bluuebunny/crossref_metadata_2025 huggingface dataset:
Cxcr4 expression and risk of bone metastasis in patients with early breast cancer
Authors: Conforti R. , Xia W. , Boulet T. , Michiels S. , Delaloge S. , Spielmann M. , Hortobagyi G. N. , Pustzai L. , Andre F. , Cristofanilli M.
Published: March 2020

10610

Background: CXCR4, a receptor for SDF1, has been reported to be involved in early metastatic process. This study aimed at evaluating i. prognostic value of CXCR4, ii. correlation between CXCR4 expression in primary tumors and occurrence of metastases in SDF1- expressing organs. Patients and Methods: CXCR4 expression in the primary tumor was analyzed by immunohistochemistry (Human CXCR4 MAb 170, R& D System, MN, USA) in 823 patients included in two randomized trials evaluating efficacy of anthracyclines-based chemotherapy over a no-chemotherapy arm. The prognostic value of CXCR4 expression was assessed by the Cox regression model adjusted for tumour grade, stage, estrogen-receptor (ER) status and age. Distant metastasis rates for a specific site (either as first event or as subsequent metastases) were calculated by time untill occurrence of metastasis or death. We predefined 4 recurrence sites of interest: liver, brain, lung and bone that are organs expressing SDF1. Results: CXCR4 was expressed in 92 of 794 assessable primary tumors (12%). There was no significant association between CXCR4 expression and clinical characteristics, except a trend for a higher rate of ER- positive disease in CXCR4+ tumors (p=0.05). CXCR4 was not prognostic for neither overall survival (Hazard Ratio (HR) = 1.03 CI95%=[0.63 - 1.67], p=0.90), disease-free survival (HR = 0.93 CI95%=[0.63 - 1.37] , p=0.93), nor incidence of overall metastases (HR= 1.36 CI95%=[0.87–2.12], p=0.17). We next assessed the incidence of metastases in SDF1-producing organs according to CXCR4 staining. While CXCR4 was not associated with an increased risk of liver (HR=0.67 [0.27–1.70] p=0.40), lung (HR=0.89 [0.20–3.87] p=0.87) or brain metastases (HR=1.04 [0.40–2.70] p=0.94), CXCR4+ tumors presented a higher risk of bone metastases (HR=2.17 [1.30–3.65] p<0.01). The 10 year incidence of bone metastases were 23% [14–33%] and 12% (10–15%] in CXCR4+ and CXCR4- tumors respectively. Conclusions: This study suggests that expression of CXCR4 in breast cancer is associated with higher rate of bone metastases, a finding concordant with data from mouse models (Kang et al, Cancer Cell). This finding might lead to further development of adjuvant strategies using bone-targeting agents (e.g. biphosphonates, CXCR4 inhibitors).

No significant financial relationships to disclose.
Prominent vascular endothelial proliferation in clinically aggressive neuroblastoma
Authors: Peddinti R. , Zeine R. , Luca D. , Seshadri R. , Chlenski A. , Cole K. , Pawel B. , Salwen H. , Maris J. , Cohn S. L.
Published: March 2020

10611

Background: Tumor blood vessels are disorganized and vascular endothelial cell proliferation (VEP) has been identified as a poor prognosticator in many adult cancers. To determine the clinical significance of VEP in neuroblastoma (NB), we evaluated blood vessel architecture in tumor sections from 51 children diagnosed at Children's Memorial Hospital, Chicago (CMH) and in 154 NB tumors on a Tissue Microarray (TMA) constructed at Children's Hospital of Philadelphia (CHOP). Methods: H&E-stained tumor sections were examined for the presence of structurally abnormal vessels and further characterized by immunostaining with anti-CD31 and von Willebrand factor (vWF) antibody to highlight endothelial cells. Tumors that contained vessels with disorganized walls and more than one endothelial cell layer were classified as VEP positive. Tumor sections that contained only thin walled vessels with no more than one layer of endothelial cells were classified as VEP negative. Associations between VEP and established clinico-pathologic features and outcome were assessed. Results: In the CHOP series, VEP was associated with high-risk group classification and MYCN amplification (p<0.001 and p=0.006). In the CMH series only 5 of the 10 children with MYCN amplification had VEP but 4 of these 5 patients have died, while there were no deaths in the subset of patients with MYCN amplified tumors that lacked VEP (n=5). In both study groups, VEP was significantly associated with Schwannian stroma-poor histology (CMH series: p=0.008; CHOP series: p<0.001) and decreased survival probability (CMH series: p=0.017; CHOP series: p= 0.014). Conclusions: The association between structurally abnormal vessels and poor outcome provides further support for the concept that angiogenesis plays an important role in determining the biologic behavior of NB tumors. Our results also indicate that angiogenesis is regulated differently in Schwannian stroma-rich versus stroma-poor NB tumors. Further studies investigating the activity of angiogenic inhibitors in children with clinically aggressive stroma-poor NB are warranted.

No significant financial relationships to disclose.
Survival benefit of gefitinib treated non-small-cell lung cancer patients with exon 19 deletion mutations in epidermal growth factor receptor (EGFR), detected by a new sensitive PCR-based method
Authors: Nakajima E. , Sugita M. , Dziadziuszko R. , Tsuboi M. , Kato H. , Bunn P. A. , Franklin W. A. , Hirsch F. R.
Published: March 2020

10614

Background: As for two common types of EGFR mutations, patients with exon 19 deletion mutations have longer survival than those with the L858R point mutations in exon 21 after treatment with EGFR inhibitors. We have developed a simple, polymerase chain reaction (PCR)-based method to detect exon 19 deletion mutations, and evaluated survival benefit of gefitinib treated patients with exon 19 deletion mutations versus patients without these mutations. Patients and methods: Tumor tissue was microdissected under stereoscopic microscopy from formalin-fixed paraffin-embedded sections, and DNA was extracted from tumor cells with DNeasy (Qiagen). Our method consisted of two different semi-nested PCRs with the deletion screening PCR and the common deletion specific PCR. All of the known deletions present in cell lines were detected by this method without direct sequencing. The result was validated by sequencing of exon 19. 73 non-small-cell lung cancer (NSCLC) Japanese patients treated with gefitinib were analyzed with this method. Study group consisted of 28 females (38%), 29 never smokers (40%) and 57 patients with adenocarcinoma (78%). Results: The PCR-based method detected mutations at mutant to wild type DNA copy ratio of 1/600, and in samples as small as 30 ng of purified DNA. Exon 19 deletion mutations were found in 25 (34%) patients. This method was more sensitive than conventional sequencing. The sequencing was performed in 19 patients with mutations and could not detect 3 deletions. Among 60 assessable patients 14 had overall response (23%). Objective response rates to gefitinib were observed in 7/21 patients with exon 19 deletion mutations (33%), and 7/39 patients without exon 19 deletion mutations (17%) (P = .211). Patients with exon 19 deletion mutations survived significantly longer than those without exon 19 deletion mutations (P = .017). Conclusions: The PCR-based method to detect exon 19 deletion mutations is cost effective and very sensitive, compared to previously described methods. We demonstrated survival benefit in NSCLC patients with exon 19 deletion mutations treated with gefitinib, and our PCR-based method is easily applicable for clinical use.

No significant financial relationships to disclose.
Gemcitabine oxaliplatin (GEMOX) is an active combination in heavily pretreated metastatic breast cancer (MBC)
Authors: Penault-Llorca F. M. , Nayl B. , Mouret-Reynier M. , Leheurteur M. , Van Praagh I. , Durando X. , Ferriere J. , Cure H. , Chollet P.
Published: March 2020

1082

Background: This study was performed to evaluate retrospectively the efficacy and tolerance of gemcitabine plus oxaliplatin (GEMOX) as salvage chemotherapy in patients with metastatic breast cancer (MBC) in a mono-institutional series. Methods: From January 2003 to March 2005, 38 MBC patients were treated at disease progression according to three schedules: (a) gemcitabine 1000 mg/m2 on day 1 and 8 and oxaliplatin 100 mg/m2 on day 1 every three weeks (n=30); (b) gemcitabine 1,000 mg/m2 on day 1, followed same day by oxaliplatin 100 mg/m2 every two weeks (n=7); (c) gemcitabine 1250 mg/m2 on days 1 and 8 and oxaliplatin 100 mg/m2 on day 1 every four weeks (n=1). Results: All patients (median age, 58 years) received prior chemotherapy for metastatic disease (median of four lines). Radiological response was assessed in 36 patients: 12 patients (33%) experienced a partial response and 11 patients (31%) had a stable disease. The median times to progression and survival were 4 months (range, 0–21 months) and 10 months (range, 2–24 months), respectively. A total of 233 cycles were administered with a median of 5.5 cycles per patient (range, 1–21 cycles). Grade 3/4 toxicity consisted of myelotoxicity in 26% of patients and neurotoxicity in 8%. Conclusions: This retrospective study suggests that GEMOX is an effective combination with a good tolerance profile in heavily pretreated MBC. Further evaluation of this regimen is warranted in this tumor indication.

No significant financial relationships to disclose.
Cost-effectiveness of HER2 testing and trastuzumab therapy for metastatic breast cancer (MBC) patients in Sweden
Authors: Lidgren M. , Rehnberg C. , Wilking N. , Jönsson B.
Published: March 2020

1088

Background: Trastuzumab is a monoclonal antibody that together with chemotherapy significantly improves time to progression and overall survival for MBC patients with tumours overexpressing HER2. The aim of this study was to analyse the cost- effectiveness of HER2 testing and trastuzumab in combination with chemotherapy compared with chemotherapy alone from a societal perspective in a Swedish setting. Methods: We used a Markov state transition model to simulate HER2 testing and subsequent treatment in a hypothetical cohort of 65 year old metastatic breast cancer patients based on the study by Marty et al (Marty et al, J Clin Oncol. Jul 1 2005;23(19):4265–4274). Outcomes included life-time costs, quality adjusted life years (QALY), and cost per QALY gained. Five different testing and treatment strategies were evaluated. Results: We estimated the cost per QALY gained to be about 485,000 SEK (approximately 70,000 USD) and the cost per life year (LY) gained to be about 332,000 SEK (approximately 47,000 USD) for the strategy of IHC testing for all patients, with FISH confirmation of 2+ and 3+, and trastuzumab and chemotherapy treatment for FISH positive patients. For the strategy of FISH testing for all patients, with trastuzumab and chemotherapy for FISH positive patients, we estimated the cost per QALY gained to about 561,000 SEK (approximately 80,000 USD) and the cost per LY gained to be 384,000 SEK (approximately 55,000 USD). The remaining testing and treatment strategies were dominated. Results were sensitive to changes in the quality adjustment of life years with metastatic disease, the risk of breast cancer related death, and test characteristics. Conclusions: Our analysis indicate that the present Swedish guidelines of IHC testing for all patients with metastatic breast cancer, with FISH confirmation of 2+ and 3+, followed by trastuzumab and chemotherapy treatment for FISH positive patients is a cost-effective treatment option. However, further research on budget impact of trastuzumab treatment and patient accessibility to trastuzumab treatment is needed.

No significant financial relationships to disclose.
NEAT-A: Accelerated sequential epirubicin followed by CMF using pegfilgrastim is a feasible regimen for delivering dose dense chemotherapy in early breast cancer
Authors: Rea D. , Bowden S. J. , Gross L. , Poole C. J. , Hiller L. , Agrawal R. K. , McAdam K. F. , Earl H. M. , Anwar S.
Published: March 2020

11001

Background: E-CMF [epirubicin (E) x 4 cycles every (q) 21 days (d), followed by classical CMF x 4 cycles q 28d] is established as highly effective adjuvant chemotherapy for early breast cancer (BC), reducing mortality by 30% compared with CMF alone [Poole NEJM 2006]. However, dose dense anthracycline-taxane schedules, accelerated with GCSF support, have been shown to be superior to conventional regimens [Citron JCO 2003, Burnell SABCS 2006]. Exploration of accelerated E-CMF is therefore of considerable interest. Methods: A non-randomised, multicenter trial was designed to explore the feasibility and tolerability of accelerated E-CMF chemotherapy for women with early BC. The primary endpoint was delivered dose intensity (DDI). The accrual target was 40 patients (pts). Pts were treated with 4 cycles E (100mg/m2) q 14d, with Pegfilgrastim (PF) (6mg sc) d2, followed by 4 cycles of Cyclophosphamide, Methotrexate, and 5-Fluorouracil (600/40/600mg/m2) administered intravenously d1 + 8, with PF d9, q 21d. Results: 44 pts were enrolled. Complete dose information from 40 pts and toxicity data from 336 cycles (44 pts) has been analysed. Median DDI was 96.7% of target. Delays of >2 d were recorded for 8% of cycles. Dose reductions were recorded in 4% of cycles. 90% of pts received >85% intended total dose and 85% of pts received >85% intended DDI. Percentage grade 2 and 3/4 toxicity reported per cycle were respectively: fatigue 34/12; all infections 7/4; emesis 19/4; bone pain 18/4; diarrhoea 7/3; dyspnoea 20/3; febrile neutropenia not applicable (na)/2; mucositis 12/0.3; and phlebitis 29/na. Hospitalisation occurred in 10% of cycles. One pt developed endocarditis in association with repeated line infections, and a further pt experienced severe delayed phlebitis requiring surgical intervention. Conclusions: Accelerated E-CMF with PF is feasible achieving high DDI in a majority of pts. Non-haematological toxicity was responsible for the majority of hospital admissions which were more frequent than anticipated. Relative efficacy of this regimen requires phase III evaluation. We have also completed a second study of accelerated E-CMF where 6 cycles of intensified CMF (800/50/600mg/m2) was delivered at 14 d intervals.

No significant financial relationships to disclose.
Relationships between clinical and biochemical predictors of chemotherapy-related amenorrhea in premenopausal adjuvant breast cancer patients
Authors: Su I. , Alton J. , Sherman L. , Stankiewicz C. , Ratcliffe S. , DeMichele A.
Published: March 2020

11011

Background: Premature ovarian failure (POF) is a major side effect of breast cancer adjuvant therapy. Predicting post- chemotherapy POF and reproductive status impacts decisions about fertility, contraception, menopausal issues and breast cancer treatment. We examined clinical and biochemical predictors of chemotherapy related amenorrhea (CRA) in premenopausal adjuvant breast cancer patients. Methods: We conducted a cohort study of 121 breast cancer patients with stages I-III disease, premenopausal at diagnosis, enrolled 1 to 4 years from chemotherapy. All patients received 4 cycles of doxorubicin and cyclophosphomide with or without 4 cycles of paclitaxel or docetaxel, at q2 (dose-dense) or q3 week intervals. The primary endpoint was CRA (amenorrhea > 12 months from chemotherapy start). Pretreatment menstrual status and clinical factors were collected prospectively; subjects were recontacted for additional information and venipuncture. Regression models were used to examine risk factors for CRA and log FSH. Results: Mean age was 43.2 years (range 26.7–57.8). Mean follow up from chemotherapy start to enrollment was 2.1 years (range 1.0–4.1). 68 subjects developed CRA, while 53 continued menstruating. In a model including age, tamoxifen use, dose density, chemotherapy regimen, ovarian suppression during chemotherapy, smoking, body mass index and race, only age (OR 1.57[CI 1.29–1.89], p<0.001), tamoxifen use (OR 7.25 [CI 5.89–34.87], p=0.01), and dose density (OR 3.38 [CI 1.16–16.50], p=0.03) had independent associations with CRA. Serum FSH at enrollment (n=112) was higher in CRA than in non-CRA (11.8 vs 45.8, p< 0.001). However, 39% (25/65) of CRA subjects had FSH < 40 mIU/mL, the biochemical threshold for menopause (mean 26.4, range 10.1–39.9). FSH was not associated with chemotherapy regimen (p=0.51) or schedule (p=0.21). Conclusions: Age, tamoxifen use, dose density and subsequent FSH were independently associated with CRA. Clinically, amenorrhea for more than 12 months did not always represent biochemical menopause. Better methods are needed to characterize ovarian function in patients after adjuvant chemotherapy.

No significant financial relationships to disclose.
Mechanisms of bone metastasis (BM) growth in patients with metastatic breast cancer (MBC): An exploratory study
Authors: Ooi W. S. , Popovic S. , Kalina M. , Harriette K. , Singh G. , Gainford M. C. , Clemons M.
Published: March 2020

1102

Background: The benefits of bisphosphonates (BPs) in reducing or delaying skeletal related events (SREs) in patients with BM have been attributed to their potent osteoclast (OC) inhibiting effect. However, despite the use of modern systemic anti-cancer therapy including potent BPs, many patients with BM continue to suffer from the consequences of their bone disease. An improved understanding of the basic mechanisms of bone destruction would allow further appropriate targeted treatment strategies to be developed. Methods: Archival paraffin embedded BM specimens from patients with MBC were examined for expression of OCs, receptor activator of nuclear factor kappa B (RANK), RANK Ligand (RANKL) and Osteoprotegerin (OPG). Histological specimens were also available for primary breast cancer, lymph node (LN) metastasis, normal breast and bone tissues for comparison. Results: BM specimens were available for 20 BP naïve pts and 2 pts treated with BP. OCs were significantly increased in the BM of the BP naive group compared to controls. There were no OCs seen in the BP treated group. RANK was expressed on tumor cells (TCs) in the both bone and nodal metastases but not on the primary cancer cells. It is also expressed on the OCs which were present in both BM and normal bone. While RANKL was absent in TCs, it was strongly expressed in all stromal cells (SCs) in all specimens and in osteoblasts. The OPG, while present in TCs of the BM and LN metastases, is not detected in the primary cancer. Conclusion: The mechanism of bone destruction in MBC are not fully understood and are clearly multifactorial. OCs may not be the singular obligatory factor for osteolysis in BM. Further investigation of various inhibitors of the RANK/RANKL/OPG pathways, may allow novel treatment strategies to be developed.

No significant financial relationships to disclose.
Results of first-line weekly paclitaxel (P) + gemcitabine (G) in metastatic breast cancer (MBC): An AERO phase II trial
Authors: Mousseau M. , Serin D. , Petit T. , Priou F. , Zelek L.
Published: March 2020

1103

Background: Three weekly paclitaxel and gemcitabine (PG) combination is recognised as an efficient treatment of metastatic breast cancer. Weekly paclitaxel has shown improved results comparatively with the three weekly administration. We conducted a study to evaluate a weekly schedule of PG combination in fist line treatment of metastatic breast cancer (MBC). Patients and methods: Patients with MBC were enrolled in this study to evaluate the feasibility and efficacy of P 80mg/m2 D1, 8, 15 and G 1,250 mg/m2 D1, 8 (at fixed dose rate of 10mg/m2 /min) and cycles were repeated every 21 days. This phase II trial had a 2 stages design. Overall response rate was the primary end point. Results: In the first step of the trial 19 pts were enrolled with a median age of 59.5 (range 40 - 74). Baseline ECOG < 2 in 89% of pts. Main metastatic sites were: bone (36 %), lung (36%), liver (36%) and lymph nodes (32%). 52 % of pts had only one metastatic site. Previous treatments included surgery (89%), radiotherapy (73%), anthracycline based chemotherapy (74%) and adjuvant hormontherapy (52%). 18 pts were evaluable for efficacy and toxicity. 6 achieved PR, 5 SD and 6 PD resulting in an ORR of 33%. All patients were evaluable for toxicity. Main grade 3–4 toxicities per patient were neutropenia (67%), febrile neutropenia (5%), anemia (17%), thrombocytopenia (33%), trasnsaminases leveations (11%) and dyspnia (5%). Chemotherapy was delayed frequently for toxicity reasons (delays or arrest for toxicity in 15 pts). Conclusion: This weekly PG regimen has some activity in MBC. Although life-threatening toxicities were uncommon, delays in haematological recovery are frequent, making the investigated schedule unsuitable for further studies.

[Table: see text]
The statistical distribution of involved axillary lymph nodes in breast cancer: A SEER population-based study
Authors: Vinh-Hung V. , Guern A. , Storme G.
Published: March 2020

11031

Background: The number of involved lymph nodes in patients with breast cancer is highly variable. It might be important to examine the frequency distribution (FD) of these numbers in order to characterize their variability. This study examines the FD’s statistical properties and determines what they imply in terms of statistical analyses. Methods: The data was based on the National Cancer Institute’s Surveillance, Epidemiology and Ends Results (SEER). It covered 109618 patients, in whom axillary dissection had been performed between 1973 and 2002, in 9 states or towns of the USA. The involved lymph nodes were fitted to different statistical distributions adapted to count data using the maximum likelihood method (ML). The fittings were evaluated with the Kolmogorov-Smirnov (KS) statistic (KS close to 1 indicates lack of fit and KS close to 0 indicates good fit) and with the chi2 statistic (large chi2 indicates lack of fit). Results: The FD showed a logarithmically decreasing frequency, i.e. log-concave type. The mean number of involved nodes was 1.1465 and the variance was 9.54. The fit with a Poisson distribution gave a chi2=7.18*106 and the KS was 0.389. The fit with a negative binomial distribution using the ML gave a chi2=291.7, and the KS was 0.0086, i.e. 45-fold improved fit. Discussion: The FD’s variance 9-fold larger than the mean number of involved nodes indicates important overdispersion, i.e. the variability increases when the number of involved nodes increase. The Poisson distribution is inappropriate as was shown by the chi2 and KS. Overdispersion implies that nodal metastases are not independent random events. Overdispersion might be explained by 1) subsets of patients had a higher than expected propensity of nodal involvement, and/or 2) nodal involvement is a cascade process in which the likelihood of involvement increases when more nodes are involved. The implication for further analyses is that building predictive models of nodal involvement should take into account overdispersion and use appropriate modeling distributions such as the negative binomial. Conclusion: The FD characterization indicated a log-concave type with overdispersion. This might be important to gain an insight into the mechanisms of nodal involvement and to improve their analyses.

No significant financial relationships to disclose.
Correlation between clinical response according to WHO criteria and pathological response according to Chevallier and Sataloff in inflammatory breast cancer (IBC)
Authors: Bonneterre J. , Mailliez A. , Giard S. , Chaveron C. , Belkacemi Y. , Vanlemmens L. , Baranzelli M.
Published: March 2020

11033

Introduction: IBC has a very poor prognosis ; the first treatment is first primary chemotherapy, followed by surgery and radiotherapy. It has been shown that patients experiencing a complete pathological response haved a longer survival . The pathological response has thus to be carefully assessed. Material and Methods: The aim of this retrospective study was to determine whether there islook for a correlation between clinical response with (WHO criteria) and pathological response using Chevallier’s and Sataloff’s classifications. 56 successive patients received an anthracycline- based chemotherapy regimen for IBC before surgery; for all of these patients a pathological analysis had beenwas performed before chemotherapytreatment and after surgery. Alll the specimens werehave been reviewed by the same pathologist. Results: There is a very good correlation between the 2 pathological classifications fAmong the 56 patients, there were 3 complete clinical responses, which were also pathological complete responses according to both classifications.or the complete responders only. In all the other cases, no correlation wascould be found between the 3 classifications . It was particularly striking for all the 41 patients tumours classified grade 3 according to Chevallier who could be classified clinically (with WHO) or pathologically (with Sataloff) in either of the 4 groups from complete responseders to progressive disease . Overall , in this our series , 3 patients according to Chevallier and 11 according to Sataloff were complete pathological responders. Discussion: The lack of correlation between clinical and pathological classifications could be explained , at least in part, by the fibrosis often observed after primary chemotherapy. The differences observed between the 2 pathological classifications highlight the fact that there is no standard and that further research is neede in that perspective.

[Table: see text]

No significant financial relationships to disclose.
The FinXX trial: Safety results in 600 patients (pts) randomized to either docetaxel (T) followed by cyclophosphamide (C) + epirubicin (E) + 5-FU (F) (CEF) or T + capecitabine (X) followed by CEX as adjuvant therapy for early breast cancer (BC)
Authors: Joensuu H. , Hemminki A. , Huovinen R. , Tanner M. , Kokko R. , Asola R. , Jukkola-Vuorinen A. , Lahtela S. , Lindman H. , Kellokumpu-Lehtinen P.
Published: March 2020

11035

Background: Adding X to T extends survival in pts with metastatic BC. The primary objective of the FinXX trial is to compare recurrence-free survival with XT→CEX vs T→CEF as adjuvant therapy in pts with early stage BC. Secondary objectives were comparison of safety and overall survival. Methods: Between Jan 2004 and May 2005, 600 of a planned 1,500 pts were randomized to receive T x 3 → CEF x 3 (T 80 mg/m2 d1 → C 600 mg/m2 d1, E 75 mg/m2 d1, F 600 mg/m2 d1) or TX x 3 → CEX x 3 (T 60 mg/m2 d1 + X 900 mg/m2 bid d1–15 → C 600 mg/m2 d1, E 75 mg/m2 d1, X 900 mg/m2 bid d1–15) q3 wks. Results: Grade 3/4 toxicities (CTCAE, v3) in >5% of pts are shown below. 62 pts required G-CSF. Nos. of cycles with G-CSF were: T 34; XT 15; CEF 17; CEX 15. Adverse events (AEs) led to interruption of T in 7 pts (2%) and XT in 50 pts (16%). Median dose intensities at cycle 3 were T: 95%; XT: 84/97%; CEF: 98/97/98%; CEX: 98/98/84%. T dose reductions of =20% in cycle 3 were needed in 18% and 8% of pts receiving T and XT, respectively. 4 pts died during treatment: pulmonary embolism (n=1) with T and suicide, sudden death and colitis/sepsis (each n=1) with XT. Conclusions: XT→CEX is generally well tolerated. Treatment interruptions were more common with XT→CEX, but were effective in reducing development of grade 3/4 AEs. Neutropenic infections were less frequent with XT vs T and infrequent with XT, CEF and CEX. Rates of grade 3/4 diarrhea and HFS were acceptable with XT and minimal with CEX. Accrual is nearly complete; efficacy data are expected in 2009. [Table: see text]

[Table: see text]
Dose-dense (DD) two-weekly docetaxel/doxorubicin/cyclophosphamide (TAC) with G-CSF support compared to standard adjuvant TAC in breast cancer patients
Authors: Latifzadeh S. Z. , Salimi M. , Naghnaeian M. , Entezari V.
Published: March 2020

11052

Background: TAC confers a significant disease free and overall survival benefits vs. FAC for patients with node positive breast cancer and prophylactic use of G-CSF is a reasonable supportive therapy to minimize myelosuppresive complications of this regimen. DD scheduling has shown improved clinical outcomes in breast cancer therapy. This study is trying to compare toxicities and tolerability of DD TAC with G-CSF support with TAC every 3 wks supported with G-CSF. Methods: Thirty seven patients were enrolled during the period 1/04 to 1/06. Cohort A (N=25) received six cycles of TAC (75/50/500 mg/m2 every 3 wks) plus GCSF started on day 5 and Cohort B (N=12) received six cycles of TAC (75/50/500 mg/m2 every 2 wks) plus GCSF started on day 2. All patients had normal cardiac, renal and liver function. Toxicities were evaluated by clinical assessment, CBC and liver function tests. Results: The incidence of febrile neutropenia was 15.8% and 16.7% in cohort A and B respectively (RR =1.06, 95% CI = 0.20–5.42). Grade III/IV anemia was detected in 5.3% of cohort A patients and 8.0 % of cohort B patients (RR=1.58, 95% CI=0.10–22.99). Ten percent of cohort A patients developed stomatitis grade III/IV while none of cohort B patients had this toxicity (RR=1.06, 95% CI = 0.94–1.17). Hospitalization due to chemotherapy complications (mainly neutropenia) in cohort A and B were 5.3% and 8.3% (RR =1.58, 95%CI = 0.10–22.99). Conclusions: DD two weekly TCA was reported to be feasible in patients with stage II - III breast cancer (Margolis et al. JCO, 2005). This study shows that DD TCA plus G-CSF has comparable toxicity profile with standard TCA regimen with shorter treatment period.
Lack of effect of pegfilgrastim on anemia in breast cancer patients treated with dose-dense chemotherapy
Authors: Manzoni M. , Bencardino K. , Rovati B. , Mariucci S. , Cappuzzo F. , Chatzileontiadou S. , Grasso D. , Delfanti S. , Danova M.
Published: March 2020

11071

Background: A greater risk of anemia has been evidenced among breast cancer (BC) pts receiving dose-dense CT. A recent report showed that filgrastim may play a role in worsening anemia in BC pts receiving intensified Epirubicin (E) + Cyclophosphamide (CTX), by inducing stem cells to differentiate into more committed hematopoietic progenitors (Papaldo P. JCO, 2006). No data are available about the impact of pegfilgrastim-induced leucocytosis on Hb levels without prophylactic erythropoietic support. Methods: We have focused on this point in 36 BC pts. 14 N+ pts received 4 cycles of E 90 mg/sqm + CTX 600 mg/sqm every 14 days in adjuvant setting. 22 pts with locally advanced disease received 4 cycles of E 75 mg/sqm + Docetaxel 80 mg/sqm every 14 days as primary CT. All pts received prophylactic pegfilgrastim 6 mg s.c, after CT. Three groups were defined on the basis of WBC: A = <10 x 103/mL; B = between 10 and 20 x 103/mL and C = > 20 x 103/mL. WBC and Hb levels at the beginning of treatment were normal in all pts and were subsequently determined on day 1 of each treatment cycle. Results: All pts received the planned CT dose intensity. Only 3 pts developed G2 anemia and were excluded from the analysis, because of receiving darbepoietin alpha support. Among the 14 pts treated in adjuvant setting, 5 dropped in group A, 6 in group B and 3 in group C. The mean Hb decrease from the baseline to the last CT course was - 1.5 g/dL; -1.4, -1.8 and -1.4 in group A, B and C, respectively. In the primary setting, 4 pts dropped in group A, 12 in group B and 4 in group C. The mean Hb decrease was -1.5 g/dL; -1.3, -1.4 and -1.8 in group A, B and C respectively. No statistically significant correlation was found between the Hb levels and the degree of leukocytosis. Conclusions: Pegfilgrastim does not worsen anemia in BC pts treated with dose- dense CT, even when its use is related to some degree of leucocytosis.

No significant financial relationships to disclose.
Sentinel lymph node micrometastasis detection using immunohistochemistry and reverse transcription-polymerase chain reaction for cytokeratin 19 in breast cancer
Authors: Cao Q. , Wang S. , Liu X. , Lin L. , Zhao J.
Published: March 2020

11074

Background: In breast cancer, the sentinel lymph node (SLN) can be used to assess the axillary nodal status to guide the axillary surgery, tumor staging and adjuvant systematic therapy. Histology and immunohistochemistry (IHC) are currently the routine methods of SLN assay. The facts that about 30% of node-negative breast cancer patients relapse within five years and that micrometastasis were found in 9%∼30% negative lymph nodes when they were re-examined using serial sectioning suggest that current histological detection methods are inadequate for identifying metastatic tumor cells in lymph nodes. The primary objective of this study was to develop an assay by using a combination of reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry for cytokeratin 19 (KT19) expression in SLN. Methods:139 SLN samples were collected from 139 breast cancer patients undergoing SLN biopsy using Isosulfan Blue dye during modified mastectomy between June 2002 and June 2005. The SLNs were dissected into two parts, half were frozen in liquid nitrogen during sugery for RT-PCR detection and another half were kept in liquor formaldehyde for routine hematoxylin-eosin (H&E) examination and IHC detection. In 62 tumor-negative SLNs at routine H&E examination (pN0), we performed IHC and RT-PCR for KT19. Results: Of the 62 tumor-negative SLNs at routine H&E examination, 11% (7/62) were positive on extensive IHC analyses for KT-19, which were all positively identified by RT-PCR assay. Six SLNs (10%) were negative for micrometastases (with H&E and IHC for KT-19) but RT-PCR positive. There was asignificant difference in detective rate between these two methods statistically (χ2 = 4.1667 , P = 0.0412) and the coincidence were high ( kappa = 0.6483) Conclusions: As IHC analysis resulted in a 11% detection rate in H&E negative SLNs, IHC is essential to avoid false- negative SLN micrometastases. Molecular analysis with KT19 allows detection of breast cancer micrometastases with an additional 10% detection rate in H&E negative SLNs and resulted in a high coincidence with IHC analysis. However, the clinical value of these histologically negative but RT-PCR positive SLNs can only be determined with long term follow up.

No significant financial relationships to disclose.
Effect of zoledronic acid on bone loss by letrozole
Authors: Jung S. S. , Cha S. , Bae J. , Park W. , Seo Y. , Oh S. , Kim J. , Jeon H. , Song B. J.
Published: March 2020

11077

Background: The aromatase inhibitors cause bone loss by estrogen depletion. Zoledronic acid (ZA) can prevent bone mineral density (BMD) loss associated with the use of aromatase inhibitors. Accordingly interest has arisen in measuring surrogate markers of bone resorption to monitor the response of treatment of BMD loss in place of radiologic assessment. This study was designed to determine whether ZA would prevent bone loss that is known to occur with letrozole and identified surrogate markers of bone resorption in an animal model. Methods: In ovariectomized or sham-operated rat, we administrated ZA and letrozole to 5 different groups including: a sham operation control group (OC), a group in which an ovariectomy was performed followed by saline administration (OS), an ovariectomy with ZA treatment group (OZ), an ovariectomy with letrozole treatment group (OL) and an; ovariectomy with ZA and letrozole combined treatment group (OZL). The levels of serum osteocalcin, serum bone alkaline phosphatase (BALP), serum calcium and urine N-telopeptide (NTX) and BMD were estimated and compared at the same periods for each group. The distinct microscopic findings of proximal tibia at week sixteen were also compared. Results: Significantly intense increment of BDM in the OZ group and the OZL group and lower increment in the OL group were valued in correlation to the OS group, 31.3%, 35.0%, 10.5% and 13.0% respectively. Serum osteocalcin levels and urine calcium levels were close to each group. Serum calcium levels and BALP levels were relatively lowering in the OZ group and the OZL group than other group. Meaningfully lower levels of urine NTX were measured in the OZ group and the OZL group, 6.6% and 16.5% respectively. In the OL group levels of urine NTX were rise of 55.9%. Less cancellous bone loss and increase bone trabeculae were noted in the microscopic findings of tibia. Conclusions: The combination treatment with ZA and letrozole are effective in the inhibition of bone resorption and in the maintenance of BMD. Measurement of serum osteocalcin, urine NTX, and BMD, levels are recommended as surrogate markers for determining the response for the treatment of bone loss.

No significant financial relationships to disclose.
Nipple-sparing mastectomy and immediate reconstruction: Indications, technique, and results of 110 patients with breast cancer
Authors: Son B. , Ahn S. , Kim H. , Jang M. , Park E. , Lee T. , Um J. , Kim S. , Ahn J. , Gong G.
Published: March 2020

11088

Background: Nipple-sparing mastectomy (NSM) and immediate reconstruction has recently been accepted as a new surgical procedure that provides good cosmetic results, although it is necessary to establish oncological safety. We reported our experience to evaluate indications, technique, results, and complications of NSM. Methods: Between 1999 and 2005, medical records of 113 patients with breast cancer undertaken NSM at the Asan Medical Center were analyzed retrospectively. Median age of the patients was 40 years and complications were assessed 3 months later postoperatively. Results: For preoperative indications of NSM, mulifocal or multicentric cancers were 60 cases (53.1%), diffuse microcalcifications on MMG were 27 cases (23.9%), failure of breast conserving surgery due to tumor involvement of resection margin were 12 cases (10.6%), central located small cancers were 11 cases (9.7%). Immediate reconstruction methods were 85 cases (75.2%) in TRAM and 28 cases (24.8%) in direct implant. Intraoperative frozen section biopsy for evaluation of tumor involvement at the NAC showed accuracy of 100%. Pathologic tumor size were 24 cases (21.2%) in Tis, 56 cases (49.6%) in T1, 33 cases (29.2%) in T2, respectively. Lymph node status showed 81 cases (71.7%) in N0, 24 cases (21.2%) in N1, 7 cases (6.2%), and one case (0.9%) in N3, respectively. During 20 months of the median follow-up, four patients developed recurrences; one local recurrence (subcutaneous), two (lung, brain) distant failures, and one local and distant failure. The rate of major NA necrotic complication was 14.6%, but all cases were improved with conservative management. 91.7% of patients were satisfied with their cosmetic results. Conclusions: Although the presented study does not establish conclusion with regard to oncological safety due to short follow-up period, the procedure of NSM with intraoperative pathologic assessment of the subareola tissue, and immediate reconstruction is a reasonable option for a selected patients. Good candidates for NSM are patients unsuitable for breast conservation either for multicentric or multofocal cancers, or because of extensive microcalcification, or involvement of resection margin during breast conserving surgery.

No significant financial relationships to disclose.
Neoadjuvant chemotherapy (NACT) with prolonged high-dose (HD) doxorubicin (A) and cyclophosphamide (C) with G-CSF support in locally advanced breast cancer (LABC): Long-term follow-up data
Authors: Altintas S. , Huizing M. T. , Spoormans I. , Van den Brande J. , Wilmes P. , Tjalma W. , Van den Weyngaert D. , Van Goethem M. , Vermorken J. B.
Published: March 2020

11090

Background: NACT improves survival in LABC. The optimal regimen, dose and duration is still under study Objective: To determine the efficacy and safety of prolonged preoperative HD-AC plus G-CSF. Methods: LABC patients (pts) were treated with AC for 6 cycles (Cy): Cy 1: A 90 mg/m2, C 1000 mg/m2; Cy 2–3: A 82.5 mg/m2, C 875 mg/m2; Cy 4–6: A 75mg/m2, C 750 mg/m2) with prophylactic (peg)filgastrim q3wks. In case of cardiotoxicity or poor tumor response (TR) pts switched to Docetaxel (D) 100mg/m2 q3wks. Within 5 weeks after NACT, pts underwent mastectomy with axillary lymph node dissection followed by radiotherapy. In case of positive estrogen (ER) or progesteron receptor (PgR), hormonal treatment was given for 5 yrs. Toxicity was scored weekly (NCI-CTC 2), response every 3 wks (WHO). Kaplan-Meier analysis was performed to calculate disease free survival (DFS) and overall survival (OS). Results: Between 8/1997 and 10/2003 21 pts (median age 55 years, range 22–74) were enrolled. One pt had stage IIB, 6 stage IIIA, 14 stage IIIB disease (10 T4d). 10 tumors were ER+, 5 PgR+, none overexpressed Her-2/Neu. A total of 130 NACT Cy was given. 15 pts completed all 6 AC Cy, 6 switched to D because of a decrease in left ventricular ejection fraction (LVEF? >10%, n=2) or insufficient TR (n=4). Dose reduction of AC was needed in 1 pt (last Cy), dose delays in 4 pts. Nausea and vomiting were generally mild; grade 4 anorexia occured in one pt. Grade 4 leucopenia and neutropenia in 14 and 18 pts, respectively. Neutropenic fever requiring hospitalization occurred in 5 pts, thrombocytopenia grade 4 in 7 pts and grade 3 anemia in 3 pts. Two pts developed cardiomyopathy (9.5%) < 2 years after NACT. The overall TR rate (PR and CR) was 81%, clinical CR rate 14%, pathologic CR rate 10% and 14% had minimal residual disease. Three pts showed SD and only 1 pt had PD. The median follow up of all pts was 51 months (range 9–110), 5 yrs DFS 47%, OS 56%. 5 yrs DFS and OS for pT4d pts was 50% and 56%, respectively. Conclusions: NACT with HD-AC plus G-CSF for 6 Cy in this poor risk population is active and further supports the use of prolonged preoperative CT. The routine use of D after a restricted number of AC Cy may further improve results and decrease (cardio)toxicity.

No significant financial relationships to disclose.
Audit of open breast biopsies in a Nigerian teaching hospital
Authors: Adisa A. C.
Published: March 2020

11091

Background: Open biopsy is an accurate method for diagnosis of breast tumors especially where facilities for needle biopsies like tru cut needle biopsy or aspiration cytology method are not readily available. We report a 10-year retrospective study of the clinical and pathological characteristics of excised breast masses in our centre. Methods: Clinical records and pathological results of all breast biopsies of consecutive patients referred to the Breast Clinic of the Abia State University Teaching Hospital, Aba, Nigeria were studied from January 1994 to December 2003. We present the outcome of the histology reports from breast biopsy for a period of 10 years (1994- 2003) in Abia State University Teaching Hospital. Results: A total of 421 patients had open biopsies for breast masses. The age ranged from 12 years to 80 years with the median age of 34 years. The commonest symptom was painless breast lump in 90% of patients; breast pain was present in less than 5% of cases. Malignancies were discovered in 24% of the cases and the predominant histological type was infiltrating ductal carcinoma (NOS) which was found in 78% of cases, lobular carcinoma was found in 2% of cases. 79% of the breast cancers occur in pre menopausal women and the majorities (85%) were late stages. 79% of the patients with cancer of the breast were 50 years old or younger and the youngest patient was 14 years. The benign lesions in order of frequency were fibroadenoma (45%), fibroadenosis (41%), granulomas (5%), breast cyst (3%), and galactocele (2%).Other less common pathologies include lipoma, chronic abscesses and parasitic cysts. Conclusions: Majority of breast masses in Nigerian women are benign. The preponderance of late staged tumors and pre menopausal patients call for early detection, public awareness and improved screening methods

No significant financial relationships to disclose.
Gemcitabine and vinorelbine as third-line therapy in elderly patients (pts) with advanced breast cancer (ABC) pretreated with taxanes and anthracyclines
Authors: Botto H. G. , Botto M. E.
Published: March 2020

1110

Background: Gemcitabine (G) and vinorelbine (V) combinations are active in ABC pts. In this trial our purpose was to study in elderly pts with ABC and pretreated with T and A, the response rate (RR), the time to progression (TTP), the overall survival (OS) and the tolerance, with G and V as third line therapy. Methods: Sixteen pts with ABC pretreated with T and A combinations, median age 69 years (range 66–81 y). PS: 0=7, 1=8, 2=1, with normal organic functions, sites of disease: hepatic 8, bone 7, lung 5, soft tissue 3; two or three sites of disease 9 pts, more than three sites 7 pts. Treatment: G/1,200 mg/m2 and V 35 mg/m2, day 1, every 21 days. Median N° of cycles 4 (range 2–8). Total N° of cycles 71. All pts were evaluated for RR, OS and toxicity. Results: PR 25%, SD 37%. All PR pts and one SD pt, have previously showed response to T and A combinations. The total median TTP was 4 months (range 2–20 m), the total overall survival was 7 months (range 3–36 m). In non responders and responders pts to previous T and A combinations, the median TTP was 3 and 5 months respectively, and the median OS was 5 and 10 months respectively. Tocixity, neutropenia Gr.3–4: 6 pts, Gr.2: 10 pts, anemia Gr.2: 7 pts, thrombocitopenia Gr.2: 3 pts. Conclusions: In this trial the gemcitabine and vinorelbine as third line therapy, in elderly pts with ABC, pretreated with T and A combinations, showed good response rate, good overall survival and acceptable toxicity. Pts who have responded to the previous T and A regimens obtained better response than pts who have not responded.

No significant financial relationships to disclose.
Predictors of response to primary systemic therapy (PST) with docetaxel and trastuzumab in HER2-positive breast cancer
Authors: Rao M. , Griggs J. J. , Schiffhauer L. M. , Messina P. , Bourne P. , Ahrendt G. M.
Published: March 2020

11100

Background: The purpose of this study was to assess the relationship between estrogen receptor (ER) status, amplification of HER-2, and tumor response to PST with docetaxel and trastuzumab in breast cancers positive for HER-2 by immunohistochemistry (IHC). Long-term disease-free survival data are also reported. Methods: Eligible patients were those with T2 or T3 tumors and overexpression of HER-2 via IHC. Docetaxel 100 mg/sq m q. 3 weeks × 4 with growth factor support and weekly trastuzumab × 12 were given before surgery. The Miller-Payne system was used to define pathologic responses (PR) in the excision specimen (0, 1, 2 - no/minimal response; 3 - 4 partial response, pPR; 5 - complete response, pCR). Adjuvant therapy was given at the discretion of the treating oncologist. Results: Of 22 enrolled patients, 19 were assessable. 17 of the 19 subjects had subsequent FISH confirmation of HER-2 status. Six subjects (31%) had a pCR. Of these, 5 had strong amplification of HER-2 and 5 had tumors that were ER-negative. A pPR occurred in an additional 2 subjects (10%). Of the 11 subjects who had no or minimal PR (Miller-Payne 0 - 2), 8 were found to have no amplification for HER-2 and 9 had tumors that were ER-positive. Postoperative (adjuvant) chemotherapy was given to 17 patients. All 12 patients with ER-positive tumors received adjuvant hormonal therapy. Three patients had an asymptomatic decline in left ventricular ejection fraction (LVEF) of 10 - 15% after anthracycline containing chemotherapy, and one had symptomatic non-ischemic cardiomyopathy of unclear etiology 4 years after completion of study therapy and an anthracycline. With a median follow up of 56 months, all 19 participants are alive and disease-free. Conclusion: PST with a 12-week course of trastuzumab and docetaxel is safe and effective, produces a substantial pCR rate, and may result in excellent long-term recurrence-free and overall survival. The subset of patients with tumors that were IHC-positive, but FISH-negative for HER-2, and ER-positive had minimal or no response to therapy, highlighting the importance of identifying patients most likely to respond to trastuzumab-based regimens.

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