bluuebunny/crossref_metadata_2025 huggingface dataset:
Mammography screening in France: Results of EDIFICE study
Authors: Serin D. , Namer M. , Cals L. , Rixe O. , Roussel C. , Coscas Y. , Blay J. , Pivot X.
Published: March 2020

10701

Background: The EDIFICE study aimed to allow better understanding of population’s adhesion to the screening tests available for the 4 most frequent cancers: breast, colorectal, prostate and lung. Implementation of breast cancer screening (CS) was generalized since 2003 in France: women aged between 50 and 74 years are invited to do a mammography (M) every second year. Methods: This nationwide observational study was the first implemented in France (from January 18th to February 2nd, 2005) among a representative sample of 1504 subjects aged between 40 and 75 years including 773 women and a representative sample of 600 general practitioners (GPs). Information about participating subjects included socio-demographic characteristics, attitude towards CS and actual experience of CS, and about GPs’ medical practice regarding CS. Results: Among the 507 participating women (PW) aged between 50 and 74 years, 93% had done at least one M: 55% underwent this test on their own initiative and 45% of PW had it during a systematic screening plan. Most PW in the systematic screening (89%) had a M dating from less than 2 years vs 74% of the others (X2 = 18.9; p < 0,01). Main reasons for not performing the biennial screening test were: lack of care (18%), “it’s not a priority” (18%) and no advice from the GPs (15%). 79% of the PW had at least one M before 50 years (1st test at the mean age of 37.9±6 years). Among the 600 GPs, 68% systematically recommended M to their patients. GPs’ perceptions of the reasons for women’s avoidance of screening test were their unwillingness to be aware of M results (44%) and their belief in painful symptoms related to M (52%). Conclusions: This first nationwide study has shown the high rate of PW’s attendance at M screening. It pointed out that systematic and organized screening played a major role in regularity of screening over 2 years, and GP is a key actor in heightening public awareness.

No significant financial relationships to disclose.
Phase II study of mitomycin-C and cisplatin in heavily pretreated advanced breast cancer
Authors: Hu X. , Guo H. , Yang X. , Zhao X. , Cai Y. , Wang Z. , Leaw S. , Li J.
Published: March 2020

10713

Background: There were no standard chemotherapy regimen to patients with advanced breast cancer who had been exposed to anthracyclines, vinorelbine and taxanes. The mitomycin-C and cisplatin combination was investigated in this subgroup of patients. Methods: Three-weekly regimen consisted of mitomycin, 6 mg/m2 administered intravenously on day 1, and cisplatin, 25 mg/m2 intravenously on day 1–3. Results: 38 patients aged 25–75 years (median: 46 years) were treated with an overall response rate of 31.6%. The median time to progression (TTP) was 4.0 months. Median TTP for 12 patients with a complete or partial response was 9.0 months, while stable disease and progression of disease 4.0 months, p = 0.002. Grade 3/4 side effects of neutropenia, thrombocytopenia and nausea/vomiting were documented in 4 (10.5%), 4 (10.5%) and 3 (7.9%) patients, respectively. The median overall survival was 13+ months. Conclusions: The mitomycin-C/cisplatin doublet showed antitumor activity for anthracycline-, vinorelbine-, and taxane-resistant breast cancer comparable to other regimens. This well-tolerated regimen provides an affordable option for patients in China.

No significant financial relationships to disclose.
Evaluation of early response to primary systemic chemotherapy in breast cancer patients by 18FDG PET: Preliminary findings from the Arianna Project 01
Authors: Zamagni C. , Fanti S. , Bernardi A. , Sperandi F. , Quercia S. , Santini D. , Musto A. , Castellucci P. , Taffurelli M. , Martoni A.
Published: March 2020

10722

Background: Pathological complete remission after primary systemic chemotherapy (PSC) for early breast cancer (BC) correlates with a better prognosis in terms of survival. The Arianna Project 01 was designed to study the relationship between clinical, hystological, biological, gene-expression profile characteristics and response to PSC in BC pts. Methods: Pts treated with 6 cycles of adriamycin 60 mg/m2 and paclitaxel 200 mg/m2 were evaluated at baseline and before each cycle by physical exam, 18FDG-PET, circulating tumor cells and bio-markers (serum EGFR, VEGF, UPA, plasma PAI-I and the circulating portion of HER2/neu receptor). At baseline and every other cycle mammography, ultrasound and breast MRI were also done. This preliminary report is focused on the correlation between PET monitoring and pathological response. Changes in tumoral 18FDG uptake, expressed as Standardized Uptake Value (SUV), were compared with the hystopathological response assessed according to Miller-Payne scale, which estimates the Tumour Regression Grade (TRG). Results: Up to now 12 pts (T > 2 cm) have been enrolled in the study and 9 completed PSC and were submitted to surgery. Baseline PET was abnormal in all pts (SUVmax range: 3.9–17.1). No cases of complete pathological remission have been observed so far. In 2 pts the TRG was grade 4 ( > 90% reduction of tumor cells), TRG was grade 3 (30 to 90% reduction) in 3 cases, grade 2 (minor loss of tumor cells) in 4 cases. After the 1st, the 2nd and the 3rd cycle of PSC the SUV decrease (Δ SUV) in primary tumors was ≥ 50%, ≥ 75% and ≥ 85% only in the two pts that at the end of PSC obtained a TRG grade 4 (see table ). Conclusions: Our preliminary results suggest that an early prediction of pathological response by PET is possible and the optimal timing to perform PET during PSC could be after 2 or 3 cycles. The study is still ongoing and the relationship between evaluation performed by PET and by mammography, ultrasound and breast MRI will be presented at the ASCO meeting.

[Table: see text]

No significant financial relationships to disclose.
Breast cancer (BC): May intra-arterial (IA) chemotherapy (CT) play a role in the treatment of locally advanced disease or liver metastases? Report of our experience
Authors: Milandri C. , Calzolari F. , Passardi A. , Giampalma E. , Tison C. , Cecconetto L. , Calpona S. , Ridolfi L.
Published: March 2020

10726

Background: IA infusion of CT increases drug concentrations within a tumor. We investigated if it is effective in BC patients (pts) with locally advanced disease or liver metastases. Methods: Twenty-five pts were treated with IA CT using angiographic technique in the Department of Medical Oncology, Morgagni-Pierantoni Hospital in Forlì. Pts received a short IA infusion through the proper hepatic artery (liver metastases) or the internal mammary artery (locally advanced disease). Drugs were: Epirubicin (EPI) 30 mg/m2, Mitomycin-c (MMC) 7 mg/m2 and 5-fluoruracil (5FU) 1000 mg on day 1 every 21 days. EPI was not administered in anthracycline pretreated pts. Results: Median age was 54.3 years (31–75 years) and ECOG Performance Status (PS) was ≤2. Nine pts had liver metastases and 16 had locally advanced disease. Twenty-three (96%) of the 25 pts had received adjuvant treatment (21 CT, 7 endocrine therapy), 20 (80%) had had at least one treatment for metastatic disease (20 CT, 11 endocrine therapy, 8 radiotherapy), and 11 pts (40%) had received concomitant therapy (3 CT and 8 endocrine). Fifteen pts were anthracycline-naïve. A total of 88 angiographic sessions were carried out, with a median number of 3.5 cycles per patient (1–8 cycles). One transitory ischaemic attack occurred during angiographic procedure . No other serious complications were observed. The only cases of toxicity higher than grade 2 were one grade III neutropenia and one grade IV thrombocytopenia. A dose reduction was necessary in 4 pts (2 due to PS, 1 to toxicity and 1 to pre-treatment) and treatment was interrupted in 4 pts (2 due to PS, 1 to early progression and 1 to technical problems). Among the 19 pts assessable for response, 13 (68%) had a partial response, 2 (11%) showed stable disease and 4 (21%) progressed. Median time to progression and median overall survival will be given. Conclusions: Our results suggest that IA CT may play a role in the treatment of advanced pre-treated BC pts.

No significant financial relationships to disclose.
Clinical efficacy of capecitabine as first-line chemotherapy in metastatic breast cancer
Authors: Yap Y. , Kendall A. , Banerji U. , Walsh G. , Smith I. E.
Published: March 2020

10727

Background: Capecitabine is commonly used in metastatic breast cancer (MBC), but there are limited data on its efficacy in the first-line setting. The clinical efficacy of capecitabine monotherapy was evaluated in our institution. Methods: Patients who received capecitabine monotherapy (starting dose 1 g/m2 twice daily every 2 out of 3 weeks) between April 2001 and April 2005 as first-line treatment for advanced disease were retrospectively identified from our prospectively maintained database. Endpoints included response rate (RR), response duration, time to progression (TTP) and overall survival (OS). Results: 63 patients were evaluated. The median age was 57 (30–79) years. The sites of disease were soft tissue and/or bone only in 24 (38%) patients, and involved visceral sites in 39 (62%) patients. 45 (71%) patients had previously received adjuvant or neoadjuvant chemotherapy. The median number of cycles administered was 5 (1–40). 48 (76%) had measurable disease with a RR of 29% (14/48). Chemotherapy-naive patients with measurable disease had a RR of 33% (5/15), while patients previously exposed to neoadjuvant or adjuvant chemotherapy had a RR of 27% (9/33). The median response duration was 24(9–68) weeks. The median TTP was 18 (range 2–122) weeks. However 12(19%) had a TTP of 9 months or more, including 7 (11%) with a TTP of >1 year (14–28 months). Of these, 6/7 were oestrogen receptor +ve and 5/7 had bone and/or soft tissue disease only. 21 (33%) patients developed disease progression on treatment, and response was not evaluable in 4 (6%) patients who stopped capecitabine after 2 or fewer cycles due to medical co-morbidities. Conclusions: These audit results on first line capecitabine monotherapy in MBC are consistent with a previously published study(1). The overall RR may be less than for anthracyclines and taxanes (generally 30–50%) in this setting, but for a subgroup of patients with predominantly soft tissue/bone disease capecitabine can result in prolonged TTP with minimal toxicity. This should be evaluated further in a randomized clinical trial. References 1. O’Shaughnessey JA et al. Ann Oncol 2001 Sept; 12 (9): 1247–54.

[Table: see text]
Neoadjuvant chemotherapy with epirubicin and cyclophosphamide followed by docetaxel (ECT) in locally advanced and inflammatory breast cancer (BC): Saint Louis experience
Authors: Giacchetti S. , Habdous M. , Hocini H. , Cuvier C. , De Roquancourt A. , Perret F. , Espié M.
Published: March 2020

10729

Background: Neoadjuvant chemotherapy is increasingly used in locally advanced breast cancer ptes. We studied the histological response after neoadjuvant chemotherapy in ptes with locally advanced and inflammatory breast cancer. Methods: From 2003 to 2005, 50 ptes with locally advanced and inflammatory breast cancer received neoadjuvant chemotherapy (Epirubicin 75 mg/m2, Cyclophosphamide 750 mg/m2 (d1-q21, 4 courses (c)) followed by Docetaxel 100 mg/m2 (d1-q21, 4 c). All ptes had a surgical biopsy prior chemotherapy, initial conservative surgery was impossible. Clinical responses were evaluated by the same oncologist and the surgery slices reviewed by the same pathologist. Histological complete response is defined as no infiltrative and/or in situ tumor in the breast and negative lymph nodes. Results: Ptes characteristics: median age 50 y (30–74), 30 premenopausal ptes; T2: 5 ptes, T3: 24, T4: 21, median tumor size 60 mm; N0: 12, N1: 38, 11 ptes had inflammatory tumor. Histological features: 43 infiltrating ductal carcinoma, 7 infiltrating lobular carcinoma, SBR grade 1/2/3: 2/23/24; vascular embols (13 positive, 37 negative), RH+: 28 ptes (16 RE+/RP+; 12 RE+/RP-) and 22 RH-, C-erb2 status (43 negative and 7 positive). All the ptes received 8 courses of chemo. Clinical response at 8 c: 22 (44 %) ptes had a complete response, 14 (32%) partial response, 9 (20%) stable disease, 4 ptes (8%) had progressive disease, 1 was not evaluated. 42 ptes had breast surgery, 5 are too early, 2 progressed and received a second line chemo, 1 refuse surgery. Out of 42 operated ptes, 37 had mammectomy, 5 tumorectomy, 39 had axillary dissection. Histological response: 7 ptes had a complete pathological response (pCR) (17 %), 3 had pCR with persistant in situ carcinoma (7%), 32 ptes (76%) had persistant infiltrative carcinoma [histological response >50% 14 ptes (33%), <50% 18 ptes (43%)]; 11 (26%) ptes had negative lymph nodes, 28 (66 %) had positive lymph nodes [10 1–3 N+; 18 ≥ 4 N+]. Conclusion: In this population with a large amount of T3-T4 (median size 60mm) and inflammatory cancers the complete histological response rate of 17% (24% with in situ) is close to the series with smaller tumors. The rate of breast conservation is low (12%).

No significant financial relationships to disclose.
Central nervous system metastases after trastuzumab therapy in patients with breast cancer
Authors: Daw Sr. H. , Muslimani A. , Ahluwalia M. , Kundranda M.
Published: March 2020

10747

Background: trastuzumab (Tz), a humanized anti-HER-2/neu antibody, has been shown to improve survival in patients with HER2-positive breast cancer. A high incidence of brain metastases (BM) has been noted in patients receiving trastuzumab. Here we report 4 cases of HER-2 positive advanced breast cancer patients who developed BM while on TZ therapy. Cases: all 4 patients were treated initially with a combination of taxane-trastuzumab followed by maintenance trastuzumab. Tumors were classified as HER-2 over expressing if they were scored 3+ by immunohistochemistry or showed amplification by fluorescence in situ hybridization. Mean age at diagnosis was 48. Mean duration of trastuzumab therapy prior to BM was 20 months. All patients had achieved a complete remission of extracranial disease at the time of BM diagnosis. Mean number of intracranial lesions as determined by magnetic resonance imaging was 4. Treatment included radiosurgery, surgical resection, whole brain radiation, temozolomide, high dose methotrexate, thalidomide and in one patient, intra-arterial chemotherapy. All 4 patients are alive at the date of last follow-up (median =3 years) after BM diagnosis. Conclusions: this report suggests that patients who develop BM after trastuzumab can have a relatively long survival rate. The importance of a multidisciplinary approach to these patients cannot be overemphasized. Development of BM on TZ therapy does not represent resistance to TZ, but instead likely reflects the inability of TZ to cross the brain-blood barrier. Further research in this area is needed to optimize management while minimizing late effects. In this regard, alternatives to whole brain radiation should continue to be studied. In addition, the role of prophylactic cranial irradiation and the search for drugs that target HER-2 and cross the blood-brain barrier should be investigated.

No significant financial relationships to disclose.
A pilot study of weekly versus 3-week docetaxel in combination with capecitabine in patients with anthracycline-pretreated metastatic breast cancer
Authors: Jiang Z. , Zhang S. , Xie X. , Liu J. , Ren J. , Wang H. , Sun Q. , Bai Y. , Cheng Y. , Liang X. , Jiao S.
Published: March 2020

10771

Background: Capecitabine in combination with docetaxel given every 3 weeks has shown a high degree of activity in anthracycline-pretreated metastatic breast cancer (MBC), but with high toxicities. To improve the therapeutic index, we performed a clinical pilot trial to evaluate the efficacy and safety of weekly or 3-week docetaxel in combination with capecitabine given for 14 days every 21 days. Methods: Patients with at least one measurable lesion were randomized to receive the treatment arms: docetaxel 75mg/m2 on days 1, oral capecitabine 950 mg/m2 twice daily on days 1–14 (Arm A); docetaxel 37.5mg/m2 on days 1 and 8, oral capecitabine 950 mg/m2 twice daily on days 1–14 (arm B). Each cycle was repeated every 3 weeks. Patients remained on study for a maximum 6 cycles or until tumor progression or unacceptable toxicity occurred, response assessments were scheduled every two cycles. Results: 64 pts were enrolled, 62 eligible for safety and tumor assessment. Key baseline variables were well balanced. Dominant site of disease was visceral in 66.1%; 24.2% had ≥3 organ sites of disease; all patients had previously received anthracyclines, 24.2% for MBC. 43. 6% were ER negative and 46.8% were HER-2 overexpress. The overall clinical response rate of all groups was 59.7% (37/62). There was no progressive disease (PD) after two cycles. Efficacy outcomes were similar in the two arms. The response rate of group A and B were 60% (18/30) and 59.4% (19/32) respectively. There were no drug-related deaths observed. Neutropenia was the most common toxicity. In all, the frequence of Grade 3/4 neutropenia were similar in two arm, but Grade 4 neutropenia of Group A 66.7% (20/30) was higher than Group B 34.4% (11/32), P = 0.021. Conclusions: The study confirmed the superior activity of docetaxe-capecitabine combination therapy in anthracycline resistant MBC, and comparing with 3-week schedule, weekly docetaxel plus capecitabine has same high efficacy with a favourable safety profile.

No significant financial relationships to disclose.
Changing demographics of locally advanced breast cancer: Data from a regional cancer centre
Authors: Segal R. , Dent S. F. , Verma S. , Canil C. M. , Azzi J. , Vandermeer L. , Spaans J.
Published: March 2020

10780

Background: Locally advanced breast cancer (LABC) (including inflammatory breast cancer (IBC)) accounts for less than 5% of women diagnosed with breast cancer in North America each year. This population of women continues to represent a challenge in terms of timely diagnosis and treatment. Methods: A retrospective database was developed using the American Joint Committee on Cancer (AJCC)2002 staging classification for all women who presented to TOHRCC with LABC between Jan 1/02 - April 1/05. Information was abstracted from clinic charts and the patient self-reported health questionnaires. Results: These results reflect the demographics of the first 50 women entered into our database. Median age at presentation was 57 years (range 28–88); 62% were post-menopausal and 28% had a 1st/2nd degree relative with breast cancer. Clinical diagnosis was made by: self-detection (79%); mammography (5%), routine physical exam (9%) and CT scan (2%). Clinical tumour stage at presentation was: IIIA (25.6%); IIIB (53.5%) and IIIC (9.3%). The majority of women were diagnosed with infiltrating ductal carcinoma (72%). Women with T4d tumours (IBC) (38%) tended to be younger (54.5 vs 59.2 years); presented earlier (2.7 vs. 6.3 months); had larger tumours at the time of diagnosis (9.7 vs 5.5 cm); were more likely grade III (30 vs 20%) and were more often ER negative (42.1% vs 33.3%) and PR negative (63.2% vs. 50%). Only 13% of women in this database were tested for HER-2 of whom 70% were positive. Conclusions: This data utilizing the new AJCC (2002) staging system reflects important shifts in LABC that will influence clinical care in the future. Compared to historical databases, patients tended to be younger and have more aggressive disease including ER negative and HER-2 positive disease. Supplemental microarray studies to further explore this entity are planned. We will present clinical management outcomes in an additional submission.

No significant financial relationships to disclose.
Sentinel lymph nodes navigation surgery for stage I or IIA breast cancer patients
Authors: Hirata M. , Kawabata H. , Tanaka K.
Published: March 2020

10784

Background: We applied indigocarmine for sentinel lymph nodes staining for Stage I or IIA breast cancer patients. We compared patient survival between sentinel lymph nodes navigastion surgery group and ordinary surgery with axillary lymph nodes dissection group. Methods: Patients consisted of 160 histologically proven breast cancer women (Stage I: 108 cases, Stage II: 52 cases, 51.8 ± 11.1 years, SN group) and other 320 breast cacner women (Stage I: 187 cases, Stage II: 146 cases, 53.4 ± 9.7 years, non-SN group). All patients underwent partial resection of their breast with histologically proven cancer cells negative margin (SN group: May 2000–December 2003, non-SN group: January 1996–December 2003). Fifteeen minutes before surgery, 0.4% Indigocarmine (10 ml) was injected around the tumor by use of 24 gauge syringe. Sentinel lymph node (SN) was defined as the stained lymph node. Intra operative cytology and histopathological examination was performed for SN and one or two lymph nodes around the SN. When any cancer cells were found in either of SN or the lymph nodes around the SN, axillary lymph nodes dissection was performed. When all of SN and several lymph nodes around the SN were diagnosed as cancer cells negative, axillary lymph nodes dissection was omitted. Patient survival and disease free survival were calculated by Kaplan-Meier method. Results: About patients characteristics including age, diameter of the tumor, hormone receptor status, treatment after surgery, etc., no significant difference was found between two groups. We could find SN in 156 patients (97.5%) out of 160 cases in SN group. Four years patient survival was 97.6% (stage I, SN group), 96.6% (stage I, non SN group), and 96.6% (stage IIA, SN group), 93.5% (stage IIA, non SN group), respectively (no significant difference). Four years disease free survival was 97.6% (stage I, SN group), 95.4% (stage I, non SN group), and 82.5% (stage IIA, SN group), 86.4% (stage IIA, non SN group), respectively (no significant difference). Conclusions: Sentinel lymph nodes navigation surgery for stage I or IIA breast cancer patients by use of 0.4% Indigocarmine revealed comparable patient survival and disease free patient survival to ordinary surgery.

No significant financial relationships to disclose.
Axillary lymphadenectomy can be safely avoided in patients with breast cancer and negative sentinel lymph node biopsy
Authors: Millastre E. , Ruiz-Echarri Sr. M. , Ortega M. , Mayordomo J. I. , Lastra R. , Prats E. , Lambea J. , Aguirre E. , Razola P. , Andrés R. , Tres A. , Banzo J.
Published: March 2020

10787

Background: Patients with breast cancer in which sentinel lymph node biopsy is histologically negative for tumor cells, have a low probability of having involvement of additional regional lymph nodes. Lymph node dissection may be avoided in these cases. Methods: Ninety-six consecutive patients with invasive breast cancer and tumour size less than 2 centimeters by mammography, had lymphoscintigraphy with colloidal 99Tc and radioisotope-guided sentinel lymph node biopsy in the University Hospital of Zaragoza from 1999 to 2005.Pathological assessment included serial sections of the sentinel lymph node with immunohistochemistry for cytokeratins in selected cases. Results: Sentinel lymph node biopsy was negative in 57 patients. There were 56 females and 1 male. Median age was 57 years (range 24–87). Median pathological tumor size was 15 mm (range 5–31). Location of the sentinel lymph node was axillary in 47patients, internal mammary in 0 patients, and both in 10 patients. Median number of resected lymph nodes was 2 (range 1–4). With median follow-up of 33 months, no local or systemic relapses have occurred. Conclusions: Avoidance of regional lymph node dissection is safe in patients with breast cancer and histologically negative sentinel lymph node biopsy.

No significant financial relationships to disclose.
Disparities in breast cancer among 236,101 patients in Florida
Authors: Bowen-Wells C. P. , Sumner W. E. , Moffat F. , Avisar E. , Fraceschi D.
Published: March 2020

10790

Background: For minorities with breast cancer, access to healthcare has been an issue. A number of studies have reported racial differences in the pattern of care for women with breast cancer. A recent publication in New England Journal of Medicine indicated that the trend has narrowed between whites and black. In our institution we have noted a persistent higher rate of advanced breast cancer in minority patients. Studies have also showed that minority patients present with more advance disease and are more likely to have receptor negative tumors. Minority patients have higher mortality than whites. Younger minorities appear to do worse than older minorities as a result of lack of insurance. Minorities are less likely to be part of clinical trials. Method: We reviewed the Florida Cancer Data System (FCDS), a large cancer registry. 236,101 cases of breast cancer patients were identified between 1981–1992. Comparisons were made by Chi Square test. Results: Ninety one percentages (91%) of the patients were Whites, 6.8% were Blacks and 2.2% represented all others. Most patients presented with localized disease: Whites had 49%; Blacks had 36% and the other minority 36.3%. Blacks had a significantly higher incidence of regional disease (see figure), and had the highest percentage of metastatic disease at presentation (p < 0.01). Conclusion: Disparities in breast cancer care still clearly exist amongst ethnic group in Florida. The disparities are resulting in higher mortality among non-whites as compared to whites. Better results could be achieved with sets at prevention, education about early detection, screening and access.

No significant financial relationships to disclose.
A clonogenic study of arsenic trioxide (ATO) and temozolomide (TMZ) together and in combination with radiation therapy (RT) in a human glioma cell line
Authors: Portnow J. , Gaur S. , Synold T. W.
Published: March 2020

11506

Background: ATO is effective in the treatment of acute promyelocytic leukemia, but its role in the management of solid tumors has yet to be defined. Post-operative therapy consisting of TMZ with and without RT is considered the standard of care for patients with newly-diagnosed glioblastoma multiforme (GBM). ATO has been shown to potentiate the effects of RT in preclinical models. Therefore, we investigated the cytotoxicity of ATO and TMZ both together and in combination with RT in the U251T human glioma cell line. Methods: U251T cells in log phase growth were treated with ATO (0.05–5 μM) and/or TMZ (0.05–5 μM) for 24 hours or sequentially according to the following schedules: ATO for 18 hours followed by TMZ for 6 hours or the reverse sequence. For RT experiments, cells were treated with 0–10 Gy of ionizing RT using a Cesium-137 source. Following drug and/or RT treatment, cells were replated onto 1.5 cm tissue culture dishes in triplicate and incubated at 37oC for 8 to 10 days to form colonies. Colonies of more than 40 cells each were counted and the IC50 values and combination indices (CI) were derived using Calcusyn software (Biosoft, Cambridge, UK). Each combination was repeated at least 3 times. Results: The mean single agent IC50 for ATO, TMZ, and RT were 1.10 ± 0.28 μM, 1.88 ± 0.91 μM, and 2.62 ± 0.23 Gy, respectively. Simultaneous treatment with ATO and TMZ was slightly synergistic, while sequential treatment was either additive (TMZ→ATO) or synergistic (ATO→TMZ). Combinations of RT with ATO, TMZ or both were all synergistic, with the triple agent combination showing the greatest synergy. Conclusions: RT followed by ATO and TMZ given sequentially demonstrated striking synergy in U251T human glioma cells. A clinical trial of this combination therapy in patients with newly-diagnosed GBM is currently under development.

[Table: see text]

No significant financial relationships to disclose.
A phase I study of pegylated doxorubicin (DOX) and weekly topotecan (TOP) in patients (pts) with advanced solid tumors
Authors: Masters G. A. , Guarino M. , Schneider C. , Biggs D. , Grubbs S.
Published: March 2020

12018

Background: The primary endpoint of this prospective phase I study of DOX-TOP in pts with advanced solid tumors was to identify the maximum tolerated dose and dose-limiting toxicities (DLT) of this combination. Other objectives included a description of additional toxicities and efficacy in this patient population with refractory cancers. Pharmacokinetic sampling of TOP plasma levels will be reported separately. Methods: Eligible pts had advanced solid tumors and had either failed standard chemotherapy (chemo) or were pts for whom no standard therapy existed. They had ECOG PS = 0–2, adequate organ function, and gave written, informed consent. Initial doses included DOX 40 mg/m2 day 1 and TOP 2 mg/m2 days 1, 8 and 15 q 28 days. TOP was to be escalated in cohorts of pts. DLT was defined as febrile neutropenia, grade 4 thrombocytopenia, any grade 3 non-hematologic toxicity, or the inability to receive subsequent treatment due to ongoing toxicity. Treatment was held for ANC < 1000 or platelets < 75,000. Results: Fourteen pts have been enrolled on this phase I study, all of whom were evaluable for toxicity. There were 12 males and 2 females, and the median age was 57 years (range 25–86). Four had ECOG PS = 0, 9 had PS = 1, and 1 had PS = 2. Cancer types included head and neck (3), renal (2), and breast, pancreas, liver, esophagus, germ cell tumor, sarcoma, and others (one each). In the 6 pts treated at dose level 1, toxicities included grade 3 anemia (1) and neutropenia (2), and grade 4 neutropenia (1). DLT consisted of grade 4 thrombocytopenia (1) and inability to deliver day 15 TOP in 3/6 pts at this dose. Thus, TOP was reduced to 1.5 mg/m2 weekly for dose level -1, and 8 pts have been treated. Toxicities included grade 3 anemia (1)and neutropenia (2), and grade 4 neutropenia (1) and thrombocytopenia (1). Enrollment continues at this dose level to confirm tolerability. No patient achieved an objective response to therapy, but 2 pts have stable disease for up to 4 cycles. Conclusions: DOX-TOP can be safely combined in pts with advanced solid tumors, with hematologic toxicity as the DLT. The preliminary recommended phase II dose is DOX 40 mg/m2 and TOP 1.5 mg/m2. We plan to explore an additional dose level of DOX 30 mg/m2 and TOP 2 mg/m2. Phase II evaluation is contemplated in selected tumor types.

[Table: see text]
Antitumoral effect of gemcitabine metronomic schedule in a xenograft pancreatic model
Authors: Laquente B. , Lacasa C. , Morell M. , Casanovas O. , Figueras A. , Galán M. , Viñals F. , Capella G. , Germá J.
Published: March 2020

12031

Background: Human tumor xenografts in mice can be remarkably predictive of response in humans to cytotoxic chemotherapeutic drugs. Tumor endothelial cells are sensitive to the action of conventional cytotoxic drugs when they are regularly administrated at low doses. This concept, known as metronomic chemotherapy, has been demonstrated in preclinical studies using transplanted tumor models. We aim to investigate the potential anti-tumoral activity of Gemcitabine (G) when administered in a low-dose schedule in an ortothopic implantation model of human pancreatic carcinomas. Methods: Standard gemcitabine schedule: NP18 tumor orthotopically implanted nude mices were randomly distributed to experimental (n = 13, G100 mg/kg intraperitoneally on days 0, 3, 6 and 9 post-implantation) and control group (n = 13, saline). Animal were sacrificed after 4 weeks and we compared weigths (grams) and volume (cm3) of tumors betwen the two groups by the Mann-Whitney U test. Metronomic schedule: After a toxicological study an optimal metronomic dose of 1 mg G /kg per day was chosen. Thirty xenografted mices were randomly distributed to experimental group (n = 15, intraperitoneal G1 mg/kg) and control group (n = 15, saline) and treated for 30 days. Animal were analysed as described before. Results: Standard schedule: Tumor weight mean of treatment group was 0.01 grams ± 0.01 versus 0.54 grams ± 0.48 of the control group. Tumor volume mean in G group was 0.01 cm 3 ± 0.01 versus 0.51 cm 3 ± 0.67) in the control group.Treatment significantly inhibited NP18 tumour growth (p < 0.001). No differences in mice weight were observed between both groups. Metronomic schedule: Tumor weight mean in the treatment group was 0.04 grams ± 0.08 versus 0.53 grams ± 0.46 in control group. Tumor volume mean in G group was 011 cm 3 ± 0.19 versus 0.37 cm 3. Treatment with low-dose of G significantly inhibited NP18 tumour growth (p < 0.003). There were no differences in mice weight between the two groups. Conclusions: Our data show that G administered in a metronomic schedule is effective in inhibiting the growth of NP18 tumor orthotopically implanted in the nude mice. We now aim to study the angiogenic profile of tumors receiving the standard and metronomic schedule and to set up a new experiment to compare survival benefit in the animal model.

No significant financial relationships to disclose.
A phase I clinical trial of MVA expressing 5T4 and high-dose interleukin-2 (IL-2) for metastatic renal cell carcinoma
Authors: Kaufman H. L. , Deraffele G. , Mitcham J. , Moroziewicz D. , Kim-Schulze S. , Petrulio C. A. , Harrop R. , Naylor S.
Published: March 2020

12500

Background: Metastatic renal cell carcinoma (RCC) is an immune responsive tumor. 5T4 is a tumor antigen expressed on the cell surface of clear cell and papillary RCC. We sought to evaluate the safety and immunologic effects of vaccination with modified vaccinia virus Ankara (MVA) expressing 5T4 followed by IL-2 in patients with advanced RCC. Methods: A single dose Phase I clinical trial was conducted in patients with metastatic RCC and who were eligible for high-dose IL-2. Vaccination was given every three weeks by intramuscular injection and was followed immediately by standard high-dose bolus IL-2 (600,000 IU/kg) after the second and third vaccinations. The regimen could be repeated if there was no evidence of disease progression. Peripheral blood and serum was collected before treatment and every three weeks for analysis. Routine blood counts, chemistry, and pituitary functions were monitored. Anti-5T4 antibody titers were determined by ELISA assay and 5T4-specific T cell responses were monitored by interferon-γ ELISPOT assay using overlapping peptides. Results: 25 patients with RCC are being sequentially enrolled. There have been no serious vaccine-related adverse events although typical Grade 3 IL-2 related toxicity has been seen in all patients. To date, all patients tested have developed an increase in 5T4-specific antibody titers following three initial vaccinations. T cell assays are currently in progress. Seven patients have completed the trial through at least one course of treatment (mean age 62.3 years). Of these 7, one patient who presented with a primary tumor in place and synchronous metastatic disease had an objective complete response of all metastatic disease and underwent a post-treatment nephrectomy; the primary tumor demonstrated highly necrotic tumor. Two additional patients have had stable disease and are receiving booster vaccinations every three months. Conclusions: These results demonstrate that local vaccination with an MVA virus expressing 5T4 administered in combination with high-dose IL-2 is safe and induces 5T4-specific antibodies in all patients. Additional T cell responses and clinical follow-up will be presented. The use of MVA-5T4 and IL-2 appears to be a promising approach for the treatment of advanced RCC.

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Anti-EpCAM XmAb antibodies with improved cytotoxicity
Authors: Vafa O. , Kharki S. , Vielmetter J. , Chamberlain A. , Hammond P. , Dang W. , Carmichael D. , Kunkel L. , Barbosa M. , Desjarlais J.
Published: March 2020

12506

Background: The epithelial cell adhesion molecule (EpCAM), also known as epithelial protein 2 (EGP-2) or 17–1A antigen, is a trans-membrane protein expressed on the surfaces of most carcinomas, including those of pancreatic, colorectal, prostate, breast, kidney, lung, and ovarian origins. Moderate affinity antibodies (Abs) such as 17–1A (Kd ∼ 10−7 nM) have been safe in humans albeit with limited clinical efficacy. Attempts to improve clinical efficacy by enhancing antigen affinity (Kd ∼ 10−9 nM) have led to serious clinical toxicity, including pancreatitis. These observations raise the question of whether a moderate affinity Ab with enhanced effector function will be both safe and clinically efficacious. Methods: We applied our proprietary XmAb™ technologies to humanize the 17–1A variable domain and engineer a human IgG1 Fc domain to increase affinity for the activating receptor FcγRIIIa. Ab binding to Ep-CAM or to Fc receptors was tested with Biacore and/or AlphaScreen binding assays. In vitro cytotoxic activity against representative cancer cell lines was measured with Antibody Dependent Cell-mediated Cytotoxicity (ADCC) assays, using human PBMC as effector cells. Results: Humanized anti-EpCAM Abs have affinity for EpCAM similar to the parent 17–1A. Affinity for the activating FcγRIIIa was increased 100-fold relative to a control Ab with an IgG1 Fc domain. As expected, these Abs exhibit dramatically enhanced ADCC against multiple cancer cell lines relative to 17–1A and IgG1 control Abs. Despite their moderate affinity for EpCAM, these novel Abs have in vitro cytotoxicity comparable to the high affinity Ab ING-1. CDC activities of these Abs were similar to chimeric 17–1A. Conclusions: We have demonstrated that antibodies with moderate affinity for EpCAM and increased FcγRIIIa affinity exhibit superior cancer cell killing via an ADCC mechanism. The humanized nature and the increased cytotoxicity of anti-EpCAM XmAb™ antibodies make them promising candidates for clinical development of a novel pan-carcinoma Ab that is superior to 17–1A.

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Ovarian cancer: Autologous immunotherapy optimized by remote adjuvancy of a silicate-induced granuloma
Authors: Garcia-Giralt E. , Lasalvia-Prisco E. , Cucchi S. , Lasalvia-Galante E. , Vazquez J. , Golomar W. , Vincent J. P.
Published: March 2020

12515

Background: Advanced ovarian cancer has been included in several studies about an immunotherapy procedure using an Autologous Thermostable Hemoderivative Vaccine (ATHV) with anti-progressive tumor effect in metastatic malignant disease from different primary tumors (Cancer Biol Ther 2003). Like in most cancer vaccines, the net anti-tumoral effect of ATHV has low intensity despite the addition of several adjuvant steps: immune response enhancement by GM-CSF, immune tolerance break by cyclophosphamide or interference with CD4+CD25+ regulatory cells (E. Lasalvia-Prisco et al. ASCO 2003–2005). The inclusion of another adjuvant immunomodulatory step to ATHV in patients with advanced ovarian cancer was explored in this study. The tested adjuvancy was the local and remote immune-stimulation elicited by a subcutaneous silicate-granuloma (SSG), a phenomenon well proven in preclinical models (RM Fauve et al. Immune Lett 1987; E Fontan et al Proc Nat Acad of Sci 1983). Methods: Twenty four metastasic ovarian cancer patients, chemotherapy resistant, performance status ≤ 2 and CA-125 progressing serum level, were included in this institutional-IRB approved phase I/II trial. The patients were 3-group randomized, submitted to 3 different treatments: I only sympthomatic; II the previously reported ATHV and III ATHV + SSG. Tumor Growth was assessed in each case by the tumor size increase (RECIST measured). Mean difference in the 3 groups was statistically assessed (Student’s test). Results: Tumor Growth was slower in Group II and III than in Group I (p<0.02, p<0.005). Tumor growth was slower in Group III than in Group II (p<0.02). No relevant toxicities were detected. Conclusions: The results support that in advanced ovarian cancer an additional subcutaneous silicate granuloma as adjuvant agent optimizes the tumor growth inhibition through immunotherapy with an autologous thermostable hemoderivative vaccine. The bypass of the immune-ignorance could be discussed as its mechanism of action.

No significant financial relationships to disclose.
EGFR expression using immunohistochemistry (IHC) testing as a tool for selecting patients (pts) for treatment with cetuximab
Authors: Ervin-Haynes A. L. , Schinagl R. M. , Dalesandro M. R. , Roecker J. , Youssoufian H. , Rowinsky E.
Published: March 2020

13000

Background: EGFR expression, as determined by IHC, is currently used to select patients for cetuximab therapy. Based on prior studies in colorectal cancer patients, approximately 60 to 75% of patients express EGFR. There is increasing evidence that EGFR expression is not predictive of response to cetuximab therapy, and does not properly select patients who might benefit from such therapy (Chung et al 2005, Saltz et al 2005, Scartozi et al 2004, NCCN 2005). Such selection limits access to a considerable number of patients who might otherwise benefit. Methods: A clinical trial of cetuximab (Erbitux®) monotherapy is being conducted in 60 EGFR-undetectable patients with metastatic colorectal cancer at 14 sites in the US and Canada to explore the relationship between EGFR expression and cetuximab activity. Results: As of January 5, 2006, 112 patients have been screened. Of these patients, 33 (29%) were EGFR-undetectable and continued screening for study enrollment; 52 (46%) tested positive for EGFR expression; and 2 (2%) did not have enough tissue to evaluate EGFR status and were not enrolled onto the trial. The remaining 25 pts (22%), were initially found to be EGFR-undetectable by IHC testing at local labs, but were subsequently identified as EGFR-positive after reevaluation at a highly experienced, centralized laboratory. Conclusion: The majority of patients tested for EGFR expression are tested using the EGFR pharmDx™ IHC assay. Results of the IHC-based assay for EGFR expression are highly dependent upon sample preparation and the methods used in conducting the assay. Variability in methods among labs may result in poor identification of pts expressing EGFR. This finding, together with the growing evidence that EGFR expression is not predictive of response to cetuximab therapy, indicate that the current routine practice of tumor IHC EGFR testing for the purpose of selecting cetuximab therapy may be inappropriate and pts who could potentially benefit from cetuximab therapy are being excluded from a treatment option.

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A randomized phase II trial with gemcitabine with or without pertuzumab (rhuMAb 2C4) in platinum-resistant ovarian cancer (OC): Preliminary safety data
Authors: Glenn D. , Ueland F. , Bicher A. , Dizon D. , Gold M. , Makhija S. , Fleming G. F. , Matulonis U. , McGuire W. P. , Lieberman G.
Published: March 2020

13001

Background: Pertuzumab (P), a humanized HER2 antibody, represents a new class of targeted agents called HER dimerization inhibitors (HDIs). P inhibits dimerization of HER2 with EGFR, HER3 and HER4, and subsequently inhibits signaling through MAP and PI3 kinases. Single agent P has demonstrated clinical benefit in advanced OC (ASCO 2005 abstract #5051). Methods: 40 pts with platinum-resistant OC (progressed within 6 months of receiving a platinum-based chemotherapy) were enrolled in this 1:1 randomized, double blind, placebo controlled trial of gemcitabine with or without P. Gemcitabine was administered IV on day 1 and 8 at 800 mg/m2 of a 21 day cycle. Blinded placebo or 420 mg P was administered IV on day 1. Gemcitabine was dose reduced for neutropenia or thrombocytopenia. P was not dose reduced. Results: 40 pts have been enrolled and treated with at least 1 cycle of gemcitabine in combination with blinded study drug. The median age was 58.5 (range 18–82); 26 had PS ECOG 0, 13 ECOG 1, 1 ECOG 2. The most common grade 3/4 events were neutropenia in 7 pts (17.5%), thrombocytopenia in 6 pts (15%), small bowel obstruction in 4 pts (10%), constipation in 3 pts (7.5%) and elevated ALT in 3 pts (7.4%). There was one grade 3 diarrhea, but no grade 3 or 4 rash. There were 4 serious adverse events (SAEs) attributed to study drug. These were a pleural effusion, thrombocytopenia, febrile neutropenia, and a deep vein thrombosis. Nine pts required one or two dose reductions of gemcitabine for hematological toxicity. Of 29 pts with post-baseline echo or MUGA values obtained, no pt had LVEF drop to <50%. The adverse events evaluated after 40 pts did not meet the prespecified criteria to call for an independent safety monitoring board evaluation of unblinded data. Conclusions: Preliminary safety data indicate that pertuzumab or placebo combined with gemcitabine is well tolerated with no unexpected additive toxicity. The nature and frequency of the adverse events are similar to what has been observed with either single agent gemcitabine or P. Updated data will be presented at ASCO.

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GCS-100, a galectin-3 antagonist, in refractory solid tumors: A phase I study
Authors: Grous J. J. , Redfern C. H. , Mahadevan D. , Schindler J.
Published: March 2020

13023

Background: Galectin-3 is a galactoside-binding protein implicated in inhibition of apoptosis, and promotion of angiogenesis, metastasis, cellular proliferation by a direct association with oncogenic K-ras. Modified citrus pectin (MCP) is a complex carbohydrate derived from citrus fruit and is rich in galactoside residues. GCS-100 is an MCP capable of binding to and antagonizing galectin-3, resulting in anti-tumor activity in vitro and in vivo. Methods: GCS-100 was administered to patients with refractory solid tumors in a Phase I dose-escalating study using standard eligibility criteria. Objectives were to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK) and efficacy. Study drug was delivered by IV infusion over 1–2 hours for 5 consecutive days of a 21 day cycle. Results: 24 patients (17 F, 7 M, age 45–80 yo) were enrolled at 6 dose levels between 30–200 mg/m2. DLT and MTD for this dosing regimen were established at 200 mg/m2 and 160 mg/m2, respectively. DLT was a Grade 3 erythematous, maculopapular rash, resolving with systemic steroid treatment. There were no associated systemic findings, and the rash did not preclude further GCS-100 therapy. Skin biopsy revealed a vasculitis similar to findings seen in dog models. 9 other patients experienced Grade 1–2 rashes that did not require systemic treatment. The majority of adverse events (AEs) were Grade 1 or 2; the most common being nausea, vomiting, diarrhea, fatigue, fever and hyperglycemia. AEs thought to be related to treatment were rash, nausea and fatigue. Linear PKs were observed with a terminal half-life (t1/2) between 30–40 h and an effective t1/2 of 36 h. Peak GCS-100 concentrations reached 424 μg/mL at MTD. The median number of cycles was 4 (range 1–17). Best overall response per RECIST was stable disease observed in 16 patients with 6 of these patients on study for ≥ 6 months. Conclusion: Overall tolerability of GCS-100 was excellent with serum concentrations at MTD reaching levels associated with preclinical activity. Sustained periods of stable disease were achieved in patients with previously treated advanced solid tumors warranting Phase II studies.

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