bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linking altered cell motility and proteolytic activity to tumor invasion—An active role of CD97 in tumor progression
Authors: Aust G. , Loeffler M. , Hanisch I. , Wobus M. , Wandel E. , Galle J. 
Published: March 2020

10103 Background: Tumor cells at the invasion front of several carcinomas differ in their molecule pattern from cells in central tumor regions. As recently shown by us, this includes the cell surface receptor CD97 (Am J Pathol 2002,161:1657–67). Here, we link related differences in cell biological and biomechanical properties to the characteristics of tumor invasion. We combine in vitro and in vivo experiments with computer simulations of tumor progression and analyze the particular role of CD97 in this process. Methods: We compared the cDNA pattern of clones with adjustable expression of normal or C- terminal truncated CD97 using microarrays and confirmed the results at the protein level. Clonal cell motility was analyzed by time-lapse video microscopy. The scid mouse model was used to monitor tumor growth in vivo. Additionally, we introduce a novel class of individual cell-based computer models of tumor invasion into stroma. The approach enables us to analyze the impact of different cellular alterations on the organization and dynamics of the tumor invasion front and we can study several assumptions about the origin of these alterations. Results: CD97 overexpression stimulates single cell motility and increases proteolytic activity and IL-8 secretion in vitro and promotes growth of tumors in scid mice. In contrast, tumor cells overexpressing truncated CD97 show lower proteolytic activity, impaired in vitro motility and in vivo tumor growth. By computer simulation studies we demonstrate that the observed effects induced by CD97 can strongly increase the invasion capacity of tumors. Furthermore, they can cause a specific morphology of the invasion front which is known to correlate with poor prognosis. Thus, as a consequence of our computer simulations and findings in vitro and in vivo, we suggest that CD97 plays an active role in the propagation of de-differentiated carcinomas. Conclusions: Our combined experimental and theoretical computer analysis provides a novel insight in how variations of individual cell properties can be linked to different patterns of tumor cell invasion. Our results suggest that proteolytic activity at the tumor front in conjunction with elevated and directed cell motility are key steps to aggressive tumor invasion. No significant financial relationships to disclose.
MORAb-003 inhibits folate-driven growth mediated by the human folate receptor alpha
Authors: Routhier E. , Turchin H. , Patel R. , Ebel W. , Sass P. , Nicolaides N. , Grasso L. 
Published: March 2020

10108 Background: MORAb-003 is a therapeutic humanized antibody currently in Phase I clinical trials for advanced ovarian cancer, and is directed against the human folate receptor alpha (FRα), an antigen which is highly overexpressed on the surface of the majority of ovarian cancers. Overexpression of FRα has been shown to confer a growth advantage to tumorigenic cells in vitro, under conditions of reduced folate availability. We have previously determined that MORAb-003 elicits robust antibody-dependent cellular cytotoxicity (ADCC) and complement-directed cytotoxicity (CDC) in vitro, and is effective in mouse xenograft models of human ovarian cancer. We now show that MORAb-003 possesses novel, growth-inhibitory functions distinct from its immune effector properties. This activity can be recapitulated, using a cell-based assay to score inhibition of folate-dependent growth. Methods: Chinese Hamster Ovary (CHO) cells were engineered to express surface FRα. The cells were cultured under a low folate (< 20 nM) regimen, then re-fed medium supplemented with various concentrations (0–10 μM) of 5-methyltetrahydrofolate (5-MTF), a folate preferentially internalized by the FRα. Cellular proliferation was measured as a function of added 5-MTF, in the presence or absence of MORAb-003. Results: FRα-expressing CHO cells were found to require approximately 100-fold lower 5-MTF than a matched, non-expressing cell line. This increased proliferation could be reduced in a concentration-dependent manner by MORAb-003. Conclusions: MORAb-003 can antagonize the activity of human FRα, resulting in the loss of growth advantage conferred by overexpression of FRα under conditions which bracket physiological (10–100 nM) folate concentrations. [Table: see text]
Contralateral prophylactic mastectomy in affected carriers of deleterious BRCA1 or BRCA2 mutations: Does timing of genetic testing matter?
Authors: Tchou J. , Sonnad S. , Sargen M. , Weber B. , Nathanson K. , Domchek S. 
Published: March 2020

10512 Introduction: Prophylactic mastectomy (PM) reduces breast cancer risk by >90% in women who are carriers of deleterious BRCA1 or BRCA2 mutations. Genetic testing prior to breast cancer surgery has been reported to affect PM decision in high-risk patients. The ideal timing of genetic testing as well as the clinical characteristics of affected mutation carriers electing PM remain unclear. This is a pilot study to identify significant clinical characteristics associated with affected carriers who had undergone PM. Methods: Retrospective chart review was performed on 103 breast cancer affected BRCA1 or BRCA2 mutation carriers that were seen at our high risk clinic who had undergone genetic testing between 1995 and 2005. Clinical characteristic, initial surgery treatment modalities, and dates of genetic testing and prophylactic mastectomy were collected and analyzed using the chi-square or Fisher exact tests. Results: Of the 103 affected mutation carriers, 30 (29%) underwent prophylactic mastectomy (PM) where as 73 (71%) did not (no PM). Ethnicity, age of diagnosis, tumor size, nodal status, family history and initial breast cancer surgery types (BCT vs. mastectomy) were not significantly different between the two groups. Of the 30 women who underwent PM, 19 (63%) vs. 9 (30%) underwent PM before and after their genetic testing respectively. Of the 19 women who had PM before their genetic testing, 4 (21%) had BCT as initial treatment whereas 15 (78.9%) had mastectomy as initial treatment and 9 of 15 (60%) had synchronous contralateral prophylactic mastectomy. For the 9 women who had PM after their genetic testing, 5 (56%) had BCT vs. 4 (44%) had mastectomy as their initial surgical treatment (p < 0.001). Conclusion: In this study, we found a significant correlation between the initial breast cancer surgical modality of mastectomy with women undergoing prophylactic mastectomy. The impact of family history of breast cancer does not appear to be significant. Physician recommendations or patient preference are unknown. Our data suggest that high risk women who elect mastectomy as their initial surgical management to treat their breast cancer are more likely to undergo prophylactic mastectomy regardless of knowledge of their mutation status. No significant financial relationships to disclose.
Incidence and risk factors for central nervous system (CNS) metastases in HER2-positive (HER2+) metastatic breast cancer (MBC) patients (pts)
Authors: Gori S. , De Angelis V. , Rimondini S. , Mosconi A. M. , Moretti G. , Bisagni G. , Sidoni A. , Aristei C. , Franceschi E. , Colozza M. , Crino L. 
Published: March 2020

10516 Background: Recently, an increased incidence of CNS metastases in HER2+ MBC has been reported. Aims of the observational study were to evaluate the incidence and risk for CNS metastases in HER2+ MBC pts. Methods: We reviewed the occurrence of CNS metastases in 122 consecutive HER2+ MBC pts treated with chemotherapy (CT) and trastuzumab (T)between April 1999 and June 2005. Patient characteristics included: median age 48 yrs (28–79); G3 in 58.1%;ER- in 53.2%; DFS <24 mos in 48.3% and ≥24 mos in 51.7%. Visceral metastatic disease was dominant site of relapse in 67.2% of the pts. T+CT represented the 1st line of treatment in 54% of pts, 2nd line in 28.6% and ≥3th line in 17.2%. Results: At median follow up of 28 mos (2–167) from the occurrence of metastatic disease, 43 pts (35.2%) developed CNS metastases, confirmed by CT or MRI scanning. In 42 pts were present one or more parenchymal brain metastases and in 1 pt leptomeningeal carcinomatosis. Neurological symptoms were present in 90% of pts. Out of the 43 pts developing CNS metastases, 37.2% were in response in other metastastic sites and CNS represented the only site of progression. Median time of occurrence of CNS metastases (from diagnosis of metastatic disease) was 12 mos (0–78).Using the presence/absence of CNS metastases as dependent variable in logistic regression analysis, we obtained that age (p = 0.020) and visceral metastases (p = 0.024) were significantly associated with increased risk of CNS metastases. Panencephalic RT was given in 31 out of 43 pts; 16 pts (37.2%) received T ± further CT and 18 pts (41.8%) only cytotoxic CT. Median OS was 51.2 mos (1.9+-167.4) in the all population. Median OS was 35 mos (4–105) in pts with CNS metastases; at the present analysis median OS has not been reached in pts without CNS metastases (p = 0.002). Conclusions: CNS metastases is common, late event in the natural history of HER2-positive MBC. Age and visceral metastases were significantly associated with increased risk for CNS metastases. Clinical trials are indicated to evaluate:1) any clinical, pathological and molecular risk factors for CNS metastases; 2) if there is indication to specific treatment in a population at high risk of CNS metastases. No significant financial relationships to disclose.
Toxicity of epirubicin and cyclophosphamide (EC) vs. docetaxel (D) followed by EC in the adjuvant (adj) treatment of node positive breast cancer. A multicenter randomized phase III study (GOIM9902)
Authors: Lopez M. , Brandi M. , Foggi P. , Giotta F. , Gebbia N. , Massidda B. , Filippelli G. , Cicero G. , Vici P. , Colucci G. 
Published: March 2020

10526 Background: Due to high activity of taxanes (T) and anthracyclines (A) in advanced breast cancer (BC) and to the lack of cross-resistance between them, several adjuvant (adj) trials have been performed to test the efficacy of combination or sequential schedules of T and A adjuvant. In most of the sequential trials A followed T. The sequence T->A was proven active in metastatic BC, but no data are available in the adj setting. This multicenter randomized phase III study was designed to evaluate the efficacy of the sequence T->A vs an A containing regimen Methods: Pts with pT1–3 pN1 M0 (UICC1997) BC, age 18–70, PS(ECOG) 0–1, normal cardiac function, adequate bone marrow, hepatic and renal function were eligible for the study. Pts were stratified according to institution, age (≤ 50 vs > 50), hormonal receptor status and number of involved nodes (≤ 3, 4–9, ≥ 10) and were randomized to receive either 4 cycles of EC (Epirubicin 120 mg/m2 + Cyclophosphamide 600 mg/m2 on day 1 q21) in arm A or 4 cycles of D (100 mg/m2 on day 1 q21) followed by 4 cycles of EC in arm B. Primary endpoint was DFS. Secondary endpoints OS and toxicity. Results: Between april 1999 and october 2005, 750 pts were enrolled (374 in arm A and 376 in arm B) in 25 Italian institutions. Pts characteristics are as follows: Arm A: age ≤ 50 yrs 185/374; ≤ 3 nodes 182/374, 4–9 nodes 129/374, ≥ 10 nodes 63/374; positive HR 287/374 Arm B: age ≤ 50 yrs 197/376; ≤ 3 nodes 184/376, 4–9 nodes 131/376, ≥ 10 nodes 61/376; positive HR 289/376 Toxicity data (Arm A vs Arm B) of the first 495(241/254) pts are the following: Neutropenia G3 (29% vs 21.3%), neutropenia G4 (32.7% vs 48.8%), febrile neutropenia G3–4 (3.7% vs 9.5%), thrombocytopenia G3–4 (3.3% vs 1.6%), anemia G3 (0% vs 2.4%), N/V G3–4 (6.2% vs 3.1%), mucositis G3–4 (3.7% vs 3.9%), diarrhea G3–4 (0.4% vs 2.8%), peripheral neuropathy G1–3 (0% vs 9.9%), hypersensitivity reactions G3–4 (0% vs 4.3%), cardiac toxicity G3 (0.4% vs 0%) Conclusions: Treatment was generally well tollerated in both arms with a higher incidence of neutropenia, usually short lasting, in arm B. The use of prophylactic G-CSF in those patients experiencing neutropenia G3–4 may be advisable. There were no significant differences in cardiac toxicity. No significant financial relationships to disclose.
SWOG 0338: A phase II trial of imatinib mesylate in combination with capecitabine in metastatic breast cancer
Authors: Chew H. K. , Barlow W. E. , Albain K. S. , Lew D. , Budd G. T. , Allen G. , Gralow J. , Livingston R. 
Published: March 2020

10529 Background: Imatinib mesylate targets c-kit and platelet derived growth factor receptor (PDGFR) tyrosine kinases, and both are variably expressed in breast cancer. Inhibition of PDGFR by imatinib mesylate may decrease tumor interstitial pressure and improve delivery of chemotherapy. Based on preclinical synergy, SWOG conducted a phase II trial in metastatic breast cancer. Methods: Patients were eligible if they had adenocarcinoma of the breast that had progressed on at least 1 but ≤ 2 prior chemotherapy regimens for metastatic disease. No prior 5-FU or capecitabine for metastatic disease was allowed. Patients had to be > 18 years with a Zubrod performance status ≤ 2 and have adequate organ function. Patients with brain metastases were ineligible. Patients received imatinib mesylate 400 mg orally daily and capecitabine 1000 mg/m2 orally twice daily on days 1–14 of a 21-day cycle. If tolerated, the imatinib mesylate was increased to 600 mg daily in subsequent cycles. This was a 2-stage design with 25 patients with measurable disease accrued in the first stage. A total of 70 patients was planned, including those with nonmeasurable disease, if accrual proceeded to the second stage. The primary endpoint was to determine the confirmed response rate (RR) to the combination therapy. Secondary endpoints were to estimate the 6-month progression free survival, to determine the toxicities, and to explore c-kit and PDGFR in this population. Results: 27 patients were accrued; 6 were ineligible. 19 patients received therapy and were evaluable for toxicity. The median age was 59 years (36–78). Four responses were seen: 1 complete, 1 confirmed partial, and 2 unconfirmed partial (RR 21%). The 6-month progression free survival was 16%. There were no grade 4 toxicities. The most common grade 3 toxicities, seen in 7 patients, were diarrhea, fatigue, and hand-foot syndrome. As 2 of the 4 responses were unconfirmed, accrual did not proceed to the second stage. Conclusions: The combination of imatinib mesylate and capecitabine was well tolerated in patients with metastatic breast cancer, but the RR was not better than was seen in a prior study of single agent capecitabine. Correlative studies to explore c-kit, PDGFR, and estrogen receptor expression and response are in progress. No significant financial relationships to disclose.
Intensified local treatment and systemic therapy significantly increase time to progression and survival in patients with brain metastases from advanced breast cancer
Authors: Bartsch R. , Muschitz S. , Wenzel C. , Roessler K. , Dieckmann K. , Weitmann H. , Pluschnig U. , Poetter R. , Zielinski C. C. , Steger G. G. 
Published: March 2020

10536 Background: Brain metastases (BM) have evolved from a rare to a frequently encountered event in advanced breast cancer (ABC) due to advances in palliative systemic treatment. Especially since the introduction of trastuzumab, different groups reported an increased incidence of BM. In this study, we retrospectively tried to establish factors predicting a prolonged survival in those patients (P). Methods: All P treated at our centre from 1994 to 2004 with whole brain radiotherapy for BM from ABC were included. Cerebral time to progression (cTTP) and overall survival (OS) were calculated using the Kaplan-Meier product limit method. A multivariate analysis (Cox regression) was performed to explore which factors are able to influence significantly cTTP and OS (metastatic sites [visceral versus non-visceral], Karnofsky performance score [KPS], age, intensified local treatment [boost irradiation, neuro-surgical resection], further palliative systemic treatment). Results: Overall 174 P, median age 51 years (y), range 27–76 y, were included. Median cTTP was 3 months (m), range 1–33+ m (95% CI 4.67–7.37). Median OS was 7 m, range 1–44 m (95% CI 5.08– 8.92). Factors significantly influencing cTTP were KPS (p = 0.0024), intensified local treatment (p < 0.0001), and palliative systemic treatment (P = 0.0003). Factors significantly influencing OS were intensified local treatment (p = 0.004), metastatic sites (p = 0.008), KPS (p = 0.006), and palliative systemic treatment (p < 0.001). Conclusion: As shown by the significant influence of metastatic sites, some P die from their advanced systemic disease situation before they would experience cerebral progression, in part explaining the influence of systemic treatment. In other individuals however, intensified local treatment and systemic treatment appear to influence both cTTP and OS significantly, implicating a direct influence of systemic therapy on BM. This might result from an impaired blood brain barrier around metastatic sites, making sufficient tissue concentrations of cytotoxic agents possible. No significant financial relationships to disclose.
Impact of mammographic screening in staging, treatment and prognosis of breast cancer: Early assessment
Authors: Lluch A. , Chirivella I. , Insa A. , Martinez-Ruiz F. , Santaballa A. , Herranz C. , Ibañez J. , Miranda J. , Pons C. , Sala D. 
Published: March 2020

10537 Background: The use of breast cancer mammographic screening (MS) leads to early detection and has been shown to reduce the mortality rate and to increase the proportion of breast-conserving surgery. The aim of this study is to analyze the impact of mammography in the staging, treatment and prognosis of breast carcinoma. Methods: In 1993, a population-based mammographic screening among women aged from 45 to 70 years was introduced in the community of Valencia. We examined the effects of this MS program by the comparison of two populations. The first one included all the women with screen-detected invasive breast carcinoma between 1993 and 2002 in the community of Valencia. The second one was comprised of all the women with invasive breast carcinoma, diagnosed in the same period, aged 45–70, not attending the MS and treated at H. Clinico of Valencia. Results: Between January, 1993 and December, 2002, 2313 new invasive breast cancer patients were detected by the MS program in the community of Valencia, and 1349 women aged 45–70, not attending de MS were diagnosed with invasive breast carcinoma in H.Clinico of Valencia. The median follow-up period was 45.5 months for the screen-detected breast cancer and 51.9 months for not screen-detected patients. The screen-detected tumors had smaller pathological size (pT1 tumors 70.2% vs 40.5%, p < 0.0001), were more likely to have pathologically confirmed negative nodal status (66.4% vs 52.2%, p < 0.0001) and stage I disease (55.3% vs 26.1%, p < 0.0001). Breast-conserving surgery was performed in 50.4% of patients with screen-detected tumors and in 31.9% of women who had not undergone MS (p < 0.0001). The 5-year estimated survival was 95.5% (SE 0.57) for women with screen-detected breast cancer and 85.5% (SE 1.17) for those with not screen-detected tumors (p < 0.0001). Conclusions: Our data demonstrate a better prognosis in terms of 5-year survival in screen-detected breast cancer patients that may explain why breast carcinoma mortality rates have decreased in recent decades. These patients have also been found to have smaller tumors, a more favorable tumor stage and a higher proportion of breast-conserving surgery. No significant financial relationships to disclose.
Comparison of mammography, sonography and MRI in patients receiving neoadjuvant chemotherapy for breast cancer: Final results of a prospective study
Authors: Andreetta C. , Russo S. , Londero V. , Mansutti M. , Minisini A. , Cardellino G. , Valent F. , Zuiani C. , Bazzocchi M. , Puglisi F. 
Published: March 2020

10538 Background: Imaging techniques used to evaluate response during neoadjuvant chemotherapy for breast cancer include mammography (Mx), sonography (US) and MRI. This study prospectively evaluated the ability of each technique to determine pathologic response in breast cancer patients undergoing neoadjuvant chemotherapy. Methods: Forty women with operable breast cancer (T ≥ 2 cm, N0–1, M0) were treated with four cycles of anthracycline-based and taxane-based neoadjuvant chemotherapy as part of a phase II clinical trial. The longest diameter of each tumor (n = 48 neoplastic foci) was measured by Mx, US and MRI at baseline, after two cycles and after 4 cycles of chemotherapy, before surgery. Tumor size at pathology was determined and considered as gold standard of response. Differences among techniques in measuring tumor diameters were evaluated by means of t-test. Results: At baseline, US provided statistically higher measures than Mx (mean difference: 6.3 mm, p < 0.0001) or MRI (mean difference: 5.6 mm, p < 0.0001). No difference was observed between Mx and MRI (mean difference: 0.59 mm, p = 0.5). After two cycles of chemotherapy, tumor diameter measured by US was significantly longer than that measured by Mx (mean difference: 8.8 mm, p < 0.0001) and significantly shorter than that measured by MRI (mean difference: −5.1 mm, p = 0.0009). Mx provided longer measures than MRI (mean difference: 4.4 mm, p = 0.0034). After four cycles of chemotherapy, US provided significantly shorter measures than Mx (mean difference: 11.8 mm, p < 0.0001) and MRI (mean difference: −3.3 mm, p = 0.007), whereas tumor size measured by Mx was significantly longer than that measured by MRI (mean difference: 6.75 mm, p = 0.0027). In addition, the tumor diameter measured by the pathologist was longer than that measured by US (mean difference: 2.6 mm, p = 0.09) and significantly shorter than that measured by Mx (mean difference: −7.8 mm, p < 0.0001). No statistically significant difference was observed between MRI and pathological measures (mean difference: −1.0, p = 0.5). Conclusions: This study provides further evidence that, among imaging techniques, MRI is the best method to evaluate the tumor size after neoadjuvant chemotherapy for breast cancer. No significant financial relationships to disclose.