bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical factors that affect breast cancer risk reduction decisions in high risk women tested for the BRCA1/2 genetic mutation
Authors: Uyei A. R. , Broglio K. R. , Solomon T. L. , Vogel K. J. , Amos C. I. , Lu K. , Meric-Bernstam F. , Strong L. , Arun B. 
Published: March 2020

1013 Background: Women with an increased risk for breast cancer have many risk reduction options including: prophylactic mastectomy, prophylactic oophorectomy, chemoprevention, and screening. Women without breast cancer make such decisions in a purely preventive setting and factors that affect their decisions are unclear. Method: We performed an IRB approved retrospective review of the medical records on women who underwent BRCA testing. We evaluated the women without a history of breast cancer to assess clinical characteristics and their relation to decision making. The risk reduction categories analyzed were: prophylactic mastectomy, prophylactic oophorectomy, tamoxifen, increased surveillance with MRI, and standard screening (clinical breast exam and mammography). Patient characteristics were tabulated by clinical decision group and the chi-square test or Fisher’s exact test was used. Results: From 2001, 627 patients have undergone genetic testing. 202 of these women did not have a history of breast cancer among whom 58 were mutation carriers. Most patients chose standard screening (47%) or increased surveillance (38%). 4% chose tamoxifen, 7% chose prophylactic mastectomy, 3% chose both prophylactic mastectomy and oophorectomy, and 5% chose oophorectomy. The tamoxifen group was too small to do further analysis. Increased surveillance did not show any significant association with any of the clinical factors that we evaluated. The majority of women who chose standard screening had a personal history of ovarian cancer (p<0.0001) and had no family history of ovarian cancer (p=0.02). Prophylactic surgeries were significantly associated with positive BRCA status (p=0.01). Women with a family history of ovarian cancer tended to have prophylactic surgery (p=0.02). Women who had DCIS or a breast biopsy tended to have prophylactic mastectomies (p=0.0001 and p<0.001 respectively). Conclusion: In breast cancer free women, BRCA status, family history of ovarian cancer, DCIS, and breast biopsy were associated with prophylactic surgeries. Having ovarian cancer or no family history of ovarian cancer were associated with standard screening. We are performing a questionnaire study to determine the reasons behind these women’s choices. No significant financial relationships to disclose.
Neoadjuvant chemotherapy (NCT) in 710 patients for operable breast cancer: Comparison of 2 pathological classifications
Authors: Penault-Llorca F. , Abrial C. , Raoelfils I. , Amat S. , Mouret-Reynier M. , Leheurteur M. , Durando X. , Dauplat J. , Curé H. , Chollet P. 
Published: March 2020

10502 Background: In a database harbouring the patients of several prospective phase II neoadjuvant trials (avcf, avcfm, fec 50–100, nem, net, tncf, taxotère/tncf, taxotere alone), clinical and pathological responses rates were studied in 710 women with stage II-III operable breast cancer treated 1982–2004. Pathological review was conducted to assess the residual disease in breast and nodes according to the 2 most used classifications in Europe: CHEVALLIER’s and SATALOFF’s (Am J Clin Oncol 1993; J Am Coll Surg 1995). Methods: Median age of the patients was 49.5 years [26–81]. Median diameter of the invasive tumour was 40 mm [10–130]. 555 (78%) patients had a canalar, 90 (13%) a lobular, 18 (2.5%) a mixed or invasive carcinoma, 36 (5%) neoplasic cells only and 11 (1.5%) another carcinoma. 25.6% of the tumours were grade III SBR, 28.3% grade 4 or 5 MSBR. The median number of NCT courses was 6 [1–9] followed by a surgery for 92%, a radiotherapy for 95%, an adjuvant chemotherapy (17%) and/or a hormonotherapy (52%). A breast evaluation was realized before, during and after NCT (Amat et al, Breast Cancer Res Treat 2005). Results: Intent to treat (n = 710), overall response rate was 68% (16% complete). The complete pathological response (pCR) rate was 14.18% according to Chevallier’s and 22.50% according to Sataloff’s classification. On 656 patients operated, 470 (72%) had a conservative surgery. On 520 patients with an axillary dissection, 272 (52.3%) had involved nodes (median number:1 [0–20]). After a median follow-up of 93 months, DFS and actuarial survival at 120 months were 54.9% and 66.5%, respectively.Chevallier’s classification level 1 (pCR in breast and axilla) was the most predictive of a good DFS, with a plateau appearance near 80%. Chevallier’s classification level 2 (in situ only) and Sataloff grade A (pCR and isolated tumor cells) yielded a lesser DFS (p < 0.01). With a long follow-up, a complete pCR is the most favourable prognostic factor, followed by in situ only or isolated tumor cells, then residual tumor. Conclusions: Sataloff’s gives higher pCR figures than Chevallier’s without evidence of superior predictive value. The classification used is important to predict outcome after NCT. No significant financial relationships to disclose.
Molecular risk estimation and adjuvant chemotherapy in node-negative breast cancer patients—A status report of the prospective clinical trial NNBC 3-Europe
Authors: Paepke D. M. , Herbst F. , Annecke K. , Gaskill N. , Sweep F. , Meisner C. , Schmitt M. , Jaenicke F. , Harbeck N. , Thomssen C. 
Published: March 2020

10503 Background: Feasibility of risk assessment in node negative breast cancer using the invasion markers urokinase-type plasminogen activator uPA and its inhibitor PAI-1 has been demonstrated in several prospective and retrospective studies and in a large meta analysis. Patients with low uPA and/or PAI-1 concentrations in tumor tissue levels have an excellent 5-year overall survival (>95%) even without any adjuvant therapy. Use of these molecular markers may spare adjuvant chemotherapy in approximately one half of node-negative breast cancer patients. Particulary, patients with an intermediate grade tumor can easily be differentiated in low and high risk. In addition, patients with high uPA and/or PAI-1 level seem to benefit from adjuvant chemotherapy. The NNBC-3-Europe trial seeks to answer two questions: 1. Is risk assessment by molecular markers uPA/PAI-1 superior to that by clinico-pathological factors regarding identification of low-risk patients? 2. Is adjuvant chemotherapy with anthracycline-taxane sequence (FEC-Docetaxel) superior to standard FEC in high-risk patients? Methods: In the NNBC-3-Europe trial, participating centres opt to either perform risk estimation by clinico-pathological factors or by the uPA and PAI-1 concentration in tumor tissue biopsies. Low-risk patients will be observed without adjuvant chemotherapy. High-risk patients are randomised based on the kind of adjuvant chemotherapy. Patients with steroid hormone receptor positive tumors receive adequate endocrine therapy. Results: Of the first 506 patients in the study arm with molecular risk assessment, 62 had a grade 1 tumors, and 184 had grade 3 tumors. Among grade 2 tumors (n = 260), 87 had low uPA/PAI-1. 173 patients presented with high levels. About 30% of the patients were allocated to the low-risk group using uPA/PAI-1. Conclusions: An adjuvant chemotherapy trial based on uPA/PAI-1 determination in the primary tumor is feasible in a multicentre setting. Applying these molecular markers for risk assessment, at this stage of the study, adjuvant chemotherapy could be spared in almost one third of N0 patients. It is performed in association with the EORTC PathoBiology Group Receptor und the German AGO Breast Group. [Table: see text]
Letrozole (Femara) causes potent suppression of breast cancer tissue estrogen levels in the neoadjuvant setting
Authors: Geisler J. , Helle H. , Ekse D. , Duong N. K. , Evans D. , Lønning P. E. 
Published: March 2020

10532 Background: Aromatase inhibitors of the third generation like letrozole, anastrozole and exemestane are known to suppress plasma estrogens by 90–99% in postmenopausal women. However, little is known about their influence on tissue estrogen levels. Methods: We investigated the effect of neoadjuvant treatment with letrozole (2.5 mg o.d.) given for 16 weeks to patients with locally advanced breast cancers on tissue levels of estradiol (E2), estrone (E1) and estrone sulfate (E1S) measured with a previously published, highly sensitive, HPLC-RIA method (J. Steroid. Biochem. Mol. Biol. 72, 259–264, 2000). All patients had either estrogen receptor (ER) and/or progesterone receptor (PGR) positive tumors (at least one of the receptors expressed in > 50% of the tumor cells). Results: Mean tissue levels of E2, E1 and E1S were found to be 475.8, 272.4, and 160.5 fmol/g tissue at baseline (geometric mean values). Following 16 weeks of treatment with letrozole, these levels fell to 11.3, 18.2, and 16.0 fmol/g corresponding to a suppression of tissue levels of E2, E1 and E1S by 97.6%, 90.7%, and 90.1%, respectively. All plasma levels of E2, E1 and E1S were in the normal range expected for postmenopausal women prior to treatment with letrozole. The individual plasma estrogen fractions were found suppressed by 96.6%, 99.1% and 99.5%, respectively, during treatment with letrozole. Conclusions: Treatment with neoadjuvant letrozole 2.5 mg o.d. potently suppressed tissue estrogen levels in postmenopausal breast cancer patients by 90.1 to 97.6%, surpassing the results previously reported for anastrozole in a similar setting (Clin. Cancer Res. 7, 1230–1236, 2001). While a significant superiority of letrozole versus anastrozole concerning total body aromatase inhibition and plasma estrogen suppression has previously been recorded (J. Clin. Oncol. 20 (3), 751–757, 2002), we are now able to extend this observation to tissue estrogen levels as well. Letrozole (2.5 mg o.d.) seems superior to anastrozole 1 mg daily with respect to plasma as well as tissue estrogen suppression, advocating head to head comparison of these compounds in early breast cancer. [Table: see text]
Changes to the hormone receptor expression in patients treated with either tamoxifen or aromatase inhibitors as endocrine therapy for breast cancer
Authors: Djahansouzi S. , Rostock V. , Niederacher D. , Rath W. , Bender H. , Hanstein B. 
Published: March 2020

10543 Background: Endocrine therapy (ET) of patients with hormone receptor (HR)-positive breast cancer (BC) is thought to adversely affect the HR expression of the tumor with time. In order to evaluate this, a study was undertaken comparing the HR status prior to adjuvant Tamoxifen (Tam) therapy and after progression in estrogen receptor (ER)-positive BC patients. Similarly, ET with aromatase inhibitors (AI) was investigated by comparing the HR status prior to AI therapy and after progression in ER-positive metastatic BC patients. Methods: A retrospective analysis of all stage I-III ER-positive BC patients who presented to the department between 1999 to 2004 and received adjuvant Tam for ≥ 6 month and had the tumor relapse (local recurrence or distant metastasis) confirmed by tumor biopsy. All patients were evaluated for ER and progesterone receptor (PR) status prior to ET as well as after relapse using immunohistochemistry. Similarly, stage IV ER-positive metastatic BC patients who received AI for ≥ 3 month with tumor biopsy prior and after AI therapy, were also analyzed in regards to their HR expression. Results: 44 eligible ER-positive BC patients constituted the Tam group. After relapse, 55% of the patients remained ER-positive, while 45% lost their positive ER status. For PR, 34 out of 44 patients were initially receptor positive (77%). Similarly, 15 out of 34 patients retained a positive PR expression (44%) and the 10 PR-negative patients showed no change in receptor expression following Tam. 5 eligible patients with ER-positive metastatic BC constituted the AI group. After progression, 4 out of 5 patients remained receptor positive, while 1 patient lost ER expression. For PR, 3 out of 5 patients were initially PR positive. After AI, only 2 patients showed a positive PR status. 2 patients were PR negative before and after AI therapy. Conclusions: Contrary to the belief that clinical progression under ET is probably as a result of the loss of HR expression, our data suggests that progression under ET does not necessarily result in the loss of HR expression. In fact, 55% of relapses under Tam and 80% of the progressions under AI remain ER positive, indicating potential susceptibility to other endocrine therapeutic agents. No significant financial relationships to disclose.
Relationship between thymidylate synthase expression and p53 levels with the treatment of cyclophosphamide, methotrexate, 5-fluorouracil chemotherapy(CMF) versus docetaxel (TXT) in locally advanced carcinoma of the breast
Authors: Brandi M. , Calascibetta A. , Cabibi D. , Martorana A. , Aragona F. , Fulfaro F. , Valerio M. , Dispenza J. , Sanguedolce R. 
Published: March 2020

10546 Background: Adjuvant chemotherapy is used in the treatment of breast carcinoma independently of axillar node involvement. Different drug combinations such as CMF, FAC, FEC are still used; recently new drugs such as TXT (NEJM 332:1004,1997) show activity and are used also in adjuvant chemotherapy. 5 Fluorouracil (5Fu), a drug involved in main therapeutic regimens, blocks Thymidylate Synthase (TS), an enzyme involved in the DNA synthesis. TS not only links its own mRNA, but also p53 mRNA, inhibiting post transcriptional p53 protein synthesis. TS protein overexpression (Cancer Res 55:1407,1995), and/or its absence (Cancer Res 61:1421,2001) are some of the main mechanisms of 5-Fu drug resistance; moreover TS protein could inhibit p53 protein synthesis. Many clinical studies demonstrate that tumours with mutations of p53 are resistant to anthracyclines chemotherapy, 5Fu and radiotherapy (Carcinogenesis 17:1417,1996). Other studies show that the relationship between p53 and taxanes chemosensitivity seems to be more complex, because p53 mutations are associated with better taxanes drug response (Nature Med 2:255,1996). Aim of the study is to find association between TS and p53 levels, and relation with CMF or TXT treatment. Methods: We detected TS and p53 protein levels with immunohistochemistry assay in 84 paraffin embedded tumour samples from untreated patients (pts) who underwent surgery for primary breast cancer. Stage was T2N2M0 and pts were divided into two groups depending on the drug treatment received. One group (44 pts) was treated by 6 cycles of adjuvant CMF chemotherapy, the other by 4 cycles TXT alone. Results: 30% of pts showed lower TS and higher p53 levels, and had better TXT, while worse CMF treatment response; 30% of pts showed higher TS and lower p53 levels and all had worse response to all treatments; 40% of pts showed intermediate TS and p53 levels and different response to both CMF or TXT. Conclusions: On the basis of these results we identified a sub-group of pts showing lower TS and higher p53 levels that could be treated by a first line therapeutic regimen including Taxanes, not by drug combinations including 5 FU. No significant financial relationships to disclose.
Adding paclitaxel to trastuzumab enhances antibody-dependent cell-mediated cytotoxicity via increment of natural killer cells in patients with Her-2 overexpressing breast cancer
Authors: Miura D. , Kitagawa D. , Tsutsumi K. 
Published: March 2020

10548 Background: One of the mechanisms by which trastuzumab (TZ) inhibits the growth of Her-2 overexpressing breast cancer cells is the activation of a host tumor response via antibody-dependent cell-mediated cytotoxicity (ADCC). We questioned whether adding PTX to TZ enhances ADCC and also investigated kinetics of effector cells in ADCC. Methods: In ADCC, 5 cases with metastatic breast cancer receiving TZ (4mg/kg as a loading and 2 mg/kg weekly) with PTX (2qw, 100 mg/m2) were investigated. ADCC was analyzed by 51Cr releasing assay using SK-BR-3 cell line and white blood cells taken at the time of pretreatment, after 4 mg/kg of TZ, before/after 2 mg/kg of TZ, and before/after 2 mg/kg of TZ plus PTX. In of effector cell studies, we investigated fractions of natural killer (NK) cell, monocyte, and neutrophil taken at pre-administration and 10 minutes post-administration in 16 patients with Her-2 overexpressing breast cancer receiving weekly TZ and PTX (80 mg/m2). We defined NK cells as being both CD16+ (FcγRIII) and CD56+ and neutrophils as CD64+ (FcγRI) by flow cytometry. Results: Compared with pretreatment ADCC level, cytotoxicity were enhanced to 220% (median, ranging 30–259) after 4 mg/kg of TZ, 129% (78–210) after 2 mg/kg of TZ, and 148% (42–557) after the combination of TZ and PTX, whereas suppressed to 94% (48–163) after PTX alone. 2 weeks after the combination therapy, ADCC was significantly enhanced to 169% (113–257, p<0.05), compared with pre-treatment. In effector cells, NK cells increased in 131% (74–175, p<0.05) by TZ and in 224% (169–286, p<0.05) by the combination therapy. No significant changes were found in monocytes (98%, 50–160) and in neutrophils (100%, 50–160) by TZ alone, however monocytes decreased to 44% (34–50, p<0.05) and also neutrophils did to 49% (9–133) by the combination. Conclusions: Higher doses of TZ induced NK cell recruitment and the combination of TZ and PTX has a significant increase in recruitment and activation of NK cells. Adding PTX to TZ significantly enhanced ADCC via the rapid kinetics of NK cells. This may reflect that the combination of TZ and PTX has a strong synergistic effect than we expected in patients with Her-2 overexpressing breast cancer. [Table: see text]
The experience of a sample of Canadian men with breast cancer
Authors: Pituskin E. N. , Williams B. , Martin-Mcdonald K. , Au H. 
Published: March 2020

10549 Background: Breast cancer is the most frequently diagnosed malignancy among North American women, accounting for about 30% of all new cases each year. Although male breast cancer accounts for less than 1% of all breast cancer cases, recent reports indicate significantly increasing incidence. Research suggests that men diagnosed with breast cancer experience serious psychologic issues including feeling less masculine by having a woman’s disease, feeling isolated with a rare malignancy and feeling uncomfortable seeking or receiving support. Men may also experience post-surgical effects including changed appearance of the male chest and decreased arm strength. There have been numerous large-scale studies examining womens’ experiences with breast cancer. To date, there have been no North American studies examining what a man experiences with a breast cancer diagnosis. The objective of this qualitative study was to determine the experiences of a sample of Canadian men diagnosed with breast cancer. Methods: After ethics approval, an invitation letter and consent form were mailed to those individuals listed as “male”, “breast cancer”, and “alive”, in the Alberta Cancer Registry. 20 men responded indicating their interest. After written consent, audiotaped interviews were conducted. As little is known about a man’s experience with breast cancer, an exploratory qualitative methodology was utilized. Results: We found a great variability among the participants with respect to whom they disclosed their diagnosis, how they viewed their masculinity after a breast cancer diagnosis and their views on life after a cancer experience. All participants stated that there was a major lack of awareness about male breast cancer, both in the public and health professional domain. All participants identified a lack of written information specific for men with breast cancer. All participants denied interest in traditional “support” groups, but would have welcomed the opportunity to speak with a man who had gone through similar diagnosis and treatment. Conclusions: Needs identified by the respondents include increased medical and public awareness of male breast cancer as well as specific written information. Further research is necessary to identify supports and resources helpful for male patients. No significant financial relationships to disclose.
15-Hydroxyprostaglandin dehydrogenase (PGDH) is an aberrant tumor suppressor in human breast cancer
Authors: Wolf I. , O’kelly J. , Rubinek T. , Tong M. , Lin B. T. , Tai H. , Karlan B. Y. , Koeffler H. P. 
Published: March 2020

10550 Background: Prostaglandin E2 plays a growth stimulatory role in breast cancer; and the rate-limiting enzyme in its synthesis, cyclooxygenase-2 (COX-2), is over-expressed in breast cancers. However, little is known about the expression pattern and activities of the key prostaglandin catabolic enzyme PGDH, in breast cancer pathogenesis. Methods: 5-aza-2’-deoxycytidine and suberoyl anilide bishydroxamide (SAHA) were used to unmask epigenetically silenced genes. DNA and RNA were extracted from tumors and cell lines using standard methods, and bisulfite sequencing was used for methylation analysis. Western blotting and real time PCR were used for expression analysis, and PGDH expression vector and PGDH-directed siRNA were used for overexpression and downregulation of PGDH, respectively. Athymic mice were utilized for xenograft models. Results: Using a pharmacologically based, genome-wide screen for epigenetically silenced genes, we found low levels of PGDH in MDA-MB-231 cells (estrogen receptor- (ER) and HER2-negative), but high levels in MCF-7 cells (ER-positive, HER2-negative), and observed upregulation of this enzyme following demethylation treatment. Methylation analysis revealed methylation of the PGDH promoter in one breast cancer cell line and in 3 of 10 primary tumors. Analysis of PGDH expression demonstrated low levels in 40% of primary breast tumors and identified a correlation between PGDH and ER expression. Upregulation of PGDH levels in MDA-MB-231 cells decreased their clonal growth and reduced their ability to form tumors in athymic mice. In contrast, silencing of PGDH in MCF-7 cells increased proliferation and enhanced in-vivo tumorigenicity. Further analysis revealed upregulation of aromatase following silencing of PGDH and inhibition of the ER pathway by forced expression of the enzyme. PGDH levels were downregulated by estrogen but upregulated by the tumor suppressor gene C/EBPα. Conclusions: Our results identify for the first time, that PGDH, the COX-2 antagonist, is aberrantly silenced in breast cancer. Activation of this enzyme, particularly in ER- and HER2-negative tumors, now becomes an interesting target for clinical studies. No significant financial relationships to disclose.