bluuebunny/crossref_metadata_2025 huggingface dataset:
Engaging human tumor microvascular endothelium to improve ionizing radiation outcomes in solid tumor treatment
Authors: Lewin S. N. , Barakat R. R. , Haimovitz-Friedman A. , Kolesnick R. , Fuks Z. , Poynor E. A.
Published: March 2020

10097

Background: Recent genetic and pharmacologic mouse model studies have shown tumor microvascular endothelium is a primary target in single-dose radiotherapy, required for induction of tumor cell death. The goal of this study is to establish the human tumor microvascular response to ionizing radiation (IR), and to determine whether targeting this response with IR might improve solid tumor treatment. Methods: Fresh epithelial ovarian cancer (EOC) tissue was obtained and irradiated within 30 minutes from patients undergoing surgical resection. Tumors were sliced into 0.5cm fragments, bathed in Dulbecco’s Modification of Eagle’s Medium (DMEM) and irradiated ex vivo at 0, 7, 13, 17, 20, 25 Gy. Specimens were incubated at 37°C post-irradiation for 0, 2, 3, 4 hours, fixed in formalin and paraffin embedded. Immunohistochemistry using TUNEL-CD34 double staining was subsequently performed to detect apoptotic tumor endothelial cells. Results: 10 EOC specimens were initially studied. Tumor microvascular endothelium underwent a linear dose and time dependent apoptotic response mirroring the range reported in mouse models. Three to four hours post irradiation, 60% of endothelial cells underwent apoptosis at 17–25 Gy compared to a baseline rate of 5% in unirradiated controls. Response heterogeneity among the tumor samples was not seen. Of interest is our observation that a maximal apoptotic response obtained in glioblastoma, classically considered radioresistant, was only 30%. Conclusion: The endothelial compartment is an important target in EOC radiation response at the clinically-relevant dose range. Studies assessing endothelial cell radiosensitivity of human EOC and the impact of endothelial cell radiosensitizing agents may provide opportunities to improve radiation responsiveness of EOC.

No significant financial relationships to disclose.
Androgen-dependent regulation of Her-2/neu in prostate cancer cells
Authors: Berger R. , Lin D. I. , Nieto M. , Signoretti S. , Hahn W. C. , Loda M.
Published: March 2020

10099

Background: The mechanisms underlying the progression of prostate cancer to androgen independence remain poorly understood. Overexpression of Her-2/neu (c-ErbB2) activates the androgen receptor pathway and confers a survival and growth advantage to prostate cancer cells in an androgen-deficient milieu. Methods: Androgen-sensitive prostate cancer cell line LNCaP was used as a model system in vitro and in vivo. Experiments in mice were undertaken by injecting cells orthotopically into the ventral lobe of the mice prostate. Results: Here, we report that androgen receptor (AR) and Her-2/neu reciprocally regulate each other in LNCaP human prostate cancer cells. Absence of androgens, AR blockade with Casodex (bicalutamide) or suppression of AR with RNAi induced Her-2/neu protein expression and phosphorylation in vitro and in vivo. Similarly, suppression of Her-2-neu expression resulted in AR upregulation. In contrast, upon re-administration of androgens, Her-2/neu mRNA, protein and phosphorylation levels decreased linearly with increasing concentrations of androgens as LNCaP cells re-entered the cell cycle. Conclusions: Thus, induction and activation of Her-2/neu occurs in an androgen-depleted environment or as a result of AR inactivation, promoting androgen-independent survival of prostate cancer cells.

No significant financial relationships to disclose.
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.
A retrospective pilot study of serum lipid levels and the risk of breast cancer
Authors: Raghupathy R. V. , Seidler C. W. , Emani S. , Rooney J.
Published: March 2020

10539

Background: Prior prospective cohort studies have provided conflicting data regarding lipid levels as a breast cancer risk factor. These studies were either designed to study cardiovascular diseases or included a small number of incident cases. This retrospective pilot study compared the lipid profiles of breast cancer patients to a normal cohort obtained from a large community based HMO database. Methods: Fallon Clinic automated outpatient billing and laboratory databases were used to identify patients with breast cancer (ICD9–174.9) and retrieve average lipid profiles at least two years prior to the first identified diagnosis date. The outpatient billing record of a central Massachusetts HMO was used to randomly generate a control group without an ICD9 diagnosis of breast cancer. Patients were classified into two groups based on age to approximate menopausal state (pre menopausal <50 yr, post menopausal ≥50 yr). T-tests were conducted to compare the total cholesterol, LDL, HDL and triglycerides of the two groups. Results: See table. Conclusions: In the pre-menopausal population, total cholesterol and LDL were significantly higher in the breast cancer group. In the post-menopausal group, triglycerides were higher and HDL lower. Though the HDL association is in concurrence with two large prior studies, other associations have not been demonstrated. An average of fasting levels obtained more than two years before diagnosis eliminates the lipid profile response to meals, variability in isolated values and influence of pre-clinical cancer on the data. However, the patients have not been matched for other breast cancer risk factors or variable menstrual phase while obtaining samples in the pre-menopausal population.

[Table: see text]

No significant financial relationships to disclose.
Cardiac tolerability of trastuzumab in metastatic breast cancer (MBC) patients previously treated with high-dose chemotherapy (HDC) with autologous hemopoietic support: Retrospective analysis from Gruppo Italiano Trapianto Midollo Osseo (GITMO) Solid Tumor Working Party
Authors: Bengala C. , Zamagni C. , Pedrazzoli P. , Matteucci P. , Ballestrero A. , Da Prada G. , Martino M. , Rosti G. , Danova M. , Jovic G. , Conte P.
Published: March 2020

10558

Background: HER-2 overexpression is associated to a poor prognosis in high-risk and MBC patients treated with HDC. HER-2 status is also a predictive factor of response to trastuzumab: when trastuzumab is administered in combination with or sequentially to chemotherapy, a significant DFS and/or survival improvement has been observed in HER2+ early and MBC. Unfortunately, in both settings, trastuzumab was associated with an increased risk of cardiac dysfunctions (CD). Patients and Methods: In order to evaluate the cardiac safety of trastuzumab after HDC, we have reviewed the clinical charts of HER2-overexpressing MBC patients treated with HDC and trastuzumab at 11 centres of the GITMO group. Age, baseline LVEF, radiation therapy on cardiac area, exposure to anthracycline, single or multiple transplant, high-dose agents, trastuzumab treatment duration were recorded as potential risk factors. Cardiac dysfunction (CD) was defined as: 1) decline of LVEF ≥ 10% to below 50%, 2) decline of LVEF between 5 and 9% to below 50% with symptomatic (NYHA class III-IV) congestive heart failure (CHF), 3) any symptomatic CHF event. Results: Fifty-three patients treated between 1999 and 2005 have been included in the analysis. Median age was 47 years (range 29–66). Median interval between HDC and trastuzumab was 6 months. Median LVEF at baseline was 60.5%; at the end of trastuzumab (data available for 28 patients only) it was 55% (p = 0.01). Five out of the 28 (17.9%) pts experienced CD. Two out of 53 (3.8%) pts developed a symptomatic (NYHA class III) CHF. Age ≥ 50 years was the only factor significantly associated with CD. However age ≥ 50 years and multiple transplant procedure were associated with a significant decline of LVEF (p: 0.02). Conclusion: The incidence of CD is not superior to that reported with trastuzumab after standard chemotherapy. However pts with age ≥ 50 years or receiving multiple course of HDC, should be considered at risk for CD.

No significant financial relationships to disclose.
Combination therapy with gefitinib and capecitabine in metastatic breast cancer (MBC): A phase I trial
Authors: Mayer E. L. , Harris L. N. , Partridge A. H. , Gelman R. S. , Schumer S. T. , Comanaru R. S. , Long M. , Sampson E. , Burstein H. J. , Winer E. P.
Published: March 2020

10564

Background: Preclinical models have suggested synergy between the EGFR tyrosine kinase inhibitor gefitinib (G) and the 5-FU prodrug capecitabine (C), an active treatment for MBC. This phase I study was designed to explore the safety of this all-oral regimen in patients (pts) with MBC. Methods: Pts were treated in sequential cohorts (n = 3–6) using a fixed dose of G (250 mg qd continuously) and escalating doses of C (1500 mg/m2/day, 1750 mg/m2/day, and 2000 mg/m2/day) in a 21-day cycle. An additional 10 pts were enrolled in a validation cohort at the maximum tolerated dose (MTD). Dose limiting toxicity (DLT) was defined during the first cycle as any grade 3/4 toxicity or a delay >3 weeks due to unresolved toxicity. The primary endpoint was safety; secondary endpoints included assessments of tumor response (using RECIST criteria), adherence to the oral regimen, and biomarker measurements. Results: 19 pts were enrolled; the mean age was 49 y, 58% of tumors were hormone receptor positive, and 10% were HER2 positive. The mean number of prior MBC chemotherapy regimens was 1.2 and 74% had visceral spread. No pts in dose escalation cohorts had DLT during cycle 1. The 10 pts in the validation cohort (MTD C 2000 mg/m2) had 3 DLTs in cycle 1 and 1 DLT in cycle 2 (95% CI 12–74%). For all pts at C 2000 mg/m2 (n = 13), there was no grade 4 toxicity, however 5 (38%) had grade 3 toxicity, 7 (54%) required a C dose reduction, and 2 (15%) came off study for persistent toxicity. 3 pts (23%) experienced grade 3 diarrhea, and 4 pts (31%) had moderate to severe hand/foot syndrome. There were no objective responses (PR or CR) observed out of 18 evaluable pts. The mean number of completed cycles of therapy was 4.8, and 3 pts (16%) were treated for > 24 weeks. An exploratory analysis of serum EGFR measurements demonstrated no association of pre- or post-therapy values with lack of progression. Monitoring adherence to oral therapy using a microelectronic monitoring system (MEMS) was feasible, and detailed data will be presented. Conclusions: In this phase I dose escalation trial of G/C therapy in women with MBC, treatment was generally well tolerated, with a confirmed C MTD of 2000 mg/m2. Moderate toxicity and dose reductions were common. In this small cohort, the G/C combination did not appear to have substantial anti-tumor activity.

[Table: see text]
Circulating regulatory T cells in advanced breast cancer patients
Authors: Karamouzis M. V. , Perez S. A. , Gritzapis A. D. , Ardavanis A. , Skarlos D. V. , Baxevanis C. N. , Rigatos G. , Papamichail M.
Published: March 2020

10567

Background: It has been recently shown that regulatory CD4+CD25bright T cells (Tregs) are increased in patients with several malignancies and this increase correlates with advanced stage and dismal prognosis. Breast cancer (BC) patients represent a heterogeneous population with unpredictable natural history, even at advanced stages. We sought to monitor advanced stage (III and IV) BC patients, overexpressing HER-2/neu (HER) or not, for circulating Tregs before, during and after the administration of chemotherapy, either alone or in combination with Trastuzumab. Methods: Determination of circulating Tregs was performed in 50 μl whole peripheral blood by a Lyse NoWash FACS procedure and staining for CD45, CD4 and CD25. Tregs were determined as the lymphocytes expressing lower CD4 within the CD4+ T cell compartment and higher CD25 expression compared to the CD4 negative lymphocytes. Clinical evaluation of the patients was done according to RECIST criteria. Results: 24 HER+ and 19 HER- stage III / IV BC patients have been compared to 14 healthy donors, before therapy. The percentage of Tregs among the CD4+ T cell population of HER+ patients was significantly increased compared to both HER- patients and healthy donors (8,74 ± 2,68 vs 6,07 ± 1,85 and 6,55 ± 1,49, respectively). Trastuzumab combined with chemotherapy resulted in a progressive decrease in the percentage of circulating Tregs, reaching normal levels after the fourth cycle of treatment (6,95 ± 1,17). On a per patient basis, decrease in Tregs correlated either with documented partial response or stable disease, while increased Tregs during treatment coincided with progressive disease. No statistically significant change in the percentage of Tregs after chemotherapy was observed in HER- patients. Conclusions: 1) Increased Tregs do not directly correlate with clinical stage in BC, as stage III and IV HER (+) and (−) patients exhibit significantly different Tregs profiles. 2) HER+ advanced BC patients exhibit increased percentages of circulating Tregs and respond to the combination of Trastuzumab and chemotherapy by decreased Tregs. This decrease is either due to a reduction of the tumor burden or neutralization of circulating HER antigen by Trastuzumab, or a combination of both.

No significant financial relationships to disclose.
Pegylated liposomal doxorubicin (PLA) at a metronomic schedule for patients with advanced breast cancer (ABC)
Authors: Nolè F. , Verri E. , Sanna G. , Munzone E. , Catania C. , Ascione G. , Adamoli L. , Dellapasqua S. , Colleoni M. , Goldhirsch A.
Published: March 2020

10571

Background: The anti-angiogenic efficacy of chemotherapy (CT) is probably best obtained by administration of low doses of cytotoxics on a frequent or continuous schedule. The aim of this pilot study was to assess feasibility, clinical efficacy and tolerability of PLA, using a “metronomic” schedule in ABC. This schedule has been previously tested in the treatment of Kaposi sarcoma. Methods: From January to November 2005, 36 pts with ABC were treated with PLA, at a dose 20 mg/m2 q14. Almost all the pts were heavily pretreated for ABC and 44% of them received previous anthracycline therapy in adjuvant or metastatic setting. Results: Thirty-four pts were evaluable for toxicity and 29 for response. One pt (3%) had CR, 3 (11%) PR, 12 (41%) NC and 13 (45%) PD, for an overall clinical benefit of 28%. Median response duration was 2.59 mos; median TTP was 3.38 mos (95% CI 2.11–4.64). Treatment was well tolerated with neither G3-G4 NCI-CTC hematological toxicity. Only one pt experienced G3 palmar-plantar erythrodysesthesia (PPE). PPE was observed in other 15 pts (39%), with G2 occurring in 7 (21%). Other common G2 non-hematological toxicities were mucositis in 3 pts (9%) and constipation in 3 pts (9%) Dose reduction, due to subjective or hematological toxicity, was required in 10 pts (36%). No decrease in LVEF > 10% from baseline was observed. Conclusions: Metronomic PLA schedule in pretreated ABC pts seems to be an active and well-tolerated regimen. As to dose-dense CT, targets of metronomic CT might be, in addition to malignant cells, also endothelial and other stromal cells of the progressing metastasis, leading ultimately to the stability and eventually regression of the neoplastic lesion. The lower toxicity profile of the metronomic schedules make their use in pts with ABC very attractive and their testing in the adjuvant setting extremely challenging.

No significant financial relationships to disclose.
Incidence of brain metastases after first line chemotherapy in breast cancer patients treated with or without trastuzumab
Authors: Ferretti G. , Felici A. , Pino M. , Carlini P. , Fabi A. , Nuzzo C. , Sperduti I. , Cognetti F. , Papaldo P.
Published: March 2020

10582

Background: Brain metastases during trastuzumab therapy have been frequently observed. Only a few studies have compared the risk of brain metastases in patients (pts) treated with or without trastuzumab. Methods: In our hospital, between Jun 2000 and September 2005, we conducted a retrospective study in 72 metastatic breast cancer pts treated with first-line mono-chemotherapy (CT) with paclitaxel or docetaxel or vinorelbine ± Trastuzumab (T). Results: Thirty-five pts with HER2 pos disease were treated with T associated with 1st line CT, while 37 pts (16 with HER2 positive tumor, 21 HER2 negative) were not treated with T (NT). Ten HER2 pos NT pts subsequently received T. The median follow-up was 21 months (range1–129); the median age was 54 (range 32–82); the median treatment duration was 5 months (range 1–29). The incidence of recurrence (R), progressive disease in brain (BR), progression free survival (PFS) after first line CT, and overall survival (OS) were reported below: (see Table) Conclusions: This study showed that, after first line chemotherapy, the use of T did not affect the incidence of BR in HER2 pos metastatic breast cancer pts. On the other hand, Her-2 neg seems to predict ‘per se‘ a lower incidence of cerebral spread of disease.

[Table: see text]

No significant financial relationships to disclose.
Clinical availability of chemotherapy response assay using adenosine triphosphate in breast cancer patients
Authors: Jeong J. , Lee S. , Yoon S. , Jung W. , Lee H. , Lee I.
Published: March 2020

10592

Background: The response to chemotherapeutic agents of breast cancer is heterogeneous from patient to patient. Several methods were developed to decide chemotherapeutic agents which were sensitive to individual patients but so far, there are no ways which is commonly used in the clinic to tailor the treatment. In this study, we performed the chemotherapy response assay using adenosine triphosphate (ATP-CRA) in breast cancer patients and assessed the clinical availability. Methods: From March 2004 to February 2005, 65 breast cancer patients were enrolled in this study. After elimination of normal contaminated cells, cancer cells were evenly divided and treated with commonly used chemotherapeutic drugs in breast cancer(doxorubicin, epirubicin, 5-FU, paclitaxel, docetaxel, vinorelbine, and gemcitabine). 7 Drug-treated cancer cells and untreated cancer cells were cultured for 48 hours and then ATP was measured. To verify in vitro ATP-CRA indirectly, we analyzed the correlation between cell death rate of doxorubicin and epirubicin, and between doxorubicin and paclitaxel. We also analyzed the mean death rate of doxorubicin, epirubicin and paclitaxel by HER-2 status. Results: The ATP-CRA was performed sucessfully in 62 patients. (95.4%) In all cases, we can get the results within 7 days. The range of cell death rate was very wide, from 0 to more than 50%, except gemcitabine. Epirubicin showed the highest mean cell death rate (35.7%) and doxorubicin, paclitaxel in order. According to the chemosensitivity index, paclitaxel is the most frequently first-ranked and doxorubicin, epirubicin in order. Correlation coefficient between the cell death rate of doxorubicin and epirubicin is 0.58 and 0.2 between paclitaxel and epirubicin. In HER-2 positive group, mean cell death rate of epirubicin and paclitaxel was significantly higher than in HER-2 negative group (p = 0.017, p = 0.036) and same trend was seen in doxorubicin but not statistically significant (p = 0.060). Conclusions: ATP-CRA showed heterogeneous results in individual patients. ATP-CRA was successful and can be performed within short time period. With indirect comparison, it showed similar results with in vivo studies but for clinical use, the prospective randomized controlled trial should be preceded.

No significant financial relationships to disclose.
Pharmacogenomic analysis of needle biopsies obtained before preoperative docetaxel/capecitabine/FEC (TX/FEC) chemotherapy for breast cancer
Authors: Holmes F. A. , O’Shaughnessy J. A. , Hellerstedt B. , Pippen J. , Vukelja S. , Kocs D. , Asmar L. , Fenske E. , Lin F. , Symmans W. F. , Pusztai L.
Published: March 2020

10595

Background: Our goal was to evaluate the feasibility of obtaining fine needle biopsies, for pharmacogenomic analysis, in community based oncology practices and develop gene expression-based predictors of pathologic complete response (pCR) to preoperative sequential docetaxel/capecitabine and 5-fluorouracil, epirubicin, cyclophosphamide chemotherapy. Methods: One hundred seventy-five patients were accrued at 29 sites in the US Oncology Research network. FNA specimens were mailed to a central laboratory (MDACC) and gene expression profiling was performed on Affymetrix U133A chips. Results: RNA extraction was started on 140 specimens, 112 of these (80%) yielded ≥1 μg total RNA, 69 were hybridized and 65 (94%) gene expression profiles have passed quality control as of abstract submission date. The analysis plan is to develop a multigene predictor of pCR from the first 80 cases and test its performance independently in the remaining cases. Conclusions: Collection of mandatory research FNA biopsies for pharmacogenomic research is feasible in community practice. Approximately 80% of biopsies yield sufficient RNA for gene expression profiling. In 20% of patients, either technical factors, which can be addressed, or tumor biology (necrotic, rapidly growing tumors) were limiting. Supported by Roche Laboratories, Inc., Nutley, NJ; Pfizer, New York, NY; and Precision Therapeutics, Pittsburgh, PA.

[Table: see text]
Improved differentiation of 300 breast lesions using real-time elastography
Authors: Thomas A. , Kümmel S. , Landt S. , Warm M. , Fritzsche F. , Lichtenegger W. , Fischer T.
Published: March 2020

10608

Background: Differences in tissue elasticity are useful in the diagnosis of breast tumors. With elastography the elastic properties of breast tissue can be imaged in real time by means of color-coded superimposition on the B image and then used for evaluating focal lesions. The goal of the present study was to compare the sensitivity and specificity of elastography with that of B-mode sonography. Methods: A total of 300 patients with histologically confirmed breast lesions (168 benign, 132 malignant) were included in the study. The patients’ average age was 51 years, the range 16 to 86 years. Evaluation was by means of the 3D finite-element method. The data is color-coded and superimposed on the B-mode ultrasound scan (HITACHI EUB 8500). A second examiner was employed to improve the objectivity of the method. The results were compared with histology and the data obtained by previous ultrasound investigations. Sensitivities and specificities were calculated. Results: B-mode sonography yielded a sensitivity of 95.5% and a specificity of 84%. The two examiners were almost in complete agreement in their evaluation of the elastography images (McNemar Test: weighted kappa: 0.86): elastography yielded a sensitivity of 82%, a specificity of 88%. Conclusion: The diagnostic results for elastography in breast lesions showed a higher specificity and a somewhat lower sensitivity in comparision with B-mode sonography.

No significant financial relationships to disclose.
Raman spectroscopy to distinguish progression stages in breast cancer
Authors: Clare S. E. , Neubauer H. , Schuetz C. , Kurek R. , Solomayer E. , Wallwiener D. , Dye D. F. , Zaleski J. M. , Goulet R. J. , Fehm T.
Published: March 2020

10619

Background: The concept of early breast cancer detection has evolved to mean the discovery of a premalignant lesion or an early stage invasive lesion prior to metastasis. Therefore, methods must be developed to identify the actual primogenitors of cancer, those lesions which with certainty will progress to cancer. Currently, two technologies are employed for routine imaging of the breast: mammography and ultrasonography. Neither of these techniques can unequivocally distinguish between benign and malignant tissue limiting them to detection but not diagnosis. We hypothesize that differences in Raman spectra will enable the accurate discrimination of breast lesions one from one another and from normal breast epithelia. Therefore, preliminary studies were performed to investigate the potential of Raman spectroscopy. Methods: Cyropreserved breast tissue was selected, sectioned (10 μM) and stained with Hematoxylin and Eosin to verify the histologic diagnosis and to guide the acquisition of Raman spectra from a consecutive section (30 μM). This “analysis” section is mounted on Permanox (polyolefin; Nunc, Rochester, NY) over an area of the slide perforated with small holes (dia. 1mm) to provide the laser with direct access to the tissue without background Raman scattering from the polyolefin. Using a Raman microscope spectra were obtained from multiple areas of five breast tumors to address the reproducibility of spectral similarities across different tumors, to identify spectral differences between malignant and benign tissue, to identify spectral differences between invasive and ductal carcinoma in situ (DCIS) and to optimize the integration time. Results: In general, the spectral profiles for each tissue type are conserved with distinct differences in the predominance and peak widths of specific vibrations. Even in the absence of complex algorithms, malignant vs. benign tissue identification is possible. An analysis of the ability to reliably distinguish between invasive ductal carcinoma and DCIS will have to await additional spectra. A sound vibrational fingerprint of the tissue, consistent with that of the high signal/noise scan at 10 minutes, can be obtained within 30 seconds. Conclusions: Raman spectroscopy with short collection times shows promise and warrants further investigation.

No significant financial relationships to disclose.