bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined MEK and mTOR suppression is synergistic in human NSCLC and is mediated via inhibition of protein translation
Authors: McDaid H. M. , Legrier M. , Yang C. H. , Yan H. G. , Lopez-Barcons L. , Keller S. M. , Horwitz S. B.
Published: March 2020

10615

Background: Lung cancer is a heterogeneous disease characterized by the acquisition of somatic mutations in numerous protein kinases, including components of RAS and AKT. These intersect at various points rendering the network highly redundant. Hence, dual suppression of both, using MEK and mTOR inhibitors may be a promising rational drug combination that can overcome the intrinsic plasticity of this signaling network. Methods: The concurrent combination of the MEK inhibitor CI-1040 and the mTOR inhibitor AP23573 was evaluated in non-small cell lung cancer (NSCLC) cell lines, using the combination index method of Chou and Talalay. The concurrent combination of Rapamycin and the MEK inhibitor PD0325901 was also evaluated in animal models of human lung cancer. Results: The MEK inhibitors, CI-1040 or PD0325901, in combination with the mTOR inhibitor rapamycin, or its analog AP23573, were synergistic in human lung cancer cell lines. Statistically significant enhancement of cell death by the combination of MEK and mTOR inhibitors was not observed. Rather, synergism was associated with suppression of proliferation and inhibition of protein translation. Concurrent suppression of both MEK and mTOR inhibited ribosomal biogenesis by forty percent after twenty-four hours and was associated with a block in the initiation phase of translation. Furthermore, the combination of PD0325901 and rapamycin was significantly superior to either drug alone, or PD0325901 at the maximum tolerated dose, in xenograft and human heterotransplanted lung tumor models grown in nude mice. Conclusions: These data support therapeutic strategies in lung cancer that simultaneously suppress RAS and mTOR signaling networks, and provide evidence that both pathways converge on factors that regulate protein translation initiation.

No significant financial relationships to disclose.
Phase II study of docetaxel, carboplatin and trastuzumab (THC) in patients with locally advanced breast cancer
Authors: Dirix L. Y. , Prové A. , Sweldens C. , Van Dam P. , Vermeulen P. , Benoy I.
Published: March 2020

1062

Background: Preclinical and clinical data suggest that docetaxel, trastuzumab and platinum compounds act synergistically. Studies in the metastatic disease are conflicting. In this phase II study the activity of this regimen was assessed and correlated with changes in circulating biomarkers. Methods: Patients with locally advanced, FISH+ HER2 amplified, breast cancer were treated in this protocol with TCH as initial neo-adjuvant treatment. Patients received Docetaxel 75 mg/sqm, carboplatinum AUC 6mg/mL.min and trastuzumab 6 mg/kg (with a loading dose in cycle 1). Six cycles were intended provided no progression occured. No prophylactic G-CSF or antibiotics were administered. Measurement of circulating ECD HER2, CTC (RT-PCR mammaglobin and CK-19), and total plasma DNA was performed prior to the start of therapy, after cycle 1 and after 3 and 6 cycles. A cardiac MUGA exam was performed every three cycles. All patients were intented to undego mastectomy and axillary clearance after the end of chemotherapy. Results: 40 patients have been treated with a median age of 56 year. No patient suffered from progression of disease while on THC. All patients received 6 cycles, 4 patients received respectively 7, 7, 8 and 9 cycles. In total 247 cycles were administered. No cases of CHF were observed. 5 patients suffered from a asymptomatic decline > 10% in LVEF. A clinical CR and PR was obtained in 32 (80%). A pathological CR both in breast axilla was obtained in 16/39 (41%). Tumor response was predicted by changes in both CTC and ECD HER-2. Conclusions: THC was confirmed to be a very active and safe regimen in patients with HER-2 amplified breast cancer. Changes in biomarkers rapidly predicted response.

No significant financial relationships to disclose.
Chemoprotection by VEGF: Rationale for combination nab-paclitaxel and bevacizumab
Authors: Trieu V. , Ran S. , Bivens C. , Desai N.
Published: March 2020

1064

Background: Nanoparticle albumin-bound (nab-) paclitaxel (ABX) has shown greater efficacy and less toxicity than solvent-based paclitaxel (TAX) in xenograft models and clinical trials. The goal of this study was to determine the effects of VEGF modulation in human MDA-MB-231 breast tumor cell line and the effects of ABX and VEGF-neutralizing antibody bevacizumab (AVA) combination on the growth and metastasis of orthotopically implanted MDA-MB-231 tumors. Methods: VEGF expression was evaluated by ELISA in MDA-MB-231 tumor extract one week after treatment (qdx5) with saline, doxorubicin (10 mg/kg), TAX (10 mg/kg), or ABX (15 mg/kg). VEGF-receptor expression in MDA-MB-231 was quantitated by RT-PCR. MDA-MB-231 cytotoxicity with ABX, VEGF, AVA alone or in combination was measured by cytotoxicity and clonogenic assays. Implanted MDA-MB-231 tumors expressing luciferase were treated with saline, 2 cycles of ABX (10 mg/kg, two qdx5 cycles separated by 1 week, N=5) alone or in combination with AVA (2, 4 and 8 mg/kg, 2/wkx6). Tumor lymph node and pulmonary metastasis was determined by measuring luciferase activity. Results: Compared with saline, MDA-MB-231 tumors following chemotherapies exhibited significant tumor shrinkage (p≤0.006, t-test) and VEGF induction (p<0.0001, t-test). MDA-MB-231 was shown to express VEGFR2. Exogenous VEGF had a protective effect on MDA-MB-231 tumor cells by reducing cytotoxicity of ABX in both cytotoxicity and clonogenic assays. Sequestration of VEGF with AVA increased cytotoxicity of ABX in vitro. Treatment of MDA-MB-231 breast tumors with ABX and AVA combination resulted in greater than additive antitumor response and significantly reduced metastasis to the lungs (p=0.025 vs control) and LN (p=0.022) at the highest AVA dose. Conclusions: Chemotherapies induced VEGF expression in MDA-MD-231 breast tumor in vivo. In vitro, VEGF exerted a protective effect against ABX chemotherapy in VEGFR2-expressing MDA-MD-231 cells, which was abrogated by addition of AVA. In vivo, ABX and AVA combination significantly inhibited the metastatic potential of MDA-MB-231 tumor cells. These data provide a rational basis for the combination of nab- paclitaxel and bevacizumab in VEGF-receptor expressing tumors.

[Table: see text]
Inter- and intra-country variations in the use of trastuzumab in Norway, Spain and Sweden
Authors: Wilking N. , Bergh J. , Wilking U. , Jönsson B.
Published: March 2020

1069

Background: Breast cancer mortality is similar in Norway, Spain and Sweden (14–16/100,000 Age Standardized Rate). There are only small regional differences in incidence and mortality within the countries. Trastuzumab (T) was approved for metastatic breast cancer (MBC) in Norway, Spain and Sweden in second half of year 2000. T represents a unique new treatment for MBC that delays disease progression and improves survival. HER2 over expression (H+) is used to identify patients eligible for trastuzumab treatment (T). Methods: This study use sales data from IMS Health and incidence and mortality data from regional and national cancer registries as well as data from International Agency for Research on Cancer. We examines the variation in the use of T in different health care regions of Norway (4 regions), Spain (19 regions) and Sweden (6 regions) as well as differences in use between the countries. These results were also put into a global comparison. Results: There are marked differences in both the rate and level of uptake between the countries. Three years after approval the Spanish uptake was close to 90 % and twice the Swedish and 3–4 times the Norwegian uptake. The regional variations within the countries are of the same magnitude, a factor 2–3. Based on an assumed H+ rate of 25% and a treatment time of 38 weeks we estimate the proportion of H+ MBC patients that have been treated with T during the period 2000–2005 to be 24% in Norway; 66% in Spain and 44% in Sweden. In all countries there has been an increase in the use during the second half of 2005, indicating a use also in the adjuvant situation. T was approved for adjuvant treatment of BC in Europe in April 2006. Conclusions: Access of trastuzumab to patients with MBC in Norway, Spain and Sweden has been very variable. Spanish MBC patients have had earlier access to T than Swedish patients. Norwegian patients have had the lowest access. Regional differences in the use are in the magnitude of a factor 2–3. On a global level the Spanish uptake is in line with the uptake in the USA, Switzerland and Austria; the Swedish uptake is at an average European level and the Norwegian uptake is at a low level, similar to Czech Republic, Hungary, New Zealand, Poland and the UK.

No significant financial relationships to disclose.
Translational correlates, including outcome for patients with ER-/PR-/HER2- (triple negative (TNeg)) disease from N0234, a phase II trial of gemcitabine and erlotinib for pts with previously treated metastatic breast cancer (MBC)
Authors: Thome S. , Hobday T. , Hillman D. , Aubry M. , Lingle W. , Reinholz M. , Graham D. , Flynn P. , Moreno A. , Perez E.
Published: March 2020

1071

Background: N0234 is a phase II trial of gemcitabine at 1000 mg/m2 days 1 and 8 of a 21 day cycle and erlotinib at 150 mg daily in patients with previous therapy with either an anthracycline or a taxane for MBC. A partial response (PR) rate of 17% has been reported (ASCO 2005). Recent information suggests that over-expression of the EGFR pathway is frequent in patients with TNeg MBC. Methods: Tissue and serum were obtained for translational studies of ER, PR, HER2, and proteins related to EGFR pathway on tissue using immunohistochemistry; CK19, mammoglobin, and TTK on circulating tumor cells (CTCs). Markers were evaluated centrally, blinded to patient outcome. Complete data were available in 57 of 59 eligible patients; 20/57 patients (pts) were TNeg. Results: A PR rate of 25% and clinical benefit rate (PR + stable disease > 6 months)of 25% was observed in TNeg pts as compared to a PR rate of 14% (p = 0.30) and clinical benefit rate 22% (p= 0.75) for non-TNeg pts. Median progression free survival 72 days vs 98 days (p=0.13) and overall survival 227 days vs 738 days (p<0.001) were shorter for TNeg pts. Translational results for the EGFR pathway proteins and CTC analysis is forthcoming. Conclusions: The combination of gemcitabine and erlotinib appears to be as active in the non-TNeg and TNeg subset of patients on this trial. TNeg patients had an inferior clinical result, confirming the poor outcome seen in these patients. Data for the remaining biomarkers potentially predictive of activity will be presented. Supported by CA-25224, CA-37404.

[Table: see text]
Multicenter study of weekly trastuzumab, paclitaxel and carboplatin followed by a week of rest every 28 days in patients with HER2+ metastatic breast cancer (MBC)
Authors: Ruiz M. , Salvador J. , Bayo J. , Lomas M. , Moreno A. , Valero M. , Bernabé R. , Vicente D. , Jiménez J. , Lopez-Ladrón A.
Published: March 2020

1083

Background: The addition of Carboplatin to Trastuzumab and Paclitaxel improves the efficacy in HER2+ metastatic breast cancer (MBC). We have conducted a multicenter Phase II study to investigate the efficacy and safety of this combination given weekly × 3 followed by 1 week of rest. Primary endpoint was objective response rate and secondary endpoints were time to progression, overall survival and to study the toxicity profile of the combination. Methods: Between August 2003 and April 2006, 40 patients with HER2+ MBC (IHC 3+ or FISH+) have been included in the study. Pats received Trastuzumab (loading dose of 4 mg/kg/wk and 2 mg/kg/d following wks), Paclitaxel (80 mg/m2) and Carboplatin (AUC 2) all given weekly × 3 followed by 1 week of rest. Treatment was given until disease progression or unacceptable toxicity. Results: 40 pats had baseline data available. Median age was 54 yrs (range 29–75). 38 (95%) pats received prior adjuvant or neoadjuvant treatment. 11 (27,5%) pats have received one prior CT line for metastatic disease. 87,5% pats had PS 0 or 1 at study entry. Disease sites were liver 16 (40%), bone 12 (30%), lymph nodes 13 (32,5%) and lung 8 (20%). 19 (47,5%) had = 2 lesions. 97,5% had measurable disease. 36 pats have been evaluated for response: 11 CR (31%, 95% CI: 15–46%), 11 PR (31%, 15- 36%), 9 SD (25%, 9–36%), 5 PD (14%, 2–26%) and 4 NE resulting in an ORR of 61% (95% CI: 45–77%) and tumor growth control rate (RR+SD) of 86% of patients (95% CI: 75–97%). Median TTP was 12.1 mo (95% CI: 8.8–19.9 mo) and median duration of response and OS have not been reached yet. For a time of observation of 35 mo, the OS is 80,6%. 37 patients have received 194 cycles with a median of 5 cycles. Grade 3–4 toxicities/pats were: 3(7.5%) anaemia, 2 (5%) leucopenia, 8(20%) neutropenia, 1 (2,5%) febrile neutropenia, 1 (2,5%) trombopenia, 2(5%) asthenia, 2(5%) diarrhea, 3(7.5%) nausea, 2(5%) vomiting, 3(7.5%) mucositis Conclusions: This interim analysis shows an interesting activity with this regimen. One week of rest may be of better convenience for the patient and hospital but also may improve the tolerability profile and efficacy of the combination. Further results would be available for presentation.

No significant financial relationships to disclose.
Efficacy and safety of trastuzumab plus vinorelbine as second-line treatment for women with HER2-positive metastatic breast cancer beyond disease progression
Authors: Bachelot T. , Mauriac L. , Delcambre C. , Maillart P. , Veyret C. , Mouret-Reynier M. , Van Praagh I. , Chollet P.
Published: March 2020

1094

Background: There is increasing evidence that women with HER2-positive metastatic breast cancer (MBC) benefit from continued trastuzumab (H) therapy beyond disease progression (PD). In a Phase II multicentre 2-step trial we evaluated women for their response to second-line treatment with H + vinorelbine (N) following PD after receiving first-line H + taxane for HER2-positive MBC. Methods: Women aged =18 years with HER2-positive MBC received H (8 mg/kg loading dose followed by 6 mg/kg q3w or 4 mg/kg loading dose followed by 2 mg/kg qw) + N (30 mg/m2 days 1 and 8 q3w) until PD. The primary end point was overall response rate (ORR); secondary end points included time to progression, time to treatment failure, overall survival and safety. Data from a planned interim analysis are presented. Results: Seventeen out of a planned 50 patients (pts) were enrolled between June 2003 and October 2006, with a mean age of 54 years (range 42–70). Nine pts had hormone receptor-positive disease at baseline and 17 pts had HER2-positive disease (16 pts IHC 3+; 1 pt IHC 2+ and CISH+). Pts had previously received H in combination with paclitaxel (9 pts) or docetaxel (8 pts) as first-line therapy for MBC. Pts received a median of 6 treatment cycles with H + N (range 2–14), with 2 pts receiving H q3w and 15 pts receiving H qw. ORR was 29%, with 2 pts showing a complete response, 3 pts experiencing a partial response and 4 pts achieving stable disease lasting 6 months. Eight pts experienced PD. Re-treatment with H + N was well tolerated beyond PD, with grade 3/4 haematological toxicities being the most common serious adverse events, leading to a delay and dose reduction of N. No relevant cardiac toxicities were reported, with only 2 grade 1 cardiac events. All pts withdrew, 14 due to PD. Conclusions: This interim analysis indicates that treatment with Herceptin plus chemotherapy beyond PD is active (ORR 29%) and well tolerated, and provides further evidence that re-treatment with H is a promising therapeutic option. Pt accrual is ongoing and updated results will be presented.

No significant financial relationships to disclose.
Monitoring of circulating tumor cells during systemic therapy allows distinguishing breast cancer patients at risk for relapse
Authors: Pachmann K. , Camara O. , Lobodasch K. , Clement J. , Dengler R. , Hoeffken K.
Published: March 2020

11006

Background: Recent refinement of methods, allowing detection of minimal numbers of residual cells from malignant tumors have reactivated the debate, to what extent single tumor cells in lymph nodes, bone marrow and peripheral blood can be considered as “micrometastases”. The presence of such cells, indeed, reflects only the first step in the metastatic process, dissemination, and the formation of metastases from such cells seems to be quite ineffective. If, however these cells react to therapy in an identical way as the tumor itself, these cells can be used to monitor therapy response very early during primary systemic (neoadjuvant) therapy, during adjuvant therapy, where no other target is available to control therapy success and already during therapy initiation in metastatic disease. Methods: Circulating epithelial cells were enumerated from 1 ml of anticoagulated blood after red blood cell lysis, staining of live cells with a fluorochrome labeled anti-epithelial antibody and automated microscopy before and after each chemotherapy cycle for monitoring of therapy success. Results: The response of the peripherally circulating cells of 35 patients with breast cancer treated with neoadjuvant chemotherapy varied from marginal (less than tenfold) to highly responsive (more than thousand fold) already during the first three to four courses and showed identical response to therapy as the whole tumor with a correlation of p > 0.9. The method was subsequently applied to monitor the response of such cells in the adjuvant treatment. In the first 25 patients with a follow up of more than 4 years, an increase in cell numbers already from the begin of therapy or following an initial response was observed in 20% of patients and all of these patients have subsequently relapsed (p<0,0001). These results have now been corroborated in a total of 148 patients, confirming a hazard ratio of 25 for relapse in the following 5 years for patients with increasing cell numbers during therapy independent of therapy regimen and a significance of p<0.0001. Conclusions: Quantitative monitoring of circulating tumor cells can be used as a tool for therapy survey in breast cancer in the absence of manifest tumor.

No significant financial relationships to disclose.
Bevacizumab and albumin-bound paclitaxel treatment in metastatic breast cancer
Authors: Link J. S. , Waisman J. R. , Nguyen B. , Jacobs C. I.
Published: March 2020

1101

Background: Miller, et al demonstrated the combination of bevacizumab and paclitaxel has significant activity in metastatic breast cancer. Because paclitaxel albumin bound (PAB) has been shown to have less toxicity, a better tumor delivery and possibly better response for metastatic breast cancer, we combined it with bevacizumab (B) to treat women with metastatic breast cancer. Methods: This is a retrospective analysis. Billing records from March 2005 through December 2006 were reviewed to obtain all patients treated consecutively with a combination of PAB (80–125mg/m2 days 1,8,15 or 170–200 mg/m2 every 14 days on a 28 day cycle) and B (10mg/kg every 14 days). A total of 40 women were identified. A minimum of two courses were given. All women had received a minimum of 3 prior chemotherapy regimens including anthracyclines 34/40 and taxanes 35/40. Patients were monitored for response using RECIST criteria based on PE, and PET/CT imaging. Six women with bone only disease were monitored with PET, CT/MRI and tumor markers. All response data were confirmed by independent review. Results: 20 women had objective responses to the PAB/B regimen (3CRs and 17PRs) for an overall response rate of 50%. Another seven women had stable disease (SD) for a mean duration of 212 days. Thirteen women progressed. The mean time to progression for the responders was 132 days. Toxicity was acceptable with fatigue (9 gr 2), neuropathy (4 gr 2, 1 gr 3), anemia (2 gr 2, 2 gr 3), and hypertension (3 gr 2) being the most common complaints. Two patients were discontinued due to a possible CNS hemorrhage into a metastatic brain lesion. There were no other treatment discontinuations due to non-tolerance Conclusions: In our limited series of consecutive woman with advanced, heavily pretreated metastatic breast cancer treated with PAB (Abraxane) and bevacizumab (Avastin), we saw a 50% objective response rate (3CR, 17PR). The regimen was well tolerated with acceptable toxicity. Another seven women had stable disease for an average duration of >200days giving an objective response rate + SD of 67%.

No significant financial relationships to disclose.
MammoSite brachytherapy for low-risk breast carcinoma: Toxicity, cosmetic evaluation and quality-of-life results of a phase II study
Authors: Belkacemi Y. , Chauvet M. , Giard S. , Villette S. , Lacornerie T. , Bonodeau F. , Baranzelli M. , Bonneterre J. , Lartigau E.
Published: March 2020

11016

Background: The MammoSite is a device that was developed with the goal of making breast-conserving surgery more widely available. Our objective was to evaluate the MammoSite device performances after an open cavity placement procedure and quality of life in highly selected patients with early-stage breast cancer. Methods: From March 2003 to March 2005, 43 patients with T1 breast cancer were enrolled in a phase II prospective study. Twenty-five (58%) patients were qualified for HDR brachytherapy delivery. The median age was 72 years (range: 60–75). Twenty-five (58%) were treated with high-dose rate brachytherapy using the MammoSite applicator to deliver 34 Gy prescribed at 1 cm from the balloon surface in 10 fractions over 5 to 8 days. Results: The main disqualifying factor was pathologic sentinel node involvement. After a median follow-up of 13 months, there were no local recurrences. Seventeen (68%), 13 (52%), 7 (28%), 5 (20%) and 4 (16%) patients had erythema, seroma, inflammation, hematoma and infection, respectively. Only 2 patients developed telangiectasia. At 3 months breast erythema grade ≥ 2 was significantly correlated to cosmetic results (12.5% in the ‘good to excellent‘ versus 57% in the ‘poor to fair‘ group; p = 0.045). The strongest trend of excellent cosmetic outcome was observed in patients with skin spacing ≥ 19 mm (50%) compared to patients with < 19 mm (11%; p = 0.087). At 1 year the rate of ‘good to excellent‘ cosmetic results was 84%. Significant changes in QoL were observed for emotional and social well-being between 3 and 12 months. At 24 months only emotional well-being subscore changes were statistically significant (p = 0.015). Param Conclusions: To our knowledge, this is the first study since the initial FDA clinical study showing the feasibility of MammoSite brachytherapy procedure as a sole therapy in highly selected patients older than 60 years. This is also the first report on QoL during and after APBI using HDR brachytherapy with a MammoSite device. The toxicity and cosmetic results are in the range of other series. Higher range of skin spacing allowed a significant reduction of the risk of telangiectasia. QoL evaluation indicate that baseline scores were satisfactory. Changes concerned mainly emotional and social well-being.

No significant financial relationships to disclose.
BRCA mutation status and risk of secondary malignancy following chemotherapy for breast cancer
Authors: Wesolowski R. , Choueiri T. K. , Rybicki L. , Shealy A. G. , Casey G. , Weng D. , Moore H.
Published: March 2020

11017

Background: Since the BRCA gene is responsible for excisional DNA repair, we hypothesized that breast cancer patients with BRCA mutation would be more susceptible to the induction of second malignancies following chemotherapy treatment than breast cancer patients who tested negative for BRCA mutations. Methods: Breast cancer patients tested for BRCA1 and BRCA2 mutations at the Cleveland Clinic were identified and evaluated for history of neoadjuvant or adjuvant chemotherapy and for the occurrence of subsequent non-breast primary invasive cancer. Patients with inadequate follow-up and those with inoperable disease at diagnosis were excluded from the analysis. Fisher’s exact test was used to compare different cohorts. The IRB at Cleveland Clinic approved the study. Results: Of 115 identified breast cancer patients tested for BRCA mutations, 77 met the inclusion criteria. Twenty-seven of these patients carried BRCA1 or BRCA2 mutations and 50 tested negative for these mutations. Twelve patients (44%) in the BRCA positive group and 8 patients (16%) in the BRCA negative group underwent prophylactic oophorectomy. Median follow-up for the two groups was 53.5 months (75 months in the BRCA positive group and 48.5 months in the BRCA negative group). Median age at diagnosis was 42 years (40.5 years in the BRCA positive group and 44.5 in the BRCA negative group). In the BRCA positive group 3 of 25 patients (12%) treated with chemotherapy developed second malignancies (ovarian cancer, transitional cell cancer in urinary tract and renal cell carcinoma) compared with none of the 2 patients who did not get chemotherapy (p= 1.0). In the BRCA negative group, 2/34 patients (6%), treated with chemotherapy developed second cancers compared with 2/16 patients (12%), who were not treated with chemotherapy (p=0.58). Cancers in the BRCA negative group included two bladder carcinomas in the chemotherapy treated patients and in the non-chemotherapy group, non-small cell lung cancer, uterine, ovarian, endometrial and peritoneal cancers. Conclusions: At more than 4-years of follow up, chemotherapy in operable breast cancer patients was not associated with an increase in the risk of secondary malignancy or with a differential effect on this endpoint by BRCA mutation status in this retrospective study.

No significant financial relationships to disclose.
Validity of sentinel lymph node biopsy in breast cancer patients after neoadjuvant chemotherapy
Authors: Jinno H. , Asaga S. , Sakata M. , Kubota T. , Kitajima M. , Mukai M. , Kubo A. , Ikeda T.
Published: March 2020

11023

Background: Sentinel lymph node biopsy (SLNB) is a potential alternative procedure to conventional axillary lymph node dissection (ALND) in clinically node-negative breast cancer patients. Neoadjuvant chemotherapy (NAC) is a standard of care for patients with locally advanced breast cancer and indications of NAC have been widespread to operable breast cancer patients to facilitate breast conserving surgery. However, the validity of SLNB in breast cancer patients who received NAC is still controversial. Methods: Forty-six patients with stage II or III breast cancer who were treated with NAC from January 2002 to May 2006 were included in the study. Consecutive 122 patients who had SLNB without NAC during the same period were used as a control group. All patients underwent SLNB followed by completion ALND. Sentinel lymph node (SLN) was detected using a combined method of injecting isosulfan blue dye and small-sized technetium- 99m-labeled tin colloid (particle size: 200–400 nm in diameter) peritumorally and subcutaneously. SLNs were evaluated by means of H&E and immunohistochemical staining. Results: SLNs were successfully identified in 42/46 patients (91.3%) treated with NAC and 112/113 patients (99.1%) without NAC (p=0.01). Metastases in the SLNs were found in 16/42 patients (38.1%) with NAC and 32/112 patients (28.6%) without NAC (p=0.2). There were 5 false negative cases (false negative rate: 23.8%) in the NAC group and 2 false negative cases (false negative rate: 5.9%) in the control group (p=0.05). Accuracy of SLNB in the NAC group was also significantly inferior to the control group (88.1% vs. 98.2%, p<0.01). The presence of clinically positive axillary lymph nodes before NAC was not correlated with false negative rate. Conclusions: These data suggest that NAC might be considered a contraindication to SLNB even in patients with clinically negative axillary lymph nodes before NAC.

No significant financial relationships to disclose.
Pattern of presentation and treatment of early primary breast cancer in the elderly
Authors: Parker H. K. , Winterbottom L. , Hassell K. , Ellis I. O. , Morgan D. A. , Cheung K. L.
Published: March 2020

11030

Background: There is a high prevalence of breast cancer in the elderly population; however the majority of data available is obtained from younger patients. This study aimed to identify the patterns of presentation and treatment subsequently received by elderly women with early breast cancer. Methods: Patients included were >70 years and had operable primary breast cancer (<5 cm) managed in a dedicated clinic. Personal characteristics, patterns of presentation, pathological features of diagnostic needle core biopsies and treatments both recommended and received were reviewed in 265 consecutive female patients diagnosed over a 30-month period (between January 2004 and June 2006). Results: The mean age was 78.5 (range: 70–100 years). Majority (83%) presented with symptomatic cancer with the remaining ones detected through mammographic screening. These cancers were predominantly oestrogen receptor positive (histochemical (H) score >10) (84%) with high H scores (83% had H scores >200). Most of them were grade 2 (63%), followed by grade 1 and 3. Treatment undertaken was often in compliance with the clinicians’ advice if specifically recommended; however, when choice was given, there was a tendency to accept non-operative intervention. Documented reasons include surgical refusal, feeling un-fit for surgery and personal commitments disallowing post-operative recovery time. In addition, patients who received primary hormone therapy were on average 7 years older and suffered significantly more co-morbidity than those who had surgery. Conclusions: The elderly breast cancer population often receive different treatments possibly due to biological characteristics and personal reasons distinct from their younger counterpart. Further work is ongoing to link these findings to long-term clinical outcome.

[Table: see text]

No significant financial relationships to disclose.
The margins effect: Residual tumor after breast conserving surgery
Authors: Meirovitz A. , Rennert H. S. , Peretz T. , Salmon A. , Rennert G.
Published: March 2020

11045

Background: Resection of breast cancer with good surgical margins is one of the fundamental aspects of breast conserving surgery. Most studies have shown that women with positive margins after breast conserving surgery (BCS) fared worse compared to those with negative margins, regardless of chemotherapy or radiation therapy. Nowadays, when partial breast irradiation is gaining popularity, understanding the natural history of positive or close margins is particularly important. We studied the surgical process in a large cohort of Israeli women with breast cancer to estimate the frequency of tumor margin involvement in the primary and subsequent surgical procedure. Methods: The National Israeli Breast Cancer Detection Programs has been monitoring the detection process of all new cases of breast cancer in Israel since 1996. Full data on tumor histology and surgical procedures, including indication of margins in the pathology report were available for 16,925 malignant breast tumors. Margins were classified as positive margins (PM), close (= 2mm) (CM) or negative margins (greater then 2mm)(NM). Results: BCS was identified in 14,815 women with invasive cancer and 2,110 with pure ductal carcinoma in situ (DCIS). Only 7,751 (52.3%) of the 14,815 women with invasive cancer had NM, while 2,868 (19.4%) had CM and 4,196 (28.3%) had PM. Among those with PM, 2,276 (54.6%) had a re-operation within 6 months from the index surgery and 1,265 (55.6%) of them were found to be malignant; 58% of them were invasive cancers and 42% DCIS. Among the invasives on re-operation, 24.4% still had PM and another 12.1% had CM while among the DCIS 14.4% had PM and 17.6% had CM. Of the 717 women with DCIS and positive margins at first surgery, 67.9% had a second operation. Of them, 59.8% had malignancy, 8.8% of them invasive. Overall 10.6% of all invasive cancers and 3.7% of all DCIS had PM on relumpectomy within 6 month regardless of initial margin status. Conclusions: A relatively high proportion of all women undergoing BCS were found to have positive or close margins, even after re-operations. If a failure to reach clean margins is a reflection of an aggressive tumor phenotype, special attention should be given to these patients and treatment should be adjusted accordingly.

No significant financial relationships to disclose.
Effects of different chemotherapy regimens and tamoxifen for HER2 over-expressed breast cancer adjuvant therapy
Authors: Zhang J. , Liu Y. , Hao X. , Fang Z. , Ning L.
Published: March 2020

11048

Background: To evaluate effects of different adjuvant chemotherapy regimens and TAM in HER-2-overexpressed breast cancer patients. Methods: To study 1625 primary breast cancer cases after operation from 2002.7 to 2005.11 given adjuvant chemotherapy ,600 cases given CMF, 600 cases given CEF, and 425 cases given T-regimen (anthracyclines follow taxanes),1090 HR+ cases given tamoxifen. HER-2 expression were measured by immunohistochemistry (IHC). Median follow-up time is 42 months. Results: (1)3yr DFS of HER-2 over-expression is inferior to HER-2 negative ones in CMF group(p<0.05), no difference between HER-2- overexpressed and HER-2-negative group treated with either CEF or taxanes-based regimen (p>0.05). Subgroup analysis suggested: patients treated with CMF, 3yr DFS of HER-2 over-expression is inferior to HER-2-negative ones in node-positive subgroup, but no difference in node-negative ones; HER-2 expression has no influence on effects of CEF or T-regimen in node-positive or node-negative subgroup. (2) 425 HER-2 over-expressed patients(183 cases given CMF , 121 cases given CEF , and 121 cases given T-regimen): compared to CMF, anthracyclines and taxanes are more effective, but no difference between anthracyclines and T-regimen. (3) 235 patients with HER-2 over- expression and node-postive (72 cases given CMF , 68 cases given CEF, and 95 cases given T-regimen):, anthracyclines and taxanes are more effective than CMF, but no difference between anthracyclines and T-regimen. (4)3yr DFS is 91.23% in HER-2 over-expressed group and 93.42% in HER-2-negative group (p=0.04) with TAM. HER-2 over-expressed patients are resistant to TAM. (5) Subgroup analysis suggested that: 3yr DFS is 88.67% with HER-2 over-expression and 92.20% with HER-2-negative in postmenopausal node-positive subgroup(p=0.0069), postmenopausal patients with HER-2 over-expression and node-positve are resistant to TAM; no difference in either premenopausal or postmenopausal node-negative subgroup (p>0.05). Conclusions: No difference between Anthracyclines based and T-regimens for HER2 over-expressed patients with node-positive for 3yr DFS.Postmenopausal ER+/PR+ patients with HER2 over- expression are resistant to Tamoxifen endocrine therapy.

No significant financial relationships to disclose.
Comparison of the effectiveness and complications of half and full doses of pegfilgrastim in breast cancer patients
Authors: Lower E. E. , Bartelt M. E. , Harman S.
Published: March 2020

11058

Background: Pegfilgrastim (G-CSF) is a longer half-life synthetic growth factor used to reduce the incidence of infection following myelosuppressive chemotherapy but is associated with bone pain and hypergranulocytosis. Little data exists regarding efficacy and possible reduced toxicity with lower doses. Methods: A retrospective review identified early stage breast cancer pts who received reduced doses of G-CSF. Data collected prior to and after each dose of G-CSF included total white blood cell count (WBC), absolute granulocyte count (AGC),patient age, type and dose of chemotherapy, and stage of breast cancer. The occurrence of fever and infection was compared between the full and reduced dose groups. Pts completed a Likert scale (1–5) rating bone pain after each dose of G-CSF. Results: Thirty four pts received adjuvant treatment including adriamycin-cyclophosphamide (AC) followed by taxane (T) in 12, dose dense AC-T in 13, other regimens in 9. The median age was 53 years (range of 36 to 82). Thirty-two pts initially received 6 mcg but were reduced to 3mcg due to drug toxicity. Two pts received only 3mcg doses. There was a significant difference in the WBC post chemotherapy for the 98 treatments with 6 mcg (8400 (3000–49,600) cells/cu mm (Median (Range)) versus 116 treatments with 3 mcg (7600 (3000–18,900) cells/cu mm (p<0.02). There was no significant difference between the post chemotherapy AGC for the 6 mcg (6000 (2200–38,000) cells/cu mm versus the 3 mcg (5800 (1000–16,600) cells/cu mm. Six pts receiving 6 mcg had a post G-CSF WBC > 20,000 cells/cu mm vs none receiving 3 mcg (Fisher exact test, p<0.01). No WBC < 2,000 cells/cu mm or neutropenia of <1000 cells/cu mm was noted with either regimen. Reported fever and infection was not significantly different between the 6 and 3 mcg doses (Fever: 6 mcg 3/98 (3.1%) vs 3 mcg 5/116 (4.3%); Infections: 6 mcg 5/98 (5.1%) vs 3 mcg 7/116 (6.0%)). Bone pain was more severe after 6 mcg dose than the 3 mcg dose (P < 0.02). Conclusions: Although 6 mcg G-CSF was associated with a significantly higher total WBC, pts receiving 3 mcg G-CSF did not experience a difference in incidence of fever, infections, or neutropenia. However, lower doses were associated with significantly less bone pain and hypergranulocytosis.

No significant financial relationships to disclose.
Radiomodification with fluor-pyrimidines in radiation therapy of breast cancer
Authors: Malyshev N. V. , Kostrova E. V. , Bochkova N. V. , Dosakhanov A. H. , Sirota V. B.
Published: March 2020

11073

Background: to assess the effectiveness of fluor-pyrimidines used in altered fractionated radiation therapy (RT) of breast cancer. Methods: 122 breast cancer patients (stage II) were included in this trial. Mean age - 51.3 years. All of them were randomly assigned to three groups. The first group - 41 patients treated by preoperative course of extra-beam radiation therapy, with double daily fractionation by 2 Gy (time between fractions - 4.5 hours, 4 Gy per day, 8 days), total dose - 32 Gy. The second group - 39 patients treated by the same regimen of radiation therapy, but with the concurrent application of the factory-made papers, sodden with 5-fluorouracil, on the irradiated breast. Papers covered the breast for 8 days, and were removing only during irradiation (2 times a day). The third group - 42 patients treated by the same regimen of radiation therapy, but with the concurrent radiomodification by capecitabine (1000mg/sq.m. per os twice daily before each irradiation, 8 days). In all three groups the radiation therapy was always followed by radical mastectomy in 1–2 days. The endpoints were: frequency of clinical effect and of level 3–4 pathological response. Results: positive clinical effect (complete response and partial response) and stabilization of disease were observed in the first group in 34.1% and 65.9% of patients, in the second group in 33.3% and 66.7% and in the third group in 42.9% and 57.1%. Progression was never observed. There were no signs of pathological response in 17% of patients of the first group, in 5.1% of patients of the second group and in 16.7% of patients of the third group. Level 1–2 and level 3–4 pathological response were observed in the first group in 63.4% and accordingly in 19.6% of patients, in the second group in 12.8% and 46.2% of patients and in the third group in 57.2% and 23.8% of patients. Conclusions: Therefore, using of papers with 5-fluorouracil in preoperational RT of breast cancer demonstrated more frequent level 3–4 pathological response. Using of capecitabine, on the contrary, demonstrated the highest clinical effect, but lower rate of level 3–4 pathological response.

No significant financial relationships to disclose.
Efficacy and safety of neoadjuvant chemotherapy of sequential doublets and dose dense plus trastuzumab in HER2-positive locally advanced breast cancer patients
Authors: Grande E. , Sanchez-Muñoz A. , García-Tapiador A. , Ortega-Granados A. , Jaén-Morago A. , Dueñas-García R. , Farnández-Navarro M. , Dueñas B. , Martínez-Ferrol J. , Grande E. , Sánchez-Rovira P.
Published: March 2020

11089

Background: Neoadjuvant therapy for breast cancer constitutes an excellent test to evaluate the sensitivity to chemotherapeutic agents and/or new biological agents against specific targets as trastuzumab and Her2. Furthermore, pathologic complete response (pCR) is a surrogate marker for disease-free and overall survival. Methods: The objective was to determine the efficacy in terms of pCR rates and the safety profile of the doublets plus trastuzumab schedule administered for the neoadjuvant setting of locally advanced breast cancer patients. A total of 20 patients with histologically confirmed locally invasive Her2-positive breast carcinoma were included. The median age was 43. Mean tumour size was 5.1 cm. Treatment consisted of a first sequence with epirubicin 90 mg/m2 and cyclophophamide 600 mg/m2 for 3 cycles, and a second sequence with paclitaxel 150 mg/m2 and gemcitabine 2500 mg/m2 for six cycles. All drugs were administered on day 1, every two weeks with prophylactic growth factor supports. Weekly trastuzumab was administered at a dose of 2mg/kg (4 mg/kg loading dose), concomitantly with paclitaxel and gemcitabine. Subsequently, patients underwent surgery and received radiotherapy and/or adjuvant hormonal therapy according to institutional practice Results: Objective clinical response was achieved in all patients. 10 (50%) pCR were obtained. With a median follow up of 18.2 months (3–38), 17 patients (85%) are alive without disease progression, and 3 (15%) showed recurrence and 1 of whom died. Treatment was well tolerated, 1 patient experienced 1 episode of grade 4 neutropenia and 2 patients had grade 3 neutropenia. 1 patient discontinued the treatment due to hypersensitivity reaction to paclitaxel. Asymptomatic decrease in cardiac ejection fraction with subsequent normalization was seen in 1 case. Conclusions: Despite of the small number of patients, results have shown a high pCR rate in this group of breast cancer patients with poor prognostic. The schedule seems to be feasible and tolerable and further studies with the doublet sequences plus trastuzumab are warranted on the neoadjuvant Her2 positive breast cancer patients

No significant financial relationships to disclose.
Anthracycline-containing regimen in early breast cancer: Analysis of toxicity
Authors: Jagiello-Gruszfeld A. I. , Lowczak A. , Zbrzezniak-Smilgiewicz J. , Szablowska-Siwik S. , Licznerska G. , Wasilewska-Tesluk E.
Published: March 2020

11104

Background: The anthracycline-containing regimens is considered to be more beneficial to patients (pts) with early breast cancer (EBC). However at this moment is not clear which kind of regimen should be used in adjuvant setting. Methods: In our center, from Jan 2004 to Sep 2006, 248 breast cancer pts, who were qualified to the adjuvant chemotherapy received FEC100 (104 pts), AC (126 pts). or sequentially AC- taxans (18). Pts with many poor prognostic factors (N+, T3, G3, HER2/neu 3+) received 6 cycles of FEC100 or AC-taxans. Pts with better prognosis (Intermediate Risk Group according St.Gallen’s guidelines for 2005) received usually 4 cycles of AC. Besides, in most cases, internet access to the adjuvantonline! program was used during making decision. ER-ve or PR-ve positive pts received sequentially hormonal treatment. The radiotherapy (if needed) was delivered at the end of the chemotherapy. Results: During the treatment, toxicity of the chemotherapy was evaluated by NCI CTC v. 3. There was no toxic deaths. Median follow-up period was 19 months (range: 6–36). The febrile neutropenia was observed in 4 pts in FEC100 and in 5 pts in AC group. There was also no significant differences in the grade 3 or 4 neutropenia, anemia, thrombocytopenia and alopecia. In 3 pts treated with FEC100 and 1 with AC, cardiotoxicity grade 2 or 3 was diagnosed. Grade 2 or 3 asthenia was frequent in FEC100 group (44% vs 21% vs11%). In all pts prophylaxis of nausea/vomiting was used. However pts treated with FEC100 needed more 5HT3. Vomiting grade 2 or 3 were observed significantly more often in pts who received FEC100 (58% vs 26% vs 23%). Only at 1 pts in each group the chemotherapy was interrupted due to toxicity (asthenia gr 3, vomiting gr 3 and weight loss gr 2). The relative dose intensities of FEC100 and AC were 87% and 96% of planned doses, respectively. Conclusions: The acute symptoms of toxicity were important for breast cancer pts who received the adjuvant chemotherapy. According the adjuvantonline! 6 cycles of FEC100 were more effective than 4 cycles of AC. Nevertheless tolerability of AC is better. Many pts prefer only the hormonal treatment, even if it is not the optimal option, in fear of nausea or vomiting. The ongoing clinical trials should further define the best choice of anthracycline-containing regimen in the adjuvant setting.

No significant financial relationships to disclose.
Effect of new anti-neoplastic agent, MK615, from Japanese apricot, ume, on growth of breast cancer cells in vitro
Authors: Nakagawa A. , Sawada T. , Okada T. , Ohsawa T. , Adachi M. , Kubota K.
Published: March 2020

11105

Background: MK615 is an extract mixture from Japanese apricot, UME. In this study, the anti-neoplastic effects of MK615 against breast cancer cells were investigated. Methods: Two breast cancer cell lines, MDA-MB-468 (MDA) and MCF7, were cultured with (600, 300, 150 μg/ml) or without MK615. After 72 hours of incubation, growth inhibition was evaluated by MTT assay, and the mechanism of the anti-neoplastic effect of MK615 was evaluated by cell cycle- and apoptosis assay. Results: MK615 inhibited the growth of MDA and MCF7 in a dose-dependent manner. The percentage growth inhibition of MDA at dosages of 600, 300, and 150 μg/ml was 59.2%, 52.4%, and 23.3%, respectively, and that for MCF7 was 83.5%, 52.7%, and 16.6%, respectively. Cell cycle analysis showed that MK615 increased the proportion of cells in G2-M phase in both MDA (7.8% to 11.7%) and MCF7 (8.1% to 18.7%), and finally both cell lines became apoptotic. The proportion of apoptotic cells increased with incubation time. Conclusions: MK615 effectively inhibits the growth of breast cancer cells in vitro, possibly by cell cycle modification and apoptosis induction.

No significant financial relationships to disclose.