bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes of an organized breast cancer screening program over the past 15 years.
Authors: Rajapakshe Rasika , Parker Brent , Araujo Cynthia , Chu Christina , Wilson Christine , Sam Janette
Published: February 2017

14

Background: Founded in 1988, The Screening Mammography Program of British Columbia (SMPBC) is a large, and stable screening program and a formal review of its effectiveness provides suggestions for further improvements. The purpose of this study is to quantify and report trends of the SMPBC and to assess if there have been any major changes in outcomes over the past fifteen years as this program has matured. Methods: A retrospective review of the SMPBC was performed by extracting data from the past 15 years from the SMPBC Annual Reports. The changes and trends in percentage of eligible population screened/participation rate, number of screening exams and number of first screens performed, overall cancer detection rate, and DCIS detection rate was extracted and reported. Furthermore, cost analysis data was extracted, and adjusted to compensate for inflation using The Bank of Canada Inflation Calculator, which bases its calculations from the Canadian Consumer Price Index (CPI) from Statistics Canada. Results: Over the past 15 years, the total number of exams provided per year has almost doubled from 166,746 in 1996 to 303,157 in 2010, and this increase accommodates the overall and aging growth of the BC population. An increasing participation rate is seen from 1999-2009 for women from rural sites and traditionally underserved areas of British Columbia, while the overall participation rate over this time period remains stable (range 48%-51%). The cancer detection rate also remains stable (range: 3.4-4.5 cases per 1000 screens). After adjusting for inflation, a 12.6% increase in the cost per screen from 1995-2009 is observed. This increase is multifactorial and includes an increase in operating costs central services and physician reading fees. Conclusions: The province of British Columbia has consistently had the lowest rates of breast cancer related mortality in Canada, and this may be, in part, because of the long term stability of the BC Screening Mammography Program. Our report suggests that the SMPBC has been effective in accommodating the growing aging population, although there is still room for improvement, as a target participation of 70% is considered the standard to effectively reduce mortality through screening.
Chemotherapy treatment patterns for early-stage breast cancer (ESBC): Decreasing use of anthracycline-based regimens.
Authors: Serrurier Katherine M. , Hwang Jimmy , McGuire Joseph P. , Griffin Ann C. , Melisko Michelle E. , Rugo Hope S.
Published: February 2017

141

Background: Anthracyclines (A), given in sequence or combination with other agents, have been the mainstay of adjuvant chemotherapy (CTX) for ESBC for more than two decades. Recent molecular studies have questioned the value of A for lower risk disease. A single prospective trial presented in 2005 and published in 2006 (Jones et al) compared docetaxel and cyclophosphamide (TC) to doxorubicin and cyclophosphamide and reported improved disease free survival (2006) and overall survival (2009) with TC. We sought to understand the impact of this study on the type of CTX regimens used to treat ESBC. Methods: Using the UCSF Cancer Registry database and including patients who received at least one cycle of CTX at UCSF, we recorded use of A or non-anthracycline (NA) based CTX regimens in women with ESBC and correlated type of CTX with tumor stage, receptor status, and age. Based on the publication date of TC we looked at the use of A versus NA based CTX during two time periods, 2000-2005 and 2006-2010. Results: 1,116 patients met criteria for inclusion; 17 were excluded due to inadequate information. Patient characteristics were: median age 49 (range 21-78), stage I (24%), stage II (56%), and stage III (20%), 50% hormone receptor (HR) +, 25% HER2 +, 17% HR-/HER2-. From 2000-2010, 80% received A CTX. Overall use of A decreased from 95% to 65%, while use of NA based CTX increased from 5% to 35%. The table compares use of NA CTX during the two time periods by clinical variables. Conclusions: Use of NA CTX increased significantly over the 2nd half of the last decade in all cases except those patients with stage III disease. The timing of this marked change correlates with publication of TC, and emphasizes the impact of positive phase III trials on treatment practice. This study was supported by the UCSF Cancer Registry. [Table: see text]
Intraoperative electron radiotherapy in early-stage breast cancer: A report on 226 patients.
Authors: dall'Oglio Stefano , Maluta Sergio , Marciai Nadia , Gabbani Milena
Published: February 2017

143

Background: We report the results of a single-institution phase II trial of accelerated partial breast irradiation (APBI) using a single dose of intraoperative electron radiotherapy (IOERT) in patients with low-risk early-stage breast cancer. Methods: From July 2006 to December 2009, 226 patients suitable for BCT were enrolled in a phase II trial with IOERT as radical treatment immediately after surgical resection. All patients had biopsy-proven cancer. After the surgeon temporarily re-approximated the excision cavity, a dose of 21 Gy using IOERT was delivered to the tumor bed with a margin of 2 cm laterally. Results: No acute reactions were reported after irradiation. Three patients experienced a transient edema. In 7 others a haematoma was observed. No cases of liponecrosis were observed. With a mean follow-up of 49 months (range 31-66 months), only one case of local recurrence has been reported. The observed toxicity was considered acceptable. As to cosmetic results, at 6 months after the end of IORT, 71/226 patients (31.4.%) had a score of 2 for symmetry and contour (asymmetry exhibited by 1/3 or less of volume breast), while 19/226 (8.4%) had a score 3 (asymmetry greater than 1/3 of breast volume). These findings remained unchanged at the following examinations. No breast oedema, discoloration at site or scar prominence were observed. Conclusions: IOERT offers the advantage of an excellent delineation of the tumor bed under visual control and high sparing of normal tissue, including the skin. IOERT delivers a very high biologically dose at the time of the surgery, when residual tumor cells are more rapidly proliferating. IOERT is insensitive to chemotherapy sequencing since all of the radiation is given during the surgery. The absolute recurrence rate of 0.4% and the recurrence rate per year of 0.2% of the present study are very encouraging. APBI using a single dose of IOERT can be delivered safely in women with early, low-risk breast cancer. A longer follow-up is needed to ascertain its efficacy compared to that of the current standard treatment of whole breast irradiation.
Primary and secondary prophylactic nipple-sparing subcutaneous mastectomy (NSSM): A retrospective single-center analysis.
Authors: Paepke Stefan , Allhorn Svenja , Kiechle Marion
Published: February 2017

162

Background: Given a strict indication the NSSM is a oncologically safe surgical procedure and allows breast reconstructive interventions with a good cosmetic result. With regard to prophylactic mastectomy (PM) the (radical) ablatio mammae is so far regarded as the therapy of choice, since a maximal removement of the breast glandular tissue seems ensured. So far, it is unclear if NSSM is a oncologically safe treatment option also in the context of prophylactic surgery. The introduction of new materials for tissue extension in plastic-reconstructive interventions such as porcine acellular dermis (Strattice) or titanized polypropylene meshes (TiLoopBra) permits the reconstruction of the natural breast shape and size and thus the preservation of the body integrity also in prophylactic operations. Methods: This is a retrospective analysis of the PM performed at the Department of OB/GYN of the TU München (Munich, Germany) between 01/2005 and 12/2011 (76 cases). Primary PM were done in 13 cases due to positive family history (n=3), BRCA mutations (n=9) or at the request of the patient (n=1). 63 breast cancer patients were operated (secondary contralateral mastectomies) because of a positive familiy history (n=21), BRCA mutations (n=17) or high need for security (n=25). 19 mastectomies and 57 NSSMs were performed. With all NSSMs an instant reconstruction was done (17x expander, 25x implants, 1x TRAM, 14x DIEP), in 42 patients using a tissue extension (titanized poylpropylene meshes or acellular dermis). 9 patients with ablatio mammae received a breast reconstruction. Results: There was a continuous increase in prophylactic operations and NSSMs over the past five years. In four patients there was a coincidental pathological finding diagnosed in the healthy breast (2x DCIS, 1x Ca, 1x CLIS). In the group of primary prophylactic operated patients there were no (pre-)cancerous lesions found. In the secondary PM patients there were no recurrences, secondary cancers or metastases. Conclusions: In conclusion there was no difference between both surgical techniques with regard to oncologic safety. As far as breast reconstructive possibilities are concerned there are clear advantages in NSSM.
Breast cancer and vitamin D in postmenopausal minorities.
Authors: Gokalp Yasar Demet , Khosla Pam
Published: February 2017

17

Background: Bone health is a particular concern for breast cancer survivors, because these women have 15% higher fracture risk than women without a history of breast cancer. Many studies have suggested that vitamin D deficiency may be involved in breast cancer initiation, progression, and prognosis. This study examines the prevalence of vitamin D deficiency among postmenopausal breast cancer patients in minority population. Methods: This retrospective study reviewed the electronic records of 200 postmenopausal breast cancer patients from ethnic groups of blacks, Hispanics and Asians. Results: Of the 200 patients, 84 (42%) had their 25-OHD levels checked at least once. Of patients, 42.7% found body mass index (BMI)>30kg/m2. There was significant difference between race and BMI (p<0.05). Black Vitamin D deficiency (level< 20ng/mL) found in 35 (41.7%), vitamin D insufficiency (level range 20-30ng/mL) found in 30 (35.7%) of the patients. The median serum 25-OHD level was 21 (range 4-65ng/ml). The serum 25-OHD levels did not have significant difference among blacks and Hispanics. Tumor stages found negatively correlated with 25-OHD levels r=-0.227 and p=0.04. Conclusions: This study revealed that vitamin D deficiency has a high prevalence among postmenopausal breast cancer minority population. Data from Third National Health and Nutrition Examination survey showed that mean serum 25-OHD levels among white, Hispanic and black women were 76ng/ml, 56.7ng/ml and 45.3ng/ml, respectively. Also, prevalence rate of vitamin D deficiency is reported in the studies among breast cancer patients are approximately 30%. Our data compared with this general population’s numbers is low; our median 25-OHD level was 21ng/ml. Our study found negative correlation with Vitamin D levels and stages of the breast cancer. Information is lacking on direct prognostic effect of vitamin D in breast cancer but this findings including our study support the hypothesis that vitamin D has a role in the pathogenesis of breast cancer. In the setting of breast cancer diagnosis either for bone health, or for breast cancer prognosis in postmenopausal women, we advocate routine 25-OHD levels screening for the vitamin D deficiency especially in minority populations would be beneficial.
In-breast tumor recurrence rate of breast CT-guided lumpectomy: A prospective multi-institutional study in Japan.
Authors: Sato Nobuaki
Published: February 2017

170

Background: We have conducted the prospective multicenter study to evaluate the usefulness of breast CT in delineating tumor extent and preoperatively determining the optimal surgical procedure (Sadako Akashi-Tanaka et al, Ann Surg in press). Breast CT, carried out in the supine position, was useful since breast CT correctly changed the extent of surgery in 13.1% of patients. Here, we present the in-breast tumor recurrence (IBTR) of these patients undergoing CT guided breast conserving surgery. Methods: The follow-up records of 271 women treated with local excision (complete removal of gross tumor with a margin) for breast cancer at 3 Japanese hospitals were reviewed. CT guided surgery was performed as follows; the surgeon marked the line of planned excision prior to CT on the skin, which was also recorded on the CT image. Contrast-enhanced breast CT was performed in the supine surgical position. The CT results were used to determine the extent of surgery. IBTR was defined as a recurrence in the treated breast without regional or distant metastases. Results: The median age at surgery of them was 55 years (range, 21 to 88 years). The median palpable tumor size was 1.6cm (range, 0 to 3.5 cm). Tumor histology was as follows: ductal carcinoma in situ 13, invasive ductal carcinoma 234, invasive lobular carcinoma 10, mucinous carcinoma 6, and special type 8. The median follow-up after treatment was 3.8 years (range, 3.0 to 5.3 years). The rate of IBTR was 10/271 (3.7%). The 3.8-year rate of IBTR was 4.5%. Discussion: Without prospective randomized controlled studies, it is unlikely that a definitive conclusion can be reached on whether imaging-guided diagnosis of tumor extent will reduce the rate of IBTR. However, it seems almost ethically impossible to conduct such a clinical study in Japan, because preoperative imaging-guided diagnosis of tumor extent is routinely performed prior to surgery. Conclusions: Although this was not the randomized controlled study, CT-based preoperative diagnosis of tumor extent has the potential to improve the accuracy of breast-conserving surgery. The long-term results of IBTR need to be assessed.
Surgical treatment and outcome of patients with invasive breast carcinoma age 80 or older.
Authors: Besic Nikola , Zmuc Jan , Peric Barbara , Pilko Gasper , Petric Rok , Perhavec Andraz
Published: February 2017

171

Background: Because the population ages, the proportion of breast cancer (BC) patients over age 80 is increasing. To date, there is no consensus as to what the best treatment is for older patients with BC. The aim of our retrospective study was to analyze data about surgically treated BC patients with ≥80 years of age and their outcome. Methods: A chart review of 158 early BC patients (mean age 83; range 80-90) that were surgically treated at our institute from 2000 to 2008 was performed. The data on the extent of disease, morphologic characteristics, mode of therapy, recurrence and survival were collected. Correlation between possible prognostic factors, mode of therapy and cause-specific survival was analyzed by univariate and multivariate test. Results: Extension of BC was local, locoregional and unknown in 37%, 46% and 17% of cases; pT1/pT2 and pT3/pT4 tumor stage was present in 75% and 25%, respectively. Conservative breast surgical procedure, mastectomy, axillary lymphadenectomy, sentinel lymph node biopsy and no lymph node surgery was done in 27%, 73%, 57%, 18%, and 25%, respectively. Adjuvant hormone therapy (tamoxifen in 56 and aromatase inhibitors in 47 cases), chemotherapy and external radiotherapy were used in 65%, 1.2% and 15% of patients. Recurrence occurred in 23% of cases during the follow-up period of 0.2-11 years (median 4.3 years); local, regional and/or distant in 10%, 6% and 22% of cases, respectively. Because of BC and other reasons died 20% and 20% of cases, respectively. The 5-year cause-specific survival in patients with local and regional extension of BC was 86% and 74%, respectively. Univariate statistical analysis showed that pT3/pT4 tumor, pN1 stage, mastectomy, sentinel node biopsy and lymphadenectomy correlated with shorter cause-specific survival. Multivariate analysis showed that only pT3/pT4 tumor and pN1 stage correlated with shorter cause-specific survival. Our results indicate that our patients were locoregionally treated adequately to tumor stage Conclusions: Short cause-specific survival indicates that BC in patients with ≥80 years of age and regional metastases may be aggressive. Adjuvant chemotherapy might be considered in selected cases to prolong survival.
Postmastectomy radiation for stage ll breast cancer patients with T1/T2 lesions.
Authors: Libson Shai , Ma Charles , Takita Cristiane , Avisar Eli
Published: February 2017

175

Background: Post mastectomy radiation (PMR) is usually recommended for T3 or N2 breast cancer (BC). The role of PMR for stage ll BC with T1/T2 lesions remains controversial. The aim of this study was to assess the role of PMR in this subgroup of patients. Methods: A retrospective analysis of a prospectively collected database of all stage ll BC patients treated with mastectomy at our institution between 2005-2008 was performed. Demographics, tumor stage, histology, receptor status, adjuvant therapy, nodal status, failure patterns and disease free survival rates (DFS) were compared between the patients who received PMR vs.those who were not radiated. Results: Eighty-two patients underwent mastectomies for stage II disease with a T1/T2 lesion. Twenty two of those (27%) received PMR. The average follow up time was 47 months. The patients in the PMR group had significantly larger tumors (90% vs. 64%), more advanced stages (55% vs. 17%) and higher grade histology (59% vs. 32%). Menopausal status, nodal disease, histology, multifocality and receptors status did not differ significantly between the groups. Three patients in the non radiated (NR) group had a distant recurrence compared to 2 patients in the PMR group. There was one contra-lateral cancer in the NR group. The overall DFS was 86.6% in the NR group vs.91% in the PMR group, (p=0.72). Four patients had a chest wall recurrence (CWR) in the non-radiated (NR) group compared to none in the PMR group; however this was not statistically significant. In a sub-groups analysis comparing only T2, Stage IIB and high grade tumors respectively between the PMR and NR groups there was also no statistical difference in local or distant recurrence and in DFS. In the NR group, high grade tumors (p=0.0024) and estrogen receptors (ER) negativity (p=0.0168) were prognosticators of CWR. Conclusions: In our series PMR did not result in a statistically improved outcome for stage ll BC with T1/T2 lesions. A prospective trial randomizing patients with high grade or ER negative tumors only between PMR vs. NR could further clarify the role of PMR for stage II (T1/T2) lesions.
Analysis of interleukin-8, alpha1-antitrypsin, and tumor necrosis factor-alpha as biomarkers of breast cancer in women of northeastern Mexico.
Authors: Reyes-Lopez Miguel Angel , Sanchez-Meza Alberto Onofre , Bocanegra-Garcia Virgilio , Barrera-Saldana Hugo Alberto , Garza-Rodriguez Maria de Lourdes , Sanchez-Dominguez Celia Nohemi
Published: February 2017

18

Background: Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease and variations of protein values in plasma. Interleukin (IL)-8, alpha 1-antitrypsin (AAT) and tumor necrosis factor-alpha (TNF alpha) have been related to carcinogenesis in breast tissue. Whether polymorphisms of the genes and protein values also influence breast cancer risk is unclear. The objective was to analyze the levels and polymorphisms of biomarkers in breast cancer patients for diagnostic purposes. Methods: In this cases-controls study a total of 30 patients with breast cancer confirmed by histopathology and 21 healthy individuals were studied, both groups were of three generations born in the Northeast of Mexico. Two polymorphisms of the AAT gene (Alleles Z and S), a polymorphism of IL-8 (-251 A/T polymorphism of the IL-8 promoter), and the polymorphism of TNF-alpha [-308 G/A (TNF1/TNF2) polymorphism of the TNF-alpha promoter gene] were analyzed using PCR-RFLP. Additionally, the plasma protein values of the biomarkers were measured by ELISA. Results: The IL-8 (-251T) and TNF-alpha (-308G) polymorphisms were significantly associated with breast cancer. Odds ratios for women with one high-risk allele versus women homozygous for the low-risk allele were 4.06 for -308G TNF-alpha (95% confidence interval, 1.298-13.678; P = 0.006) and 2.44 for -251T IL-8 (95% confidence interval, 1.277-4.7; P = 0.003). Significant differences between protein values of patients and controls were observed (ATT U=63, Z=4.81, p (2) <0.0001; IL-8 U=112.5, Z=3.87 p (2) =0.0001; TNF-α U=135.5, Z=3.43, p (2) =0.0006), AAT and IL-8 were over-expressed in patients with breast cancer. The presence of the polymorphism does not influence the protein values (TNF rs=0.1203, IL-8 rs=0.2246), apparently. No association between presences of the polymorphism. Conclusions: In this study, the presence of the IL-8 (-251T) and TNF-alpha (-308G) alleles may increase the risk of breast cancer in these Mexican women. Over-expression of IL-8 and AAT may directly correlate to the pathogenesis of breast cancer. Both biomarkers may be combined with other markers for presumptive diagnosis.
Axillary recurrence (AR) after negative sentinel node biopsy (SNB): Who is at risk?
Authors: Farkas Rachel Leah , Hicks David G. , Tang Ping , Shayne Michelle , Huston Alissa , Ling Marilyn N. , Skinner Kristin A.
Published: February 2017

180

Background: AR after negative SNB is a rare event. The purpose of this study was to identify factors associated with AR. Methods: A breast cancer (BC) database was reviewed identifying 4 cases of AR among 424 (0.9%) patients with a negative SNB over a 5 year period. Demographic, pathologic and treatment data were collected. Patients with AR were compared those without using standard methods for contingency tables to identify factors associated with AR. Results: Tumor and treatment factors are shown in the table. There was no difference in age, race, menopausal status, tumor size or palpability, or the average number of SLNs harvested between the groups. Recurrences were only seen in patients with triple negative (TN), high grade tumors. AR occurred in 12.5% of pN0(i+) BCs compared to 6% of pN0 BCs (p<0.05). AR occurred in 3.5% of BCs with LVI compared to 0.5% of BCs without LVI (p<0.05). AR occurred in 4.3% of high grade BCs compared to 0% of non-high grade BCs (p<0.05). When comparing those with AR to TN patients without AR, patients with AR were less likely to have received chemotherapy(CT) (3 of the 4 patients declined). Both AR patients who received radiation therapy (XRT) had fields limited by anatomic constraints and the recurrence occurred outside of the radiated fields. AR occurred in 2% of TN BCs treated with CT compared to 19% of TN BCs not treated with CT (p<0.05). Conclusions: For a patient to develop AR there must be retained occult disease in the axilla that is not controlled by adjuvant therapies given. Factors such as high grade tumors and LVI that increase the chances of node positivity or increase SNB false negative rates increase the chances of retained occult disease in the axilla. If these patients do not receive optimal adjuvant therapies, there is a substantial risk of AR. Care should be taken when using SNB in such high risk patients. [Table: see text]
Clinical outcomes of patients with tumor bed-to-skin distance (TBS) ≤ 7 mm treated with accelerated partial breast irradiation (APBI) using multilumen catheter.
Authors: Abboud Mirna , Nitsch Paige , Paulino Arnold , Blanco Angel Ignacio , Bass Barbara Lee , Shadle Kathleen M. , Teh Bin S.
Published: February 2017

182

Background: The initial single-lumen Mammosite trial has shown that skin spacing had an important implication on cosmetic outcomes. In this study, we reviewed the patients who were treated with APBI using multilumen catheter and assessed the outcomes for patients with minimal TBS of ≤ 7mm. Methods: Between August 2008 and April 2011, 79 patients were treated with breast-conserving therapy and adjuvant APBI using the Contura Multi-Lumen balloon or strut-adjusted volume implant (SAVI) device. All patients received 3,400 cGy in 10 fractions delivered twice daily using high dose rate radiation with Iridium 192. The dose was prescribed to 1 cm from the applicator surface. Thirty-six patients had a TBS of ≤ 7mm. We analyzed the clinical outcomes according to RTOG 9517 and skin toxicities as per RTOG 9804 in this patient subgroup. Results: The median age was 65 years (range, 50-86 years). All patients had Tis-T1N0 carcinomas; 39% had DCIS and the rest had invasive carcinoma. The majority (92%) were treated with Contura Multi-Lumen balloon and 8% with SAVI. Median follow-up was 18 months (range 6-42 months). The average TBS was 4.8 mm (range 1-7). 21 patients (57%) had a TBS of ≤ 5mm. The median maximal skin dose was 116% (range 82-134%). The median V90, V95 and V100 were 98%, 96% and 92% respectively. The average V150 and V200 were 31.2 and 9.6 cc respectively. At a median of 3 weeks after treatment, 95% of the patients had good to excellent cosmetic outcome. 54% had grade 1, 21% patients had grade 2 skin toxicity and 25% did not have any skin reaction. At last follow-up, 82% of the patients did not have any residual late skin reaction. Grade 1 skin toxicity was reported in 13%, and grade 2 in 1 patient. Cosmesis was excellent in 72% and good in 28% of the patients. There was no loco-regional recurrence. Conclusions: In our patient population, APBI proved to be an effective treatment with a good to excellent cosmetic outcome and acceptable toxicity. Further investigation with larger patient populations and longer follow-up is warranted to confirm the safety and efficacy of APBI for patients with small TBS.
Evaluation of autophagy as a therapeutic target for DCIS.
Authors: Espina Virginia A. , Edmiston Kirsten H. , Liotta Lance A.
Published: February 2017

189

Background: Survival of intraductal, preinvasive proliferating cells under stress may promote genetic instability and the selection of invasive carcinoma cells. Our analysis of the mechanisms used by DCIS cells to survive in the hypoxic, nutrient deprived intraductal niche has revealed autophagy as a therapeutic target. Methods: DCIS spheroid forming cells have been isolated and propagated from fresh human DCIS lesions. We characterized the DCIS cells by organ culture, xenograft transplantation, molecular cytogenetics (300,000 SNPs) and 59 signal pathway profiling endpoints (Reverse Phase Protein Microarray [RPMA]). Results: DCIS spheroid forming cells were tumorigenic in xenograft models. Autophagy is up-regulated in: human DCIS lesions, DCIS spheroid-forming cells, and the xenograft tumors they generate. Autophagy is a means for intraductal neoplastic cells, accumulating in the duct, to digest intracellular contents and generate energy to survive in the face of severe metabolic, oxidative, and hypoxic stress. Suppression of autophagy by chloroquine kills human DCIS spheroid forming cells in culture and prevents them from forming tumors in xenografts (p < .0003). Based on these preclinical insights we have opened a neoadjuvant therapy trial for DCIS (NCT01023477 PINC Trial) to examine the safety and effectiveness of oral 30-day chloroquine for patients with any stage/grade DCIS. At the conclusion of treatment, all patients receive standard of care surgical therapy. MRI is performed before and after the treatment period. Endpoints compared before, versus after, therapy are lesion shrinkage, pathologic regression, disruption of lesion autophagy and proliferation (Ki67), induction of apoptosis, and suppression of xenograft tumorigenicity. Each patient serves as her own control because effectiveness is judged by comparing the patient’s DCIS lesion before and after oral therapy. Conclusions: We hypothesize that the intraductal pre-neoplastic cellular niche will be preferentially sensitive to a short term, anti-autophagy based prevention therapy which targets survival pathways used by pre-invasive carcinomas. Our unique trial design offers a means to functionally screen investigational agents that kill premalignant breast lesions.
Association of dyslipidemia with the aggressive molecular subtypes and pathologic profile of newly diagnosed nonmetastatic breast cancer patients.
Authors: Luna Herdee Gloriane Cristal , Luna Cher Alaine Cristal , Cristal-Luna Gloria R. , Luna Cesar Vilela
Published: February 2017

19

Background: To investigate the association of dyslipidemia with the aggressive pathologic profile and molecular subtypes among the premenopausal and postmenopausal breast cancer patients. Methods: A retrospective review of Filipino breast cancer patients from 1990 to 2010 from an oncology clinic was done. Patients were grouped to pre- and post-menopausal and each group were divided to those with and without dyslipidemia. Association of dyslipidemia with breast cancer aggressiveness, (1) by pathology (histopathologic diagnosis, grade, invasion, TNM stage) and (2) by molecular phenotype (using the hormone status: estrogen and progesterone receptor positivity) and HER-2 neu status (overexpression by immunohistochemical stain / gene amplification by fluorescent in situ hybridization), was assessed using Fisher exact test. Results: Among 728 breast cancer patients, 201 met the inclusion criteria with 103 premenopausal (36 with dyslipidemia, 67 without dyslipidemia) and 98 were postmenopausal (42 with dyslipidemia, 56 without dyslipidemia). Significant association was noted only among pre-menopausal in terms of the molecular phenotypes (p value 0.002) when compared to individual parameters: total cholesterol (p value <0.001), LDL (p value <0.001), HDL (p value 0.006), and triglyceride (p value <0.001). Conclusions: Dyslipidemia was not found to be a factor associated with aggressiveness of breast cancer in terms of the pathology for both pre-menopausal and post-menopausal groups. Only among premenopausal patients was dyslipidemia shown to be a significant marker of aggressiveness in terms of poorer molecular subset (luminal B, HER-2, basal like). This finding was not observed among post-menopausal group.
Evaluation of one-step nucleic acid (OSNA) molecular assay for intra-operative diagnosis of sentinel lymph node metastasis.
Authors: Banerjee Shramana Mitul , Davidson Timothy , Michalopoulos Nikolaus , McDermott Nuala , El Sheikh Soha , Tran-Dang My-annh , Davison Stephen , Keshtgar Mohammed R.
Published: February 2017

194

Background: One step nucleic acid (OSNA) is a recently developed molecular diagnostic assay to detect lymph node metastases. Aim of the present study was to assess OSNA for intra-operative detection of sentinel node metastases with use of standard histopathology as the “gold standard.” Moreover, discordant cases were further investigated to assess their impact on patients’ management. Methods: 157 breast cancer patients with clinically and ultrasonographically negative axilla underwent axillary staging with sentinel node (SLN) biopsy. 244 SLNs were evaluated by OSNA and standard histopathology (alternate slices were submitted to OSNA and standard test). The “turn-around time” taken for an intra-operative OSNA result was recorded. Results: Sensitivity and specificity of OSNA were 92.3% and 95.6% respectively with positive predictive value of 80% and negative predictive value of 98.4%. The average time taken for an intra-operative result in this group was 34 minutes. Concordance rate was 95% while 12/244 nodes showed discordant results between OSNA and Histology. The discordant cases were re-evaluated by histopathologists and characteristics of this subgroup analysed. Patient’s management was altered by OSNA alone in 5 patients as they underwent axillary lymph node dissection on the basis of a positive OSNA when histopathology did not show evidence of metastasis. Two patients with nodes negative on OSNA had histopathology results showing metastases requiring delayed axillary clearance. The rest of the discordant nodes belonged to patients who had other nodes biopsied concurrently that were concordant in OSNA and histology. Conclusions: OSNA is a fast, valuable and highly accurate standardised method for the intra-operative evaluation of axillary lymph node metastasis and is part of our routine intra-operative assessment tool for sentinel nodes in breast cancer.
Clinical relevance of the use of FDG PET/CT in locally advanced breast cancer.
Authors: Vrancken Peeters Marie-Jeanne TFD , Koolen Bas , Rutgers Emiel J. , Rodenhuis Sjoerd , Valdés Olmos Renato O.
Published: February 2017

195

Background: As opposed to patients with early-stage breast cancer who are in general treated with primary surgery, patients with locally advanced tumors are usually treated with neoadjuvant chemotherapy (NAC). Optimal locoregional treatment after NAC starts with optimal staging before the start of NAC. Methods: Patients with stage II-III breast cancer underwent an FDG PET/CT of the thorax in prone position with hanging breasts. A panel of experienced reviewers blindly interpreted PET/CT images. Results: In 154 patients the FDG PET/CT was compared with conventional staging procedures (bone scintigraphy, ultrasound of the liver and chest radiography). We have shown that PET/CT has a higher sensitivity for the detection of distant metastases as no metastases were missed with the PET/CT and in 16 (80%) of 20 patients with proven metastases, one or more lesions were exclusively found with PET/CT. This resulted in a change of treatment in 13 (8%) of 154 patients. Furthermore we have shown that the FDG PET/CT offers a non-invasive procedure for the assessment of number of tumor-positive axillary nodes prior to NAC, enabling guidance for postoperative radiotherapy planning. In 311 patients a PET/Ct scan was performed prior to the start of NAC for this purpose. A substantial proportion of patients (16%) has been upstaged because of the detection of occult lymph node metastases in the internal mammary chain and periclavicular region, changing treatment in the majority of them. Conclusions: Based on these results we recommend performing an FDG PET/CT as a standard diagnostic procedure in stage II and III breast cancer patients prior to NAC. Current research regarding the use of PET/CT in breast cancer focuses on monitoring the response of the primary tumor and axillary node metastases to NAC in order to optimize locoregional treatment after NAC according to the tumor response.
Characteristics of medullary breast carcinoma compared with invasive ductal carcinoma.
Authors: Park Inhye , Kim Jiyoung , Lee Se-Kyung , Choi Min-Young , Bae Su Yeon , Jung Seung Pil , Kil Won Ho , Lee Jeong Eon , Nam Seok Jin
Published: February 2017

20

Background: Medullary carcinoma (MC) represents a rare breast cancer subtype associated with a rather favorable prognosis compared with invasive ductal carcinoma (IDC). It is characterized by the high-grade structure and lymphocytic infiltration, hemorrhagic necrosis. The purpose of this study is to compare the clinicopathologic characteristics and outcome of MC to IDC. Methods: We retrospectively reviewed the medical records of patients with invasive breast cancer managed with operation at Samsung Medical Center in Korea from January 1995 to June 2010 except patients diagnosed with ductal carcinoma in situ, patients with distant metastasis at diagnosis or neoadjuvant chemotherapy. 52 cases were identified with MC; 5,716 patients with IDC. The clinicopathologic features, disease-free survival (DFS) and overall survival (OS) for patients with MC were compared with those of the IDC patients. Results: The medullary group presented at younger age (43.9 ± 8.8 vs 47.7 ± 9.9, p=0.006). Also the medullary group was significantly associated with higher histological grade (poor; 80.0 vs 38.3%, p=0.003) and nuclear grade (grade3; 82.8 vs 41.7%, p<0.001) as well as negative ER (84.8 vs 31.0%, p<0.001) and PR status (91.3 vs 38.8%, p<0.001) regarded as poor prognostic factors. But lymphatic invasion was rare (0.0 vs 29.8%, p<0.001) and N stage was low (N0; 86.5 vs 58.4%, p<0.001). The DFS and OS were not significantly different between the medullary and IDC groups. (5-yr DFS : 88.0 vs 89.2 %, p=0.917, 5-yr OS : 94.4 vs 93.4%, p=0.502) In multivariable analysis, factors associated with DFS and OS included nuclear grade, histological grade, tumor size, lymph node metastasis, ER/PR/C-erbB2 status, chemotherapy and hormone therapy. When adjusting for other factors, histological type itself did not show significant difference from IDC in DFS and OS. Conclusions: Despite MC present specific clinicopathologic features, prognosis is not different from IDC and determined by already known prognostic factors such as tumor size, lymph node metastasis. Therefore, the patients with MC also need aggressive treatment like IDC.
The usefulness of ultrasonography in a ductal carcinoma in situ screening program for Japanese woman.
Authors: Kosaka Taijiro
Published: February 2017

24

Background: Although varying among areas, the mammogram (MMG) screening rate is very low in Japan as compared to the U.S. at approximately 20% versus nearly 80% in the U.S. On the other hand, rates of ductal carcinoma in situ (DCIS) detection among diagnosed breast cancers differ minimally: 20% in the U.S., and 15% in Japan. This is a small difference considering the difference MMG screening rates. Racial differences have been suggested to be attributable to the organization of screening programs in Japan, which also use ultrasonography (US) breast cancer screening, as well as breast size in Japanese women. Methods: We retrospectively evaluated MMG and US images of 91 DCIS cases, all 91 Japanese women who under underwent surgery between May 2010 and February 2012. US (TOSHIBA Aplio, probe 9MHz) was performed with knowledge of MMG findings. The 91 cases were divided into group with tumor detected by MMG and US (M&U), MMG detection only (M), and US detection only (U). The following parameters were analyzed: US shape (Tumor-forming lesion: TFL, Non-tumor-forming lesion: NTFL, Cystic-forming lesion: CFL), Skin-Muscle distance: SMD. We excluded asynchronous bilateral breast cancers and micro-invasive DCIS. Results: Sixty-eight lesions (73.0%) were identified by US, which revealed a NTLF in 52 cases, TLF in 9 cases and CFL in 7 cases. All cases with false-negative findings on US (Group M, n = 23) showed micro-calcifications on MMG (n=22) and with the tumor (n=1). In the U group, SMD was only 23 mm versus 43.4mm in the M group. No difference was observed in body mass index or pathological tumor diameter between the U and M. Conclusions: We found US to reveal DCIS in 73% of our cases upon reevaluation. Although US examination would not likely increase the screening detection rate for DCIS in Japanese women, US may reveal more DCIS in Japanese women, in which the breasts are comparatively small, than in western women. Further comparison of possible racial difference is warranted.
Kinase activity signature of breast cancer using peptide phosphosensors.
Authors: Mori Miki , Coppe Jean-Philippe , Chen Zhongzhong , van't Veer Laura
Published: February 2017

27

Background: Improper control of phosphorylation networks represents one of the most relevant regulator and biomarkers of cell dysfunctions leading to cancer. Surprisingly however, measuring the phosphorylation activity of kinases, and potentially monitoring the functionality of the entire kinome at once, remains largely unexplored. Specifically, a highly convenient tool for clinical applications or research purposes would be the advent of a microarray-like chip to comprehensively map phosphorylation networks. While developing such a kinase-sensing platform, we had to establish a library of probes capable of reporting on the catalytic activity of kinases. We present here strategies and results supporting such methodology. Methods: The devised kinase activity-sensing system we are currently exploiting, relies on peptide probes that act as beacons to evaluate enzymes functionality, which emit distinctive signals before and after (de-)phosphorylation. As presented below, computational and molecular biology methods were used to create and test such (phospho-)peptide sensors. Results: First, in order to use baits relevant to human cancer etiology, we created a protein and peptide repertoire from thousands of publications and >30 public databases computationally curated, filtered and merged. Such library catalogues 6173 distinctive kinase-substrate active nodes and compiles 2702 unique biological kinase peptide targets that all represent latent nano-sensors usable to comprehensively track kinase signaling networks. Second, real-time kinetics, kinase inhibitor and dilution experiments using 5 recombinant enzymes and cell extracts in ATP consumption assays demonstrated peptide 50 probes can directly and specifically assess the functionality of kinases. A panel of 10 peptides shows that the increased presence of activated Src kinase protein in breast cancer cell extracts is related to a significantly elevated kinase activity signature. Conclusions: Biological peptides can serve as phospho-sensing probes to evaluate the activity of kinases. Our efforts will now focus on expending this approach into a functional kinomic-screening platform to map phosphorylation signatures relevant for breast cancer.
Mutation analysis of PALB2 in high-risk and lower-risk patients negative for BRCA1 and BRCA2 mutations.
Authors: Cummings Shelly , Peterson Jenny , Hughes Elisha , Kaldate Rajesh R. , Chen Sonia , Trost Jeffrey T. , Arnell Christopher , Saam Jennifer R. , Roa Benjamin , Fernandes Priscilla H.
Published: February 2017

30

Background: PALB2 has been identified as a breast cancer susceptibility gene conferring ~ 2-4 fold increased risk of breast cancer. A number of studies have estimated the PALB2 mutation prevalence to range from 0.5% - 2.9% in populations of breast cancer patients. We performed an analysis to determine the PALB2 mutation prevalence in a large U.S. referral testing population. Methods: DNA samples were anonymized from two subsets of patients: 955 early onset breast cancer patients with severe family history, and 524 patients with later onset of breast cancer and/or less severe family history. All patients were negative for deleterious sequence mutations or large rearrangements in BRCA1 and BRCA2. Results: We identified 10 disease associated PALB2 mutations in the high risk group of 955 patients and 2 deleterious PALB2 mutations in the lower risk group of 524 patients. Identified PALB2 mutations included 8 nonsense, 3 frameshift mutations and a splice site mutation. The mutation prevalence for the high risk population was 1.05% (95% C.I., 0.5 -1.92) whereas that for the lower risk population was 0.38% (95% C.I., 0.05-1.37). The observed rate of PALB2 variants of unknown significance (VUS) identified in this study was ~5% (78 VUS were in 75 of the 1479 patients that were tested). Our variant classification program which successfully decreased the VUS rate in BRCA1 and BRCA2 is similarly expected to enhance mutation classification on an on-going basis for PALB2 genetic testing. Conclusions: Genetic testing for PALB2 may be indicated as a reflex test for breast cancer patients who test negative for BRCA1 and BRCA2.
Identification of AGR3 as a potential biomarker though public genomic data analysis of triple-negative (TN) versus triple-positive (TP) breast cancer (BC).
Authors: Umesh Anita , Park Jenny , Shima James , Delaney Joseph , Wisotzkey Robert , Kelly Erin , Chiu Elizabeth Beatrice , Madhusoodanan Jyoti , Shekar Mamatha , Kupershmidt Ilya
Published: February 2017

31

Background: TNBCs have an aggressive clinical phenotype with worse prognosis than TPBC. Here we sought to identify other genomic changes in patients with TN vs. TPBC, by mining TCGA breast cancer genomic data using the NextBio Clinical platform. Methods: Breast cancer patients with decreased (n=51) and increased (n=46) ER/PR/HER2 mRNA levels were selected with the molecular filter in NB Clinical. Top-ranked differentially expressed genes were identified then analyzed via NB Research, which comprises a library of individually curated publically available research and clinical grade genomic data. Results: Whole transcriptome analysis of TNBC and TPBC patients identified anterior gradient-3 (AGR3), a protein disulfide isomerase, as most downregulated (TNBC vs. TPBC, fold change = -178.2, p=2.7E-32). AGR3 mRNA was reduced in 94% of TNBC and increased in 96% of TPBC patients. AGR3 was hypomethylated in 50% of TPBC vs. 4% of TNBC patients, suggesting regulation by methylation. When the entire breast cancer cohort was stratified by AGR3 expression, underexpression was prevalent in younger patients (<50 yr, 39%) compared to those with overexpression (<50 yr, 23%). Further, 63% of AGR3 underexpressing patients had severe TP53 mutations vs. 19% with AGR3 overexpression. Breast cancer was most correlated to AGR3 in the NextBio Disease Atlas, with supporting data from 110 studies. AGR3 expression was decreased in ER- vs. ER+, PR- vs. PR+, HER2- vs. HER2+, and G3 vs. G1 tumors, and AGR3 promoter was hypermethylated in ER- vs. ER+, consistent with the TCGA results. Body Atlas showed strongest AGR3 expression in mucosa, fallopian tube, breast, and epithelial cells, in line with its proposed role in epithelial barrier function. Knockdown Atlas results showed TP53 mutation associated with reduced AGR3 mRNA, and the PharmacoAtlas showed positive regulation of AGR3 by estrogen analogues. Conclusions: Using the NextBio Clinical and Research platforms, we identified AGR3 as a marker of TNBC vs. TPBC that correlates with TP53 mutation status. AGR3 may provide an alternate route of TNBC treatment. Its potential in regulating epithelial barrier function may provide insights into the mechanism of disease progression.
Implications prognostics of methylation 14-3-3 sigma promoter in peripheral blood cell DNA with nodal involvement status and tumor size for breast cancer patients.
Authors: Martínez-Galán Joaquina , González Rivas Cynthia S. , Ruiz Vozmediano Julia , Ballesteros Pedro , Delgado Juan Ramón , Ríos Sandra , Núñez M. Isabel , Lopez-Peñalver Jesus , Torres-Torres Blanca
Published: February 2017

33

Background: Expression of 14-3-3 σ is a tumor suppressor gene induced in response to DNA damage, and has been implicated in G2/M cell cycle arrest by p53. Hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is now firmly established as an important mechanism for gene inactivation. To correlation methylation levels of promoter 14-3-3σ with association prognostic factors in breast cancer. Methods: This is a prospective study we quantified methylation levels of promoter 14-3-3σ gene in 107 women with breast cancer and 108 control subjects by Real Time QMS-PCR SYBR green and analyzed association with prognostics factor in breast cancer. Results: Median age was 58 years (32-88); 69% were postmenopausal women. Nodal involvement N0; 63%,N1;30%,N2;7%), tumor size (T1;58%,T2;35%,T3;4%,T4;4%) and grade G1; 20%,G2;37%,G3;30%). The methylation of 14-3-3σ were 60% of sporadic breast cancer patients and were 34% of normal breast (p=0.0047). The methylation of 14-3-3σ gene in serum was markedly related with T3-4 stage (p<0.05),nodal positive status (p<0.05) and poor outcome. With a median follow up 6 years we saw more probability of developing distance metastasis in patients with methylation 14-3-3σ (p>0.05). Conclusions: Hypermethylation of the 14-3-3σ a promoter is an early and frequent event in breast neoplastic transformation, leading to the suggestion that silencing of 14-3-3σ may be an important event in tumor progression and particularly in breast carcinogenesis.Therefore, it is possible that loss of σ expression contributes to malignant transformation by impairing the G2 cell cycle checkpoint function, thus allowing an accumulation of genetic defects. Perhaps in the detection of CpG methylation of 14-3-3σ may be used for diagnostic and prognostic purposes.