bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of C-reactive protein (CRP) as a prognostic biomarker in patients with early breast cancer (EBC) treated with neoadjuvant chemotherapy (NACT).
Authors: Kolberg Hans-Christian , Edimiris Alexandra , Hoffmann Oliver , Wetzig Sarah , Shaheen Mohamed , Stephanou Miltiades , Kolberg-Liedtke Cornelia
Published: June 2021

e12545

Background: C-reactive protein (CRP) is an acute phase reactant influenced by inflammation and tissue damage. It has been demonstrated that elevated CRP levels are associated with poor outcome of cancer including metastatic breast cancer. However, evidence regarding an impact of CRP levels on outcome in early breast cancer (EBC) are missing. Methods: Patients after neoadjuvant chemotherapy (NACT) for EBC and with available data regarding CRP levels before therapy, pathologic complete remission (pCR) and follow-up were included. The association between CRP at baseline and outcome parameters was analyzed. Results: 156 women were included in this analysis, median follow up was 5.8 years. No association between CRP at baseline and pCR rates could be detected. 6.4% of the patients developed a local recurrence, 10.3% developed a distant recurrence and 5.1% died from breast cancer. A negative correlation (Spearman-Rho) between CRP at baseline and overall survival (OS) (Correlation coefficient (CC) -0.255; p = 0.45), disease free survival (DFS)(CC -0.348; p = 0.075), local recurrence free survival (LRFS)(CC -0.245; p = 0.327) and distant disease free survival (DDFS)(CC -0.422; p = 0.057) was not statistically significant, although especially in DFS and DDFS a strong trend was detected. The probability of death from breast cancer was 2% if the CRP was < 0.08 mg/dl and 40% if the CRP was > 2.08 m/dl, this association was highly statistically significant (Chi Square; p < 0.001). These results were independent from age, estrogen and progesterone receptor status, HER2 status and grading. Conclusions: CRP at baseline is not predictive for pCR in EBC after NACT in our patient dataset. However, an association of parameters of long-term prognosis with CRP could be demonstrated. Although the correlations of higher CRP at baseline and shorter OS, DFS, LRFS and DDFS were not significant, a strong trend could be detected that was reproduced in the analysis of different cut-offs for CRP and the probability of breast cancer mortality. Higher CRP-levels are indicating a worse prognosis in early breast cancer after NACT in this retrospective analysis. These results justify further investigation of CRP as a biomarker of long-term prognosis in early breast cancer in prospective trials.
Association of triple negative breast cancer (TNBC) with high thermogenesis with worse survival and unfavorable tumor microenvironment (TME).
Authors: Gandhi Shipra , Oshi Masanori , Repasky Elizabeth A. , Takabe Kazuaki
Published: June 2021

e12546

Background: Norepinephrine released during cold stress by housing 4T1 TNBC mice at 22°C increases tumor growth with a pro-tumorigenic TME [lower CD8+ T-cells, higher myeloid derived suppressor cells (MDSC) and regulatory T-cells (Treg)] compared with mice housed at 30°C. Norepinephrine activates thermogenesis in adipose tissue. Worse survival has been reported among females with malignancies living in cold versus warm climate. These findings led us to hypothesize that TNBC with enhanced thermogenesis is associated with worse outcome and unfavorable TME. Methods: mRNA expression data for 298 and 143 TNBC patients was accessed from METABRIC and GSE96058 breast cancer cohorts, respectively. TNBC were classified into “high” (top tertile) and “low” thermogenesis (bottom two-third) using Gene Set Variation Analysis (GSVA) with KEGG thermogenesis pathway. Computer algorithms xCell and Gene Set Enrichment Analysis (GSEA) were used. Interferon (IFN)-γ signature was calculated using GSVA. Gene expression data was used to quantify adipocytes, angiogenesis, chemokines and cytolytic activity (CYT). R software was used for analysis. False discovery rate (FDR) < 0.25 for GSEA and p < 0.05 was considered statistically significant. Results: High-thermogenesis TNBC was associated with a worse median disease specific survival 14.7 years vs. not reached [HR 1.49 (95% CI 1.02-2.18)], p < 0.05 in METABRIC and a trend towards worse overall survival in both METABRIC and GSE96058. Higher fraction of adipocytes (p < 0.001) and angiogenesis markers including CD31, vWF, Vascular endothelial cadherin, claudin 5, JAM2 and sphingosine-1-phosphate related gene S1PR1 (p < 0.01) were observed explaining the worse survival in high-thermogenesis TNBC. This group was significantly enriched in fatty acid metabolism and adipogenesis pathways (FDR < 0.25) on GSEA. On the other hand, low-thermogenesis TNBC was enriched in mitotic spindle, E2F targets, G2M checkpoint, MYC targets consistent with higher Ki67 (p < 0.05) in this group; and also in IFN-α and IFN-γ response (FDR < 0.25). High-thermogenesis TNBC was associated with lower IFN-γ and granzyme B expression (p < 0.05). Favorable cytotoxic-T cell attracting chemokines CCL5, CXCL9, CXCL10 and CXCL11 were lower; MDSC-, Treg-favoring chemokine CXCL12 was higher (p < 0.05). There were lower M1 and more M2 macrophages (p < 0.001) with lower CYT. There was higher expression of dual-specificity phosphatase-1 ( DUSP1)(p < 0.05), which is upregulated following glucocorticoid receptor activation. Conclusions: We investigated the clinical relevance of preclinical findings and observed that high-thermogenesis TNBC is associated with worse survival and unfavorable TME. Further research is warranted to validate if high thermogenesis could reflect tumors under thermal stress and develop novel strategies to abrogate stress and improve outcomes.
Gasdermin D as a potential prognosis and treatment response prediction biomarker for invasive breast cancer.
Authors: Xia Xianghou , Yin Wenjuan , Mao Jiefei , Hu Jiejie , Zou Dehong , Yang Hongjian , Yu Yang
Published: June 2021

e12548

Background: Pyroptosis is a type of inflammatory cell death mediated by gasdermins. Pyroptosis is critical for macrophage against pathogen infection. Recently growing evidences show that pyroptosis may affect development and progression of many cancers. We aim to explore the expression and related function of pyroptosis executioner Gasdermin D (GSDMD) in breast cancer. Methods: We investigated the expression level of GSDMD using TNM plotter and Breast Cancer landscape proteome with TCGA, GTEx and TARGET databases, and the prognostic value of GSDMD in invasive breast cancer using Kaplan-Meier plotter with TCGA, GEO and EGA databases. The treatment response prediction values of GSDMD in invasive breast were calculated using ROC-plotter with GEO database. Further validation of the prognostic value and chemotherapy response prediction value of GSDMD were carried out with immunohistochemical staining on tissues from 165 cases of breast cancer patients receiving neoadjuvant chemotherapy in our cancer center. Results: TNM plotter and breast cancer landscape proteome portal analysis shows that overall expression level of GSDMD in invasive breast cancer tissue is 1.67 folds higher than it is in breast normal tissues ( p=1.05*e-06). Expression of GSDMD in LuminalB subtype (p=0.019) and Her2 subtype(p=0.04) is significantly higher than it is in TNBC subtype. Calculations with Kaplan-Meier plotter show expression of GSDMD is negatively correlated with overall survival(OS), HR=0.61(0.4−0.95) p=0.027 and relapse free survival (RFS), HR =0.65(0.58−0.63), p=8.7*e-14 and distant metastasis free survival (DMFS) HR =0.75(0.61−0.91), p=0.0038 in breast cancer patients. ROC-plotter calculations show high GSDMD expression is a powerful endocrine therapy (AUC=0.731 p=6*e-09 ) and chemotherapy response (AUC=0.64 p=8*e-05 ) predictor based on 5-year RFS in overall breast cancer patients. Our IHC staining analysis shows consistent prognostic and chemotherapy prediction value of GSDMD expression in TNBC patients. Conclusions: In conclusion, our findings suggest that high expression of GSDMD is positively correlated with prognosis and therapeutic response in breast cancer. GSDMD is a promising prognostic marker and therapeutic response predictor in invasive breast cancer.
Ki-67 and mitotic index in triple-positive breast cancer.
Authors: Urezkova Maria Mikhailovna , Semiglazova Tatiana , Artemyeva Anna , Kudaybergenova Asel
Published: June 2021

e12551

Background: A grade in breast cancer is the strongest prognostic factor. In the new edition of the AJCC 8th, the tumor grade is one of the criteria that determines patients with breast cancer in the prognostic groups. According to the Nottingham system the mitotic count (MC) mostly determines the grade. Interobserver reproducibility for MC is not as good as for IHC marker phh3. The group of triple-positive breast cancer (TPBC) is characterized by the presence of a crosstalk mechanism between the signaling pathways of ER and HER2, which leads to the development of resistance to therapy. However, according to the 8th AJCC, patients with ER+/HER2+ belong to a more favorable prognostic group. Methods: We selected 284 patients with early BC who received treatment at our centre from 2012 to 2020 and didn’t receive presurgical therapy. The patients were divided according to the surrogate subtype into triple-positive (n = 90) and other subtypes (n = 194). The Ki-67, the number of nuclei of tumor cells stained with anti-phh3 antibody, the cell density of the tumor per 1 mm2 and the number of phh3 + per 1000 tumor cells were assessed. Results: Visually accessed number of mitoses was grade 3 in 30% of tumors in the TPBC group and 29% in the second group. There was no statistically significant difference in the Ki-67 index of proliferative activity in the two studied groups. In the TPBC group the median Ki-67 was 16.8%, in the second group - 18.3% (p = 0.376516), while the groups differed significantly in terms of the phh3 index (the median in the TPBC was 23.7/mm2, the median in the second group - 16.06/mm2, p = 0.024703). The groups also significantly differed in the number of nuclei of tumor cells that directly entered the mitotic phase (5.1/1000 nuclei in the TPBC group versus 3.2/1000 nuclei in the second group, p = 0.003901). Conclusions: Despite similar indices of proliferative activity in the TPBC and non-TPBC groups, mitotic activity and the number of directly dividing tumor cells in the TPBC group are significantly higher than in the rest of the BC population. Considering the criteria for assessing phh3 (MC 1 < 4/mm2, MC 2 2 4 to 7/mm2, MC 3 > 7/mm2), most TPBCs will have a histological malignancy grade of 3, which according to AJCC 8th places them in the group of poor outcome. We suggest that these differences may be due to the crosstalk mechanism. The second conclusion of our study is the fact that Ki-67 is a poor predictor of the MC.
Racial disparity in OncotypeDX score in early stage, hormone receptor positive, HER-2 negative, node negative breast cancers: A systemic review and meta-analysis.
Authors: Lee Yi , Liu Ruolin , Bean Alexis K. , Garshasebi Madison J. , Jehangir Qasim , Kaur Jasmeet , Krishnamoorthy Geetha , Goodman Judie R.
Published: June 2021

e12555

Background: Oncotype DX Breast Recurrence Score (RS) is the currently used risk-assessment tool for early-stage, hormone receptor-positive, HER-2 negative, node-negative breast cancer in the US. Studies showed inconsistency in RS distribution and treatment among races. Causes may include variations in somatic mutations like Ki-67, which have been reported to express higher in African American (AA) and Asian populations than in Non-Hispanic White (NHW) population, germline mutations in BRCA and TP53, that are not in the RS algorithm, and financial burden of the testing. We analyzed data from different countries to investigate racial disparity in RS. Methods: We searched Medline, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials, indexed from January 2010 to January 2021. More than 85% of studies were conducted in the pre-TAILORx study phase. To include data that are available and better represent different races, we included studies that used the previous cutoff value, low-risk ( < 18), intermediate-risk (18-30), high-risk ( > 30). Retrospective studies using Surveillance, Epidemiology, and End Results or National Cancer Database were excluded to avoid overlap data. A total of 17 studies, 9789 patients from seven countries (US, Japan, China, Taiwan, Kuwait, UAE, Israel) were pooled. The Odds Ratio (OR) was extracted with a 95% confidence interval (CI) for RS distribution and post-RS treatment. Both fixed-effect and random-effect meta-analysis were performed. Results: Among AA and NHW, AA were 1.7 times more likely to have high recurrence score (OR = 1.75; 95% CI = 1.46 - 2.10; P < 0.0001), with no heterogeneity among studies (I2 = 0%, heterogeneity P = 0.59). Asian were 1.59 more likely than NHW to be high-risk using a random effects model (OR = 1.59; 95% CI = 1.06 - 2.40; P = 0.0259). High-risk Asian were two times more likely to receive adjuvant chemotherapy post-RS comparing to NHW (OR: 2.31, CI: 1.07 - 4.98, fixed effect model; OR: 2.85, CI: 0.48, 17.05, random effects model), while high-risk AA were less likely to receive chemotherapy comparing to NHW (OR: 0.74, CI: 0.54-1.01, fixed effect model; OR: 0.73, CI: 0.54-0.99, random effects model). Intermediate-risk Asian and AA were more likely to receive chemotherapy compared to NHW (Asian to NHW; OR: 1.68, CI: 1.16-2.43, with fixed effect model, OR: 1.68, CI: 0.94-3.02, with random effects model; AA to NHW; OR: 1.16, CI: 0.93-1.46 with fixed effect model; OR: 1.06, CI: 0.62-1.79 with random effect model). Conclusions: We identified racial disparity in RS and post-RS treatment. Future research is required to elucidate the causes for AA and Asian receiving higher recurrence scores, a need for tailoring RS cutoffs for different races, and the utilization in adequate post-RS treatment.
Prognostic subset of metastatic and non-metastatic luminal B breast cancer (LBBC) subtype based on Ki67 index.
Authors: Puii Lalnun , Sangi Lalram , Varayathu Hrishi , Koramati Samuel Luke , Thomas Beulah Elsa , Mathew Smruthy Ann , Somayaji Shalaka , Thungappa Satheesh Chiradoni , Bj Sriniivas , Munirathnam Vinayak , Swamy Shivakumar , BN Tejaswini , Mufti Suhail Sayeed , Naik Radheshyam , Ajaikumar Basavalinga Sadasivaiah
Published: June 2021

e12570

Background: Gene expression profiling for breast cancer has classified ER positive subtype into luminal A and luminal B. Luminal B breast cancer (LBBC) have a higher proliferation and poorer prognosis than luminal A tumors. Ki-67 index is the commonly used proliferation marker in breast cancer; however Ki67 expression can also be used to identify a subset of patients among LB with a favorable prognosis. This study attempts to verify this subset of LBBC patients based on DFS and PFS in non-metastatic and metastatic patients respectively. Methods: We retrospectively analyzed 80 IDC breast cancer patients diagnosed in 2013-2016 with complete follow-up till January-2021. We defined LBBC as ER+, PR+ or PR- , HER2+ or HER2- with a Ki67 index >20%. PFS was considered as the endpoint in patients presenting with metastatic disease whereas DFS was used in non-metastatic disease. The cut-off for ki67 was calculated using an X-tile plot (version 3.6.1, Yale University) by dividing Ki67 data into two populations: low and high, with randomized 1:1 “training” and “validation” cohorts. Results: Median age was 51.5 years. 18.7% (n=15) presented with metastasis at the time of diagnosis and their overall median PFS was found to be 25.8 months. The incidence of HER2 positive LBBC was found to be 15% (n=12) and none of them were found to be presented with metastasis. Survival and frequency of various sub groups in our study are enlisted in the given table. We estimated a Ki67 cut-off of 30% in patients with upfront metastatic disease and PFS was found to be higher in <30% compared to a Ki67 index >30% (38.9 months vs 19.7 months, p-0.002). Overall median DFS was not achieved in non-metastatic group (Mean DFS: 64.7 months) where as a statistically significant difference was observed in the survival of HER2 positive (median DFS: 53.5 months, mean DFS: 50.9) than HER2 negative patients (median DFS not achieved, mean: 66.97 months) ( p-0.021). We obtained a Ki67 cut-off of 32% in non- metastatic group and mean DFS was found to be higher in Ki67<32% (69 months) compared to Ki67>32% (61.4 months), however it failed to exhibit a statistically significant relationship ( p-0.373). Conclusions: Our study indicates that a subset of patients exists within metastatic and non-metastatic LBBC with differing prognosis based on Ki67. Larger studies are further required to confirm the findings and therapeutic implications.[Table: see text]
Predictive value of topoisomerase II alpha protein for clinicopathological characteristics and prognosis in early breast cancer.
Authors: Yun Wu , Han Yiqun , Xu Hangcheng , Li Qing , Xu Binghe , Zhang Pin , Yuan Peng , Ma Fei , Luo Yang , Fan Ying , Chen Shanshan , Cai Ruigang , Li Qiao , Wang Jiayu
Published: June 2021

e12586

Background: Topoisomerase II alpha (TOP2A) has been identified as a proliferation marker, of which the most common method for detection is immunohistochemistry (IHC). However, the optimal cut-off of TOP2A expression regarding prognostic value remains controversial. This study was to identify the optimal cut-off value of TOP2A expression and its correlation with clinicopathological variables and prognosis in early-stage breast cancer in China. Methods: Between January 2013 and January 2015, a total of 1084 early breast cancer patients were enrolled. The optimal cut-off of TOP2A expression was assessed using the minimum P value approach. Correlations between TOP2A expression and clinicopathological characteristics were explored by the Spearman’s correlation analysis, while the impact of TOP2A expression on disease free survival (DFS) and overall survival (OS) was evaluated by the Kaplan-Meier methods. Univariate and multivariate Cox regression analyses were executed to identify statistically significant prognostic factors. Results: The optimal cut-off value of TOP2A was recommended as 15%. Overall, 603 (55.6%) patients were TOP2A over-expression and 481 (44.4%) patients were TOP2A low-expression. TOP2A over-expression was in positive associations with a higher ki67 index (r = 0.83, P < 0.001), HER2 positive (r = 0.24, P < 0.001), a larger tumor size (r = 0.15, P < 0.001), and a higher histologic grade (r = 0.59, P < 0.001), and in a significantly negative correlation with hormone receptor (HR) positive expression in early breast cancer (r = -0.40, P < 0.001). TOP2A over-expression significantly associated with worse DFS (P = 0.001) and OS (P < 0.001) and was an independent prognostic factor for both DFS (hazard ratio [HR] = 1.71; 95% confidence interval [95%CI]: 1.13-2.59, P = 0.02) and OS (HR = 3.53; 95%CI: 1.53-8.23, P = 0.003) in stage I-II breast cancer patients. Conclusions: To our knowledge, this is the first study to recommend the optimal cut-off value of TOP2A expression in breast cancer. The TOP2A expression is significantly correlated with HER2 status, ki67 index, tumor size, histologic grade, and HR status, and could be a surrogate indicator for poor prognosis of early breast cancer.
Combination of individual tumor gene expression profiles and quantitative ultrasound and mammography imaging to understand the response to neoadjuvant chemotherapy among Hispanic-Latina women with early stages of triple-negative breast cancer.
Authors: Philipovskiy Alexander , Gaur Sumit , Chambers Karen , Gamez Roberto , Aguilera Renato , Ayyappan Anoop , Roy Souvrav
Published: June 2021

e12605

Background: Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer (BC) characterized by the absence of targetable receptors. Traditionally, neoadjuvant chemotherapy (NACT) has been used to downstage the tumors and increase the chance for breast-conserving surgery. The pathological complete response (pCR) has been traditionally considering the best predictive marker for the disease recurrence. Patients with residual disease (RD) have a poor prognosis with a high risk of recurrence, and therefore additional chemotherapy was recommended. Therefore it is an important task for clinical researchers to identify markers to predict the individual tumor response to chemotherapy and avoid in patients potentially resistant tumors. Instead, a surgical approach can be used or combined approach with chemotherapy and immunotherapy. It is not clear yet which approach is optimal for those patients with chemotherapy-resistant tumors since there is no clinical data available and no clinical tool that helps predict the individual tumor response. In this study, we examined breast ultrasound(US) images of patients before and after the completion of NACT and correlated with response to chemotherapy. To better understand the biology of resistance to chemotherapy, we also analyzed the gene expression profile of 15 patients with RD after NACT. Methods: In this study, we retrospective analyzed breast US data from 37 Hispanic patients diagnosed with TNBC and treated with NACT. Patients underwent breast US before and after NACT with documentation of clinical complete response (cCR) or clinical residual disease (cRD). Post-operatively, the pathologic response was defined as the absence of tumor cells (pCR) or presence of residual invasive tumor (RD). A multivariable logistic regression model assessed the influence of patient- and tumor-associated covariates as predictors for pCR. Also, we analyzed formalin-fixed paraffin-embedded tumor samples from 15 patients with RD after NACT. Results: Seventeen patients (45.9%) achieved pCR, and twenty (54.1%) had RD after NACT. The most common US findings connected with RD was the deposition of calcium before NACT six (30%) patients. Gene expression analysis of RD samples identified 446 upregulated and 275 downregulated genes. Among commonly upregulated genes related to cancer, we identified GLI1, IGF1, SERPINE1, ATF3, KLK 5; 7, and TUBB2b, and genes belonging to pathways encoding extracellular matrix–related proteins, DNA-damage response proteins, and pathways related to resistance to chemotherapeutic agents such as Taxol. Conclusions: Our data suggested that gene expression profiling in combination with imaging study can be used to identify patients with TNBC potentially resistant to chemotherapy.
Does fertility preservation affect the start of the oncological treatment and the response to neoadjuvant chemotherapy in breast cancer.
Authors: Baulies Sonia , Izquierdo Maxim , Devesa Marta , Rodriguez Ignacio , Tresserra Fransec , Fabregas Rafael
Published: June 2021

e12613

Background: Study in breast cancer patients to assess whether fertility preservation (FP) can affect the onset of the oncological treatment and the pathological response in those patients who underwent neoadjuvant chemotherapy (NAC). Methods: Patients with breast cancer who underwent fertility preservation and NAC are matched 1:2.45 to non-FP controls by age and date al diagnosis and are studied: -Timing between the diagnosis of breast cancer and the onset of oncological treatment was performed. The following variables were chosen: 1.- Confirmation (pathologic result), 2.- FP visit, 3.- Onset FP, 4.- Final FP, 5. – Onset oncological treatment. The periods analyzed (median in days) were: 1.- Period of FP visit (AP result-FP visit), 2.- Period of FP (FP beginning –FP ending), 3.- Period of onset of oncological treatment (FP ending-onset of oncological treatment), 4.- Overall period (AP result-onset of oncological treatment). -Studying the pathological complete response (Miller Payne scale) among patients with FP compare to non-FP control group was also performed. Results: 20 patients with FP and NAC are studied between 2010-2019 and were compared to 49 non-FP patients. The median age at diagnosis was 36 years (28-39). The oncological characteristics of the patients are shown in Table 1. The time analysis in FP group was: 1.- Period of FP visit was 4 days (1-26), 2.- the period of FP (start of the stimulation treatment until the recovery of the oocytes) 12 days (7-20), 3.- the Period of onset of oncological treatment 7 days (1-27). The overall period took 26 days (18-51) compared to 17.5 days (1-60) in non-FP group (NS). Pathological complete response (Miller Payne 5): The pathological complete response was 80% (16/20) in FP group versus 40.8% (20/49) in non-FP group. Analyzed by tumor subtype in FP group, a MP5 was achieved in 72.7% luminal tumor (8/11), 75% positive-HER2 (3/4), 100% triple negative (5/5) versus 19% luminal tumor (4/21), 41.6% (5/12) positive-HER2 and 68.7% triple negative (11/16) in non-FP group. Conclusions: FP does not delay the onset of oncological treatment and our data do not suggest an adverse impact of FP on pathological complete response to NAC. [Table: see text]
Association of tumor infiltrating lymphocytes with pathological response after neoadjuvant therapy in breast cancer: A retrospective study.
Authors: Grover Punita , Phan Kim , Magge Tara , Chou Andrew , Naffouje Rand , Jandarov Roman , Grate Lisa , Hinrichs Benjamin H , Charif Mahmoud
Published: June 2021

e12621

Background: Tumor infiltrating lymphocytes (TILs) are thought to represent favorable host anti-tumor immunity and play an important role in mediating response to chemotherapy in breast cancer. TILs are heterogenous across breast cancer subtypes and are increasingly being studied as prognostic and predictive biomarkers. We undertook a retrospective study to establish the relationship between pre-treatment density of TILs and subsequent quality of response to neoadjuvant chemotherapy in patients with early-stage breast cancer. Methods: We retrospectively identified women with breast cancer who had received neoadjuvant therapy (NAT) at the University of Cincinnati from 2012-2018. Clinical and pathological variables were extracted from medical records. Pre-treatment core biopsies were assessed for intra-tumoral TILs through independent pathology review and were graded as mild (grade 1), moderate (grade 2) or severe (grade 3). Post-treatment resection samples were assessed for pathological complete response (pathCR). Univariate analysis was done to determine the association between TILs and pathCR. Results: We identified 148 patients with breast cancer who received NAT, median age 53 years (25-90), 77 were Caucasian. 32 patients had stage I disease at diagnosis, 87 stage II and 29 stage III. Most patients had tumor grade 2 (n=50) or 3 (n=91). 50 patients were HER2+, 65 ER/PR+ HER2- (HR+) and 33 had triple negative breast cancer (TNBC). 69 patients received anthracycline based NAT, 29 non-anthracycline based NAT and all HER2+ patients received anti-HER2 therapy. 72 patients had TILs grade 1, 54 grade 2 and 22 had grade 3. 50 patients achieved pathCR. On univariate analysis grade 2 and 3 TILs were associated with higher likelihood of pathCR compared to grade 1 (42.1% vs 25%, OR 2.18, [1.08 – 4.4], p = 0.029). There was no difference in pathCR between grade 2 and grade 3 TILs (40.7% vs 45.5%, OR 1.21 [0.45-3.29], p=0.12). Tumor grade 3 was associated with higher pathCR than grade 1 or 2 (41.8 vs 21.1%, OR 2.69 [1.26-5.75], p=0.01). Amongst breast cancer subtypes, pathCR was lower in HR+(13.8%) compared to TNBC (45.5%) or HER2+ (52%) with OR 0.15 (0.06-0.36), p<0.01. Age, race, stage and type of chemotherapy were not associated with pathCR. On multivariate analysis, none of the variables retained significance. Conclusions: Our analysis shows that increased TILs density (grade 2 or 3) and higher tumor grade are associated with pathCR whereas HR+ breast cancer have a lower rate of pathCR after NAT. Immune characterization of TILs might be helpful in further refining the prognostic impact of TILs.[Table: see text]
Analysis of disseminated tumor cells (DTCs) in primary breast cancer patients with various molecular subtypes.
Authors: Nel Ivonne , Weydandt Laura , Höhn Annekathrin , Aktas Bahriye
Published: June 2021

e13000

Background: Despite successful treatment of the primary tumor, recurrence occurs in about 30% of breast cancer patients. One reason might be hematogenous spread during early disease stages. Disseminated breast cancer cells (DTCs) preferentially migrate into the bone marrow (BM) at early stages of the disease. Due to low proliferation, DTCs are persistent against systemic chemotherapy and might cause metastatic relapse at a later stage. Methods: BM aspirates were collected from the anterior iliac crest of patients with primary mamma carcinoma during surgery. After density gradient centrifugation cell suspensions were transferred onto glass slides and subjected to immunocytochemical staining against pan-cytokeratin. DTCs were visualized in pink using alkaline phosphatase and short counterstaining with hematoxylin which colored the nuclei light blue. DTCs were semi-automatically detected and enumerated using the Aperio Versa microscope based scanning system with a rare events algorithm that was trained to identify DTC candidates according to color, shape, intensity and size. As a positive control with each run, we used reference slides with a mix of bone marrow cells and a defined number of HCT116 cells. Results: Between February 2019 and December 2020 BM aspirates from 158 primary breast cancer patients were collected. Per patient about 4 million BM cells were analyzed. DTC detection revealed a positivity rate of 29% (46 patients). Molecular subtype analysis of DTC positive patients showed that 37% of the primary tumors (17 patients) were luminal A and 37% (17 patients) luminal B. In 9% of the cases (4 patients), tumors were HER2 enriched and 15% (8 patients) were triple negative. DTC count indicated that the majority of luminal B patients had 11-20 DTCs whereas luminal A patients tended to have lower DTC quantities varying between 1 and 10 DTCs. Conclusions: DTCs may serve as independent prognostic markers. Follow-Up data might reveal whether DTC quantification and molecular subtypes at primary diagnosis can be used to stratify patients at elevated risk for recurrence.
Cardiac function in patients receiving dual anti-Her2 antibodies (trastuzumab and pertuzumab) combined with chemotherapy for breast cancer in routine practice.
Authors: Zekri Jamal , Rasool Haleem J. , Rizvi Syed Azhar J , Mahmoud Ehab Mosaad Abdel Ghany , Rasmy Ayman Ahamd , Al-Gahmi Aboelkhair , Farag Kamel
Published: June 2021

e13009

Background: Chemotherapy regimens (C) containing a combination of anti-Her2 antibodies are associated with a risk of cardiac toxicity in landmark clinical trials. We evaluate the cardiac function of patients with Her2 over-expressed (Her2OE) breast cancer (BC) receiving C combined with trastuzumab (T) and pertuzumab (P) in routine clinical practice setting. Methods: The initial cohort of patients who started C in combination with TP (CTP) in standard doses and schedules before September 2019 in 4 cancer units were included. All patients had regular measurement of left ventricular ejection fraction (LVEF) by Doppler ultrasound studies. Data was collected retrospectively and was limited to the first 24 months after initiation of CTP treatment. The paired sample T-test was used to test the significance of the difference in LVEF. Results: Sixty seven patients were identified. CTP treatment was administered in the neoadjuvant and palliative settings in 28 (41.8%) and 39 (58.2%) respectively. None of the patients received concomitant anthracycline with TP. All patients underwent LVEF assessment prior to starting CTP treatment and at 3 and 6 months later. Subsequently LVEF was measured at 9, 12, 15, 18, 21 and 24 months as long as patients are still receiving CTP treatment (table). LVEF was measured in 11 patients for 24 months. Compared to baseline, mean LVEF was not significantly different at any of the subsequent time points (range; decrease by -0.936% to increase by 1.087%) (Table). Dual anti-Her2 antibodies (TP) administration was omitted temporarily once for 2 patients due to clinically suspected cardiac toxicity which was excluded on further investigations. Conclusions: In this cohort describing our limited initial experience, dual anti-Her2 antibodies (T&P) combined with chemotherapy is not associated with significant cardiac toxicity when LVEF is measured every 3 months. Further studies investigating less frequent LVEF monitoring (e.g. every 5-6 months) may be warranted.[Table: see text]
First-line treatment with a cyclin-dependent kinase 4/6 inhibitor combined with an aromatase inhibitor for hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer: Population-based outcomes for patients treated in Alberta, Canada.
Authors: Amaro Carla Pires , Batra Atul , Lupichuk Sasha M.
Published: June 2021

e13020

Background: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in combination with an aromatase inhibitor (AI) has emerged as the standard first line treatment in patients with hormone receptor positive, human epidermal growth factor receptor-2 (HER-2) negative metastatic breast cancer (MBC). In this analysis, we describe population-based outcomes for first-line treatment with a CDK4/6i combined with an AI. Methods: All patients who were prescribed CDK4/6i + AI from January 2016 through June 2019 in a large Canadian province were included. Descriptive statistics were used to summarize patient demographics, tumor and treatment characteristics. Survival distributions were estimated using the Kaplan-Meier method. Multivariate analysis (MVA) using a Cox proportional hazards model was constructed to examine associations between potentially prognostic clinical variables and progression free survival (PFS). Results: A total of 316 patients were included. Median age was 61 years (interquartile range, 53-70 years), 82% were postmenopausal women, 39% had de novo MBC, and 48% had non-visceral disease. Palbociclib was prescribed in 94% of patients and the remaining patients received ribociclib. The CDK4/6i was dose-reduced upfront or during treatment in 47%. While 70% of the patients discontinued treatment due to progression, 30% stopped due to toxicity/patient preference/physician recommendation. With a median follow-up of 28.1 months, the median PFS was 37.9 months (95% CI, 26.7-NR). In the MVA, PR-negative tumour (HR, 2.37; 95% CI, 1.45-3.88; P = 0.001) and dose reduction of the CDK4/6i (HR, 1.51; 95% CI, 1.06-2.16; P = 0.022) predicted worse PFS. Median overall survival (OS) was not reached. The 30-month and 36-month OS rates were 74% and 68%, respectively. Of patients who progressed (n = 131), 89% received second-line treatment (chemotherapy in 46%, single agent hormonal therapy in 35%, hormonal therapy plus a targeted agent in 15%, and other in 4%). Median time to progression on second line chemotherapy was 9.0 (5.8-17.6) months and second line hormonal therapy +/- targeted agent was 4.0 (3.4-8.6) months (P = 0.012). Conclusions: The real-world outcomes of first-line use of CDK4/6i and AI are encouraging. PR negative tumors and dose reduction appear to be negative prognostic markers. CDK4/6i + AI as first-line treatment for HR-positive, HER2-negative MBC in Alberta is justified based on favorable PFS and early OS outcomes.
Initial real life experience with ribociclib in breast cancer: Outcome with focus on tolerance and cardiac toxicity.
Authors: Nawaz Azhar , Zekri Jamal , Rasool Haleem J.
Published: June 2021

e13024

Background: CDK4/6 inhibitors, such as ribociclib, are a new class of medications that are used in combination with hormonal therapy to treat advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The primary objective of this study is to evaluate the tolerance and cardiac toxicity of ribociclib in all patients at our institution. Secondary objectives include progression free survival and response rates. Methods: Patients who received ribociclib between December 2018 and August 2020 were included. Rates of dose reduction and discontinuation of ribociclib were used as surrogate markers for intolerance and were compared to those reported in land-mark trials. QTc changes and cardiac adverse events (AEs) were also collected. Results: Thirty one patients were included. Ribociclib was administered in the first-, second-, third-, and fourth-line palliative hormonal therapy settings in 5 (16%), 14 (45%), 11 (35%) and 1 (3%) patients respectively and 8/31 (26%) received prior 1-4 palliative chemotherapy lines. Ribociclib was combined with letrozole in 21 (68%) and with fulvestrant in 10 (32%) patients. QTc interval was ≤ 470 msec in all patients prior to treatment and 11 (35%) patients had preexisting cardio vascular (non electro-conductive) co-morbidities. AEs related dose reduction was reported in 12 (39%) patients [bone marrow toxicity 6 (19%), QTc prolongation 4 (13%), abnormal liver function tests 1 (3%) and abdominal pain 1 (3%)]. Ribociclib was permanently discontinued due to AEs in 5 (16%) patients (2: prolonged QTc, 2: coronary events and 1: suspected allergic reaction). The median duration of follow up was 14 months. Objective response was evaluable in 28 patients [CR: 1 (3.6%), PR: 1 (3.6%), SD: 20 (71.4%) and PD: 6 (21.4%)]. The median progression free survival was 18 months (95% CI: 12.3-23.7). Conclusions: Although objective response rates were low in this mixed cohort of heavily pretreated patients, ribociclib combined with letrozole or fulvestrant has shown a robust progression free survival in real life practice. Treatment discontinuation rate is higher than that reported in clinical trials with stringent inclusion criteria. Ribociclib associated cardiac toxicity can be appropriately managed with careful monitoring.[Table: see text]
First-in-human phase 1/1b expansion of PMD-026, an oral RSK inhibitor, in patients with metastatic triple-negative breast cancer.
Authors: Beeram Muralidhar , Chalasani Pavani , Wang Judy S. , Mina Lida A. , Shatsky Rebecca Arielle , Trivedi Meghna S. , Wesolowski Robert , Hurvitz Sara A. , Han Hyo S. , Patnaik Amita , Pambid Mary Rose , Jayanthan Aarthi , Huynh My-my , Los Gerrit , Dunn Sandra Elaine , Dorr Andrew
Published: June 2021

e13043

Background: P90 ribosomal S6 kinase (RSK) is an actionable molecular target against metastatic triple negative breast cancer (mTNBC). RSK is a major convergence point in the integral TNBC signaling pathways, MAPK and PDK-1. PMD-026 is a first-in-class oral RSK inhibitor with high selectivity. The dose escalation portion of this study established the RP2D of PMD-026 as 200 mg Q12. PMD-026 demonstrated good plasma exposure following oral dosing, with a T1/2 of ̃ 6 h (range 4-8 h), and achieved the targeted preclinical efficacious concentrations using a Q12h dosing schedule. PMD-026 also demonstrated a tolerable safety profile and initial signs of efficacy in patients with metastatic breast cancer. The intensity of RSK2 activation ranged from an H Score of 110-268 based on a CLIA companion immunohistochemistry assay. We present initial data from the expansion cohort. Methods: The primary aim of this single-arm, open-label, first-in-human phase 1/1b study is to evaluate the safety of single agent PMD-026 in patients with mTNBC. Secondary endpoints are clinical activity, pharmacokinetics, and correlative biomarker expression on tumor specimens. Patients are dosed at 200 mg twice daily in 21-day cycles. Eligible patients have measurable disease as per RECIST v1.1 and have had disease progression on or after standard of care treatment. Tumor tissue is assessed to retrospectively correlate RSK2 activity by immunohistochemistry (IHC) with clinical outcomes. Pharmacokinetics are assessed along with a food effect (sub-study with n=12). In addition, a pharmacodynamic marker, YB-1 phosphorylation, is being explored in peripheral blood mononuclear cells before and during treatment. Results: As of February 16, 2021, 7 patients with mTNBC (median age 62 years, range 33-74) have been enrolled in the phase 1b Expansion (median of 7 prior lines of therapy). Notable prior therapies in the phase 1b include sacituzumab govitecan (n=4) and atezolizumab/nab-paclitaxel (n=1). Patients in escalation and expansion treated with the RP2D had median progression free survival of 30 vs 99 days for low vs high RSK2 expression, respectively. This cut-off will be further evaluated in the expansion phase of the study. Conclusions: Updated safety, clinical activity, pharmacokinetic, and biomarker analyses will be presented. Target accrual for phase 1b Expansion is a minimum of 20 patients with mTNBC. Clinical trial information: NCT04115306.
A precision dosing application for prostate cancer patients treated with docetaxel and G-CSF.
Authors: Villette Claire , Hurry Christian , Mistry Hitesh , Millen Jim , Chassagnole Christophe
Published: June 2021

e13585

Background: The aim of this study is to produce a precision dosing application for clinicians to control neutropenia in prostate cancer patients treated with both docetaxel and G-CSF. Chemotherapy-induced neutropenia (CIN) poses serious harm to patients due to the heightened risk of severe infection. Accordingly, chemotherapy dose is assessed at the beginning of each cycle. The therapeutic window of chemotherapy is determined from population studies, with an individual’s dose often scaled by their body surface area. This leads to a large number of patients being over- or under- dosed. We previously developed an application [1] which uses weekly neutrophil counts from the first cycle of docetaxel treatment to predict the level of neutropoenia in subsequent cycles for a given dose of docetaxel. However, in the original app the administration of G-CSF, used as a prophylactic treatment for neutropenia, was not considered. G-CSF administration lacks standardisation and the COVID-19 pandemic has created a highly risk adverse environment to infections, raising the prospects that a clinician will administer G-CSF. Methods: We adapted and combined representations of endogenous and exogenous G-CSF action on CIN from the literature [2,3,4] to capture the inherent feedback effect of circulating neutrophils on progenitor proliferation as well as the stimulatory action of G-CSF injection on proliferation and maturation of progenitor cells. Using data in the public domain from the comparator arm of a phase III clinical trial for metastatic hormone-resistant prostate cancer (NCT00617669), we identified 134 patients treated with docetaxel with recorded weekly blood tests in the first and second cycle, including 27 also receiving G-CSF. We calibrated individualised patient models against neutrophil counts measured in the first cycle by minimising a Bayesian objective function and evaluated their ability to predict the levels observed in the second cycle. Results: The model was able to capture the main features of endogenous and exogenous G-CSF action on neutrophil count described in the literature, including endogenous-G-CSF-mediated rebound above baseline after chemotherapy-induced depletion [4], rapid rise in neutrophil count following exogenous G-CSF administration [5], as well as reduced chemotherapy-induced depletion and earlier recovery under G-CSF treatment compared to chemotherapy alone [5]. Conclusions: This tool has the potential to help determine how a docetaxel patient may best benefit from G-CSF treatment and/or a change in dose of docetaxel. References: Villettte C., et al., AACR; Cancer Res, 2019;79(13 Suppl): Abstract nr 677. Pastor, M.L., et al. 2013. Pharm. Res, 30(11), pp.2795-2807. Krzyzanski, W., et al. 2010. J. Clin. Pharmacol, 50(S9), pp.101S-112S. Quartino, A.L et al., 2014. Pharm. Res, 31(12), pp.3390-3403. Crawford, J., et al. 1991. N. Engl. J. Med, 325(3), pp.164-170.
Attributes and disease characteristics of patients seeking online second opinion for cancer.
Authors: Goud Rakesh Shankar , Jotwani Amit Kumar , Poovaiah Thirtha , Rajan Rejil , Waghmare Rama , Gururao Shashidhar
Published: June 2021

e13620

Background: As we see rising cancer incidence in India, there is a parallelly increasing trend in patient-driven second medical opinions (SMO) in oncology. We analysed different attributes of patients seeking online second opinions through onco.com to help us understand the driving factors for patients. Here we present the patient and disease attributes to understand the reasons and perceived value of SMOs in oncology through an online platform. Methods: We did a retrospective analysis of 1,142 patients who availed online tumor board opinion through Onco.com between August 2018 & December 2020. Patient characteristics like age, gender, city of residence (metro or non-metro) & disease characteristics like cancer type and stage were recorded. Tumors included both solid and hematological malignancies. Results: Of the 1,142 patients, 87% (991) cases were solid tumors and the rest 13% (151) were hematological malignancies. Top 6 cancer types for which patients sought SMOs- Breast- 13%, Head & neck- 8.7%, Lung- 7.5%, Leukaemia- 5.8%, Lymphoma- 5.4%, & Ovarian- 5% cancers. Of the 991 solid tumour cases, 13% had early (stage I & II) disease, 24% had locally advanced (stage III) disease, 52% had metastatic disease & and 11% had recurrent disease. The mean age of patients was 50 years with equivalent gender distribution. 23% of patients seeking SMOs were young adults (17-44 years), 59% were older adults (45-70 years), and 9% patients were from elderly (>70 years) age group. City of residence- 39% patients were residents of metro (tier 1) cities and 61% were residents of non-metro (tier 2/3) cities. Conclusions: Advanced stage of disease (metastatic + recurrent) and non-metro city of residence were found to be the commonest attributes for majority of patients. Desperate nature of the situation in advanced stage of disease and lack of access to specialised oncology care in non-metro cities respectively appear to be the reasons for higher SMOs in these groups. Higher number of SMOs for younger age patients was disproportionate to the incidence of cancer in this age-group. A larger analysis of the contrarian opinions, compliance and clinical impact of second opinions in terms of better survival outcomes is warranted to see if patients get true value out of this exercise.