 23 (EORTC QLQ BR23). ClinicalTrials.gov: NCT01622361. Results: 187 patients were randomly assigned to chemotherapy (n = 95) or endocrine therapy (n = 92), and 174 patients completed the 24 weeks of neoadjuvant treatment period (n = 87, both). Baseline scores were similar between arms. No statistically significant between-treatment differences were observed for the function scales including body image, sexual functioning, and sexual enjoyment although endocrine treatment showed significant improvement in future perspective (HR = 8.3, 95% CI:1.72-18.38; P= 0.021). Even though no alopecia was reported in NET group, no statistically significant difference between both arms in the “upset by hair loss” was observed, in which NET group showed even worse score. Conclusions: Patients who received NET had significant improvement in a future perspective, however, a similar emotional negative impact on hair loss was observed compared with NCT despite no reported alopecia. Key words: breast cancer, patient-reported outcomes, quality of life, hair loss, EORTC QLQ-BR 23. Clinical trial information: NCT01622361.
21-gene recurrence score assay as a predictor of pathological response in neoadjuvant chemotherapy administration for ER-positive/HER2-negative early-stage breast cancer.
Authors: Murillo Serafin Morales , Gasol Cudós Ariadna , Rodriguez Alvaro , Canosa Morales Carles , Olivé Jordi Melé , Vilardell Felip , Sanchez Guzman Douglas
Published: May 2020

e12630

Background: Neoadjuvant chemotherapy (NAC) is an optimal option in early breast cancer, but in ER-positive/HER2-negative (luminal) is still controversial, although a survival benefit has recently been observed when a histological response by symmands method type 0 or I is achieved. The 21-Gene recurrence score assay (Oncotype DX) is a validated test to assess the survival benefit of adjuvant chemotherapy in these patients but its role in neoadjuvant setting is not yet well established unknown. We analyze the correlation between Oncotype DX Recurrence Score result and the pathological response assessed by symmands method. Methods: We analyzed a prospective cohort of 63 early luminal breast cancer patients who received NAC after performing an Oncotype DX test. Patients with an Oncotype DX Recurrence Score result lower 11 were excluded. The median age was 54 years (31-84), initial tumor size was 37 mm (12 -97), 41 patients (65%) had initial nodal involvement and the median Ki67 index was 34% (8 – 85). Results: An Oncotype DX results inferior or equal to 25 (considered as a limited benefit of chemotherapy treatment) was observed in 25 patients (40%) and a Recurrence Score higher than 25 in 38 (60%). Pathological response type 0 was achieved in 5 patients (8%) and type I in 16 (25%). A strong correlation between pathological response type 0 and I and Recurrence Score result in the univariate and multivariate analysis (OR 0,946 p:0,023) was found. We have performed a threshold analysis finding the Oncotype DX the most significant predictor of pathological response (AUC:0,75 p:0,0 01 ) compared to Ki67 (AUC:0,61 p:171), Estrogen receptor (AUC:0,41 p:0,21) and initial tumor size (AUC:0,671 p:0,028). All the patients who achieved a complete pathological response had a Recurrence Score result ≥ 26. Conclusions: The Oncotype DX Recurrence Score could be a useful tool to select early breast cancer patients who will benefit from neoadjuvant chemotherapy. Oncotype DX is the most significant predictor variable of pathological response and patients with a Recurrence Score of 25 or greater are five times more likely to obtain a histological response type 0-1 (OR: 5,3 p < 0,016). In our series the Oncotype DX test reaches the highest rate of complete pathological responses in this group of patients.
Perfusion kinetics from clinical DCE mris increase the accuracy of predictions of tumor response to chemotherapy.
Authors: Cole John A , Peterson Joseph R , Earnest Tyler M , Hallock Micahel J , Pfeiffer John R , Pandey Tushar , Braun Eduardo
Published: May 2020

e12651

Background: Nutrient and drug penetration into any solid tumor are critical determinants of the tumor's response to treatment. They depend on both the density of microvasculature within the tumor microenvironment, as well as the exchange rates of nutrients between the microvasculature and the extracellular space. But these parameters are heterogenous, varying considerably from location to location within the tumor and surrounding tissues. The Toft's model and its analogues date back to the early 1990s, and have been used to estimate vascular density, exchange rates, and extracellular-extravascular volume in a spatially-resolved manner using dynamic contrast enhaced (DCE) MRI's. Unfortunately, accurately extracting kinetic parameters from a DCE time-series requires the images to have a time-resolution of just a few seconds, which is rarely done in clinical practice. Methods: We employ a custom designed parallel algorithm to fit DCE MRI data to an exactly-solved ODE model of tissue perfusion kinetics. Results: Here we describe a simplified model of tissue perfusion that can be fit to DCE time traces with temporal resolutions of 90 seconds or more. We show that for many breast tumors, the vascular density and tissue-vascular exchange rate are such that they give rise to a halo of fast-perfusing tissue on the tumor periphery, and slower-perfusing tissue inside. We then use this model as part of a more comprehensive tumor simulation methodology to predict how different patients will respond to neoadjuvant chemotherapy (NACT). We find that the incorporation of our microvascular model gives rise to significantly more accurate predictions of post-treatment tumor volume. Conclusions: Performing perfusion kinetics analyses on clinical MRIs is both challenging, but critical for accurately predicting how a patient will respond to treatment. Our model, which relaxes the requirement for fine DCE temporal resolution, allows for these analyses to be performed on a larger swath of patients without the need for small volumes of interest, or ultra-fast MRI techniques. Moreover, when used within a broader tumor-modeling framework, our model increases the accuracy of predictions of tumor response to NACT.
Pathological outcomes of HER2-positive early breast cancer patients treated with neoadjuvant trastuzumab or dual anti-HER2 therapy and carboplatin with docetaxel: A Maria Sklodowska-Curie National Research Institute of Oncology experience.
Authors: Jagiello-Gruszfeld Agnieszka I. , Lemanska Izabela , Sienkiewicz Renata , Szombara Ewa , Dubianski Roman , Brewczynska Elzbieta , Pogoda Katarzyna , Konieczna Aleksandra , Kunkiel Michal , Majstrak-Hulewska Anna , Olszewski Wojciech P , Niwinska Anna , Nowecki Zbigniew
Published: May 2020

e12655

Background: Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) for breast cancer predicts the risk of recurrence and increasingly may indicate the need for additional therapy postoperatively. Methods: A retrospective analysis was performed in two cohorts of patients (pts) treated with docetaxel, trastuzumab and carboplatin (TCH) or with docetaxel, carboplatin and dual blockade (TCH-P) in the neoadjuvant setting in patients with early breast cancer (tumor size < 50 mm and > 10 mm and cN0 or cN1) in our Clinic, and who had definitive surgery was conducted. Demographic data, size, grade, tumor type, receptor status prior to neoadjuvant treatment, pathological complete response (pCR) rates, and adverse effects were analyzed. The pCR was defined as ypT0 ypN0. Results: Patient in cohort A (n = 58) received TCH x 6 cycles and in cohort B (n = 25) TCH-P x 6 cycles. Median age was 51 (range 23 to 76 years) in cohort A and 46 (range: 30-68) in cohort B. In cohort A 37 (64%) of pts was HR-positive, in cohort B only 9 (36%) pts . The most common adverse events in both groups were neutropenia, diarrhea, chemotherapy induced polyneuropathy and febrile neutropenia. There are no significant differences in the frequency of adverse events in two cohorts. There was no symptomatic heart failure, but 6 pts (10%) in cohort A and 5 pts (16%) in cohort B had > 10% asymptomatic decrease in LVEF. All patients were evaluable for pCR. Higher rates of pCR were achieved in the HER2pos/HRneg pts: 66% (n = 14) in cohort A, and 87% (n = 14) in cohort B. In group HER2pos/HRpos pts, the pCR rate was 48% (n = 18) vs 55% (n = 5) respectively. Conclusions: In HER2positive early breast cancer, a dual blockade (trastuzumab and pertuzumab) together with carboplatin and docetaxel neoadjuvant chemotherapy achieved higher rates of pCR ( 76%) compared with pts treated with trastuzumab, carboplatin and docetaxel (56%). However, a much higher percentage of pCR was observed in the group of patients with non-luminal cancers, who received a double blockade (87% vs 66%).
Spatiotemporal modeling with SimBioSys TumorScope to predict chemotherapeutic response in breast tumor microenvironments.
Authors: Mamillapalli Chaitanya K , Markwell Timothy K , Ellis Jason K , Pfiefer John , Pandey Tushar , Cole John A , Peterson Joseph R , Fox Daniel J
Published: May 2020

e12656

Background: Predictive models of the efficacy of different tumor therapies will provide significant enhancements to current standard of care practices. Predicting a given tumor’s growth and treatment response, however, is an intricate process that requires not only an understanding of the tumor's intrinsic characteristics, but also spatial- and temporal-resolved tumor shape descriptions, surrounding tissue dynamics, and a complete account for the milieu of diffusible molecules that drive tumor behaviors and interactions. Here we report an ongoing retrospective study designed to validate SimBioSys TumorScope as a computational tumor therapy prediction model in a real-world clinical setting. Methods: Fully-deidentified and HIPAA-compliant data were assessed from real-world clinical records and cases. Subjects comprised early stage breast cancer patients who were treated with neoadjuvant chemotherapy (NACT) and subsequent surgical resection. Data fields included imaging data, biomarker status, tumor sizing, demographic data, digital pathology, and genetic lab test data. Half of the data, including all data fields, were used as a training dataset for TumorScope. The second half of the data, with blinded diagnoses and results, will be used to test TumorScope’s prediction accuracy. Simulations will be initialized with pre-treatment MRI data and processed through the entirety of each patient's specified treatment regimen. Predicted tumor volume and longest dimension will be compared against measured values at several time-points after therapy initiation. Overall accuracy will be statistically assessed by the Pearson correlation coefficient between predicted and measured tumor volume and longest dimension at each time-point, as well as their root-mean-squared-errors. Results: Final statistical analysis is currently underway. Thus far, SimBioSys TumorScope has trended high accuracy levels with the non-blinded “training” cohort just as it has in previous database studies, with a Pearson correlation coefficient greater than 0.94. Conclusions: SimBioSys TumorScope for Breast Cancer accurately predicts patient NACT responses via spatio-temporal modeling of drug and nutrient perfusion, metabolic behavior, and the physio-chemical interactions between surrounding tissues. Future prospective studies may assess TumorScope’s capacity to support efficient patient treatments and enhance overall standard of care.
Targeted therapies: How can CT imaging improve evaluations and help understand mechanism of drug action?
Authors: Beaumont Hubert , Iannessi Antoine , Chamorey Emmanuel , Faye Nathalie , Klifa Catherine , Hsieh Chih-Yi
Published: May 2020

e13012

Background: We compared the therapeutic response between Varlitinib plus Capecitabine (VC) and Lapatinib plus Capecitabine (LC) by stratifying changes in tumor’s longest diameter (LD) and volume (VOL) per tumor location in patients with HER2+ metastatic breast cancer after trastuzumab therapy. Methods: We retrospectively analyzed the ASLAN001-003 double-arm trial (NCT02338245). We first tested the intra and inter-arm equivalence in number and size of tumors at each location of the disease.Second, we compared the inter-arm average changes in 1) tumor burden according to RECIST; 2) stratified tumor burden in summing, for each patient, the target lesions from the same organ locations; 3) tumors considered independent but grouped per organ location of the disease.Third, we tested the intra-arm differential responses of pairwise groups of tumor locations: breast-lung, breast-liver, breast-lymph nodes, lung-liver, lung-lymph nodes and liver-lymph nodes. A sensitivity analysis tested the robustness of our results. Results: We followed 74 tumors in 35 patients (14 VC; 21 LC) after 12 weeks of treatment. Primary breast tumors had a larger size than metastasis (p < 0.002). Tumor proportions at each organ location of the disease were not significantly different. The inter-arm difference in changes of tumor burden yielded: p = 0.086 (LD) and p = 0.13 (VOL); in stratifying patients per breast tumors: p = 0.002 (LD) and p < 0.001 (VOL); and for independent breast tumors: p = 0.001 (LD) and p < 0.001 (VOL). We found differential responses in the LC arm for breast-liver (p = 0.007 (VOL)) and Liver-Lymph node (p = 0.06 (VOL)). After outlier’s removal, the inter-arm difference was confirmed for breast tumors (p = 0.004 (LD); p < 0.001 (VOL)) and when considering all tumors as independent (p < 0.01(LD); p = 0.04 (VOL)). The differential Breast-Liver response in the VC arm was confirmed p < 0.05 (LD or VOL). Conclusions: Differential imaging responses were found across treatment arms and tumor locations. The stratification of changes provides new insights into responses of targeted therapies and more accurate drug comparisons. The stratification is a promising approach to better understand therapy mechanisms of action behind tumor heterogeneity.
Pyrotinib combined with capecitabine as first-line therapy for HER2-positive metastatic breast cancer: A pooled analysis of three randomized controlled trials.
Authors: Jiang Zefei , Xu Binghe , Yan Min , Ouyang Quchang , Hu Xi-Chun , Li Wei , Feng Ji Feng , Zhang Qingyuan , Tong Zhongsheng , Yan Ping , Zhu Xiaoyu , Rong Shangyi , Zou Jianjun
Published: May 2020

e13022

Background: Anti-HER2 agents combined with chemotherapy is the treatment strategy for treatment-naive HER2-positive relapsed or metastatic breast cancer. This pooled study was conducted to investigate the efficacy of pyrotinib plus capecitabine as first-line treatment in patients with HER2-positive relapsed or metastatic breast cancer. Methods: Data were derived from three randomized controlled trials. In the phase 2 (NCT02422199) and the PHOEBE phase 3 (NCT03080805) studies, patients were randomized to receive pyrotinib plus capecitabine or lapatinib plus capecitabine. In the PHENIX phase 3 (NCT02973737) study, patients were randomly assigned and given pyrotinib plus capecitabine or placebo plus capecitabine. Patients who had received neither anti-HER2 agents nor chemotherapy for the relapsed or metastatic disease were included in the analyses, and the pooled tumor response data (per blinded independent central review) were reported herein. Results: In the pooled analysis of all three studies, 145 patients received pyrotinib plus capecitabine. The median progression free survival (PFS) was 12.4 months (95% CI, 11.1 months to not reached). The objective response rate (ORR) reached 72.4% (95% CI, 64.4% to 79.5%). In the pooled analysis involving the phase 2 and PHOEBE phase 3, 84 patients were treated with pyrotinib plus capecitabine and 62 patients with lapatinib plus capecitabine. The PFS was significantly prolonged with pyrotinib plus capecitabine vs lapatinib plus capecitabine (median, 12.4 months [95% CI, 11.1 months to not reached] vs 8.2 months [95% CI, 5.5 to 9.7 months]; hazard ratio, 0.40 [95% CI, 0.25 to 0.66]; p = 0.0001). The ORR was 71.4% (95% CI, 60.5% to 80.8%) with pyrotinib plus capecitabine compared with 58.1% (95% CI, 44.8% to 70.5%) with lapatinib plus capecitabine. Conclusions: The pooled analysis demonstrated pyrotinib plus capecitabine was efficacious as first-line therapy in patients with HER2-positive relapsed or metastatic breast cancer, offering a potent treatment option for these patients.
A national real-world prospective study to assess the effectiveness of adjuvant trastuzumab-dkst in HER2 breast cancer.
Authors: Alves Leandro Ladislau , Facó Lara Lopes , Cardoso Ana Carolina , Alcantara Alexandre , Figueiredo Augusto Theodoro , Rodrigues Rafaella , Gandufe Fatima , Silva Fernanda Cristina , Castilho Vivienne Carduz
Published: May 2020

e13023

Background: Real-World Evidence (RWE) are gain importance once they are designed to evaluate the effectiveness of drugs whose efficacy has already been demonstrated in randomized controlled trials. In 2017, Brazil approved the first biosimilar of trastuzumab for treatment of breast cancer (BC) with overexpression of HER2. The anti-HER2 treatment significantly improves outcome in patients with HER2-positive BC. Trastuzumab-dkst is clinically effective biosimilar and help to increase access to BC treatment. The aim of this RWE is to address the effectiveness of adjuvant biosimilar trastuzumab-dkst in Brazilian women with early HER2+ BC. Methods: This is a national, multicenter, observational, prospective, RWE study conducted in Brazilian institutions. A hundred and seventy female adult patients, with diagnosis of early stage HER2-positive BC, who received at least one dose of trastuzumab-dkst as adjuvant therapy will be included. The follow-up period will be 5 years after the first dose of trastuzumab-dkst, unless tumor recurrence or death. The safety endpoints are the occurrence adverse events. The effectiveness endpoints are invasive disease relapse-free survival rate at 18, 24, 30 and 36 months after the start of biosimilar use, the invasive disease relapse-free survival after curative-intent surgery and overall survival after curative intent surgery. Given the inexistence of a specific hypothesis to be tested, sample size was based on the accuracy of the two-sided 95% confidence interval (95% CI) for the invasive disease relapse-free survival rate. Results: The recruitment planning covered 21 sites across the five regions of Brazil: North, Northeast, Midwest, Southeast, and South. From those 21 sites, 14 ( > 50%) have already been approved by their local ethical committee for patient recruitment. At 7 months, we have enrolled 50 patients over the five Brazilian regions, which means 29.4% of the total. Conclusions: To conduct RWE in Brazil is still challenging and we have listed 5 possible reasons: (1) there are few RWE studies running in the country, (2) we do not have trialists experienced in RWE design; (3) low medical commitment to adverse event report in RWE; (4) low budget for RWE; (5) slow ethics and regulatory process approval in Brazil. Considering the pioneering and challenges to develop the RWE in Brazil, we are achieving optimum adherence from medical sites. Moreover, roughly one quarter of the target recruitment was reached in the first 7 months after the study start date. Clinical trial information: NCT03892655 .
Real-world clinical outcomes in patients receiving cyclin-dependent kinase 4/6 inhibitors (iCDK 4/6) for hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer in Mexico.
Authors: Rodriguez Benigno , López Zepeda Lorena , Noguez-Ramos Alejandro , Vazquez Juarez Daniela , Camacho Limas Christian Patricio , Regalado Porras Gabriela Olivia , Salcedo Ivonne , Rivera Samuel , Aguayo Alvaro , Blanco Vazquez Yazmin Carolina , Lopez Galindo Angel Azael , Shveid Gerson Daniela , Perez-Zincer Fernando , Serrano Juan Alberto , Martínez-Herrera José Fabián , Olivares Guillermo , Villalobos Alberto , Gonzalez De Leon Cesar , Gerson Raquel
Published: May 2020

e13053

Background: Breast cancer was the second most common malignant tumor diagnosed in 2018 worldwide, and the main cause of cancer death in women. In Mexico is the leading cause of cancer deaths, the most common molecular subtypes is HR+/HER2- (63%). The addition of iCDK 4/6 can enhance the benefit seen with endocrine therapy (ET) alone. In this work we will describe the experience in a “real world” model, of two tertiary-level hospitals in Mexico, with the use of iCDK 4/6 in a period of 3 years. Methods: Retrospective review of medical records of all consecutive pts with histological diagnosis of metastatic breast cancer HR+/HER2- and iCDK 4/6 treatment at our Institutions from July 2016 to January 2019. Clinical and pathological variables at diagnosis were recorded. Progression free survival was estimated using Kaplan-Meier method and survival distributions were compared using the Log-rank test. To assess association variables and progression we use Chi square. Results: 65 pts were treated, all with iCDK 4/6 in combination with ET, either aromatase inhibitor or irreversible estrogen receptor antagonist. 62 with palbociclib and 3 with ribociclib; Median age was 53 y/o (IQR 42-63), ECOG 0-1 (92.3%), 80% was metastatic recurrent disease, 92% of these patients received endocrine adjuvant treatment. Median estrogen receptor percentage was 90 (IQR 61-92), progesterone 50 (9-83), KI67 20 (10-30). The metastatic sites were bone (64.6%), liver (41.5%), nodal (33.8%), lung (21.5%), CNS (3.1%) and others (18.5%). 26 pts (40%) received iCDK 4/6 in the first line, 21 (32.3%) in the second line, and 27% in subsequent lines. Any grade of toxicity was presented in 44 pts (67.7%), Most common toxicities were neutropenia (63%), fatigue (16.9%), anemia (9.2%), grade 3-4 toxicities were presented in 21.5% and 17 pts (26.2%) required any dose adjustment. At the cut-off date, 28 pts (43.1%) had disease progression, median time to progression for the 65 pts was 10 months (1-84). OR for first line treatment vs subsequent lines was 0.14 (0.04-0.47, 95%, p = 0.001). OR for pulmonary metastases were 4.21 (1.15-15.31, 95%, p = 0.03), for other sites of metastasis were NS. Conclusions: Our outcomes suggest that the PFS is better when iCDK 4/6 are used as a first line treatment. Pulmonary metastases are may associated with poorly outcomes. In low- and middle-income countries, efforts should be focused on early therapy with iCDK 4/6.
Retrospective analysis of ribociclib and letrozole as first-line therapy in patients with hormone receptor (HR) positive metastatic breast cancer (MBC) within a managed access program (MAP) in Turkey.
Authors: Basaran Gul , Demirci Umut , Yildiz Fatih , Cicin Irfan , Aktas Burak Yasin , Ozturk Banu , Sezgin Goksu Sema , Coskun Hasan Senol , Oyan Basak , Sonmez Ozlem , Eralp Yesim , Gokmen Erhan , Gunduz Seyda , Korkmaz Taner , Sendur Mehmet Ali Nahit , Keskin Serkan
Published: May 2020

e13055

Background: The combination of ribociclib with ET significantly increased progression free survival (PFS) and OS compared with ET in first line treatment of HR positive HER2 negative MBC. We aimed to evaluate the efficacy and safety of ribociclib and letrozole within Turkish MAP in order to present clinical outcome with the real-world use of ribociclib, outside of clinical trial setting. Methods: Turkish MAP enabled access to ribociclib in combination with letrozole as first-line therapy for MBC patients with HR positive and Her-2 negative tumors. Adequate bone marrow reserve, a normal QTc interval, normal renal and liver functions were required for eligibility. Patients received 600 mg ribociclib once daily for 3 wks followed by 1wk off. A retrospective chart review of patient demographics, clinical and treatment characteristics have been performed. Results: Between July and November 2017, 178 patients were included from 47 institutions in Turkey. We report the results of first 101 patients analyzed. The median age was 53 years (33–81 years) and median follow up was 16 months. Forty-six patients had de novo disease, 78% patients were postmenopausal, 22% had ovarian function suppression. Thirty-six % patients had adjuvant chemotherapy, 49% received adjuvant ET. Forty % had visceral disease. Thirty patients had grade 3 neutropenia, 3 patients had febrile neutropenia, 5 patients have grade 2-3 elevation of liver function tests. There was no QT prolongation. Dose reduction to 400 mg was required for 16 patients. Four patients discontinued ribociclib due to toxicity, 22 patients due to progression, one patient refused treatment. Twelve patients had complete remission as their best response. Median PFS was 24.12 months (95%CI 22.2-26.2). None of the clinical and pathologic factors were significantly associated with prolonged PFS. Conclusions: The efficacy and toxicity of first-line ribociclib and letrozole within Turkish MAP is similar to the results from randomized clinical studies for patients with HR positive, Her-2 negative MBC.
Prescribing preferences for hormone sensitive (HR+) metastatic breast cancer (mBC) in the CDK 4/6 inhibitor (CDK 4/6i) era.
Authors: Feinberg Bruce A. , Wojtynek Jeffrey , Dokubo Igoni , Jeune-Smith Yolaine , Kish Jonathan , Gajra Ajeet
Published: May 2020

e13058

Background: CDK 4/6i is a category 1 guideline-recommended therapy for HR+/HER2- mBC in both first-line (1L) with an aromatase inhibitor and second-line (2L) with fulvestrant and without prior CDK 4/6i. We sought to understand community oncologists’ (c-oncs) prescribing preferences and sequencing for 1L, 2L, and third-line (3L) HR+/HER2- mBC patients across several common clinical scenarios (CS). Methods: C-oncs were presented 4 hypothetical HR+/HER2- mBC clinical scenarios (CS 1-4) via web-based survey. CS differed by menopausal status, prior adjuvant therapy and nature of metastases (mets) (i.e., bulky liver, lung, bone), but otherwise uniform: asymptomatic presentation, PI3K negative, identical response extent and duration in 1L, 2L, and 3L. Treatment preferences: hormonal (H), single agent (SA) or combination chemotherapy (CC) for 1L, 2L, and 3L in each CS were queried. We describe these preference patterns. Results: 47 U.S. c-oncs participated: mean years in practice was 22.7 and mean mBC patients under active treatment was 23.3. Preference for treatment and sequence, regardless of CS, per LOT were: 1L = 71% H, 14% SA, 16% CC; 2L = 51% H, 31% SA, 16% CC; and 3L = 35% H, 59% SA, 6% CC (Table). Of the 71% who preferred 1L H, the CDK4/6i % were: 73% overall, 58% when mets described as bulky liver, 94% when described as bone and or lung. The preference for pre-planned sequential chemo-hormonal therapy in 1L resulted in 63% of initial chemotherapy followed immediately by H; of which CDK 4/6i was preferred in 47%. In total, the initial and post-chemo CDK4/6i 1L preference was 80%. 2L hormonal preferences by frequency were: everolimus + exemestane = 38%, CDK 4/6i + fulvestrant = 20%, fulvestrant = 19%. SA preferences: 2L = capecitabine 46%, taxane 25%; 3L = capecitabine 40%, eribulin 32%. CC preferences included atezolizumab + nab-paclitaxel 24% in 1L and 16% in 2L. Conclusions: 1L HR+/HER2- mBC treatment is highly variable and preferences that warrant further research include: the role of CC, specifically atezolizumab + nab-paclitaxel; repeated CDK4/6i line of therapy; H therapy post CDK4/6i progression; and optimal SA sequencing. [Table: see text]