bluuebunny/crossref_metadata_2025 huggingface dataset:
P2-15-06: Breast Cancer Liver Metastases – Possibilities and Limits of Surgical Treatment.
Authors: Narsanska A , Treskova I , Treska V , Skalicky T , Sutnar A
Published: June 2012

Background

Breast cancer liver metastases (BCLM) are often considered as a sign of a systemic disease with little hope of therapeutic success. The aim of study was to assess the possibilities and determine the limits of the surgical treatment of BCLM.

Method: 646 patients were operated for malignant and benign lesions of the liver between 1999 and 2010. Liver surgery for BCLM was performed in 21 women of the average age of 48.5 years (33-71). The average time from the primary surgery for breast cancer till BCLM diagnosis was 4.7 years (2 months - 9 years). BCLM were solitary in 17 and in four cases multiple. Patient selection for liver surgery was based on sufficient future remnant liver volume, the absence of systemic non-resectable tumor dissemination and response to chemotherapy. The authors performed six right-sided hepatectomy, four segmentectomies, three left lobectomies, one metastasectomy, six radiofrequency ablations (RFA), one combined procedure -liver resection and RFA. Histological examination revealed ductal carcinoma in fourteen and lobular carcinoma in seven cases. All patients were treated with the curative adjuvant chemotherapy after surgery. The data were statistically evaluated by statistical software Statistica 9.0.

Results: 30 - days mortality rate was 0%. One patient had a complicated hepatectomy with iatrogenic bile duct injury. According to statistical analysis the probability of patients survival twelve, resp. thirty months after surgery was 100, resp. 66.7% and the probability of the tumor relapse anywhere in the body was at the same time intervals 0, resp. 71. 5%.

Conclusion: Liver surgery combined with the adjuvant chemotherapy are a therapeutic methods of choice for highly selected patients with metastases limited to the liver and objective response to neoadjuvant chemotherapy.

The study was supported by the research projects IGA MZ NS 9727 and IGA MZ NS 102 40.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-15-06.
P2-16-12: Skin Reducing Nipple Sparing Mastectomy – A Treatment Option for Patients with Significant Ptosis or Macromastia.
Authors: Ott Young A , Alizadeh K , Hodyl C , Pronovost M , Davenport T
Published: June 2012

Background: With new data showing the oncologic safety of nipple sparing mastectomy with immediate reconstruction - nipple sparing mastectomies are now offered to an increasing number of mastectomy patients. Unfortunately cosmetically acceptable reconstruction of nipple sparing mastectomies is technically limited to women with perfect breast anatomy - where the skin envelope shows no or little redundancy and where the nipple areolar complex is located in the perfect location on the breast mount. Especially in countries with a high incidence of obesity and associated macromastia only a small percentage of women fall into this category. A high percentahge of patients who would otherwise be good candidates for nipple sparing procedures are excluded based on their unfavorable breast anatomy. We describe a surgical technique that reduces the redundant mastectomy skin envelope in a breast reduction pattern and places the native nipple areolar complex as a free skin graft into proper anatomical position. This technique in conjunction with implant or autologous reconstruction combines the benefits of shorter better vascularized skin flaps with the cosmetic and emotional benefits of preserving the nipple areolar complex even in the anatomically difficult cases.

Methods: To investigate the safety and efficiency of this method we reviewed medical records of 40 patients who underwent 60 nipple preserving skin reducing mastectomies over the last 4 years. All procedures were performed by the senior author and follow up ranged from 4 weeks to 50 months.

The charts were analyzed for the occurrence of complications such as infection, seroma, hematoma, mastectomy flap necrosis, nipple-areolar loss and loco regional recurrence.

All patients were asked to rate their reconstruction on a scale of poor- good - excellent.

Results: In 60 reconstructed breasts we encountered one case of seroma, four cases of limited mastectomy flap necrosis treated with local wound care and one case of partial areolar necrosis treated with local excision. No loco regional recurrences, hematomas or infections were encountered. Out of the group of 40 patients, 31 patients rated their result as excellent, 8 as good, and one as poor.

Conclusion: Our results compare favorably with data published in the literature. Patient satisfaction rates are high and complication rates are low in a patient population that historically has been a challenge for the breast surgeon, as well as, the plastic surgeon. The use of a skin reducing mastectomy in conjunction with a free nipple graft enables the breast surgeon to offer nipple sparing procedures for all patients who are good oncological candidates regardless of their breast anatomy.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-16-12.
P2-17-02: Increased Progression Free and Overall Survival in Breast Cancer Patients with Menopausal Symptoms or Arthralgia/Myalgia during Adjuvant Treatment with Exemestane or Tamoxifen – Results of the German TEAM Trial.
Authors: Hadji P , Kieback DG , Hasenburg A , Tams J , Ziller M
Published: June 2012

Background

Previous studies have suggested a correlation between the occurrence of vasomotor or joint symptoms during tamoxifen or aromatase inhibitor treatment and improved clinical response. We assessed if there was any correlation between treatment-emergent adverse events during exemestane or tamoxifen treatment and clinical response.

Methods: A retrospective analysis of the German cohort of the TEAM trial was performed to assess progression-free survival and overall survival in patients with and without menopausal symptoms or arthralgia/myalgia during adjuvant treatment with exemestane or tamoxifen.

Results: A total of 1502 patients were included in this analysis; 739 patients received tamoxifen and 763 received exemestane. Patients reporting menopausal symptoms and patients reporting arthralgia/myalgia during tamoxifen or exemestane treatment had significantly longer overall survival and progression-free survival. The effect on overall survival was irrespective of treatment. Progression-free survival was significantly improved in exemestane-treated patients reporting menopausal symptoms or those reporting arthralgia/myalgia versus those not reporting these adverse events. There was no significant difference in progression-free survival between tamoxifen-treated patients reporting these symptoms versus those who did not. A combined analysis of patients reporting either menopausal symptoms or arthralgia/myalgia showed that overall survival and progressionfree survival was significantly improved in patients reporting one of these symptoms versus those not reporting either symptom. In this analysis, the effect on overall survival and progression-free survival was irrespective of treatment.

Conclusions: Our results suggest that the occurrence of menopausal symptoms or arthralgia/myalgia during treatment with tamoxifen or exemestane is associated with significantly improved overall survival.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-17-02.
P2-17-03: Incomplete Uptake and Diminished Adherence to Endocrine Therapy in Women with Hormone Receptor Positive Breast Cancer 4 Years from Diagnosis: An Australian Cohort Study.
Authors: Bell RJ , Fradkin P , Schwarz M , Davis SR
Published: June 2012

Background: Tamoxifen(T) and the aromatase inhibitors (AIs) are associated with side effects which impair adherence to therapy. Our aim was to investigate the uptake of, and adherence to, endocrine therapy (ET) in a cohort of women with invasive breast cancer (BC) nearly 4 years post-diagnosis.

Materials and Methods: The BUPA Health Foundation Health and Well being After Breast Cancer study is a prospective questionnaire-based cohort study of 1684 women with their first episode of invasive BC recruited between 2004 and 2006 through the Victorian Cancer Registry (VCR), Australia. An enrolment questionnaire (EQ) was completed within 12 months of diagnosis, with questionnaires every 12 months thereafter (FQ1-FQ3). Tumor pathology was provided by the VCR. FQ3 was completed on average 3.8 years from diagnosis. Active disease included a new primary BC, local recurrence or metastatic disease.

Results: Of 1684 recruits, 1370 were HR+. At diagnosis, average age was 58 years and 50% were stage 1. The table shows the number of HR+ women retained in the analysis at each questionnaire, the average time of each questionnaire from diagnosis and the proportions of women at each questionnaire on any ET on T, an AI or on no ET.

Switching of ET from T to an AI was predominantly a clinician decision. Cessation of T was patient initiated, mainly for vasomotor symptoms and vaginal bleeding. For the change from an AI to T, or cessation of an AI, the main reason was joint pain.

At FQ3, nearly 4 years from diagnosis, 215 (18%) women were not on any ET. Compared with women on ET at this time, these 215 women were more likely to have been stage 1 (rather than > stage 1) at diagnosis, have active disease by FQ3, be seeing an alternative therapist (all p<0.01) and were less likely to be seeing an oncologist (p<0.001).

The 215 women not on ET nearly 4 years from diagnosis consisted of 117 previous users and 98 never-users. Compared with the 117 previous users, the 98 never-users were more likely to be stage 1 at diagnosis (p<0.01) and be less likely to see an oncologist (p<0.001). Compared with women on ET at FQ3, both previous- and never users were more likely to have active disease and see an alternative therapist (all p<0.01).

Discussion: By nearly 4 years from diagnosis, an increasing proportion of women with HR+ BC are not on ET, despite the evidence for the benefit of therapy for at least 5 years. Differences between ET users and nonusers at this stage are not simply explained by previous users not continuing ET, with or without active disease. There is a small (8.2%) but important subgroup who appear to have never been on ET, which raises serious concerns.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-17-03.
P2-18-01: The Magnitude of Trastuzumab Benefit in HER2−Positive (HER2+) Lobular Breast Carcinoma (BC): Results of a HERA Trial Sub-Group Analysis.
Authors: Metzger O , Procter M , de Azambuja E , Viale G , Leyland-Jones B , Dowsett M , Gelber R , Gresko E , Loi S , Sotiriou C , Piccart M
Published: June 2012

Background: Invasive lobular carcinoma (ILC) represents the second most common BC subtype and is often characterized as hormone receptor positive and HER2−negative. However a small subset of ILC is found to be HER2+. Isolated case reports have demonstrated high responsiveness to trastuzumab in patients with advanced HER2+ ILC. The HERA trial compares 1 or 2 years of trastuzumab treatment with observation and 1 versus 2 years of trastuzumab treatment after standard chemotherapy in women with HER2+ breast cancer. We sought to evaluate the incidence of HER2+ ILC and the magnitude of trastuzumab benefit in HER2+ ILC in the context of the HERA trial. In addition, we sought to describe the pattern of hormone receptor positivity in the subsets of ILC and invasive ductal carcinoma (IDC) Methods: The database used in the analysis had a clinical cut-off date of 9th June 2008 and 4-year median follow-up (Gianni et al., 2011). Patients randomized to the 1-year trastuzumab and observation arms were included in the present analysis. Central assessment of hormone receptor status was considered. Histological BC subtype was assessed locally.

Results: Of the 1703 women randomized to one-year of trastuzumab and 1698 to observation, 5.5% (n=187) and 94.5% (n=3213) were diagnosed as HER2+ ILC and IDC, respectively. Central hormone receptor status was available in 88.3% (n = 2838) of IDC and 86.1% (n=161) of ILC. ER and/or PR positivity was more common in ILC than IDC (63.4% [102/161] vs. 46.3% [1314/2838]; p<0.001). Allred scores for ER are shown in the table below. The DFS hazard ratios comparing one year of trastuzumab versus observation were 0.63 (95% CI 0.34−1.14) for ILC and 0.77 (95% CI 0.67−0.89) for IDC. There was no evidence of an interaction between histological subtype and trastuzumab benefit (interaction [subtype lobular and subtype ductal and not lobular] p=0.49).

Conclusion: HER2+ ILC accounts for 5.5% of patients included in a large population of over 3,000 HER2+ BC. While only a limited number of patients with ILC was enrolled, this analysis suggests an increased ER positivity in ILC compared to IDC. There was no suggestion that patients with HER2+ ILC derived a different magnitude of benefit from adjuvant trastuzumab when compared to the HER2+ IDC cohort. The lack of central pathology review for BC subtype assessment is a caveat of our study. Future research in the field of ILC and particularly in the HER2+ subset should be encouraged.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-18-01.
P3-01-02: EC 304: A Novel Progesterone Receptor (PR) Antagonist Inhibits Transcription and Induces Cell Cycle Arrest in T47D Breast Cancer Cells.
Authors: Bhaskaran SS , Kesavaram N , Nickisch KJ , VandeBerg JL , Nair HB
Published: June 2012

Progesterone receptor (PR) is a ligand activated transcription factor which plays a crucial role in female reproduction. PR antagonists have been shown to repress estrogen dependent proliferation in the uterus and mammary gland. Even though PR antagonists are potent therapeutic candidates for breast cancer, partial agonism towards glucocorticoid receptor (GR) and androgen receptor (AR) lead to undesirable side effects. Evestra's rational design and development approach in the synthesis of EC304 was aimed at minimizing these side effects as well as to deliver more potent and selective antiprogestins. We used select screen® (Invitrogen) to determine relative binding affinity of EC304 with AR,GR and PR. The binding affinity of EC304 showed strong antagonism towards PR with mild or negligible agonism with AR or GR. PR transactivation was inhibited by EC304 with IC50 of 0.04nM in the presence of progesterone (5nM).

EC304 showed superior cytotoxicity over known antiprogestins ZK230211, ORG33628, CDB2914, CDB4124 and RU486 in T47D cells. IC50 of EC304 was found to be 0.5nM in a 6-day cytotoxicity assay (MTT) in T47D cells stimulated with 1nM estrogen (E2). In a 21-day in vitro tumorigenicity assay, EC304 inhibited 80 and 100% of colony formation of T47D cells in the presence of E2 at 1 and 10 nM respectively. Further studies revealed that EC304 induced apoptosis and G1-phase arrest in cell cycle progression when co-incubated with E2 for 24 h. Treatment with EC304 down regulated PR target genes and up regulated cell cycle dependent kinase (CDK) inhibitor P21 in vitro. Ongoing studies address whether EC304 is specifically acting on PR-A or PR-B isoform at gene expression, protein levels and PR isoform specific knockdowns in T47D and other metastatic breast cancer cells. Considered together, these data indicate that EC304 might be a safer but efficacious novel antiprogestin for hormone sensitive postmenopausal breast cancer patients.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-01-02.
P3-01-06: NF-kB Inhibition Promotes Radiosensitivity of Breast Cancer Cells in Three-Dimensional Culture through Abating b1-Integrin Expression.
Authors: Ahmed KM , Zhang H , Park CC
Published: June 2012

Therapy-associated tumor resistance, giving rise to recurrence and mortality, is a critical issue in cancer therapy. The molecular mechanisms causing tumor resistnace to the therapeutic radiation remain elusive. Nuclear factor-KB (NF-KB), a stress-sensitive heterodimeric transcription factor in the regulation of the stress-responsive genes, has been shown to initiate prosurvival signaling pathways. The cooperative function of NF-KB with other key stress elements in radioresistance remains to be elucidated. We have previously reported that induction of α5β1-integrin is associated with the enhanced cell survival of breast cancer cells after exposure to high dose IR (ionizing radiation). Because a typical NF-KB binding site was located in human β1-integrin promoter region, β1-integrin-mediated resistance to radiation may be regulated by NF-KB. The aim of the present study was to reveal a connection between NF-KB and β1-integrin pathways in radioprotection of malignant T4-2 mammary epithelial cells in 3D ***lrECM (three-dimensional laminin-rich extracellular matrix). We show that the elevated NF-KB activity was correlated with enhanced clonogenic survival, and increased NF-KB heterodimer p50/p65 levels were associated with an increase in total and phosphorylated (Thr 788/789) β1-integrins. Inhibition of NF-KB activation significantly reduced clonogenic survival with the inhibition of β1-integrin. These results indicate that NF-KB-mediated induction of β1-integrin is associated with an increased radiation resistance. Treatment of T4-2 colonies, formed at day 4, with NF-KB activation inhibitor in 3D lrECM before exposure to IR (4-Gy X-ray) resulted in a reduction of the size of colonies. The surviving colonies were associated with a decrease in proliferation and increase in apoptosis, indicating a decrease of resistance to IR. Together, these results provide the first evidence that NF-KB-mediated β1-integrin expression is responsible for tumor radioresistance. The NF-KB/β1-integrin pathway may serve as an efficient drug target to re-sensitize radioresistant tumor cells.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-01-06.
P3-01-11: Increased Gene Copy Number of c-KIT and VEGFR2 at 4q12 in Primary Breast Cancer Is Related to an Aggressive Phenotype and Impaired Prognosis.
Authors: Rydén L , Johansson I , Ebbesson A , Grabau D , Wigerup C , Aaltonen KE , Hedenfalk I
Published: June 2012

Introduction: Triple-negative breast cancer (TNBC) accounts for approximately 15% of all female breast cancer and is associated with aggressive clinical behaviour. No targeted treatments are available for TNBC. Drugs inhibiting tyrosine kinases, such as vascular endothelial growth factor receptor 2 (VEGFR2) and c-KIT, have however shown some promising results for patients with TNBC. The aim of the present study was to investigate whether gains and/or amplifications of VEGFR2 and c-KIT occur in TNBC. These genes may constitute novel candidate biomarkers for selecting TNBC patients for treatment with tyrosine kinase inhibitors.

Material & Methods: Fluorescence in situ hybridization (FISH) was used to quantify gene copy numbers of VEGFR2 and c-KIT in 83 primary human breast cancers, of which 31 were classified as TNBC. Gains were defined as ≥4 gene copies in more than 40% of the cancer cells, while amplification was defined as gene copy/CEP ratio >2 in more than 10% of the cancer cells. A tumour was considered FISH positive for c-KIT and/or VEGFR2 if it displayed copy number gain and/or amplification. Immunohistochemical (IHC) staining was performed for assessment of c-KIT protein expression.

Results: Ten (32%) of the TNBCs were VEGFR2 FISH positive and nine (29%) were c-KIT FISH positive, whereas non-TNBCs were FISH positive for VEGFR2 and c-KIT in nine (18%) cases for both genes. No significant difference in frequency between TNBCs and non-TNBCs was found. There was a correlation between FISH positivity for VEGFR2 and c-KIT (c2 test, P<0.001), and VEGFR2 and c-KIT FISH positivity correlated to ER/PgR negativity and high Nottingham histological grade (NHG). A significantly worse breast cancer specific survival (BCSS) was seen for FISH positive cases in the whole cohort as well as among untreated patients and non-TNBCs, but not among TNBC cases.

Discussion: The high correlation between VEGFR2 and c-KIT FISH positivity suggests that the genes are co-amplified. Increased copy number of both genes was related to aggressive disease and a worse prognosis, and thus has the potential of functioning as a novel predictive biomarker for selected targeted therapy particularly in the difficult-to-treat TNBC patient category.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-01-11.
P3-01-15: The Role of Src Homology Phosphotyrosyl Phosphatase-2 in Basal-Type/Triple-Negative Breast Cancer – Implications for Targeted Therapy.
Authors: Agazie YM , Matalka F , Hartman ZR
Published: June 2012

Background: Of all breast cancer subtypes, the basal-type/triple-negative breast cancer (BTBC) has the worst clinical outcome. The major reasons are the highly invasive nature of the disease and the limited treatment options available to patients. As opposed to the HER2−positive and the hormone-positive breast cancers, targeted therapy against BTBC is unavailable. These premises underscore the need for discovering and characterizing drug targets in BTBC. In this study, we have focused on the Src homology phosphotyrosyl phosphatase 2 (SHP) which seems to play pivotal roles in BTBC. The major reason for focusing on SHP2 is that it is an essential downstream effector of mitogenic and cell survival signaling downstream of receptor tyrosine kinases such as EGFR (HER1) and IGF-1R, and the cytoplasmic tyrosine kinase Src, which are known to be elevated in BTBC.

Materials and Methods: The state of SHP2 and EGFR expression in BTBC tumors was determined by immunohistochemistry. The functional significance of SHP2 in BTBC cells was investigated by ablating its expression with specific shRNA and then assessing impact on mitogenic and cell survival signaling using immunoblotting with phospho-specific antibodies, effect on transformation using 3D cultures such as growth in soft agar and matrigel, consequence on cell motility and invasiveness using florescent-tagged matrigel. Furthermore, the impact of SHP2 inhibition on tumorigenesis was tested by intramammary transplantation in vivo and monitoring and analyzing tumor growth and metastasis.

Results: We have shown that the SHP2 protein is elevated in BTBC tumors. More importantly, the elevated expression of SHP2 is highly correlated with overexpression of the EGFR (HER1), suggesting their potential synergistic role to promote BTBC. Inhibition of SHP2 in BTBC cells reversed transformation and suppressed proliferation, indicating their dependence on the function of SHP2. Moreover, inhibition of SHP2 abolished EGF-induced mitogenic and cell survival signaling, which is in agreement with its role in cell proliferation and transformation. More dramatic was that the invasive phenotype of BTBC cells in 3D matrigel was completely blocked by inhibition of SHP2, suggesting that the invasive property of these cells is dependent on SHP2. Even more dramatic was that the tumorigenic and metastatic potential of BTBC cells was abolished by SHP2 inhibition.

Discussion: The current study demonstrates that SHP2 plays a pivotal role in promoting BTBC. Given that SHP2 is a tyrosine phosphatase with positive signaling role, its promotion of BTBC must occurs through promotion of tyrosine kinase signaling. Together, our results provide the first glimpse on the potential of SHP2 as a drug target in BTBC.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-01-15.
P3-01-16: Expression of Basal Markers in Correlation with PTEN and BRCA 1 in Triple Negative Breast Carcinomas (TN) Treated with Chemotherapy Versus PARP Inhibitors.
Authors: Chivukula M , Carter G , Puhalla S
Published: June 2012

The link between the BRCA1 tumour-suppressor gene and hereditary breast and ovarian cancer is established. The morphologic and immunohistochemical features of basal like phenotype carcinomas have shown to be correlated with the BRCA 1 expression. PTEN (phosphatase and Tensin Homolog) is a novel tumour suppressor gene located on chromosome 10. PTEN mutations are believed to exert their effects through the putative PI3K-AKT-mTOR signaling pathway. Lack of PTEN expression, suggests that PARP inhibitors may be therapeutically useful for a subset of invasive breast cancers. The data on PTEN status in breast carcinomas is emerging. The aim of our study is to assess the immunohistochemical expression of basal markers, PTEN and BRCA 1 in a subset of triple negative breast carcinomas with known BRCA status. Results: Results are shown in Table 1.

Conclusions: 1. Initial results from our study indicate high expression of PTEN is seen in TN breast carcinomas. 2. There appears to be decreased BRCA 1 protein expression in TN patients who tested positive for BRCA mutations. 3. Given the loss of PTEN in a subset of TN Chemo group, PARP inhibitors may be suggested to be therapeutically useful and needs to be evaluated further. 4. The lack of CK 5 basal keratin in some patients needs to be addressed further. The study is on going with addition of new cases. The updated data and preliminary data with patient responses on PARP inhibitor will be presented.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-01-16.
P3-03-08: microRNAs in Mammary Stem-Like Cells and Triple-Negative Breast Cancer; Conserved Functions and Treatment Potential.
Authors: Williams C , Aydogdu E , Katchy A , Lin C-Y , Baldosen L-A , Helguero L
Published: June 2012

Background: Mammary stem and progenitor cells are thought to be precursors of different subclasses of breast cancer. Triple-negative breast cancer exhibit similarities to stem or progenitor-like cells. microRNAs (miRNAs) play pivotal roles in both stem cell biology and oncogenesis. Given their potential as therapeutic targets, little is known, however, regarding miRNAs expression and functions in normal and breast cancer cells. Our objective was to identify which miRNAs are involved in mammary stem cell maintenance and differentiation and study their potential roles in triple-negative breast cancer. We investigated their expression during induced differentiation of mammary stem-like cells, correlated their expression to that of triple-negative breast cancer cells and studied the functions of the most regulated and conserved candidates.

Material and Methods: Using large-scale profiling and extensive qPCR confirmation we defined miRNAs regulated during stem-like cell differentiation. We investigated their expression in different breast cancer cell lines, and performed functional studies using miRNA mimics and inhibitors in normal stem-like cells and triple-negative breast cancer cells.

Results: Twenty-one miRNAs were strongly regulated in repeated rounds of mammary cell differentiation. The majority, including the miR-200 family and known tumor suppressor miRNAs, was upregulated during differentiation. Only 4 miRNAs, including the oncomiR, miR-17, were upregulated in the stem cell-like stage. Pathway analysis indicated complex interactions between regulated miRNA clusters and major pathways regulated during this transition, including stem cell maintenance, proliferation and differentiation. The cell model used exhibited gene expression profiles resembling basal-like poor prognosis breast cancer. Morover, we present data of miRNAs that target the genes and networks responsible for this correlation. miRNAs detected in this study can also differentiate between human non-cancer and breast cancer cell lines, and a subclass of miRNAs, was specifically downregulated in a basal-like breast cancer cell line. The functions of five miRNAs (miR-200a, -200b, -146b, -148a and -206) were further investigated. Discussion: Our findings suggest that the identified miRNAs have significant roles in biological pathways and networks associated with mammary stem/progenitor cell maintenance and triple-negative breast cancer and support their further evaluation as potential prognostic markers and therapeutic targets in the treatment of breast cancer.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-03-08.
P3-05-08: Hormone Receptor Heterogeneity in Ductal Intraepithelial Neoplasia (Ductal Carcinoma In Situ) of the Breast.
Authors: Sowden M , Flynn C , Bossuyt V , Lannin D , Chagpar AB
Published: June 2012

Background: Ductal Intraepithelial Neoplasia [DIN] often shows heterogeneity of both morphology and nuclear grade within the same patient. It is unknown whether this implies heterogeneity with respect to hormone receptor status that may affect treatment. We sought to determine the rate of heterogeneity in terms of nuclear grade and receptor status in DIN patients.

Methods: A hospital tumor registry was queried for patients diagnosed with DIN between 1980 and 2010. Of the 746 patients identified, 579 (77.6%) had a concomitant invasive tumor. Of the remaining 167 patients, 70 were diagnosed prior to 2007 (when ASCO-CAP guidelines for hormone receptor measurements were released), 2 were found to have lobular intraepithelial neoplasia rather than DIN, and in 11 cases, pathology slides were not available for review. Of the 84 remaining patients with DIN, 17 (20.2%) had DIN 1 alone, 19 (22.6%) had DIN 2 alone, and 7 (8.3%) had DIN 3 alone. 41 (48.8%) of the patients had more than one grade of DIN. These patients formed the cohort of interest. Slides were reviewed by a single pathologist who evaluated ER and PR positivity within the different grades of DIN in each patient, classifying tumors staining 1% or greater as positive. Statistical analyses were performed using SPSS.

Results: The median patient age was 53 years old. Of the 41 patients with multiple grades of DIN, 32 (78.0%) had DIN 1 and 2, 6 (14.6%) had DIN 2 and 3, and 3 (7.3%) had DIN 1, 2, and 3 within the same tumor. 93.8%, 94.7% and 88.9% of DIN 1, 2 and 3 lesions respectively were ER-positive. A difference in hormone receptor status between different grades of DIN within the same tumor was noted in 12 (29.3%) of patients; of these 3 (10.3%) varied in ER status and 10 (34.5%) varied in PR status. Of the 2 patients with ER-negative DIN 1, both had ER-positive higher grade DIN within the same tumor. Of the 2 patients with ER-negative DIN 2, one had ER-positive DIN 1 while the other had ER-negative DIN 3. Therefore, of the total 41 patients, 40 (97.6%) had at least one component of DIN that was ER-positive, and evaluating more than one grade of DIN for ER allowed 75% of patients with at least one ER-negative component to be offered hormonal therapy.

Conclusions: Nearly 50% of patients with DIN will have more than one nuclear grade in the same tumor. These different nuclear grades vary in hormone receptor status in approximately 30% of patients. The majority of patients (97.6%) have at least one component of their DIN that is ER-positive. For those who have at least one component that is ER-negative, up to 75% may be offered hormonal therapy by considering other grades of DIN in treatment decision-making.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-05-08.
P3-06-02: Identification of Redundant, Tumor Subtype Specific Fusion Transcripts in Primary Breast Tumors.
Authors: Thompson EA , Asmann YW , Necela BM , Andorfer CA , Cunliffe HE , Hossain A , Getz JE , Hostetter G , Schroth GP , Perez EA
Published: June 2012

Background: The role of fusion genes and associated fusion transcripts has long been recognized in hematopoietic malignancies. Until quite recently it has been difficult to detect such events on a genomic scale in solid tumors. Consequently, little is known about the potential role of fusion genes, transcripts, and proteins as driver mutations, biomarkers, or therapeutic targets in breast cancer.

Methods: We have developed a novel analytical pipeline, Snowshoes-FTD, for detection of fusion transcripts in breast cancer cell lines and tumor samples (Asmann, et al. NAR 2011; May 27 ePub ahead of print). Preliminary analyses have been carried out with a panel of 8 each ER+, HER2+, and triple negative (TN) primary breast tumors, 8 primary human mammary epithelial cell (HMEC) lines from biopsy samples, plus 16 normal tissues from the Illumina Body Map dataset.

Results: We have identified 120 redundant, tumor-specific fusion transcripts, expressed in two or more tumors and in no non-transformed samples. Sixteen of these represent intrachromosomal fusions and 104 arise from fusion of transcripts that map to two different chromosomes. Every breast tumor expressed one or more fusion transcripts. Twenty-nine fusion transcripts appeared to be tumor subtype specific. Among these, we have identified 2 HER2+, 10 ER+, and 17 triple negative specific redundant transcripts. In general, HER2+ tumors expressed fewer fusion transcripts (range 4 to 28/tumor) compared to TN (range11 to 44/tumor). Chromosomal distribution patterns were also markedly different among the tumor subtypes. For example, ER+ tumors expressed a preponderance of redundant fusion transcripts that involve chr1 and 2, whereas TN tumors had no fusion transcripts that map to either chromosome. Conversely, the predominant locus for TN fusion transcripts was chr19, which contains only one HER2+ fusion and no ER+ fusion transcripts.

Conclusions: Primary breast tumors express many chimaeric transcripts, which we presume to arise primarily from genomic rearrangements. The majority of these transcripts are redundant, and a subset are tumor subtype specific. These transcripts may mark regions of chromosomal instability. HER2+ tumors, in general, appear to evidence less chromosomal instability, as inferred from fusion transcripts; although some HER2+ tumors appear to be quite unstable. TN tumors contain many more redundant fusion transcripts, implying increased genomic instability, particularly in chr19. We conclude that these fusion transcripts represent a class of heretofore unrecognized biomarkers that may be used for sub-classification of breast tumors. Some of these transcripts appear to encode proteins that may function as tumor-subtype-specific driver mutations and may have potential as therapeutic targets in breast cancer.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-06-02.
P3-06-08: SCAN-B: An Accelerated Translational Pipeline from Profile to Prognosis and Prediction for Individual Breast Cancer Patients.
Authors: Loman N , Saal LH , Häkkinen J , Vallon-Christersson J , Ringnér M , Hegardt C , Jönsson G , Gruvberger-Saal SK , Kvist A , Reuterswärd C , Schulz R , Karlsson A , Jönsson M , Grabau D , Manjer J , Carlson J , Malina J , Larsson C , Rydén L , Borg Å
Published: June 2012

The South Sweden Cancerome Analysis Network - Breast (SCAN-B) Initiative is a multidisciplinary network of clinical providers of breast cancer (BC) treatment and pre-clinical scientists whose multiyear purpose is to 1) prospectively collect and analyze the “-omes” of a very large, consecutive, and population-based sample of BCs for translational research; 2) utilize this genomic data to develop new clinically-relevant biomarker assays; and 3) to build the infrastructure for future real-time clinical implementation of resultant biomarkers for individualized treatment. Patient enrollment began in the Fall of 2010 at the seven BC surgical units of the South Sweden Healthcare Region, where approximately 1500 new breast cancer diagnoses are treated yearly following the guidelines of the South Sweden Breast Cancer Group. Currently, tumor and blood samples are being collected at the rate of 80–100 patients per month, which represents approximately 75% of the catchment population. SCAN-B will initially focus on tumor transcriptome analysis using mRNA-sequencing on Illumina HiSeq 2000 instruments, and in the future multimodal data generated from other genomic platforms will also be integrated. Here we present initial experiences from this multidisciplinary collaboration including descriptions of the clinical routines, specimen handling, laboratory processing, mRNA-seq data quality control, short- and long-term projects and future directions. We believe large initiatives like SCAN-B could significantly reduce the time to discovery, validation, and clinical implementation of more powerful diagnostic, prognostic, and treatment-predictive tests for breast cancer.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-06-08.
P3-07-04: Does Omission of Axillary Dissection after a Positive Sentinel Node Biopsy Influence Indication to Adjuvant Chemotherapy in Operable Breast Cancer Patients?
Authors: Montemurro F , Maggiorotto F , Valabrega G , Kubatzki F , Rossi V , Marocco F , Magistris A , Gatti M , Sarotto I , Aglietta M , Ponzone R
Published: June 2012

Introduction: Based on the recently published ACSOG Z0011 study (JAMA 2011;305:569), axillary dissection (AD) may be avoided in breast cancer (BC) patients with a clinically negative axilla and a positive sentinel lymph node (SLN) biopsy receiving breast conserving surgery (BCS). Because the number of positive axillary lymph nodes (ALN) is a widely accepted prognostic marker, we evaluated the potential impact of omission of AD on indication to adjuvant chemotherapy (ACT).

Patients and methods: Among 1497 patients operated at our Institution over 10 years, we identified 321 patients fulfilling the inclusion criteria of the ACSOG Z0011 study (BCS plus SLNB, cT1-2, cN0 breast cancer and 1 to 2 positive SLN). All patients underwent AD. Each case, which was anonymized, was reviewed by our breast team in two rounds. In the first round, patient age, histopathology, linfovascular invasion, tumor grade, hormone receptor, HER2, and ki67 status and number of positive SN nodes (micro and/or macrometastatic) were available. In the second round, the information on ALN was added. At each round, the panel chose between three indications: 1) Recommend ACT; 2) Discuss ACT; 3) No ACT. Results: SN was micrometastatic in 145 (45%) and macrometastatic in 176 patients (55%). ALD revealed non-SNs metastases in 96 patients (30%). Forty-four of these patients had >3 positive ALN (range 4–24). Indications at round 1 and 2 are summarized below.

As a result of the disclosure of the total number of involved ALN, a change in the indication occurred in 51 patients (16%). The most frequent change was a recommendation to ACT (35 patients, 69% of the changes). Among these patients, 9 changed from No-ACT to recommend ACT. All except one change in the indication to ACT occurred in patients with immunohistochemically defined Luminal A and Luminal B/HER2 negative tumors and were mostly towards ACT. Conclusions: Omission of AD in patients with a positive SLN receiving BCS would have altered the indication to ACT in 16% of the patients at our Institution. Changes occurred almost exclusively in patients with hormone receptor positive/HER2−negative tumors. The implications of omission of AD must be taken into account before its widespread acceptance, including the possibility of a biologically tailored surgical approach.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-04.
P3-07-20: An Independent Assessment of Seven Nomograms for Predicting the Probability of Additional Axillary Nodal Metastasis after Positive Sentinel Lymph Node Biopsy in a Cohort of British Breast Cancer Population.
Authors: Nadeem RM , Gudur LD , Saidan ZA
Published: June 2012

Background

Axillary lymph node dissection (ALND) is currently the recommended procedure in patients with positive sentinel lymph node (SLN) biopsy. A significant proportion of patients with positive SLNs will not have any additional metastasis in non-sentinel lymph nodes (NSLNs). Nomograms could identify a subgroup of patients with low risk of further disease in whom completion ALND can be avoided. The aim of this study is to assess the accuracy of currently available seven nomograms in a cohort of British breast cancer population.

Methods: 138 patients with positive SLNs who underwent completion ALND between October 2006-April 2011 were identified. Multiple pathological variables including the histological size of the SLNs metastasis were analysed. Data was then used to calculate the probability of further metastasis in non-SLNs according to the seven nomograms that are currently in use: MSKCC, Cambridge, Turkish, Stanford, MDACC, Tenon and MOU models.

The area under the receiver-operator characteristic (ROC) curve (AUC), 95% confidence intervals, false negative and positive rate were calculated for each nomogram. Subgroup analysis includes pathological tumour size (≤ 2 cm and >2 cm) and macro- or micrometastasis in SLNs. AUC value ≥ 0.80 has an excellent discriminative power.

Results: 56 of 138 patients (41%) had additional metastasis in non-SLNs.

AUC values with 95% confidence intervals and false negative rate are shown in table 1.

46/138(33.3%) had tumour size ≤ 2cm and 18/46( 39 %) had additional NSLNs metastasis. AUC values for the subgroups are shown in table 2.

19/138(14%) who had micrometastasis in SLNs, additional non-SLNs metastasis was seen in only one patient and AUC values were imprecise.

Subgroup analysis identified 6 patients with micrometastasis and tumour size ≤ 2 cm, none had additional NSLNs metastasis so AUC values cannot be computed. 19/138(14%) who had extracapsular extension, additional non-SLNs metastasis was seen in 12/19(63%).

Conclusion: MOU nomogram was more predictive than the other nomograms with a better AUC value and false negative rate. Subgroup analysis also shows persistently better AUC value for MOU nomogram. None of the models were able to achieve an AUC value ≥ 0.80 in a cohort of British breast cancer patients.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-20.
P3-07-26: How Generalizable Is the Patient Population Enrolled in ACOSOG Z11?
Authors: Lannin DR , Killelea BK , Grube BJ , Horowitz N , Chagpar AB
Published: June 2012

Background: The recently published Z11 trial of observation vs. axillary dissection for patients with a positive sentinel lymph node showed amazingly low axillary recurrence rates in both groups, and has the potential to dramatically alter practice. However questions remain about whether the Z11 population is representative of the larger population of breast cancer patients.

Methods: An institutional database was queried to identify all patients who underwent sentinel node biopsy at our breast center from 2004 to 2010. These cases were retrospectively reviewed to determine the percentage of patients who would have met the Z11 eligibility requirements, and the demographics and outcomes for this subset were compared to those for Z11.

Results: Out of 1215 patients undergoing sentinel node biopsy, 282 (23%) had at least one positive sentinel node. However when patients were eliminated who had T3 or T4 tumors, more than 2 positive sentinel nodes, neo-adjuvant chemotherapy, or who underwent mastectomy, only 88 remained who would have been eligible for Z11 (31% of those with a positive sentinel node). These patients are compared to the Z11 patients in the following table.

Our lumpectomy patients were generally quite similar to those of Z11 except ours had a lower percentage of micrometastases and a higher percentage of 4 or more positive nodes. As with most other published prediction models, the chance of having 4 or more positive nodes in our patients was directly proportional to tumor size and number of positive sentinel nodes, and inversely proportional to number of negative sentinel nodes.

Conclusions: A relatively small percentage of node positive patients at our institution actually met the eligibility requirements for Z11, but this subset was similar in most respects to the Z11 population. We have developed an algorithm that can be prospectively tested that will allow the majority of these patients to forego axillary dissection but that will exclude patients most likely to have 4 or more positive nodes.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-26.
P3-07-33: Are Single Node Metastases More Common in Patients with Breast Cancer in the Sentinel Node Era?
Authors: Shetty G , Randhawa S , Mohammed I , Harries S , Jones L , Clarke D
Published: June 2012

Background: The axillary recurrence rate after axillary lymph node dissection has been reported as approximately 3%. Since the introduction of sentinel node biopsy (SNB), it has become apparent that, there is a significant decrease in axillary recurrence, ranging from 0.26% to 0.9% in published literature. One of the concerns that arises from this data is that, the sentinel node may have been missed when routine axillary node clearance were being performed. The aim of this study was to compare the results of a cohort of patients who had an axillary staging procedure prior to the introduction of SNB (axillary clearance) with patients after the introduction of SNB in relation to the number who had only one positive node in the axilla.

Methods: From June 2003 to November 2010 data was collected on demographics, histopathology and procedure performed. All patients with invasive breast cancer prior to April 2005 had an axillary node clearance (ANC) with either wide local excision or mastectomy. Since April 2005 all patients with invasive breast cancer had a SNB and patients with a positive sentinel node (SN) underwent ANC. Patients with a negative SNB had no further axillary surgery.

Results: 702 patients had axillary node surgery between June 2003 and November 2010. 251 patients had axillary node clearance (pre SN period) and 451 had SNB (SN period). Average age was 57 years. 509 patients (156 in pre SNB period and 353 in post SNB period) had no nodal metastases. Amongst the 193 node positive patients, 100 had single node involvement. In the pre SNB period 33 (34.7%) patients had single node involvement, compared to 67 (68.3%) in SNB period. The histopathological type of cancer did not vary significantly between the one node positive, multiple node positive and node negative groups.

Conclusion: Our study confirms a significant rise in patients with a single node positive in the sentinel node period. This could be due to the SLN being “missed” during surgery when an axillary node clearance was performed, which would explain the reported higher axillary recurrence rates in the pre sentinel node period compared to the sentinel node period. Another possibility is that the SN is undergoing more detailed histopathological assessment as there are fewer number of lymph nodes to be examined.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-07-33.