bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcome of 116 cases of pleuropulmonary blastoma type I and type Ir (regressed): A report from the International PPB Registry (IPPBR).
Authors: Messinger Yoav H. , Williams Gretchen M , Priest John R. , Harris Anne , Doros Leslie Ann , Schultz Kris Ann Pinekenstein , Dehner Louis P , Hill D Ashley
Published: March 2020

9522

Background: Pleuropulmonary blastoma (PPB) is a rare dysembryonic lung neoplasm of early childhood with progression from a purely cystic Type I (T-I) lesion to cystic solid and solid high grade sarcoma (Type II and Type III). A regressed form of PPB (T-Ir) has been recognized pathologically. The outcome of both T-I and T-Ir has been only partially described. Methods: Retrospective analysis of 345 IPPBR cases showed 116 T-I or T-Ir. In all cases the PPB diagnosis was made on surgically removed cysts. The treating physician decided whether to use chemotherapy after surgery. Results: The pathologic diagnosis of the 91 PPB T-I and 25 T-Ir is now confirmed by central review (LPD and DAH). Patients with T-I were younger than T-Ir (median: 8 months vs. 48 months).Diagnosis after age 6 years included only one T-I compared to 10 T-Ir patients. Therapy is not known for 28 T-I and 2 T-Ir. Surgery was followed by chemotherapy in 31 T-I and 2 T-Ir. Six (5%) recurred with the same type, all were alive at last follow-up: 5 (5.5%) T-I, 1 (4%) T-Ir. Progression to high-grade Type II or III occurred in 9/91 (10%) T-I and 2/25 (8%) T-Ir. The addition of chemotherapy did not significantly reduce progressions (Fisher’s exact test). All of the tumor progressions were seen by 75 months of age; this finding is similar to broader IPPBR data: > 95% of patients are diagnosed with Type II/III by 72 months of age. Of the 9 patients with T-I who progressed, 5 ultimately died, whereas the 2 T-Ir who progressed were alive. At last follow-up 111/116 (95.6%) were alive. Conclusions: A cyst in an older individual most likely will be Type Ir. Type I and Type Ir are clinically similar with a small risk of progression to the advanced Type II/III up to 6 years of age. Outcome for those whose cystic PPBs progressed is poor. The role of chemotherapy remains uncertain for the prevention of progression in the pure cystic PPB Type I or Ir. [Table: see text]
Serial assessment of regulatory T cells (Tregs) in pediatric AML: A prospective study.
Authors: Bansal Anuj Kumar , Sharawat Surender Kumar , Gupta Ritu , Sreenivas Vishnu kumar , Bakhshi Sameer
Published: March 2020

9549

Background: Data of Tregs in pediatric AML is lacking. The study objectives were determining Tregs in pediatric AML at diagnosis and follow up; and correlating with outcome. Methods: From Nov 2010-May 2011, 30 consecutive AML patients ≤ 18 years were prospectively enrolled with 6 healthy controls. All patients received daunorubicin / cytarabine induction and 3 courses of cytarabine. Tregs (CD4+CD25+FoxP3+) were assessed at diagnosis, post-induction, post-consolidation, 3 and 6 months follow up and relapse. Results: 30 cases with median age 9.5 years; male/female ratio 14:16 had significantly higher baseline Tregs than healthy controls (12.36±4.65% vs 3.16±1.49%; p=0.0001). Patients with high Tregs frequency were females (p=0.044), WBC>50,000/mm3 (p=0.023), hypoalbuminemia (p=0.002), absence of lymphadenopathy (p=0.04) and linear correlation with peripheral blood blast% (r=0.55, p=0.0014). CR rate was 83.3% (25/30); EFS 38% and OS 73% at 14 months follow up. When Tregs were categorized as high and low based on median value, CR rate (86.6% vs 80%, p=NS), EFS [17% vs 60%, HR 1.46 (0.51-4.14) p=0.46] and OS (66% vs 80%, HR 0.58 (0.13-2.44) p=0.45) were not different. Amongst those who achieved CR, there were 7/13 relapses in those with high Tregs versus 3/12 in those with low Tregs (p=0.226).Tregs reduced post-induction (12.1±4.6 vs 6.32±2.8, p<0.000) from baseline. Using generalized estimating equation regression model, average Tregs reduction from post-induction till 3 month follow up was 0.785 units/visit (p<0.005) in those with continuous CR(n=15) and 1.25 units/visit (p<0.001) in those whom relapsed (n=10). Difference between these two groups was not significant. Tregs significantly increased at relapse as compared to post consolidation value (15.3±5.2 vs 4.5±1.9, p=0.003). Conclusions: This first study in pediatric AML demonstrates that Tregs is increased at diagnosis and is significantly associated with females, high WBC count, hypooalbuminemia, absence of lymphadenopathy and high peripheral blood blast%. Tregs significantly reduced post-induction on follow up; however, it increased at relapse. Baseline Tregs did not predict CR, EFS, or OS. However, there were more relapses in those with high baseline Tregs.
Minimal residual disease by flow cytometry at the end of chemotherapy for remission induction in pediatric patients with acute lymphoblastic leukemia: Experience from a center in a low-income country.
Authors: Perez Eloy , Cruz-Borja Primo , Chavez-Gallegos Silvia
Published: March 2020

9554

Background: The presence of minimal residual disease (MDR) following therapy for acute lymphoblastic leukemia (ALL) has been shown to be an important prognostic marker in many studies. MRD is typically detected either by polymerase chain reaction amplification or by flow cytometry. Flow-based MRD assessment has the potential for rapidly identifying patients at increased risk of relapsed, allowing for prompt changes in therapy, including earlier intensification. There are not many information about the response by MRD in countries with limited resources. Methods: The patients included were 90 ALL patients treated at the Hospital Infantil de Morelia from June 1, 2009 to January 5, 2012. MRD positivity (+) was defined as >0.01% of the gated population. Results: MRD was obtained in 90 patients, 38 males and 36 females. The median age was 7 years (10 months to 15 years). The levels of MRD were: <0.01, 74 (82.2%), 0.01-1%, 9 (10%), ≥1%, 7 (7.7%). There was not a statistically significant association between the most important ALL prognostic factors (Gender, Age at diagnosis, White blood cell count at diagnosis, Central Nervous System disease, Prednisone response, DNA Index, Immunophenotype). Conclusions: The good response found is similar to that reported by international groups, a situation which suggests that the response to chemotherapy is appropriate. However, cure rates are still not equal making it necessary to review institutional treatment protocols and social characteristics of the population to achieve cure rates reported by international groups.
Effect of insulin-like growth factor 2 gene expression on pleuropulmonary blastoma and embryonal rhabdomyosarcoma.
Authors: Venkatramani Rajkumar , Triche Timothy J. , Larry Wang , Wai Daniel , Shimada Hiroyuki , Schaub Betty , Mascarenhas Leo
Published: March 2020

9564

Background: The sarcomatous element in pleuropulmonary blastoma (PPB) often cannot be differentiated from embryonal rhabdomyosarcoma (ERMS) by histology, particularly when characteristic elements like cartilage and respiratory mucosa are inapparent. The initial diagnosis is often ERMS. A diagnosis of PPB is based on a combination of clinical (age, location) and pathologic features. We hypothesized that the sarcomatous portions of PPB are a form of ERMS indistinguishable from typical ERMS. We reasoned that a detailed comparison of RNA expression could clarify this hypothesis. Methods: Samples from 7 PPB patients were obtained from the rhabdomyosarcomatous portion of the tumor by macro-dissection after pathologic review of all material. Representative ERMS tumor tissue was selected from 21 ERMS cases. FFPE tissue scrolls from each case were analyzed using Affymetrix Human Exon arrays after RNA extraction with Agincourt Formapure extraction kit and amplification using the NuGEN Ovation FFPE WTA kit and labeling with the Encore Biotin Module. Data analysis utilized Partek and Genetrix software. Results: All PPB cases and 7 of 21 ERMS cases were < 4 years old. 20 transcripts (10 annotated, 10 non-coding RNAs) were significantly differentially expressed in ERMS when compared to PPB patients. Insulin-like growth factor 2 (IGF2) was uniformly overexpressed in ERMS (19/21 > 200) but was expressed at low levels in PPB (p<0.001). 2 ERMS cases which had low level IGF2 expression were < 4 years of age. Expression in the other 5 ERMS aged <4 years was similar to ERMS overall (range, 500-2,000). No other differences between the two approached this degree of significance, despite a common rhabdomyogenic phenotype in the sarcomatous areas of PPB. Conclusions: We conclude that PPB is a distinct entity from most ERMS, and is not driven by IGF2 signaling. Rare cases of ERMS in the very young are more similar to PPB than common ERMS. This observation is highly significant, as IGF2 is known to drive growth in ERMS, generally related to demethylation secondary to LOH of 11p.
Do children, adolescents, and young adults with soft tissue sarcoma benefit from early detection of recurrences? Results of a population-based study.
Authors: Dantonello Tobias M. , Winkler Peter , Kube Stefanie , von Kalle Thekla , Kosztyla Daniel , Handgretinger Rupert , Veit-Friedrich Iris , Kaatsch Peter , Fengler Ruediger , Bielack Stefan S. , Leuschner Ivo , Niggli Felix , Ljungman Gustaf , Klingebiel Thomas , Koscielniak Ewa ,   Cooperative Weichteilsarkom Studiengruppe (CWS)
Published: March 2020

9573

Background: Most patients with pediatric soft tissue sarcoma (PSTS) achieve a 1st remission with primary therapy, but recurrences are frequent and drive mortality. Relapse detection (RD) is the foundation of post-treatment surveillance. The rationale for frequent follow-up investigations is RD in an early stage with better salvage options. There is however little evidence regarding the value of early asymptomatic RD and it was not investigated by any larger or population-based study in PSTS. We determined whether early radiographic RD in asymptomatic patients improves post-relapse outcome. Methods: Patients aged < 18 years at first reference-reviewed PSTS-diagnosis registered with CWS were enrolled if a 1st relapse occurred between 1/2003 and 7/2010. The methods of RD and their impact on outcome were evaluated. The data were correlated with the German Childhood Cancer Registry (GCCR), which receives all information about cancer patients < 18 years. Results: 235 patients from Germany (n = 212) and Sweden/Switzerland (n = 23) were eligible. In 2010 all German PSTS-patients were registered both with the GCCR and CWS. The most common PSTS-histiotypes were embryonal (n = 76) and alveolar (n = 74) rhabdomyosarcoma. 156 patients had primary nonmetastatic PSTS. The median time to relapse diagnosis (TTRD) was 1.4 years. 118 recurrences were locoregional, 38 combined and 79 metastatic. In 229 patients, the methods leading to RD could be evaluated. 139 recurrences were detected because of clinical signs and symptoms, primarily observed by patients and/or parents in 72%. 90 RDs were radiographic in asymptomatic patients. TTRD did not differ between symptomatic and asymptomatic patients. As of 12/2011, 77/235 patients are currently alive with a median follow-up of 5.4 years. Overall survival from primary surgery at 3-, 5-, and 10-years for all 235 patients was 49%, 34% and 22%. It was 43%, 29% and 23% for the symptomatic and 59%, 40% and 21% for the asymptomatic group (p = 0.05). Conclusions: In this series, early radiographic RD in asymptomatic PSTS-patients had no significant impact on TTRD or post-relapse survival, although asymptomatic patients tended to survive longer.
A multidisciplinary treatment comprising standard chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide for Ewing sarcoma family of tumor (ESFT) in Japan: Results of the first Japan Ewing Sarcoma Study (JESS) 04.
Authors: Makimoto Atsushi , Chin Motoaki , Sumi Minako , Yokoyama Ryohei , Ishida Tsuyoshi , Okita Hajime , Matsuzaki Akinobu , Kikuta Atsushi , Watanabe Hiroyoshi , Ozaki Toshifumi , Isu Kazuo , Yano Michihiro , Hatori Masahito , Tsurusawa Masahito , Ohta Hideaki , Kawano Yoshifumi , Ishii Takeshi , Kawamoto Hiroshi , Morita Satoshi , Mugishima Hideo ,   Japan Ewing Sarcoma Study Group (JESS)
Published: March 2020

9574

Background: Survival rate of ESFT in Japan was reportedly less than 50% in 1990s. The JESS started in order to improve this condition by conducting clinical trials for ESFT in Japan. Methods: This is a phase II, non-randomized trial to test safety and efficacy of multidisciplinary treatment for non-metastatic ESFT. Age under 30 is eligible. Chemotherapy regimens are alternating vincristine 1.5 mg/m2 on day 1, doxorubicin 37.5 mg/m2 on days 1 and 2, cyclophosphamide 1200 mg/m2 on day 1 (VDC) and ifosfamide 1800 mg/m2 on days 1 through 5 and etoposide 100 mg/m2 on days 1 through 5 (IE) repeating every 21 days for 52 weeks. Local treatment includes surgical resection and/or radiation therapy, of which dosage varies from 0 to 55.8 Gy based on margin of the resection and pathological response. Primary endpoint is 3 year progression free survival (PFS). Statistical design was made to test whether the lower limit of 90% confidence interval (CI) of PFS will exceed the threshold of 60%. Planned sample size is 53 patients including 10% ineligible patients. Results: Fifty-three patients were registered from December 2004 to May 2008. Among the 53 patients, 7 patients were judged ineligible after the registration (metastatic disease 1, changed diagnoses 6). Forty six patients were considered as per protocol set and used for efficacy analyses. Three year PFS is 71.7% (90% CI: 0.59 – 0.81). Estimated 5 year PFS and OS are both 69.6%. Radiographic response rate (RR) in evaluable 38 patients is 71.1% and pathological RR in 25 is 52.0%. In safety data, hematological toxicities are significant such as grade 4 neutropenia observed in 98%. Although there is no previously unknown adverse event reported, there are three patients who experienced secondary malignancies (ALL 1, MDS 1, osteosarcoma 1). Conclusions: A multi-disciplinary treatment comprising standard multi-agent chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide improved outcome of Ewing sarcoma family of tumor in Japan although statistical confirmation of absolute efficacy was not successful.
A phase II trial of docetaxel and irinotecan (DI) in children and young adults with recurrent or refractory Ewing sarcoma family of tumor (ESFT).
Authors: Yoon Jong Hyung , Park Hyeon Jin , Park Byung-Kiu
Published: March 2020

9579

Background: Patients with ESFT resistant to second-line therapy, such as topotecan plus cyclophosphamide, have a dismal prognosis and few therapeutic options. Docetaxel (D), a microtubule inhibitor, demonstrated activity in patients with ESFT (Zwerdling T et al. Cancer 2006:106:1821-1828). Irinotecan (I), a toposiomerase I inhibitor, is being evaluated in clinical trials for ESFT. Despite the different mechanisms of action of D and I, and their activities as a single-agent against ESFT, DI combination has not been previously evaluated in ESFT. Thus, we prospectively performed a single-arm, phase II trial of DI in a single center in Korea. Methods: Patients <30 years with ESFT, who failed second-line therapy, were eligible for the study. D was administered IV over 60 minutes at a dose of 100 mg/m2 on Day 1, and I at a dose of 80 mg/m2 over 90 minutes on Days 1 and 8 of a 21-day cycle until disease progression. The primary end-point was objective response assessed by RECIST; the secondary end-point was safety. All toxicities were graded according to the National Cancer Institute’s Common Toxicity Criteria (version 4.0). Results: Of seven eligible patients (4 males; median age, 17 years (range 5-21)), 4 were recurrent/refractory cases, and 3 refractory cases. Median number of previous regimens was 6 (range 3-6). One CR, 1 PR, and 5 PD were obtained by DI combination (median number of cycles, 2 (range 1-15)), with objective response (CR+PR) rate of 2/7 (28.6%). One patient with PR achieved CR with subsequent surgery. CR of these two patients lasted 8.9 months and 10.6 months. Of all seven patients fully evaluable for toxicity, grade 4 neutropenia occurred in 7 (100%); grade 3 and 4 thrombocytopenia in 1 (14%) and 6 (86%), respectively; grade 3 pericardial effusion, paresthesia, motor weakness, oral mucositis, each in one (14%). Two patients required ≥1 dose delay; 2 required ≥1 dose reduction due to adverse events, but no one experienced treatment-related mortality. Conclusions: DI combination demonstrated activity in children and young adults with ESFT who were heavily pre-treated, and was feasible.
Integration of genomic and proteomic data to identify MYCN-regulated genes, proteins, and interaction networks in neuroblastoma cells.
Authors: Kristjansdottir Kolbrun , Bontempo Kelly M. , Regan Kelly E. , Khan Saira , Volchenboum Samuel Louis
Published: March 2020

9584

Background: Neuroblastoma is the most common extracranial solid tumor found in children. The most common marker prognostic of poor outcome is amplification of the MYCN oncogene, yet the biological programs by which MYCN affects its aggressive phenotype are largely unknown. In order to identify biological pathways affected by MYCN amplification, we performed global analysis of genes and proteins in the Tet 21/N neuroblastoma cell line. Methods: MYCN expression in Tet21/N cells is regulated by tetracycline. Gene arrays were performed on MYCN-high and MYCN-low Tet21/N cells and SH-EP parental cells using Affymetrix GeneChip Human Exon 1.0 ST. For proteomic analysis, the cells were labeled with stable isotopes for relative quantitation, enriched for phosphoproteins to enhance detection of signaling proteins, and analyzed by GeLC-MS/MS analysis. Integrative pathway analysis was performed on the genomic and proteomic datasets using DAVE and GeneGo. Results: Integrating genomic and proteomic data in MYCN-high and MYCN-low expressing cells identified 88 proteins and 300 genes that change in abundance. We compare these results with previous studies and find both novel and previously identified genes and proteins. Integrating proteomic and genomic data identified over 50 gene products that are present in both analyses and are altered in abundance in response to modulating MYCN expression. The majority of these have discordant abundance changes, with protein levels more frequently altered with no change in gene expression. We have validated changes in protein levels using Western blots including NPM1 and MATR3. We present interaction networks and pathways that correlate with MYCN expression. Conclusions: We showed a significant discordance between gene and protein expression, underscoring the need for integrative genomic and proteomic analysis to describe complex systems. Our analysis identified previously reported and novel genes and proteins and networks regulated by MYCN expression that may provide new insights into the biology of MYCN-amplified tumors.
A national survey of general internists' preferences and knowledge gaps regarding the care of childhood cancer survivors.
Authors: Henderson Tara O. , Nathan Paul C. , Rasinski Kenneth , Suh Eugene , Kigin Mackenzie , Wroblewski Kristen , Ford Jennifer , Tonorezos Emily S. , Oeffinger Kevin C. , Daugherty Christopher
Published: March 2020

9586

Background: Although most childhood cancer survivors (CCS) report obtaining health care in the community, primary care physicians’ views and knowledge regarding the long-term follow-up (LTFU) care of CCS are largely unknown. Methods: Surveys were mailed to a random sample of 1,907 general internists under age 65 years from the American Medical Association Physician Masterfile in November 2011. A second mailing to non-responders is ongoing. Results: 892 (47%) physicians have responded. Respondents have practiced a median of 10 years (range: 3-20), and see a median of 70 patients/week (range: 40-100). 46% are in solo/group practice, 17% in multi-specialty practice, and 14% in academic practice. In the last five years, 53% have seen at least one CCS, 71% of whom have never received a treatment summary. 85% prefer to care for CCS in consultation with a cancer center based physician. A vignette of a 29-year-old female treated for Hodgkin lymphoma with mantle radiation at age 16 was provided and participants were asked a series of questions regarding monitoring for late effects. The percentage of responses that were concordant with available LTFU Surveillance Guidelines were: breast cancer, 29%; cardiac, 15%; thyroid, 77%; and all three recommendations, only 5%. By logistic regression, greater likelihood of concordance with at least one surveillance recommendation was associated with being female (OR=2.0 95% CI 1.3-3.1), seeing more patients/week (OR=1.4 per SD increase, 95% CI 1.1-1.7) and more years in practice (OR=1.3 per SD increase, 95% CI 1.0-1.6). The two modalities felt to be most useful for independent care of CCS by internists were access to LTFU guidelines and receiving a patient-specific care plan from the cancer center. Conclusions: Although the majority of internists are willing to follow CCS, they appear unfamiliar with the available LTFU guidelines and prefer to care for patients in collaboration with a cancer center based physician.
Patient preference between pazopanib (Paz) and sunitinib (Sun): Results of a randomized double-blind, placebo-controlled, cross-over study in patients with metastatic renal cell carcinoma (mRCC)—PISCES study, NCT 01064310.
Authors: Escudier Bernard J. , Porta Camillo , Bono Petri , De Giorgi Ugo , Parikh Omi , Hawkins Robert E. , Sevin Emmanuel , Negrier Sylvie , Khan Sadya , McCann Lauren , Mehmud Faisal , Cella David
Published: March 2020

CRA4502

The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Saturday, June 2, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Evaluation of variables that may impact the use of Oncotype DX testing.
Authors: Szabo Stephen , Gilmore James W. , Haislip Sally , Hassell Robert , Cooper Joseph , Richardson Steve , Fitzgerald Meghan , Feinberg Bruce A.
Published: March 2020

e11002

Background: Cardinal Health Specialty Solutions (CHSS) partners with payers to manage clinical care pathways in oncology and rheumatology. Observations from one such pathway with CareFirst BlueCross Blue Shield revealed that in patients with estrogen receptor-positive early-stage breast cancer (ESBC), there was an underuse of Oncotype DX testing. To better understand physician behavior as it relates to Oncotype DX testing, CHSS examined patterns of Oncotype DX use in a large private practice oncology group with a robust electronic medical record (EMR), Georgia Cancer Specialists (GCS). We aimed to determine the variables that most impacted the use of Oncotype DX testing. Methods: Using the GCS EMR from 2009 to 2011, we retrospectively identified patients diagnosed with ESBC who were eligible for Oncotype DX testing (stage I-II, node-negative, estrogen receptor-positive, HER2-negative). The use of Oncotype DX testing was analyzed by patient age, tumor size, tumor grade, and physician prescribing patterns. Results: Of the 1908 patients identified with ESBC, 788 were eligible for Oncotype DX testing and 288 (37%) underwent testing. In an analysis by age, Oncotype DX was utilized in 34% of patients ≤ 45 years, 49% in patients 46-55 years, 37% in patients 56-65 years, 34% in patients 66-75 years, and 13% in patients > 75 years old. Oncotype DX use was 37% and 36% in patients with tumor sizes <2 cm and 2-5 cm, respectively; and, 45%, 43%, and 67% in patients with grade 1, 2, or 3 tumors, respectively. Of the 41 physicians who were evaluated, 10 (24%) used Oncotype DX <15% of the time, 13 (32%) used Oncotype DX 15-40%, 10 (24%) used ODX 41-60%, and 8 (20%) used Oncotype DX > 60% of the time. There were no significant differences in patterns of chemotherapy use. Conclusions: Based on this analysis, eligible patients with ESBC between 46-55 years of age, with small and intermediate sized tumors (<2-5 cm), and with grade 3 tumors were most likely to undergo Oncotype DX testing. Although some trends in use were observed with specific tumor characteristics, physician behavior (choice) was the most significant variable in Oncotype DX testing.
Loss of nuclear p27KIP1 (p27) expression as a predictor of lymph node spread in T1 breast cancer.
Authors: Ling Huichung Tina , Smith Julia Anne , Kwa Maryann , Dilawari Asma Ali , Cangiarella Joan , Goldberg Judith D. , Hochman Tsivia , Andreopoulou Eleni , Guth Amber Azniv , Roses Daniel F. , Formenti Silvia , Muggia Franco
Published: March 2020

e11010

Background: We originally reported that p27 loss in T1a/b breast carcinomas was associated with lack of estrogen and progesterone (ER/PR) hormone receptors, but not in T1c node negative tumors (Mirchandani et al, Anticancer Research 2011). The current study explored the association of p27 expression with lymph node (N) status. Methods: 217 consecutive patients with T1 tumors were identified from 2001-2003. All patients underwent sentinel node biopsy (and complete lymphadenectomy when positive on frozen section): 111 were N0 and 106 were N+. Immunohistochemistry was performed for ER/PR, Her2, and nuclear p27 (low vs normal) and tumors were graded (well, moderate, and poorly differentiated). Analysis was conducted to define associations between standard variables and p27 expression among node positive and node negative tumor carriers (Table). Results: Low p27 expression was found in 21% of N0 and 36% of N+ T1 breast cancer patients (Chi-square=6.14, p-value=0.01). However from a series of multivariable analyses, only tumor size was significantly associated with node positivity. Conclusions: Poorly differentiated tumors, T1c tumors, and low p27 expression were associated with lymph node positivity, but only tumor size was significant in multivariable analysis. Contrary to our prior report, the relationship between low p27 and ER/PR- is strongest in the T1c subset (data not shown). Future studies will expand study cohorts to explore whether low p27 expression is a biomarker of poor outcome at 10 years in patients with T1 tumors treated with antiestrogens. [Table: see text]
Predicting Oncotype DX score with clinicopathological variables.
Authors: Ramos-Lamboy Valmarie , Cabanillas Fernando , Echenique Miguel M. , Carlo Victor , Negron Viviana , Pavia Orestes Antonio , Bruno Margarita , Santiago Karen J.
Published: March 2020

e11015

Background: Oncotype Dx (OD) is a commercially available gene-profiling test that has been shown to be effective in predicting risk of recurrence after therapy with CMF or Tamoxifen. The aim of our study is to develop a method that uses easily available clinical data to predict cases with favorable OD category (ODC). Methods: We identified 145 ER+/Her-2 neg cases that had information on histologic grade (HG), PR status and Oncotype Dx Category (ODC). Of these, 75 also had information on Ki-67. We evaluated HG, ER status, PR status, Nottingham score and tumor size for their correlation with ODC using multiple regression analysis. Results: The median tumor size was 12.0 mm (0.6-45). 33.7% were HG 1, 54% were grade 2, and 12% were grade 3. 88% were invasive ductal carcinomas, 9% were invasive lobular carcinomas, 3% were other types. The median OD score was 15 (0-57) with 86 (59%) ODC=1, 53 (37%) ODC=2 and 6 (4%) ODC=3; median Ki-67 was 11% (1-50). In a multivariate analysis excluding Ki-67, the only factors that were significantly correlated with ODC were PR status and HG (p= 0.004). PR status had the strongest overall association with ODC (P=0.008). Defining PR> 60% with HG=1 as a positive result we calculated the positive predictive value (PPV) or the capacity to predict cases with ODC=1, as 85% and negative predictive value (NPV) as 46%. None of the cases with PR> 60% and HG=1 had an ODC=3 (high risk). A patient with a favorable ODC=1 was considered as a positive case for purpose of calculating PPV, NPV, sensitivity and specificity. Sensitivity to detect positive cases was 26% and specificity was 93%. We explored a 2nd model that included Ki-67 and found that only PR >60% and Ki-67 >11% significantly correlated with ODC (p=0.004). PR status again had the strongest overall association with ODC (P=0.007) followed by Ki-67 (P=0.019). HG was not significant in the 2nd multivariate model because of its strong correlation with Ki-67. PPV for this 2nd model was 79% and NPV=50%. Conclusions: 1-Pts who have PR>60% with HG=1 are highly likely to have a favorable ODC=1, however the ODC of pts with either PR<60% or HG>1 is not predictable with either of our two models. 2- The use of Ki-67 doesn’t add much to the capacity of the model to predict ODC. 3- PR is the strongest predictive factor in the model.
Association of response to neoadjuvant chemotherapy (NAC) in premenopausal patients with hormone receptor-positive early breast cancer with chemotherapy-induced ovarian function suppression by NAC.
Authors: Yamamoto Yutaka , Yamaguchi Risa , Fujiki Yoshitaka , Ibusuki Mutsuko , Murakami Keiichi , Iwase Hirotaka
Published: March 2020

e11017

Background: The purpose of this study is to assess the additive endocrine effect by chemotherapy-induced ovarian function suppression (CIOS) for premenopausal women with early breast cancer in neoadjuvant chemotherapy (NAC). Methods: We retrospectively compared the clinical efficacy to NAC between premenopausal and postmenopausal patients with early breast cancer to evaluate the endocrine effect by CIOS. One-hundred twenty two patients received NAC with anthracycline-containing regimen and/or taxane in Kumamoto University Hospital between April 2004 and March 2011. Results: Objective response rate by NAC in premenopausal ER-positive/HER2-negative patients is greater than that in postmenopausal ER-/HER2+ patients (premenopausal 93% vs. postmenopausal 63%, p=0.0121). Reduction rate of primary tumor by NAC on imaging studies in premenopausal ER+/HER2- patients is greater than that in postmenopausal ER-/HER2+ patients (premenopausal 54% vs. postmenopausal 40%, p=0.006). However, no significant difference in response rate between in premenopausal patients with other subtypes and postmenopausal patients with those was found (ER+/HER2+; premenopausal 50% vs. postmenopausal 48%, ER-/HER2+; premenopausal 43% vs. postmenopausal 77%, Triple-negative; premenopausal 86% vs. postmenopausal 65%). All of premenopausal women were suppressed ovarian function within two months after initiation of NAC. Expression levels of progesterone receptor on primary tumor in premenopausal ER+ cancer were significantly decreased after NAC compared with that in postmenopausal ER+ cancer (premenopausal -40.3% vs. postmenopausal +3.6%, p<0.001). Conclusions: These data suggests that CIOS by NAC contributes the additive effects through the endocrine fashion in premenopausal patients with ER+/HER2- breast cancer.
Estimation of maximum tolerated dose and minimum efficient dose of BP-C1 in the treatment of stage IV breast cancer patients: A phase I response surface pathway designed study.
Authors: Larsen Stig Einride , Dewi Sagita , Srimuninnimit Vichien , Lu Yen-Shen , Manuaba Tjakra , Jensen Steen Lindkaer
Published: March 2020

e11022

Background: The aims were to establish a treatment routine and to estimate the Maximum Tolerated Dose (MTD) and the Minimum Efficient Dose (MED) of a novel anti-cancer agent named BP-C1. Methods: The material consists of 15 Stage IV breast cancer patients with a mean age of 51 years. The study was performed as a non-randomized multi-centre trial with between patient 3-level Response Surface Pathway design. BP-C1 was given intramuscularly once daily during 32 days. The given cumulative dose window was 0.16 to 1.12 mg/kg bw, resulting in a starting dose of 0.64 mg/kg bw. The main variable was the National Cancer Institute common toxicity criteria (NCI-CTC) Bethesda. If the increase in toxicity was classified as moderate or less, the next patient in the sequence was allocated to an increased dose. In case of severe toxicity increase, the dose was reduced. Patients receiving cumulative dose of 0.96 mg/kg bw or higher was defines as the high-dose group. Results: Three of the five patients on the first design level recorded unchanged toxicity, one mild and one moderate increased Max NCI-CTC. Of the four patients receiving 0.96 mg/kg bw, three obtained no change and one a mild toxicity increase. The four patients on the third design level received the maximal dose of 1.12 mg/kg bw without any change in Max NCI-CTC. The Sum NCI-CTC increased (p= 0.07) in the low-dose group, but reduced (p=0.09) in the high-dose group. The cumulative dose of BP-C1 was found significantly (p=0.048) and negatively correlated (r = - 0.52) to the increase in toxicity. Only mild to moderate Adverse Events were reported and the prevalence was found largest in the high dose group (p=0.06). In the high-dose group 62.5% of the patients were classified as responders compared to 28.6% in the low-dose group. One of the patients in the high-dose group was classified as complete responder. The development in both Karnofsky Scale of Performance Status and patient wellbeing was found obviously better in the high-dose group. Conclusions: BP-C1 can safely be administrated continuously during a period of 32 days. The MTD seem to be at least 1.12 mg/kg bw and the MED to be 0.96 mg/kg bw.
Comparison of breast cancer subtypes detected by mammography screening and tumors diagnosed with palpable masses.
Authors: Gomez Raposo Cesar , Suarez-Garcia Ines , Lopez-Gomez Miriam , Esteban Isabel , Andreu Monica , Vazquez Osorio Jose Lorenzo , Sereno Maria , Zambrana Tevar Francisco , Merino Maria , Carballo Mar , Garcia de Santiago Clara , Heras Javier , Pelayo Eva , Dominguez Franjo Purificacion , Alvarez Bernardi Julio , Casado Enrique
Published: March 2020

e11028

Background: Recent studies have reported a greater mean breast density associated with estrogen receptor (ER)-positive disease than with ER-negative tumors, but controversial results have been published. The purpose of our study was to compare the difference in the distribution of breast cancer subtypes detected either by mammography screening or tumors diagnosed with clinically palpable masses in our centre. Methods: Between June 2008 and December 2011 157 patients with age between 40 and 70 years-old were diagnosed of early stage breast cancer. Tumors were classified in three major breast cancer subtypes by immunohistochemistry: TN (ie, ER, PR and Her2 negative), Her2-positive (ie, Her2 positive; ER and PR may be positive or negative), and ER-positive/Her2 negative (ie, ER positive, Her2 negative, PR may be positive or negative) types. Tumor characteristics and type of diagnosis (mammography screening or palpable masses) were obtained by retrospective chart review. Associations between categorical variables were evaluated with the X2 test. Results: Seventy patients (44.6%) were diagnosed of breast cancer with screening mammography, whereas 85 (54.1%) cases were detected by clinical suspected masses. Distribution according to molecular subtype defined by IHC were as follows: 123 (78.3%) ER-positive/Her2-negative tumors, 15 (9.6%) TN tumors, and 19 (12.1%) Her2-positive tumors. Less Her2-positive and TN tumors were significantly diagnosed with mammography screening (p=0.039 and p=0,020, respectively). No statistical differences were showed between ER-positive/Her2-negative tumors diagnosed with mammography screening and clinical palpable masses (p=0.78). Conclusions: The results presented in our study suggest that biologically aggressive subtypes of breast cancer are less frequently diagnosed with mammography screening in comparison with ER-positive/Her-2 negative tumors. Nevertheless, given the limited number of patients included and the bias related to retrospective studies these results must be interpreted with caution.
The effect of cholesterol depletion in resistant breast cancer cells.
Authors: Villeda Virgilio Alexander , Benakanakere Indira , Freter Carl
Published: March 2020

e11031

Background: A leading cause of breast cancer chemotherapeutic treatment failure is resistance of cancerous cells towards current anti-estrogen agents. This project investigated the relationship between inhibition of cholesterol synthesis and its effect on resistant breast cancer cells. Methods: MCF-7 cells were maintained in phenol red free media and pretreated with charcoal stripped media for 24 hours prior to the experiments (ensure all exogenous estrogen was taken out). Cells were plated in 96 well plates at 10,000 to 15,000 cells/well. MCF-7 cells were tested for their sensitivity to BIBB515 and whether the proliferation of cells with estrogen could be blocked with BIBB515. The cells were grown for 6 days, on day 7 the cell proliferation was determined by adding MTT and read at 570nM. Results: Estrogen, tamoxifen and anastrazole induced cell proliferation that was controlled by 10µM BIBB515. Inhibiting the cholesterol pathway in combination with tamoxifen induced cell death in MCF-7 cells (cell proliferation of 0.13 ±0.15) compared to tamoxifen alone (0.57±0.041) p<0.001 by one way ANNOVA and multiple comparison by DUNN test. Anastrozole alone induced statistically significant cell proliferation 0.403 ±0.03 compared to combination treatment with BIBB515 (0.05 ± 0.007 p<0.001 by one way ANNOVA and multiple comparison by DUNN test). BIBB515 treatment could also inhibit the estrogen induced cell proliferation in MCF-7 cells. These results indicate that cholesterol inhibitors can be developed to fill a niche area in breast cancer disease management where clinicians would prolong treatment on first-line anti-hormone therapies of tamoxifen and anastrazole for advanced disease patients. Conclusions: Results show that inhibition of cholesterol sensitizes resistant cells to current anti-estrogen chemotherapeutic agents. This finding is significant because it could potentially translate into reduce rates of breast cancer relapse due to regiment failure. Exploiting this mechanism could alter the current treatment regimens, leading to control of the diseases in advanced stages by either inducing tumors to be static or to regress. This strategy may also limit the toxicities involved with chemotherapy.
Evaluation of the Oncotype Dx recurrence score (RS) in hormone-positive ipsilateral breast tumor recurrences.
Authors: Wapnir Irene , Florero Marilyn
Published: March 2020

e11032

Background: IBTR (ipsilateral breast tumor recurrence) is considered a marker of risk for metastasis. Most IBTRs occur in the vicinity of the index tumor while elsewhere recurrences may represent new primaries. Oncotype DX®, 21-gene expression assay, quantifies a recurrence score (RS) in node negative, ER+ breast cancer. This modality can guide treatment decisions and has been extended to select node positive patients. Concordance of RS between the primary and IBTR is presented here. Methods: Archival blocks corresponding of 11 patients were obtained but only 8 were evaluable. The blocks were submitted using a blinded identification scheme to link the primary and recurrent tumor blocks. All were ER positive breast cancers. Six were N0, one N1, and one NX. Some assay results were preexisting. RS and single gene expression profiles for ER, PR and HER2 were compared. Scatterplots and descriptive statistics were produced for this exploratory hypothesis-generating (but not hypothesis-testing) study. Results: The time interval between primary and recurrence ranged from 12 to 216 months (mean 73.5 months). Among the 8 paired samples, RS’s were similar in 5 and different in 3. In the latter, RS shifted from 2 to 29, 15 to 23 and 25 to 14. These IBTRs occurred in a different quadrant, were simultaneous with axillary recurrence, or appeared after trastuzumab therapy. Overall, the Pearson correlation coefficient was 0.68 (95% CI -0.09, 0.93). Only one case shifted from ER+ to ER-; two cases from PR+ to PR- and one from PR- to PR+. No change in HER2 status was noted. The paired differences for ER were -0.01 (95% CI -1.09, 1.07), PR -0.74 ( 95% CI -2.43, 0.96) and HER2 -0.51 (95% CI -1.20, 0.17). The Pearson correlation coefficients and 95% CI were ER 0.72 (-0.02, 0.94); PR 0.61 (-0.22, 0.91); and HER2 0.89 (0.45, 0.98) respectively. Conclusions: The RS of the IBTR was similar to primary breast cancer in 5 of 8 cases in this exploratory pilot study. Hormone receptor status changed in only one of 8 cases. The clinical significance of these observations and the utility of these results in guiding therapeutic strategies is unknown.
Safety of trastuzumab, alone or in combination, in elderly patients with HER2-positive breast cancer: A 5-year case series.
Authors: Adamo Vincenzo , Ricciardi Giuseppina R. R. , Adamo Barbara , Ferraro Giuseppa , Franchina Tindara , Rossello Rosalba , Zanghì Mariangela , Russo Antonio , Valerio Maria Rosaria , Caristi Nicola
Published: March 2020

e11056

Background: Breast cancer (BC) is frequent in the elderly and is burdened by high recurrence and death rates, due mostly to undertreatment. Trastuzumab (T), in combination with chemotherapy (CT) or hormonotherapy (HT), is a well-established treatment strategy for early and advanced HER2-positive (HER2+) breast cancer, but has been poorly studied in the elderly setting due to its infrequency. The aim of our study is to assess the safety of T in elderly patients with HER2+ BC. Methods: Between 2005 and 2010, consecutive HER2+ breast cancer patients of ≥70 years of age referred to two oncology centers and that received T-based therapy were retrospectively reviewed. All patients were treated according to multidimensional geriatric assessment (MGA) and clinical criteria. Results: Of 59 patients, 51 were evaluable with a mean age of 76 years (range 70-86). Trastuzumab was well tolerated overall. Median left ventricular ejection function (LVEF) at baseline was 61% and at the end of treatment was 55%. The most relevant adverse events consisted of only one case (2%) of symptomatic congestive heart failure, which required treatment withdrawal and six (12%) asymptomatic decreases of LVEF (3 pts >15% and 3 pts >10% versus baseline). Mild to moderate hypersensitivity reactions associated with T-containing infusions occurred in 3 patients (5.8%). Hypertension, obesity and previous anthracycline-based treatment and combination with CTs gave a trend towards a higher incidence of toxic events. Previous radiotherapy, concurrent HT and the different T schedules did not influence toxicity. Conclusions: Our data shows a good trastuzumab safety profile in non-frail women age 70 and older. These favourable findings may be related to the limited number of anthracycline pre-treatments, a substantial patient selection by MGA and close cardiologic monitoring. [Table: see text]
Hormone replacement therapy and its effect on HER2 neu status in primary breast cancer.
Authors: Khair Tina Ashley , Mittar Priyanka , Boolbol Susan K. , Boachie-Adjei Kwadwo , Klein Paula
Published: March 2020

e11057

Background: Controversy has developed over the use of hormone replacement therapy (HRT) and its association with the future risk of breast cancer. The biology of breast cancer diagnosed after the use of HRT is different than in non HRT users. One such pathologic feature that may be affected by the use of HRT is HER2 neu. While there is existing data illustrating the relationship between HRT and breast cancer, there is little data examining the relationship between HRT and HER2 neu. The purpose of this study is to investigate that relationship and determine whether or not the use of HRT has any effect on the HER2 neu status of primary breast cancers. Methods: A retrospective review of a prospective database identified 2,928 patients with primary breast cancer with a history of prior/current HRT use. Tumor specimens were evaluated for HER2 neu expression at the time of surgery using either IHC or FISH. Pearson’s χ² test along with evaluation of odds ratios were used to determine whether or not there was an association of HER2 neu expression with HRT use. Results: Table 1A illustrates the lack of a correlation between increasing HER2 expression and HRT. There was no significant change in odds of HRT use as HER2 expression increased. After confirming HER2 neu status using FISH, the odds of HER2 positivity among HRT users was OR= 1.05 times the odds of HER2 neu positivity among non-HRT users [C.I. 0.85, 1.29; p = 0.63] (Table 1B). Conclusions: Contrary to our expectation of an inverse relationship between HRT use and HER2 negative phenotype, we found no clear association between the two. Limitations of this study include the inability to discriminate from our data set between current and prior users, and between estrogen alone and combination estrogen/progesterone supplementation. Additionally, the definition of HER2 positivity by membranous staining has changed over the last decade, which may be contributory. We plan on determining the relationship between HER2 status and ER status as it relates to HRT use in future studies. [Table: see text] [Table: see text]
Development of preclinical models of human BT474 and MDA-MB-361 breast cancer that endogenously overexpress HER2 and that respond to trastuzumab.
Authors: Francia Giulio , Rodriguez Cynthia , Xu Ping , Man Shan , Cruz-Munoz William , Bocci Guido , Kerbel Robert S
Published: March 2020

e11061

Background: The anti-Her-2 antibody trastuzumab can be effectively combined with chemotherapy to treat Her-2 positive metastatic breast cancers. However, Her-2 positive breast cancers readily develop resistance to trastuzumab based therapies, and new models are needed to study such resistance, and to find new therapeutic options. Methods: We began the in vivo selection of human Her-2 positive breast cancer cell lines, BT474 and MDA-MB-361, in Severely Compromised Immunodeficient (SCID) mice. Tumor cells were implanted orthotopically into the mammary fat pad of SCID mice, and resulting tumors were serially passaged into new hosts over a 3 year period. Results: The resulting variants grow rapidly in SCID mice. Variants of both BT474 and MDA-MB-361 respond in vivo to trastuzumab monotherapy (20mg/kg twice weekly, i.p.) compared to controls (p<0.05). After 2-6 months of trastuzumab monotherapy, all variants developed resistance to trastuzumab; such resistant variants were adapted to tissue culture. BT474 variants produced a spontaneous lymph node metastasis in SCID mice, 10 months after the surgical resection of the orthotopically implanted primary tumor; this metastatic variant was also adapted to tissue culture. BT474 variants were tagged with luciferase and then implanted intracranially into SCID mice; the progressive growth of the tumors cells in the mouse brain was thereafter monitored for 3 months by bioluminescence imaging, which provides ample opportunity to test new treatments for brain metastases. MDA-MB-361 variants growing orthotopically responded (i.e. p<0.05 vs. controls) to the combination therapy of trastuzumab (20mg/kg twice weekly, i.p.) plus chemotherapy; chemotherapy consisted of a bolus of cyclophosphamide (CTX, 100mg/kg, i.p) followed by a maintenance metronomic CTX (20mg/kg/day, p.o.) regimen. Conclusions: We developed two preclinical models of human Her-2 positive breast cancer which may be used to study trastuzumab based therapies, Her-positive metastatic breast cancer, the growth of Her-2 positive breast cancer at a secondary site (i.e. the brain), as well as the evolution of tumor resistance to trastuzumab based therapies.