bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of routine tumor genotyping on enrollment in targeted therapy trials for metastatic breast cancer (MBC): 4-year review.
Authors: Bardia Aditya , Juric Dejan , Isakoff Steven J. , Borger Darrell R. , Dias-Santagata Dora , Higgins Michaela Jane , Iafrate Anthony John , Flaherty Keith , Moy Beverly , Ellisen Leif William
Published: February 2017

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Background: Major barriers to enrollment in therapeutic clinical trials (<5% in United States) include low response rate in phase I/II trials and low enthusiasm among oncologists. Stratified clinical trial enrollment based on molecular profiling of tumors represents a potential paradigm shift in drug development. Here we assess the clinical utility of tumor genotyping for identification of oncogenic driver mutations and enrollment in therapeutic clinical trials for patients with metastatic breast cancer (MBC). Methods: A robust, high-throughput tumor genotyping assay (Snapshot), was developed at our institution to assess for presence of potentially actionable oncogenic driver mutations (15 genes, 130 mutations) using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. The tumor genotyping assay was ordered by oncologists in clinic for patients with MBC. Relevant clinical information was gathered from chart reviews. Descriptive statistics were used for analysis. Results: From 2009-2012, 347 breast tumors were prospectively genotyped in the study population (median age = 50, range 27-90). The common oncogenic mutations were seen in all breast cancer subtypes. PIK3CA mutation (23.3%) was the most common mutation detected overall, albeit at varying frequency in tumor subtypes: HR+ (29.1%, N= 210), HER-2+ (21.5%, N = 65), TN (8.3%, N = 72). Unanticipated mutations in KRAS, BRAF, IDH, and HER-2 were also discovered. Clinical genotyping helped identify breast origin for carcinomas of unknown primary and revealed changes in mutation profile in metastatic tumors from primary tumors. Enrollment in clinical trials for MBC almost quadrupled from 2005-2008 to 2009-2012, with approximately one-third of patients undergoing tumor genotype testing enrolling in clinical trials, particularly phase-I genotype-directed targeted therapy, such as PI3K inhibitor, Akt inhibitor, and PI3K/MEK inhibitor combination. Conclusions: Routine tumor genotyping can be successfully incorporated into clinical practice to significantly enhance therapeutic clinical trial enrollment and potentially accelerate development of genotype-directed targeted therapies for MBC.
Prospective observational trial of re-antiestrogen therapy after becoming resistant to ethinylestradiol treatment in hormone-dependent metastatic breast cancer.
Authors: Iwase Hirotaka , Yamamoto Yutaka , Ibusuki Mutsuko , Murakami Kei-ichi , Inao Touko , Okumura Yasuhiro , Omoto Yoko
Published: February 2017

161

Background: After heavily treated estrogen deprivation therapy by aromatase inhibitors (AIs), an additional estrogen therapy may be useful in a certain condition. Furthermore, the estrogen therapy might sensitize a subsequent anti-estrogen therapy after the acquired resistance to estrogen. Methods: In the patients who obtained disease control (SD or more) by ethinylestradiol (EE2) therapy (1.5-3mg TID), the efficacy of anti-estrogen therapy using AI or fulvestrant was examined as a subsequent endocrine therapy. Primary endpoint was clinical benefit rate (CBR), and secondary endpoints were response rate (RR) and time to treatment failure (TTF). (Registration; UMIN000002831, prospective observational trial, sub-protocol analysis) Results: EE2 therapy was performed in 22 of postmenopausal breast cancer patients with ER-positive HER2-negative in primary or recurrent tumor, who had heavily pre-treated by endocrine therapies, including chemotherapies. At the median observation period of 13.6 months, RR of 41% (9/22) and CBR of 50% (11/22) were obtained (CR; 0, PR; 9, long SD; 2, SD; 4, PD; 3) and 4 patients withdrew this trial due to adverse events of early endocrine related symptoms and cerebral infarction. Although two patients were still ongoing, the median of duration of disease-control was 46 weeks (range; 23-62+). In thirteen patients who obtained disease control (SD or more) by EE2 therapy, fulvestrant for 6 patients or AI for 7 patients was used as a subsequent therapy. Fifty percent of fulvestrant group (3/6) and 43% of AI group (3/7) showed clinical benefit (PR or long SD). TTF of fulvestrant group was 15 weeks (median; range; 5-55+) and that of AI group was 19 weeks (median; range 5-33+). Furthermore, two patients who were responders to previous AI, got long SD to the subsequent EE2 re-treatment. Conclusions: EE2 therapy after resistance to estrogen deprivation therapy could be very useful, and a subsequent anti-estrogen therapy by AI or fulvestrant could be also effective in a certain condition. Thus, the changes of the endocrine environment by EE2 may induce the sensitization to hormone dependency in acquired hormone-resistant tumors. Clinical trial information: 000002831.
Low-dose metronomic cyclophosphamide/methotrexate (LDCM) and aspirin for patients without pathologic complete response (pCR) after neoadjuvant treatment for stage II-III breast cancer.
Authors: Burdette-Radoux Susan , Holmes Chris E. , Khan Farrah B. , Dittus Kim , Wilson Karen M. , Wood Marie
Published: February 2017

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Background: Patients (pts) who fail to achieve pCR after neoadjuvant chemotherapy have a 20% risk of recurrence at two years. Data for effective postsurgical chemotherapy in this population is lacking. LDCM is an all-oral chemotherapy regimen with anti-angiogenic activity and acceptable toxicity in metastatic breast cancer. Aspirin is associated with a lower risk of breast cancer recurrence in retrospective studies and has anti-angiogenic activity. Here we combine LDCM and aspirin for high risk pts with poor response to neoadjuvant chemotherapy. Methods: Pts with stage II-III HER-2 negative breast cancer who had residual invasive cancer after neoadjuvant chemotherapy were eligible. Pts completed surgery and radiotherapy prior to enrolment and began study treatment within 180 days of surgery. Pts received four 28-day cycles of LDCM (cyclophosphamide 50 mg po daily, and methotrexate 2.5 mg po twice daily on days 1 and 2 each week ). Aspirin 325 mg daily was added on cycles 3 and 4. Pts were evaluated for the primary endpoint of toxicity and safety every 28 days. Secondary endpoint was 2 year relapse free survival. Results: 10 of 13 planned pts were evaluable for toxicity as of May 4, 2013. Pathologic stage ranged from T2N0 to T3N3. 70% of tumors were chemoresistant (stable or upstaged at time of surgery). 60% of pts had hormone receptor positive tumors and received concurrent hormonal therapy. Median age was 59 years (range 38-76). All pts completed 4 cycles of study treatment without dose reduction. There were no grade 3 or 4 related toxicities. Worst hematologic toxicity was grade 2 leukopenia. Worst nonhematologic toxicity was grade 2 fatigue; all other related toxicities were grade 1. 9 pts were evaluable for recurrence and one had recurred at a median followup of 16 months (range 10-26). Conclusions: This antiangiogenic regimen is well tolerated in patients at high risk for recurrence after neoadjuvant chemotherapy, resulting in one recurrence at 16 months median followup, and it may be a candidate for future trials in this setting. Subsequent analyses will include longer term followup and biomarkers for angiogenesis. Clinical trial information: NCT01612247.
Safety and feasibility of adjuvant chemotherapy with S-1 and concurrent radiotherapy for Japanese patients with breast cancer after primary systemic chemotherapy.
Authors: Shigekawa Takashi , Osaki Akihiko , Sato Nobuaki , Kanbayashi Chizuko , Sano Hiroshi , Saeki Toshiaki
Published: February 2017

165

Background: Advanced breast cancer can respond to S-1. Other oral fluoropyrimidine-based regimen, tegafur-uracil (UFT) was proven to be effective as adjuvant chemotherapy in Japanese breast cancer patients. Adjuvant chemotherapy with S-1 was useful in gastric cancer patients and S-1 with concurrent radiotherapy was safe and effective in several kinds of cancer patients. We tested S-1 and concurrent radiotherapy as adjuvant therapy in curatively resected breast cancer patients after standard primary systemic chemotherapy. Methods: Adjuvant chemotherapy with S-1 consisted of eighteen courses (2-week administration and 1-week withdrawal), at 80-120 mg/body per day. In cases judged to require postoperative radiotherapy, it was concurrently initiated on day1 of the study (a fractional daily dose of 1.8 Gy, up to a total dose of 50.4Gy). If estrogen receptor and/or human epidermal growth factor receptor 2 were positive, endocrine therapy and/or trastuzumab were permitted concurrently. Results: Among 45 patients enrolled between September 2007 and September 2009 from 3 institutions, 43 patients were eligible. 32 patients (74.4%) received concurrent radiotherapy. 22 patients (51.2%) completed the scheduled courses of chemotherapy. The most common reason for withdrawal of treatment was the request to discontinue in 8 patients (38.1%) between 6 courses of the beginning due to subjective symptoms, such as anorexia. It was followed by the detection of recurrence in 7 patients (33.3%). Among 36 patients without recurrence, the planned courses of S-1 were administered to 22 patients (61.1%), and the cumulative rates of administration for 365 days were 66.4% (95%CI: 50.8-79.1%). Although grade 3 neutropenia (8.9%), leukopenia (4.4%), and diarrhea (4.4%) were observed, they were manageable, and no grade 4 adverse effects appeared. Conclusions: Except for a relative many withdrawal of treatment due to subjective symptoms in early courses, adjuvant chemotherapy with S-1 and concurrent radiotherapy have an acceptable toxicity profile, and it seems feasible. A phase III trial investigating the usefulness of adjuvant S-1 is now ongoing in Japan.
Inhibition of cardiomyocytes late INa with ranolazine to prevent anthracyclines cardiotoxicity in experimental models in vitro and in vivo.
Authors: Maurea Nicola , Coppola Carmela , Piscopo Giovanna , Cipresso Clemente , Rea Domenica , Tocchetti Carlo G. , De Laurentiis Michelino , Arra Claudio , Iaffaioli Rosario Vincenz
Published: February 2017

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Background: Anthracyclines are first line drugs against cancer, but produce a well-known cardiomyopathy through multiple mechanisms, which also include Ca2+ overload due to reduced SERCA2a activity and inappropriate opening of the RyR2, and impaired myocardial energetics. Anthracyclines generate Reactive Oxigen and Nitrogen Species, posing the heart at increased demand for oxygen, thus setting the stage for a metabolic ischemia that also activates late INa, the target of ranolazine (RAN). Here, we aim at assessing whether RAN, diminishing intracellular Ca2+ through its inhibition of late INa, and enhancing myocardial glucose utilization (and/or reverting impairment of glucose utilization caused by chemotherapy) blunts anthracyclines cardiotoxicity. Methods: To assess for cardiotoxicity in vitro, rat H9C2 cardiomyoblasts were pretreated with RAN (0.1-1µM) for 72 hours and then treated with doxorubicin (DOX, 0.1 µM)for additional 24 hours. Cells counts were assessed by Trypan exclusion test. To evaluate cardiac function in vivo, fractional shortening (FS) and ejection fraction (EF) were measured by echocardiography in C57BL6 mice, 2-4 mo old, pretreated with RAN (370mg/kg/day, a dose comparable to the one used in humans) per os for 3 days. RAN was then administered for additional 7 days, alone and together with DOX (2.17mg/kg/day ip), according to our well established protocol. Results: After DOX, only 68% of the cells were viable. RAN alone did not affected cell survival, but blunted DOX toxicity, rescuing % cell survival to 87% (p=.01 vs DOX alone). In our in vivo studies, after 7 days with DOX, FS decreased to 50±2%, p=.002 vs 60±1% (sham), and EF to 81+2%, p=0.0001 vs 91+1% (sham). RAN alone did not change FS (59±2%) nor EF 89+1%. Interestingly, in mice treated with RAN and DOX, the reduction in cardiac function was milder: FS was 57±1%, EF was 89+1%, p=0.01 and 0.0009, vs DOX alone. Conclusions: RAN blunts DOX cardiotoxic effects in 2 different models, in vitro and in vivo. We plan to test RAN as a cardioprotective agent with other antineoplastic cardiotoxic drugs in our experimental models, and to better characterize the cardioprotective mechanisms of RAN in all these settings.
Open-ended concept elicitation with breast cancer (BC) patient advocates to inform patient-reported outcome (PRO) endpoints in neoadjuvant and adjuvant trials of trastuzumab emtansine (T-DM1).
Authors: Campbell Alicyn K. , Guardino Ellie , Caplan Elyse S. , Glazer Jenna , Sabelko Kimberly , Smith Mary Lou , Venticinque Joan , Wohl Hope
Published: February 2017

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Background: There is no standard for measuring health-related quality of life (HRQoL) using PROs in (neo)adjuvant BC clinical trials. Further, in (neo)adjuvant treatment (tx), pre-surgical cytotoxic therapy may initially worsen HRQoL. The development of tools to measure PRO endpoints in (neo)adjuvant clinical trials could be improved with a better understanding of the issues that impact HRQoL in this population. Patient (Pt) advocates, many of whom are BC survivors, may provide valuable insight to inform PRO strategy and optimal selection of PRO endpoints in clinical trials. Methods: A workshop with BC pt advocates was conducted to inform T-DM1 BC PRO strategy. It consisted of open-ended concept elicitation to identify symptomatology, tx-related side effects, and common reasons for tx discontinuation during (neo)adjuvant therapy for BC. Results: For younger pts, hot flashes and issues with sexuality and fertility were described as the most concerning issues. For older pts, peripheral neuropathy was described as the most concerning issue. Regardless of age, most pts reportedly struggle with cognitive dysfunction, anxiety, and depression. Chemotherapy-associated side effects considered most distressing to pts of all ages were alopecia, fatigue, diarrhea, neutropenia, peripheral neuropathy, and hand-foot syndrome (HFS). Neutropenia was considered most likely to cause a physician-instigated tx break, and HFS was most likely to precipitate a pt-instigated tx break. Assessing post-operative pain and satisfaction with post-surgical tx outcome (whether breast conserving or mastectomy) were emphasized. Conclusions: Open-ended concept elicitation with pt advocates is a collaborative and informative way to identify the most relevant concepts for further study. Increased collaboration with advocates to support qualitative research may improve the ability of trial results to assist pts in making informed tx decisions. Earlier engagement of pts and advocates can support the development of new PROs that offer more precision and inform PRO instrument selection to adequately quantify tx impact.
dtectDx Breast: A serum biomarker test for breast cancer detection used in conjunction with traditional mammography screening.
Authors: Henderson Meredith C. , Sweeten Keri , Borman Sherri , Corn Christa , Gordon Lindsey , Reese David E.
Published: February 2017

18

Background: Provista Diagnostics has developed a test that analyzes serum concentrations of 5 protein biomarkers in order to detect breast cancer. The dtectDx Breast test utilizes a proprietary algorithm that has been described previously (Weber et al. 2010). In this study, it was noted that the algorithm performs best in women under age 50. The aim of this study was to evaluate the performance characteristics of dtectDx Breast in women under age 50 in a commercial setting and compare the results with data from the previous clinical study. Methods: The dtectDx Breast test measures the concentrations of IL-8, IL-12, VEGF, CEA, and HGF via ELISA. These data combined with select patient characteristics and Provista’s proprietary algorithm result in a test value that is characterized as normal or elevated. dtectDx Breast test reports issued for women under age 50 were reviewed from a 3-year time period and prescribing physicians were interviewed regarding follow-up care and outcome measures (largely imaging studies, if warranted). Results: Of the 908 patients, 8 samples were rejected based on serum quality. Of the remaining 900 patients, 121 were reported as elevated (12.7%). In 4 cases, these elevated results were confirmed cases of breast cancer. Of these, 2 patients initially showed no screening evidence of cancer, but upon further evaluation (after receipt of dtectDx Breast results) were diagnosed with breast cancer. dtectDx correctly identified DCIS 66% of the time (n=2). Conclusions: These results describe the use of dtectDx Breast in a clinical setting and confirm that the assay behaves similarly to previously published results (Weber et al 2010). While the false-positive rate is higher than predicted (12.7% vs 6.8%), the assay correctly identified 4 of 4 invasive cancers and 2 of 3 DCIS cases. Since two of the invasive cancer cases were originally not detected via standard screening procedures, the assay has demonstrated important clinical utility when used in conjunction with mammography/standard of care. Here we show that, in the commercial patient population, when combined with standard of care, dtectDx Breast improves the detection of breast cancer in women under 50.
Methylation ESR1 as a potential factor of resistence to HER2/neu therapy in patients with breast cancer.
Authors: Martínez-Galán Joaquina , González Rivas Cynthia S. , Ruiz Vozmediano Julia , Portellano Lucia , Delgado Juan Ramón
Published: February 2017

24

Background: Estrogen receptor (ER)-positive breast cancers are considered prognostically more favorable than ER-negative tumors and are often responsive to anti-estrogen therapy. Whereas tumors overexpressing HER2 are endocrine resistant and they require the blockage of the HER2 pathway in addition to estrogen deprivation. To evaluate epigenetics differences in tumor-related genes to ESR1 and HER2/neu status in primary breast cancer is the objective of this study. Methods: We quantified methylation levels of promoter of ERS1 which are to confer growth adventage to cells in 107 women with breast cancer. Real Time QMS-PCR SYBR green (methylation-specific PCR) was used to analyze the hypermethylation. Tumours were classified as phenotype basal, luminal A, Luminal B, and phenotype HER2+. Results: Presence of methylated ESR1 in serum of breast cancer patients was associated with ER-negative phenotype (p=0.0179). Of the available cases, 60 pts (56%) were Luminal A, 10 pts (9.3%) Luminal B, 13 pts (12%) Basal like, and 9 pts (8.4%) HER2+. We observed that methylated ERS1 was preferably associated with phenotype Basal Like and worse interval progression free and survival global though p > 0.05 and the amplification HER2+ was correlation with significant more frequent methylation gene (p<0.05). Thet hypermethylation of normal ERS1 and 14-3-3σ combined differentiated between breast cancer patients and healthy controls (p = 0.0001) with a sensitivity of 81% (95% CI: 72–88%) and specificity of 88% (95% CI: 78–94%). Conclusions: This study identifies the presence of variations in global levels of methylation promoters genes in healthy controls and breast cancer with different phenotype classes and shows that these differences have clinical significance. These showed that frequent methylation had a strong association with molecular phenotype of breast cancer and perhaps in the future can explain therapy resistance related to RE and HER2/neu status and this may be of significance in the assessment of targeted therapy resistance related to ER and HER2/neu status in breast cancer patients.
Recurrence Score across the age spectrum: Is there an age discrimination?
Authors: Smith Franz Omar , Lee Marie Catherine , Acs Geza , Fulp William J. , Lee Ji-Hyun , Khakpour Naznin , Kiluk John , Laronga Christine
Published: February 2017

27

Background: Treatment planning for early-stage estrogen receptor (ER) positive, lymph node negative breast cancer was based on prognostic factors with limited predictive power such as age. The Recurrence Score (RS) from the Oncotype DX assay (ODX) provides predictive power transcending age but is rarely applied to the elderly or young patients (pts). We examined our experience with RS along the age continuum. Methods: Retrospective review was conducted of prospectively gathered breast cancer pts having a RS obtained as part of their cancer care. Eligibility for performance of the ODX was based on NCCN guidelines or physician discretion. Comparisons on RS were made by age groups (young: <45yrs; middle: >45yrs -<70yrs: elderly: >70yrs) using general linear regression model and the exact Wilcoxon Rank Sum Test. Results: 677pts had 681 tumors with RS available (89 young, 476 middle and 112 elderly pts). Median RS for the study pts was 17 (range 0-85) and 16, 17, and 15 for the young, middle, and elderly respectively. Median age was 58yrs (range: 27-95); young, middle, and elderly was 42, 58, and 74yrs respectively. Age as a continuous or categorical variable was not predictive of RS (p value = 0.38, 0.58 respectively). No significant differences were seen between age cohorts for histology, mitotic rate, lymphovascular invasion (LVI), grade, nodal status, stage, or strength of ER positivity. Mastectomy rates were higher in the young (57.5%), compared to the middle (42.5%) and elderly (39.6%) (p=0.02). Median invasive tumor size was 1.6, 1.5, and 1.5cm for young, middle, and elderly. Larger tumor size, as a continuous variable, equaled higher RS (p=0.046). Other significant factors predicting higher RS were increased mitosis (p<0.001), LVI (p=0.013), high grade (p<0.001), and weak (<10%) ER positivity (p<0.001). Nodal status, stage, and histology did not affect RS. Conclusions: Age has limited predictive power for treatment planning for breast cancer. Age alone should not preclude recommendations for performance of ODX in estrogen receptor positive lymph node negative early stage breast cancer as the RS distribution across the spectrum of age is well matched.
Integrated analyses of DNA copy number variations and gene expression in inflammatory breast cancer (IBC).
Authors: Xie Mian , He Chao-sheng , Wei Shen-hai
Published: February 2017

28

Background: Inflammatory breast cancer (IBC) is an aggressive form of BC poorly defined at the molecular level. We aim to perform genome-wide analyses of copy number variation and gene expression to identify genes reproducibly associated with survival in IBC patients. Methods: We performed concurrent genome-wide microarray analyses of copy number variable regions (CNVRs) and gene expression in IBC patients. Fifty-six pairs of breast cancer and normal specimens from IBC patients were analyzed by using Affymetrix SNP 6.0 and Affymetrix U133 plus 2.0 microarrays. To investigate genomic alterations, we used an Affymetrix Genome-Wide Human SNP 6.0 array containing 1.8 million SNP and CNV probes in total. The microarray data were imported into the Partek Genomic Suite to perform CNV analysis. Ingenuity Pathway Analysis was carried out to describe gene-gene interaction networks and canonical pathways. Cox regression model was used to evaluate the association between expression of these CNV-driven genes and survival outcomes. Results: The genomic landscape of frequent copy number variable regions (CNVRs) in at least 35% of samples was revealed. Further statistical analysis for genes located in the CNVRs identified 387 genes differentially expressed between tumor and normal tissues (p < 0.001). We demonstrated the concordance between copy number variations and gene expression changes by elevated Pearson correlation coefficients. Fisher’s exact test identified five canonical pathways that were significantly enriched among the 387 CNV-driven genes. Pathway analysis revealed two major dysregulated functions in IBC: survival regulation via Rac/PAK and PTEN/PI3K/AKT signaling pathway. Further validation using three independent cohorts demonstrated prediction of survival. Conclusions: We identified genes/pathways that may serve as prognostic markers for IBC patients by integrating gene expression profiles and copy number variations.
21-gene Recurrence Score testing and subsequent treatment decisions in patients (pts) with estrogen-receptor-positive (ER+) early-stage breast cancer (ESBC).
Authors: Manders Jennifer B. , Burkhart Joan , Campbell Debra , Devitt James J. , Vacchino Judith , Sing Amy Pratt
Published: February 2017

30

Background: The utilization of the 21-gene Recurrence Score (Oncotype DX) in community settings is now well established for ER+, node negative (N-) pts with ESBC. The utility of the Recurrence Score result is to guide treatment decisions and spare exposure to chemotherapy (CT) in pts that have little likelihood of benefitting. To better understand physician behavior as it relates to OncotypeDX testing, we examined the characteristics of pts tested versus not tested, the Recurrence Score distribution and treatment patterns in approximately 160 pts with ESBC seen in 2010. In addition, provider utilization and treatment patterns were also assessed. Methods: Using data from 2010, the number of pts who were eligible to undergo OncotypeDX testing was compared to the number of pts who underwent testing. Pts were considered eligible for testing if they had node-negative, ER+, HER2-negative ESBC. We determined the number of pts with a Recurrence Score value in the low (RS <18), intermediate (int; RS 18-30), and high-risk (RS ≥31) groups along with the number of pts who subsequently received chemotherapy in each category. Results: Of the 233 pts identified with ESBC, 158 were eligible for OncotypeDX testing and 107 (67.7%) underwent testing. Fifty-five percent of pts were low, 37% int, and 7.7% high-risk, respectively. Nineteen percent of low, 56% of int, and 100% of high-risk pts received CT. In the 11 pts with a low Recurrence Score result that received CT, the reason cited was pt decision in 4 and young age in 3. Conclusions: Oncotype DX use in the community is well established. Recurrence Score-guided use of CT in the low- and int-risk groups was as expected based on adjuvant chemotherapy guidelines; however, there were still some physicians treating low Recurrence Score pts with CT-mostly based on younger age or larger tumors. Data from 2011 and 2012 will be included in the final presentation allowing greater insight into pt groups less represented in the single year experience.
Transglutaminase II expression in invasive ductal carcinomas.
Authors: Assi Jasmeet Sunny , Srivastava Gunjan , Matta Ajay , Chang Martin , Ralhan Ranju , Walfish Paul G.
Published: February 2017

34

Background: Molecular markers for predicting breast cancer patients at high risk of recurrence are urgently needed for more effective disease management. The impact of alterations in extracellular matrix components on tumor aggressiveness is under intense investigation. Overexpression of Transglutaminase 2 (TG2), a multifunctional enzyme, in cancer cells impacts epithelial mesenchymal transition and cancer stem cell phenotype, growth, invasion and interactions with tumor microenvironment. The objective of our study is to determine the clinical relevance of stromal TG2 overexpression and explore its potential to identify which IDCs are at high risk of recurrence. Methods: This retrospective study is based on immunohistochemical analysis of TG2 expression in 168 invasive ductal carcinomas with clinical, pathological and follow-up data available for up to 12 years. TG2 expression was correlated with clinical and pathological parameters as well as disease free survival (DFS) of breast cancer patients. Results: Stromal TG2 overexpression was observed in 97/168 (57.7%) invasive ductal carcinomas (IDC). Notably, IDC patients showing stromal TG2 accumulation had significantly reduced disease free survival (mean DFS = 110 months) in comparison with patients showing low expression (mean DFS = 130 months), as revealed by Kaplan-Meier survival analysis (p <0.001). In Cox multivariate regression analysis, TG2 accumulation in tumor stroma emerged as an independent risk factor for recurrence in IDC (p = 0.006, Hazard’s ratio, H.R. = 3.79). Conclusions: Accumulation of TG2 in tumor stroma is an independent risk factor for identifying breast cancer patients at high risk of recurrence. TG2 overexpression in tumor stroma may serve as a predictor of poor prognosis for IDC of the breast.
Women's understanding of personal breast cancer risk: Does ethnicity matter?
Authors: Herman Jonathan D. , Herman Sarah M.
Published: February 2017

4

Background: A woman’s understanding of her breast cancer risk is an important precursor for care. A valid estimate allows for greater opportunity to consider early detection modalities and chemopreventive medications. The USPSTF recently encouraged women who have an increased risk of developing a first breast cancer and a low risk of side effects to take tamoxifen or raloxifen. The objective of this study is to compare patients' perceived breast cancer risk with their calculated risk and then parse those findings by ethnicity. Methods: Anonymous, IRB approved, pre-piloted questionnaires were filled out by women at 21 mammography centers on Long Island. The survey included questions about patient demographics, patient’s estimates of their own breast cancer risk and personal risk factors. Results: 9,873 respondents qualified for inclusion in our analysis. Women were asked to quantify their breast cancer risk by age 90. Overall, 707 (9.4%) were in line with their risks, 3,359 (44.7%) underestimated risk and 3,454 (45.9%) overestimated their risk. When parsed by ethnicity, of the 781 African Americans, 8.7% were in line, 57.6% underestimated risk, and 33.7% overestimated risk. Of the 245 Asians, 10.2% were in line, 58.8% underestimated risk, and 31% overestimated risk. Of the 427 Hispanics, 8.9% were in line, 50.4% underestimated risk, and 40.8% overestimated risk. Of the 6850 Caucasians, only 10.2% were in line, 38.6% underestimated risk, and 51.3% overestimated risk. Conclusions: Most women lack accurate knowledge of their own breast cancer risk – 90.6% overall. When parsed by ethnicity, while there was a statistical difference between groups, the difference was not important because overall understanding was very low. Caucasian women tended to overestimate their risk compared with other ethnic groups, possibly resulting in unnecessary anxiety. African American and Hispanics tended to underestimate risk compared with Caucasians, possibly resulting in underutilization of available resources. Patients must have a better understanding of their personal risk. Study findings should help refocus educational efforts because increased knowledge of breast cancer risk will enable providers to tailor an individual’s medical treatment plan.
Can Oncotype DX Recurrence Score (RS) be used in Luminal A and Luminal B breast cancer patients (pts) to predict the likely benefit of chemotherapy? A retrospective unicentric study in Spanish population.
Authors: Estevez Laura G. , Calvo Isabel , Fernandez-Abad Maria , Cruz Juan Jose , Suarez Ana , Lopez-Rios Fernando , Hidalgo Manuel
Published: February 2017

40

Background: The 2011 St Gallen guidelines recommend the use of Ki67 as a surrogate marker for luminal A and Luminal B breast cancer subtypes. Pts with luminal B subtypes should be treated with adjuvant chemotherapy. The guidelines also recognize the Oncotype DX RS as a predictor of chemotherapy benefit. The aim of this study is to assess the distribution of the RS in luminal A and luminal B breast cancer subtypes as defined by Ki67. Methods: Data from 131 pts with invasive breast cancer for which Oncotype DX results and pathology data were available. Pathological assessment was evaluated by the same pathologist. Estrogen (ER) and progesterone (PR) receptor was assessed by immunostaining (cut-off 10% nuclear staining). Ki67 was assessed by IHC [high (≥14%) and low (< 14%)]. Histological grade was performed by using Nottingham grading system. Results: Median age: 50 (range: 35-78); premenopausal status: 53 pts (44.2%). Median tumor size: 1, 5 cm (0, 3-5); Median of Ki 67 index: 15 (range: 3-63); 79 pts (66.4%) had negative-lymph nodes. Seventy (58.3%) tumors were classified as Luminal B (Ki 67 ≥14%) and 50 (41.7%) as Luminal A. Grade III were more common in Luminal B 14 (20.3%) than in Luminal A 1 pts (2%) patients (p=0.003). Chemotherapy was the first recommendation in 29 pts (41.4%) with Luminal B vs. 7 pts (14%) with Luminal A; hormonotherapy was the first recommendation in 32 pts (45.7%) with Luminal B and 37 pts (74%) in Luminal A (p =0.003). In the Luminal B group, Recurrence Score results was low in 42 (60%) pts, intermediate in 19 (27.1%) and high in 9 (12.9%) while in the Luminal A group 31 (62%) had low; 16 (32%) intermediate and 3 (6%) high Recurrence Score results (p=0.433). RS changed the first treatment recommendation in 35 (50%) cases of Luminal B subtype vs. 14 (28%) cases in Luminal A subtype (p=0.016). Conclusions: The results show that a substantial number (60%) pts with Luminal B breast cancer subtype had a low RS, therefore preserving them from adjuvant chemotherapy treatment. The wide range of RS in both Luminal B and Luminal A breast cancer subtypes confirm the important role of Oncotype DX in treatment decision making.
Clinicopathologic characteristics and survival outcomes in multifocal and multicentric breast cancer.
Authors: Fushimi Atsushi , Yoshida Atsushi , Takahashi Osamu , Hayashi Naoki , Yagata Hiroshi , Suzuki Koyu , Tsunoda Hiroko , Yamauchi Hideko
Published: February 2017

41

Background: Although multifocal and multicentric (MF/MC) breast cancers are a common entity, their clinical behaviors are not well characterized. We evaluated the impact of MF/MC on the disease-free survival (DFS) and distant disease free survival (DDFS) of breast cancer patients and compared clinicopathological characteristics between MF/MC breast cancers and breast cancers with single lesion. Methods: We retrospectively analyzed 734 consecutive patients who had invasive breast carcinoma and underwent definitive surgery at the St Luke’s International Hospital from January 2004 to December 2006. MF or MC ware defined as more than one lesion in the same quadrant or in separate quadrants, respectively. DDFS and DFS ware calculated by The Kaplan–Meier method. Univariate analysis was performed using the log rank test and multivariate analysis by Cox proportional hazards models. Results: Of 734 patients, 136 (18.5%) had MF/MC disease. MF/MC disease was associated with smaller tumor size (P <0.001). Multivariate analysis shows that MF/MC disease did not have an independent impact on DDFS or DFS adjusting by age, ER status, tumor size, lymphovascular invasion, lymph node metastases and nuclear grade. Conclusions: MF/MC breast cancers were not associated with poor prognostic factors, and were not independent predictors of worse survival outcomes. Our findings support the current TNM staging system of using the diameter of the largest lesion to assign T stage.
High levels of proliferation regulators and an impaired senescence response pathway to identify early-stage breast tumors with a poor prognosis.
Authors: Lanigan Fiona T. , Dunne Eiseart J. , Brien Gerard L. , Al Oraifi Fatima , Fan Yue , Quinn Cecily , Flanagan Louise , Fridberg Marie , Jirstrom Karin , Geraghty James G. , Gallagher William M. , Bracken Adrian P.
Published: February 2017

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Background: Predicting the risk of tumour recurrence, and thus the need for chemotherapy, for lymph node-negative breast cancer patients is a significant problem for clinicians and patients. Methods: We have identified a ‘core proliferation signature,’ which is consistently high in proliferating primary cultures, and is downregulated during cellular senescence. Using a reverse engineering approach on a breast cancer-specific regulatory network, and confirmed by ChIP-seq analysis, we have identified a hierarchy of several highly interconnected Master Transcriptional Regulators upstream of these core proliferation genes. Results: Further analysis of the expression of these factors in breast cancer cohorts at the mRNA and protein levels reveals a remarkable ability to reliably predict recurrence risk for early-stage breast cancer. Strikingly, in our analyses, a combination of just two of these factors outperforms the currently used clinical biomarkers for breast cancer recurrence risk, as well as recently developed multi-gene prognostic assays. Moreover, the addition of the senescence regulator p16INK4A to this panel further increases its prognostic capability. Conclusions: We propose that this novel approach has succeeded in identifying ‘drivers’ of breast cancer proliferation which, when combined with a marker of senescence such as p16INK4A, successfully identify actively proliferating tumours with an impaired senescence response pathway. Furthermore, we suggest that this gene combination has the potential to become an improved prognostic assay for early-stage breast cancer.
A prospective study on behavioral symptoms’ impact to the quality of life in patients with early-stage cancer receiving radiotherapy.
Authors: Xiao Canhua , Felger Jennifer , Mister Donna , Liu Tian , Miller Andrew H. , Torres Mylin Ann
Published: February 2017

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Background: Fatigue, sleep problems, and depression are the most common behavioral symptoms experienced by breast cancer patients. The purpose of this study was to examine these behavioral symptoms’ impact on quality of life (QOL) for early stage breast cancer patients receiving radiotherapy (RT). Methods: This was a prospective study of 46 patients receiving whole breast RT (50 Gy plus a 10 Gy boost) following lumpectomy. Data were collected at pre-RT, week 6 of RT, and 6-weeks post-RT. QOL was measured by Short Form-36, fatigue by Multidimensional Fatigue Inventory, sleep by Pittsburgh Sleep Quality Index, depression by Inventory for Depressive Symptomatology-Self-Rated, and stress by Perceived Stress Scale. No patients were treated with chemotherapy. Demographic/clinical variables, including age, race, marriage, smoking history, hormone treatment, and cancer stage, were collected at the time of enrollment. Mixed effect modeling was utilized to observe behavioral symptoms’ impact on QOL over time. Results: Fatigue and depression, along with stress, had significant impact on QOL after controlling for body mass index (BMI; the only one significant demographic/clinical variable; see Table). Patients with more fatigue, depression, or stress were more likely to have worse QOL during and post-RT. Patients having a higher BMI at baseline also reported worse QOL over time. Sleep was significantly correlated with QOL in univariate analyses, while this effect disappeared in multivariate models. Conclusions: Behavioral symptoms, in particular fatigue and depression, along with stress, have significant impact on the QOL of early breast cancer patients’ receiving RT. Future research on the underlying biological mechanisms will improve our understanding of these symptoms and their relationships, which will help to find potential targets for multiple related symptoms and, ultimately, improve patients’ QOL. [Table: see text]
The prospective estimation of blood serum free IGF-1, insulin concentration, and body mass index as a prognostic factor for breast cancer patients.
Authors: Nowara Elzbieta , Huszno Joanna , Drosik-Rutowicz Katarzyna , Nowara Ewa , Maslyk Barbara
Published: February 2017

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Background: Numerous epidemiologic findings suggest that an increase in IGF-1, insulin concentration and body mass index correlates with the risk of developing certain types of malignant tumors, including breast cancer. They may also have an influence on the cancer stage. The purpose of this study was to prospectively evaluate the correlation of body mass index (BMI), insulin, and free IGF-1 concentration with cancer stage. Methods: Prospective analysis has been conducted in 2011 in Cancer Center and Institute of Oncology in Gliwice, Poland. This study has been approved by Bioethics Committee according to national regulations. The pilot group included 138 patients with breast cancer treated with chemotherapy, 76% in adjuvant setting and 24% due to cancer dissemination. Results: Patients’ median weight was 70kg (range 52-106kg) and median BMI was 27 (range 18.8-40.8). Patients with HER2 overexpression had diabetes more frequently (8% vs. 0%), p=0.06. Patients with higher BMI more frequently had negative steroid receptor status (42% vs. 25%) p=0.06, and significantly more often were in postmenopausal period (81% vs. 52%), p=0.00029. Tumor stage was significantly more advanced in patients with lower physical activity, p=0.04. Tumor stage was insignificantly more advanced in patients with higher plasma insulin level, p=0.09. Multivariate analysis had shown that overweight patients with more advanced stage of breast cancer had negative steroid receptors more often, p=0.033. Patients with metastatic breast cancer often had higher insulin plasma levels in comparison to patients with early breast cancer (7% vs. 1%), p=0.09. The multivariate analysis also showed that patients with diabetes had more frequently more often overexpression of HER2 and were in a more advanced cancer stage, p=0.03. Conclusions: Hyperinsulinemia may be a risk factor for more advanced stage of disease. There is a possibility that the effect of being overweight on breast cancer stage is mediated by estrogen metabolism. This analysis is scheduled to be performed later in the project.
Receptor status change from primary to residual breast cancer after neoadjuvant chemotherapy (NCT) and analysis of survival outcome.
Authors: Parinyanitikul Napa , Lei Xiudong , Chavez-Mac Gregor Mariana , Mittendorf Elizabeth Ann , Litton Jennifer Keating , Woodward Wendy A. , Zhang Hong , Hortobagyi Gabriel N. , Gonzalez-Angulo Ana M.
Published: February 2017

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Background: Treatment and prognosis of breast cancer is determined by tumor subtype. Tumor heterogeneity and lack of stability in ER, PR and HER2 has been described. We evaluated the changes receptor status between primary and residual disease after NCT and its association with outcome. Methods: 398 women with known ER, PR and HER2 status in primary and residual disease were identified. Patients were classified as no receptor change vs. any receptor change. For ER and PR we explored absolute percent changes. Descriptive statistics were used. Kaplan-Meier method was used to estimate overall (OS) and recurrence-free (RFS) survival. Cox proportional models were fit to determine the association of receptor status changes with outcomes after adjustment for patient and disease characteristics. Results: From the 398 patients, 162 (40.7%) had a change in at least one biomarker. Twenty-three (10.9%) of the 211 ER-positive tumors changed to ER-negative and 39 (20.8%) of the 187 ER-negative tumors changed to ER-positive. Fifty-seven (35.2%) of the 162 PR-positive tumors changed to PR-negative and 28 (11.9%) of the 235 PR-negative tumors changed to PR-positive. Lastly, 29 (40%) of the 72 HER2-positive tumors changed to HER2-negative and among the 35 trastuzumab-treated patients, 16 (45.7%) had HER2 status changed. At a median follow up of 40 months, 128 women (32%) had died, and 167 (41.8%) had experienced a recurrence. Five-year OS estimates were 73% and 63% for patients with or without any receptor change, (P=0.07); 5-year RFS estimates were 63% and 48% for patients with or without any receptor change, (P=0.003). Among patients with baseline ER-positive tumors, 5-year OS estimates was 73% and 87% (P=0.03), and the 5-year RFS estimates was 59% and 71% (P=0.03) for those whose absolute ER percent decrease was less than 20% or more than 20%, respectively. A change in any receptor was associated with better RFS (HR: 0.63, 95% CI 0.44-0.9) but not with OS, (HR: 0.79, 95% CI 0.53-1.18). Conclusions: Changes in ER, PR and HER2 status between the primary and the residual disease after neoadjuvant chemotherapy are frequent. In this study, a change in biomarker status was associated with significant improved RFS.
Outcomes of sentinel lymph node-positive breast cancer patients treated with mastectomy without axillary therapy.
Authors: FitzSullivan Elizabeth , Kuerer Henry Mark , Bassett Roland L. , Mittendorf Elizabeth Ann , Yi Min , Hunt Kelly , Babiera Gildy , Caudle Abigail Suzanne , Black Dalliah M. , Bedrosian Isabelle , Meric-Bernstam Funda , Hwang Rosa F.
Published: February 2017

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Background: Early-stage breast cancer patients with minimal axillary disease identified by sentinel lymph node dissection (SLND) have a low rate of regional recurrence when treated with breast conserving surgery and radiation. Patients who fit criteria for the ACOSOG Z0011 trial are candidates to avoid completion axillary lymph node dissection (CLND). As the incidence of total mastectomy (TM) has increased, it has become important to characterize which TM patients with a positive SLN may not benefit from further axillary treatment, including CLND and/or radiation therapy (XRT). Methods: We utilized an institutional database to identify patients who were treated with a TM for invasive breast cancer and had a positive SLN from 1994-2010. CLND was defined as removal of 10 or more lymph nodes. Clinicopathologic factors were analyzed and the rate of regional recurrence as well as overall and disease-free survival were determined. Results: A total of 730 patients with invasive breast cancer and a positive SLN were treated with TM including 71 patients who did not have CLND or XRT and 27 patients who did not have CLND but did receive XRT. Median follow-up was 66 months. The 10-year actuarial rate of regional recurrence was not significantly different for patients who received no further axillary treatment when compared to those who underwent CLND and XRT (4.9% vs 3.1%) or to those who underwent CLND without XRT (4.9% vs 1.4%). Survival was not significantly different between patients who did not receive further axillary treatment compared to those who underwent CLND without XRT or those who underwent both CLND and XRT. Using a nomogram previously developed by our group, the predicted probability of additional non-SLN involvement was significantly lower for patients who did not undergo CLND compared to those who did (10% vs. 23%, p<0.0001). Conclusions: In select patients with early stage breast cancer treated with mastectomy with a positive SLN, CLND may be avoided without adversely affecting recurrence or survival.