bluuebunny/crossref_metadata_2025_split huggingface dataset:
Results of ENCORE 301, a randomized, phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive (ER+) breast cancer progressing on a nonsteroidal aromatase inhibitor (AI).
Authors: Yardley D. A. , Ismail-Khan R. , Klein P. 
Published: February 2017

268 Background: Hormonal therapy, including AIs, is the mainstay of ER+ breast cancer (BC) treatment; however, both acquired and intrinsic resistance limits its clinical benefit. Entinostat is a novel, oral, class I selective histone deacetylase inhibitor that has been shown to inhibit growth factor signaling pathways that mediate AI resistance. This study was designed to evaluate the impact of the addition of entinostat to exemestane therapy on progression-free survival (PFS). Methods: Postmenopausal women with ER+ advanced BC who had progressed on a non-steroidal AI were randomized to exemestane 25 mg daily + entinostat 5 mg or placebo weekly. Results: A total of 130 women were enrolled (66 exemestane+placebo; 64 exemestane+entinostat). All but 1 patient had Stage IV disease, and 82% had measurable disease. All patients had received prior hormonal therapy (1 prior line 42%; >1 prior line 58%), and 62% had received prior chemotherapy (33% in the advanced BC setting). Analysis of the intent-to-treat population showed that PFS was significantly (defined prospectively as p <0.10) longer with exemestane+entinostat than with exemestane+placebo (4.28 versus 2.27 months, respectively; hazard ratio [HR] = 0.73; p=0.06). Entinostat combined with exemestane was well-tolerated with the most frequent adverse events (AEs) consisting of fatigue, gastrointestinal disturbances, and hematologic abnormalities. AEs with a ≥20% higher incidence with exemestane+entinostat than with exemestane+placebo were fatigue (46% versus 26%, respectively) and uncomplicated neutropenia (25% versus 0%, respectively). The serious AE rate was similar for exemestane+entinostat (13%) and exemestane+placebo (12%). Conclusions: Exemestane+entinostat significantly prolonged the median PFS and reduced the risk of disease progression by 27% versus exemestane+placebo (HR = 0.73). In light of these positive data, a phase III evaluation of this combination is planned.
Human papillomavirus infection and increased risk of breast cancer in north of Iran.
Authors: Naghshvar F. , Sigaroodi A. , Nadji S. A. , Janbabaei G. 
Published: February 2017

28 Background: Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer deaths among women worldwide. Human papillomaviruses have been related to the pathogenesis of breast cancer. In this study, we have analyzed the possible relevance of HPV infection for breast cancer risk among Iranian women from north part of Iran, Mazandaran province. Methods: Polymerase chain reaction method with three different primer sets was applied for detection of HPVs in formalin-fixed paraffin-embedded breast cancer and breast fibroadema as case and control tissues, respectively. HPV genotypes were determined by phylogenetic analysis of viral genome sequences. Results: Of the 58 women with breast cancer, 25.9% (15 isolates) had positive test results for HPV DNA in breast tumor samples in contrast to 2.4% of women (1 out of 41) with non cancer status (P + 0.002). The infection of HPV had an OR of 14.247 (95% CI 1.558-130.284; P + 0.019). The HPV genotypes in samples of breast cancer patients were 26.67% for HPV-16 (4 isolates) and HPV-18 (4 isolates), 13.3% for HPV-23 (2 isolates) and HPV-6 (2 isolates), 6.67% for HPV-11 (1 isolate), HPV-15 (1 isolate) and HPV-124 (1 isolate) and one isolate could not be genotyped compared to HPV reference sequences, while the sole detected HPV in control specimens was HPV-124. Conclusions: Our study reveals that HPV infection and age are the risk factors in breast cancer development in the north part of Iran, Mazandaran province. The association between risk of breast cancer development and viral infection is open and deserves further investigation.
A phase II neoadjuvant trial of concurrent trastuzumab and paclitaxel without anthracycline in women with HER2-positive operable breast cancer.
Authors: Jinno H. , Hayashida T. , Takahashi M. , Hirose S. , Kitagawa Y. 
Published: February 2017

283 Background: Neoadjuvant paclitaxel plus trastuzumab followed by 5-fluorouracil, epirubicin, and cyclophosphamide plus trastuzumab revealed the high pathologic complete response (pCR) rate of up to 60% in patients with HER2-positive breast cancer. However, combination of trastuzumab and anthracycline has been associated with an increased incidence of cardiac dysfunction. The objective of this study was to determine the efficacy of concurrent administration of trastuzumab and paclitaxel without anthracycline as neoadjuvant chemotherapy. Predictive factors of pCR including deregulation of the phosphatidylinositol 3-kinase (PI3K) pathway were also investigated. Methods: Patients with HER2-positive operable breast cancer received 12 cycles of weekly paclitaxel (80 mg/m2 IV) plus weekly trastuzumab (4mg/kg loading dose followed by 2 mg/kg IV) before surgery. PTEN status was evaluated by IHC with PTEN antibody (Thermo Scientific, CA). PTEN expression level was scored semiquantitatively based on staining intensity (0; no staining , 1+; reduced staining, and 2+; equal staining as compared to the internal control). PIK3CA mutation status was evaluated by sequencing of PIK3CA exons 9 and 20 using PCR amplification and direct sequencing. pCR was defined as no residual invasive carcinoma in the breast. Results: Among 37 patients enrolled, ER and PgR were positive in 18 (48.6%) and 16 (43.2%) patients, respectively. The overall response rate was 86.5% (32/37) and the pCR rate was 48.6% (18/37). pCR rate was significantly correlated with PgR negativity (p=0.004) and higher Ki67 (p=0.01). PTEN loss was observed in 33.3% (8/24) of the tumor examined. PIK3CA sequence analysis of the 13 tumors identified 2 mutations in exon 20 and 2 mutations in exon 9, corresponding to a PIK3CA mutation frequency of 30.8%. PTEN loss and/or PIK3CA mutation were not significantly associated with pCR rate. Conclusions: These data indicate that the combination of trastuzumab and paclitaxel without anthracycline is effective neoadjuvant chemotherapy with high pCR rate. PTEN loss and/or PIK3CA mutation were not useful predictors of resistance to trastuzumab.
The effect of trastuzumab on pCR in locally advanced HER2-positive breast cancer.
Authors: Lavasani S. M. , Pritchard K. I. , Kiss A. , Verma S. , Wright F. , Boileau J. , Trudeau M. E. , Czarnota G. J. , Dent R. A. 
Published: February 2017

286 Background: Neoadjuvant therapy (NAT) is now standard of care for locally advanced breast cancer (LABC). Evidence shows that pathological complete response (pCR) predicts for disease free and overall survival. The pCR rates for LABC vary widely in the literature but prognosis still remains poor for this group of pts. Increases in pCR have been reported in clinical trials with the addition of trastuzumab (T) but these studies have predominantly included operable pts. The aim of this study was to evaluate whether the addition of T to NAT has improved the rates of pCR in HER2+ LABC pts at our center. Methods: Pts from the LABC prospective database at the Sunnybrook Odette Cancer Center in Toronto were included if they had confirmed HER2+ LABC [primary tumors greater than 5cm (T3) with skin or chest wall involvement (T4) or with matted axillary adenopathy (N2)]. Two cohorts of LABC pts, pre-T and post-T groups were compared for baseline characteristics and pCR. Chi square tests and p values were used for comparing proportions. Results: 43 pts were diagnosed between Jan 2002 to Dec 31, 2006 who had HER2+ breast cancer and received NAT without T (pre-T cohort). 17 HER2+ pts were diagnosed with LABC between Jan 1, 2007 to Dec 31, 2009 who received neoadjuvant T (post-T cohort). Baseline characteristics were similar in two cohorts (Table) except more pts in pre-T cohort received neoadjuvant hormonal therapy. The rate of pCR in the pre-T cohort was 9.3% and in the post-T cohort 29% (p value=0.02). Conclusions: The pCR rate dramatically improved in our LABC patients with the addition of T to NAT. The pCR rates still remain lower than in published clinical trials likely reflecting the more advanced nature of LABC in clinical practice. [Table: see text]
A vaccine approach for breast cancer immunotherapy by targeting HER2/neu antigen to B cells via CD19 molecule.
Authors: Xiang D. , Ma Y. , Ding C. , Kloecker G. H. , Yan J. 
Published: February 2017

287 Background: Trastuzumab has been proven to be effective in the immunotherapy for Her-2/neu-positive breast cancer. However, this adoptively transferred therapeutic Ab must be continuously given to the patient with huge financial cost. Thus, it would be desirable if tumor vaccines could elicit long-lasting trastuzumab-like Ab. Methods: Constructing fusion protein of anti-mouse CD19 single chain variable fragment (anti-CD19-scFv) with human Her-2/neu extracellular domain P3-4 (P3-4) by extracting total RNA from Rat anti-mouse CD19 hybridoma (1D3) and first strand cDNA was synthesized accordingly. VH and VL were amplified using designed primers. Single chain Fv (VL-VH) was then synthesized by overlapping PCR. Then constructs were sequenced and cloned into pET-20b(+) vectors. Fragments P3-4 of extracellular domains of human Her-2/neu was cloned from pcDNA3.1-Her2 and then cloned into pET-20b(+)-scFv. Series of constructs were expressed and purified according to standard protocol and verified by Western Blot. Results: Both in vitro and in vivo studies demonstrated that fusion proteins anti-CD19-scFv and anti-CD19-scFv-P3-4 but not P3-4 could specifically bind to B cells with high affinity. Mice immunized with anti-CD19-scFv-P3-4 secreted higher titers of IgG and IgM than those from controls (p<0.05). Studies also demonstrated that sera from anti-CD19-scFv-P3-4 but not anti-CD19-scFv or P3-4 immunized mice stained with Her-2/neu expressing SKOV-3 tumor cells. These Abs also competitively inhibited trastuzumab-mediated Ag binding, suggesting that trastuzumab-like Ab responses were elicited. WT mice immunized with anti-CD19-scFv-P3-4 fusion protein then challenged with D2/F2-Her-2 mammary tumor cells showed significantly reduced tumor burden compared to those immunized with control fusion proteins (p<0.05) and had enhanced median overall survival to 45 days versus 34 days in WT mice immunized with either anti-CD19-scFv or P3-4. Conclusions: Targeting of Her-2/neu antigens to B cells stimulates Th-dependent humoral immune responses with anti tumor effect in mouse model. These findings provide a novel avenue for successful development of breast cancer vaccination strategy and help to fight for cancer.
Predicting nipple-areolar involvement using preoperative breast MRI and primary tumor characteristics.
Authors: Steen S. T. , Chung A. P. , Han S. , Vinstein A. , Yoon J. L. , Giuliano A. E. 
Published: February 2017

40 Background: Preoperative assessment of the nipple-areolar complex (NAC) is invaluable when considering nipple-sparing mastectomy (NSM). We hypothesized that breast MRI could predict involvement of the NAC with tumor. Methods: We compiled clinical, pathologic and imaging data for patients who underwent preoperative breast MRI followed by mastectomy or NSM between 2006 and 2009. Blinded rereview of all MRI studies was performed by a breast MRI imager and compared to initial MRI findings. Multivariate analysis identified variables predicting NAC involvement with tumor. Results: Of 77 breasts, 18 (23%) had tumor involving or within 1 cm of the NAC. The sensitivity of detecting pathologically confirmed NAC involvement was 61% with history and/or physical exam, and 56% with MRI. Univariate analysis identified the following variables as significant for NAC involvement: large tumors close to the nipple on preoperative MRI, node-positive disease, invasive lobular carcinoma, advanced pathologic T stage, and neoadjuvant chemotherapy. On multivariate analysis, only tumor size > 2 cm and distance to the NAC < 2 cm on MRI maintained significance. Pearson correlation coefficient for MRI size compared to pathologic size was 0.53 (p<0.0001). Conclusions: MRI is not superior to thorough clinical evaluation for predicting tumor in or near the NAC. However, MRI-measured tumor size and distance from the NAC are correlated with increased risk of NAC involvement. Preoperative history and physical examination, tumor characteristics, plus breast MRI can aid the surgeon in planning for successful NSM.
Topoisomerase II alpha (TopoIIa) and MAPtau: Potential predictive markers of response in locally advanced breast cancer (LABC) treated with epirubicin and docetaxel (ET) in neoadjuvant setting.
Authors: Cristofano A. , Inno A. , Arena V. , Nicosia L. , Jocollè G. , Campitiello M. , Carassai P. , Pozzo C. , Numico G. , Barone C. 
Published: February 2017

57 Background: Neoadjuvant chemotherapy can achieve a high objective response rate in patients with LABC. This allows breast conservation surgery in those patients who are initially not suitable for this procedure. The patients who mainly benefit from neoadjuvant chemotherapy are those who achieve a pathological complete response (pCR) with no residual microscopic tumour. This occurs in only 3–16% of patients, who have substantially improved disease-free survival (DFS) and OS compared to those with pathological evidence of residual cancer. In order to identify patients most likely to achieve benefit from neoadjuvant chemotherapy, it would be useful to identify predictors of pCR. ET is a valid doublet therapy in the neoadjuvant setting; Topo-IIa and MAP-Tau are the principal targets of anthracyclines and taxanes, respectively. We evaluated a possible role of the two proteins in predicting a pathological response rate in LABC. Methods: TopoIIa and MAPtau expression was evaluated by immunohistochemistry (IHC) in tumour biopsy from 22 women with LABC treated with ET as neoadjuvant chemotherapy, and protein levels were correlated to the outcome. Results: TopoIIa over-expression was significantly associated with ductal histology (58.3% in ductal carcinoma vs 0% in other hystotypes, p=.038) and hormone receptors (HRs) expression (63.6% in HR+ vs 0% in HR- tumours), whereas no significant correlation was observed with HER2 expression. MAP-tau did not correlate with histology, grading, HRs and HER2 status. Pathological complete response (pCR) rate was higher in tumours with MAPtau low/normal expression compare to those over-expressing the protein (36.4% vs. 14.3%), although not significantly. Pts with TopoIIa over-expression achieved a significantly higher pCR rate than those with a low/normal expression (57.1% vs. 9.1%; p=.047). Data on the RFS are not available because of the short period of follow-up. Conclusions: IHC evaluation of TopoIIa might be useful in identifying pts potentially responsive to neoadjuvant chemotherapy with anthracyclines and taxanes. Data on RFS will be available later.
Measurement of gamma-H2AX in circulating tumor cells (CTC) from patients receiving ABT-888 (veliparib) in combination with carboplatin on a phase I dose-escalation study (OSU-10080/NCI8609).
Authors: Garcia-Villa A. 
Published: February 2017

58 Background: Non-invasive methods to accurately measure DNA damage induced by PARP inhibitors in the tumors are crucial in identifying the optimal biological dose and schedule of these novel agents. With the use of an antibody that targets the histone H2AX, which becomes phosphorylated on serine residue 139 (γ-H2AX), it is possible to measure DNA DSB in the cell. But repeated biopsy in patients with metastatic breast cancer is not feasible. We propose here to quantify γ-H2AX in CTCs as a measurement of DNA damage in the tumor in patients receiving veliparib (ABT-888), an oral PARP inhibitor and carboplatin on a phase I study. Methods: CTCs were isolated in 10 mL of peripheral blood using negative selection with immunomagnetic tagging and removal of CD45 positive cells at 3 time points. Immunocytochemical staining for nucleus (DAPI), pan-cytokeratin CD45, and γ-H2AX was completed on available samples. Double staining for nucleus and cytokeratin with high nucleus to cytoplasm ratio defined a CTC. The γ-H2AX foci present in the nucleus of the CTCs will be counted by immunocytochemistry (ICC) analysis. Results: We negatively enriched blood sample from enrolled patients with metastatic breast cancer (n=6). CTCs were observed in all samples (55CTCs/mL of blood - 2000CTCs/mL of blood). Thus far 3 out of 6 patient samples have been analyzed. The number of CTCs per mL of blood after enrichment at baseline has a mean of 293, a median of 140 and a range of (684-140) At time point 1 the mean is 1071.33, the median is 1151 and the range is (1151-63). ICC analysis on the CTCs demonstrated the presence of γ-H2AX positive cells. Conclusions: Our novel negative depletion method for isolating CTCs allows for separation of a wider range of CTCs, since it does not assume presence of epithelial markers before separation. This leads to improved yield and purity allowing better ICC detection of various markers directly on CTCs. Development and validation of the above methodology to determine γ-H2AX foci in CTCs will help in identifying a novel, non-invasive biomarker that can be used to assess the effect of DNA damaging agents during therapy.
Incidental breast lesions detected on diagnostic CT scans: A 3-year prospective study.
Authors: Ismail A. R. 
Published: February 2017

69 Background: With increasing usage of diagnostic cross sectional radiology tests, patients are presenting to rapid access one-stop breast clinic with incidental breast lesions. Methods: A prospective study over a 3-year period, collecting details of all patients shown to have breast abnormalities detected by computed tomography (CT) scans done for various reasons. These patients were assessed by clinical breast examination coupled with mammography, ultrasonography and tissue biopsy if indicated. Results: An increasing trend has been seen in the total number of thoracic CT scans with 1,939 scans in 2005 and 5,215 scans in 2010 (169% increase). 26 patients were included in this study with CT scans showing incidental breast lesions in the last three years. They were all women with age range of 50-92 (median 82.5) years. The clinical indications of CT scans included evaluation of the abnormal chest radiograph (8, 31%), preoperative evaluation of non-breast malignancy (3, 11%), infectious diseases (3, 11%), weight loss (7, 27%) and miscellaneous (5, 20%). These 13 breast cancer patients constitute 1.36% of 956 breast cancers diagnosed over this three-year period. 8 out of 13 breast cancer patients in this group (62%) had metastases at the time of diagnosis. Conclusions: A significant number of breast lesions incidentally found on CT scans are shown to be breast cancers (50%). These patients need rapid access to one-stop breast clinic for full evaluation. [Table: see text]
Axillary node staging for microinvasive breast cancer: Is it justified?
Authors: Lyons J. M. , Stempel M. , Van Zee K. J. , Cody H. S. 
Published: February 2017

7 Background: DCIS with microinvasion (DCISM) is a lesion for which prognosis may be intermediate between that of DCIS and invasive breast cancer, but for which the role of axillary lymph node staging remains controversial. Here we report clinical characteristics and outcome in 112 patients with DCISM, with a particular focus on the role of sentinel lymph node (SLN) biopsy. Methods: From our prospective database we retrospectively identified 112 patients with a diagnosis of DCISM who had undergone SLN biopsy between 1996 and 2004 at Memorial Sloan-Kettering Cancer Center. Median follow up was 6 years. Results: We found positive SLN in 12% (14/112) of all patients, macrometastases in 2.7% (3/112) and micrometastases in 10% (11/112). We performed axillary dissection (ALND) in all patients with macrometastases (3/3), finding additional positive nodes in 66% (2/3), and in 27% of those with micrometastases (3/11), finding no additional positive nodes. Among patients with negative SLN (38% of whom received systemic therapy), there were 5 loco-regional recurrences (1 in the ipsilateral axilla, and 4 in the ipsilateral breast, all DCIS) and 4 contralateral second primary breast cancers. Among patients with positive SLN (86% of whom received systemic adjuvant therapy), there were no loco-regional or distant recurrences. Conclusions: Positive SLN were present in 12% of our patients with DCISM, none of whom experienced recurrence at 6 years’ follow up. SLN biopsy may be justified for DCISM, but is clearly most beneficial to identify a very small subset of DCISM patients (2.7%, with SLN macrometastases) who could benefit from systemic adjuvant therapy. Our data imply that between 125 and 250 SLN biopsy procedures would be required to avoid breast cancer mortality in 1 patient, and do not support the routine use of ALND for SLN-positive patients. We recommend a critical reappraisal of routine SLN biopsy for DCISM.
Recurrence rates and long-term survival in women diagnosed with breast cancer at age 40 and younger.
Authors: Buckley J. M. , Coopey S. , Samphao S. , Specht M. C. , Hughes K. S. , Gadd M. , Taghian A. G. , Smith B. L. 
Published: February 2017

70 Background: Young age at diagnosis of breast cancer has been reported to be an independent risk factor for disease recurrence. However, there is little data on long term survival of young patients. We present long term follow up of a large cohort of women diagnosed with breast cancer at age 40 and younger. We determined rates of loco-regional recurrence (LRR), distant recurrence, and overall survival and adjusted for the patient and tumor characteristics which potentially predict outcomes. Methods: Following Institutional Review Board approval, data from the medical records of 628 women diagnosed with breast cancer at age 40 or younger between 1996 and 2008 were collected. Survival curves were estimated using the Kaplan Meier method. Results: Median age was 37 years (range: 21-40) and median follow-up was 72 months (range: 5-177). The rates of LRR as a first site of recurrence were 5.56% at 5 years and 12.11% at 10 years. In the entire population, with median follow-up of 72 months, there was no difference in the rates of loco-regional failure between patients who underwent breast conserving therapy (7.34%) compared to mastectomy (7.40%) (p=0.980). The rates of distant recurrence as a first event were 10.65% at 5 years and 14.58% at 10 years. Overall survival was 93.1% at 5 years and 87.26% at 10 years. 79.1% of patients received systemic therapy. For patients who developed disease recurrence, either LRR or distant, median time to first recurrence was 35 months (range: 3-167). Conclusions: Women aged 40 and younger at diagnosis of breast cancer have a good prognosis, with low overall recurrence rates at 5 and 10 years. Local recurrence in our cohort is lower than in prior studies, suggesting advances in therapy have made breast conservation a safe option in young breast cancer patients.