bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic testing in early breast cancer (EBC) for low middle income countries (LMIC): Is it worth the cost?
Authors: Shrivastav Gunjan , Arya Devavrat , Chaturvedi Aditi , Garg Charu , Jain Shubham , Mukhiya Sheetal , Chaturvedi Harit Kumar , Rohatgi Nitesh
Published: May 2020

e12521

Background: Chemotherapy is crucial for EBC management but has toxicities. Attempts are made to identify patients where chemotherapy can be safely skipped. Genomic testing offers advantage over clinico-pathological tools but given the cost, its utility in clinical practise, especially in LMIC remains questionable. Methods: 50 EBC patients who underwent risk stratification by oncotypeDX were retrospectively studied. Their clinico-pathological characteristics, Nottingham prognostic index (NPI) and PREDICT recommendation (v 2.1) were recorded. Tumor board(TB) made treatment recommendations based on age and histopathology, blinded to recurrence score(RS). The results were compared. Results: 32% patients were < 50 years, 68% were > 50 years. 32% and 68% patients were pre and post menopausal respectively. On pathological examination, T1, T2 & T3 comprised 26%, 70% and 4% respectively. 96% were node negative, 2% node positive, 2% had unknown nodal status. Tumors had Grade 1, 2 and 3 in 8%, 88% and 4% respectively. 4% had unknown estrogen receptor (ER), progesterone receptor (PR) score. ER and PR were low (Allred 3-5) in 2% and 12% respectively. NPI was low ( < 3.4) in 96% and intermediate (3.5- 5.4) in 4%. On PREDICT, all showed low benefit of chemotherapy ( < 3% at 10 years). TB prescribed chemotherapy in 58% and hormonal therapy (HT) in 42% patients. RS was low, intermediate and high in 66%, 26% and 8% patients respectively. Patients with low and high RS were supposed to receive HT and chemotherapy respectively. In the intermediate group, 4% patients were recommended HT as per age. 22% patients could not be assigned a treatment based on RS alone. In remaining 78%, TB’s decision matched RS recommendation in 38% (19) patients. In 2% (1), TB recommended HT while OncotypeDX showed high RS. In 38% (19) patients, TB recommended chemotherapy while OncotypeDX showed low RS. Despite all having low/intermediate NPI with < 3% chemotherapy benefit on PREDICT, 8% showed chemotherapy benefit on OncotypeDX. In 40%, OncotypeDX recommendation deferred from TB. In more than one third patients, when TB recommended chemotherapy, RS came low. In these patients we could avoid chemotherapy, saving ~900 USD treatment costs. As 68% patients were elderly ( > 50), genomic testing avoided chemotherapy in this subgroup, likely to suffer treatment toxicities. Conclusions: In LMIC where all patients don’t have access to hospitals with adequate infrastructure for chemotherapy administration, genomic testing has significant implications. We recommend using it more in clinical practise.
Is the toxicity of breast radiotherapy higher in patients with collagen vascular disease? A systematic review of the literature.
Authors: Liu Wei , Leung Aaron , Park Jane , Liu Brandon , Boldt Gabriel , Palma David A.
Published: May 2020

e12527

Background: Collagen vascular disease (CVD) has been described to be a relative contraindication for radiotherapy (RT) due to increased toxicity. As a result, RT to the breast or chest wall is underutilized in patients with CVD, despite known benefits in local control and overall survival after breast conserving surgery or mastectomy. We sought to characterize the acute and late toxicity rates associated with curative-intent RT for breast cancer patients with CVD. Methods: A systematic review per the PRISMA guidelines was performed using Pubmed database (inception to July 2019), for English-language articles. Key search themes included collagen vascular disease, connective tissue disease, including specific subtypes, along with terms for radiation and cancer. Title and abstract review were followed by full-text review. Inclusion criteria were reports of toxicity of five or more patients with CVD and treatment with curative-intent RT to the breast or chest wall. Data abstracted included: type of study, CVD diagnosis, number of patients who received breast RT, acute grade ≥3, and late grade ≥1, grade ≥3, and grade 5 toxicity. Primary endpoint was late grade ≥3 toxicity for patients with pre-existing CVD. Acute and late toxicity were classified as per CTCAE version 5.0. Results: The initial search yielded 3286 unique abstracts. 34 articles were determined appropriate for full-text review. From these, a final set of 10 articles met all inclusion criteria. All studies were retrospective. In these studies, more than 30 000 patient cases were reported. 184 patients with CVD who underwent curative-intent RT to the breast or chest wall and had available toxicity data were identified, including 128 patients with CVD diagnosed before RT. In the 5 case control studies, 100 patients were matched to 225 controls. Most studies did not report the incidence of all grades of toxicity. Among patients with available data, 7/102 patients (7%) with pre-existing CVD had late grade ≥3 toxicity, including 4/6 (67%) with pre-existing scleroderma and 3/96 (3%) with pre-existing non-scleroderma CVD. 32/88 patients (36%) with pre-existing CVD and available data had late grade ≥1 toxicity. 1/142 (1%) had late grade 5 toxicity, in the form of chronic pericarditis. 6/66 patients (11%) with pre-existing CVD had acute grade ≥3 radiation dermatitis. No patients had acute grade 5 toxicity. Conclusions: Retrospective data suggest that patients with pre-existing CVD, aside from scleroderma, have acceptable acute and late toxicity rates after RT to the breast or chest wall.
Comparison of pathological features of estrogen receptor-positive/HER2-negative early breast cancer in the intermediate-risk group of the 21 gene recurrence score (Oncotype Dx) divided into low and high-risk groups by the 95 gene classifier (Curebest 95GC Breast).
Authors: Kamada Yoshihiko , Tsuchiya Seiko , Takigami Naoko , Tamaki Kentaro , Uehara Kanou , Tamaki Nobumitsu
Published: May 2020

e12535

Background: Oncotype Dx is becoming the standard assay for chemotherapy decision making for estrogen receptor positive / HER2 negative early breast cancer. Issues concerning the choice of therapy for the intermediate risk patients are currently being addressed. We are using a 95-gene classifier developed by Osaka University and Sysmex Corporation (Curebest 95 GC Breast) which divides patients into "low" and "high" risk groups, which obviates this issue. In this study, we analyzed the histopathological characteristics of low and high risk patients by the 95-gene classifier that would be classified as intermediate risk by 21-gene-recurrence score (21RS). Methods: Fresh tissue samples collected at surgery was sent for 95-GC analysis. Cel-files containing the gene expression data of each sample was uploaded to Recurrence Online (recurrenceonline.com) and the 21-RS was obtained. Histopathological analysis of the tumor specimens including the pathological tumor size, degree of tumor infiltrating lymphocytes ("TIL"s) (0, 1+, 2+, 3+), nuclear pleomorphism (NP score 1, 2, 3), and number of mitoses (M score 1, 2, 3) was done. The age of the patient and the Ki-67 percentage of the preoperative biopsy specimen was also noted. Results: There were a total of 38 cases. The cases with a matching 21RS and 95GC "Low" (Group L-L) was 10, a matching "High" (Group H-H) was 15, 21RS "Intermediate / 95GC "Low" (Group I-L) was 4, 21RS "Intermediate / 95GC "High" (Group I-H) was 7, and discordant 21RS "High" / 95GC "Low" (Group H-L) was 2, respectively. There was no age related differences (average 53.3 y.o.). There was a significant difference between the L-L and H-H groups in all categories (i.e. pT 14.5 mm v.s. 30.0 mm / p = 0.0262, NP score average 2.1 v.s. 2.5 / p = 0.287, M score average 1.2 v.s 2.4 / p < 0.001, TILs average 0.4+ v.s. 1.2+ /p = 0.0413, Ki67 25.0% v.s. 33.2%). The trend was the same between the I-L and I-H group with the exception of the mitosis score, which showed an inverse trend of a high of 2.25 in the I-L v.s. low of 1.43 in the I-H group (p = 0.9522). The H-L group had high NP score (average 3.0), low M score (average 1.0), and high TILs (average 2+). Conclusions: The 95-gene classifier might be more sensitive compared to 21RS in picking up histio-morphological information, and also may be able to differentiate the type of immune response of TILs. We are planning further immunohistological evaluation.
Molecular profiling and quantitative image analysis reveal spatial intratumor heterogeneity in TNBC.
Authors: Mittal Karuna , Li Hongxiao , Wylie Dennis , Kaur Jaspreet , Kolachina Rishab , Sahoo Bikram , Wei Guanhao , Toss Michael S , Green Andrew R. , Arasappan Dhivya , Yang Jianchen , Yankeelov Thomas , Bhattarai Shristi , Rakha Emad A. , Gogineni Keerthi , Kong Jun , Kowalski Jeanne , Aneja Ritu
Published: May 2020

e12536

Background: Triple negative breast cancer (TNBC) is a molecularly complex and heterogeneous subtype with distinct biological features and clinical behavior. Extensive intra-tumor heterogeneity is suspected to be a major cause of therapeutic failure. Spatially-distinct parts of the tumor harbor diverse and divergent clonal populations of cancer cells. Thus it is likely increasing the likelihood that some of those clones resist treatment, expand in numbers and eventually, repopulate the tumor leading to recurrence and spread. Therefore, a deeper understanding of this complexity is fundamental to gaining insights into this clinically important issue. In this study, we used RNA sequencing and machine learning approaches to examine the molecular and phenotypic/cellular profiles of various tumor samples from the same patient tumor to reveal spatial intra-tumor heterogeneity in TNBCs. Methods: We used 34 samples (2-4 samples from each patient tumor) from a total of 11 unique TNBC patients. RNA-sequencing was performed to quantify differential gene expression and machine learning (ML) approaches (deep learning regression modeling) were used to quantify the percentage of tumor and tumor-infiltrating lymphocytes (TILs) in the H&E stained tissue sections. The extent of concordance/discordance between the multiple tumor samples that originated from the same patient was analyzed by analyzing the intra- and inter-patient variance of normalized tumor cell, TIL % and gene expression. We also performed pathway analysis to identify signaling pathways dysregulated within (intra-tumoral heterogeneity) and between tumors (inter-tumoral heterogeneity) and performed molecular subtype analysis. Results: We observed that gene expression variance as higher within-patient (intra-tumor) compared to between-patient (inter-tumor). Tumor samples from 70% of patients showed different molecular subtypes representing extensive intra-tumor heterogeneity. Our ML-based image analysis showed that intra-patient tumor cell and TILs density/percentage variance was greater than inter-patient variance. In addition, patients with high within-patient gene expression variability had a high tumor and TIL variance. Among the within-patient expression variability, the genes associated with the PLK1 and Notch signaling were enriched. Conclusions: Our results suggest that TNBCs exhibit higher intra-tumor gene expression and cellular variance compared to inter-tumor gene expression and cellular variance suggesting higher intra-tumor heterogeneity in TNBCs.
Prevalence of trastuzumab-induced cardiotoxicity in Uruguayan HER2-positive breast cancer patients treated in a real life setting during a 10 year period.
Authors: Camejo Natalia , Castillo Cecilia , Artagaveytia Nora , Etcheverría Crisitian , Ferradaz Jessica , Ferreira Agustín , Fontán Analía , Gabín Ana Sofía , Delgado Lucia Beatriz
Published: May 2020

e12537

Background: To estimate the prevalence of Trastuzumab (TTZ) induced cardiotoxicity in Uruguayan women diagnosed with early HER – 2 positive breast cancer (BC) over a period of ten years, treated under the financial coverage of the National Resource Fund (FNR). Methods: A prospective descriptive observational study based on the analysis of an anonymized database provided by the FNR of Uruguayan HER-2 positive early BC patients treated with TTZ between 2006 and 2016. Variables analyzed included: age, menopausal status, stage, presence of cardiovascular risk factors, use or not of anthracyclines, left ventricular ejection fraction prior and during treatment, and temporary or permanent suspension of treatment. Statistical analysis was performed using SPSS Statistics version 25. The variables were assessed through the use of measures of central tendency, dispersion, contingency tables and proportions. To analyze the relationship between the different variables, the Chi-Square test of independence was performed. Results: The analysis included 1401 patients diagnosed with HER-2 + stage I to III breast cancer who received adjuvant TTZ. The mean age at diagnosis was 52.45 years. The prevalence of cardiotoxicity in evaluable patients (1065 pts) was 20.3%. The proportion of patients who had symptomatic heart failure was 3% (32 pts) and in those who discontinued treatment for asymptomatic cardiac toxicity managed to resume trastuzumab prevalence was 92.6 %. About 9,7 % (21 pts) of patients had drop of left ventricular ejection fraction (LVEF) below 50%, whilst 10% drop of LVEF below their baseline levels were found in 75% of patients (162 pts) There is significant difference in the risk of cardiotoxicity according to the type of chemotherapy (anthracycline containing vs non-anthracycline based) (Chi-square = 3.9, p-value < 0.005). There was no evidence of a relationship between cardiovascular risk factors and the development of cardiotoxicity as well there was no evidence between sequential or concurrent use of TTZ with chemotherapy. Conclusions: The prevalence of cardiotoxicity in this study was similar to that reported internationally. The majority of patients did not develop cardiac toxicity and those who presented it did so asymptomatically and reversibly.
Correlation between five-year overall survival by PREDICT and 21 gene recurrence score (RS) in a Mexican private institution.
Authors: Amador García Geovani , Serrano Villamayor Omar , Andrade Moreno Raul Alejandro , Rodríguez Meléndez Elina Alexandra , Martínez-Herrera José Fabián , Sánchez Rodríguez Alain , Reyes Eduardo , Olivares Guillermo , Villalobos Alberto , Aguayo Alvaro , Perez-Zincer Fernando , Camacho Limas Christian Patricio , Lazaro Jesus Miguel , Serrano Juan Alberto , Gerson Cwilich Raquel
Published: May 2020

e12543

Background: In México the 5-year overall survival of Early Breast Cancer (EBC) reaches to 82-97%. Oncotype Dx evaluates the expression of 21 genes associated with recurrence and classifies patients into risk groups. PREDICT (https://breast.predict.nhs.uk/tool) is an online tool which assesses 5 and 10 year overall survival in breast cancer patients who receive adjuvant chemotherapy, adjuvant hormonal therapy and trastuzumab therapy for HER2(+) patients. Methods: Retrospective review of medical records of early stage breast cancer patients with (HR+) and HER2 (-) treated at our institution. Clinicopathological characteristics and (RS) were collected. 5-year overall survival was calculated with the PREDICT online tool. Both scores were compared and the correlation was estimated with Spearman’s Rho and global agreement with intraclass correlation coefficient (CCI), statistical software: STATA SE ver11.0 (StataCorp LLC Texas,USA). Results: From January 2008 to December 2018, 136 patients with EBC (IA-IIB), HR(+) HER2(-), N0-1 were included. The Median age at diagnosis was 55.03 years (30-80). Stage IA patients accounted for 68.38% of the population. Patients were classified into risks according to the original description of Oncotype. 72 patients (53%) were classified as low risk (LR), 49 (36%) at intermediate risk (IR) and 15 (11%) patients at high risk (HR). When reclassifying the risk categories using the cut-off values in TAILORx trial, the population distribution was modified, with a notable increase in the population in IR with 86 (63.2%) patients in this group, 28 patients in the LR group ( 20.5%) and 22 patients (16.1%) in HR. We decided to use TAILORx cut-off values for the aim of this work. Mean overall survival established by the 21 gene RS was 98% for the overall population. The mean overall survival calculated by PREDICT was 93%. Spearman’s correlation coefficient was 0.16 (Spearman’s Rho = 0.16 p = 0.065) with intraclass correlation coefficient (ICC) = 0.04 (IC 95% -0.15 – 0.22, p = 0.33). Conclusions: The results do not show a clear correlation between the tests. Lack of such correlation may be due to a low number of patients. In our population PREDICT couldn't replace the RS test for therapeutic decision making.
Real-world data on adjuvant bisphosphonate use in a breast cancer center in Mexico.
Authors: Peña-Curiel Omar , Villarreal-Garza Cynthia , Díaz-Pérez Héctor , Martinez Trevino Enrique Francisco
Published: May 2020

e12544

Background: Results from the Early Breast Cancer Trials Collaborative Group (EBCTCG) meta-analysis published in 2015 showed a significant reduction in risk of distant recurrence, bone recurrence and a 10-year breast cancer mortality reduction1. Moreover, Cancer Care Ontario and ASCO issued a guideline regarding the use of adjuvant bisphosphonates (AB) in breast cancer postmenopausal patients2. While these data are compelling, we have no information to support the implementation of this recommendation at Hospital San José’s Breast Cancer Center (HSJBCC). Methods: A retrospective analysis was performed to evaluate our compliance to the current recommendations for AB administration from 2015 through 2019. Inclusion criteria were based on the ASCO guidelines and comprised invasive breast cancer, postmenopausal status and early or locally advanced stage. Furthermore, in AB-treated patients we assessed the percentage of baseline calcium and creatinine measurement, prior dental evaluation, and concurrent calcium and vitamin-D supplementation during AB use. Results: A total of 106 patients met the inclusion criteria. Within the 4-year timeframe, AB was prescribed to 28/106 (26%) patients. Stratifying by year, we observed an increase of AB use rate from 4% in 2015 to 32% in 2019. Moreover, we observed a 93% baseline calcium and creatinine measurement, a 60% prior dental evaluation, and a 43% concurrent calcium and vitamin-D supplementation in the AB-treated population. Conclusions: HSJBCC recommendation for AB use is less than expected in the evaluated eligible patients in the 4-year timeframe. Despite an increase in our compliance to current ASCO guidelines it is not yet the standard of care at HSJBCC. Based on these results, we are currently planning a quality improvement initiative to undertake our low percentage of AB usage. [Table: see text]
Depression in women breast cancer patients receiving radiation therapy: A pilot study.
Authors: Chen Fang , Yu Hao , Zhao Caining , Zhang Fan , Nong Yaqing , Xu Zhiyuan , Yang Li , Chen Wenqi , Wang Qian , Zhou Yong , Han Yin , Jing Haiman , Kong Feng-Ming
Published: May 2020

e12546

Background: The purpose of this study is to study depression and its risk factors at baseline and explore the changes of depression status during the course of radiation therapy in breast patients. Methods: This is part of a prospective study of treatment toxicity and quality of life. Breast cancer patients, aged 18-year old and above requiring adjuvant radiation therapy were eligible. The primary endpoint depression was assessed by a self-addressed “depression” questionnaires according to NCI “PROMIS”. The Questionnaires were completed one day prior to, during and at the end of treatment. Patient, tumor and prior treatment factors were collected. Cancer specific symptoms were collected by treating physicians and graded according to NIH/NCI CTCAE v4.0. The variables of our interest included age, menopausal status, N-stage,pathology stage, immunohistochemisty, surgical approaches,margin,prior treatments and radiation models. Data are presented as mean (95% confidence interval) unless otherwise specified. Statistical significances were tested using generalized linear model, pearson correlation and t-text. Ps less than 0.05 were considered to be significant. Results: Between July 2019 and January 2020, a total of 185 patients enrolled and completed the PROMIS questionaires. Before RT commencement, 50/185 (27.0%) had some levels of depressive feeling including 40/185 (21.6%), 10/185 (5.4%), and 0/185 (0%) patients for “rarely” (score = 5-8), “sometimes” (score = 9-12), “often” (score = 13-16), and “always” (score 17-20), respectively. Interestingly, N stage and pathology staging group were significantly associated with the depression at baseline while age, menopausal status, immunohistochemistry, previous chemo cycles, chemo regimens and anti-Her2 taget therapy were not. At the end of RT, 51/149 (34.2%) patients had depression level changed, though the absolute lumped scores of depression did not change significantly (p = 0.437). Changes in depression during were significantly associated with menopausal status (p = 0.015) while grade 2 and above toxicities were not (p = 0.421). Conclusions: Depression feeling is not uncommon in breast patients receiving adjuvant radiation. Future study may identify patients with depression and associated risk factors so that proper intervention may be applied to improve long-term survival and quality of life in patients.
Survival outcomes in post-menopausal patients with underlying cardiovascular disease receiving endocrine therapy for the treatment of breast cancer.
Authors: Parajuli Priyanka , Lara Garcia Odalys Estefania , Maini Ruby , Regmi Manjari Rani , Tandan Nitin , Mirihagalle Noupama , Cheema Asad , Abedrabo Sabree , Niaz Zurain , Koester Cameron , Sahib Hamsa , Bhandari Bishal , Johnson Alexander , Ibrahim Abdisamad M. , Delfino Kristin , Robinson Kathy , Desai Meghna R. , Kulkarni Abhishek
Published: May 2020

e12549

Background: Breast cancer remains the number one threat to women’s health while cardiovascular disease (CVD) continues to be the leading cause of mortality in women worldwide. Adjuvant therapy with endocrine therapies (selective estrogen receptor modulators (SERM), estrogen receptor blockers (ERB), and aromatase inhibitors (AI) although known to reduce the recurrence of breast cancer in hormone receptor positive breast cancer patients, raise a concern for increased risk of cardiovascular disease. Our study aims to examine breast cancer survival outcomes on patients receiving endocrine therapy who have pre-existing CVD including heart failure. Methods: An institutional database of 478 patients with histologically confirmed hormone receptor positive breast cancer diagnosed between 01/01/2014 to 12/31/2017 was reviewed after IRB approval. Preexisting CVD included coronary artery disease (CAD), history of myocardial infarction (MI), and prior diagnosis of heart failure (HF). Patients were divided in groups depending on treatment with endocrine therapy and underlying CVD. Statistical analysis was performed with SAS v9.4. software. Survival curves were estimated using Kaplan-Meier methodology and analyzed with a log rank test. Predictors of survival were assessed with Cox proportional hazards regression analyses. All significance was assumed at the p < 0.05 level. Results: Of 478 patients who met the inclusion criteria, 336 (70%) patients were postmenopausal. Out of those 336 patients, 62.2 % (n = 209) received at least one of the endocrine therapies consisting of AI, SERM or an ERB. Of these patients, 2.9 % (n = 6), 9.6% (n = 20) and 5.7% (n = 12) had a significant medical history of underlying MI, HF and CAD, respectively. Survival analysis was performed on 80% (n = 168) patients of the 209 patients with 2.3% (n = 4), 8.9% (n = 15) and 5.2% (n = 11) with underlying MI, HF and CAD respectively. There was no statistically significant difference in survival in these postmenopausal women who received endocrine therapy despite preexisting cardiovascular disease (HR 3; 95% CI, 0.5-16, p > 0.05). Conclusions: A commonly known toxicity related to the adjuvant therapy including endocrine therapy of breast cancer is cardiac toxicity. Patients with history of CVD might be at the highest risk for such toxicity. Our finding is reassuring that endocrine therapy in patients with preexisting CVD including heart failure did not result in reduced survival for our patient cohort.
ER-/PgR+ breast cancer is a separate entity characterized by distinct phenotype: Comprehensive reevaluation of cases from Polish and Hungarian centers.
Authors: Senkus-Konefka Elzbieta , Kunc Michał , Pęksa Rafał , Łacko Aleksandra , Radecka Barbara , Braun Marcin , Pikiel Joanna , Litwiniuk Maria , Pogoda Katarzyna , Cserni Gabor , Iżycka-Świeszewska Ewa , Szwajkosz Anna , Biernat Wojciech
Published: May 2020

e12554

Background: ER negative (-)/PgR positive (+) breast cancer (BC) is very uncommon and questioned by many experts. We comprehensively reevaluated ER-/PgR+ BCs in the large cohort from Polish and Hungarian centers. Methods: FFPE blocks from 105 ER-/PgR+ tumors (45 breast biopsies and 64 post-operative samples from tumors not exposed to systemic therapy) were collected from 10 Polish and 3 Hungarian centers. In 60 cases available original slides with ER/PgR staining underwent reevaluation by 3 pathologists (MK, RP, WB) for ER and PgR expression by ASCO/CAP criteria. Subsequently, all samples were stained with 3 antibodies against ER (Dako monoclonal (MC) mouse anti-ERα, clone 1D5; Dako MC rabbit anti-ERα, clone EP1; VENTANA Roche MC rabbit anti-ERα, clone SP1), and PgR (Dako MC mouse anti-PgR, clone 636). If available, > 1 tissue block was used (av. 2.04 blocks/case, range 1-6). In 5 cases ESR1/PGR/ERBB2/MKi67 mRNA was measured by the Xpert® Breast Cancer STRAT4 (Cepheid, Sunnyvale, CA, USA). Results: 13 cases were excluded from immunohistochemical steps of the study due to insufficient amount of tissue and 8 - due to misdiagnosis after ER/PgR reevaluation of original slides. After re-staining, 42 cases (41.5%) retained the original phenotype, in 34 (33.67%) the ER status was corrected to ER+, and 16 (15.84%) tumors were ER/PgR-double-negative. The general agreement between anti-ER clones was moderate (Fleiss’ κ = 0.54). There were 56 ER- and 16 ER+ cases across all three assays. Five cases showed ER positivity with 2 antibodies (either SP1/EP1 or SP1/1D5), 5 tumors reacted exclusively with SP1 clone, and 2 - with 1D5 clone. Xpert Breast Cancer STRAT4 confirmed the ER-/PgR+ phenotype in 4 of 5 analyzed cases. The confirmed ER-/PgR+ BCs were characterized by lower percentage of PgR+ cells (median 5%) than BCs reclassified to ER+ (median 70%) (p = 0.022) and higher Ki67 expression than ER+ cases (median 54.5% vs 25%, respectively; p = 0.003). 39 (92.85%) ER-/PgR+ BCs presented with grade 3. Besides “conventional” high-grade cancers, we identified two distinct morphologies of ER-/PgR+ BC: resembling apocrine carcinoma (n = 5, 11.9%) and carcinoma with central acellular zone (n = 4, 9.5%). Conclusions: ER-/PgR+ BCs confirmed in the current study were defined by high-grade histology, high proliferation index and low percentage of PgR+ cells. We postulate ER-/PgR+ BC is a real albeit rare entity, and its diagnosis should be made cautiously, utilizing retesting with an alternative tissue block and anti-ER antibody.
Significance of PDL1 positive in TNBC.
Authors: Imanishi Seiichi , Morishima Hirotaka , Oda Naofumi , Hasegawa Junichi
Published: May 2020

e12557

Background: Atezolizumab was approved for PD-L1-positive advanced recurrent triple negative breast cancer. However, it is controversial about when and when to measure PD-L1. Here we retrospectively reaearched how PD-L1 positivity rates in biopsy, surgical, and recurrent specimens for triple-negative breast cancer (TNBC) treated with neo adjuvant chemotherapy (NAC). We also investigated the relationship between androgen receptor (AR) and PD-L1, and researched the significance of PD-L1 positivity on TNBC. Methods: 28 TNBC biopsy samples before NAC, 16 surgical specimens with residual tumor after NAC, and 5 cases reccurence specimens were obtained subjected to stain for PDL1 using the SP142 antibody. AR staining was also performed on biopsy specimens. PD-L1 score determination was performed according to the Ventana OptiView PD-L1 (SP142) inspection guide, and AR positive cuttoff was setted 1% or more. Results: The PD-L1 positivity rates of the biopsy samples were IC0: 46.4%, IC1: 25.0%, IC2: 21.4%, IC3: 7.1%, TC0: 28.6%, TC1: 28.6%, TC2: 42.9%, TC: 0%. In the surgical specimens after NAC, PD-L1 showed almost no change in IC ( P = 0.38), but the score significantly decreased in TC ( P < 0.001). The recurrence specimesn that could be collected were IC0: 60%, IC1: 20%, IC2: 20%, IC3: 0%, TC0: 60%, TC1: 20%, TC2: 20%. There were four AR-positive cases, one of which showed TC2, but the others were negative.In terms of prognosis, both the DFS and OS in the PD-L1 strongly positive group (IC≥2 and TC≥2) and other groups Poor in PD-L1 strongly positive group ( P < 0.01, P = 0.041, respectively). Conclusions: TC was affected by NAC, the score decreased markedly, and the positive rate at the site of recurrence also tended to decrease. The PD-L1 strong positive had a significantly worse prognosis than the others. It was suggested that PD-L1 immunostaining may be effective in predicting prognosis by considering TC as well as IC.
The clinical impact of the expression of the cancer stem cell marker CD44v9 in early triple negative breast cancer (TNBC).
Authors: Tokunaga Eriko , Tajiri Wakako , Takizawa Katsumi , Ijichi Hideki , Ueo Hiroki , Koga Chinami , Nakamura Yoshiaki , Taguchi Kenichi , Okamoto Masahiro
Published: May 2020

e12566

Background: The adhesion molecule CD44 is expressed in cancer stem-like cells (CSCs). CD44 variant 9 (CD44v9), a splicing variant of CD44, has emerged as a novel marker of cancer stemness. CD44v9 was reported to be associated with the resistance to chemotherapy in several malignancies. We recently reported that the high expression of CD44v9 is associated with the poor prognosis of the patients with triple negative breast cancer (TNBC), who received neoadjuvant chemotherapy (NAC). In this study, we investigated the clinical impact of the expression of CD44v9 in early TNBC who underwent surgery without NAC. Methods: Among 2257 primary breast cancer patients at clinical stage I-III who underwent surgery without NAC form 2002 to 2015, 201 patients with TNBC were included in this study. The expression of CD44v9 was analyzed immunohistochemistry (IHC). The associations between the CD44v9 expression and the clinicopathological characteristics and the prognosis were investigated. The tumors with the positive staining in more than two third of the cancer cells were regarded to be high expression of CD44v9. Results: CD44v9 high expression was observed in 62 cases (30.8%) and the low expression was in 139 cases (69.2%). Many of the CD44v9 high tumors were low grade than the tumors with low CD44v9. There were no significant associations between the expression levels of CD44v9 and the tumor size, lymph node metastasis and the pathological stage (pStage). There were no differences in the prognosis between the high and low CD44v9 expression in pStage I. However, in the patients with the tumors with pT1c or more (pT2, pT3) and the patients with pStage 2 and more, the high CD44v9 expression was significantly associated with the poor prognosis in terms of distant recurrence-free survival (DRFS) and overall survival (OS). In addition, high CD44v9 was associated with significantly shorter survival after recurrence. Many of these patients received various chemotherapy in the adjuvant setting and after recurrence. Therefore, CD44v9 high expression is considered to be associated with the poor prognosis due to the resistance to various chemotherapeutic agents. Conclusions: The prognosis of the TNBC patients with the high expression of CD44v9 is poor, which might be induced by the resistance to various chemotherapeutic agents. These results suggest that CD44v9 might be a novel therapeutic target for TNBC.
Real-world clinical analysis and overall survival-related biomarker of breast cancer (BC) patients under 35 years old.
Authors: Yu Jinpu , Li Yang , Li Xuesong , Yang Beibei , Wang Shuaibing , Lu Su , Shi Yehui , Hao Chunfang , Zhang Geng , Wang Xiaohong , Ma Jie , Liu Hong , Shi Xiaoliang , Qiao Huidong , Liu Zhenzhen
Published: May 2020

e12569

Background: Breast cancer (BC) is one of the most common malignant tumors among women in the world. Although under 7% of all BC cases, young BC is more difficult to diagnose and can be aggressive and less likely to respond to treatment. Exploring and identifying potential biomarkers for the diagnosis and prognosis of younger BC patients is necessary. Methods: A total of 1,202 BC patients under 35 years old (YD) were enrolled. Deep sequencing targeting 450 cancer genes was performed in a laboratory accredited by College of American Pathologists (CAP) and certified by Clinical Laboratory Improvement Amendments (CLIA) for genomic alteration identification. Statistical analysis was performed by Fisher’s exact test. Results: Of 1,202 young BC patients, 3 were under 20 YD, 85 were 20-25 YD, 371 were 26-30 YD, and 747 were 31-35 YD. Based on pathological, there were 899 infiltrative duct carcinomas, 10 infiltrative lobular carcinomas, and 292 BCs with unclear pathological type. According to molecular features, 587 HR+/HER2- (group I), 118 HR+/HER2+ (group II), 75 HR-/HER2+ (group III) and 193 HR-/HER2- (group IV) were included. Chemotherapy, radiotherapy, endocrine therapy and targeted therapy were received and 1074 patients were followed up. The median overall survival (OS) was 76 (5-156) months. There was no significant difference in OS between different treatments. The median OS was 81 (range 5-156) months, 67 (range 10-153) months, 76 (range 14-146) months, and 78 (range 13-151) months for group I, II, III, and IV, respectively. The significantly lower OS was observed in group II ( P=0.044). Although group II and group III had similar proportion of targeted treatment (43.22% vs 43.24%, respectively), the OS rate was different (67 vs 76 months, P=0.064). Samples from 46 young BC patients were performed on deep sequencing targeting 450 cancer genes. The most common mutations were TP53 (56%), GATA3 (29%), ERBB2 (27%), CDK12 (20%), and FGFR1 (20%). Different from previous studies, only 4.35% (2/46) of BRCA1/2 mutations were detected in this cohort. The mutation frequency of GATA3 in group II was significantly lower than that in group III (0% vs 71.43%, P=0.017). Conclusions: The most common pathological type of young BC was infiltrative duct carcinoma. The OS of HR+/HER2+ patients were significantly lower than that of others. Our results showed that GATA3 could be a potential biomarker for OS prediction for BC with HER2+, which help to further guide targeted therapy in young BC patients.
Biological and clinical features of early triple-negative invasive lobular carcinomas of the breast.
Authors: Conforti Fabio , Pala Laura , Guerini Rocco Elena , Pagan Eleonora , Bagnardi Vincenzo , Montagna Emilia , Peruzzotti Giulia , De Pas Tommaso Martino , Fumagalli Caterina , Pileggi Silvana , Pesenti Chiara , Marchini Sergio , Marchiò Caterina , Sapino Anna , Gelber Richard D. , Viale Giuseppe , Colleoni Marco , Goldhirsch Aron
Published: May 2020

e12570

Background: Hormone receptors and HER2 negative (triple negative, TN) invasive lobular carcinomas (ILCs) are very rare, accounting for 1-2% of all TN breast cancers (BCs). Methods: We extracted data from our prospectively collected institutional database on all consecutive patients (pts) with early stage TN ILC operated at the European Institute of Oncology (IEO) between June 1994 and December 2012. Invasive disease-free survival (iDFS) and cumulative incidence of distant metastases (CI-DM) were calculated. Biological features of these tumors, including molecular intrinsic subtypes based on PAM50 assay, expression of androgen receptor (AR) and mutational status of c-erbB2 gene were also evaluated. Additionally, NGS data of 45 TN ILCs were obtained from 3 large public databases, to confirm mutations in c-erbB2 gene and to identify other recurrently mutated genes. Results: Among 2952 ILCs treated at IEO, 44 (1.5%) were TN and were included in the analysis. All pts received adjuvant chemotherapy. The iDFS rates at 5 and 10 years of follow-up were 47.4% (95% CI, 31.1-62.0) and 29.5% (95% CI, 14.8-45.8), respectively. The corresponding CI-DM percentages were 17.6% (95% CI, 7.6-31.2) and 20.8% (95% CI, 9.5-35.1). The molecular intrinsic subtype was defined through PAM50 for 31 out of 44 TN ILCs: 48% were classified as luminal A, 3% luminal B, 32% HER2-enriched, and only 16% basal-like. The group of pts with luminal A or B tumors had a significantly better CI-DM as compared with pts with non-luminal tumors (i.e. HER2-enriched and basal-like; p=0.003). Luminal tumors expressed AR more frequently than non-luminal tumors (AR≥1% in 96% of luminal tumors versus 53% in non-luminal tumors; p=0.001), and at significantly higher levels (median percentage of AR-positive cells was 80% in luminal tumors versus 15% in non-luminal tumors; p=0.01). Higher AR expression was associated with significantly better iDFS in the whole cohort of TN ILCs (p=0.01), as well as in the group of luminal tumors (p=0.05). 27 TN ILCs of the IEO cohort were analyzed for mutations in c-erbB2 gene, and 9 (33%) harbored mutations. Analysis of the 3 public databases, confirmed c-erbB2 mutations in 9 out of 45 (20%) TN ILCs. All the c-erbB2 mutations found were previously reported to be pathogenetic in BCs and to predict response to neratinib. ErbB signaling and DNA damage response were among the top 10 pathways significantly enriched for mutated genes in TN ILCs. Conclusions: TN ILCs are rare tumors with dire prognosis. Their specific biological features require newly defined targeted therapeutic strategies.
Clinical relevance of miR-143 expression in ER-positive breast cancer patients.
Authors: Tokumaru Yoshihisa , Oshi Masanori , Katsuta Eriko , Matsuhashi Nobuhisa , Futamura Manabu , Yoshida Kazuhiro , Takabe Kazuaki
Published: May 2020

e12574

Background: MicroRNA-143(miR-143) is a well-known tumor suppressive microRNA in various malignancies, including breast cancer. Recently, the tumor immune microenvironment has been reported to associate with progression of breast cancers. However, the association with the tumor immune microenvironment and miR-143 in breast cancers remains ambiguous. Given these backgrounds, we hypothesized that high expression of miR-143 is associated with favorable effect to the tumor immune microenvironment which leads to better survival of ER positive breast cancer patients. Methods: Two major publicly available breast cancer cohorts were used for this study. A total of 753 patients from The Cancer Genome Atlas (TCGA) and total of 1283 patients from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used. Results: We defined the higher quartile of miR-143 expression levels as high and the remainder as low expression groups. There was no significant difference in patient clinicopathlogical features between two groups. Gene set enrichment analysis (GSEA) revealed that miR-143 high expression tumors enriched Helper T cell type 1 (Th1) related gene sets indicating the upregulation of anti-cancer immune cells. Also, the cell composition of anti-cancer immune cells, such as Th1 and Macrophage M1 were higher with miR-143 high tumors (p < 0.001 and p < 0.01 respectively) in whole group. On the contrary, pro-cancer immune cells such as Th2 and M1 were lower with miR-143 high tumors (p < 0.01 and p < 0.001 respectively) in whole group. Interestingly, among the subtypes, we found that ER positive subgroup followed this trend of high infiltration rate of anti-cancer immune cells and low infiltration rate of pro-cancer immune cells. Furthermore, only ER positive subgroup demonstrated the survival benefit with miR-143 high expression tumors. Conclusions: We demonstrated that high expression of miR-143 in ER breast cancer associate with favorable tumor immune microenvironment, upregulation of the anti-cancer immune cells and suppression of the pro-cancer immune cells, and associate with better survival of the breast cancer patients.
Functional hotness score based on three genes predicts long-term survival of triple-negative breast cancer independent from tumor mutational burden.
Authors: Katsuta Eriko , Yan Li , Opyrchal Mateusz , Kalinski Pawel , Takabe Kazuaki
Published: May 2020

e12583

Background: Cytotoxic T-lymphocytes (CTLs) infiltration into tumor is a positive prognostic factor in breast cancer. Infiltration of CTLs are believed to be driven by mutation-induced neoantigens, thus, higher tumor mutation burden (TMB) is considered an important predictor of tumor immunogenicity and response to immunotherapy, but the association between intratumoral CTL counts and TMB in the overall cancer prognosis remains unclear. Methods: Utilizing publicly available breast cancer cohorts, we established Functional Hotness Score (FHS), based on CD8A, GZMB and CXCL10 gene expression levels of bulk tumors. The associations of FHS and breast cancer patient prognosis as well as distinct immunity markers were analyzed. Results: Breast cancer patients with high-FHS tumors demonstrated significantly better survival. FHS was lower in metastatic breast cancer. Among breast cancer subtypes, triple-negative breast cancer (TNBC) showed the highest FHS. FHS predicted patient survival not in hormone receptor (HR)-positive but in HR-negative, especially TNBCs. The high-FHS TNBCs enhanced not only CD8+ T cell infiltration, but also a broader type-1 anti-cancer immunity. The patients with the high-FHS patients showed better prognosis not only in high-TMB tumors but also in low-TMB TNBCs. The combination of high-TMB with high-FHS identified the unique subset of patients who did not recur over time. Conclusions: In conclusion, TNBCs with high-FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with higher anti-cancer immunity regardless of TMB, and constituting an independent prognostic marker of survival, particularly robust when combined with TMB.
4-gene score to predict response to neoadjuvant chemotherapy, metastasis, and survival.
Authors: Oshi Masanori , Katsuta Eriko , Yan Li , Endo Itaru , Takabe Kazuaki
Published: May 2020

e12592

Background: At this point, there is no treatment to cure metastatic breast cancer. On the other hand, improvement of treatment of metastatic breast cancer is the key to further improve breast cancer survival. One possible opportunity is to detect metastatic breast cancer in it’s “early” phase when it many respond to treat such as immune therapy. We hypothesized that a scoring system generated from metastatic clone predict metastasis and survival. Methods: A gene signature score was generated using differentially expressed genes between MDA-MB-231 human breast cancer cell-line and its highly metastatic variant, LM2-4, and TCGA breast cancer dataset. METABRIC cohort as well as six neoadjuvant therapeutic cohorts and four metastatic cohorts were used as validation cohort. The totals of 4,199 samples from a large number of cohorts were analyzed in the study. Results: Among the 297 genes that were up-regulated in LM2-4, tumor expression of four genes had the strongest association with disease-free survival in TCGA breast cancer dataset (hazard ratio [HR] > 1.2 with p < 0.02). A 4-gene score calculated from the combined expression of these genes correlated with overall survival in TCGA data, with HR of 1.44 (95% confidence interval [CI] = 1.52-2.98; p < 0.001). The association of higher scores with worse survival was also observed for disease-specific survival in the METABRIC breast cancer cohort (HR = 1.57, 95% CI = 1.23-1.72, p < 0.001). Tumors with high score enriched gene sets related with cancer aggressiveness such as E2F, G2F, MYC v1 and v2 (FDR = 0.23, 0.19, 0.20, 0.21, respectively), whereas those with lower score enriched estrogen response pathway related set (FDR = 0.13) in TCGA and it was validated with METABRIC cohorts. We also found that the score associated with distant metastasis to brain or lung (p < 0.001). Kaplan-Meier analyses of site-specific metastasis-free interval demonstrated that for all three cohorts, patients with high scores had significantly increased risk for development of metastasis to the lung (p≤0.02). This association of the score with metastasis risk was also seen for brain for two cohorts, and it was seen for bone in one cohort. Importantly, we found that the high score group had a higher pCR rate than the low score group for especially ER+/HER2- breast cancer in two cohorts (p = 0.003 and p = 0.004). And the score significantly decreases with good response to neoadjuvant chemotherapy (p = 0.022) or hormonal therapy (p = 0.013). Conclusions: This novel gene score may be clinically useful with both prognostic and predictive values for breast cancer.
Five day accelerated partial breast irradiation (APBI) using stereotactic body radiation therapy (SBRT) in stage 0-II breast cancer: A report of 135 cases with up to two-year follow-up.
Authors: Mark Rufus J. , Gorman Valerie , McCullough Steven
Published: May 2020

e12596

Background: Randomized trials in stage 0-II breast cancer have proven that APBI given via HDR implant in 5 days is equivalent to whole breast External Radiation Therapy (XRT) given in 5-6 weeks in regard to breast tumor local recurrence (LR). However, complications have been significant. Recently APBI using non-invasive IMRT given in 5 fractions has been shown in another randomized trial to be equivalent to XRT in 6 weeks, with respect to LR. IMRT was superior in regard to acute effects, late effects, and cosmesis. In the randomized clinical trial of APBI IMRT, the Clinical Target Volume (CTV) was defined by the injection of individual fiducial markers bordering the surgical cavity. At our institution, we have used the Biozorb fiducial system to localize the CTV for IMRT. We sought to confirm the APBI IMRT results with this simpler less labor intensive fiducial placement system. Methods: Between 2017 and 2020, 135 patients have undergone SBRT targeted to a Biozorb defined CTV with the walls of the surgical cavity sewn to the Biozorb device. Eligible patients were older than age 40, had tumor sizes < 3 cm, negative surgical margins, and negative sentinel node dissections. SBRT dose was 30 Gy given in 5 fractions. Dose Constraints were as follows: V-30 Gy < 105%, Ipsilateral Breast V-15 Gy < 50%, Ipsilateral Lung V-10 Gy < 20%, Contralateral Lung V-5 Gy < 10%, Heart V-3 Gy < 20%, Contralateral Breast Dmax < 2 Gy and Skin Dmax < 27 Gy. The Planning Target Volume (PTV) ranged from 27 to 355 cc with a median of 80 cc. PTV = CTV + 1-2 cm. Results: Follow-up ranged from 1-26 months with a median of 12 months. LR has been 0% (0/135). There have been no skin reactions or seromas. Infection has occurred in one patient (0.7%). Three (2.2%) patients developed pain around the Biozorb site. This resolved within 2 days on a short course of steroids in all cases. Cosmetic results as rated by the Surgeon, Radiation Oncologist, and Nurse, were rated excellent in 98.5% (133/135) of cases. Conclusions: Non-invasive APBI with SBRT given qd over 5 days targeted to Biozorb has resulted in LR, complications, and cosmetic results which compare favorably to invasive APBI given bid with HDR implant. At last follow-up, there have been no LR, skin reactions, or significant complications. Cosmesis has been excellent in 98.5% of patients.